Essentials of Clinical Nephrology (Shorouk Press, Cairo, 2000, ISBN ...

ESSENTIALS 

OF 

CLINICAL NEPHROLOGY 

Edited by 

Mohamed A. Sobh 

Professor and Head of Nephrology Department 

Urology and Nephrology Center, 

University of Mansoura, Mansoura, Egypt. 

Dar El Shorouk

Essentials 

Of 

Clinical Nephrology

Essentials of Clinical Nephrology 

This is a 422 page book with 47 coloured pathology photographs 

and 27 coloured illustrations. 

This book could be considered practical, applicable and concised 

guide in nephrology, expressing the international and the local 

experience. It contains 16 chapters with references for suggested 

readings up to the year 1999. 

This book is written to cover the needs of the nephrology trainees 

and specialists and those in the field of internal medicine. Also, 

medical students will find it easy to go through this book and collect 

informations fitting to their requirements. 

© 2000 Dar El Shourouk, All Rights Reserved. 

No part of this book may be reproduced in any form or by any 

means, electroonic or mechanical by an information storage and 

retrieval system, without written permission from the publishers. 

This book is for educational and reference purposes only. 

First Edition, 2000. 

Revenues of this book are donated to 

Mansoura Orphan Institution. 

Published by: 

Dar El Shorouk 

8, Sebawieh Al masry, Nasr City, Cairo, Egypt 

P.O. Box: 33 Panorama 

Tel.: +202 4023399 - Fax: +202 4037567 

email: dar@shrouk.com 

Cover & Internal Design: 

Hisham Howaidy 

Printing & Color Separation: 

Shorouk Press 

ISBN: 

1-1887165-11-8

Essentials 

Of 

Clinical Nephrology 

Edited by: 

Mohamed A. Sobh 

Professor and Head of Nephrology Department, 

Urology and Nephrology Center, 

University of Mansoura, Egypt. 

Dar El Shorouk

Dedication 

To the soul of my dear father 

To my dear mother 

To my lovely wife, and 

To my children.

ACKNOWLEDGEMENT 

Professor Jacob Churg, USA and IGAKU-SHOIN Medical Publishers, 

Inc Japan are acknowledged for granting a permission to reproduce some of 

their histopathology figures. Also, Novartis, Egypt, is acknowledged for 

facilitating the permission to reproduce some of Frank Netter's illustrations 

(The Netter Collection of Medical Illustrations, Vol. 6, illustrated by M.D. all 

rights reserved). 

The gratitude is for Dr. Fatma El-Husseini, professor of pathology for 

providing some of her pathology figures. Dr. Tarek El-Diasty, consultant 

radiologist, is acknowledged for providing the radiology figures. The valuable 

help provided by Dr. M. Ashraf Foda, Dr. Ahmed Donia and Dr. Mahmoud 

Mohasseb is highly appreciated. 

The clever secretarial work of Mrs. Hend Sharaby and Heba Zaher are 

greatly acknowledged.

FOREWARD 

Although this country is plagued by the highest prevalence of renal 

disease worldwide, only very few Egyptian nephrologists have attempted to 

write a book on renal medicine. The dream has always been there, but the 

major barrier was the pain it takes to produce a work that competes with the 

plethora of excellent international textbooks and monographs. 

No wonder that Mohamed Sobh pioneered the challenge, as he has 

always done. I have admirably witnessed this young man's progress over the 

years since he had made one of his earliest contribution in the first Egyptian 

Society of Nephrology in 1980. His star continued to shine in the horizons of 

renal medicine until he became one of the best known in Africa and the Arab 

world, while at home he became the Professor and Chief of Nephrology in 

renowned Mansoura University. He published a lot on basic renal physiology, 

schistosomal nephropathy and renal transplantation among many other 

topics. In addition, he was the author or co-author of a number of excellent 

monographs published in Egypt and abroad. He made outstanding 

presentations in a lot of local and international conferences, and received 

many awards of great honor. 

Despite his academic interests, Professor Sobh has a vast clinical 

experience, which enriches this book. In over 400 pages he intelligently mixes 

theory with practice, bench with bedside, and international with local 

experience. He offer the post-graduate student the long-waited practical an 

applicable concise guide in nephrology. 

I confidently promise the reader a most enjoyable cruise through the 

very well written and carefully illustrated chapters of the book. 

Professor Rashad Barsoum 

MD, FRCP, FRCPE 

Professor and Head of Department of 

internal Medicine, Cairo University. 

President of The Egyptian 

Society of Nephrology and the 

Arab Society of Nephrology 

and Renal Transplantation. 

Secretary General of the International 

Society of nephrology

The Author 

Dr. Mohamed A Sobh, MD, FACP 

Professor and Head of Nephrology 

Department, Urology and Nephrology 

Center, University of Mansoura, Egypt. 

Professor Sobh was graduated in 1973. He obtained his MSc in 1977 and the 

MD in 1982. Both are in Internal Medicine from Mansoura Faculty of 

Medicine. 

In 1978, he passed the ECFMG exam and was affiliated to the residency 

training program in the Nephrology Department in Sherbrooke University, 

Quebec, Canada. Since his return in 1982, he has hold the responsibility of 

organizing the Nephrology activity in Mansoura University Hospital. 

In 1982 he was promoted as lecturer of Internal Medicine and was then 

assigned as the head of the Nephrology Department in the Urology and 

Nephrology Center, Mansoura University. In 1993, he obtained the title of a 

full Professor in Medicine; and the title of Professor of Nephrology. 

So far, Professor Sobh has 20 MDs and PhDs candidates in addition to 38 

Masters; both in Nephrology and Internal Medicine. He also published more 

than 75 papers in the different International journals of Nephrology. 

Prof. Sobh was elected as a member in The American College of Physicians 

in 1996; then as a fellow in the following year. He is also a member of the 

Egyptian, African, Arab, European and The International Societies of 

Nephrology. 

Prof. Sobh was honoured several times. He was awarded the National 

Encouragement Prize for medical sciences in 1987; Mohamed Fakhry prize 

for the most distinguished research in Internal Medicine, (awarded by the 

Egyptian Academy of Research and Technology) in 1987; the Jordan Prize of 

Abd El-Hamid Shoman for the Arab Scientists in The Clinical Medical 

Sciences in 1988; and The Arab Prize for the most distinguished Medical 

Research, (awarded by the President of the Algerian Republic) in 1993.

CONTENTS 

Forward ................................................................................................. i 

The author ........................................................................................... ii 

PART I: RENAL FUNCTIONS AND STRUCTURE 

• Kidney functions ................................................................................. 1 

• Anatomy of the kidney ........................................................................ 9 

• Anatomic physiology ........................................................................... 19 

PART II: INVESTIGATIONS FOR KIDNEY DISEASES 

• Biochemical investigations ............................................................... 25 

• Microbiological examination of urine .............................................. 32 

• Immunological tests ............................................................................ 33 

• Radiologic examination ..................................................................... 34 

PART III: GLOMERULAR DISEASES 

• Pathogenesis of glomerulonephritis................................................. 53 

• Classification of glomerulonephritis.................................................. 57 

• Nephrotic syndrome ............................................................................ 63 

• Acute post-streptococcal glomerulonephritis ............................... 69 

• Primary glomerulonephritis................................................................. 71 

• Lupus nephritis ................................................................................... 80 

• Renal involvement in vasculitis ......................................................... 84 

• Henoch-Schönlein purpura ............................................................. 85 

• Essential mixed cryoglobulinaemia .............................................. 87 

• Progressive systemic sclerosis ................................................... 88 

• Diabetic nephropathy ...................................................................... 88 

• Alport syndrome ............................................................................... 92 

• Fabry's disease................................................................................. 93 

• Nail-patella syndrome .................................................................... 95 

• Bacterial endocarditis ..................................................................... 95 

• Shunt nephritis ................................................................................ 96 

• Malarial nephropathy ..................................................................... 96 

• Schistosomal nephropathy ........................................................... 98 

• Glomerulopathy secondary to virus infections .......................... 104 

• Treatment of glomerulonephritis........................................................ 108

PART IV: VASCULITIS 

• Classification ......................................................................................... 113 

• Polyarteritis nodosa ............................................................................. 114 

• Wegener's granulomatosis ................................................................ 117 

• Churg-Strauss syndrome .................................................................. 118 

• Temporal arteritis ................................................................................. 120 

• Takayasu's arteritis .............................................................................. 121 

• Relapsing polycondritis ....................................................................... 121 

• Goodpasture's syndrome .................................................................... 122 

• ANCA and vasculitis .......................................................................... 125 

PART V: THROMBOTIC MICROANGIOPATHY................................. 127 

PART VI: ACUTE RENAL FAILURE ........................................................ 133 

PART VII: CHRONIC RENAL FAILURE: 

• Definitions ............................................................................................. 147 

• Etiology ................................................................................................. 148 

• Pathophysiology ................................................................................. 150 

• Clinical features .................................................................................. 158 

• Investigations ....................................................................................... 164 

• Management ........................................................................................ 164 

• Dialysis .................................................................................................. 169 

• Transplantation .................................................................................... 1 

PART VII: RENAL TUBULAR DISORDERS 

• Renal glycosuria ................................................................................ 185 

• Amino acids tubular transport defects ........................................... 186 

• Renal tubular acidosis (RTA) .......................................................... 187 

• Nephrogenic diabetes insipidus ...................................................... 193 

• Water retention .................................................................................. 195 

• Cystinosis ............................................................................................ 195 

• Wilson's disease ............................................................................... 196 

• Oxalosis ............................................................................................... 196 

• Bartter's syndrome ............................................................................ 197 

• Vitamin D resistent rickets ............................................................. 197 

• Pseudohypoparathyroidism ............................................................ 198 

• Fanconi syndrome ............................................................................ 198

PART IX: TUBULAR AND INTERSTITIAL DISEASES 

• Interstitial nephritis............................................................................. 201 

• Analgesic nephropathy....................................................................... 205 

• Reflux nephropathy............................................................................. 209 

• Pyelonephritis...................................................................................... 212 

• Urinary tuberculosis ........................................................................... 218 

PART X: RENAL CYSTIC DISEASES 

• Classification of renal cystic diseases ........................................ 231 

• Autosomal dominant polycystic kidney diseases ....................... 231 

• Autosomal recessive polycystic kidney diseases....................... 234 

• Medullary cystic kidney diseases .................................................. 236 

• Medullary sponge kidney ................................................................ 236 

• Acquired renal cystic diseases ...................................................... 238 

• Tuberous sclerosis ............................................................................ 239 

• Von Hipple-Lindau syndrome ......................................................... 239 

• Simple renal cysts............................................................................. 239 

PART XI: RENAL STONE DISEASES ................................................ 241 

PART XII: WATER AND ELECTROLYTE DISORDERS 

• Disorders of plasma osmolality ...................................................... 247 

• Disturbances of plasma sodium concentration .......................... 253 

• Disturbances of plasma potassium concentration...................... 256 

• Disturbances of plasma calcium concentration.......................... 260 

PART XIII: DISORDERS OF ACID-BASE BALANCE 

• Physiology of acid-base system ..................................................... 265 

• Metabolic acidosis ............................................................................. 266 

• Respiratory acidosis .......................................................................... 269 

• Metabolic alkalosis ............................................................................. 270 

• Respiratory alkalosis .......................................................................... 271 

PART XIV: HYPERTENSION AND THE KIDNEY 

• Etiology and classification ................................................................ 273 

• Essential hypertension ...................................................................... 274 

• Renovascular hypertension .............................................................. 286 

• Ischaemic nephropathy ..................................................................... 291

• Conn's syndrome .............................................................................. 291 

• Pheochromocytoma .......................................................................... 292 

PART XV: MISCELLANEOUS 

• Proteinuria............................................................................................ 295 

• Haematuria .......................................................................................... 298 

• Value of urine in medical diagnosis ................................................ 301 

• Polyuria and oliguria .......................................................................... 302 

• Renal manifestations of systemic diseases..................................... 309 

• Renal diseases in hepatic patients .............................................. 315 

• Malignancy and the kidney .............................................................. 321 

• Drugs and the kidney ........................................................................ 333 

• Kidney and the heart ......................................................................... 345 

• Kidney and the lung ......................................................................... 348 

• Renal diseases in the elderly ......................................................... 348 

• Kidney in pregnancy........................................................................... 352 

PART XVI: ENVIRONMENTALLY-INDUCED KIDNEY 

DISEASES ................................................................................... 359

RENAL FUNCTIONS AND STRUCTURE 

KIDNEY FUNCTIONS: 

The function of the kidney is to keep the internal environment (internal 

milieu) of the body stable within the physiologic limits. This is achieved 

through the following functions: 

1. EXCRETORY FUNCTION AND PRODUCTION OF URINE: 

The production of urine from the blood perfusing the kidney occurs in two 

steps: the first is filtration of plasma in the glomerulus; and the second is 

selective reabsorption or excretion of various substances in the renal tubules. 

Through urine production there are: 1. elimination of wasts (metabolic 

products, ingested toxins such as drugs). 2. control of water balance 

(maintenance of total body water and plasma osmolarity), and 3. control of 

electrolyte balance (sodium, chloride, calcium, phosphate, potassium, acidbase, 

magnesium and others). For more detail see anatomic physiology of the 

nephron, page 20. 

2. REGULATION OF THE ACID-BASE BALANCE OF THE BODY: 

When excess acids are released into the circulation (e.g. through metabolic 

process, acid intake, or respiratory failure), the kidney prevents acidosis 

(accumulation of H + and drop in pH) through different mechanisms such as: 

a. Excessive proximal tubular reabsorption of bicarbonate filtered from 

blood through the glomeruli. This reabsorbed bicarbonate will go 

through the blood and acts as a buffer to neutralize excess H + in the 

circulation (H + + HCO 3 ∅ H 2 CO 3 ∅ H 2 O + CO 2 ). 

b. Excessive consumption and excretion of H + by the renal tubules 

through the increase in the formation of ammonia and titratable acids 

(phosphates, sulphates and phenols). 

In case of alkalosis (low H+ concentration pH of body fluids), the kidney 

will compensate by increasing bicarbonate loss in urine. This compensation

occurs by increasing its reabsorbsorption which will then lead to increase of 

H + in the blood through the reaction H 2 CO 3 → H + + HCO 3 -. Also formation of 

ammonia and secretion of titratable acids by renal tubules will decrease. This 

results in retention of H + in blood and tissue fluids with correction of alkalosis. 

In states of acidosis, in a patient with normal kidney, urine will be maximally 

acidic (less than 5.5) and in state of alkalosis the urine will be alkalotic. 

3. HEMOPOIETIC FUNCTION: 

Kidney has an important role in erythropioesis in the bone marrow 

through secretion of erythropoietin. 

Erythropoietin is a hormone of glycoprotein nature which regulates red blood 

cell development in the bone marrow. Ninety percent of erythropoietin is 

produced in renal cortex (by interstitial, tubular or endothelial cells). The main 

stimulus for erythropoietin secretion is tissue hypoxia, other stimuli are 

androgens, PGE, thyroid hormone and B-adrenergic agonists. Inability to 

secrete sufficient amount of erythropoietin as in chronic renal failure results in 

anaemia. In contrary, in conditions as renal artery stenosis, cystic kidney 

diseases and renal cell carcinoma, erythropoietin is secreted in excess 

resulting in polycythaemia (Erythrocytosis). Human recombinant erythropoietin 

is now commercially available for the treatment of anaemia in uraemic 

patients. 

4. ENDOCRINE FUNCTIONS OF THE KIDNEY: 

Many hormones and vasoactive substances are either formed, activated, 

or degraded by the kidney. Examples of these functions are:- 

A- Hormones synthesized by the kidney:- 

1. Renin (Fig. 1.1): 

This is secreted by cells of the iuxta-glomerular apparatus (see 

page 18). Renin will act on a circulating protein (angiotensinogen) 

changing it into angiotensin I which is then converted by 

converting enzyme into angiotensin II which has a vasopressor 

activity and also stimulates suprarenal gland to secrete 

aldosterone. This system (Renin- Angiotensin- Aldosterone) is of 

great importance for the control of blood pressure and body fluid 

and electrolyte balance.

Juxtaglomerular 

apparatus 

Liver 

Renin 

Angiotensinogen 

(Renin substrate) 

Low blood pressure, 

salt depletion etc. 

Angiotensin I (10 AAs) 

Angiotensin II (8 AAs) 

Angiotensin 

converting 

enzyme 

(Lung 

kidney, 

brain) 

Adrenal 

cortex 

Brain 

Vascular 

smooth 

muscle 

Vasoconstriction 

Thirst 

Aldosterone 

Kidney 

Sodium 

retention 

Potassium 

excretion 

Rise in 

blood 

volume 

Rise in 

blood 

pressure 

(Fig. 1.1) 

The renin-angiotensin system and its interactions 

2. Activation of vitamin D (Fig. 1.2): 

Vitamin D reaching the body through oral intake or formed 

subcutaneously (by exposure to sun or ultraviolet rays) is 

biologically inactive. The activation of this vitamin occurs through 

hydroxylation (OH). The first step of hydroxylation occurs in the 

liver (25-OH- Vitamin D), whereas the second step occurs in the 

kidney (1, 25- (OH) 2 Vitamin D). The 1,25-dihydroxy vitamin D is 

100 times as active as 25-hydroxy vitamin D.

7-Dehydroxycholesterol 

UV light 

on skin 

Diet 

Cholecalciferol 

(vitamin D3) 

Liver 

25-Hydroxycholecalciferol (activity =1) 

Hypophosphataemia 

Kidney 

Parathormone 

1,25- Dihydroxycholecalciferol (activity =100) 

(1,25-DHCC) 

Gastrointestinal 

calcium 

absorption 

Formation of 

bone 

(anti-rachitic) 

(Fig. 1.2) 

Activation of Vitamin D 

Parathormone and hypophosphataemia are the main stimuli for 

renal production of 1,25- (OH)2 vit.D. 

The exact site of synthesis is unknown, although the 1-hydroxylase 

enzyme is found in proximal tubular cells. 

The major effects of vitamin D are to increase gastrointestinal 

calcium absorption and to promote normal bone calcification. Also 

vitamin D and its metabolites have important effects on skeletal 

muscle strength.

3. Prostanoids (Prostaglandins) (Fig. 1.3): 

These are derived from oxidation of arachidonic acid and other 

polyunsaturated fatty acids and have great diversity of structure and 

biological effects. They are not strictly hormones, since they act in the 

organ in which they are produced. The term "autacoids" has been 

introduced to describe such locally acting agents. The kidney has 

enzymes to produce all known primary prostanoids, and appears to be 

able to adapt this process according to various circumstances. 

Prostanoids may be divided into those with vasodilator, diuretic and 

antithrombotic effects (prostacyclin, PGE2, PGD2), and those with 

opposing actions (thromboxane). 

(Fig. 1.3) 

Production and function of different renal prostanoids

Renal actions of prostanoids. 

1- Regulation of renal blood flow: The kidney contains both the vasodilator 

prostaglandins PGE2, PGI2, PGD2 and the vasoconstrictor 

thromboxane. 

When renal perfusion is compromised (e.g. dehydration or hypotension) 

the vasodilator prostanoids help to maintain renal blood flow. 

Accordingly, in such circumstances non-steroidal anti-inflammatory 

drugs (NSAIDs) can precipitate acute renal failure by inhibiting cyclooxygenase 

and thus vasodilator prostanoids production. The production 

of vasodilator prostanoids is most probably mediated through the high 

level of angiotensin II. 

2- Effect on sodium excretion: Natriuretic prostanoids (e.g. PGE2) act both 

directly on tubular cells and by enhancing renal perfusion. NSAIDs as 

antiprostanglandins have an antinatriuretic action which decreases the 

effect of thiazide diuretics and can precipitate cardiac failure in patients 

with heart disease. 

3- Effect on water excretion: PGE2 inhibits tubular effect of ADH (i.e. has 

diuretic action) while NSAIDs can potentiate the antidiuresis (i.e. water 

retention). 

4- Interaction with the renin-angiotensin system. Prostanoids stimulate the 

release of renin from the juxta glomerular apparatus. Furthermore, local 

prostaglandins (particularly prostacyclin and PGE2) decrease the 

vasoconstrictor effect of angiotensin II within the vascular pole of the 

glomerulus. 

4. KalliKrein-BradyKinin: 

Are vasodilator autacoids found particularly in renal cortex. Effects of 

kallikrein-kinin include: 1. decrease the renal vascular resistance, 

particularly in low sodium states; 2. augment renal sodium and water 

excretion; and 3. activate prostaglandin synthesis and appear to have a 

role in complex interrelationships with other regulatory substances. 

5. Erythropoietin: 

(See above).

B- Peptide hormones degraded by the kidney: 

The kidney removes many peptide hormones from circulation to be 

degraded by renal tubules. This removal may come through reabsorption from 

the glomerular filtrate (from inside) or through binding of the peptide to specific 

receptors in the basolateral tubular cell membrane. 

1. Insulin: 

Nearly 25% of insulin, pro-insulin and c-peptide are removed from 

circulation by the two mechanisms previously described. So, in diabetics 

insulin requirements often fall in end stage renal failure. On the other hand, 

uraemia may cause peripheral resistance to insulin with a consequent 

carbohydrate intolerance. 

2- Parathormone (PTH): 

About 30% of overall PTH metabolism occurs in the renal tubules. The 

intact hormone, c-terminal and amino-terminal are removed through 

glomerular filtration, while intact hormone and amino-terminal are removed 

from the peritubular circulation by binding to specific receptors. Elevated 

plasma PTH in uraemia is partially due to failure of its renal metabolism. 

3- Prolactin: 

Most prolactin metabolism is via renal (glomerular filtration) mechanism. 

Elevated prolactin levels are observed in 60% of uraemic patients suggesting 

deranged pituitary feedback as well. Probably this is responsible for 

gynaecomastia, galactorrhea, infertility and impotence in chronic renal failure. 

4- Growth hormone: 

The kidney removes 40-70% of growth hormone from circulation 

(glomerular filtration). 

5- Vasopressin: 

The kidney removes 30-50% of this hormone through glomerular filtration. 

6- Glucagon: 

About 30% of this hypoglycaemic hormone is renally excreted. 

7- Gastrointestinal hormones: 

Gastrin, VIP, and gastric inhibitory polypeptide are all partially renally 

excreted.

C- Hormones acting on the kidney: 

1- Antidiuretic hormone (vasopressin): ADH is produced by the cells of 

the supraoptic nucleus of the hypothalamus and is released from the 

posterior pituitary. 

The major effects of ADH are: (1) it increases collecting tubule 

permeability to water allowing it to flow back to circulation. This leads to 

urine concentration and water retention; and (2) it causes 

vasoconstriction, leading to a rise in the arterial blood pressure. 

Stimuli to secretion of ADH include: (1) decrease in effective blood 

volume, this triggers pressure sensors in cardiac atria, aortic arch and 

carotid sinuses. The response curve is exponential. Therefore, the 

volume stimuli override osmolar stimuli. By this mechanism decreased 

effective blood volume as in cirrhosis and cardiac failure results in 

excess secretion of ADH with water retention irrespective of the 

developing hyponatremia (dilution) and hypo-osmolarity; (2) increase in 

plasma osmolarity, sensitive osmoreceptors exist in the hypothalamus, 

and the response is linear. Sodium chloride is a powerful stimulant for 

secretion of ADH, while urea, glucose and ethanol are very weak 

stimulants; and (3) Many other stimuli, including nausea, 

hypoglycemia, high ambient temperature, anxiety and stress are also 

associated with release of ADH. 

Synthetic analogues of ADH include the following : (1) 8-arginine 

vasopressin-AVP, which is available for parentral or intranasal use in 

ADH deficiency; and (2) Desamino-D-arginine vasopressin (DDAVP) is 

a synthetic analogue which has increased antidiuretic but decreased 

vasoconstrictor effect compared with AVP. 

2- Atrial natriuretic peptide (ANP), ANP is a 28 amino acid peptide 

which is released from granules in the cardiac atria in response to 

stretch. ANP has renal (diuretic and natriuretic) and hemodynamic 

(hypotensive) effects. It also has important hormonal actions such as 

suppression of renin and aldosterone. 

3- Mineralocorticoids and glucocorticoids: Aldosterone is a steroid 

hormone produced by the adrenal cortex in response to 

adrenocorticotrophic hormone, hyperkalaemia or angiotensin II. Its

main action is on the late distal tubule and the early collecting duct. It 

reduces excretion of sodium; and consequently increases excretion of 

potassium. Aldosterone excess can occur as primary phenomenon 

(Conn's Syndrome) or more commonly secondary to excess renin as in 

oedema states, renal artery stenosis and with malignant hypertension. 

Glucocorticoids at high doses have mineralocorticoid effects. 

4- Dopamine: Is released by renal nerves probably secondary to 

stimulation by baroreceptors. It causes renal vasodilatation and 

natriuresis mainly through stimulation of kallikrein-kinin system. It may 

be used in some cases of acute renal failure to maintain renal 

perfusion and urine output. 

ANATOMY OF THE KIDNEY: 

Each kidney is a bean-shaped structure measuring approximately 11 

cm x 6 cm x 3 cm and weighing 120-170 grams in adult. The kidney is 

contained in a fibrous capsule. The hilum of the kidney which is present 

medially contains renal artery, vein, lymphatics and pelvis of the ureter. The 

kidney is contained in peri-renal fat. The kidney lies in the paravertebral gutter 

on the posterior abdominal wall retroperitoneally and opposite the twelfth 

thoracic down to the third lumbar vertebra. The right kidney is slightly lower 

than the left (liver effect), lower pole reaches one finger breadth above the 

iliac crest. Figure 1.4 shows a longitudinal section of the kidney. It shows the 

hilum containing the renal vessels and pelvis of the ureter which branches 

inside the kidney into 2-4 major calyces, each of which in turn branches into 

several minor calyces. The kidney parenchyma is divided into outer cortex (1 

cm thick) and inner medulla. The medulla is formed of 8-18 pyramids which 

are conical-shaped, with its base at cortico-medullary junction and its apex 

projects into minor calyces as papillae. The medullary pyramids are striated in 

shape. The cortex which is granular-looking may extend between pyramids 

forming columns of Bertini. Medullary rays are striated elements which 

radiates from the pyramids through the cortex.

(Fig. 1.4) 

Right kidney sectioned in several planes exposing the parenchyma and renal sinus. 

(Reproduced with permission from Novartis, Switzerland). 

BLOOD SUPPLY OF THE KIDNEY: 

The renal arteries arise from the aorta opposite the intervertebral 

disc L 1-2. In the hilum it gives anterior and posterior branches, which when 

penetrate the kidney tissue form the interlobar arteries, running between renal 

pyramids. At corticomedullary junction they turn to run along the base of the 

pyramids, forming the arcuate arteries and at 90° get out the interlobular 

arteries (Figure 1.5) which penetrate into the cortex and from them get the 

afferent arterioles. At the glomerulus, afferent arteriole invaginates the 

Bowman's capsule forming the glomerular tuft which is a modified capillaries 

structure from which glomerular filtrate gets out to the urinary space of 

Bowman's capsule. From the glomerulus the efferent arteriole gets out. 

Efferent arterioles of the outer and middle cortical glomeruli get down between 

tubules where they divide into capillary networks called peritubular capillaries. 

The efferent arterioles of the inner cortical glomeruli penetrate deeply into 

medullary pyramids forming vasa recta which share in the medullary counter 

current exchange system. The vasa recta vessels dip deeply into medullary 

pyramids, then make a hairpin turn returning to the corticomedullary junction.

- Renal venous system follows the same pattern as the renal arteries. 

- Lymphatic vessels run in association with the blood vessels. 

-The kidney receives sympathetic and parasympathetic fibers from the caeliac 

plexus. 

(Fig. 1.5) 

Terminal branches of renal artery 

(left kidney viewed from in front) 

(Reproduced with permission from Novartis, Switzerland).

REGULATION OF THE RENAL BLOOD FLOW (RBF) AND GLOMERULAR 

FILTRATION RATE (GFR). 

Normally the kidney receives 20-25% of the cardiac output. Extrarenal 

(prerenal) factors including blood pressure and circulating blood volume will 

affect RBF and GFR. When blood pressure or circulating blood volume 

decreases RBF and GFR decrease and vice versa. 

Autoregulations of renal haemodynamics: 

There are intrarenal mechanisms which control RBF and GFR to keep 

it within normal when there is a decrease in the renal perfusion pressure (e.g. 

hypotension). Of these are the Juxta-glomerular apparatus and the tone of the 

afferent and efferent arterioles. With hypotension or hypovolaemia renal blood 

flow and renal perfusion pressure decrease. This stimulates Juxta glomerular 

apparatus to secrete Renin which changes a circulating protein called 

Angiotensinogen into Angiotensin-I. This is changed by a converting enzyme 

into Angiotensin II, which causes spasm in the efferent arteriole, which will 

increase the intraglomerular pressure (filtration pressure), this maintains the 

GFR. Such renal autoregulation mechanisms keep satisfactory renal 

hemodynamics and GFR down to a mean renal perfusion pressure about 70 

mmHg below which renal hemodynamics and GFR fail and renal functions 

are impaired. 

THE NEPHRON: 

Is the functional unit of the kidney (Fig. 1.6). Each kidney contains 

approximately one million nephrons. The first part of the nephron is the 

glomerulus (renal corpuscle) which lies mainly in the renal cortex, followed by 

proximal convoluted tubule which also lies mainly in the renal cortex. This is 

followed by a loop of Henle which is partly in the cortex and partly extends 

deep into the medulla. Loop of Henle is composed of a thin part and a thick 

part. This is followed by the distal convoluted tubule which lies in the renal 

cortex. Part of the distal convoluted tubule comes into contact with the hilum 

of the glomerulus and afferent arteriole. Cells in the hilum of the glomerulus 

and those in distal convoluted tubule and afferent arteriole are modified to 

form the Juxta glomerular apparatus (Fig. 1.7). Distal convoluted tubule ends 

into the collecting duct which lies partly in the cortex and partly in the medulla. 

In the medulla, collecting ducts descend in the pyramids, at the renal papillae 

collecting ducts unite together to form ducts of Bertini which discharge urine 

into renal pelvis.

(Fig. 1.6) 

Diagrammatic illustration of the nephrons and collecting tubules.

Bowman's capsule 

Glomerulus 

-3- Epithelial cells 

(renin granules) 

Afferent 

arteriole 

Sympathetic 

nerve ending 

(B2 adrenergic) 

-1- Macula 

densa cells 

Tubular 

lumen 

Distal 

tubule 

Efferent arterioles 

-2- Juxtaglomerular 

(lacis) cells 

Mesangial cells and matrix 

(Fig. 1.7) 

The Juxtaglomerular apparatus. Note: (1) Macula densa of distal tubule. 

(2) Juxtaglomerular (lacis) cells. (3) Granular renin-secreting epithelial 

cells of afferent arterioles. 

The glomerulus (renal corpuscle): 

The renal corpuscle is formed essentially of two modified structures of 

different embryonic origins: 

A. The first is the Bowman's capsule which is present at the beginning of 

the proximal convoluted tubule and is formed of a space lined by 

basement membrane and flat epithelial cells. 

B. The second is modification of the end of the afferent arteriole, which 

divides into several primary branches. These in turn give rise to several 

lobules of capillaries (tuft of capillaries). The other end of this capillary 

tuft gives rise to the efferent arteriole. Each capillary is lined with 

basement membrane, lined from inside by endothelial cells and from 

outside by epithelial cells which lie on the capillary basement membrane 

by foot process (so it is called podocyte). The capillary tuft will invaginate 

and occupy the Bowman's capsule to form the renal corpuscle.

Figure 8 shows a cross section of the glomerulus which is composed of: 

1. Bowman's capsule with its outer (parietal) layer lined by flat epithelial 

cells, and inner visceral layer in contact with capillary tuft lined with 

visceral epithelial cells (podocytes). Between the two layers there is a 

space called urinary space. 

2. Glomerular capillaries are lined by basement membrane which is 

covered from inside with endothelial cells and from outside by epithelial 

cells (podocytes). The capillary wall basement membrane is chemically 

formed of type IV collagen and negatively charged glycosaminoglycans. 

By electron microscopy, the basement membrane is formed of three 

layers, inner layer (lamina rara interna), outer layer (lamina rara externa) 

and in between the lamina densa. The thin cytoplasm of the endothelial 

cells show multiple open fenestrae, and the outer epithelial cells show 

elongated foot processes which rest on the outer surface of the 

glomerular basement membrane. These foot processes interdigitate with 

those of nearby epithelial cells and in between we can see slit pores. 

The fenestrae of endothelial cells and slit pores of epithelial cell foot 

processes are of great value in glomerular filtration. 

Fig. (1.8a) 

Electron Photomicrograph Of Renal 

COPPUSCLE, X1100 

Pa=Partial Epithelium Nucleus 

U= URINARY SPACE 

Ca=PODOCYTE (Visceral Epithelium) 

NUCLEUS 

En=Endothelium Nucleus 

M= Mesangial Cell nucleus 

A= Afferent Arteriole 

E= Efferent Arteriole 

J= Juxataglomerular Cell 

D= Macula Densa Of Distal Tubule 

(Tangentially Cut) 

P= Proximal Tubules

(Fig. 1.8b) 

PAS stained kidney section (X 260), which shows a normal glomerulus cut 

through the hilus. The branching mesangial stalk is clearly seen (arrow-1). The 

capillaries are attached to the stalk, forming peripheral capillary loops (arrow-2). 

Podocyte 

(epthelial cell) of capillary membrane 

Bowman's capsule 

Epitheial cell 

of Bowman's capsule 

Glomerular 

filtrate in 

urinary space 

Basement 

membrane 

Mesangial cell 

Endothelial cell 

of capillary 

membrane 

Plasma 

in capillary 

(Fig. 1.8c) 

Diagrammatic representation of the cell types of the renal glomerulus

(Fig. 1.8d) 

Electron micrograph (X 18,000). Part of a glomerular capillary wall under 

higher magnification. Endothelial pores are visible in places. The basement 

membrane shows three layers: Lamina rara interna (LRI), lamina densa (LD), 

and Lamina rara externa (LRE). L= Capillary lumen, U= urinary space. 

3. Mesangium is composed of special cells and matrix. It is located 

mainly at the hilum of the glomerulus, and extends between capillary 

loops. Its main function is to support the capillary tuft, also, it may 

have a phagocytic function and contractile function. Phagocytic 

property of the mesangium helps in clearing the glomerulus from any 

circulating immune complexes or antigens. The contractile function 

may help in modulating the renal blood flow and the capillary wall 

filtration surface. 

Juxta-glomerular apparatus: 

Juxta-glomerular apparatus is a specialized structure which is present 

at the hilum (vascular pole) of the glomerulus (Figure 1.7&1.8). It is composed 

of four groups of cells which contain granules in their cytoplasm (most 

probably renin). These cells are: 

1. The macula densa cells which are modified cells in distal convoluted 

tubules.

2. The epithelioid cells which are modified cells in the wall of the afferent and 

to less extent efferent arterioles. 

3. The lacis cells which are interstitial cells in continuity with mesangial cells. 

4. The peripolar cells which are present at the vascular pole of the 

glomerulus, separating the podocytes from the flat parietal epithelial cells 

of Bowman's capsule. More details about JGA will be given on discussing 

renovascular hypertension (Page 316). 

Proximal convoluted tubule: 

Is the longest segment of the nephron, lined by a single layer of cells 

with prominent brush border towards the lumen. The basal part of these cells 

contains large mitochondria which are important for the high reabsorptive 

activity of these cells. 

Loop of Henle: 

Morphologically and according to the type of epithelial cells covering it, 

loop of Henle can be divided into thick descending limb, thin descending limb, 

then thin ascending limb and the thick ascending limb. The loops of Henle of 

superficial and middle cortical nephrons are short while those of deep cortical 

and corticomedullary junction nephrons are long and go deep in the medulla 

to reach renal papillae before they ascend up. These later loops are arranged 

in bundles in association with the collecting ducts and vasa recta (all are 

participating in the counter current system). Since the morphology of these 

segments is different, their function is also different. 

Distal nephron: 

Begins with distal convoluted tubule which starts at juxta-glomerular 

apparatus and end at the renal papilla. Morphologically and functionally, this 

can be sub-divided into: 

A. Distal convoluted tubule with its early part somewhat similar to the 

proximal convoluted tubule and distal part is similar to the cortical 

collecting tubule. 

B. Cortical part of collecting tubule. 

C. Medullary part of collecting tubule. 

D. Papillary part of the collecting tubule.

ANATOMIC PHYSIOLOGY (FUNCTION OF DIFFERENT SEGMENTS 

OF THE NEPHRON): 

1. The glomerulus (glomerular filtration): 

As the blood enters the glomerular capillary tuft through the afferent 

arteriole, a process of ultrafiltration occurs through the capillary wall to 

the Bowman's (urinary) space. The total ultrafiltrate in human ranges 

from 90-120 ml/min. (i.e. 130-180 liters/24h). Through the ultrafiltrate the 

body gets red of toxins. The ultrafiltrate is cell free, protein free but 

contains water and different solutes (e.g. Na + , K + , Ca ++ , Urea, and 

HCo 3 

- .......). The amount and quality (nature) of the filtrate depend on 

the following factors: 

a. Glomerular capillary wall membrane including its total surface area 

(which could change such as by contraction and relaxation of the 

mesangium) and its structure (including the slit pores of the podocytes, 

fenestrae of the endothelial cytoplasm and the pores), and the 

negative charges of the basement membrane. These factors together 

determine what is called the filtration coefficient (Kf) of the glomerular 

capillary wall. 

b. Filtration pressure which is the net pressure pushing fluid from the 

capillary lumen to the urinary space. It depends mainly on the 

glomerular capillary hydrostatic pressure (normally + 45 mmHg) which 

is determined by the systemic blood pressure and tone of the afferent 

and efferent arterioles. Spasm of the efferent arteriole increases the 

glomerular hydrostatic pressure and increases the glomerular filtration 

and vice versa. Spasm of the afferent arteriole decreases the 

hydrostatic pressure and glomerular filtration and the reverse is also 

true. Forces acting against filtration (opposing the hydrostatic 

pressure) are the oncotic pressure of the plasma proteins in the 

glomerular capillaries and the hydrostatic pressure of the fluid in the 

urinary space. So, the net filtration pressure = Hydrostatic pressure in 

the capillaries (45 mm Hg) – plasma oncotic pressure in the glomerular 

capillaries (10 mm Hg) – the hydrostatic pressure of the fluid in the 

urinary space (25 mmHg) = 10 mm Hg. 

c. Size and charge of the molecule: The smaller the molecular weight of a 

solute, the easier it passes through the capillary wall. Also, the

molecule of positive or neutral charges passes easier than those with 

negative charges. 

2. Proximal Convoluted Tubule (PCT): 

a. The daily glomerular filtration is 130-180 liters. This amount enters the 

PCT where 65-80% of its H 2 O, Na + , K + and Cl - are reabsorbed. 

b. In addition, there is a selective reabsorption of important metabolites 

such as active reabsorption of glucose, amino acid, and HCO 3 

- . 

c. At the distal part of PCT, the secretion of weak acids and weak bases 

occurs. Glomerulo - tubular balance is a unique property of PCT in which 

it adjusts reabsorption rate so as to keep the proportion of reabsorbed to 

filtered H 2 O and salts constant despite the variation in the flow rates. 

3. Loop of Henle: 

25% of filtered Na + is reabsorbed in the ascending thick limb 

selectively, i.e. not in conjunction with water as this segment is impermeable 

to H 2 O. The fluid leaving this segment is hypotonic to plasma. 

4. Distal Nephron: 

The function of the distal convoluted tubule is to reabsorb some Nacl 

and calcium. It is impermeable to water and is relatively insensitive to 

aldosterone or ADH. 

The collecting duct- particularly the cortical part- has three functions: 

a. It reabsorbs Na + actively under the influence of aldosterone to 

achieve fine adjustment of its blood level. 

b. It excretes K + and H + (related to Na + reabsorption and also related to 

aldosterone). 

c. It reabsorbs water under the control of ADH. For example, when there 

is dehydration (hyperosmolar state), osmoreceptors are stimulated, 

which stimulate the hypothalamus, which in turn stimulates posterior 

pituitary, which secretes ADH which increases permeability of distal 

nephron to water, which becomes reabsorbed and urine becomes 

concentrated. The reverse occurs in state of excess water intake 

(hypoosmolar state).

Concentration And Dilution Of Urine: 

This function is very important to regulate body water and tissue 

osmolarity. Normal body tissue and fluid osmolarity is 280-300 mosmol/Liter. 

This is maintained despite the wide variation in fluid intake (increased intake 

decreases osmolarity and vice versa) and load of osmotically active 

substances e.g. salt. Through biologic activity, there is a basal production of 

600 mosmol/day. This can increase to over 1200 mosmol/day in states of 

severe catabolism as in patients with extensive burns. 

The kidney is responsible for the control of secretion of water and 

solutes through process of urine formation so as to keep normal plasma 

osmolarity. The urine volume is around 1.5 litter/day but can vary from 400 ml 

to over 20 liter/day according to water and solute intake. 

The urine osmolarity may vary from 30 mosmol/liter (when urine is 

maximally diluted) to 1400 mosmol/liter (when urine is maximally 

concentrated). The minimum urine output to maintain adequate excretion of 

waste products (600 mosmol/day) is 400 ml with maximum osmolarity of 1400 

mosmol/liter. 

Under normal circumstances, over 99% of filtered water is reabsorbed. 

Water is reabsorbed in an iso-osmotic fashion with sodium chloride i.e. as 

NaCl is reabsorbed water flows back into the circulation. In addition, further 

water is reabsorbed in the process of urine concentration which occurs in the 

distal nephron. 

Dilution of urine is achieved through the removal of NaCl from the 

tubular lumen fluid in the segment which is impermeable to H 2 O (thick part of 

the ascending loop of Henle, DCT), or from the segment which becomes 

impermeable to H 2 O as an effect of ADH (collecting tubule and duct). The 

most important of them is the loop of Henle which secretes more H 2 O and 

less Nacl in urine making it hypotonic (diluted). 

Urine concentration results from the reabsorption of water in excess of 

nitrogenous wastes and other solutes. Therefore, in urine the concentration of 

urea is about 60 times that in plasma. In states of maximal urine 

concentration, urine osmolarity is about 1200 mosmol/liter. Further increase in 

urine osmolarity to 1400 mosmol/liter can be achieved with persistence of the 

stimulus for urine concentration. Urine concentration, through excess 

reabsorption of free water occurs mainly in collecting tubules.

The mechanism of urine concentration depends on passage of 

collecting tubules through the hypertonic renal medulla. The tonicity of renal 

medulla is maximum at the tip of renal papillae and decreases gradually 

towards the direction of the corticomedullary junction. ADH when secreted will 

increase the collecting tubule permeability to water which gets out to the 

interstitium leaving tubular contents hypertonic. The interstitial water is picked 

up by the vasa recta and renal venules and will be drained away. 

Hypertonicity of the renal medulla is achieved through the 

countercurrent multiplier system which is generated by the pump mechanism 

present mainly in the thick ascending part of loop of Henle. By this pump, 

sodium and chloride and to less extent urea get out free of water, thus 

increasing the tonicity of the interstitium. The descending thin limb of loop of 

Henle is permeable to sodium, chloride and water which pass freely from the 

interstitium to the lumen (i.e. there is equilibrium between it and interstitial 

tonicity). There is a sort of recirculation of solutes in the renal medulla (from 

ascending to interstitium to descending loop to ascending again). The pump 

system in the loop of Henle is adjusted to achieve maximal tonicity at the tip of 

the loop and renal papillae of around 1300 mosmol/litre. Also, there is a 

difference between comparable points in ascending and descending loops of 

around 200 mosmol/litre. Moreover, the deeper in the renal medulla, the more 

is the osmolarity (Fig. 1.9). 

In states of diuresis the medullary tonicity decreases and in states of 

anti-diuresis the tonicity gradually builds up to 1400 mosmol/litre. The vasa 

recta is permeable to water and solutes accumulating in renal medulla. Its 

loop structure minimizes the loss of sodium chloride and urea from renal 

medulla maintaining its tonicity which could be lost if the blood flow is in one 

direction only.

(Fig. 1.9) 

Countercurrent mechanisms in the kidney. 

In the kidney the loop of Henle acts as a countercurrent multiplier system, capable of 

generating a deep medullary (tip of the papilla) concentration of about 1400 mmol/litre 

under conditions of severe dehydration. Sodium chloride is pumped by the thick 

ascending limb into the interstitium, which it renders hypertonic, and then diffuses into 

the permeable thin descending limb. In the late distal convoluted tubule and in 

collecting tubule ADH renders the walls permeable to water but not solutes. Accordingly 

water diffuses by osmosis into the interstitium, leaving the tubular fluid progressively 

more concentrated.

Suggested Readings: 

- Bruzzi I, et al: Endothelin: a mediator of renal disease progression. J 

Nephrol, 10: 4, 179-83, 1997. 

- Nambi P: Endothelin receptor in normal and diseased kidney. Clin Exp 

Pharmacol Physiol, 23: 4, 326-30, 1996. 

- Kohan DE: Endothelins in the normal and diseased kidney. Am J 

Kidney Dis, 10: 4, 179-83, 1997. 

- Rabelink TJ: Endothelial function and the kidney. An emerging target 

for cardiovascular therapy. Drugs, 53 Suppl 1: 11-9, 1997. 

- Klahr T: Angiotensin II and gene expression in the kidney. Am J Kidney 

Dis, 31: 1, 171-6, 1998.

INVESTIGATIONS FOR KIDNEY DISEASES 

These include biochemical, microbiologic, immunologic, histopathologic 

and radiologic investigations. 

A. BIOCHEMICAL INVESTIGATIONS: 

Include the examination of urine, tests for kidney functions, 

microbiologic and immunologic tests. 

I. URINE EXAMINATION: 

Simple urinalysis and blood pressure measurement could be a 

valuable method for screening for renal diseases. However, negative 

urinalysis does not exclude renal disease. Urinalysis is an essential part of 

physical examination for kidney disease. The urine should be fresh and 

examined for the following: 

1. Physical characteristics: these include examination for colour, odour, 

transparency, froth and foreign materials. 

Normal colour of urine is amber yellow due to the pigment urochrome, it 

could be diluted or concentrated according to the patient hydration status 

and the diluting and concentrating capacity of the kidney. 

A red coloured urine is seen mainly with haematuria, hemoglobinuria 

which could be differentiated by microscopic examination which can 

demonstrate RBC's in cases of haematuria but not in cases of 

haemoglobinuria. 

A milky urine is seen in chyluria (lymph in urine). Turbid urine is seen with 

pyuria or presence of salts (phosphate, urate or oxalates). Cloudy and 

offensive urine could be seen with infection. Abnormal foreign bodies seen 

in urine are for example gravels or sloughed renal papillae. 

2. Dip-stick test: These are plastic strips, attached to it are pieces of paper 

impregnated with different enzymes. Each piece contains an enzyme 

which reacts specifically with certain urine chemicals (e.g. glucose, 

albumin, acetone, H+, nitrite, haemoglobin, etc.). According to the 

concentration of the chemical tested, a certain change in colour occurs (0, 

1+, 2+, 3+, 4+). 

By Dip-Stick we can semiquantitatively determine proteinuria (mainly 

albumin), haemoglobin (haematuria or haemoglobinuria), nitrites (when 

positive means urinary infection), pH (acidic or alkaline urine), glucose 

(glucosuria). (Fig. 2.1)

(Fig. 2.1) 

DIPSTICK TEST 

3. Microscopic examination of urine is a method for detection of cells 

(RBC's, leukocytes, pus, epithelial cells), casts (hyaline casts, red cells 

casts, leucocyte casts, granular casts or broad casts), or crystals 

(triple phosphate, uric acid, oxalate or cystine) (Figure 2.2) . 

4. Quantitative estimation of proteinuria: This is achieved through 

quantitation of protein in 24 hours urine collection (normally less than 

150 mg/24hours) or through examination of spot urine for albumin and 

creatinine and estimation of albumin/creatinine ratio (normally < 0.1). 

5. Examination of urine for Bence Jones protein: Normally this could not 

be detected by Dip-Stix and needs immunoelectrophoresis. This 

protein precipitates on heating at 56°C and redissolves at 100°C or 

more. It is present in cases of multiple myeloma, amyloidosis and other 

types of macroglobulinemias.

(Fig. 2.2a) 

An Illustration of Urinary Sediment Showing Different Organized Elements 

(Reproduced with permission from Novartis, Switzerland)

(Fig. 2.2b) 

ILLUSTRATION OF DIFFERENT TYPES OF CRYSTALS WHICH MAY BE FOUND IN URINARY 

SEDIMENT (Upper are mainly seen in alkaline urine while lower are mainly seen in acidic urine). 

For more details on value of urine examination in medical diagnosis see page 

301.

II. RENAL FUNCTION TESTS: 

These includes tests for glomerular and tubular functions. 

A. TESTS FOR GLOMERULAR FUNCTION 

These include test for serum creatinine, blood urea nitrogen and 

glomerular filtration rate (GFR). 

1- Serum creatinine: In routine practice serum creatinine level is the 

best indicator of kidney function (normally is 0.6-1.2 mg/dl or 53-106 µmol/L). 

It is higher in male than in female and in those with bulky muscles than 

cachectic ones. Creatinine is normally released with stable level from the 

muscles (unless there is a muscle disease) and is secreted by the kidney. 

2- Plasma urea and Blood Urea Nitrogen (BUN) :Unlike creatinine, 

urea is affected by protein diet, liver disease (because liver changes ammonia 

to urea), and dehydration (excessively reabsorbed from proximal convoluted 

tubules giving higher level in blood out of proportion to renal dysfunction). The 

normal value of blood urea is 15-40 mg/dl (2.5-7.0 mmol/L). Its production is 

increased by infection, trauma, surgery and corticosteroid intake. 

However, blood urea is considered a less reliable measure for kidney 

function. Still, measuring serum creatinine and urea together may give useful 

clinical information. For example, if urea concentration is out of proportion to 

that of creatinine it suggests a state of salt and water depletion, 

gastrointestinal haemorrhage, increased protein intake, diuretic therapy, 

infection or, corticosteroid therapy. Serum creatinine is out of proportion to 

plasma urea in cases of rhabdomyolysis and muscle diseases. Blood urea 

nitrogen (BUN) is sometimes used as a test for kidney function. Normal value 

is 8-13 mg/dl (2.9-8.2 mmol/L). 

3- Glomerular Filtration Rate (GFR): This is measured by studying 

the clearance of a substance which is ideally freely filtered through the 

glomerulus; and not reabsorbed or excreted by the renal tubules (e.g. inulin). 

In practice, we use endogenous creatinine which is filtered through the 

glomerulus but some excretion occurs by the renal tubules, so creatinine 

clearance slightly overestimates GFR. 

Clearance (C) of a substance is a measure of volume of plasma cleared by 

the kidneys of this substance per time unit (e.g. minute or second). Thus 

C= UXV 

P

Where 

C= creatinine clearance 

U= urine concentration of creatinine 

V= urine flow rate (minute or second) 

P= plasma concentration of creatinine 

Normal creatinine clearance in adult male is 90 -150 ml/minute. To 

estimate creatinine clearance, the patient should collect 24 hours urine from 

which V and U could be estimated then, blood is withdrawn for P estimation. 

The major disadvantage of clearance study is the possible faulty 

collection of 24 hours urine, especially in females. 

99mTc-DTPA or 151Cr-labeled EDTA or iothalamate isotope renal 

scan is an alternative method which does not require urine collection. The 

199mTc-DTPA is injected I.V. and multiple images of the kidney are obtained 

over 30 minutes. This study provides the total and split (right and left) kidney 

GFR. 

B. TESTS FOR TUBULAR FUNCTIONS: 

1. Urine Acidification Test: This is indicated to test for the ability of the 

kidney to acidify urine (excrete H+). This is done by decreasing 

plasma pH (i.e. inducing acidosis) by giving gelatin-coated ammonium 

chloride capsules 0.1 g/kg with water and checking the urine pH hourly 

for 6 hours. Normally, it should drop < 5.4. Otherwise, it will indicate 

renal tubular acidosis (RTA). If blood pH is already low (acidosis), 

there will be no need for giving ammonium chloride and check urine 

pH directly. As a screening test we can look for urine pH of the first 

morning voided urine (the highest acidic urine), which should be < 5.4. 

Presence of urinary infection with urea- splitting organism makes the 

urine alkaline and interferes with these tests. Therefore, irradication of 

this infection is mandatory before doing this test. 

2. Urine Concentration Test: for screening purpose examine early 

morning specimen for osmolality. If it is > 700 mosmol/L, concentrating 

capacity is considered normal and there would be no need for further 

investigation. Otherwise, we may either do water deprivation test or 

vasopressin (ADH) test. 

In water deprivation test the patient is asked to stop fluid intake 

completely. This results in a progressive increase in plasma osmolality 

(normal 290 mosmol/L). In a normal person this should be followed by a

progressive decrease in urine volume and increase in its osmolality 

(maximum 1200 mosmol/L). In cases of lost ability to concentrate urine 

(e.g. in diabetes insipidus), this will not occur and urine volume will not 

decrease so that the patient may pass into severe hypotension, so we 

have to watch patient body weight (not to decrease by > 5%) and blood 

pressure (More details, are in page 270). 

In vasopressin test we inject 5 IU vasopressin tannate in oil s.c.. This 

results in urine concentration if the inability to concentrate urine is due to lack 

of ADH (central diabetes insipidus); but not in cases of renal causes 

(nephrogenic diabetes insipidus). 

3. Urinary B 2 -microglobulin: This is a small molecular weight protein 

(MW 1800) which is normally present in all body fluids. It is formed in 

the body at a constant rate and is removed through glomerular filtration. 

Then, it is reabsorbed and catabolised by renal tubules. The urine 

concentration of this protein is usually 6 to avoid false readings. It is measured by 

radioimmunoassay. 

B 2 -microglobulin could be used as a marker for tubular diseases e.g. 

analgesic and toxic nephropathies, Fanconi's syndrome and Wilson's 

disease, in these conditions urinary B2-microglobulin is increased. 

4. Urinary Enzymes: Enzymes as lactic dehydrogenase (LDH) and N- 

acetyl-B-glucosaminodase (NAG) are normally present in high 

concentrations in renal tubules especially proximal convoluted tubules. 

They are released in higher concentrations in urine with tubular 

damage of any etiology (toxic, ischemic or infection). 

5. Urinary excretion of sodium (UNa): Many factors- other than renal 

diseases- affect urinary sodium excretion e.g. body hydration status 

(extra cellular fluid volume), adrenal function, diuretic therapy and 

effective circulating blood volume. Fractional excretion of Na (FeNa) 

means measuring the part of filtered sodium that is excreted to urine. 

This is helpful in differentiating impaired kidney function which is due to 

acute tubular necrosis from prerenal failure (see acute renal failure). 

The FeNa is calculated by dividing Na clearance over creatinine 

clearance i.e.

FeNa = UNa X v ÷ Ucr X v = UNa X v XPcr = UNa X Pcr 

PNa Pcr PNa X V X Ucr PNa X Ucr 

i.e. we need only to measure plasma, urinary Na and creatinine. Urine 

volume is not required. Normal FeNa is less than 0.1. 

B. MICROBIOLOGICAL EXAMINATION OF URINE: 

In cases of urinary tract infection, urine specimens are examined for 

identification of bacteria as well as for its sensitivity to antibiotics by culture 

techniques. Taking a proper urine sample is mandatory to avoid false results. 

A midstream urine sample is required i.e. when the bladder is full, the 

first 200 c.c. is passed to clean the urethra. Then, 10 c.c. is taken in a sterile 

container from the urine stream. In the male, glans penis should be cleaned 

by sterile water, and in the female the vulva is cleaned properly and during 

micturition labia are held away by fingers. In neonates and young children 

suprapubic aspiration of urine by fine needle is safe. The presence of more 

than one type of organisms in culture, usually means contamination rather 

than infection. 

When prostatic infection is suspected, three specimen technique of 

Stamey is followed. VB1 is the first voided 10 ml of urine (which represents 

urethral bacterial flora). VB2 is the midstream urine (which represents the 

bladder flora). After that the patient stops micturition and the prostate is firmly 

massaged and any discharge comes out is cultured. Then, the patient passes 

another 10 ml of urine (VB3) which represents prostatic flora. 

In urine culture, a bacterial count of 100,000 or more is needed for the 

diagnosis of urinary tract infection. However, a smaller number may be 

considered significant in pregnant women, children, and immunosuppressed 

patients. When there is pyuria; and urine culture is persistently negative (at 

least three cultures should be done), this is called sterile pyuria. In this 

condition, urine should be examined by specific types of cultures e.g. 

Lowenstein-Jensen media for Mycobacterium; anaerobic culture for 

anaerobes; human blood agar for Gradnerella vaginalis; urea plasma agar for 

ureaplasmas; irradiated McCoy cells for chlamydia. If the cultures are still 

negative, we are mostly dealing with either viral infection or non-infectious 

causes of pyuria e.g. foreign body, malignancy or immunologic disease as 

SLE or kidney graft rejection.

C. IMMUNOLOGICAL TESTS FOR DIAGNOSIS OF 

KIDNEY DISEASES 

1. Complement: 

See pathogenesis of glomerulonephritis (Page 53) to know the value of 

complement system in renal diseases. Complement System is activated and 

consumed in immune-complex formation. Hypocomplementemia 

consequently occur in diseases such as: post infectious glomerulonephritis, 

shunt nephritis, nephritis associating subacute bacterial endocarditis, lupus 

nephritis and idiopathic mesangio-capillary (membrano-proliferative) 

glomerulonephritis. Usually, the complement system is assessed by 

measuring the total haemolytic complement (CH50) activity, C3 and C4 

concentrations. Other complement components are measured if CH50 is 

low, while C3 and C4 are normal. Low C4 concentration indicates an 

activated complement system through the classic pathway, while low C3 and 

C4 indicates the activation of the alternative pathway. C3 nephritic factor (C3 - 

NeF) is detected in mesangio-capillary glomerulonephritis. 

2. Immunoglobulins: 

Serum IgA concentrations could be high in IgA nephropathy and 

Henoch-Schönlein disease. Serum IgE concentration could be high in minimal 

change nephritis and all allergic nephropathies. 

Paraproteins could be detected by immunoelectrophoresis in multiple 

myeloma, amyloidosis and mixed cryoglobulinemia. Bence Jones protein 

could be detected in urine also. 

3. Circulating Immune Complexes (C.I.C.): 

Circulating immune complexes (C.I.C.) are detected in diseases such 

as cryoglobulinaemias, SLE and collagen diseases. C.I.C. assays have a 

limited role in clinical practice. 

4. Autoantibodies: These include antinuclear antibodies (ANA), anti- 

DNA, anti-neutrophil cytoplasm auto antibodies (ANCA), and anti-glomerular 

basement membrane antibodies (anti-GBM). For more details see vasculitis 

(Page 123). 

D. KIDNEY BIOPSY: 

Kidney Biopsy is performed to obtain kidney tissue for histological 

examination to take therapeutic decision and to judge the prognosis of the 

renal disease.

Indications: 

For all adults with nephrotic syndrome, children with steroid resistant 

nephrotic syndrome and patients with renal impairment of unknown etiology. 

Precautions and Technique: 

Assure that the patient has two functioning kidneys, a normal 

coagulation profile (bleeding, clotting, prothrombin time), controlled blood 

pressure and gave an informed consent. 

Patient lies in prone position with a pillow under the rib cage pressing the 

kidney back to posterior abdominal wall. Skin over the right kidney is sterilized 

and lower pole of the kidney is localized in deep inspiration by real-time 

ultrasound. Local anaesthetic is injected subcutaneously and along the biopsy 

track. Under ultrasound guidance a tru-cut biopsy needle is introduced while 

the patient is holding his breath in deep inspiration and core of kidney tissue 

is obtained from the cortex of the lower pole. Two cores are usually taken for 

light, immunofluorescent and electron microscopy. Firm pressure is applied 

over biopsy site for 10 minutes. After biopsy the patient should be kept in 

supine position for at least four hours with observation every 30 minutes for 

pulse, blood pressure and for haematuria. The patient should be kept in bed 

for 24 hours with no strenuous activity for two weeks. 

Complications: 

1. Peri-renal haematoma which is extremely common but of significance 

only in 1% of cases. 

2. Bleeding which could be microscopic or gross with clot retention. 

3. Intra-renal A-V fistula which usually closes spontaneously. 

E. RADIOLOGIC EXAMINATION OF THE KIDNEY AND THE URINARY 

TRACT 

During the last decade a great progress has been achieved in imaging 

techniques of the kidney and urinary tract. We have to select the procedure 

which is the simplest, least invasive, most informative and which saves time 

for the patient. 

1. Ultrasonography (U.S.) 

Ultrasound examination of the kidney and urinary tract is either through 

B-mode scan, Doppler flow examination of renal vessels or duplex ultrasound 

scanning.

B-mode U.S. imaging is the usual examination requested. Renal 

ultrasonography should be the first radiologic procedure performed on patient 

with renal or urologic disorder; and in most instances it will be the only one 

that is required. Renal ultrasonography carries the advantages of being noninvasive, 

less costly and does not require special preparation. It can 

demonstrate clearly the renal size, contour, echotexture (Figure 2.3), stone, 

back pressure (due to chronic obstruction), renal mass or cyst (Figure 2.4), 

and perirenal collection. Pelvic ultrasonography may show bladder mass and 

calculate the residual urine (amount of urine remaining in the bladder after 

micturation). Ultrasonography can also show the upper and lower parts of the 

ureter. In addition, ultrasonography can help in examining surrounding organs 

and help in guiding needle for renal biopsy or aspiration of peri renal or perivesical 

collection. 

(Fig. 2.3) 

Normal renal ultrasound: it shows longitudinal scan through the right kidney 

demonstrating the relationship to the right lobe of the liver anteriorly and the 

paraspinal muscle posteriorly. The kidney shows echogenecity less than that 

of the adjacent liver

Fig. (2.4a) 

It shows a well-circumscribed right upper polar cyst (c) with a sonolucent 

"echo-free" pattern, thin wall, well-defined posterior margin and posterior 

echo-enhancement (due to good transmission of the ultrasound waves 

through the fluid content). 

Fig. (2.4b) 

It shows marked left hydronephrosis demonstrating marked dilatation of the 

calyces and the renal pelvis with thinning of the renal parenchyma.

(Fig. 2.4c) 

It shows a longitudinal scan of each kidney with bilateral variably sized 

non-communicating cyst throughout renal parenchyma. Neither backpressure 

changes nor communication with the collecting system can be 

identified. 

Fig. (2.4d) 

It shows a LS of the left kidney with a stone upper calyx (arrow) as echodense 

focus casting posterior acoustic shadow.

Doppler flow imaging of the renal vessels will assess the integrity of the 

blood supply of the kidney (Figure 2.5). It may be displayed with standard 

gray scale or in colour (colour Doppler). It may help in diagnosis of renal 

artery occlusion or stenosis, renal vein thrombosis and kidney transplant 

rejection. This examination needs special experience. Colour Doppler 

ultrasonography increases the sensitivity of this technique. Recently, it has 

been suggested that colour Doppler U.S. may be useful in diagnosing 

vesicoureteric reflux. 

(Fig. 2.5) 

Doppler US of a case with renal artery stenosis, it shows 

Damped wave form with marked delay in the systolic rise 

time, a reduction in the pulsatility index with low flow 

velocities (Parvus tradus pattern). Sampling was from an 

intrarenal vessel.

Duplex ultrasonography shows the standard B-mode image with 

superimposed Doppler flow informations (Figure 2.6). 

 

(Fig. 2.6) 

Duplex US (Normal) 

Combined real time US (top) and Doppler US (bottom) showing normal lowresistance 

waveform with high forward flow throughout systole and diastole. 

2. Plain abdominal X-Ray: 

For examination of urinary system, this is called plain X-ray abdomen 

or KUB (kidney, ureter, bladder). KUB may show : 1-stones (80-90% of 

stones are radio-opaque), 2-Calcification of the kidney, urinary bladder, 

seminal vesicles or prostate, and 3-In a well prepared patient with no bowel 

gases, or by nephrotomogram, soft tissue shadow and renal contour could be 

seen (size and shape of the kidney) (Fig. 2.7). 

3. Intravenous urography (IVU): 

The patient should come for this investigation after a thorough bowel 

evacuation (laxative is to be given the night before and enema on the morning 

of the day of examination) and with the fluid intake restricted (to allow 

concentration of the dye and consequently proper visualization of the urinary 

tract). An iodinated contrast media is injected intravenously and x-ray films 

are taken immediately, 1 minute and 15 minutes after injection. Sometimes 

late films are taken (e.g. when artery stenosis is suspected).

(Fig. 2.7) 

Oxalosis (UTP) 

Calcified soft tissue shadow of both kidney 

(simulating a nephrogram of IVU). Multiple, 

bilateral radioopaque stones are noted as well. 

Nephrogram is the film obtained immediately after injection of contrast 

medium. It shows the dye concentrated in the nephrons and the kidney 

appears opacified but no dye yet in the renal pelvis. This film shows the site, 

the size, the contour of the two kidneys. It also shows whether the kidneys are 

functioning equally or not. In cases of renal artery stenosis, the nephrogram of 

the affected kidney appears delayed than the other healthy kidney. After 

nephrogram, dye will appear in the renal pelvis, ureter then the bladder (Fig. 

2.8). So, IVU shows the anatomy of the kidney and urinary system, any mass, 

stones, back pressure changes and also demonstrates the kidney function.

(Fig. 2.8) 

Intravenous urography (IVU) showing: 

- Normal excretion and concentration of contrast medium 

by both kidneys. 

- Normal configuration of both kidneys. 

- Normal course and calibre of both ureters 

- Normal cystogram. 

As the contrast media used is ionic and with high viscosity and the 

technique is done with dehydration, this can result in kidney damage (contrast 

media nephropathy) with rise in serum creatinine-even acute renal failure may 

occur. There is a group of patients who are more vulnerable to contrast media 

nephropathy. These are diabetics, elderly, hyperuricaemics, patients with 

multiple myeloma, presence of renal dysfunction, patients receiving other 

nephrotoxic drugs (e.g. gentamycin), and those with congestive heart failure.

To avoid contrast media nephropathy in high risk patients we have to: 

1. Do it only when strongly indicated. 

2. Avoid dehydration. 

3. Avoid concomitant use of nephrotoxic drug. 

4. Premedicate the patient with verapamil (80 mg orally, one hour before 

exposure to contrast media). 

5. Use special type of contrast (low viscosity, non-ionic), but this is very 

expensive and even still risky. 

6. Immediately after taking the last film inject 12.5 gm mannitol I.V. to wash 

the contrast out with the diuresis. If the patient has renal impairment, the 

dye can be washed immediately by haemodialysis. 

Anaphylactoid reaction is another possible risk of the contrast media. 

Therefore, steroids and antihistaminic drugs should be at hand. 

4. Cystography and voiding cystourethrography: 

Diluted contrast is injected into the bladder through urethral or 

suprapubic catheter. When the bladder becomes full, the patient is asked to 

micturate and films are taken. This is called micturating or voiding 

cystourethrogram (VCU). Normally the dye does not appear in the ureters 

because of the normally present antireflux mechanism at ureterovesical 

junction. If the dye appears in the ureters during VCU. This is called 

vesicoureteric reflux (VUR); which could be classified according to its severity 

into five grades (Figure 2.9). 

In advanced VUR reflux, the dye may regurge to the nephrons during 

VCU and the renal parenchyma is visualized. This is called intrarenal reflux. 

VUR reflux can damage the kidney through pressure atrophy (in Grade 

IV), precipitation of chronic infection and through a special type of 

glomerulopathy (reflux nephropathy). 

VUR reflux could also be diagnosed by colour Doppler ultrasonography 

(which may show the abnormal direction of urine flow at lower end of ureters 

during micturation) and by radionuclide micturating cystography. 

5. Urodynamic studies: 

Measuring the intravesical pressure (cystometry) and urine flow will 

give full anatomic and physiologic assessment of the lower urinary tract.

(Fig. 2.9): 

The grading system adopted by the International Reflux Study in 

Children. Contrast material in the collecting system is represented 

in black. Grade I is assigned if the contrast material enters the 

ureter, but does not enter the renal pelvis. Grade II means that 

contrast material reaches the renal pelvis, but does not distend the 

collecting system. Grade III occurs when the collecting system is 

filled and either the ureter or pelvis is distended, but the calyceal 

demarcations are not distorted. Grade IV is assigned when the 

dilated ureter is slightly tortuous and the calyces are blunted. Grade 

V occurs when the entire collecting system is dilated and the 

calyces have become distorted and indistinct. 

6. Angiography: This includes 

a. Renal Arteriography 

A catheter is introduced percutaneously into the femoral artery and 

proceeded under television (screen) control through the aorta. The dye could 

be injected into the aorta, above the level of renal arteries (flush aortography) 

and films are taken which will show renal arteries and nearby vessels or the 

catheter could be advanced selectively into renal artery and dye is injected 

(selective renal angiography). 

Renal arteriography is mainly indicated for diagnosis of renovascular 

hypertension or persistent haematuria following trauma. 

Digital subtraction angiography (DSA) 

This technique is characterized by: 1. A smaller amount of dye to be 

injected into the artery. 2. Using a smaller catheter.3. the images obtained 

can be processed by a computer program, through which gases and soft 

tissue images are substracted from the final image. DSA shows mainly the 

examined vessels in better quality than the ordinary angiography (Fig. 2.10).

(Fig. 2.10a) 

Intra-arterial digital subtraction angiography (IA-DSA) of 

the abdominal aorta of a potential kidney donor shows 

single left renal artery and double right renal arteries. 

In another approach the dye could be injected into a peripheral vein 

(less invasive) and through special computer program we can visualize any 

artery (e.g. renal arteries) and images could be obtained but the quality of 

these images are far inferior to those obtained by direct intra-arterial injection 

of contrast media.

(Fig. 2.10b) 

IA-DSA of left kidney showing normal main renal artery 

and intrarenal (segmental, interlobar, interlobular and 

arcuate) arteries in a delayed arterial phase. Normal 

parenchymal perfusion is seen as well in the 

nephrographic phase. 

b. Renal Venography 

This is indicated mainly for diagnosis of renal vein thrombosis. A 

catheter is introduced percutaneously into the femoral vein then advanced 

through inferior vena cava to the renal vein where the contrast medium is 

injected. 

7. Computerized tomography (C.T.) 

Generally C.T. carries two advantages over the conventional 

radiography, 1. It produces axial cross-sectional images. 2. It produces more 

radiographic contrast which allows different types of soft tissue to be 

distinguished. The degree of attenutation of the X-ray beam by different 

tissues and media is expressed as Hounsfield units (H). Water and urine are 

nearly 0, bone + 1000 H, while air is- 1000 H. Normal kidney and muscle

density is about 30 H and fat is about - 60 H. Injecting contrast media with 

C.T. scanning will enhance the renal cortical image to 60-80H. C.T. (Figure 

2.11) scanning may be superior to other radiologic investigations in the 

following areas: 1. To characterize lesions in peri-renal, para-renal and 

retroperitoneal space as lymphadenopathy, tumours or retroperitoneal 

fibrosis. 2. Solid renal masses, for diagnosis and staging of the tumour. 3. 

Low density or radiolucent stones. Therefore it is strongly indicated in patients 

with obstructive uropathy with non-evident cause. 

(Fig. 2.11) 

CT scan of the kidney (Normal) 

- Axial CT scan of the kidney early after administration of I.V. 

contrast medium showing normal corticomedullary definition as the 

medullary pyramids are less enhancing than the cortex. The central 

hypodense structure represents the renal sinus. 

8. Radionuclide Imaging 

There are two types of isotope renal scanning: 1. Static imaging, in 

which the tracer injected is retained by proximal convoluted tubules, giving 

best chance to visualize the morphology of functioning part of the kidney 

using gamma camera. So, it is helpful in diagnosing renal scarring (Figure 

2.12), renal tumours and anatomic abnormalities. Also, according to the 

differential isotopic activity, quantification of relative function between kidneys 

and within a kidney could be achieved. The tracer used for this type of scan is 

99m technetium-labelled dimercaptosuccinic acid (DMSA). 2. Dynamic renal 

imaging in which the tracer is not retained by the kidney, but is immediately

excreted, either by glomerular filtration alone e.g. 99m TC- diethylenetriamine 

penta acetic acid (DTPA) or by glomerular filtration and tubular secretion 

(MAG3), and 123I, sodium iodohippurate (Hippuran). This type of scan is 

helpful in examining renal perfusion (vascular phase) and dynamic 

parenchymal images expressing isotope transit and excretion into the 

bladder. 

(Fig. 2.12) 

DMSA scan (chronic pyelonephritis) 

small-sized left kidney with irregular 

outline and multiple photopenic areas. 

A photodeficient area is also noted at 

the lower pole of right kidney. 

The vascular dynamic imaging (Figure 2.13) help in diagnosing renal vascular 

occlusion (embolism or thrombosis) or narrowing (renal artery stenosis). The 

isotope does not appear in the completely obstructed kidney and show 

delayed appearance in the case of renal artery stenosis. The dynamic 

parenchymal imaging (Figure 2.14) helps in diagnosis of ureteric obstruction 

in which delayed washout of the tracer from the kidney will be observed. 

Furthermore, the dynamic scan can be helpful in the measurement of the total 

or individual kidney GFR (DTPA) or effective renal plasma flow (MAG3 or 

Hippuran).

(Fig. 2.13) 

(a) Perfusion study: Reduced perfusion of the 

right kidney, in comparison to the normal left 

kidney, with loss of the flow peak. 

(b) Renogram: 

The right kidney shows prolonged time 

maximum activity (second, accumulation 

phase), flat peak, and slow rate of excretion.

(Fig. 2.14) 

Diuretic Renogram (obstruction) 

It shows a non-obstructed right kidney as 

evidenced by a rapid response to frusemide 

injection while the recographic curve of the left 

kidney signifies obstructed pattern as no 

response is seen after lasix infection. 

9. Magentic Resonance Imaging (MRI) 

The principle of MRI is the excitation of the nuclei of atoms such as 

hydrogen in tissues with radiowaves, and detection of echo radiation from 

these nuclei when the radio source is removed. Thus, the MRI provides 

information at the cellular level. Currently, this recent technique provides 

excellent anatomical informations (Figure 2.16) which are very helpful in 

studying malignancies of the urinary tract. In the future, this technique is 

expected to provide a very reliable physiologic and metabolic assessment. 

MRI angiography is being developed which can provide a non-invasive and 

sensitive technique for assessment of renal vessels.

(Fig. 2.15a) 

MRI Kidenys (Normal) 

Axial T1-weighted sequence demonstrating hypointensity of the renal 

parenchyma. The perinephric fat is hyperintense and easily 

demarkated from the adjacent renal cortex. The renal sinus fat is 

hyperintense as well. 

(Fig. 2.15b) 

MR urography (obstruction) 

Bilateral hydroureteronephrosis in a patient with 4.8 mg/dl 

serum creatinine (IVU is not feasible). Note the 

hypointense ureteric stone bilaterally (arrows).


- Wilcox CS: Ischemic nephropathy, non invasve testing. Semin 

Nephrol, 16: 1, 43-52, 1996. 

- Platt JF: Doppler ultrasound of the kidney. Semin Ultrasound 

CT MR, 18: 1, 22-32, 1997. 

- Rudnick MR et al: Contrast media-associated nephrotoxicity, 

Semin Nephrol, 17: 1, 15-26, 1997. 

- Murphy KJ: Power Doppler: it's a good thing. Semin 

Ultrasound CT MR, 18: 1, 13-21, 1997. 

- Prince MR: Renal MR angiography: a comprehensive 

approach. J Magn Reson Imaging, 8: 3, 511-6, 1998. 

- Kramer LA: Magenetic resonance imaging of renal masses. 

World J Urol, 16: 1, 22-8, 1998. 

- Soltes GD et al: Interventional uroradiology, World J Urol, 16: 

1, 52-61, 1998. 

- Roy C, et al: MR Urography in the evaluation of urinary tract 

obstruction. Abdomen Imaging, 23: 1, 27-34, 1998.

GLOMERULONEPHRITIS 

(GN) 

Are group of diseases of inflammatory or non-inflammatory nature 

involving the renal glomeruli. 

PATHOGENESIS OF GLOMERULONEPHRITIS: 

Many pathogenic mechanisms are responsible for the development of 

glomerular injury. These mechanisms are: 

I. Immunologic mechanisms II. Metabolic abnormalities 

III. Hyperfiltration injury IV. Hereditary abnormalities 

I. Immunologic Mechanisms: 

Most of the cases of glomerulonephritis encountered in clinical practice 

are secondary to immunologic attack affecting the renal glomeruli. This attack 

usually occurs in genetically predisposed person after exposure to toxin or an 

infection. This will provocate the immune system to attack the glomerular 

structures. This could be through the formation of antibodies or through a cell 

mediated glomerular injury. 

Antibodies formed by the immune system could be directed to intrinsic 

(endogenous) antigen (i.e. autoantibodies) or to extrinsic (exogenous) 

antigens. 

A. The endogenous antigen could be either in the glomerular basement 

membrane (GBM) and antibodies are therefore called anti-GBM (causing 

anti-GBM disease or Goodpasture syndrome) or it could be 

extraglomerular antigens. Examples of extraglomerular antigens are: 1- 

nuclear DNA and their antibodies are called anti-DNA (as in systemic 

lupus erythematosus), 2- circulating immunoglobulin molecules (as in 

cryoglobulinemia), 3- Neutrophil cytoplasmic antigens and their antibodies 

are called anti-neutrophil cytoplasmic antibodies (ANCA, as in vasculitis), 

and 4- tumour antigens. 

In experimental animals other intraglomerular antigens have been 

identified. These are: 1- epithelial cell antigens (in the coated pits of the 

glomerular epithelial cell surface (subepithelial deposits); 2- mesangial 

antigens, and 3- endothelial antigens along the filtration slits.

B. Extrinsic antigens include bacterial products (e.g. streptococci), virus (e.g. 

HBV, HCV), parasite (Malaria, Schistosoma) or drug (e.g. penicillamine, 

gold). 

The formed antibodies attach to the responsible antigen forming immune 

complex. 

Circulating immune complex (CIC) may be trapped in the glomerulus. 

Alternatively, the antigen may be trapped first (planted) in the glomerulus 

and immune complex formation occurs in the glomerulus (In-situ immune 

complex formation). 

By immunofluorescent microscopy linear deposition of IgG along the GBM 

is seen in cases of anti-GBM disease while granular deposition of 

immunoglobulins in the capillary wall and/or the mesangium is seen in 

cases of immune-complex mediated diseases. 

Persistent antigenemia (e.g. subacute bacterial endocarditis, infected A-V 

shunt, hepatitis B virus) or recurrent antigenemia (e.g. Malaria) are 

important for immune complexes formation. 

Formation of immune complexes are not always associated with 

glomerulonephritis. There are many factors necessary for immune complex 

to be nephritogenic, these include: 

1. The charge of the antigen, cationic antigens are easily implanted in the 

glomerulus and cause disease. 

2. The size of the immune complex, those formed at antibody-antigen 

equivalence are more nephritogenic. 

3. The antibody class and affinity. 

4. The capacity of the body's mononuclear cell phagocytic system to clear 

immune complexes. 

5. The local glomerular hemodynamic factors. 

Immune complex-mediated glomerular injury 

The mechanisms through which an immune complex can induce 

glomerular injury include the following: 

1. Antibody: The glomerular damage can be induced directly by high 

amount of immunoglobulin deposited as in cases of anti-GBM disease.

In cases of I.C. mediated glomerulonephritis, glomerular lesions occur through 

antibody mediated activation of other humoral and cellular components 

including complement and inflammatory cells (monocytes and neutrophils). 

2. Complement: Binding of antibody with antigen activates the 

complement cascade. There are two pathways for complement activation, the 

classic pathway which starts with the activation of CIq and the alternative 

pathway which starts with the activation of C3. Activation of complement 

results in a series of reactions with liberation of by-products (activated 

complement components) into target tissue. Some of these complement 

components have direct damaging effects (vasoactive, chemotactic) or 

through leucocyte activation. Complete activation of all components of the 

cascade forms glomerular membrane attack complex (MAC) which causes 

lysis of the GBM. 

The high rate of activation and consumption of the complement components 

in the inflammatory process results in hypocomplementemia. 

Of the diseases which induce hypocomplementemia are: 

(a) Post-streptococcal GN and some cases of bacterial endocarditis 

(transient hypocomplementemia), 

(b) Primary mesangiocapillary glomerulonephritis (persistent hypocomplementemia), 

and 

(c) Systemic lupus erythematosis (SLE). 

3. Coagulation factors: There is a relationship between the major 

molecules of intrinsic coagulation cascade which normally activates factor VII 

and mononuclear cells and macrophages which when activated (through 

receptor on their wall) by these molecules will produce cytokines which cause 

tissue damage. Also, fibrin has strong relationship with formation of 

glomerular crescents in anti-GBM disease and immune complex-induced 

glomerulonephritis. Anticoagulants and tissue plasminogen activators (as 

Ancord) have been reported to be of benefit in experimental 

glomerulonephritis. 

4. Eicosanoids: As Prostaglandins (synthesized from arachidonic acid by 

cyclooxygenase) and leukotrienes (synthesized from arachidonic acid by 

lipooxygenase) play a role in immune response and glomerular 

haemodynamics. These compounds could be synthesized by the intrinsic 

glomerular cells as well as by the invading inflammatory cells.

5. Neutrophils: have an important role especially in proliferative types of 

glomerulonephritis. These cells are attracted to the glomerulus by the 

chemoatractant fragment of the complement cascade (activated by antibody). 

Cytokines (e.g. IL-8) derived from monocytes and endothelial cells also 

participate in recruitment of neutrophils in the glomerular injury. Neutrophils 

will induce injury by the release of reactive oxygen species including hydrogen 

peroxide, hydroxyl and superoxide ions as well as by producing lysosomal 

proteolytic enzymes as myeloperioxidase. 

6. Macrophages: have a potent role especially in proliferative 

glomerulonephritis. They are recruited and activated within the glomeruli by 

interaction with cell adherence receptor on the Fc fragment of the glomerular 

immunoglobulin and by lymphokines secreted by sensitized T cells (migration 

inhibition factor and procoagulant-inducing factor). Macrophages can control 

variety of outcomes in glomerulonephritis. For example, they 

a. can produce a vast array of biologically active molecules (e.g. 

reactive oxygen species, lysosomal enzymes ) producing proteinuria. 

b. induce coagulation (procoagulant activity, plasminogen activator and 

its inhibitor). 

c. have an important role in inducing proteinuria and fibrin deposition. 

d. affect the function of intrinsic glomerular cells by their release of 

cytokines and growth factors. 

e. may be involved in glomerular repair or sclerosis. 

7. Cytokines and growth factors: These are released from infiltrating 

monocytes and glomerular cells especially mesangial cells. They 

include: 

a. Tumour necrosis factor (TNF) and interleukin-1 (IL-1): activate 

inflammatory cells as well as targeting glomerular cells and so, they 

augment the inflammatory process. 

b. Interleukin-6 (IL-6): stimulates mesangial cell proliferation. 

c. Tumour growth factor-B (TGF-B) facilitates mesangial matrix 

proliferation in experimental glomerulonephritis. 

8. Intrinsic glomerular cells: These include: 

a. Mesangial cells: Inflammatory signals (complement components, 

I.C., growth factors, cytokines) cause proliferation of mesangial 

cells which produce IL-6, IL-1, TNF, TGF-B, Prostaglandins and 

platelet activating factor.

. Endothelial cells: Normally these cells have many important 

functions including: (i) maintenance of the anticoagulation state of 

the glomerular capillary bed. (ii) maintenance of capillary 

permeability, and (iii) formation of extracellular matrix. 

c. Epithelial cells: produce plasminogen activator inhibitor molecule. 

In response to immune injury, they proliferate and-with monocytes 

in the urinary space- form the glomerular crescent. 

Cell Mediated Immune Injury of the Glomeruli: 

This has been documented in proliferative, crescentic and minimal 

change nephritis. In these types of glomerular diseases, glomerular T cells 

are activated and produce expression of IL-2 receptor and production of 

cytokines including IL-4 and α-interferon. 

In minimal change nephritis these cytokines induce proteinuria. 

In crescentic glomerulonephritis, activated T cells activate monocytemacrophage 

with production of fibrin and expression of procoagulant activity. 

II- Metabolic Abnormalities: See diabetic nephropathy, gouty nephropathy 

and renal amyloidosis. 

III- Hyperfiltration injury: See diabetic nephropathy. 

IV- Hereditary Abnormalities: See Alport's Syndrome. 

CLASSIFICATION OF GLOMERULONEPHRITIS: 

Glomerulonephritis can be classified on the basis of (I) the etiologic 

cause; (II) the histopathologic findings on examination of kidney biopsy; (III) 

or according to the clinical presentation. 

(I) Etiology of glomerulonephritis: 

This could be either: 

a) Primary (idiopathic) when the glomerular disease is not part of systemic 

disease and the cause is unknown. 

b) Secondary when glomerular disease is part of a systemic disease (e.g. 

diabetes mellitus) or due to a known cause (e.g. post-streptococcal 

glomerulonephritis). Secondary glomerulonephritis may be the result of: 

1. Infection which may be bacterial (e.g. post-streptococcal), viral (e.g. 

HBV, HCV, CMV), parasitic (e.g. Schistosoma mansoni, malaria).

2. Collagen disease (e.g. SLE, polyarteritis nodosa, rheumatoid arthritis). 

3. Drug (e.g. Penicillamine, Paradione, Aspirin, Heroin). 

4. Metabolic disease (e.g. Diabetes mellitus, amyloidosis). 

5. Malignancy (e.g. lymphoma). 

6. Heredofamilial (e.g. Alport syndrome). 

(II) Histopathologic classification of glomerulonephritis: 

A paraffin section from a percutaneous needle biopsy of the kidney of 

a patient with glomerulonephritis (whether primary or secondary), when 

examined by light microscopy may show any of the following: 

1. Minimal change (Nil-change) disease (lipoid nephrosis) (Figure 3.1): 

Light microscopy may show either no abnormality or minimal increase in 

mesangial cellularity. Also, immunofluorescent microscopy may show no 

immune deposits. Electron microscopy may show fusion of foot 

processes of epithelial cells (podocytes). 

Idiopathic type of this lesion usually clinically presents as steroid 

sensitive nephrotic syndrome with good prognosis. 

(Fig. 3.1) 

PAS stained kidney section(X 410) from 

a patient with minimal change nephritis. 

Light microscopic examination 

shows a normal glomerulus. 

(Reproduced with permission from 

IGAKU-SHOIN Ltd, Japan). 

2. Focal and segmental glomerulosclerosis (Figure 3.2): The 

glomerular lesions under light microscopy are sclerotic. These lesions 

involve only parts of the affected glomeruli (i.e. segmental) and some 

glomeruli look normal, but in between a glomerulus is affected (i.e. 

focal). 

This disease usually presents with nephrotic syndrome with impairment 

of kidney function and hypertension. Response to steroid treatment is 

much less than that in minimal change glomerulonephritis.

(Fig. 3.2a) 

PAS stained kidney section (X260) from 

a patient with FSGS. Light microscopic 

examination of an affected glomerulus shows 

segmental sclerosis in the hilar region. 



(Fig. 3.2b) 

The same case when examined by 

immunofluorescent microscope shows 

segmental deposits of complement (C3) 



3. Membranous glomerulonephritis (Figure 3.3): 

In this type of glomerulopathy, light microscopic examination shows 

diffuse thickening of the glomerular capillary basement membrane with 

no proliferation in the mesangium. 

This disease usually presents as nephrotic syndrome with spontaneous 

remissions and exacerbations. It may be steroid sensitive. 

(Fig. 3.3a) 

PAS stained kidney section (X320) from a 

patient with membranous glomerulonephritis. 

Light microscopic examination shows marked 

thickening of the capillary walls with no 

cellular proliferation. 


IGAKU-SHOIN Ltd, Japan).

(Fig. 3.3b) 

The same case in Fig. 3a, examined by 

I.F., it shows diffuse granular deposits 

of IgG along the capillary walls (X260). 



4. Proliferative glomerulonephritis: 

According to the site of proliferation within the renal glomeruli, this type 

could be sub-divided into: 

a. Mesangial proliferative glomerulonephritis (Figure 3.4): There is an 

increase in mesangial matrix and mesangial nuclei by light 

microscopic examination. 

This disease usually presents with haematuria or with nephrotic 

syndrome. 

(Fig. 3.4) 

PAS stained kidney section (X 410) from 

a patient with mesangial proliferative 

glomerulonephritis. Light microscopic 

examination shows diffuse proliferation 

in the mesangium with normal capillary 

walls 



b. Mesangiocapillary (or membranoproliferative) glomerulonephritis (Figure 

3.5): There are both diffuse thickening of glomerular capillary wall and 

mesangial proliferation. 

This disease may present as nephrotic syndrome. The disease is usually 

steroid resistant and slowly progresses to chronic renal failure.

(Fig. 3.5) 

Hx & E stain of a case of 

mesangio-capillary 

glomerulonephritis,there is 

mesangial proliferation (arrow-1) 

with lobulation, (arrow-2), 

thickening of the GBM (arrow 

-3), also there is periglomerular 

fibrosis (arrow-4) 

(Reproduced with permission 

from IGAKU-SHOIN Ltd, Japan). 

c. Crescentic glomerulonephritis (Figure 3.6): There is extensive cellular 

proliferations in the Bowman's capsule giving the appearance of 

crescent surrounding the glomerular tufts. This disease is serious and 

usually presents as rapidly progressive glomerulonephritis. 

(Fig. 3.6) 

Periodic acid- schiff stain. 

High power view of a 

glomerulus showing 

Crescentic glomerulo- 

Nephritis (arrow) 

(Reproduced with 

permission from 

IGAKU-SHOIN Ltd, 

Japan). 

d. IgA nephropathy: This is a proliferative type of glomerulonephritis 

characterized with predominant immunoglobulin A deposition in renal 

glomeruli when kidney sections are examined by immunofluorescence. 

IgA nephropathy is the commonest glomerular disease presenting with 

gross or microscopic haematuria.

(III) Clinical manifestations of glomerulonephritis: 

Patient with glomerulonephritis may present with any of the following 

five syndromes: 

1. Nephrotic syndrome: 

This is characterized clinically with massive oedema of insidious onset. 

In some cases, it may progress slowly to renal failure. Urine analysis 

shows massive proteinuria (> 3.5 gm/24 hr/1.37 m 2 ), microscopic 

haematuria and lipiduria. Serum analysis may show hypoalbuminaemia 

and hypercholesterolaemia. Serum creatinine is usually normal. 

2. Acute nephritic syndrome (acute nephritis): 

Characterized clinically with rapid onset of oedema (less in severity than 

in nephrotic syndrome), oliguria and hypertension. Urine analysis may 

show red cell casts, proteinuria (less in amount than in nephrotic 

syndrome), haematuria and leukocyturia. Serum analysis may show 

increased serum creatinine, normal serum albumin and cholesterol. 

Prognosis is usually good and recovery occurs. 

3. Rapidly progressive glomerulonephritis (RPGN): 

Characterized clinically with rapid (within days to weeks) loss of kidney 

function with development of manifestations of uraemia and the patient 

needs dialysis treatment. If not treated early and aggressively, the renal 

damage may be irreversible. Urine analysis may show findings which are 

similar to acute nephritic syndrome. Serum analysis shows rapidly 

increasing serum creatinine while serum albumin remains within normal. 

4. Chronic nephritic syndrome: 

Characterized by slowly (over months to years) progressive uraemia and 

the patient usually presents with manifestations of chronic renal failure. 

Urine analysis may show broad casts, loss of ability to concentrate urine 

(urine specific gravity is equal to plasma), proteinuria (mild) and 

microscopic haematuria. Serum analysis shows high serum creatinine 

and phosphate, low calcium, anaemia and metabolic acidosis. 

5. Asymptomatic urinary abnormality: 

As microscopic haematuria or proteinuria or both. The prognosis is 

usually excellent and no treatment is required.

NEPHROTIC SYNDROME 

(NS) 

Definition: is a syndrome characterized by heavy proteinuria (more than 

3.5gm/24h/1.73m 2 ), hypoalbuminaemia, hyperlipidaemia and edema. 

Etiology: 

Nephrotic syndrome could be primary or a part of a systemic disease 

(i.e. secondary). 

Secondary nephrotic syndrome may be due to any of the following: 

1. Postinfection (e.g. Schistosoma and malaria). 

2. Drug (e.g. penicillamine, phenytoin, gold and nonsteroidal antiinflammatory 

drugs as aspirin). 

3. Metabolic (e.g. D.M., amyloidosis). 

4. Collagen and autoimmune disease (e.g. SLE, rheumatoid). 

5. Malignancy (e.g. Lymphoma, multiple myeloma). 

6. Renal vein thrombosis. 

7. Congenital and familial conditions. 

Pathology: See pathologic classification of glomerular diseases (Page 59). 

Pathogenesis: 

Hypoalbuminemia Is mainly due to loss of albumin through the kidney as a 

result of the glomerular disease. However, there are other factors which 

increase the magnitude of this problem such as: 

1. The decreased intake (due to anorexia) and decreased absorption (due 

to oedema of the intestinal wall). 

2. The increased concentration of albumin in the glomerular filtrate which is 

accompanied by increase in its catabolism by the renal tubules. 

3. The partitioning of albumin between extra-and intravascular spaces; and 

4. Sometimes decreased rate of hepatic biosynthesis of albumin. 

Oedema: 

The mechanisms incriminated in pathogenesis of oedema in nephrotic 

patient include the following (Fig. 3.7).

1. Hypoalbuminaemia results in a decrease in plasma oncotic (osmotic) 

pressure which is the power keeping water in the intravascular space. 

Consequently, water leaks to the interstitial space with formation of 

edema. 

Glomerular damage 

Proteinuria 

Hypoalbuminaemia 

Decreased plasma oncotic 

pressure 

Starling 

Forces 

Water retention 

OEDEMA 

Water retention 

Increased Reninangiotensin,Aldosterone. 

decreased ANP 

Decreased effective 

circulating blood volume 

Increased 

ADH 

(Fig. 3.7) 

Mechanisms of oedema formation in patients with nephrotic syndrome 

2. Loss of intravascular fluids results in hypovolaemia (reduction of 

circulating blood volume) which a. stimulates the kidney (juxtaglomerular 

apparatus) to secrete Renin, b. stimulates volume receptors which 

stimulate the hypothalamus that stimulates pituitary secretion of

antidiuretic hormone (ADH), and c. stimulates volume receptors which will 

result in a decrease in secretion of atrial natriuretic peptide (ANP). 

3- Renin secreted by juxta glomerular apparatus converts plasma 

angiotensinogen into angiotensin I which is converted by angiotensin 

converting enzyme (ACE) to angiotensin II. The latter stimulates secretion 

of aldosterone from the suprarenal gland. Aldosterone stimulates 

reabsorption of salt and water from the distal convoluted tubules. 

4- Antidiuretic hormone stimulates reabsorption of water from the collecting 

ducts. 

5- The decrease in the secretion of the atrial natriuretic peptide (ANP) 

decreases water and salt excretion by the kidney; and 

6- Salt and water retained through the stimulation of Renin, and antidiuretic 

hormone secretion, and suppression of atrial natriuretic peptide secretion 

leak from the vascular space (due to low oncotic pressure) to the 

interstitial space with more oedema formation. 

Hyperlipidemia: 

Hyperlipidemia is secondary to hypoalbuminemia. This condition is 

accompanied with increase in concentration of plasma cholesterol, 

triglycerides, VLDL and a decrease in HDL. Urine examination may show 

lipiduria and oval fat bodies. 

Clinical Picture of Nephrotic Syndrome: 

1. Edema: is the main clinical feature of nephrotic syndrome. It starts as 

morning puffiness of the face. Then, gradually progresses to edema of 

lower limbs; especially on prolonged standing and at the end of the day. 

In severe cases edema may progress to be generalized anasarca with 

ascites- even pleural and pericardial effusion. 

2. Hypertension: may be detected in nearly 50% of the cases, according to 

the etiologic and pathologic type of nephrotic syndrome. For example 

idiopathic minimal change nephrotic syndrome cases are always 

normotensive while cases with mesangiocapillary glomerulonephritis 

whether idiopathic or secondary are always hypertensive. Hypertension 

is either due to salt and water retention or it may be due to the excess 

secretion of renin. 

3. Other manifestations of nephrotic syndrome include lassitude, anorexia, 

loss of appetite and pallor.

4. Manifestations of the etiologic cause in secondary cases as 

manifestations of diabetes in cases with diabetic nephropathy. 


1. Subnutritional State: Due to poor dieting, and urinary losses of protein 

and other substances. 

2. Infection: Especially upper respiratory, urinary, skin and peritoneal 

infections. 

Recurrent infection is due to nutritional deficiencies, urinary loss of 

immunoglobulins and complements. 

3. Clotting episodes: These manifest as a recurrent deep vein thrombosis 

(DVT), or renal vein thrombosis. It may be complicated by pulmonary 

embolism. This clotting tendency in nephrotic patients is due to: 

a. Increased concentration of coagulation factors resulting from an 

increased hepatic synthesis e.g. fibrinogen, factor III, and VIII. 

b. Urinary loss of antithrombin III and protein C which normally act 

against intravascular clotting. 

c. Abnormal vascular endothelium. 

d. Hypovolemic state. 

4. Premature atherosclerosis: it is due to hyperlipidaemia. This 

complication occurs mainly in cases with frequent relapses or cases 

resistant to treatment. 

5. Hypovolaemia: Which causes postural hypotension. 

6. Drug related complications: This category includes: 

a. Diuretics which may cause hypovolaemia, hypokalaemia, or 

hyponatraemia. 

b. Corticosteroids that may cause diabetes mellitus, cataract, D.U., 

infections, and bone disease. 

c. Other Immunosuppressive drugs as cyclophosphamide which may 

cause haemorrhagic cystitis, alopecia, infection and malignancy. 

7. Acute renal failure, this may be due to severe hypovolaemia (due to the 

severe hypoalbuminaemia and use of big doses of diuretics), or due to 

acute interstitial nephritis (drug induced as large dose of furosemide). 

8. Bone disease: Due to hypocalcemia (resulting from deficient intake and 

urinary loss of vitamin D binding globulin). It causes secondary 

hyperparathyroidism. 

9. Anemia: Due to nutritional deficiencies and urinary loss of transferrin.

Investigations of Nephrotic Syndrome: 

1. Urine analysis for proteinuria, microscopic haematuria, pus cells, casts, 

also collect 24 hours urine for quantitation of urinary protein excretion. 

2. Blood for hypoalbuminaemia, hyperlipidaemia, hypocalcaemia and for 

serum creatinine level. 

3. Investigations for diagnosis of the cause in secondary cases e.g. fasting 

and postprandial blood sugar for diabetes and anti-DNA for SLE. 

4. Kidney biopsy: in children, kidney biopsy is indicated only in steroid 

resistant or steroid dependent cases as well as in frequent relapsers and 

those with impaired kidney functions. But in adults, it is wise to obtain 

kidney biopsy to determine the underlying pathology so that specific 

treatment can be initiated if indicated. 

Treatment of nephrotic syndrome: 

The regimen for the treatment of NS is as follows: 

1. Treatment of the cause in secondary cases- for example- by proper 

control of blood sugar in D.M. and steroids and immunosuppressive 

drugs in SLE. 

2. Treatment of complications as infection by antibiotics and under 

nutrition by giving proper dieting, minerals and vitamins. 

3. Rest in bed during exacerbation to promote diuresis and early 

ambulation with remission to avoid DVT. 

4. Diet: salt restricted supported with vitamins especially vitamin D and 

calcium. Protein content should equal the daily physiologic needs (1g/kg) 

plus the amount of daily urinary protein loss e.g. a 60 kg patient who 

loses 10 gm daily should be given 70 gm protein containing diet. 

5. Diuretics: Mainly loop diuretics (e.g. Frusemide) initially can be given 

orally in variable doses (according to severity and response e.g. 20-60 

mg/d.). In severe resistant cases doses up to 120 mg. I.V. may be given. 

Addition of metolazone (a thiazide diuretic) may have a potentiating 

effect for frusemide in diuretic resistant cases. 

6. Salt poor albumin is expensive and when given is lost quickly in urine. 

So it is indicated only when there is severe oedema resistant to large 

doses of diuretics and if the nephrotic patient is to be subjected to 

surgery or invasive procedure (e.g. biopsy). Albumin infusion will 

improve the plasma oncotic pressure. This improves circulating blood 

volume and prevents hypotension or shock during the procedure.

7. Corticosteroids are given when there is no response to previous lines of 

treatment. Minimal change glomerulonephritis gives the best response 

while mesangiocapillary glomerulonephritis is always steroid resistant. 

Other types of primary glomerulopathy are in between. For patients with 

secondary glomerulonephritis, steroids are given if indicated for the 

causative disease as in SLE but not in D.M. The dose and duration of 

steroid treatment depends on the type of disease and response. In 

primary (idiopathic) minimal change nephritis 40-60 mg daily prednisone 

are given orally (for children 1-2 mg/kg/d), for 4-6 weeks followed by 

gradual withdrawal. 

8. Other immunosuppressive drugs as cyclophosphamide, azathioprine 

and ciclosporin in selected cases (See page 118).

ACUTE POST-STREPTOCOCCAL GLOMERULONEPHRITIS 

10% of patients infected with nephritogenic strains of group A, ß-haemolytic 

streptococci will develop glomerulonephritis. 

Streptococcal infection may be pharyngeal or skin infection. The period 

between infection and the appearance of glomerulonephritis (latent period) is 

1-3 weeks for pharyngeal infection and 2-4 weeks for skin infection. 

Children are more affected than adults and males are more than females. 

Clinical picture: 

Usually the patients present with manifestations of acute nephritic syndrome 

with oliguria, smoky urine, puffiness of the face and headache (as a result of 

hypertension). 20% of patients may manifest as nephrotic syndrome, 5% may 

present as rapidly progressive glomerulonephritis and some patients may be 

with asymptomatic urinary abnormalities. 

Some patients may develop encephalopathy as a result of severe 

hypertension or hyponatraemia or they develop heart failure because of 

hypertension and fluid retention. 

Pathogenesis: 

1. Nephritogenic strains of streptococci may secrete substances e.g. 

neuraminidase and sialic acid which may modify autologous 

immunoglobulin for which antibodies are formed by the patient 

(autoantibodies) and immune complexes are formed which will be 

trapped by the renal glomeruli and cause the disease. 

2. Streptococcal antigens stimulate the body to form antibodies to them 

with the subsequent immune complex formation. 

Laboratory investigations: 

1. Urine may show red cell casts, proteinuria (less than in nephrotic 

syndrome), haematuria or leucocyturia. 

2. Pharyngeal or skin culture may show streptococci. 

3. Markers of streptococcal infection as ASO titre and C-reactive protein 

are positive. 

4. Hypocomplementaemia (C3, C4) which is transient (for few weeks only).

5. Serum creatinine is usually high. 

6. Kidney biopsy (Fig. 3.8) may show diffuse proliferative 

glomerulonephritis with neutrophil and monocyte infiltration of the 

glomeruli. Severe cases may show glomerular crescents (cases 

presenting clinically with rapidly progressive glomerulonephritis). 

(Fig. 3.8) 

Hx & E stained kidney section (X 260) from 

a patient with post infection glomerulonephritis. 

Light microscopic examination shows diffuse 

proliferative endocapillary glomerulonephritis 

With marked cellularity caused by both 

mononuclear cells and polymorphoneuclear 

leukocytes. 


from IGAKU-SHOIN Lts, Japan) 

Treatment: 

Treatment of poststreptococcal glomerulonephritis is mainly 

symptomatic (rest, salt restriction, diuretics, antihypertensives, treatment of 

infection and dialysis if renal failure develops). Sometimes steroids and 

immunosuppressive drugs are given for cases presenting with RPGN. 

Prognosis: 

Most of the cases (85%) recover completely, 5% die in early phases 

from complications (hypertensive encephalopathy or heart failure). The rest of 

the cases pass to chronic glomerulonephritis and develop chronic renal 

failure. 

Prognosis is better in children than in adults. Signs of bad prognosis 

are persistently rising serum creatinine, heavy proteinuria, persistent 

hypertension with gross haematuria and presence of glomerular crescents in 

renal biopsy.

PRIMARY GLOMERULONEPHRITIS 

Minimal Change Nephritis 

(MCN) 

Etiology: 

Minimal change nephritis may be primary but as well may be 

secondary to many conditions such as Hodgkin's and Non-Hodgkin's 

lymphoma, or the non steroidal anti-inflammatory drugs. 

Histopathology (Fig. 3.2): 

Light microscopy shows no changes or there may be minimal 

mesangial proliferative changes, tubulointerstitium will be normal or 

sometimes lipid droplets may be seen in the proximal convoluted tubules. 

Early membranous glomerulonephritis and early focal segmental 

glomerulosclerosis may look like minimal change nephritis when kidney 

sections are examined by light microscopy. 

Immunofluorescence microscopy shows negative or occasionally 

mesangial C3 deposits. 

IgM nephropathy is a variant of MCN which is characterized by 

mesangial deposits of IgM. 

Electron microscopy shows only fusion of the epithelial foot processes 

and obliteration of the slit pore diaphragm. These changes are non-specific 

findings which could be seen in any case of heavy proteinuria. 

Laboratory Findings: 

Serology shows normal C3, C4, anti-dsDNA, ANA, cryoglobulins and is 

negative for anti-GBM, CIC and ANCA. 

Clinical features of primary MCN: 

Frank nephrotic syndrome is the commonest presentation of MCN, 

patient is normotensive and GFR is normal (unless there is a prerenal factor 

or drug toxicity). 

Urine examination shows heavy proteinuria which is highly selective. 

Only 20% of cases will show microhematuria. 

Nephrotic syndrome in children 2-6 years of age is due to MCN in 90% 

of cases, this incidence decreases by aging to be only 20% in adults.

MCN is more common in male (male to female ratio is 2 : 1), usually is 

preceded by upper respiratory tract infection or by immunization. Sometimes, 

there is history of atopy and there is a correlation with HLA B12. 

Pathogenesis: 

Minimal change nephritis is most probably due to altered T-cell 

functions. 

Treatment: 

See page 108. 

Focal and Segmental Glomerulosclerosis 

(FSGS) 

FSGS is responsible for 10-20% of cases of Nephrotic Syndrome in 

Western countries. 

Etiology: 

FSGS may be a primary disease or may be secondary to: 

• Schistosomiasis or bacterial endocarditis 

• SLE or vasculitis 

• Heroin abuse 

• Hyperfiltration injury or reflux nephropathy 

• Sickle cell disease 

• Aging 


Light microscopy shows focal glomerular (i.e. each affected glomerulus 

is surrounded by healthy glomeruli) involvement by segmental sclerosis or 

hyalinosis. The disease starts in the juxta medullary glomeruli (i.e. superficial 

biopsy in early phases of the disease will show normal glomeruli). There is 

deposition of hyaline materials in the subendothelial area with adjacent 

epithelial cellular proliferation with adherence to Bowman's capsule. These 

changes are segmental and may proceed to sclerosis. When the lesions are 

advanced the glomeruli become globally sclerosed.

Minimal change nephritis, FSGS and mild focal mesangial proliferative 

glomerulonephritis are believed to be either three different diseases or 

subtypes of them are one disease in different phases of evolution. 

Primary FSGS should be differentiated from FSGS involving the 

remaining nephron after another disease causing glomerular damage. 

Hyperfiltration of the remaining nephron results-by time-in FSGS in the 

remaining glomeruli. 

Immunofluorescent microscopy: FSGS of haemodynamic etiology shows 

negative immunofluorescence, but primary and other types of secondary 

FSGS show glomerular C3 and IgM deposits in segmental pattern. 

Electron microscopy shows global effacement and fusion of the 

epithelial foot processes and focal segmental subendothelial deposition of 

foam cells. 

Clinical features of FSGS 

The disease usually presents with nephrotic syndrome, haematuria, 

hypertension and decreased GFR. Decreased capacity to concentrate urine 

due to early affection of the vasa recta capillaries and the long-looped 

nephrons is more common with FSGS as the disease starts early in the 

juxtamedullary area. 

Proteinuria is poorly selective and complement components are 

normal. 

Prognosis: 

50% of patients with FSGS will develop end stage renal failure within 

10 years. Presence of mesangial proliferation is a poor sign. 

Treatment: 

See page 108. 

Membranous Glomerulonephritis 

(MGN) 

Among adults in the western countries MGN represents 17-42% of 

causes of nephrotic syndrome.

MGN could be primary or secondary to the following: 

. Infection: Malaria, schistosoma, HBV infection 

. Autoimmune disease as SLE and Rheumatoid arthritis 

. Malignancy as GIT malignancy especially in elderly. 

. Drug: Penicillamine, gold, captopril. 


Light microscopy shows that the glomeruli are uniformally affected. In 

early stages it may look within normal and may be confused with MCN. In full 

blown picture, there is thickening of the glomerular basement membrane but 

no cellular infiltration or mesangial proliferation. 

Immunofluorescent microscopy shows capillary wall granular deposits 

mainly of IgG and C3. 

Electron microscopy shows subendothelial deposits and fusion of the 

foot process. Histopathologically, primary MGN passes into four stages. 

• In stage I, the GBM is normal by L.M. but there is discrete electrondense 

deposits in the subepithelial sites. 

• In stage 2, GBM-like material is found between the deposits giving the 

appearance of spikes by LM. 

• In stage 3, the GBM-like material encircles the deposits. 

• In stage 4, the deposits become less electrondense and the 

surrounding GBM gives "Swiss cheese" appearance. 

Clinical feature: 

MGN usually follows an insidious onset. In 80% of patients, it presents 

with massive proteinuria and nephrotic syndrome, while 20% of patients may 

have only asymptomatic proteinuria. 

Hypertension and uraemia usually occur late in the disease. Proteinuria 

is either moderately or poorly selective. 

In primary MGN complement components are normal (slow 

consumption and high liver synthesis) and no CIC (in situ complex). 

Prognosis: 

In children and in 10-30% of adults spontaneous and complete lasting 

remissions occur. The remaining cases progress to CRF. The 10-year survival 

in untreated MN is 75%. 

Treatment: 

See page 108.

Mesangial Proliferative Glomerulonephritis 

This disease may be primary or secondary to the following: 

. Infection as schistosoma and malaria. 

. Autoimmune as SLE and Henoch-Shönlein purpura. 

. Metabolic as diabetic nephropathy. 


Light microscopy may show pure mesangial proliferation with 

abnormality in GBM. 

Immunofluorescent microscopy may show fine and granular mesangial 

deposits of C3, IgG, IgA, IgM. Predominance of IgA is seen in IgA 

nephropathy and predominance of IgM is seen in the entity called IgM 

nephropathy. 

Electron microscopy shows mesangial electron dense deposits and 

fusion of epithelial foot processes. 

Clinical features: 

The disease may present with asymptomatic urine abnormality, gross 

haematuria or nephrotic syndrome. 

In primary types serology is negative for C3, ANA and other 

immunologic markers. 

Prognosis: 

Prognosis is excellent in some cases but others follow a course similar 

to FSGS or MCN. 

Treatment: 

See page 108. 

Membranoproliferative Glomerulonephritis 

(MPGN) 

10% of cases of nephrotic syndrome in the west is due to MPGN. 

The disease could be primary or secondary to: 

. Infection as schistosoma, malaria, HCV, HBV, bacterial endocarditis and 

shunt nephritis.

. Autoimmune disease as SLE and cryoglobulinaemia. 

. Chronic lymphatic leukaemia. 

. Congenital complement deficiency. 

. Type II MPGN is sometimes associated with partial lipodystrophy. 


Light microscopy shows mesangial proliferation which when severe, 

will give the lobulation pattern for the glomerular tuft (lobular GN). In 

secondary types, there may be infiltration of the mesangium with mononuclear 

cells and neutrophils. The GBM is thick with a double contour appearance. 

Immunofluorescent microscopy shows granular mesangial and 

capillary wall deposits of C3, C4 and IgG. 

Electron microscopy shows subendothelial mesangial interposition in 

type I lesions and intramembraneous dense deposits in type II lesions. 

Sometimes the deposits are also seen in the subepithelial space (type III 

MPGN). 

Sometimes the mesangial proliferation is lacking but the characteristic 

GBM changes are evident. 


MPGN is responsible for 50% of N.S. with heavy proteinuria, 30% of 

asymptomatic proteinuria and 20% of acute nephritis. 50% of cases are 

preceded with upper respiratory tract infection with high ASO. About 50% of 

cases have low GFR and 30% are hypertensive at presentation. Sometimes 

patients become hypertensive only on starting steroid therapy. 

There is hypocomplementaemia which is persistent (in post-infection 

GN it is transient). The pattern of hypocomplementaemia is different between 

type I and type II. C3 is low in 75% of cases with type I or type II. In only type 

I, there is low C1 and C4 (early components of the classic pathway of 

activation). 

In 60% of cases with only type II, there is C3 nephritic factor (C3NF) 

which is an autoantibody to the enzyme C3 convertase of the alternative 

pathway protecting it from inhibitory proteins. This result in continuous 

degradation of C3 to its active form with consequent low C3 level. A similar 

substance is sometimes detected in 10% of cases with type I MPGN. 

Type II MPGN is associated with lipodystrophy and HLA-B7. 

Frequently in MPGN there is Comb's test negative normocytic normochromic

anaemia not matching with the degree of renal dysfunction. RBC's and 

platelet half life are decreased and there is a high turn over of fibrinogen and 

microangiopathy. 

Prognosis: 

10-year survival is 50%, type II carries a worse prognosis than type I. 

Hypertension, low GFR, severe NS and superimposed crescents in renal 

biopsies are all bad signs and of poor prognosis. 

Treatment: 

See page 108. 

Crescentic Glomerulonephritis 

(CGN) 

These types of proliferative GN are characterized by cellular 

proliferation in Bowman's space with crescent formation in more than 50% of 

the glomeruli. 

These could be primary lesions or secondary to systemic diseases 

(Goodpasture's syndrome, SLE, Henoch-Schönlein purpura, cryoglobulinaemia, 

vasculitis, or infection related). 

According to the immunofluorescent examination of kidney sections, 

three types of CGN are identified: 

Primary (Idiopathic) crescentic GN 

(Type I) 

Represents 30% of cases presenting with RPGN, and is characterized 

by the presence of anti-GBM (linear deposits of Ig along the GBM). 

Patients affected are mostly young or middle age males. The disease 

is either of insidious onset and progresses to uraemia or presents as acute 

nephritic syndrome. Beside the renal manifestations the patient may suffer 

from fever, myalgia, abdominal pains and rheumatoid arthritis-like symptoms. 

Kidney biopsy when examined by light microscopy may show crescents in 

more than 50% of the glomeruli. Initially the crescents are cellular (mainly

monocytes), later become fibrous. Glomerular tuft shows no proliferation. 

There is periglomerular fibrosis and tubulointerstitial changes as dilatation and 

fibrosis. 

Immunofluorescent microscopy may show IgG and C3 linear deposits 

along the GBM and fibrin deposits in the crescents. When the disease 

advances and the glomeruli are damaged the deposits may look granular. 

Electron microscopy shows gaps in the GBM (the sites of monocyte 

and fibrinogen leak to the glomeruli and crescents). Endothelial cells may be 

seen detached from the underlying GBM, usually there are no electron 

deposits seen. 

Serologically, anti-GBM could be detected in 90% of cases with no 

CIC, normal complement components and ANA. In early phase 

microangiopathic haemolytic anaemia is detected in some cases. 

Poor prognostic signs are extensive crescents, tubular atrophy and 

interstitial fibrosis. 

Treatment should start early and aggressively by plasma exchange, 

steroids and cyclophosphamide. 


(Type II) 

Responsible for 30% of cases with RPGN. 

Clinical features are similar to type I. 

Light microscopy shows crescents as in type I. There may be some 

endocapillary proliferation. But if this is marked, it may denote secondary 

rather than primary etiology. 

Immunofluorescent microscopy shows granular deposits of IgG and C3 

along the capillary walls. 

Electron microscopy may show subendothelial deposits. Serology will 

show CIC and hypocomplementaemia. 

Treatment is the same as type I.


(Type III) 

The least common type, Clinical features are similar to the other types. 

Immunofluorescence microscopy shows no deposits so it is sometimes called 

pauci-immune crescentic G.N. 

Serology shows a presence of ANCA (sometimes the disease is 

considered as renally localized form of polyarteritis nodosa). There is neither 

CIC, nor anti-GBM. 

Treatment is by steroid and cyclophosphamide.

SECONDARY GLOMERULAR DISEASES 

In many diseases renal involvement is a part of a generalized process 

e.g. diabetes mellitus and systemic lupus erythematosus. Renal involvement 

may be the dominant lesion or may be just an incidental finding. Generally, 

when the kidney is involved, the prognosis and type of treatment are changed 

drastically. 

Systemic lupus Erythematosus and lupus nephritis 

SLE is an autoimmune disease with systemic manifestations. It affects 

1/10,000 population. The incidence is higher in females than in males (9: 1). It 

affects caucasian more than black and occurs more in adolescents than in 

elderly. Most probably the disease reflects an exaggerated response to 

common environmental agents in a genetically susceptible host. 

Circulating and in-situ formation of DNA-anti-DNA immune complexes 

are thought to be the main pathogenic mechanisms for SLE. Complement 

deficiency may be a promoting factor. Not all SLE patients will show clinically 

evident renal involvement. But, if kidney biopsies are obtained and examined 

thoroughly all patients will show glomerular disease. 

In clinical practice lupus nephritis is responsible for more than 5% of 

patients presenting with glomerulonephritis. Sometimes renal manifestations 

are the main presentation of SLE patient with minor systemic disease. 

Pathology of lupus nephritis (Fig. 3.9). 

According to the World Health Organization (WHO), lupus nephritis 

could be one of five classes: 

Class I (no change) in which kidney biopsies show no changes by light 

microscopy, few immune deposits (+) may be seen in the mesangium by I.F. 

and by E.M. 

Class II (mild mesangial proliferative) where mild mesangial hypercellularity 

may be seen by L.M. and IF and EM may show deposits in the mesangium 

(++) and sometimes in the subendothelial area (+). 

Class III (focal and segmental proliferation), in this type, light microscopy 

shows evident segmental proliferation, necrosis and occasionally hyaline 

thrombi, IF and EM show more marked deposits in the mesangium (+++) and 

to less extent in the subendothelial area (+). 

Class IV (diffuse proliferation), light microscopy shows diffuse hypercellularity, 

membranoproliferative changes, glomerular tuft necrosis, crescents, and wire 

loops. IF and EM show extensive deposits (+++) in all areas (mesangial, 

subendothelial and subepithelial).

(Fig. 3.9a) 

PAS stained kidney section(X410) from a 

patient with lupus nephritis (WHO-class III), it 

shows about one third of the glomerulus 

Occupied by a necrotic lesion containing 

Fragmented polymorph-nuclear leukocytes, the 

rest of the glomerulus shows minimal changes 

(Reproduced with Permission 

from GAKU-SHOIN Ltd. Japan) 

(Fig. 3.9b) 

Hx & E stained kidney section (X260) from a 

patient with lupus nephritis (WHO-class IV), it 

shows two glomeruli with diffuse cellular 

proliferation and exudation of polymorphnuclear 

leucocytes. 


from IGAKU-SHOIN Ltd., Japan 

(Fig. 3.9c) 


patient with lupus nephritis (WHO-class IV), it 

shows cellular proliferation and prominant wire 

Loops (arrow). 

(Reproduced with Permission from 

IGAKU-SHOIN Ltd., Japan)

(Fig. 3.9d) 

Immunofluorescence stained kidney section 

from a patient with lupus nephritis (WHOclass 

IV), it shows massive deposits of IgG 

along the capillary walls (wire loops) 

(Reproduced with Permission from 

IGAKU-SHOIN Ltd., Japan) 

(Fig. 3.9e) 


patient with lupus nephritis (WHO-class IV), 

it shows cellular proliferation and many 

hyaline thrombi (arrow) 


from IGAKU-SHOIN Ltd., Japan) 

Class V (diffuse membranous), light microscopy shows capillary wall 

expansion by subepithelial deposits, with some mesangial hypercellularity. IF 

and EM show deposits mainly in the subepithelial (+++) area, but also 

deposits may be seen in the mesangium (++) and subendothelial area (+). 

Each of these classes can be further assessed according to its degree 

of activity or chronicity via Activity index (AI) and chronicity index (CI). The 

pathologist can review the biopsy for activity markers (e.g. glomerular tuft 

necrosis, wire loops, hyaline thrombi, cellular crescents, mesangial 

proliferation and cellular infiltrate) to give a score of out of 24 (e.g. AI of 18/24 

for markedly active lesion and AI of 2/24 for less active lesion). Chronicity 

markers in biopsy include fibrous crescents, glomerulosclerosis, tubular 

atrophy and interstitial fibrosis. Chronicity Index is a score of 12, (e.g. 

markedly chronic lesions may have a score of 10/12). Assessment of kidney 

lesion by WHO classification and by chronicity and activity indices is 

mandatory for proper management of the cases.

Among different pathologic lesions seen in biopsy wire loop lesion, 

haematoxylin bodies and finger printing like-pattern of electron dense immune 

deposits are lesions which are highly specific for lupus nephritis. 

Clinical Manifestations of Lupus Nephritis: 

It is known that 50-90% of lupus patients will show manifestation(s) of 

renal disease. Many of such patients may not show any clinically oriented 

renal disease, but when subjected to kidney biopsy glomerular lesions will be 

detected. 

Clinical presentation of lupus nephritis patient may vary from 

asymptomatic urine abnormality to rapidly progressive glomerulonephritis. 

Furthermore, some patients show manifestations of tubulointerstitial nephritis 

(e.g. RTA) or vasculitis. 

There is a correlation between the histopathologic findings in renal 

biopsies and clinical manifestations of lupus nephritis. Patients with class II 

may show mild haematuria or proteinuria. Patients with class IV show severe 

forms of renal disease with renal impairment, hypertension, nephrotic 

syndrome and patients with class V usually present with severe form of 

nephrotic syndrome. 

Diagnosis: 

For all patients with glomerular disease, SLE should be considered as 

a possible etiologic cause particularly in young females. However, renal 

manifestation could be the only presenting feature. Yet, most of patients show 

other systemic manifestations of SLE. 

For diagnosis of SLE, four or more of the criteria which have been 

established by The American Rheumatism Association (ARA) should be 

encountered. 

The diagnosis should be confirmed by screening for Anti-nuclear 

antibodies (ANA) and the more specific anti-double stranded DNA (antidsDNA). 

Measurement of ESR, complement component C3, C4 and 

Circulating Immune Complexes (CIC) may help in assessing disease activity. 

The ARA criteria for diagnosis of SLE include: 

1- Malar rash. 2- Discoid rash 

3- Photosensitivity 4- Oral ulcers 

5- Arthritis 6- Serositis 

7- Renal disease 8- Neurological disorders 

(seizures, psychosis) 

9- Hematologic disorders 

(haemolytic anaemia, lymphopenia, leukopenia, thrombocytopenia)

10- Immunologic disorders (positive LE cell test, anti-DNA, anti-sm antibody) 

11- Positive anti nuclear antibody. 

Treatment: 

There is no standard regimen for the treatment of lupus nephritis 

patient. But there are many therapeutic tools which has to be tailored for 

every case. Patient's age, sex, disease class, activity and chronicity indices 

and clinical presentation all determine the choice of the treatment. The 

available treatment protocols include: (1) Prednisolone, oral, 1mg/kg/d, (2) 3-5 

days pulses of methyl prednisolone 500-1000 mg each, (3) Cytoxan 

(cyclophosphamide) 2-3 mg orally/d (4) cytoxan 0.5-1.0 gm/m2 surface area 

monthly for 6 months, (5) Azathioprine 2-3 mg/kg/d, (6) Cyclosporin A 

5mg/kg/d, orally; and/or (7) Plasma exchange. 

Generally, the target of treatment is to induce remission, then to 

maintain it by small doses of either one drug (Prednisolone) or combined (e.g. 

Prednisolone and Azathioprine). The more active the disease, the more 

aggressive the treatment will be and vice versa. 

Beside the specific treatment for SLE, the patient may need other 

drugs such as hypotensives for hypertension, diuretics for oedema, and 

supportive dialysis for renal failure. 

Renal Involvement In Vasculitis 

Among different types of vasculitis, polyarteritis nodosa (PAN) and 

Wegener's Granulomatosis (W.G.) stand as the more common diseases 

affecting the kidney. Polyarteritis nodosa is either classic (involving medium 

sized-vessels as renal arteries with aneurysm formation) or microscopic 

involving small arteries and arterioles presenting with manifestation of 

glomerulopathies (mostly PRGN). 

The classic type of polyarteritis nodosa may present with ischaemic 

renal changes, hypertension, immobilization with renal infarctions or 

haemorrhage related to the kidney (haematuria, peri-renal hematoma 

resulting from rupture of aneurysm). Concomitant mesenteric, coronary or 

cerebral vessels affection could be detected. 

Wegener's granulomatosus mainly involves small vessels with early, 

major disease of respiratory tract excluding asthma. Granulomata are 

characteristic but not essential feature for diagnosis of W.G. 

For more details see chapter on vasculitis (Page 126).

Henoch-Schönlein Purpura (HSP) 

HSP is a multisystem disease with renal, gastrointestinal and 

cutaneous manifestations. It usually affects children 5-15 years old with a 

slight preponderance of males. Full recovery is common in children. But in 

adults, the course could be problematic. Renal involvement is documented in 

10-30% of the cases, but in some series, it reaches up to 90% of the cases. 

The primary abnormality is most probably defective handling of mucosally 

presented antigen. 

Pathology (Fig. 3.10): 

There is a great similarity between HSP and IgA nephropathy. Light 

microscopy usually shows changes variable from minimal abnormalities, 

mesangial proliferation, focal mesangial proliferation with crescent formation 

to membranoproliferative glomerulonephritis. Immunofluorescent microscopy 

will show predominant IgA deposits which are mainly mesangial, and this is 

usually accompanied with C3, IgG and to a lesser extent IgM. 

(Fig. 3.10a) 

PAS stained kidney section(X310) from 

a patient with Henoch-Schonleinpurpura, 

it shows segmental involvment of the 

glomerulus wth thrombosis(arrow 1) 

necrosis (arrow-2), and a small crescent 

(arrow3). The remaining of the 

glomerulus looks normal. 



(Fig. 3.10b) 

PAS stained kidney section (X410) from a 

patient with Henoch-Schonlein purpura It. 

shows diffuse endocapillary glomerulonephritis. 


from IGAKU-SHOIN Ltd, Japan).

(Fig. 3.10c) 

Immunofluorescent stained 

kidney section (X410) from a 

patient with Henoch- 

Schonlein purpura. It shows 

deposits of IgA along the 

GBM. 


from IGAKU-SHOIN Ltd., 

Japan) 


1- The disease usually occurs in winter, following upper respiratory 

infection or following exposure to allergen. 

2- Renal manifestations varies from haematuria (macroscopic or 

microscopic), N.S., to RPGN. Severe forms of the disease are more 

encountered in adults. 

3- Extrarenal manifestations include: 

a. Purpuric rash which involves mainly the buttocks and lower limbs. It 

does not blanch on pressure and may extend to other areas. 

b. Polyarthralgia or arthritis. 

c. Gastrointestinal manifestations including abdominal pain, bloody 

diarrhea and or melena. 

d. Fever, malaise, epistaxis and haemoptysis. 

e. In more than 50% of cases serum IgA is high. 

Treatment and Prognosis: 

Generally, the disease is self-limiting. However 5-20% of cases 

(especially adults) may show persistence or even progression to uraemia. 

Signs of bad prognosis include patients with: severe disease at 

presentation, persistent nephrotic syndrome, severe renal impairment and 

crescentic G.N. 

Cases with mild disease may be treated symptomatically while severe 

cases should be treated with steroids, cytotoxic drugs and plasma exchange.

Essential Mixed Cryoglobulinaemia 

(EMC) 

Cryoglobulinaemia is a wide range of diseases associated with 

formation of cryoglobulins. The cryoglobulin complex is mainly an 

immunoglobulin (antibody) attached to another immunoglobulin (antigen). The 

complex has the character of precipitation at cold. According to the nature of 

the two immunoglobulins, three types of cryoglobulinaemia are recognized: 1- 

monoclonal cryoglobulinaemia (i.e. both components are monoclonal 

immunoglobulins), detected in Myeloma, macroglobulinaemia, chronic 

lymphatic leukaemia and essential cryoglobulinaemia. 2- mixed polyclonalmonoclonal 

cryoglobulinaemia detected in Sjögren's disease, rheumatoid 

arthritis and essential mixed cryoglobulinaemia. 3- mixed polyclonal 

cryoglobulinaemia (i.e. poly-poly) in essential mixed cryoglobulinaemia, 

autoimmune disease as SLE, PAN, HSP, infection as CMV, malaria and 

HBV. 

While patients with cryoglobulinaemia usually present with the 

manifestation of the original disease, 20-30% of patients with mixed 

cryoglobulinaemia present with disease (vasculitis) caused by cryoglobulin 

itself. This is termed essential mixed cryoglobulinaemia. 

Pathology (Fig. 3.11): 

Light microscopy usually shows a diffuse proliferative or membranoproliferative 

glomerulonephritis with or without crescents. Immunofluorescent 

microscopy shows deposits of C3 and other immunoglobulins similar to those 

forming the cryoglobulin. Electron microscopy shows the cryoglobulin deposits 

in the renal glomeruli. 

(Fig 3.11) 

Hx & E stained kidney section 

(X260)from a patient with EMC, 

it shows extensive deposits in 

the capillary walls and 

mesangium and appreciable 

cellular proliferation.


Clinical manifestations of EMC include the following: 

1- Renal, including nephrotic syndrome, nephritic syndrome or RPGN. 

2- Extrarenal, including purpura, arthritis and hepatic dysfunction. 

Treatment: 

Steroid and cyclophosphamide are usually given in combination to treat 

EMC. Plasma exchange is indicated with severe disease to lower the level of 

circulating cryoglobulin. 

Progressive Systemic Sclerosis (PSS) 

(Scleroderma Syndrome) 

PSS is a disease characterized by progressive fibrosis of skin and 

internal organs of undetermined etiology. The condition may follow a long 

benign or short malignant course. 

Renal pathology: 

Almost 50-100% of PSS cases show renal involvement. Interlobular 

arteries show narrowing of lumen and thickening of the wall with onion-skin 

appearance. Glomeruli usually show intracapillary fibrin deposits, 

mesangiolysis, rarely mesangial proliferation or crescent formation. 


The basic clinical features of PSS include: 

1- Renal manifestations which include severe hypertensive, progressive 

uraemia and proteinuria which is rarely severe enough to cause nephritic 

syndrome. 

2- CREST syndrome which includes calcinosis, Raynaud,s phenomenon, 

oesophageal hypomotility, sclerodactyly and telangiectasia. 

Treatment: 

The only available treatment is symptomatic. In case of hypertension, 

ACEls are the treatment of choice. 

Diabetic Nephropathy 

Microangiopathy with neuropathy, retinopathy and nephropathy are 

complications known to develop in the majority of long-term diabetics. 

Renal failure causes death in up to 40% of diabetics, being 17 times 

more common than in non-diabetics.

The better the control of diabetes, the longer the survival is and the 

more the chance to manifest nephropathy and other microangiopathy will be. 

This explains the prevelence of this disease in countries with better health 

programs. 

The disease affects both juvenile and adult onset diabetics, but juvenile 

diabetics manifest the disease more; since they survive longer with the 

disease. Adult onset diabetics usually die earlier with coronary or cerebral 

strokes. 

In Juvenile diabetics, nephropathy passes into 6 stages: 1- very early 

stage in which GFR is supernormal, 2- stage of microalbuminuria, 3- stage of 

clinical proteinuria, 4- stage of nephrotic syndrome, and hypertension, 5- 

stage of renal impairment then, 6- stage of end stage renal failure. 

Stage of microalbuminuria and high GFR may continue for several 

years and clinical proteinuria usually settles 10-15 years later. Once clinical 

proteinuria is established, the disease becomes progressive to end stage 

renal failure. 

The above described stages are the natural history in insulin 

dependent (type I) diabetics. In type II diabetics, the renal disease is usually 

well established when first discovered clinically. 

Pathogenesis of diabetic nephropathy: 

Two mechanisms are claimed to be responsible for diabetic 

glomerulosclerosis. These are: 

1- Hyperfiltration and hypertrophy of the renal glomeruli. 

2- Glycosylation of glomerular structural proteins. 

Hyperfiltration and Hypertrophy: In early stages of diabetic nephropathy 

when proteinuria is not yet detectable, the GFR is high up to 40% above 

normal. This elevation is multifactorial, mainly due to hyperglycaemia, high 

levels of glucagons, growth hormone and prostaglandin concentrations are 

possible mediators for glomerular hyperfiltration. The increased GFR is 

associated with glomerulomegaly and increase in renal size. It is believed that 

long term hyperfiltration may result in glomerulosclerosis. 

Glycosylation of glomerular structural proteins: Non-enzymatic 

reactions of glucose with circulating and structural proteins are known to 

occur with hyperglycaemia e.g. glycosylated haemoglobin (Hemoglobin A1C). 

Glycosylation of glomerular basement membrane and mesangial protein may

e responsible for the alterations in glomerular basement membrane 

permeability and the increase in the mesangial matrix. 

Pathology: 

In the very early phases, there is an increase in kidney size, glomerular 

diameter and tubular size. As the disease advances the following will be 

recognized: 

1- progressive thickening of the GBM 2- widening of the mesangium by PAS 

positive material (Fig. 3.12a,b) 3- focal global sclerotic lesions known as 

Kimmelstiel-Wilson nodules (Fig.3.12c); and 4- narrowing of glomerular 

capillaries. Other distinctive lesions which may be seen in kidney biopsies of 

diabetic patients are fibrin caps, capsular drop lesions and gross hyalinization 

of arterioles. Also, interstitial scarring infiltarion and tubular atrophy are seen. 

(Fig 3.12a) 


(X390) from a patient with 

diabetic nephropathy. It shows 

early diffuse sclerosis with mild 

mesangial thickening (arrow-1) 

and thickening of the Bowman's 

capsule (arrow-2). 


from IGAKU-SHOIN Ltd, 

Japan) 

(Fig 3.12b) 

PAS stained kidney section (X390) 

from a patient with diabetic 

nephropathy in slightly more 

advanced stage with thickening 

the GBM (arrow). 


from IGAKU-SHOIN Ltd, Japan)

(Fig 3.12c) 

PAS stained kidney section (X260) 

from a patient with diabetic 

nephropathy with diffuse nodular 

glomeruloscelorosis. It shows the 

classic Kimmelstiel Wilson 

nodules (arrow). 


from IGAKU-SHOIN Ltd, Japan) 

(Fig 3.12d) 

Immunofluorescent stained kidney 

section (X260) in a patient with 

early diffuse glomeruloscelorosis. 

It shows linear deposits of IgG 

along the glomerular and tubular 

basement membrane. 


from IGAKU-SHOIN Ltd, Japan) 

By Immunofluorescence microscopy, IgG and albumin are deposited in 

a linear pattern along GBM (Fig. 3.12d). 

Treatment: 

Prevention of diabetic nephropathy is ideally achieved by proper 

control of diabetes and avoidance of smoking and obesity. 

If microalbuminuria; which is marker of very early disease; is detected, 

proper control of diabetes and use of small dose of ACE inhibitors (e.g. 

captopril 6.25 mg twice daily before meals) will help the normalization of 

glomerular haemodynamics and prevent progression to diabetic 

glomerulopathy. 

In the stage of clinical proteinuria and nephrotic syndrome, 

hypertension has to be controlled preferably with ACEI. This in addition to the 

control of diabetes and hyperlipidemia besides the measures for management 

of nephrotic syndrome.

When renal failure manifests, supportive treatment and renal 

replacement therapy (RRT) may be provided. Renal replacement therapy is 

usually provided earlier for diabetics (i.e. at GFR 10 ml/min). CAPD is superior 

to haemodialysis. If transplantation is to be provided, combined kidney and 

pancreas transplantation is the choice for type I diabetics and generally 

steroid sparing immunosuppressive protocols are preferable. 

In the near future, Pancreas islet-cell transplantation would 

revolutionize the management of diabetic nephropathy. 

Hereditary Glomerulopathies 

1- Alport Syndrome 

Alport Syndrome is an autosomal dominant inherited disease with 

variable penetrance, sometimes with X-linkage. Clinically, the patients show 

combination of renal disease, nerve deafness ocular defects (anterior 

Lenticonus, cataract, macular lesions) and platelet defect 

(macrothrombocytopathic thrombocytopenia). 

The basic defect is in the type IV collagen which is normally present in 

the GBM, lens and cochlea. 

Pathology: 

The characteristic feature of Alport's syndrome is seen in kidney 

sections examined by E.M. which are lamellation, splitting and thinning of the 

GBM. As the disease progresses the GBM takes the form described as 

"basket weave" appearance (Fig. 3.13). 

(Fig 3.13) 

Electron 

micrographic 

examination of a kidney biopsy 

from a patient with Alport 

syndrome showing the 

characteristic basket weave 

appearance of the lamina densa 

of the glomerular tubular 



from IGAKU-SHOIN Ltd, 

Japan)

In advanced disease stage, non specific L.M. changes could be seen 

as FSGS, mesangial proliferation, crescents tubular atrophy, interstitial 

fibrosis and interstitial foam cells. 

Immunofluorescence microscopy will be either negative or will show 

non specific deposits of IgM, C3. 

Changes similar to those seen by EM in the GBM could be seen in the 

cochlea and lens. 


Haematuria is the main feature of this disease. It is microscopic and 

may be detected even at birth. Later it becomes macroscopic with intercurrent 

illness. Proteinuria is usually absent or mild but becomes manifest as the 

disease progresses and even reaches the nephritic range. 

Renal impairment starts at the second decade of life and progresses to 

an end stage renal failure. This progression is more rapid in male than it is in 

female patients. 

Treatment: 

The basic purpose of treatment is to slow the progression of kidney 

disease (control of hypertension and restriction of protein). Dialysis support is 

provided when ESRD develops. 

When kidney transplantation is performed we have to be aware of the 

possible to develop anti-GBM disease. This is due to development of 

antibodies to type IV collagen in GBM of the transplanted kidney. This is 

because this antigen is missed from the body of Alport patient and presents in 

the transplanted kidney. If this occurs, the patient may need plasma exchange 

sessions. 

2- Fabry's Disease 

(Angiokeratoma Corporis Diffusum Universale) 

Fabry's disease results from the deficiency of the enzyme a- 

galactosidase. This, in turn, results in an accumulation in all tissues of 

glycosphingo-lipids, cerebroside dihexoside and cerebroside trihexoside. The 

disease is inherited as X-linked, the homozygous males are severely affected 

while the heterozygous females are asymptomatic. 

Clinical Features: 

1- Skin lesions in the form of angiokeratomas which are red papules in the 

mouth, lower abdomen, buttocks and pubic region (Fig. 3.14).

(Fig 3.14) 

Photograph showing the 

characteristic skin lesion in the 

medial aspect of the thigh of a 

patient with Fabry's disease. 

(Fig 3.15) 

Masson Trichroma stained 

kidney section (X400) from the 

same patient showing foamy 

vaculaization of the epithelia 

cells. 

2- Neurologic manifestations in the form of periodic episodes of severe pain 

due to involvement of dorsal root ganglia. 

3- Cardiac manifestations as hypotension and ischaemic heart disease. 

4- Renal manifestations include, haematuria, proteinuria and progressive 

uraemia. Kidney sections will show changes in visceral glomerular 

epithelial cells, endothelial cells and tubular cells in the form of fat 

accumulations as seen by light microscopy (Fig. 3.15) and myelin as seen 

by EM. Usually patients die from cardiac or renal disease in fourth of fifth 

decades of life. 

5- Screening of family members for a-galactosidase deficiency in serum, 

leucocytes, hair follicles and biopsy specimens is mandatory.

Treatment: 

Is mainly supportive, dialysis is tolerable and transplantation-inspite of 

being successful-does not provide the missing enzyme. 

3- Nail-Patella Syndrome 

(Hereditary onycho-Osteo-dysplasia) 

This is characterized by a generalized disturbance in collagen 

synthesis leading to dysplasia of nails, skeletal deformities (especially 

hypoplastic displaced patella, deformed elbow, iliac horns, scoliosis) and renal 

involvement. 

The disease is transmitted as autosomal dominant trait. Renal 

manifestations include haematuria and proteinuria, but rarely nephrotic 

syndrome or renal failure occurs. 

Histopathologically, there is an irregular thickening of the GBM with 

numerous lucent areas containing electron dense fibrils. 

Bacterial Endocarditis 

In bacterial endocarditis occurring in patients with rheumatic valve 

disease and in intravenous drug abusers the incidence of glomerulonephritis 

is high. 

Pathogenesis and Pathology: 

Renal involvement in endocarditis is mainly immunologic. It is a sort of 

immune complex mediated glomerular damage. The immune complexes are 

found to contain bacterial antigen, antibodies and complement. The disease is 

associated with complement activation and consumption. 

In cases with subacute bacterial endocarditis, lesions are mainly 

segmental, focal with necrosis, proliferation and eosinophilic infiltration and 

deposits are subendothelial. But in acute bacterial endocarditis lesions are 

diffuse proliferative as in post infectious glomerulonephritis with neutrophil 

infiltration and subepithelial deposits. 

Clinical features and diagnosis: 

The clinical features of renal involvement in endocarditis may vary from 

asymptomatic urine abnormalities especially in the focal and segmental 

lesions to severe RPGN as in the diffuse proliferative lesions.

In patients with bacterial endocarditis renal impairment could be due to 

glomerulonephritis, drug induced toxicity or secondary to cardiac failure. 

Tests for CIC are positive with transient hypocomplementaemia and 

sometimes positive ANA and rheumatoid factor. 

Treatment: 

Treatment is that of endocarditis and symptomatic treatment for renal 

disease (e.g. dialysis for renal failure). 

Use of steroids and immunosuppressives is rarely needed. 

Shunt Nephritis 

Shunt nephritis is almost due to infection of ventriculo-atrial shunt by 

coagulase-negative staphylococci. It occurs in a minority of patients, it is an 

immune complex disease with hypocomplementaemia. Kidney lesions are 

always mesangioproliferative or mesangiocapillary G.N. 

Irradication of infection is followed by a slow recovery of the glomerular 

disease. 

Malarial Nephropathy 

The disease is common in malarial endemic areas. It affects children 

more than adults. It occurs in both quartan and falciparum malaria. Quartan 

malarial nephropathy tends to be chronic and progressive while falciparum 

malarial nephropathy tends to resolve completely after antimalarial treatment. 

Quartan Malarial Nephropathy: 

The disease is caused by plasmodium malariae which is common in 

Africa. 

Histopathologically, the disease is membranous in children while in 

adults it is membranoproliferative glomerulonephritis, immunofluorescence 

microscopy will show IgG, IgM and C3 deposits. In 25% of cases P. malariae 

antigens could be detected. 

Falciparum Malarial Nephropathy: 

Falciparum malaria is a common cause of acute renal failure in tropics. 

Both glomerular and tubulointerstitial nephritis are known to occur. 

Glomerulonephritis is usually mild and transient. Histologically, it is 

mesangial proliferative G.N. with C3, IgM and malarial antigen deposits.

Tubulointerstitial Nephritis: 

Usually occurs in patients suffering from high fever, hypovolaemia, 

hemolytic jaundice, intravascular coagulation, hyperviscosity and heavy 

parasitaemia. There is acute tubular necrosis (toxic and ischaemic), 

obstruction of distal nephron with casts and interstitial infiltration with 

mononuclear cells. Peritubular capillaries are congested with erythrocytes, 

macrophages laden with malarial pigment and mono-nuclear cells. 

Renal failure in falciparum malaria is usually hypercatabolic with rapid 

rise in blood urea and serum creatinine. Hyperkalaemia and hyperuricaemia 

occur particularly with intravascular haemolysis. 

Haemodialysis is preferable to peritoneal dialysis when dialysis support 

is indicated. Exchange transfusion is indicated with heavy parasitaemia.

Schistosomal Nephropathy 

Introduction: 

Schistosomiasis is a parasitic disease which affects man and animals. 

500-600 million people are thought to be exposed to infection. Also, over 200 

million inhabitants of 74 tropical countries have documented infection. 

Although this number is almost certainly an underestimate, it still seems to be 

increasing at least in some parts of Africa. 

Among human pathogens, the three most important schistosome 

species are schistosoma haematobium, schistosoma japonicum and 

schistosoma mansoni. 

Schistosoma haematobium is responsible for schistosomiasis of the 

bladder in Africa and Asia, while schistosoma japonicum is limited to the Far 

East and schistosoma mansoni is found in Africa, South West Asia and in 

South America. The last two species cause intestinal and hepatic lesions. 

(Fig. 3.16) 

A couple of adult 

schistosoma worms. 

The female which is 

cylindrical lies in 

the ventral plica 

(gubernaculum) of 

the male which is 

broad shaped (X400). 

Adult warm pairs of schistosoma haematobium (Fig. 3.16) are located 

in perivesical venous plexuses and eggs with their characteristic terminal 

spine are passed in urine. A granulomatous inflammatory reaction in the 

bladder will be detected and ureteric wall with subsequent fibrosis which may 

be complicated by hydroureter and hydronephrosis.

Schistosoma mansoni and schistosoma japonicum are found in the 

mesenteric veins. A large number of eggs produced by female worms find 

their way to the intestinal lumen and are passed in the faeces. Granulomatous 

inflammatory reactions occur in the intestinal wall. Many eggs reach the liver 

via portal vein causing periportal hepatic fibrosis. These schistosome species 

will give rise to intestinal and hepatic disease. 

Schistosomal Antigens: 

Schistosomes are antigenically very complex organisms. Many 

antigens have been identified. The number of which differs according to the 

technique employed. Schistosoma antigens isolated in-vitro could be defined 

into three groups: 

• Tegument-associated antigens are complex set of proteins and 

glycoprotein on the surface of cercariae, schistosomules and adult worms. 

They are released with the turnover of the parasite's surface membrane. 

Tegument-associated antigens are of crucial importance in immunity to 

infection and reinfection but seem to have a limited role in the pathogenesis of 

morbidity of the host. 

• Gut-associated antigens are present in the epithelial cells of the adult 

worm's gut, primordial oesophagus and caecal bifurcation of cercariae and 

schistosomula. These antigens are released by regurgitation of the worm's 

digestive juice and constitute the main part of the circulating schistosomal 

antigen in-vivo. Of six antigens identified in-vitro, at least two are clearly 

involved in the pathogenesis of immune-complex mediated lesions. The first 

of these which is the circulating anodic antigen (CAA) is a proteoglycan 

produced in large quantities by the adult worm. The second, circulating 

cathodic antigen (CCA) is a glycoprotein with a polysaccharide moiety that 

was previously identified as "M-antigen" in the urine and milk of infected 

animals and humans. Another gut antigen of potential clinical importance is a 

protein called "antigen 4" which was detected in milk from infected patients. 

This antigen was shown much earlier to be a genus specific schistosoma 

mansoni antigen. 

• Soluble egg antigens are of a large number and have been purified by 

various techniques. They were found to be protein or glycoprotein in nature. 

They are released by diffusion through micropores in egg shell into the 

surrounding tissue fluids. The most well known of the soluble egg antigens 

are the three major serological antigens (MSA) 1, 2 and 3. Of these MSA 1 is 

species specific for schistosoma mansoni. Egg antigens are mainly involved

in the pathogenesis of local tissue cell mediated reaction with granuloma 

formation. Another egg-derived antigen, W1 was more recently described and 

was shown to be hepatotoxic. 

Acquisition of host antigens by the parasite schistosomules grown 

in-vitro in human blood develop surface antigens which show human blood 

group specificity of the ABO type. Moreover, schistosomula selectively 

acquire gene products of the K and I sub-regions of the major 

histocompatibility complex. The acquired host antigens could serve to protect 

the parasites from the immune attack by the host. 

The main bulk of circulating schistosomal antigens is gut derived, but 

soluble egg and tegument-associated antigens also contribute. 

Patient's response to schistosomal infection: 

Human infection is initiated through water exposure (planting, fishing, 

washing and swimming) where the free-swimming forked-tailed cercariae 

penetrate the intact host skin. Three major clinical syndromes are recognized 

after schistosomal infection. These are dermatitis, acute schistosomiasis and 

chronic schistosomiasis. 

Dermatitis is due to skin penetration by cercariae. Then the patients 

experience itching within one hour (swimmer's itch) skin rash may appear and 

can persist for days. The symptomatology and histologic picture are 

consistent with an anamnestic immune reaction. Both humoral and cellmediated 

mechanisms participate in the anti-cercarial skin response. 

Acute schistosomiasis is a clinical syndrome which is often seen in 

non-immune individuals (tourists, immigrants, or the indigenous population) 

who have been exposed in an endemic area to a primary infection by 

cercariae. The syndrome is sometimes called Katayama fever. Symptoms 

usually appear 4 to 10 weeks after a heavy exposure to cercariae. This 

exposure would coincide with the migratory stage of the maturing 

schistosomula in the lung and liver. The syndrome is manifest by fever, 

malaise, hepatosplenomegaly, eosinophilia, diarrhea and in some cases, 

oedema, urticaria, lymphadenopathy and arthralgia. These symptoms are 

transient and spontaneously disappear. The pathogenesis of this syndrome is 

most probably an immediate-type and immune complex-mediated 

hypersensitivity reactions. 

Chronic schistosomiasis is due to both cell mediated immune 

response resulting in granulomatous reaction or due to humoral response with

immune complex formation. Granulomatous reaction occur in the 

gastrointestinal tract in case of schistosoma mansoni and schistosoma 

japonicum or in the urinary tract in case of schistosoma hematobium. The 

humoral response is believed to occur mainly with schistosoma mansoni 

resulting in diseases such as schistosomal nephropathy. 

SCHISTOSOMAL GLOMERULOPATHY: 

Two decades ago, clinicians in Brazil introduced the concept of 

schistosomal glomerulopathy. They reported abnormal concentrations of 

protein and leucocytes in the urine of patients with the hepatosplenic form of 

schistosomiasis. This report was subsequently confirmed in man and 

experimental animals infected with schistosoma mansoni or schistosoma 

japonicum. More recently, the schistosomal specificity of kidney lesions in 

patients with hepatosplenic schistosomiasis was confirmed by detection of 

schistosomal antigens (CAA-CCA) and schistosomal specific antibodies in the 

renal glomeruli. 

Information on glomerular lesions associated with schistosoma 

haematobium infection are disputed. Some researches reported the absence 

of glomerulopathy in schistosoma haematobium infection in man, while others 

reported nephrotic syndrome in patients with concomitant schistosoma 

haematobium infection and chronic salmonellosis. Recently, a schistosomal 

specific glomerulopathy was described in experimental animals (hamsters) 

infected with schistosoma hematobium. 

Incidence: 

In Egypt, proteinuria was detected in 20 percent of asymptomatic 

patients with active schistosoma mansoni infection. In the same centre, 

schistosomal specific kidney lesions were documented in 65 per cent of 

patients with active schistosoma mansoni who present with overt nephrotic 

syndrome. 

In Brazil, abnormal proteinuria and leucocyturia were reported in 25.7 

per cent of patients with hepatosplenic schistosomiasis and 3.8 percent of 

patients with a milder intestinal form of the disease. 

There is a positive correlation between the duration of schistosomal 

infection and renal involvement. This involvement has been observed 

clinically (the disease is more common in patients with advanced 

hepatosplenic disease in comparison with early intestinal disease). It is also

well-documented in an extensive experimental study on hamsters infected 

with schistosoma mansoni. 

Clinical and histopathologic manifestations of schistosomal 

glomerulopathy: 

The disease passes through three distinct phases which are: occult 

glomerulopathy, overt glomerulopathy and end-stage glomerulopathy. Little is 

known about factors that promote its evolution from one stage to another. 

Species and strains of the parasite are important factors in schistosomal 

nephropathy. Also, HLA types and a degree of hepatic involvement are 

important factors in schistosomal nephropathy. 

(Fig. 3.17) 

Renal biopsy of a patient with 

schistosomal- specific nephropathy 

Showing mesangiocapillary 

glomerulonephritis(HX & E X 400). 

• Occult glomerulopathy is usually silent. Asymptomatic proteinuria is an 

early expression of the disease which was reported in 20% of Egyptian 

patients and 26% of Brazilian patients with active schistosoma mansoni 

infection. Patients in this phase have less hepatic and more intestinal 

schistosomal disease. Histopathologic examination of kidney biopsy by light 

microscopy will show either no change or mild mesangioproliferative lesion, 

with little or no expansion of mesangial matrix but with occasional focal 

thickening of the basement membrane. Immunofluorescence shows mostly 

mesangial deposits of IgM- containing immune complexes, schistosomal 

antigens and complement C3. 

• Overt glomerulopathy nephrotic syndrome with or without renal impairment 

is the commonest presentation in this phase. Hypertension is noticed in 30-50 

percent of patients. Less commonly, patients may present with non-nephrotic 

proteinuria. Proteinuria is non-selective and urine sediment may show

leucocytes, red blood cells and casts. Hypoalbuminaemia is severe and 

hyperlipidaemia is unusual (due to associated liver disease). There is a 

polyclonal hypergammaglobulinaemia (due to active parasitic infection) with a 

considerable increase of serum IgG but less frequently IgA. Serum 

complement is usually normal. There is usually a mild to moderate anaemia 

not proportionate to the degree of renal dysfunction. This is probably the 

result of the associated nutritional deficiency and parasitic infection. 

Patients in this phase always have hepatosplenic disease. The liver is 

firm and shrunken. The spleen is enlarged. Ascites may be present and 

oesophageal varices may be detected. Histopathologic examination of a 

kidney biopsy shows focal segmental glomerulosclerosis or mesangiocapillary 

glomerulonephritis (Fig 3.17). Other lesion have been reported such 

as membranous glomerulonephritis, epithelial crescents and renal 

amyloidosis. Immunofluorescence classically shows schistosomal gut 

antigens, IgG and C3 deposits in the renal glomeruli. IgM and fibrin are less 

frequent whereas IgA is rare. 

• End-stage glomerulopathy: Recently, through longitudinal studies 

progression of schistosomal specific glomerulopathy to end-stage renal 

disease has been reported. Patients usually present with uraemic 

manifestation in association with hepatosplenic schistosomiasis. 

Histopathologic examination of kidney biopsy may show glomerulosclerosis, 

interstitial fibrosis and tubular atrophy. 

Treatment: 

The results of treatment with both anti-parasitic agents and 

immunosuppressive drugs have been disappointing. Martinelli et al in Brazil 

observed no benefit in patients treated with a combination of anti-parasitic 

drugs (oxamniquine or hycanthone) and prednisolone with or without 

cyclophosphamide. Similarly, in Egypt, Sobh et al reported an unsatisfactory 

response to combined treatment with anti-parasitic drugs (praziquentil and 

oxamniquine) and prednisolone or cyclosporine. Sooner or later, most 

patients with schistosomal nephropathy progress to end-stage renal failure. 

Very early treatment of schistosomiasis may be the only available way of 

preventing the poor outcome of schistosomal nephropathy.

Glomerulopathy Secondary To Virus Infection 

A variety of viral infections may be associated with features of acute 

glomerulonephritis. However, it is usually milder than it is in post streptococcal 


Classification:- 

(1) Herpes virus: - cytomegalovirus 

- Epestien Bar virus. 

(2) Paramyxovirus: - measles 

- mumps 

(3) Parovirus 

(4) Hepatitis viruses: - hepatitis B 

- hepatitis C 

(5) Retroviruses: - human immunodeficiency virus. 

(6) Influenza viruses: - Influenza A & B 

Mechanism of Renal affection in viral infection: 

(1) Direct cytopathic effect of the virus on the glomerular cells. 

(2) Immune complex mediated which is due to stimulation of antibod 

response. 

(3) Direct effect on T-cells. 

Hepatitis B Virus and The Kidney 

Several major renal syndromes may occur in patients with hepatitis B 

infection including: 

1- Serum sickness-like syndrome. 

2- Membranous nephropathy. 

3- Mesangiocapillary glomerulonephritis. 

4- Systemic necrotizing vasculitis. 

5- Polyarteritis nodosa. 

6- Crescentic glomerulonephritis. 

HBV induced Membranous nephropathy: 

Incidence:- 

- The majority of cases are children. 

- The peak incidence is at a mean age of 6-7 years. 

- Usually without clinically apparent preceding history of acute hepatitis but 

serum transaminases are often mildly elevated.

Clinical manifestations:- 

(1) Proteinuria: nephrotic or non nephrotic range. 

(2) haematuria: usually microscopic but occasionally gross. 

(3) Hypertension: common. 

(4) Normal or mildly elevated serum creatinine. 

Evidence of HBV induced membranous nephropathy: 

(1) The 3 hepatitis B antigens (HBsAg-HBeAg- HBcAg) have been identified 

in the subepithelial immune complexes of patients with membranous 

nephropathy and hepatitis B infection. 

(2) HBeAg plays important role in the pathogenesis as proteinuria remits in 

HBeAg positive patients when they produce HBeAb. 

Prognosis: 

(A) Children:- 

Spontaneous recovery is the role where: 

56% of patients remit 1 year after presentation. 

85% of patients remit 2 years after presentation. 

95% of patients remit 5-7 years after presentation. 

(B) Adults:- 

Progressive course, usually terminating to chronic renal failure. 

Treatment:- 

Suppression of the active viral replication could reduce deposition of 

HBeAg in the glomerular basement membrane. Interferon therapy may be 

transiently beneficial in adults. 

Hepatitis C virus associated nephropathy 

Nephropathy could be one of the several extrahepatic syndromes 

which has been identified with chronic HCV infection. These include: 

1- Glomerulonephritis. 

2- Mixed cryoglobulinaemias. 

3- Arthritis. 

4- Sjogren's syndrome. 

5- Chronic corneal ulceration. 

6- Porphyria cutania tarda. 

7- Lichen planus.

8- Autoimmune thyroiditis. 

9- Polyarteritis nodosa. 

Glomerulonephritis: 

The following types of glomerulonephritis can be encountered with 

HCV infection:- 

(1) Membranoproliferative glomerulonephritis "usually type I" 

(2) Membranous nephropathy. 

(3) Proliferative nephropathy. 

(4) Sclerosing nephritis. 

Pathogenesis:- 

(1) Immune complex theory: 

Deposition of immune complex formed of HCV-anti HCV IgG-Rheumatoid 

factor in the glomerular basement membrane. 

(2) Auto-antibodies theory: 

- Many types of autoantibodies are present in patients with chronic HCV 

infection e.g.: • ASMA • ANCA 

• Rh factor. 

- Antibodies to glomerular antigens were found in sera of HCV-infected 

patients. 

(3) Role of chronic liver disease:- 

In patients with chronic liver disease:- 

• 9% have microhaematuria. 

• 1.6% have nephrotic syndrome. 

• High incidence of IgA nephropathy. 

Pathogenesis:- 

• Impaired clearance of circulating immune complex. 

• Defective opsonization due to impaired production of complement 

components. 

Clinical picture:- 

(1) Evidence of chronic liver disease may be absent or mild. 

(2) Renal affection. 

(3) Clinical manifestations of cryoglobulinemia. 

Diagnosis:- 

(1) Detection of HCV antibodies by ELISA test. 

(2) Detection of HCV RNA by PCR. 

(3) Positive cryoglobulins.

(4) Low complement level. 

(5) Positive Rheumatoid factor. 

(6) Detection of viral antigen in the glomerular basement membrane. 

Treatment:- 

- Optimal treatment strategy for patients with HCV-associated nephropathy 

has to be established. 

- Interferon α is the corner stone for treatment. 

Dose: 

3 million units given S.C. 3 times weekly. 

Duration:- 

6 months. 

- However higher doses and longer duration are preferable. 

Factors associated with good response to interferon therapy: 

1- Age: less than 50 years. 

2- Sex: Female sex. 

3- Sporadic HCV infection. 

4- Viral tire:

TREATMENT OF GLOMERULONEPHRITIS 

There are two main lines of treatment for patients with 

glomerulonephritis. The first is general and applicable to all types of GN and 

the second is specific for different types of GN. 

I. General Measures for treatment of GN: 

General measures include the following: 

1- Treatment of hypertension: This is very important, not only for 

symptomatic relief and the prevention of systemic complications, but also 

there is a believe that meticulous control of hypertension may slow or prevent 

the progression of glomerular lesions. ACE inhibitors are possibly superior to 

other hypotensive drugs especially in patients with diabetic nephropathy. 

2- Fluid control: 

Salt and fluid restrictions are indicated with hypertension, oedema 

causing discomfort or presence of congestive heart failure. Diureticspreferably 

loop diuretic- may be used with less salt restriction. Use of diuretics 

in the absence of oedema especially in hypotensive patient may be 

dangerous causing prerenal azotaemia. 

3- Dietary measures: 

Salt and water restriction may be necessary in oedematous and 

hypertensive patients. Protein should be limited to an amount which is equal 

to the physiologic need (0.8=1.0 g/kg/d) plus the daily urinary protein loss. 

High protein diet may increase proteinuria and could be injurious for the 

nephron while severe restriction of protein may lead to nutritional deficiency 

with high morbidity (e.g. susceptibility to infection). 

4- Measures to reduce proteinuria: 

These measures are intended to decrease the severity of N.S. and also 

to slow or prevent the damaging effect of proteinuria on the nephrons. This 

could be achieved through avoiding high protein diet and the use of ACEI. 

ACEIs could be used in small doses in normotensive patient. They 

achieve their anti-proteinuric effect most probably through combating the 

vasopressor effect of angiotensin II on the glomerular efferent arteriole i.e. it 

causes efferent arteriolar V.D. with a reduction in intraglomerular filtration 

pressure.

5- Control of hyperlipidaemia: 

Diet control will not be sufficient and antilipidemic drugs as lovastatin 

and simvastatin may be required. Diet control may be helpful in the prevention 

of progression of renal damage. 

II. Specific Treatment: 

A) Primary glomerulonephritis: 

Specific treatment involves response of different types of 

glomerulonephritis to 1- immunosuppressive, 2- cytotoxic drugs; and 3- the 

role of some procedures as plasma exchange, induction of antigen excess, 

immune diffusion (primed columns). 

1- Minimal change nephritis (MCN): 

Minimal change nephritis is known to be steroid sensitive. In 95% of 

children a full response is obtained within 8 weeks while in adult only 80% will 

show slower responses also (i.e. within 16 weeks). 

In children, prednisolone will be given in a dose of 1mg/kg/d, while in 

adults it is given as 60 mg/d. The dose is preferably given in the morning and 

after breakfast. 

Alternatively, to induce remission, methylprednisolone I.V. pulses 

(daily, for 3 days, 1 gm each) followed by smaller doses of oral prednisolone 

could be given. 

When steroids are contraindicated or when failure to induce remission 

occurs, other drugs could be used as cyclosporine A, cyclophosphamide, 

chlorambucil or azathioprine. After remission is induced, 20% of patients will 

not suffer any more, whereas 50% will show multiple relapses (frequent 

relapser) or will relapse while they are still on steroid (steroid dependent). The 

remaining 30% will show an occasional relapse over the next few years. 

For frequent relapser and steroid dependent cases, steroids will be 

given in extended course to avoid nephrotic syndrome. But steroid toxicity will 

be high. In these situations, we may use alkylating agents (cyclophosphamide 

or chlorambucil) azathioprine or cyclosporine. 

Cyclophosphamide may be given in a dose of 2-3 mg/kg/d for 8 weeks 

or in resistant cases, it may be given in a dose of 2 mg/kg/d for 12 weeks. But 

with the later regimen, risks as bone marrow depression and sterility should 

be considered. Azathioprine, however, may be less effective on the short

term, but an effect may be obtained on long term use. It is much safer than 

cyclosphosphamide. 

Cyclosporine may be given in a dose of 5mg/kg/d but the drug is 

potentially nephrotoxic and needs experience in its handling. While successful 

remission may be induced in many patients, some cases will be cyclosporine 

dependent. 

Many of the patients showing difficult course when subjected to kidney 

biopsy will disclose focal segmental glomerulosclerosis rather than the 

minimal change disease. 

2. Membranous Nephropathy (MN): 

If untreated, 20-50% of patients with MN will progress to end stage 

renal failure within 10 years of presentation. 

The risk factors for progression are: older age, female sex, impaired 

initial renal function and marked tubulointerstitial changes in renal biopsy. 

Those with non-nephrotic proteinuria with normal kidney function could 

be treated conservatively. 

For those with frank nephrotic syndrome, but with stable kidney 

function, some nephrologists prefer to keep on conservative treatment waiting 

for spontaneous remission but other nephrologists prefer to start steroid 

treatment. 

For those with N.S. and abnormal kidney functions, most nephrologists 

prefer to start immediately with immunosuppressive drugs including steroid 

alone and/or alkylating agents or cyclosporine. High dose intravenous IgG has 

been reported to induce remissions. 

3. Mesangiocapillary GN: 

In 50% of patients with mesangiocapillary lesion, progression to end 

stage renal failure occurs within 10 years. This lesion is known to be 

unresponsive to steroids, or alkylating agents in different combinations. Also, 

anticoagulants, dipyridamol and NSAIDs were shown to be ineffective. In 

many patients, hypertension appeared after commencing steroids. 

Children with this lesion presenting with frank nephrotic syndrome and 

impairment of kidney function, which are known to progress quickly to 

uraemia, deserve to receive a trial of a course of alternate day steroids with or 

without alkylating agent.

4. Mesangial IgA Nephropathy: 

In the vast majority of patients, no specific treatment is provided. 

Phenytoin, fish-oil, cyclosporine, Danazol, steroids, cyclophosphamide all 

have been tried with no favorable response. 

In subgroup of patients with heavy proteinuria, steroids have been 

claimed to be of help in controlling N.S. 

Patients with progressive disease with deteriorating kidney function 

may be offered a chance of aggressive treatment including steroids, plasma 

exchange or cytotoxic drugs. 

5- Henoch-Schönlein Purpura (HSP): 

In cases with mild nephritis (usually children), no specific treatment is 

required, but long term follow-up is mandatory. For cases with severe disease 

(usually adults) with heavy proteinuria and deteriorating kidney function, 

kidney biopsy usually shows crescent formation. These patients are usually 

treated as those with RPGN with high dose steroids and possibly plasma 

exchange and cytotoxic drugs. Antiplatelets and anti-coagulants are 

recommended by some nephrologists. 

In these types of RPGN, early institution of steroid treatment with 

induction by 3 pulses of methyl prednisolone (1gm/daily) is mandatory to save 

the kidney. Plasma exchange may be needed especially in anti-GBM 

associated disease and cyclophosphamide especially in ANCA induced 

variant. 

B) Secondary Glomerulonephritis: 

Specific treatment is required according to the cause as irradication of 

septic focus, irradication of a parasite (as malaria, bilharzia), treatment of 

malignancy and discontinuation of a drug (as Penicillamine).


- Woo KT: Recent concepts in the pathogenesis and therapy of IgA 

nephritis. Ann Acad Med Singapore, 25: 2, 265-9, 1996. 

- Merkel F, et al: Therapeutic options for critically ill patients suffering 

from progressive lupus nephritis or Goodpasteur's syndrome. Kidney Int 

Suppl, 64: S31-8, 1998. 

- Austin HA, et al: Treatment of lupus nephritis. Semin Nephrol, 16: 6, 

527-35, 1996. 

- Praditpornsilpa K, et al: Hepatitis virus and kidney. Singapore Med J, 

73: 6, 639-44, 1996. 

- Safadi R, et al: Glomerulonephritis associated with acute hepatitis B. 

Am J Gastroenterol, 91: 1, 138-9, 1996. 

- Senatorski G, et al: The role of proteolytic enzymes in the pathogenesis 

of primary glomerulonephritis. Postepy Hig Med Dosw, 51: 2, 139-48, 

1997. 

- Berden JH: Lupus nephritis. Kidney Int, 52: 2, 538-58, 1997. 

- Ponticelli C: Treatment of lupus nephritis- the advantages of a flexible 

approach. Nephrol Dial Transplant, 12: 10, 2957-9, 1997. 

- Pisetsky DS, etal: Systemic lupus erythematosus. Diagnosis and 

treatment. Med Clin North Am, 81: 1, 113-28, 1997. 

- Péchère Bertschi A, et al: Renal manifestations of viral disease. 

Schweiz Rundsch Med Prax, 86 : 31, 1204-8, 1997. 

- Couser WG: Pathogenesis of glomerular damage in glomerulonephritis. 

Nephrol Dial Transplant, 13 Suppl 1: 10-5, 1998. 

- Gibson IW, et al: Glomerular pathology: recent advances. J Pathol, 184: 

2, 123-9, 1998. 

- Julkunen H: Renal lupus in pregnancy. Scand J Rehumatol Suppl, 108: 

80-3, 1998. 

- Merkel F, et al: T cell involvement in glomerular injury. Kidney Blood 

Press Ress, 19: 5, 298-304, 1996.

VASCULITIS 

Vasculitis is a heterogeneous group of diseases ranging from a selflimited 

hypersensitivity reaction to an acute or chronic systemic illness that 

may be fatal. 

Classification of Vasculitis: 

Vasculitis may be primary vascular disease or a part of other systemic 

illness. 

Primary forms of vasculitis are: 

1- Polyarteritis nodosa (PAN) which is subdivided into the following: 

• Macroscopic (classic) PAN. 

• Microscopic PAN. 

• Overlap type of PAN. 

• The non immune deposit RPGN. 

2- Wegner's granulomatosis 

3- Allergic granulomatosis (Churg-Strauss syndrome) 

4- Giant cell arteritis, which may be 

• Temporal arteritis 

• Takayasu's disease 

Systemic disease which may be associated with vasculitis are: 

1- Connective tissue diseases 

• SLE 

• Rheumatoid arthritis 

• Rheumatic fever 

• Dermatomyositis 

• Sjogren's disease 

• Relapsing polychondritis 

2- Schönlein-Henoch purpura 

3- Anti-GBM disease 

4- Essential mixed cryoglobulinaemia 

5- Infections such as hepatitis B virus, endocarditis, poststreptococcal 

infection, trichinosis and otitis media. 

6- Drugs such as allopurinol, sulfa or hyperimmunoglobulins. 

7- Tumours as visceral carcinoma, leukaemia, lymphoma and multiple 

myeloma.

Polyarteritis Nodosa 

Incidence: 

Polyarteritis nodosa is an uncommon but not a rare disease. Male to 

female ratio of involvement is 2.5 : 1. The peak age of involvement is 45 

years, but any age can be affected. Clinical renal involvement occurs in 70% 

of cases. This is more frequent in the microscopic than in the macroscopic 

forms. 

Pathology: 

A- Classic PAN affects mainly medium sized and large vessels. In the kidney 

the main renal vessels (similar to mesenteric, coronary and cerebral 

vessels), its main branches, interlobar and arcuate vessels are involved. 

The vascular involvement is segmental with skipped zones. The involved 

segments show lesions which are eccentric i.e. not whole the 

circumference of the segment is involved. Also lesions are of different ages 

i.e. some show acute inflammation, while others are chronic or healed. By 

light microscopy, the acute lesion shows necrotizing vasculitis. glomeruli 

are generally spared or may show changes secondary to the arterial 

lesions as collapse, sclerosis or hypercellularity of the juxtaglomerular 

apparatus. Tubulointerstitium may show areas of ischaemic changes and 

areas of wedge infarction. 

In the classic PAN, the main pathology is in the arteries and arterioles with 

aneurysm formation (Fig. 4.1) which may leak with renal or perirenal 

haematoma or may be thrombosed with recurrent renal immobilization. 

B- Microscopic PAN affects the small vessels including interlobular arterioles 

and venules, capillaries and the glomeruli. The vascular involvement is 

circumferential with no aneurysm formation and the lesions are of the same 

age. The vascular inflammatory process may mimic the classic PAN or may 

be granulomatous. Glomerular involvement may range from few glomeruli 

to 100% of the glomerular population with focal, segmental necrotizing 

lesions with crescent formation (Fig. 4.2).

(Fig. 4.1) 

Renal arteriogram in a case of polyarteritis 

nodosa shows multiple aneurysms in the 

Main artery (Arrow-1) and peripheral 

Arterioles (arrow-2), also there are areas of 

Infarction (arrow-3). 

(Fig. 4.2) 

Hx & E stained kidney section (X260) from 

a patient with microscopic PAN. It shows 

fibrinoid necrosis in an arteriole at the 

glomerular hilus with exudative 




Tubulointerstitium may show infiltration with inflammatory cells. This is 

mainly perivascular or periglomerular. 

Immunofluorescence microscopy is extremely variable. It may vary from 

negative, weak positive, to strong positive. The deposits are either 

fibrinogen (40-60%), C3 (25-60%), IgG (8-30%) or others. These deposits 

are mainly detected in areas of necrosis or sclerosis.

Clinical features of PAN: 

1- Constitutional symptoms which include fever, weight loss and malaise. 

These symptoms are part of the clinical manifestations in 75% of cases. 

2- Renal manifestations are documented in 60-100% of cases. In microscopic 

PAN, these include acute nephritic syndrome, rapidly progressive 

glomerulonephritis, less commonly nephrotic syndrome or chronic nephritic 

syndrome. In classic PAN, the manifestations are hypertension, renal 

infarction, renal and perirenal haemorrhage and progressive renal failure. 

3- Gastrointestinal manifestations appear in 50% of cases with nausea, 

vomiting, bleeding, pain or perforation. 

4- Neuropathy is reported in 50% of cases with peripheral neuropathy or 

mononeuritis multiplex. These are usually sensory and motor neuropathy. 

5- Musculoskeletal manifestations appear in 50-75% with weakness, myalgia, 

myositis and arthritis (Large joints). 

6- Pulmonary manifestations are documented in 50% of cases with pleurisy, 

asthma, haemoptysis and pulmonary infiltrates. 

7- Cardiac lesions are seen in 33% of cases, with ischaemic heart disease, 

congestive heart failure, pericarditis and conduction defects. 

8- Skin manifestations are mostly in the form of palpable purpura, less 

commonly petechiae, nodules, papules or ulcerations. Skin biopsy shows 

leucocytoclastic angiitis. 

9- Other manifestations of PAN include pancreatitis, cholecystitis, eye, 

adrenal and gonads involvement. 

Investigations of PAN: 

1- Anaemia, high ESR, leucocytosis, thrombocytosis are non-specific findings. 

Absolute eosinophilia is detected in 10-40% of cases with microscopic 

PAN, overlap PAN and cases with Churg-Strauss disease. Anti-nuclear 

antibodies, anti dsDNA are negative while ANCA is positive in some cases. 

In secondary cases of PAN-like vasculitis, manifestations of the etiologic 

disease could be documented as HBsAg, cryoglobulinaemia and 

hypocomplementaemia. 

2- Angiography shows aneurysms (1-2 mm) in medium sized vessels in 70% 

of cases with classic PAN. Also, thrombosis, stenosis and irregularities 

could be seen in some cases.

When PAN is expected, angiography should precede biopsy as an 

investigative tool to avoid catastrophic bleeding. 

3- Biopsy, this is better taken from skin, muscles or testicles, rather than from 

kidney. It may show necrotizing vasculitis. 

`Treatment and Prognosis of PAN: 

Without treatment, the 5 years survival is only 15%. Bad prognostic 

signs are the following: old age, delayed diagnosis and treatment, renal and 

gastrointestinal involvement. 

The main line of treatment is the use of steroid and cytoxan in doses 

tailored according to the disease activity. This will improve the 5-year survival 

to more than 50%. Other drugs could be used as azathioprine, busulfan and 

ATG. 

Wegener's Granulomatosis 

(WG) 

Wegener's granulomatosis is an uncommon granulomatous disease 

associated with necrotizing vasculitis. It usually involves medium sized and 

small vessels. 

Renal pathology in W.G.: 

Light microscopy may be similar to the microscopic type of PAN with 

focal segmental necrotizing GN associated with crescents and intracapillary 

fibrin thrombi. Crescents could be cellular or granulomatous, mostly seen 

opposite the glomerular necrosis. Glomeruli in the domain of diseased vessels 

also show ischaemic changes (Fig. 4.3a). 

Blood vessels show necrotizing arteritis. Tubulointerstitium shows 

ischaemic changes, areas of infarcts and inflammatory infiltrates. Sometimes 

granuloma could be seen, which is necrotizing with vascular nidus (Fig. 4.3b). 

(Fig. 4.3a) 

PASM stained kidney section (X260) from a 

patient with W.G., It shows large crescent 

with collapse of the glomerular tuft. 


from IGAKU-SHOIN Ltd, Japan).

Immunofluorescence microscopy is almost negative. Sometimes, focal and 

segmental capillary wall deposits of IgG, IgM, fibrinogen and C3 are seen 

especially in the areas of glomerular necrosis. 

Clinical features of W.G.: 

(Fig. 4.3b) 

Hx & E stained kidney 

section of a case of 

Wegener's granulomatosus 

showing a non- casiating 

Granuloma (arrow). 

The clinical presentation of W.G. is extremely variable. It could present 

with insidious onset and prolonged course of constitutional and upper 

respiratory symptoms or it may present with abrupt onset with severe 

constitutional and pulmonary symptoms. The systemic manifestations of WG 

are the following: 

1- Constitutional symptoms, these are observed in 50-100% of the cases, it is 

usually in the form of fever, weakness and malaise. 

2- Upper respiratory symptoms, these are documented in 70-80% of the 

cases, mostly as nasal symptoms and/or as sinusitis. Patients with WG 

may complain of epistaxis, rhinitis, purulent discharge and nasal crusts. In 

advanced cases, perforation of nasal septum and saddle nose deformity 

may be seen. X-ray examination may show sinus fluid level, mass, or 

boney erosion. Maxillary sinus is the most commonly affected sinus 

followed by the sphenoid and ethmoid sinuses, while frontal sinus is the 

least commonly involved sinus. 

Ear may be involved in 25-50% of cases. Patients may complain of ear 

pain and tinnitus. 

3- Lower respiratory symptoms, are encountered in 65-75% of cases. Patient 

may complain of dyspnea, cough, haemoptysis and pleuretic pain. 

X-ray examination may show the following: 

• Pulmonary infiltrate 

• nodular lesions (single or multiple) 

• Cavitary lesions 

• Pleural effusion.

4- Renal manifestations which vary from asymptomatic urinary findings to 

rapidly progressive GN. 

5- Other manifestations include: 

• Arthralgia and arthritis which are symmetrical and non-deforming. 

• Skin palpable nodules, macular erythematous rash and purpura. 

These are more common on extremities. 

• Myopathies due to small blood vessels involvement. 

• Mononeuritis multiplex. 

• Heart, liver, gall bladder, eye and parotid glands have been reported 

to be involved with W.G. 

Laboratory Assessment of W.G.: 

• No specific test for W.G. is available 

• Always there are high ESR, leucocytosis or leucopenia, Eosinophilia, 

thrombocytopenia. 

• ANCA is of diagnostic value in W.G. and could be of value in follow-up. 

Treatment and Prognosis of W.G.: 

• Without treatment, the one year survival is 20%. 

• Cyclophosphamide gives striking good results when given in full dose and 

duration. 

• Initially, the patient is usually treated with pulse steroid and cytoxan then 

maintenance cytoxan with or without Prednisone is provided. 

• When remission is induced, cytoxan may be given for 1 year or may be 

replaced by imuran (azathioprine). 

Chrug-Strauss Syndrome 

(Allergic Granulomatosis) 

Allergic granulomatosis is a triad of: 

• Necrotizing granulomatous vasculitis with eosinophilic tissue infiltrate and 

extravascular granulomas. 

• Peripheral eosinophilia, and 

• Bronchial asthma. 

It is a very rare disease which affects males more common than 

females and occurs more in the third, and fourth decades of life. 

Renal involvement is less common (


• Glomeruli show mild focal segmental necrotizing glomerulonephritis, 

sometimes associated with small crescents. 

• Vessels involved are those of small size (periglomerular to arcuate). Light 

microscopy shows necrotizing granulomatous vasculitis with eosinophils 

predominating the pulmonary infiltrate. Also, thrombosis and small 

aneurysms could be detected. 

• Tubulointerstitium shows oedema, cellular infiltration and eosinophilic 

granulomas. 


The disease usually comes in 3 phases with the initial one being 

asthma or allergic rhinitis which may extend for many years (up to 30 years). 

This is followed by phase of peripheral blood and tissue eosinophilia (as 

Loffler's syndrome or eosinophilic gastroenteritis). This phase may extend for 

months with remission and exacerbation which is then followed by the third 

phase of systemic vasculitis that is rapidly fatal. 

Systemic involvement in allergic granulomatosis includes the following: 

• Constitutional symptoms with fever, weight loss, fatigue and malaise. 

• Asthma, allergic rhinitis and other allergic diatheses with peripheral 

eosinophilia. X-ray chest may show transient patchy pneumonitis, 

pulmonary nodules, cavitary lesions, interstitial infiltrate and pleural effusion. 

• Ischaemic heart disease and congestive heart failure. 

• Gastrointestinal manifestations as diarrhoea, pain, haemorrhage and 

perforation. 

• Cutaneous manifestations including skin nodules, petechiae and purpura. 

• Migratory polyarthritis. 

• Mononeuritis multiplex. 

• Renal manifestations usually include microscopic hematuria and mild 

proteinuria, rarely nephrotic syndrome or renal impairment. 

Treatment of Allergic Granulomatosis: 

Steroids stand as the main line of treatment. If this failed to control the 

disease, azathioprine and cyclophosphamide may be used. 

Temporal Arteritis 

Temporal arteritis which is a sort of giant cell arteritis affects 3/100,000 

population. Females are more affected than males, 95% of patients are above 

age of 50 years.

Pathology: 

The disease usually affects the medium-sized and the large vessels 

with necrosis and infiltration with inflammatory cells including giant cells. 

Renal involvement is rare and usually take the form of focal and 

segmental necrotizing glomerulonephritis. 


These include the following: 

1- Constitutional, non-specific symptoms include fever, malaise and weight 

loss. 

2- Polymyalgia rheumatica with proximal muscle weakness and stiffness. 

3- Temporal artery may be felt tender with nodules, sometimes temporal 

pulsation is lost. In this situation, the patient may complain of severe 

headache, facial neuralgia, vertigo, diplopia or even blindness. 

3- Involvement of the aorta and its branches with ischaemic visceral changes 

sometimes occur. 

4- Renal artery involvement is extremely rare. 

Treatment: 

Steroids usually give dramatic response. 

Takayasu's Arteritis 

(Pulseless disease, Aortic Arch Syndrome) 

This is a rare disease characterized by transmural inflammation and 

stenosis of medium-sized and large vessels with predilection of the aortic arch 

and its major branches. 

Females represent 90% of cases with a peak incidence at age of 15-20 

years. 

Renal involvement may be in the form of: 

1- Renovascular hypertension. 

2- Renal ischaemic changes with progressive renal failure. 

3- Glomerular disease which may precede the other systemic manifestations. 

This usually take the form of proteinuria and/or haematuria. The pathologic 

changes are usually mild mesangial proliferative glomerulonephritis. 

Relapsing Polychondritis 

Is a disease affecting tissues containing glycosaminoglycans (heart, 

kidney, blood vessels, sclera, cornea, and ear). It is characterized by 

recurrent inflammation and destruction of ear, nose, trachea, joints, and

larynx. Vasculitis in this disease is similar to PAN with focal and segmental 

necrotizing GN. 

From the renal point of view the patient may present with hematuria, 

proteinuria or with rapidly progressive renal failure. Differentiation from W.G. 

is difficult. Yet, external ear is not involved in W.G. and the lower respiratory 

tract is not involved in relapsing polychondritis. 

Causes of focal segmental necrotizing glomerulonephritis with crescent 

are: 

• SLE 

• Polyarteritis nodosa 

• Wegener's granulomatosus 

• IgA nephropathy 

• Schönlein-Henoch purpura 

• Goodpasture's syndrome 

• Idiopathic RPGN (type II) 

• GN associating endocarditis and 

Rheumatic fever. 

Antiglomerular Basement Membrane 

Antibody (Anti-GBM)-mediated Nephritis 

(Goodpasture's Syndrome) 

This is a disease caused by autoantibodies of IgG type directed against 

Good pasture's antigen. Goodpasture's antigen is a type IV collagen which is 

normally present in the basement membrane of renal glomeruli, pulmonary 

alveoli, cochlea and the choroid plexus. 

When the disease is restricted to the kidneys, it is called anti-GBM 

disease, while the term Good pasture's Syndrome is given when pulmonary 

haemorrhage and renal disease are manifest. 

Etiology: 

In UK the disease is known to affect one per 2 million population per 

year and 1-2% of renal biopsies in America and Europe show anti-GBM 

disease. 

The disease is more common in second and third decades of life. Anti- 

GBM disease in general affects males more than females with a ratio of 2: 1, 

while in Good pasture's syndrome the ratio is 9: 1. The disease occurs more 

in spring and early summer. Localized out breaks occur from time to time. 

Genetic predisposition and environmental triggering factors are claimed 

to be mandatory for the development of this disease. 

Genetic factors: strong family history is sometimes given and HLA DR2 

is detected in 90% of cases with anti-GBM disease

Environmental factors include upper respiratory tract infection 

especially influenza, exposure to hydrocarbon fumes (as gasoline), organic 

fumes or dust, burning oils, and glu. The exposure to these toxins is more 

among firemen, mining engineers and gas station workers. 

The antibodies are specific for GBM and the alveolar basement 

membrane. 

Clinical Aspects of the Anti-GBM Disease: 

50% of the patients give history of vague complaints as malaise, weight 

loss, headache, upper respiratory tract infection, gastrointestinal upsets then 

they manifest glomerulonephritis. Some patients develop pulmonary 

haemorrhage as well. 

Renal disease: 

Most patients have severe glomerulonephritis that progresses rapidly 

to ESRD. Less than 15% of patients have mild glomerular disease. 

Histopathologically, the glomerular disease varies from mild focal 

proliferative GN to very severe crescentic GN and acute interstitial nephritis 

(Fig. 4.4a). 

(Fig. 4.4a) 

PAS stained kidney section (X310) from 

a patient with Goodpasture's syndrome. 

It shows glomerular capillary thrombosis, 

hyperplasia and tuft necrosis and 

polymorphnuclear leukocyte infiltration. 



Presence of vasculitis in renal biopsy in cases of anti-GBM disease is 

controversial. Almost such lesions are absent. Immunofluorescence 

microscopy shows linear IgG deposits along the GBM (Fig. 4.4.b). IgM and 

IgA deposits are seen in 10-20% of cases and C3 are seen as well in 30% of 

renal biopsies. IgG linear deposits are also seen on the distal tubular 


When anti-GBM disappears from circulation it fades from biopsy. Some 

patients may develop superimposed subepithelial granular deposits.

(Fig. 4.4b) 

Immunofluorescen stained kidneyt 

section(X260) from a patient with 

anti-GBM disease. It shows linear 

deposits of IgG . 



In untreated patients, the prognosis of this disease is bad. 

Pulmonary disease: 

Occurs in 60-90% of cases, less in children and elderly women and 

more among cigarette smokers. 

In classic Good pasture's syndrome, patient presents first with 

pulmonary haemorrhage for 8-12 months then glomerulonephritis appears. 

Pulmonary manifestations could be very mild to very severe disease 

with sudden onset. These manifestations increase by time, infection and by 

smoking. This is always associated with rising anti-GBM titre. 

X-ray chest shows pulmonary haemorrhage (typically apices and 

supradiaphragmatic areas are free, not bounded by fissures). This could be 

confirmed by measuring diffusion capacity of carbon monoxide which is 

increased by 30% due to presence of blood in the alveolar spaces. 

Anaemia: 

Anaemia may be very severe and out of proportion to renal impairment. 

It is due to blood loss and bone marrow suppression. It could also be 

angiopathic haemolytic anaemia. 

Treatment: 

Prednisolone, azathioprine, cyclophosphamide and plasma exchange 

are used in different combinations and doses according to the patient status 

and the disease activity. 

Plasma exchange with use of fresh frozen plasma may be very 

effective in stopping severe pulmonary haemorrhage and clearing anti-GBM 

antibodies from circulation.

Anti-Neutrophil Cytoplasm Auto-Antibodies 

(ANCA) and Vasculitis 

These are autoantibodies specific for the constituents of neutrophil 

azurophilic granules. According to the pattern of distribution of binding of 

these antibodies (as detected by immunofluorescence microscopy) ANCA is 

divided into two subtypes, which are: 

• Cytoplasmic pattern (C-ANCA) in which the I.F. staining occupies the whole 

neutrophil cytoplasm. In this type, the auto-antibodies are directed against 

proteinase 3. 

• Perinuclear pattern (P-ANA) in which the I.F. staining is only peri-nuclear. In 

this type, the autoantibodies are directed against the myeloperioxidase. 

Diseases affecting the kidney are almost P-ANCA positive while those 

with predominant systemic vasculitis, especially with granulomatous 

pulmonary lesions, are C-ANCA positive. 

Detection of ANCA in patients serum is very helpful for diagnosis of 

vasculitis with 84% sensitivity and 90% specificity. Also, serum analysis for 

ANCA titre is useful in follow-up for disease activity and response to 

treatment. Yet, some patients, however, have high ANCA while the disease is 

quiescent. 

ANCA associated diseases include: 

• Wegener's granulomatosus. 

• Polyarteritis nodosa. 

• Leucocytoclastic (hypersensitivity) angiitis. 

• Idiopathic, type III crescentic GN.


- Griffith ME, et al: Classification, pathogenesis, and treatment of 

systemic vasculitis. Ren Fail, 18 : 5, 785-802, 1996. 

- Rees AJ: Vasculitis and the kidney. Curr Opin Nephrol Hypertens, 5 : 3, 

273-81, 1996. 

- Calabrese LH: Drug-induced vasculitis. Curr Opin Rheumatol, 8 : 1, 34- 

40, 1996. 

- Gerber O, et al: Vasculitis owing to infection. Neurol Clin, 15 : 4, 903- 

25, 1997. 

- Athreya BH: Vasculitis in children. Curr Opin Rheumatol, 8 : 5-84, 

1996. 

- Jennette JC, et al: Small-vessel vasculitis. N Engl J Med, 337 : 21, 

1512-23, 1997. 

- Gross WL: Systemic necrotizing vasculitis. Baillieres Clin Rheumatol, 

11 : 2, 259-84, 1997. 

- Sneller MC, et al: Pathogenesis of vasculitis syndromes. Med Clin 

North Am, 81 : 1, 221-42, 1997.

THROMBOTIC MICROANGIOPATHY 

This includes haemolytic uraemic syndrome, thrombotic 

thrompocytopenic purpura and the post partum renal failure. 

Pathologically, these diseases are characterized by the presence of 

thrombi which are predominantly in small-sized arteries, arterioles and 

capillaries. 

Etiology of thrombotic microangiopathy: 

1- Infection, usually by E-Coli but also infection by other organisms have been 

reported to induce thrombotic microangiopathy as pseudomonas. Shingle 

and typhoid. The disease may occur in the course of infection or following 

it. 

2- Drugs (as cyclosporine A, mitomycin, and vaccines) and toxins (as snake 

bite, and carbon dioxide poisoning). 

3- Pregnancy, post partum, eclampsia and contraceptives. 

4- Immunologic disorders as SLE, Sjögren syndrome disorders, scleroderma, 

malignancy, bone marrow transplantation and kidney transplantation. 

5- Genetic predisposition. 

Pathologic features: 

1- Haemolytic uraemic syndrome (HUS): 

The characteristic changes are found in the vascular tree including 

arteries, arterioles and glomerular capillaries; while the tubulointerstitial 

changes are secondary to ischaemia. 

Glomeruli show variable changes, according to the severity and 

duration of the disease. The characteristic changes are endothelial oedema, 

degeneration, and separation from glomerular basement membrane which 

appears thick and of double outline. Also of characteristic features are the 

intraluminal thrombi and fragmentation of erythrocytes (Fig. 5.1). Other 

glomerular changes could also be seen, but are not characteristic, such as 

slight mesangial proliferation, mesangiolysis, crescents and (in terminal 

cases) glomerulosclerosis. 

Immunofluorescence microscopy shows fibrin deposits along the 

capillary walls. 

Blood vessels show separation of endothelial cells and accumulation of 

fibrin and other plasma proteins underneeth. Later, thrombosis occurs. 

Fibrinoid necrosis in the arteriolar wall is mostly due to hypertension.

(Fig. 5.1a) 

H & E stained section(X260) 

from a child with HUS, it shows 

numerous thrombi in the glomerular 

capillaries (arrow). 



(Fig. 5.1b) 

Hx & E stained section 

of a case of haemolytic 

uraemic syndrome 

showing diffuse fibrin 

deposition in 

glomerular (arrow-10) 

and extra glomerular 

capillaries (arrow-2) 

Tubules and interstitium shows changes secondary to ischaemia. 

There is focal degeneration, necrosis and even true infarcts. 

In younger children, HUS predominantly affects glomeruli. Whereas in 

older children and adults, the disease involve mainly arteries and arterioles 

(poor prognosis). 

Lesions of arteries and arterioles outside the kidney (liver, colon and 

pancreas) are infrequent. 

2- Post partum renal failure: 

Is similar to HUS regarding changes in the glomeruli and arterioles. 

3- Thrombotic thrompocytopenic purpura: 

Is similar to HUS. Yet in contraindication to HUS, vascular thrombosis 

in TTP is widespread affecting arterioles in many organs particularly the brain, 

heart and the skin.

Clinical features of thrombotic microangiopathy: 

1- HUS in children: 

Most of patients (78%) are below the age of 3 years. Males and 

females are equally affected. Always, there is a prodroma of mild 

gastroenteritis or respiratory tract infection. In 20% of patients the prodroma 

may take the form of acute abdomen. The disease usually takes a severe 

course with abrupt appearance of weakness, pallor, oliguria, even anuria. 

Also, drowsiness, personality changes, seizures and coma are frequent 

manifestations. 

Clinical examination shows pallor, dehydration or overload, 

hepatomegaly, splenomegaly, purpura and abnormal urinalysis. 

Prognosis is poor especially with prolonged oligoanuria, hypertension 

and in the presence of cortical necrosis. Mortality up to 40% has been 

reported. 

2- Hemolytic uraemic syndrome in adults: 

As in children, the disease may present with acute renal failure, 

microangiopathic hemolytic anaemia and thrombocytopenia. However, the 

disease in adults is characterized by: 

• Higher incidence of hypertensive encephalopathy, neurologic sequelae and 

cardiac dysfunction. 

• Higher incidence of renal involvement (50%), and 

• Higher incidence of mortality (50%). 

3- Post partum renal failure: 

- This occurs within days to several months after an uneventful delivery. 

- Clinical features as well as laboratory findings are similar to those with HUS. 

- Mortality is high (50-60%) and remission of renal function is rare. 

This condition has to be differentiated from other causes of ARF with 

pregnancy as: 

• Prerenal failure owing to volume depletion resulting from hyperemesis 

gravidarum. 

• Acute renal failure with complicated pyelonephritis. 

• Acute renal failure with severe eclampsia. 

• Acute renal failure with abruptio placenta. 

• Acute renal failure with intrauterine faetal death. 

4- Thrombotic thrompocytopenic purpura (TTP): 

Females are more affected with TTP than males (2 : 1). This disease 

occurs at any age, but more common in the third and fourth decade of life.

There are 5 outstanding features for TTP which are: 

• Fever 

• Hemolytic anaemia 

• Neurologic manifestations. 

• Thrombocytopenic purpura 

• Renal disease, and 

The disease commonly starts abruptly with headache, disorientation, 

dysphasia, seizures, cranial nerve palsies or even coma. These 

manifestations usually fleet and fluctuate. 

Laboratory assessment of CSF may show high protein content, blood 

or xanthochromia. 

Less frequently, the disease may present with GIT symptoms, 

jaundice, lymphadenopathy, pallor, petechiae, retinal hemorrhage, and 

gastrointestinal haemorrhage. 

Renal abnormalities involve 90% of cases with TTP. Renal failure 

occurs in 50% of cases and is less severe than in HUS. 

Hematologic manifestations in TTP include severe anaemia, 

thrombocytopenia and rarely manifestations of DIC. Blood smear show 

fragmented erythrocytes (Schistocytes) and reticulocytosis. 

Comb's test is negative, LDH level is high, while haptoglobin level is 

low. Prothrombin time, PTT and fibrinogen are normal. 

The course of the disease is variable from acute, chronic, to relapsing. 

Treatment of thrombotic microangiopathy: 

Is rather empirical. Many therapeutic approaches has been tried, but 

none of them is satisfactory. These treatment options are used in different 

combinations. They include the following: 

• Plasma exchange 

• Plasma pheresis 

• Plasma infusion 

• Antiplatelet aggregating drugs 

• PGI2 infusion 

• Anticoagulants and antifibrinolytic drugs. 

• Corticosteroids 

• Dialysis. 

• Kidney transplantation.


- Moake JL, et al: Thrombotic microangiopathies associated with drugs 

and bone marrow transplantation. Hematol Oncol Clin North Am, 10 : 2, 

485-97, 1996. 

- Ruggenenti P, et al: Pathogenesis and treatment of thrombotic 

microangiopathy. Kidney Int Suppl, 58 : S97-101, 1997. 

- Sakakibara K: Renal thrombotic microangiopathy. Ryoikibetsu 

Shokogum Shirizu, 16 Pt 1, 316-9, 1997. 

- McCrae KR, et al: Thrombotic microangiopathy during pregnancy. 

Semin Hematol, 34 : 2, 148-58, 1997. 

- Mitarai T: Thrombolytic therapy for vasculitis and thrombotic 

microangiopathy-with special reference to the kidney. Nippon Naika 

Gakkai Zasshi, 86 : 9, 1634-8. 1997. 

- Ito K, et al: Advances in the treatment of hemolytic uremic syndrome 

(HUS). Nippon Rinsho, 55 : 3, 715-20, 1997.

ACUTE RENAL FAILURE 

(ARF) 

Definitions: 

ARF is a syndrome that can be broadly defined as a rapid deterioration 

of renal functions resulting in the accumulation of nitrogenous wastes such as 

urea and creatinine. 

Acute renal failure may be pre-renal, renal or post-renal (Fig. 6.1): 

Acute Renal Failure 

Prerenal 

Intrinsic 

Renal 

Post-renal 

Acute 

glomerulonephritis 

Acute 

tubular 

necrosis 

Acute 

interstitial 

nephritis 

Infiltrative: 

myeloma 

lymphoma 

granuloma 

Toxic Ischaemic Combined 

Fig. 6.1 

Different types of acute renal failure 

In pre-renal failure, the renal tissue is intact and kidney biopsy shows 

normal renal histology. Oliguria and high serum creatinine are due to 

functional impairment; since there is no sufficient blood reaching the kidney to 

be cleared of these toxins. 

In post-renal failure, the obstruction of the urinary tract results in 

increasing the pressure above the level of the obstruction up to the nephron 

including the urinary space of the renal glomeruli. When this back pressure 

exceeds that of the filtration pressure in the renal glomeruli, the process of

urine formation will stop with progressive accumulation of wastes and 

increase of serum creatinine and blood urea. 

In renal failure (intrinsic renal failure), there is a damage involving the 

glomeruli, renal tubules or tubulointerstitium with loss of their functions. 

Consequently wastes accumulate with increase in serum creatinine and blood 

urea. 

In this chapter we will focus on pre-renal failure and acute intrinsic 

renal failure, details of post renal failure is found in the chapter on obstructive 

uropathy. 

I. Pre-renal Failure 

Combination of hypotension, hypovolaemia resulting in diminished 

renal perfusion is the most common cause of acute renal failure in 

hospitalized patients. 

Additional causes of prerenal failure- not necessarily associated with a 

decrease in GFR- are conditions that increase urea production such as large 

protein intake and increased protein catabolism (fever, surgery, severe 

illness, steroids and tetracyclines). In patients with gastrointestinal bleeding, 

the combination of high protein load (blood in the gastrointestinal tract) and 

contracted circulating volume leads to an increase in blood urea 

concentration. 

When renal hypoperfusion (due to hypotension and/or hypovolaemia) 

is not severe enough to cause renal tubular damage, it will manifest as prerenal 

failure in the form of oliguria and a rise in serum creatinine and blood 

urea. Since there is no structural renal damage, early diagnosis and 

correction of renal hypoperfusion result in immediate diuresis and rapid drop 

in serum creatinine and blood urea levels. If hypoperfusion is severe or 

neglected, renal compensatory mechanisms will fail and acute tubular 

necrosis occurs. In this new situation, correction of hypoperfusion will not be 

followed by diuresis or drop in serum creatinine. Few days or weeks (mean 2- 

3 weeks) are needed for tubular regeneration and recovery of kidney function 

to occur. 

II. Acute Intrinsic Renal Failure 

This includes acute tubular necrosis (ATN), acute interstitial nephritis 

and acute glomerulonephritis. In this chapter we will focus on ATN. Details of 

the other two categories are found in chapters 3&9.

Acute Tubular Necrosis 

Acute tubular necrosis can be induced by renal hypoperfusion 

(ischemia) or exposure to nephrotoxins (exogenous or endogenous toxins) 

and frequently by a combination of both. These two types of insults 

(ischaemic and toxic) will now be reviewed individually. 

Causes of Ischaemic ATN: 

A- Intravascular volume depletion: 

• Major trauma, burn and crush injury. 

• Haemorrhage (post partum, surgical and gastrointestinal). 

• Pancreatitis, vomiting, diarrhea, peritonitis, dehydration. 

• Hypoalbuminemia. 

• Fluid volume depletion secondary to renal losses (diabetic 

ketoacidosis, diuretic abuse and adrenal insufficiency). 

B- Decreased cardiac output 

• Severe congestive heart failure or low cardiac output syndrome. 

• Pulmonary hypertension and massive pulmonary embolism. 

C- Increased (renal/systemic) vascular resistances ratio: 

• Renal vasoconstriction: - Alpha adrenergic agonists. 

- Hypercalcemia, amphotericin. 

• Systemic vasodilatation: - After load reduction. 

- Antihypertensive medications. 

- Anaphylactic shock. 

- Anesthesia. 

- Sepsis. 

• Liver cell failure: results in both systemic VD and renal VC. 

D- Renovascular obstruction: 

• Renal artery: Atherosclerosis, embolism, thrombosis, vasculitis. 

• Renal vein : Thrombosis, compression. 

E- Increased blood viscosity: 

• Multiple myeloma. 

• Macroglobulinaemia. 

• Polycythaemia.

F- Aggravation of renal hypoperfusion by interference with renal 

autoregulations: 

• Prostaglandin synthesis inhibitors as NSAIDs 

• Angiotensin converting enzyme inhibition in patients with renal artery 

stenosis. 

Causes of Toxic ATN 

(A) Exogenous nephrotoxins include: 

Antibiotics: Aminoglycosides Amphotericin 

Cephalosporin 

Polymyxin 

Sulfonamide 

Pentamidine 

Quinolone 

Acyclovir 

Tetracyclines 

Bacitracin 

Anaesthetic agents: 

Contrast Media: 

Anti-ulcer: 

Analgesics: 

Diuretics: 

Methoxy fluorane 

Diatrizoate, lopanoic acid 

Cimetidine, excess milk-alkali 

Phenacetin 

Mercurials 

Metals: as Mercury, lead, arsenic, bismuth, 

cadmium, antimony, 

organic solvents: carbon tetrachloride, tetrachlorethane, 

tetrachlorethylene. 

Glycols: 

as ethylene glycol, xylitol 

Poisons: paraquat, diquat, mushroom (Amanita), 

snake bite, stings, bacterial toxins. 

Chemotherapeutic and Immunosuppressive Agents 

Cis-Platinum, Methotrexate, Mitomycin, Nitrosoureas, Cyclosporine A, and D- 

Penicillamine 

(B) 

Endogenous nephrotoxins include 

Pigments: 

Crystals: 

Myoglobin 

Uric acid 

Hemoglobin 

Calcium 

Methemoglobin 

Oxalate

Tumour Specific Syndromes: 

Tumour lysis syndrome 

Plasma cell dyscrasias (e.g. myeloma kidney) 

Risk factors associated with contrast media (and other toxins) 

nephropathy include the following: 

• Renal insufficiency 

• Dehydration 

• Diabetes mellitus 

• multiple myeloma 

• Hepatic insufficiency 

• Hypoalbuminaemia 

• Cardiovascular disease • Dose of contrast 

• Increasing age 

• Hyperuricaemia 

Clinical features of ARF: 

1- Usually, the patient gives history of the etiologic cause such as trauma, 

shock, haemolysis, drug intake, infection, or stone disease. 

2- Patient may notice a change in urine volume and character, oliguria is 

common, but in 10-50% of cases urine volume will be normal or even 

higher (as in toxic ATN) this is called polyuric ATN. Absolute anuria is 

highly suggestive of obstructive ARF (post-renal) or very severe form of 

ATN (cortical necrosis). 

3- Manifestation of salt and water retention (oedema, puffiness, hypertension 

and even heart failure). 

4- By time, manifestations of uraemia appear as acidotic breathing, dyspnea, 

nausea, vomiting, headache, muscle twitches and even frank 

encephalopathy and coma. 

5- Patient may present as well with any of the following complications: 

Complications Of Acute Renal Failure: 

Cardiovascular 

• pulmonary odema 

• hypertension 

• myocardial infarction 

Metabolic 

• hyponatremia 

• acidosis 

• hyperphosphatemia 

• arrhythemias 

• pericardial effusion 

• pulmonary embolism 

• hyperkalemia 

• hypocalcemia

Neurologic 

• coma 

Gastrointestinal 

• gastritis 

Haematologic 

• anaemia 

Infections 

• pneumonia 

• UTI 

• seizures 

• gastroduodenal ulcers 

• hemorrhagic diathesis 

• septicemia 

Investigations of ARF: 

A- Urinary indices:- 

May be helpful in the differentiation between pre-renal failure and 

acute tubular necrosis. Diuretics should not be given at least during the last 

48 hours for these parameters to be valid. 

Parameter Prerenal ATN 

Concentration of urine: 

Urine specific gravity > 1.020 < 1.010 

Urine Osmolarity (mosm/lit)) > 500 < 350 

GFR and overall tubular reabsorption: 

Creatinine clearance > 20 < 20 

Urine/Plasma urea > 8 < 3 

Urine/Plasma creatinine > 40 < 20 

Tubular handling of solutes 

UNa (mEq/L) < 20 > 40 

FeNa (%) < 1 > 1 

B- Urinary sediment: 

Centrifugation of fresh urine sample and examination of the urinary 

sediment may be helpful in diagnosing different causes of ARF. See chapter 

15 on value of urine examination in medical diagnosis. In pre-renal failure and 

in ischaemic ATN urinary sediment is usually free. 

C- Renal Imaging: 

1. Plain film of the abdomen: 

This will show kidney parity, size, shape, calcification and stones.

2. Renal Ultrasonography and echo-doppler of renal vessels: 

Ultrasonography safely assesses kidney size, shape and echogenicity. 

Cortical thinning or oedema can sometimes be seen clearly. 

Also, it can exclude obstructive uropathy (back pressure changes). 

Echo-Doppler of renal vessels can exclude occlusion of the renal 

arteries and veins. 

3. Retrograde and antegrade pyelography: 

Provide the most reliable information on the patency of the ureter. 

4. Radionuclide studies (Renogram): 

The vascular phase of the isotope renogram can show the pattern of 

renal perfusion (for diagnosis of reno-vascular diseases). Diuretic 

renogram can help in diagnosis of urinary tract obstruction. Also, 

renogram may help in diagnosis of renal parenchymal diseases, but 

cannot discriminate their different etiologic causes. 

5. Angiography: 

Is useful mainly when an acute reversible renovascular event is 

suspected such as embolization, thrombosis or involvement in a 

dissecting aortic aneurysm. It carries the risk of exposure to contrast 

media which could be nephrotoxic. 

6. C.T. studies: 

Provide reliable information on kidney parity, size, shape and presence 

of hydronephrosis. 

7. Magnetic Resonance urography: 

Recently MRI urography (MRU) without use of contrast media can 

provide films similar to IVP. It is thus of great value to exclude U.T. 

obstruction without the risk of contrast media nephropathy (Fig. 6.2).

(Fig. 6.2) 

MR urography shows bilateral hydroureteronephrosis in 

a patient with 4.8 mg/dl serum creatinine (IVU is not 

feasible). Note the hypointense ureteric stone bilaterally 

(arrows). 

D. Renal biopsy: 

The indications of renal biopsy in ARF are: 

1. Equivocal case history. 

2. Renal signs suggesting glomerular, vascular or interstitial lesions. 

3. Extrarenal manifestation in patients in whom a systemic disease 

identifiable by biopsy is suggested. 

4. Prolonged renal failure (more than 3 weeks). 

Diagnostic Approach: 

On confirming renal dysfunction (by high serum creatinine) unless the 

diagnosis is clear, we have to adopt the following approach: 

1- First exclude pre-renal failure by history of fluid loss, shock, 

hypotension.....etc and physical examination e.g. hypotension, 

dehydration, collapsed neck veins. Examination of urine may help to 

confirm this diagnosis. Urine osmolality is >500 mosmol/L, U Na is

If the case proved to be pre-renal, quick approach with I.V. fluid should 

be followed by diuresis. 

2- If the case is not pre-renal failure, we proceed for renal ultrasonography. If 

it shows a backpressure changes, this could be confirmed by diuretic 

renogram using 99 Tc-DTPA. If obstruction is confirmed, we proceed by 

further investigative and therapeutic approaches such as ureteral 

catheterization, retrograde pyelography, percutaneous nephrostomy 

(PCN) and antegrade pyelography. Urologic management will depend on 

the outcome of these investigations and diagnosis will be post-renal ARF. 

3- If the case is neither pre-renal nor post-renal, we will be left with renal 

causes of ARF. 

Again, urine examination will help in the diagnosis. Look for the urine 

sediment: 

a- if there is proteinuria, hematuria, casts and the patient is hypertensive. 

The case is acute glomerulonephritis which could be confirmed and typed 

by kidney biopsy. 

b- if urine sediment is clear the case is ischaemic ATN. 

c- if urine shows minor changes (e.g. trace proteinuria, eosinophiluria), the 

case is most probably toxic ATN. 

If differentiation between b and c is not clear by history and clinical 

examination, this sometimes could be achieved by renal biopsy. 

Diagnosis of the etiology of ARF is sometimes not easy to achieve, for 

example: 

1- The urine parameters may be misleading or inconclusive as in polyuric 

ATN, if there is a pre-existing renal, cardiac or hepatic disease or if 

diuretics have been administered. In these situations, using parameters 

including plasma values may increase the sensitivity of urine parameters 

e.g. U/P osmolality (> 1.3 in pre-renal, < 1.1 in ATN) FeNa (< 1 in prerenal, 

> 1 in ATN). 

Fluid challenge may help in the distinction between pre-renal failure 

and ATN. Also if furosemide is added it will induce quick response of prerenal 

failure to fluid load and even if the case is ATN it may be changed from 

oliguric to the polyuric type of ATN which is more easy to manage and have 

better prognosis. 

2- Occasionally, obstruction may occur without dilatation of the collecting 

system e.g. in patient with extensive calculi, with acute obstruction, with 

retroperitoneal fibrosis and with extensive infiltration of the ureters.

If the doubt persisted about the patency of the urinary tract, cystoscopy 

and retrograde pyelography remain essential before excluding post-renal 

AFR. 

Acute cortical necrosis: 

Is a subset of ATN in which there is a massive necrosis of the tubules 

and glomeruli of the renal cortex. The condition may be focal or diffuse with 

irreversible damage of the kidneys. It is suspected when ATN fails to recover 

after 4-6 weeks. 

Acute cortical necrosis usually occurs with complicated pregnancy as 

postpartum haemorrhage and abruptio placenta. 

Diagnosis could be made by biopsy unless the lesion is patchy, then 

the diagnosis could be achieved by angiography which will show filling of the 

main renal arteries but failure to visualize interlobular arteries. 

When pre-renal and post-renal failure are excluded, if diagnosis of 

ATN is not sure (i.e. there is possibility of other conditions such as 

glomerulonephritis), or interstitial nephritis, kidney biopsy should be 

performed on urgent bases, since these conditions may need early 

aggressive treatment (such as steroid and cyclophosphamide) for obtaining 

response. 

Sometimes kidney biopsy may reveal an unexpected etiology for ARF 

as infiltration with myeloma, lymphoma or granuloma. 

TREATMENT OF ARF: 

A- Treatment of the cause e.g. any condition causing renal hypoperfusion, 

exposure to toxic drug or chemical or systemic disease. 

B- Prevention of acute renal failure: 

The timing of intervention to prevent ATN is important. Protective 

agents must be administered at the time of, or immediately following potential 

renal insult. This intervention may prevent or at least blunt the severity of 

ATN. 

The intervention could be through the following approaches. In 

different combinations according to the clinical situation: 

• Volume expansion by saline loading. 

• Diuretic as mannitol and furosemide. 

• Calcium channel blockers as verapamil and nifedipine. 

• Vasodilating agents as dopamine in renal dose 1-2 ug/kg/min 

• ATP-magnesium chloride.

In case of contrast media, the following additional points should be 

adopted, these are:- 

• Avoid unnecessary contrast procedures. 

• Avoid multiple contrast exposure within a few days. 

• Avoid contrast exposure in high risk patient. 

• Use the smallest dose possible. 

• Use of non-ionic contrast is to somewhat safer. 

• In high risk patient with renal impairment we can manage to wash the 

contrast out immediately after the technique (e.g. coronary angiography) by 

haemodialysis. 

• MRU is good alternative for visualization of the urinary tract obstruction. 

C- Conservative measures: 

1- fluid balance: 

Careful monitoring of intake/output and body weight is very important 

to avoid overload and hypovolaemia. The first may lead to pulmonary 

oedema while the second may aggravate renal ischaemia. 

Patient should receive fluids equal the daily urine output plus the other 

sensible losses e.g. vomitus or diarrhea fluid; plus an amount equals the 

insensible loss which is around 600 c.c. for 60kg body weight patient. For 

example, a 60kg b.w. patient with ARF who produces 200 c.c. urine daily with 

no vomiting or diarrhea will need a daily fluid intake of about 600 + 200 = 800 

c.c. With every 1°c increase in body temperature, 200 c.c. should be added to 

the daily fluid intake. Fluid requirement will increase with the increase in the 

body surface area and the atmospheric temperature and humidity (leading to 

increase in sweating). Fluids could be given orally or (if not possible), it could 

be given intravenously. 

2- Electrolytes and acid-base balance: 

• Prevent and treat hyperkalemia. 

• Avoid hyponatremia. 

• Keep serum bicarbonate above 16 mmol/L. 

• Minimize hyperphosphatemia by giving phosphate binders (e.g. Ca 

Co 3 & AL hydroxide) with meals. 

• Treat hypocalcaemia. 

3- Nutritional support: 

• Restrict protein (to 0.5gm/kg/day) but maintain sufficient caloric 

intake.

• Carbohydrate intake should be at least 100 gm/day to minimize 

ketosis and endogenous protein catabolism. 

4- Drugs: 

• Review all medications. 

• Stop magnesium-containing medications. 

• Adjust dosage for renal failure. 

5- Treatment of hyperkalemia: 

• Calcium gluconate I.V. 

• Glucose 50% + Insulin 

• Na Hco 3 I.V. 

• Salbutamol 

• K-exchange resins (e.g. resonium) • Dialysis 

• Avoid diets and drugs causing hyperkalaemia 

6- Dialysis: 

The indications of dialysis in ARF are: 

a. Clinical: • Poor clinical state, nausea, confusion. 

• Fluid overload, pulmonary oedema. 

• Preoperatively. 

b. Biochemical: • Plasma K + > 7 mmol/L. 

• Plasma bicarbonate < 12 mmol/L 

• Arterial pH < 7.15. 

Prognosis of AFR: 

The mortality of AFR remains high, ranging between 50-80% in 

surgical and post-traumatic cases. It is generally lower in ARF due to drug 

and toxins. About 75% of deaths occur in the first week of ARF, and 25-50% 

of these deaths are due to the underlying disease. The overall prognosis is 

better in non-oliguric than in oliguric renal failure. 

The factors influencing patient survival in acute renal failure include the 

following: 

• Aetiology of ARF. 

• Severity of ARF. 

• Number and severity of coexisting illness. 

• Patient's age. 

• Presence of complications.


- McCarthy JT: Renal replacement therapy in acute renal failure. Curr 

Opin Nephrol Hypertens, 5 : 6, 480-4, 1996. 

- Denton MD, et al: "Renal-dose" dopamine for the treatment of acute 

renal failure: Scientific rationale, experimental studies and clinical trials. 

Kidney Int, 50 : 1, 4-14, 1996. 

- Mandal AK: Management of acute renal failure in the elderly. 

Treatment options. Drugs Aging, 9 : 4, 226-50, 1996. 

- Slapak M: Acute renal failure in general surgery. J R Soc Med, 89 

Suppl 29 : 13-5, 1996. 

- Riella MC: Nutrition in acute renal failure. Ren Fail, 19 : 2, 237-52, 

1997. 

- Bock HA: Pathphysiology of acute renal failure in septic shock: from 

prerenal to renal failure. Kidney Int Suppl, 64 : S15-8, 1998. 

- Stark J: Acute renal failure. Focus on advances in acute tubular 

necrosis. Crit Care Nurs Clin North Am, 10 : 2, 159-70, 1998. 

- Andreucci VE, et al: Role of renal biopsy in the diagnosis and 

prognosis of acute renal failure. Kidney Int Suppl, 66 : S91-5, 1998. 

- Mucelli, et al: Imaging techniques in acute renal failure. Kidney Int 

Suppl, 66 : S102-5, 1998. 

- Solomon R: Contrast-medium-induced acute renal failure. Kidney Int, 

53 : 1, 230-42, 1998.

DEFINITIONS: 

CHRONIC RENAL FAILURE 

(CRF) 

Chronic renal failure is a progressive loss of kidney functions due to 

progressive damage of kidney tissue by a disease involving the two kidneys. 

In chronic renal failure, there is a persistent and irreversible reduction 

in the overall renal function. Not only the excretory functions are disturbed but 

also the endocrine and the haemopoietic functions as well as the regulation of 

acid-base balance become abnormal. These derangements in the internal 

environment (internal milieu) of the body will result in the uraemic syndrome. 

In this domain there are confusions caused by use of different terms 

which could be solved by putting them in acceptable definitions. These terms 

and their definitions are as the following: 

Azotaemia: This means that the concentrations of the blood urea and the 

blood urea nitrogen (BUN) are raised. It is not necessary that the patient has 

uraemic symptoms. Kidney function could even be normal and accumulation 

of urea is due to dietary causes, pre renal factors or even from laboratory 

interference. 

Uraemia : is the syndrome resulting from severe renal failure. 

Renal impairment: this means that there is a reduction in GFR which is still 

not severe enough to produce significant uraemic symptoms. 

End stage renal failure (ESRF) is considered when chronic renal failure is so 

severe that the patient cannot live without renal replacement therapy (dialysis 

or transplantation). This is sometimes called terminal renal failure or terminal 

uraemia. 

Disease involving one kidney (even if very severe and damaging this 

kidney) will not result in renal impairment or failure as the other kidney is 

capable to maintain the internal milieu or environment within normal. In this 

setting we may say compromised or non-functioning right or left kidney 

(according to the kidney damaged right or left). Sometimes we say solitary 

functioning right or left kidney (according to the side of the healthy kidney). 

INCIDENCE OF CHRONIC RENAL FAILURE: 

This varies from one country to the other. For example, in western 

Europe and Australia the incidence is about 50 new cases per million 

population per year. In USA, the incidence is 160 new patients/million per

year, while in Egypt and some developing countries it is believed to be about 

200 new patients/million population per year. This variability could be 

attributed to different socio-economic and environmental factors. 

AETIOLOGY OF CHRONIC RENAL FAILURE: 

The common causes of CFR are diabetic nephropathy, chronic 

pyelonephritis, obstructive uropathy, reflux nephropathy, chronic 

glomerulonephritis and polycystic kidney disease. The complete list of causes 

include the following: 

1. Primary glomerular diseases: 

Such as idiopathic crescentic glomerulonephritis, primary focal 

segmental glomerulosclerosis and primary mesangiocapillary 


2. Tubulo-interstitial diseases: 


• Chronic heavy metal poisoning such as lead, cadmium and mercury 

may result in chronic tubulo-interstitial nephritis and renal failure. 

• Chronic hypercalcaemia as with vitamin D intoxication and primary 


• Chronic potassium depletion resulting from prolonged use of diuretics 

without potassium supplementation as in patients with ascites or 

chronic heart failure. 

3. Renal vascular diseases: 

These may be in the main renal vessels (artery or vein) or in the 

intrarenal vessels. 

Main renal artery diseases causing renal failure: 

Renal failure may occur if there is bilateral advanced renal artery 

stenosis or a unilateral renal artery stenosis in a solitary kidney. 

Renal artery stenosis usually occurs due to advanced atherosclerosis 

which is more common in elderly males or due to fibromuscular 

dysplasia which is more common in middle aged females. 

Both atherosclerosis and fibromuscular dysplasia manifest first by 

renovascular hypertension. Later, they may end by renal failure due to 

progressive renal ischaemia. 

Renal vein diseases causing renal failure: 

Bilateral renal vein thrombosis; which is more common in patients with 

nephrotic syndrome. If bilateral or in a solitary kidney it may lead to 

renal failure.

Small renal vessel diseases causing chronic renal failure: 

Example of these diseases are nephrosclerosis secondary to long 

standing hypertension (very common), polyarteritis nodosa (less 

common) or malignant hypertension. 

4. Chronic urinary tract infection: 

Chronic pyelonephritis is considered the most common cause of 

chronic renal failure in our locality. It may be caused by a specific organism 

as in tuberculous pyelonephritis or by nonspecific organisms such as E.coli. 

5. Chronic urinary tract obstruction: 

This may be upper or lower urinary tract obstruction. It results in 

hydronephrosis which if left untreated may result in CFR. 

Causes of upper urinary tract obstruction include bilateral ureteric or 

renal stones, bilateral neoplasms and bilateral ureteric stricture. 

Causes of lower urinary tract obstruction include bladder tumour, 

senile prostatic enlargement, huge bladder stones and stricture urethra 

Association of infection and obstruction is the most common cause of 

renal failure as obstruction may invite infection and infection may lead to 

obstruction. 

6. Collagen diseases: 

Collagen diseases such as S.L.E. and polyarteritis nodosa, rheumatoid 

arthritis, and systemic sclerosis may cause chronic renal failure. These 

diseases cause renal failure either through a direct renal involvement by the 

disease itself or as a complication of the disease (in rheumatoid artheritis 

renal failure may be caused by secondary amyloidosis or by drug used as 

NSAIDs and cytotoxic drugs). 

7. Metabolic diseases: 

Renal amyloidosis; which is usually a complication of Familial 

Mediterranean Fever (FMF) or chronic suppuration (e.g. osteomyelitis) may 

end by chronic renal failure. 

Gout may cause chronic renal failure either directly (gouty 

nephropathy) or secondary to abuse of NSAIDs. More commonly it develops 

by the two mechanisms. 

Diabetic nephropathy is one of the common causes of CFR. 

Analgesic nephropathy occurs with most of non-steroidal antiinflammatory 

drugs (NSAIDs) such as aspirin. Analgesic nephropathy is a 

cumulative effect needing a long term drug administration. Nearly an amount 

of 2-3 kgm of aspirin is needed for chronic renal failure to occur. This 

condition is frequently seen in patients with chronic pain as those with 

osteoarthritis and rheumatoid arthritis.

PATHOPHYSIOLOGY OF CHRONIC RENAL FAILURE: 

I. Disturbance of water excretion: 

Total body water is a major determinant of its solute concentrations. 

Keeping the total body water within the normal range is mandatory for 

keeping the body internal milieu. The kidney is the major determinant for 

adjusting total body water. This is achieved through it's capacity to dilute and 

to concentrate urine. With chronic renal failure, this capacity is deranged as 

the following: 

a- Loss of the renal ability to concentrate urine: this occurs early in renal 

failure leading to nocturia and polyuria. This is due to the fact that with 

kidney damage the number of functioning nephrons is decreasing while 

the amount of osmotically active molecules produced by the body is stable 

(about 600 mosmol/day). This will create an osmotic load on the 

functioning nephrons with subsequent polyuria. If water intake is 

decreased or if there is fluid loss (e.g. vomiting or diarrhea), the urine 

volume will not decrease in parallel, but rather a little decrease will occur 

(due to decreased renal blood flow). As the kidney is unable to concentrate 

urine to excrete more toxins, retention of wastes will occur. Furthermore, 

dehydration will result in renal ischaemia which will aggravate the renal 

damage. When urine osmolarity is as plasma (300 mosmol/L), at least 

2000 c.c. of urine is needed for excretion of the daily produced wastes 

which is the situation in uraemic patients, while in normal kidney only 500 

c.c. of maximally concentrated urine (1200 mosmol/L) are sufficient. 

b- Loss of the renal ability to dilute urine: This occurs late in renal failure. If 

the uraemic patient receives excess fluid he may pass into fluid overload, 

even pulmonary oedema. In normal persons, urine osmolarity can drop 

down to 50 mosmol/L (specific gravity 1.001) i.e. urine which is hypotonic to 

plasma, while with advanced uraemia, dilution will drop down to only 300 

mosmol (S.G. 1.010) i.e. equal to plasma. In addition, the diseased kidney 

will dilute urine very slowly in comparison to the intact one. 

2. Disturbance of sodium excretion: 

As renal failure progresses, the ability of the nephron to adjust sodium 

balance decreases. The following disorders may occur: 

a- Hyponatraemia, this is usually dilutional hyponatraemia that is due to 

retention of excess water taken associated with salt loss such as by 

sweating, vomiting and diarrhoea.

- Salt and water retention which may cause hypertension. 

c- Salt losing nephropathy which occurs in diseases such as analgesic 

nephropathy, cystic kidney diseases and tubulointerstitial nephritis. This will 

manifest with hypovolaemia, dehydration and hypotension which if not 

treated (by excess salt intake) may lead to acute on chronic renal failure. 

3. Disturbed potassium excretion: 

The kidney has a high capacity to excrete potassium. Accordingly 

serious hyperkalaemia rarely occurs unless GFR is less than 10ml/min. Other 

reasons for hyperkalaemia should be looked for if GFR is more than 10 

ml/min, these are: 

• Excess potassium load 

• Hyporeninaemic hypoaldosteronism 

• Severe acidosis with volume contraction 

• Drugs as ACEI, B-blockers, and aldosterone antagonists. 

4. Disturbance of Acid-base balance: 

Chronic renal failure may result in metabolic acidosis which will 

manifest in advanced stages by Kussmaul's breathing (air hunger). In cases 

with tubulo interstitial diseases, acidosis may manifest earlier (discrepant with 

serum creatinine). This condition will be aggravated by increased acid load 

and sodium depletion. 

With chronic acidosis, bone will be used as a buffer with consequent 

skeletal calcium loss and bone disease. 

Metabolic acidosis in uraemic patient is due to the following (Fig. 7.1) : 

a- decrease in titratable acid (phosphates, sulfates...) excretion due to 

decreased GFR, b- decrease in ammonia production by the proximal 

convoluted tubules; and c- bicarbonate wastage.

(Fig. 7.1) 

Disturbances of Acid-base regulation in renal failure. 

5. Disturbance of calcium-phosphate metabolism: 

This disorder could be summarized as the following (see Fig. 7.2):- 

a. Retention hyperphosphataemia: As the kidney is the main route of 

phosphate elimination, decrease of GFR below 30 ml/min will be 

accompanied by hyperphosphataemia. At first, this may occur 

transiently but later it may be persistent. In earlier phases of uraemia,

hyperphosphataemia may occur post prandially especially with meals 

heavy in protein and dairy products. 

b- Hypocalcaemia: due to the dynamic equilibrium between serum 

calcium and phosphate, hypocalcaemia will occur with any increase 

in serum phosphate. Other causes of hypocalcaemia in uraemic 

patient are defective activation of vitamin D in PCT and decreased 

dietetic intake. 

c- Hyperparathyroidism: will occur in response to hypocalcaemia. 

Secondary hyperparathyroidism will result in bone demineralization 

through osteoclast activation. This occurs in attempts to correct 

hypocalcaemia. With correction of hypocalcemia, parathyroid activity 

is arrested, yet as phosphate is high, deposition of phosphate and 

calcium in soft tissues will occur to keep the dynamic equilibrium 

(serum Ca X serum Po4=50). Again, calcium level gets low and 

parathyroid gland becomes active with consequent bone 

demineralization. So far uraemia is persistent, this viscious cricle will 

keep active. Long term stimulation of parathyroid gland will result in 

development of adenoma which is autonomus i.e despite calcium is 

getting high parathyroid gland will keep secreting parathromone 

(tertiary hyperparathyroidism). This will lead to more aggressive bone 

disease and soft tissue calcification. In addition, it will lead to bone 

fibrosis and aggravation of anaemia.

(Fig. 7.2a) 

Disturbances of calcium (Ca + ) and of phosphate (P) metabolism in renal failure 

d- Bone disease, sometimes called renal osteodystrophy, it is due to 

multiple factors including negative calcium and protein balance, lack of 

active vit. D, hyperparathyroidism as well as aluminium intoxication. 

Aluminum intoxication is due to long term use of aluminum containing 

antacids as phosphate binder and the use of aluminium contaminated 

water in preperation of dialysate for patients under hemodiamysis 

treatment.

e- Soft tissue calcification: is due to hyperphosphataemia, secondary 

hyperparathyroidism, mobilization of bone calcium to blood with the 

consequent increase of the constant value (serum calcium X serum 

phosphate). Deposition of calcium occurs in all soft tissues including 

skin, conjunctiva, vessels wall and even the heart.

Calcified papillae shown in plain film of the 

renal tract in a patient with uraemia. 

Extensive periarticular calcification in a 

haemodialysis patient. 

(Fig. 7.2c) 

Vascular and soft tissue calcifications in secondary hyperparathyroidism of chronic renal disease.

6. Retention of uraemic toxins: 

These retained toxins are responsible for most of the uraemic 

symptoms, including lethargy, malaise, nausea, vomiting, pericarditis, 

pleurisy, uremic colitis, platelet dysfunctions...etc. 

Removing these toxins by dialysis will be followed by improvement in 

the manifestations of uraemic syndrome. 

The nature of uraemic toxins is yet uncertain. However, they may be: 

1- Urea, creatinine, uric acid, guanidines, phenols, products of nucleic 

acid breakdown... etc. 

2- Middle molecules which are substances of molecular weight 300 to 

2000 Dalton. 

7. Failure of the renal hormonal functions including: 

Erythropoietin, activation of vitamin D and disturbed Renin excretion 

CLINICAL FEATURES OF CHRONIC RENAL FAILURE : 

Fig-7.3 summarizes the clinical features of the uraemic syndrome. The 

details of this features include: 

I. Gastrointestinal Manifestations: 

a. Mouth: 

The high concentration of urea in saliva causes unpleasant taste (taste 

of ammonia) and uraemic odour of the mouth (ammoniacal smell). 

The tongue appears dry, dirty, brown or white coated and may be 

ulcerated. Later, stomatitis, ulceration of the mouth and pharynx may occur. 

The mouth is always dry due to dehydration and mouth breathing. Dental 

caries is also common. 

b- Stomach: 

Gastritis and sometimes gastric erosions may occur. This occurs due 

to the high concentration of urea in saliva and gastric juice causing chronic 

irritation of the gastric mucosa. The patient may suffer from anorexia, nausea 

and vomiting. Upper G.I.T. bleeding (haematemesis) and melena may even 

occur. 

Hiccough occurs in terminal stages of uraemia and is aggravated by food. 

The cause of hiccough in uraemic patient is most probably due to irritation of 

the phrenic nerve or may be due to a central effect induced by uraemic 

toxins.

Eye 

CNS 

• Malaise, lethergy 

• confusion 

• Reversal or sleep rhythm 

• Convulsions and fits 

• Coma 

• Redness of conuctiva 

• Calcification 

• Retionopathy 

Mouth 

• Uraemic breath 

• Coated tongue 

Face 

• pallor 

• sallow 

• puffness 

• Uraemic frosts 

Abdomen 

• Gastritis 

• Colitis 

• Renal pain 

• Palpable kidney 


• cardiomegaly 

• failure 

• Pericarditis 

• Hypertension 

Chest 

• Acidotic breathing 

• Pulmonary oedema 

• pleural effusion 

Hand and arms 

• scratch marks 

• bruisis 

• Tremors 

• myoclonic jerks 

Genitourinary 

• Impotence 

• Decreased libido 

• Amenorrhea 

• Infertility 

• Polyuria 

• Nocturia 

• Frequency 

Lower limbs 

• oedema 

• peripheral neuropathy 

• deformity of bone disease 

(in children) 

• peripheral vascular disease 

(Fig. 7.3) 

Clinical Features of the Uraemic Syndrome

c- Intestine: 

Usually, there is constipation due to dehydration, but diarrhea or even 

bloody dysentery (uraemic dysentery) may occur in terminal uraemia. This is 

due to urea deposition in the mucosa of the colon which leads to mucosal 

ulceration which is liable to superadded infection which may cause diarrhea. 

In severe cases of mucosal ulceration, there may be bleeding per rectum. 

II. 

Neurological manifestations: 


a- Cerebral: 

Headache, lassitude, drowsiness, insomnia, sometimes inverted 

sleep rhythm, and vertigo are common manifestations of uraemia. 

These manifestations are caused by the retained uraemic toxins. 

Uraemic coma occurs in advanced cases. 

b- Neuromuscular: 

The following are the common neuromuscular manifestations of 

uraemia: 

• Flabbing tremors (asterixis) and proximal myopathy with paradoxically 

brisk tendon reflexes. 

• Peripheral neuropathy is usually mixed (motor and sensory) and 

mainly affecting legs. Patients present mainly with paraesthesia. 

• Muscle twitches and convulsions are mainly due to hypokalaemia and 

hypocalcaemia. 

• Muscle weakness is due to hyperkalaemia, hyponatraemia and 

hypovitaminosis D. 

III. 

Hematologic and cardiovascular Manifestations: 

a- Anaemia: 

Anaemia is a common feature of uraemia and usually normocytic 

normochromic. It is partly responsible for many of the debilitating symptoms 

of uraemia such as lethargy, tiredness and exertional dyspnea. The main 

causes of anaemia in uraemic patient are the followings: 

• Bone marrow depression by the uraemic toxins and due to 

erythropoietin deficiency. 

• Short life span of R.B.Cs due to the uraemic toxins. 

• Nutritional deficiency due to dietatic restrictions and dyspepsia 

(protein, Vit. B12, and folic acid)

• Iatrogenic causes as frequent blood sampling in hospitalized patients 

and the blood loss in the dialyzer at the end of each haemodialysisb 

session. 

• Bleeding tendency as GIT bleeding and metrorrhagia. 

• Aluminium toxicity. 

• Bone marrow fibrosis due to hyperparathyroidism. 

• Hypersplenism especially in multiple transfused patient. 

Sometimes anaemia is microcytic hypochromic due to iron deficiency. 

White cell count and platelet count are normal but with decreased functions. 

b- Bleeding tendency: 

May result from: 

• Qualitative platelet defects: 

Platelet aggregation is reduced and ADP release is inhibited leading to 

increased capillary fragility and prolongation of bleeding time. 

• Increased fibrinolytic activity of the blood because fibrinolysin is 

normally eliminated by the kidney. 

• Anaemia: 

This bleeding tendency is corrected by dialysis, correction of anaemia 

or administration of DDAVP or oestrogen. 

c- Hypertension: 

Hypertension in uraemic patients is either due to high renin secretion or 

salt and water retention. It occurs in about 80% of cases. In uraemics, 

hypertension is characterised by resistance to drug treatment and by 

tendency to develop malignant hypertension more than in other forms 

of hypertension. Hypertension aggravates the renal disease which 

further increases the blood pressure and a vicious circle is produced. 

d- Uraemic pericarditis: 

This occurs due to deposition of urea on the smooth inner surface of 

the pericardial sac changing it into rough surface. Continuous friction 

between the visceral and parietal pericardium during cardiac systole 

and diastole results in dry pericarditis which manifests by pericardial 

pain and pericardial rub on auscultation. Later, haemopericardium 

develops which progresses to cause cardiac compression 

(tamponade). This manifests clinically by a triad of: 

1. progressive systemic venous congestion with congested neck veins, 

congested liver, and anasarca.

2. Progressive hypotension due to reduction of stroke volume as 

venous return is progressively decreasing. 

3. Progressive increase in cardiac size on clinical examination and by 

plain X-ray. Echo cardiography shows that the increase is mainly due 

to fluid collection in the pericardium. It also shows the defective cardiac 

filling and reduced stroke volume. 

Cardiac tamponade, if not treated urgently, will be fatal. Treatment is 

by pericardiocentesis. If recurrent, treatment is by making pericardial 

window (between pericardial sac and pleural sac) or by partial 

pericardiectomy. 

Pericarditis is one of the signs of terminal uraemia which indicates 

urgent dialysis. 

e- Heart failure: 

This is usually a left sided heart failure which is due to: 

1- hypertension 2- anaemia 

3- fluid overload 4- uraemic cardiomyopathy. 

IV. Cutaneous manifestations: 

• Muddy face (sallow skin), due to retention of some toxins (urochromogens). 

• Puffy face, due to salt and water retention. 

• Pallor, due to anaemia. 

• Dry skin with urea frost (white spots due to deposition of urea present in 

high concentration in the sweat). Also the skin is fragile, thin and bruises 

easily. 

• Pruritis results from skin dryness or from irritation of the cutaneous sensory 

nerves by calcium deposits or by parathormone. 

• Purpura and skin infection. 

• Nails may be white with tips discoloured brown. 

V. Respiratory manifestations: 


• Kaussmaul's (acidotic or hissing) breathing 

• Exertional dyspnea, paroxysmal nocturnal dyspnea with heart failure. 

• Increased incidence of pulmonary infection. 

• Rarely, dry uraemic pleurisy. 

VI. Ocular manifestations: 


• Retinopathy.

• Uraemic amaurosis (rare): which is sudden transient loss of vision. 

• Red eye due to conjunctival congestion and calcium deposition. 

• Calcium may be deposited as plaques in the conjunctiva. 

VII. 

Musculo-Skeletal and soft tissue manifestations: 


a- Muscular : fatigue, and wasting (myopathy) which is mainly 

proximal in lower limbs (Waddling gait). It is due to retained uraemic 

toxins, electrolyte disturbances, vitamin D deficiency, 

hyperparathyroidism and nutritional deficiency. 

b- Skeletal : include bone aches, fractures, and deformity in childhood 

cases. Table (1) shows the radiologic bone changes in uraemic 

patients. 

Gout (uric acid deposition) and pseudogout (calcium deposition) 

cause joint pains. 

c- Soft tissue calcification which manifests according to the tissue 

involved e.g. pruritus when skin and sensory nerves are involved, red 

eye when conjunctiva is affected, arthritis when calcium deposition 

involves periarticular tissues, and finger tips gangrene when small 

arterioles are involved (Calcifelaxis). 

Table (1) Radiology of renal bone disease. 

Secondary hyperparathyroidism 

• Generalized decreased bone density. 

• Subperiosteal bone resorption (best in phalanges) 

• Radiolucent bone cysts (brown tumours) in humerus, neck of femur 

and pelvis. 

• Pepper-pot skull appearance 

• Erosion and lucency of the lateral end of clavicle. 

Osteomalacia 

• Generalized decrease in bone density 

• Pseudofractures or looser zones mostly in pubic rami. 

Rickets may also be seen 

• Widening and fraying of epiphyseal plates. 

• Bowing of long bones especially tibia and femur. 

• Slipping of epiphyses. 

Others 

• Tissue calcification, particularly in bursae. 

• Calcification of vessels especially in pelvis and hands 

• Roggers-Jersey spine

VIII. Gonadal disturbances: 

The following gonadal disorders are commonly seen in uraemic 

patients: 

• In males : decreased libido, impotence, gynecomastia, reduced 

spermatogenesis. 

• In females : decreased libido, infertility and menstrual dysfunctions. 

IX. Endocrinal disturbances: 

The following are the endocrine disorders which are common in 

uraemic patients: 

• Hyperparathyroidism • Lack in activation of vit. D. 

• Increased renin activity 

• Lack of erythropoietin 

• Decreased testosterone level resulting in a decreased libido, potency and 

spermatogenesis. 

• Increased prolactin and L.H. causing menstrual disorders, gynecomastia 

and infertility. 

• Insulin: there are two opposing effects of uraemia on insulin. The first effect 

is tissue resistance to insulin due to the uraemic milieu. The second is 

decreased renal tubular degradation of insulin with a consequent increase 

in the insulin half life. The upper hand is usually for the second effect with 

consequent fall in insulin requirement (insulin daily dose) in diabetic 

patients when they become uraemic. 

X. Features of the underlying disease may be present: 

As manifestations of D.M., SLE or renal stone disease. 

RENAL PATHOLOGY: 

1. Gross appearance: 

Usually the kidney is small in size with granular surface and adherent 

capsule. Sometimes the kidney is normal in size as in diabetic 

nephropathy and in amyloid nephropathy. In cases secondary to PCKD 

and hydronephrosis, the kidney size may be larger than normal. 

2. Microscopically: 

Light microscopy shows diffuse interstitial fibrosis, tubular atrophy and 

hyalinosis of most of the glomeruli (Fig. 7.4). The remaining viable 

glomeruli and tubules are dilated. Sometimes microscopic examination may 

show the etiologic cause as renal amyloidosis.

INVESTIGATIONS OF A CASE WITH CHRONIC RENAL FAILURE: 

1. Urine examination may show the following : 

• Polyuria especially nocturia and anuria in terminal cases. 

• Urine specific gravity is low and fixed to 1010 (osmolarity 300 mosm/l). 

• Urine aspect is pale and watery. 

• Albuminuria and granular casts. 

2. Blood Changes: 

There is an increase in blood urea, creatinine and uric acid levels, 

metabolic acidosis, normochromic normocytic anaemia, 

hyperkalaemia, and hyperphosphataemia. Serum calcium may be 

normal or low in early phases, but it becomes high in stage of tertiary 


3. Kidney Function Tests: 

Marked impairment of the renal functions (increase in s. creatinine and 

decrease in cr. clearance). Plasma creatinine is elevated once GFR is 

decreased to less than 60 ml/min. 

4. Fundus Examination: 

May show uraemic retinopathy. 

5. Investigations To Know The Cause Of Renal Failure : 

Such as Plain X-ray for urinary tract (stone), ultrasonography 

(obstruction), blood sugar (diabetes), and anti DNA (SLE). Renal 

biopsy is indicated in cases with average kidney size and unknown 

etiology of uraemia. 

MANAGEMENT OF CHRONIC RENAL FAILURE : 

(Fig. 7.4) 

PAS stained kidney section 

(X100) from a patient with end 

stage renal failure. It shows 

complete sclerosis of the 

glomeruli, extensive tubular 

atrophy and interstitial fibrosis. 

The following steps should be adopted for a proper management of 

patients with chronic renal failure.

Step 1. CONFIRMATION OF CHRONICITY OF THE KIDNEY DISEASE. 

This could be achieved through the following: 

a. History: A long history of renal disease suggests chronicity while 

absent previous history suggests acute renal failure. 

b. Kidney size as detected by ultrasonography: A small atrophic 

kidney favours the diagnosis of chronic renal failure, while a normal 

sized kidneys is more in favour of acute renal failure. 

There are some conditions of chronic renal failure in which kidney size 

is within normal, these are: 

• Diabetic nephropathy. 

• Renal amyloidosis 

• Infiltration (leukaemia, lymphoma, sarcoidosis) 

• PCKD 

• Obstructive uropathy 

• Bilateral staghorn stone. 

c. Magnitude of the increase in serum creatinine in relation to the 

presenting symptoms: High serum creatinine with minimal symptoms 

is in favour of chronic renal disease, while relatively low serum 

creatinine with severe symptoms is in favour of acute renal disease. 

d. Hyperphosphataemia and osteodystrophy are present more with 

chronic cases. 

e. Anaemia is more with chronic cases. 

f. Renal biopsy: extensive renal interstitial fibrosis and tubular atrophy 

in renal biopsy are features of chronic cases. 

Step 2. SEARCHING FOR REVERSIBLE FACTORS: 

These factors are classified as the following: 

a. Pre-renal factors such as: 

• Bilateral renal artery stenosis. 

• Severe cardiac failure. 

• Malignant hypertension. 

• Hypotension. 

• Dehydration and hypovolaemia. 

b. Renal causes factors such as: 

• Active glomerular disease 

• Active tubulo-interstitial disease 

• Pyelonephritis

c. Postrenal factors: 

Causing obstruction of urine flow from both kidneys such as: 

• Stone 

• Stricture ureters 

• Enlarged prostate 

• Bladder neck obstruction 

Step 3. CONSERVATIVE TREATMENT OF CHRONIC RENAL FAILURE: 

a. Dietary control: 

• Protein is usually restricted to 0.6-1 gm/kg/day (an amount which 

satisfies the physiologic requirements). If uraemic symptoms are 

marked, a further restriction of protein to 0.3 g/k/d may be adopted 

with addition of supplemental mixture of ketoacids, hydroxy acids 

and amino acids (10-21 g/d). 

Protein restriction will not only decrease the uraemic symptoms but 

also may help in slowing the progression of kidney scarring. 

• Fluid restriction equivalent to the patient's daily fluid loss. This 

equals: the sensible water loss (e.g. urine, vomitus and diarrhea) 

plus the Insensible water loss (respiratory and sweat) which is about 

600 ml/d in an adult of 70 kg. Extra 200 ml fluid should be added in 

febrile patient for every one degree centigrade increase in the body 

temperature. 

• Electrolytes: Sodium restriction with hypertension or oedema, and 

potassium restriction with severe oliguria and with hyperkalaemia 

• Calories: Patient should receive about 35 K. calories/kg/day with 

carbohydrate 60% of non protein calories and fat 40%. The 

polyunsaturated to saturated fat should be 1 : 1. Total fibers should 

be 20-25 gm/d. 

b. Treatment of Bone disease: 

• Phosphate Binders such as aluminium hydroxide, magnesium oxide 

and calcium carbonate or acetate which combine with phosphorus in 

the gut and are excreted with the stool. Calcium containing 

compounds are better than aluminium and magnesium salts which 

could be dangerous on long term use. Calcium carbonate or acetate 

may be given orally t.d.s. with meals in a dose of 500-1000 mg 

orally. 

• Active vitamin D "1-OH vitamin D" which is given orally in a daily dose 

of 0.25-1.0 ug. Recently I.V. 1-0H vitamin D (one-alpha) is

ecommended for better suppression of the hyperparathyroidism. 

This is given in a dose of 0.5-2.0 ug twice or thrice weekly. 

• Acidosis is corrected by oral Na bicarbonate supplementation. 

•Parathyroidectomy may be done for cases with tertiary hyperparathyroidism. 

Three glands and part of the fourth are removed and the 

remaining is implanted subcutaneously. 

c. Anaemia: 

Is responsible for major part of uraemic symptoms. The first line of 

treatment is by giving proper nutrition, iron, folic acid, and vitamins 

especially B12. Failure to respond may indicate repeated blood 

transfusion or treatment with recombinant human Erythropoietin. Blood 

transfusion carries the advantage of being cheap but have the 

disadvantage of transmitting diseases (especially HIV, HBV and HCV) 

beside other risks of blood transfusion. Erythropoietin (EPO) is given 

S.C. 4000u three times weekly, it carries the advantage of being safe 

and effective, but it is very expensive. The dose of EPO has to be 

readjusted to maintain haemoglobin value of 9-11 gm/dl. If the patient 

can't afford for EPO, blood transfusion is preferably given only for 

symptomatic anaemia. 

d. Symptomatic treatment of: 

• Hypertension is controlled by hypotensive drugs. In cases of volume 

dependent hypertension the main line of treatment is salt and water 

restriction and diuretics. In cases of renin dependent hypertension, 

anti-renin such as β-Blockers or ACE inhibitors are used. 

• Itching is treated by skin soothing creams, anti-histaminics, treatment 

of hyperphosphataemia, hyper and hypocalcaemia. For severe, 

intractable cases, parathyroidectomy may be of help. Sometimes 

pruritus could be controlled by giving xylocain 70 mg in 100 c.c. 

saline via I.V. infusion over 20 min. at the end of each dialysis 

session. 

• G.I.T. manifestations as vomiting could be controlled by antacids and 

H2-receptors blockers. 

Failure of conservative treatment to provide the patient with a 

reasonable quality of life is an indication for renal replacement therapy, i.e. 

dialysis or renal transplantation.

Step 4. RENAL REPLACEMENT THERAPY (RRT): 

This includes dialysis (haemodialysis and peritoneal dialysis) and renal 

transplantation. Early induction of RRT and good nutritional support provide 

better response to the treatment (less patient morbidity and mortality). 

Indications for RRT: 

• Failure of conservative treatment with progressive deterioration in patient's 

general condition and blood chemistry. 

• Persistent nausea and vomiting. 

• Circulatory overload which is unresponsive to loop diuretics (e.g. frusemide) 

• Severe motor neuropathy. 

• Uraemic encephalopathy. 

• Pericarditis 

• Osteodystrophies 

• Bleeding diathesis. 

• Hypertension unresponsive to treatment. 

• Hyperkalaemia (serum K + level > 7 mEq./litre). 

• High creatinine levels and decreased creatinine clearance (Cr. clearance < 

10ml/min). 

Contraindications for dialysis treatment. 

1. Absolute: 

• Patient's decision (i.e. refusing dialysis). 

• Severe extrarenal illness e.g. severe cardiac disease, end stage liver 

disease, severe cerebrovascular disease and advanced malignancy. 

2. Relative: 

• Severe disability or handicapping. 

• Paraplegia or hemiplegia

DIALYSIS THERAPY 

Definition: 

Dialysis is a process in which the solute composition of blood is altered 

by exposing it to a physiological solution (dialysate) across a semipermeable 

membrane (dialysis membrane). Solutes will move from one compartment to 

another through the dialysis membrane. 

Principles of Dialysis: 

Solutes that can pass from blood through the pores of the dialysis 

membrane are transported by two different mechanisms: diffusion and 

ultrafiltration. 

1. Diffusion: 

Is the passage of solutes through the semipermeable membrane 

independent of water movement. 

Factors affecting solute diffusion include: 

(A) Concentration gradient: 

The net rate of transfer of a given solute from blood to dialysate is the 

greatest when the concentration gradient for that particular solute is the 

highest. 

(B) Molecular weight and size: 

The larger the M.Wt. of a solute, the slower its rate of transport will be 

across the semipermeable membrane. 

(C) Membrane resistance: 

Membrane resistance owing to the membrane itself: 

The resistance of a membrane to solute transport will be high if the 

membrane is thick; if the number of pores is small and if the pores are 

narrow. 

Membrane resistance due to "unstirred" fluid layers: 

Unstirred layers of fluid inhibit diffusion because they act to decrease 

the effective concentration gradient at the membrane surface. 

2. Ultrafiltration: 

The second mechanism of solute transport across semipermeable 

membrane is ultrafiltration (i.e. convective transport). 

Water molecules are extremely small and can pass through all 

semipermeable membranes. Ultrafiltration occurs when water deriven by 

either a hydrostatic or osmotic force is pushed through the membrane. Those

solutes that can pass easily through the membrane pores are swept along 

with the water (a process called solvent drag). 

Types of ultrafiltration: 

Osmotic ultrafiltration: 

This depends on the osmotic pressure of the dialysate. The higher the 

osmotic pressure the more the ultrafiltration. 

Hydrostatic ultrafiltration: 

This depends on the transmembrane pressure; i.e, the higher the 

transmembrane pressure the more the ultrafiltration. The semipermeable 

membrane is not permeable to cells or plasma proteins. 

Types of Dialysis 

There are two forms of dialysis therapy: (a) Haemodialysis, and 

(B) Peritoneal dialysis 

(A) Haemodialysis 

Definition: 

It is the movement of solutes and water from the patient's blood across 

a semipermeable membrane which is the dialyzer. 

This is carried out via vascular access where the blood is pumped by a 

haemodialysis machine into the dialyzer then the blood returns back filtered 

to the patients circulation (Fig. 7.5). 

(Fig. 7.5) 

The extracorporeal blood circuit 

showing the usual location of 

the different dialysis monitors


(I) Common complications: 

(A) Hypotension: This is the commonest complication and may be due to: 

1- Causes related to excessive decrease in blood volume:- 

- Fluctuation in the ultrafiltration rate 

- High ultrafiltration rate 

- Target dry body weight set is too low 

- Dialysis solution sodium level is too low 

2- Causes related to lack of vasoconstriction: 

- Acetate-containing dialysis solution 

- Dialysis solution is too warm 

- Food ingestion (splanchnic vasodilatation) 

- Tissue ischaemia 

- Autonomic neuropathy (e.g. diabetic patients) 

- Antihypertensive medications given at the day of dialysis. 

3- Causes related to cardiac factors: 

- Diastolic dysfunction may be due to 

• Left ventricular hypertrophy • Ischaemic heart disease 

• Other conditions 

- Failure to increase cardiac rate which may be due to: 

• intake of beta blockers • uraemic autonomic neuropathy 

• Aging 

- Inability to increase cardiac output for other reasons such as poor 

myocardial contractility because of age, hypertension or atherosclerosis. 

4- Uncommon causes: 

- Pericardial tamponade - Myocardial infarction 

- Occult haemorrhage - Septicaemia 

- Arrhythmia - Dialyzer reaction 

- Haemolysis - Air embolism 

(B) Muscle Cramps: 

The pathogenesis during dialysis is unknown, but the three most 

important predisposing factors are: 

(1) hypotension 

(2) patient below dry body weight 

(3) use of low sodium dialysis solution.

(C) Nausea and Vomiting: 

The aetiology is multifactorial, however, most episodes in stable 

patients are probably related to hypotension. They may be also an early 

manifestation of the so called disequilibrium syndrome. 

(D) Headache: 

May be related to the use of acetate containing dialysis solution, 

disequilibrium syndrome. Also it may occur in heavy coffee drinkers as it may 

be a manifestation of caffeine withdrawal. 

(E) Chest pain and back pain: 

May be due to complement activation; thus, there is no management 

or prevention strategy other than switching to synthetic or substituted 

cellulose dialysis membrane. 

(F) Itching: 

It is a common complaint in dialysis patients which may be due to: 

- Allergy to • Ethylene Oxide (ETO), used for sterilization of the 

dialysis membrane. 

• heparin 

• plasticizers 

- elevated calcium-phosphate product, 

- uraemic toxins, and 

- Dry skin 

It can be managed by topical emollients, antihistaminics, phosphate 

binders and the switch from ETO to gamma ray sterilized dialyzers. 

(G) Fever and chills 

May be due to a pyrogenic reaction or true sepsis transmitted to the 

patient during the dialysis session. 

(II) Less Common Complications: 

Although they are less common, they are serious complications. They 

include: 

(A) Disequilibrium Syndrome: 

Definition: 

Disequilibrium syndrome is a set of systemic and neurologic 

symptoms which are often associated with characteristic EEG findings 

that can occur either during or soon after dialysis.

Early manifestations include headache, nausea, vomiting, convulsions 

and may be coma. In severe cases, death can occur if not treated 

properly. 

Etiology: 

The etiology is controversial but many believe that it is due to brain 

odema due to aggressive and rapid dialysis. 

Treatment: 

• Prevention is better, this could be achieved by making the few initial 

dialysis sessions short and smooth (gradually increasing dialysis 

hours and blood flow rate). 

• Treatment of an established case is by stopping dialysis and giving 

symptomatic treatment, including brain dehydrating drugs as 

dexamethazon. 

(B) Dialyzer reactions: 

Type A (anaphylactic type): 

The manifestations of this type may be mild in the form of itching, 

cough, urticaria, sneezing, coryza or watery eyes; or may be severe in the 

form of dyspnea, chest tightness, cardiac arrest or even death. 

Etiology: 

• ETO sterilization 

• ACE inhibitors used at the same time with AN 69 type of 

dialyzer due to liberation of bradykinin. 

• Contaminated dialysate: this can be managed by more 

frequent cleaning and sterilization of dialysis machines 

between sessions, thus reducing the dialysis solution 

bacterial counts. 

Treatment: 

• Stop dialysis immediately 

• Antihistaminics 

• Steroids 

Type B (Non specific type): 

The patients may complain of back pain or chest pain. 

Etiology: 

Complement activation 

Treatment: 

No specific treatment

(C) Arrhythmia: 

Arrhythmias during dialysis are especially common in patients 

receiving digitalis 

(D) Cardiac tamponade: 

Unexpected or recurrent hypotension during dialysis may be a sign of 

pericardial effusion or impending tamponade. 

(E) Intracranial bleeding: 

Underlying vascular disease and hypertension combined with heparin 

administration can sometimes result in intracarnial bleeding. 

(F) Seizures: This occur more often in children 

(G) Haemolysis: 

Acute haemolysis during dialysis may be a medical emergency 

(H) Air embolism: 

It is a potential catastrophe that can lead to death if not quickly 

detected and treated. 

(B) Peritoneal Dialysis 

Definition: It is the movement of solutes and water from patient's blood 

across a semipermeable membrane (which is the peritoneal membrane) to 

the dialysis solution (dialysate). 

This is carried out via peritoneal catheter which is inserted into the 

peritoneal cavity by infusion of the dialysate which is left to dwell then; drain 

out via the catheter (Fig. 7.6). 

(Fig. 7.6) 

Basic continuous ambulatory 

peritoneal dialysis system, with 

catheter, and dialysis solution 

container. On the right, inflow 

and outflow are depicted.

Types:- 

(1) CAPD (Continuous Ambulatory Peritoneal Dialysis): 

In which the dialysate is always present in the peritoneal cavity and is 

exchanged every 4-6 hours/day. This is the commonly used form of P.D 

worldwide . 

(2) CCPD (Continuous Cyclic Peritoneal Dialysis): 

In which the dialysate is exchanged at bed time via a cycler (P.D. 

machine) 3-4 times and the last exchange fluid is left in the abdomen during 

the daytime. 

(3) NIPD (Nocturnal Intermittent Peritoneal Dialysis): 

In which the dialysate is exchanged at bed time via a cycler 5-8 

times/day and the abdomen is left dry the rest of the day. 

This is the new trend nowadays, but it is limited because of the high 

cost of the cycler. 

(4) TPD (Tidal Peritoneal Dialysis): 

This is still an experimental form of NIPD which was designed to 

optimize solute clearance by leaving large volume of dialysate in the 

peritoneal cavity throughout the dialysis session. Three litres of fluid are 

introduced first time, then every time two litres are exchanged leaving always 

3 litres in the abdomen. 

Indications for PD: 

Because it provides the best rehabilitation potential as it is safe and 

easy, it is used for all ages and all sizes of patients with end stage renal 

failure. 

Specific indications for peritoneal dialysis include the following: 

1- Infant and very young children 

2- End stage renal failure patients with cardiovascular or haemodynamic 

instability. 

3- Haemodialysis patients with vascular access failure (especially diabetics) 

4- Patients for whom vascular access can not be created (especially 

diabetics) 

5- High risk of anticoagulants 

6- Patients who desire greater freedom to travel 

Contraindications: 

Absolute: 1- Extensive peritoneal fibrosis 

2- Pleuroperitoneal leak 

Relative: 1- The same as those in haemodialysis 

2- Presence of colostomy or nephrostomy

3- Recent thoracic or abdominal surgery 

4- Inguinal or abdominal hernia 

5- Blindness 

6 - Mental retardation 

7- Poor motivation and compliance 

Advantages:- 

• Ease of performance 

• High safety margin 

• Portability 

• Fewer dialysis-related symptoms 

• No routine anticoagulation 

• Better control of PTH levels 

• More liberal diet 

• Fewer medications 

• No viral transmission 

• Used safely in haemodialysis unstable patients and those with 

difficult vascular access 

Disadvantages: 

• Low efficiency 

• Body image problem because of the catheter 

• Potential protein loss 

• Potential infection 

• Hypertriglyceridaemia 


Mechanical: 

• Pain during inflow owing to hot dialysate or rapid jetting 

• Pain during outflow due to ball-valve effect 

• Outflow failure due to constipation, obstruction or malposition of 

the catheter 

• Pericatheter leakage because of very early usage of the catheter 

• Scrotal odema 

• Intestinal perforation 

• Cuff catheter erosion 


• Fluid overload 

• Hypertension 

• Hypotension 

• Dysrhythmias

Pulmonary: 

Neurologic 

Metabolic: 

Infectious and inflammatory 

• Atelectasis 

• Hydrothorax 

• Restricted chest movement 

• Seizures and disequilibrium syndrome which are rare in 

comparison to hemodialysis 

• Hyperglycaemia 

• Hyperlipidaemia 

• Hyper or hypokalaemia 

• Hyper or hyponatraemia 

• Metabolic alkalosis 

• Protein depletion 

• Obesity 

• Peritonitis • Exit site infection • Tunnel infection 

Peritonitis: 

The incidence of peritonitis among PD patients is one episode every 

12-18 months/patient. 

Diagnosis: 

• cloudy outflow 

• Fever 

• Abdominal pain and bowel symptoms (e.g. cramps, diarrhea or 

constipation) 

• Peritoneal fluid WBCs >100 ml with > 50% 

polymorphonuclear leucocytes. 

Etiology: 

• Gram +ve organisms account for 65-75% 

• Gram -ve organisms account for 25-30% 

Treatment: 

Aggressive antibiotic therapy from the start which has to be continued 

according to culture and sensitivity. 

Tunnel infection: 

• This manifests as swelling, tenderness, redness & hotness 

• This is a dangerous form of infection, if persist inspite of proper 

antibiotics, the catheter should be removed.

KIDNEY TRANSPLANTATION 

Definition: 

Kidney transplantation means the treatment of chronic renal failure by 

surgical implantation of a kidney that is obtained from either healthy kidney 

donor or brain stem dead cadaver. 

Principle: 

- Kidney transplantation is performed by doing a unilateral nephrectomy for 

the donor to be implanted into the patient with end stage renal disease 

"The recipient". 

- The new kidney is placed in the patient's abdomen, usually in the right iliac 

fossa. The artery and vein are anastomosed to patient's vessels (usually 

internal iliac) and the ureter is implanted into the bladder (Fig. 7.7). 

Fig. (7.7) 

Kidney transplant in recipient's right iliac fossa with native kidney left in place.

- The native kidneys are left in place, unless there is an indication to be 

removed e.g. uncontrollable hypertension, infection or if they are hugely 

enlarged. 

- The immune system of the recipient considers the transplanted kidney as a 

foreign body and tries to destruct it. This is called "rejection" which can be 

prevented by: 

• Pre operative immunological investigations to be sure that tissue 

typing of the recipient and the donor is identical or similar and via. 

• Post operative suppression of the recipient's immune system by 

immunosuppression therapy. 

Indications: 

Patients with end stage renal failure requiring renal replacement 

therapy. 

Contraindications: 

1- Patient refusal 

2- Psychosis 

3- Age more than 60 years (relative) 

4- Recurrent disease, if the original kidney disease that caused renal failure 

can recur in the transplanted kidney and destroy it e.g. oxalosis. 

5- Systemic disease: Some co-existing systemic diseases may contraindicate 

transplantation because of their effect on the patient's survival or because 

of the danger of post transplant immunosuppression therapy. These include 

the following: 

• Severe respiratory disease e.g. C.O.P.D. 

• Severe cardiovascular disease e.g. severe left ventricular failure 

• Severe hepatic disease e.g. liver cirrhosis 

• Central nervous system e.g. cerebral hemorrhage 

• Active peptic ulceration 

• Malignancy 

• Active infection 

6- Unrepairable urologic abnormalities. 

Types of kidney donors: 

1- Living donors: 

a. Blood related donors: one of the relatives of the recipient 

b. Unrelated donors: ethically, the emotionally motivated donors 

such as patient's partner rather than the commercially 

motivated donors should be accepted as kidney donor.

2- Cadaveric donors: 

These are persons with brain stem death but still with 

functioning cardiovascular and respiratory system. Cadavers are 

optimal kidney donors. 

Immunological assessment of donor and recipient before 

transplantation: 

In order to prevent or minimize rejections after kidney transplantation, 

a number of immunological tests are done for both donor and recipient to be 

sure that they have identical tissue typing or at least with satisfactory 

similarity. These tests are: 

1- ABO blood grouping: 

Follows the same rules for blood transfusion 

2- Cross matching: 

- donor's leucocytes are mixed with recipient's serum. 

- The test is considered -ve and donor is suitable if none of donor's 

leucocytes was destroyed 

3- HLA typing: 

- The HLA system is a group of antigens present on the surface of all 

nucleated cells in the body. 

- This system is responsible for recognition of immune system to "self 

cells" and "foreign cells". 

- It is the major determining factor for graft rejection 

- The more similar the HLA system of recipient and donor, the less the 

incidence of post transplant rejection. 

Contraindications for donation: 

a- living donors: 

1- Donor refusal 

2- Psychosis 

3- Age below 21 and above 60 years 

4- Renal disease 

5- Family history of hereditary renal disease (e.g. polycystic 

kidney disease) 

6- Associated medical diseases: 

• Cardiovascular: (e.g. heart failure, hypertension) 

• Respiratory: (e.g. COPD) 

• Hepatic: (e.g. liver cirrhosis, hepatitis) 

• C.N.S.

• Metabolic (e.g. diabetes mellitus) 

• Malignancy 

• Infections 

b- Cadaveric donors: 

1- Absence of consent before death 

2- Age less than 3 or more than 70 years 

3- Renal disease 

4- Associated medical diseases: (vide supra) 

Immunosuppression after transplantation: 

- Definition: Immunosuppression therapy is used after kidney transplantation in 

order to modify the recipients immune system so that rejection is 

prevented. 

- Duration: Immunosuppression therapy continues for life. 

- Mode of action: 

• Immunosuppression can be achieved by different drugs. 

• Each drug has a different mechanism by which it can depress 

leukocytes which are responsible for the immune response. 

- Regimens: 

• Many regimens are present 

• Steroids are the corner stone drug used 

• Triple regimen (steroids-azathioprine-cyclosporine) is the 

commonest regimen 

• Other new drugs: (FK-506, Mycophenolate and Rapamycin). 

• Polyclonal antibodies as ATG and ALG 

• Monoclonal antibodies as OKT3 

• Cymeric and humanized antibodies as simulect (Novartis) and 

zenapax (Roche). 

Complications after kidney transplantation: 

1- Rejections: 

• Hyperacute: usually occurs Immediately postoperative. 

• Acute: Usually occurs days or weeks to months postoperatively 

• Chronic: Usually occurs months to years postoperatively. 

2- Complications of immunosuppression therapy: 

a. General complications: 

1. Infection 

2. Increased incidence of malignancy

. Complications due to individual drugs: 

1. Steroids: hypertension, D.M., atherosclerosis, Bone disease, 

GIT bleeding and cataract. 

2. Azathioprine: Bone marrow depression and hepatic dysfunction 

3- Cyclosporine: Nephrotoxicity, hepatotoxicity, hypertension and 

D.M. 

3- Recurrence of the original kidney disease into the graft (e.g. FSGS, 

MPGN) 

Outcome after transplantation: 

- The outcome of kidney transplantation is continuously improving with the 

advances in the immunosuppressive drugs and the immunologic 

assessment of donors and recipients, technique of surgery and the 

postoperative care. 

- Emergence of cyclosporine as a new immunosuppressive drug in 1980s has 

much improved the graft survival by preventing rejection which is the 

commonest cause of graft loss. 

- The current 1 year graft survival is about 90-95% and 5 years graft survival 

is about 60-70%. 

- Continuous advancement in immunosuppressive drugs is aims at ideal drug 

with maximal ability to prevent rejection and minimal side effects. 

Transplantation versus dialysis: 

Advantages of transplantation over dialysis: 

1- Better quality of life: 

a. Independence from machine 

b. Correction of manifestations of chronic renal failure that are not corrected 

properly by dialysis such as anemia, bone disease, growth retardation 

in children, fertility and child bearing in adults. 

c. More ability to work. 

2- Avoidance of diseases that may be transmitted through dialysis such as 

HIV and hepatitis. 

3- Less cost than dialysis 

Disadvantages of transplantation: 

1- Complications of immunosuppression 

2- The possibility of graft loss 

3- The need for kidney donors


- Bohle A, et al: Pathogenesis of chronic renal failure in the primary 

glomerulopathies, renal vasculopathies, and chronic interstitial 

nephritides. Kidney Int Suppl, 54 : S2-9, 1996. 

- Valderrábano F: Erythropoeitin in chronic renal failure. Kidney Int, 50 : 

4, 1373-91, 1996. 

- Steinman TI: Kidney protection: how to prevent or delay chronic renal 

failure. Geriatrics, 51 : 28-35, 1996. 

- Friedman AL: Etiology, pathiphysiology, diagnosis and management of 

chronic renal failure in children. Curr Opin Pediatr, 8 : 2, 148-51, 1996. 

- Scarpioni L, et al: Peritoneal dialysis in diabetics. Optimal insulin therapy 

on CAPD: intraperitoneal versus subcutaneous treatment. Perit Dial Int, 

16 Suppl 1 : S275-8, 1996. 

- Lee HB, et al: Dialysis in patients with diabetic nephropathy: CAPD 

versus hemodialysis. Perit Dial Int, 16 Suppl 1 : S269-74, 1996. 

- Brunkhorst R: Kidney transplantation. Indications, results, pre-and 

postoperative care. Internist Berl, 37 : 3, 264-71, 1996. 

- Thony F, et al: Detection of renal artery stenoses by MRI with surface 

reconstruction. Value in patients with chronic renal failure. J Radiol, 78 : 

9, 643-9, 1997. 

- Novikov AI: Methods of correcting hyperphosphatemia in chronic renal 

failure and in dialysis (review): Ter Arkh, 69 : 12, 63-7, 1997. 

- Simpson IL, et al: Management of guidelines for progressive chronic 

renal failure. New Zealand Nephrologists Consensus Group. N Z Med J, 

110 : 1055, 421-3, 1997.

- Ter Wee PM, et al: Dietary protein restriction for retardation of 

progression of chronic renal failure: yes or no (editoria). Int J Artif 

Organs, 20 : 6, 304-8, 1997. 

- Grzegorezewska A, et al: Some factors affecting longevity and quality of 

life in patients treated with continuous ambulatory peritoneal dialysis 

(CAPD). Pol Arch Med Wewn, 97 : 4, 364-70, 1997. 

- Betkowska Prokop A: Non-infectious complications during treatment 

with continuous peritoneal dialysis (CAPD). Przegl Lek, 54 : 2, 115-21, 

1997. 

- Takashi K: Kidney transplantation in long-term hemodialysis patients. 

Nippon Hinyokika Gakkai Zasshi, 88 : 11, 905-8, 1997. 

- Salmela K, et al: Kidney transplantation. Ann Chir Gynaecol, 86 : 2, 49- 

100, 1997. 

- Leumann E: Kidney transplantation in the child. Schweiz Med 

Wochenschr, 127 : 24, 1039-43, 1997. 

- Obrador GT, et al: Early referral to the nephrologist and timely initiation 

of renal replacement therapy: a paradigm shift in the management of 

patients with chronic renal failure. Am J Kidney Dis, 31 : 3, 398-417, 

1998. 

- Warady B, et al: Current advances in the therapy of chronic renal failure 

and end stage renal disease. Semin Nephrol, 18 : 341-54, 1998.

Renal Tubular Disorders 

These are group of disorders due to primary tubular diseases i.e. the 

disease starts in the renal tubules then secondarily affects the glomerular and 

the overall kidney function. This is to be differentiated from other tubular 

disorders which are secondary to glomerular diseases. 

Usually renal tubular disorders are genetically determined or due to certain 

drugs. 

Specific Isolated Defects Of Tubular Transport 

A) Carbohydrate tubular transport defect 

Glycosuria 

Normally glucose does not appear in the urine until plasma 

concentration reaches up to 180 mg/dl (10 mmol/L). This is called renal 

threshold. Maximum glucose excretion is reached at plasma concentration of 

270 mg/dl (15 mmol/L). This is called (tubular maximum or Tm). 

Renal glucosuria means the detection of glucose in urine while plasma 

glucose is less than 180 mg/dl (i.e. decreased renal threshold). There are two 

types of renal glycosuria, type A in which both renal threshold and Tm are 

reduced; and type B in which renal threshold is decreased but Tm is not. 

Genetics: It is transmitted as autosomal recessive, few families have 

been reported with autosomal dominant inheritance. 

Clinical features: These are persistent throughout the life with no 

symptoms unless starvation occurs, the patients will suffer from severe 

hypoglycemia, hypovolaemia and ketosis. 

Diagnosis: By detection of glycosuria while plasma glucose is less than 

135 mg/dl (7.3 mmol/L). 

Differential diagnosis: Renal glycosuria should be differentiated from: 

(1) Diabetes mellitus (by glucose tolerance curve); (2) Fanconi's 

syndrome (multiple tubular defects not isolated glycosuria); (3) Glucose- 

Galactose malabsorption (combined renal and jejunal defect); (4) Glucoglycinuria; 

and (5) phosphate diabetes. 

Treatment: No treatment is required.

B) Amino acids tubular transport defects 

1. Hartnup's Disease 

The basic defect is an abnormality in renal tubular and intestinal 

transport of free neutral (monoamine and monocarboxylic) amino acids. 

Oligopeptides containing these aminoacids especially tryptophan are not 

handled normally. 

The decreased reabsorption in the gut results in the increased 

breakdown by bacteria which in turn leads to increased amount of indoles and 

indican in both stool and urine. 

Tryptophan is needed for at least half of the normal daily requirement of 

nicotinamide so that non-absorption causes niacin deficiency. Also indoles 

may inhibit nicotinamide synthesis; thus creating a vicious cycle. 

The abnormality can affect all amino acids in the group or only in 

individual members. 


1. Aminoaciduria is a constant feature. Normally, total urinary amino 

nitrogen is less than 50 mg/d. In Hartnup's disease, it is about 500 mg/d. 

2. Pellagra-like skin rash which is scaly on the exposed surfaces, sensitive 

to sunlight and can lead to blister formation. 

3. Cerebral ataxia and nystagmus without sensory loss which gets worse 

when skin rash is worse. 

4. "Blue Diaper" syndrome in infant, the abnormality affects only tryptophan 

handling leading to excess indigo dye excretion (blue colour). 

Treatment: 

1. Nicotinamide 40-200 mg/d. 

2. High protein diet. 

3. Sunlight should be avoided and monoamine oxidase inhibitors are 

contraindicated. 

2. Cystinuria 

Is a disease characterized by abnormal transport of amino acids 

cystine, ornithine, arginine and lysine (COAL) by the intestinal mucosa and 

renal tubules. This will result in formation of cystine crystals and renal stones . 


1. The disease is more severe in males. It is a stone disease with 

recurrent urinary tract infection which may be complicated by chronic 

renal failure, usually manifests in the first to fourth decade of life.

2. In affected homozygot, they excrete more than 250 mg cystine/mg 

creatinine in urine. 

Treatment: 

1. To increase the solubility of cystine by increasing urine output to 2-4 L/d 

by increasing fluid intake and by alkalinizing the urine to pH 7.5-8 by 

sodium bicarbonate (check with pH indicator paper). 

2. To decrease the urinary cystine excretion by d-Penicillamine. 

Penicillamine could be toxic (anaemia, loss of taste, fever, rash, 

haematuria, nephrotic syndrome and agranulocytosis). 

Tiopronin is an alternative to d-Penicillamine with the same effect but 

with less frequent toxicity. 

C) Renal Tubular Acidosis (RTA) 

Is a systemic metabolic acidosis resulting from specific tubular 

abnormality in handling of H + . Usually the patient presents with metabolic 

acidosis out of proportion to the renal functional impairment. There are four 

types of RTA; distal (classic, type I), proximal (type II), type III (distal with 

bicarbonate wastage), and type IV (hyperkalaemic, hyporeninaemic, 

hypoaldos- teronaemic). 

Distal (classic) RTA 

The normal daily production of hydrogen ions (H + ) is approximately 

1mmol/kg/d in adults and 3 mmol/kg/d in children. This H + load is excreted by 

the kidney, through distal nephron. Failure to secrete this hydrogen load will 

result in metabolic acidosis. Normally, there is a pump mechanism in the distal 

convoluted tubules pushing H + to the lumen (urine). In distal RTA, there is a 

reduced pump activity or there is back diffusion of H + (from lumen to tubular 

cells and systemic circulation) resulting in systemic acidosis. 

Normally, with systemic accumulation of hydrogen ions the kidney will 

secrete these H + to the urine which will be acidified to a urine pH of 5.2 or 

less. In distal RTA, this is not possible and urine pH is always above 5.7 even 

with severe metabolic acidosis. 

Ammonia and titratable acid excretion in urine depends on urinary pH 

(needs acidic urine). So, their urinary excretion in RTA is reduced and is 

retained in the body. 

Serum Bicarbonate (HCO 3 ) is used as a buffer for the retained H + 

(HCO 3 +H + ---> H 2 CO 3 ----> H 2 O + CO 2 ) , so its blood level will be low in 

metabolic acidosis. As the proximal convoluted tubular function is intact in

distal RTA, more HCO 3 and chloride (CL − ) will be reabsorped from its lumen. 

Reabsorped HCO 3 will be used for buffering more H + . 

In incomplete RTA urine pH can usually be lowered to 5.7, at which 

level sufficient titratable acids and ammonium ion excretion can be generated 

to balance endogenous acid generation and the patient will not be acidotic. 

But if the acid generation increases (high protein diet or hypercatabolic state 

or if the incomplete RTA occurred on top of other renal injury) the kidney will 

not be able to excrete this load and the patient becomes acidotic. 

Etiology: 

1. Primary 

• idiopathic 

• genetic (autosomal dominant) 

2. Complicating a genetically transmitted systemic 

disease 

• Ehlers-Danlos syndrome • Hereditary elliptocytosis 

• Medullary cystic disease 

3. Autoimmune disease 

• SLE 

• Sjogren's Syndrome 

• Hypergammaglobulinaemia • Chronic active hepatitis 

4. Nephrocalcinosis 

• Medullary sponge kidney 

• Vitamin D intoxication 

• Hypophosphatasia 

5. Tubulo-interstitial disease 

• Chronic pyelonephritis 

• Obstructive uropathy 

6. Drugs and toxins 

• Analgesics 

• Lithium 

• Primary hyperparathyroidism 

• Idiopathic hypercalcuria 

• Acute tubular necrosis 

• Renal transplant glomerulopathy 

• Amphotericin B 

• Toluene 

7. Uretero-sigmoidostomy 


1. Male to female ratio is always 1 : 1. Primary RTA usually manifests 

clinically between the first and the third decade of life (Fig. 8.1).

X-ray showing nephrocalcinosis in patient with RTA. 

Kidney section from a patient with RTA showing nephrocalcinosis. There are massive calcium deposits 

in tubular BM. A wide mucoid layer has developed between tubular BM and epithelium. PAS (X90). 

(Fig. 8.1) 

Clinical Features of Renal Tubular Acidosis

2. Hypokalemia due to defective handling of K + in distal nephron this will 

manifest as muscle weakness even paralysis and may be complicated 

by rhabdomyolysis, respiratory arrest or cardiac arrhythmia. Prolonged 

hypokalaemia may lead to renal concentration defect which will 

manifest as polyuria and nocturia. 

3. Nephrocalcinosis and stone disease that is due to the decreased 

solubility of calcium salts (oxalate, carbonate or phosphate) due to 

persistently alkaline urine and reduced urinary citrate, Mg and 

hypercalcuria (in 50% of congenital and hereditary RTA). 

This will result in obstructive uropathy, infection and finally renal failure. 

4. Osteomalacia with bone pains and fractures. It is due to acidosis and 

use of bone as buffer with release of calcium carbonate from bone, also 

hypophosphataemia causing hyperparathyroidism and suppression of 

activation of vitamin D and hypocalcaemia. 

5. Severe acidaemia will cause tachypnea, dizziness and even coma. 

6. Severe acidaemia may decrease extracellular fluid volume and GFR. 

7. Incomplete RTA will manifest only as nephrocalcinosis or as a stone 

disease. 

Diagnosis: 

1. Suspect distal RTA in patient with metabolic acidosis with 

hyperchloraemia and hypokalemia. 

Urine pH less than 5.2 in the early morning urine or during systemic 

acidosis or with acid load (by giving ammonium chloride 0.1 g/kg orally) 

excludes RTA and the reverse is true. 

2. In distal RTA urine pH will be > 5.7 in the morning urine sample, also in 

presence of systemic acidosis. In normal subjects, in these two 

situations urine pH should be 5.2 or less. 

3. If systemic pH is not low, acidosis could be induced by giving 

ammonium chloride capsules 0.1g/kg orally and we look for urine pH. 

Treatment: 

Except in drug induced cases of RTA, the disease is always persistent 

and needs permanent treatment. 

1. First treat hypokalaemia and hypocalcaemia. 

2. Then give sodium bicarbonate to correct acidosis.

After correction of acidosis no need to given potassium 

supplementation. 

3. In incomplete RTA, give ethacrinic-acid (to reduce urine pH) 50-100 mg 

three times per week, no need to give sodium bicarbonate. 

4. Treatment of infection or obstruction if present. 

Proximal RTA 

Normally all the filtered bicarbonate is reabsorped unless the 

concentration of bicarbonate in the glomerular filtrate is above the HCO3Tmax 

which is 25 mmol/L. 80% of reabsorption of HCO 3 occurs in the proximal 

tubules through H + pump. In Proximal RTA, there is a degree of weakness in 

H + pump resulting in a decrease in its HCO 3 reabsorption capacity and a new 

steady state is settled in which Tmax of HCO 3 is decreased (e.g. to 10 mmol/L 

or 14 mmol/L). All HCO 3 filtered above this level will be lost in urine 

(bicarbonaturia) and blood level of HCO 3 will be decreased. 

The HCO 3 reaching the distal nephron will turn the urine alkaline. This 

will interfere with ammonium ion and titratable acids excretion and consequent 

retention of H + in the body. 

In this phase, the condition is characterized by metabolic acidosis, 

hyperchloraemia (excess reabsorption of CL - by PCT on expense of HCO 3 ), 

alkaline urine, decrease titratable acids and ammonium ion excretion. 

When a new steady state is reached (new Tmax) all the filtered HCO 3 

will be reabsorped. The condition is characterized by metabolic acidosis, low 

plasma HCO 3 , hyperchloraemia, normal acidic urine (less than 5.2), no 

bicarbonaturia and normal excretion of ammonium ions and titratable acids. 

Etiology: 

PRTA is more rare than distal RTA. The list of causes of PRTA 

includes: 

1. Primary single tubular defect 

• Genetic (very rare) 

• Idiopathic 

• Transient in infants 

2. Multiple tubular defect 

• Genetic 

• idiopathic 

3. Genetically transmitted systemic disease. 

• Cystinosis 

• Wilson's disease 

• Fructose intolerance

4. Autoimmune disease 


5. Tubulo-interstitial disease 

• Medullary cystic disease 

6. Drug and Toxins 

• Outdated tetracyclines 

• Lead, mercury, sulfanilamide 

• Renal transplant rejection 

• Streptozotocin 

7. Dysproteinaemia 

• Multiple myeloma 

8. Other renal diseases 

• Amyloidosis 

• Nephrotic Syndrome 


1. Usually metabolic acidosis with manifestations of other proximal tubular 

defects e.g. Fanconi Syndrome. 

2. Hypokalemia 

3. Nephrocalcinosis and renal stone disease 

4. Manifestations of acidosis with failure to thrive in children, 

hypovolaemia, and tachypnea. 

5. In contrary to distal RTA, the urine pH is variable. The morning urine pH 

is less than 5.2. Infusion of NaHCO 3 to increase plasma HCO 3 to 

normal will be followed by bicarbonaturia and increase in urine pH 

(alkaline) in proximal RTA and not in distal RTA; since in PRTA all 

HCO 3 above Tmax will be lost in urine. 

Treatment: 

A large amount of alkali is needed (3-10 mmol/kg/d). Potassium 

supplement (KHCO 3 ) is needed because the correction of systemic acidosis 

will lead to bicarbonaturia with more renal loss of potassium. 

Type III RTA 

This is a distal RAT with HCO 3 wastage (i.e. mixed type I and type II). 

Type IV RTA 

Characterized by hyperkalaemia, hyperchloraemia, hyporeninaemia 

and hypoaldosteronism.

This is mainly seen in old diabetics with mild renal impairment. Other 

causes are chronic pyelonephritis and interstitial nephritis. 

Treatment: 

9- α -Fluorocortisone (floronif) in a dose of 0.1-0.2 mg/d usually 

corrects the hyperkalaemia and systemic metabolic acidosis. 

B-blockers and ACEI should be avoided in these patients; as they may 

increase the hyperkalaemia. 

ABNORMAL WATER HANDLING 

A. Nephrogenic diabetes Insipidus (NDI) 

Normally, anti-diuretic hormone (ADH) will make the distal nephron 

tubular basement membrane permeable to water with its reabsorption from 

the tubular lumen. In NDI, the tubular basement membrane is not responsive 

to ADH either due to defect in receptor site for ADH or in the effector site; 

defect in adenylate cyclase enzyme with reduced formation of cyclic AMP. 

Other mechanisms could be reduction of the medullary hypertonicity as in 

chronic renal failure, prolonged low protein intake and with the use of osmotic 

diuretics (mannitol). 

Failure to respond to ADH will result in polyuria. 

Etiology of Nephrogenic Diabetes Insipidus 

1. Hereditary. 

• Congenital 

• Fabry's disease 

2. Non-Hereditary. 


• Cystic disease 

• Obstructive nephropathy • Interstitial nephritis 

• Chronic renal failure 

3. Electrolyte disorder 

• Hypokalaemia 

• Hypercalcaemia 

4. Drugs 

• Diuretics 

• Lithium 

• Demeclocycline (tetracycline) 

• Methoxyflurane 

• Colchicine 

• Amphotericin B 

• Propoxyphene 

• Isophosphamide 

• Sulfonyl ureas (acetohexamide Glibenclamide, Tolazamide) 

• Chlorpromazine

5. Miscellaneous 



• Multiple myeloma 

• Low protein intake 

Clinical features and diagnosis 

1. Mainly polyuria (3-6 litres/day) and polydepsia. 

2. Hypernatraemia will develop only in infants or unconscious patients 

who cannot ask for water or in patients with impaired thirst mechanism 

(hypokalaemia, hypocalcemia or hypothalamic lesion). This will be 

manifested by dehydration, hypotension, restlessness, ataxia, seizures 

and grand mal fits. 

3. NDI should be differentiated from central diabetes insipidus (CDI) and 

psychogenic polydepsia. Both NDI and CDI could be complete or partial 

syndrome. 

The three conditions could be differentiated by water deprivation test 

(Figure 1) which aims to increase plasma osmolality to 295 mosmol/kg 

by water deprivation (alternatively by giving hypertonic saline 5% Nacl 

in a dose of 0.05 ml/kg/min for 2 hours) then looking for urine volume 

and urine osmolarity. 

• Normally, as plasma osmolarity increases to 295 mosmol/kg, the 

urine volume will decrease and urine osmolality will increase to 

800-1400 mosmol/kg. 

• In psychogenic polydepsia, urine volume will gradually decrease 

and urine osmolality will increase up to 800 mosmol/kg. 

• In complete NDI or CDI the urine volume and osmolarity will not 

change (even the patient may become shocked from 

hypovolaemia so blood pressure should be watched hourly and 

body weight should not be allowed to decrease by more than 3- 

5%). 

When plasma osmolality reaches 295 mosmol/kg or hypotension 

occurs, ADH is given in the form of DDVAP intranasally or 5 units 

of aqueous vasopressin i.v. Urine volume will decrease and 

osmolality will increase up to 800 in CDI but no change will occur 

in NDI. 

In partial syndrome (NDI or CDI) water deprivation will increase 

osmolality to 400-500 mosmol/kg and some decrease in urine 

volume occurs. On giving vasopressin or DDVAP, urine 

osmolarity will increase to 800 in CDI and not in NDI.

Treatment: 

1. Treatment of the cause. 

2. Adequate free water intake (without salt) to compensate for water loss 

and avoid dehydration and hypernatraemia. 

3. Thiazide diuretic may help. The mechanism is mostly through induction 

of hypovolaemia. This will increase proximal tubular water reabsorption 

and thus reduces the amount of urine reaching to the distal nephron 

(the site of abnormality). 

B. Water Retention: 

This is usually caused by drugs increasing sensitivity of distal nephron 

to ADH leading to excess water reabsorption which will lead to dilutional 

hyponatraemia. These drugs are: cyclophosphamide, indomethacin, 

sulfonylureas (chlorpropamide, tolbutamide), acetaminophen, oxytocin and 

vasopressin. 

Clinical Features and Diagnosis: 

The picture is similar to that of the syndrome of inappropriate secretion 

of ADH (SIADH) but with low plasma ADH level. There is euvolaemic or 

hypervolaemic state (oedema, high blood pressure, decreased haematocrit 

ratio), dilutional hyponatraemia and hypoosmolality (irritability, disorientation, 

lethergy, twitching, nausea, seizures, and even coma), mortality is 10% in 

chronic hyponatremia and 50% in acute hyponatremia. 

Treatment: 

Withdrawal of the causative drug. If this is not possible, give 

demeclocycline 200-600 mg/d. 

CYSTINOSIS 

Is an autosomal recessive disorder affecting children mainly, and is 

characterized by deposition of cystine crystals in several organs including the 

kidney. The pathogenesis is unknown. In children, it causes a rapidly 

progressive renal failure, Fanconi Syndrome and rickets. 

Diagnosis depends on the detection of cystine crystals in the cornea, 

conjunctiva, bone marrow, lymph nodes, the kidney or leucocytes. 

Treatment: 

1. See cystinuria. 

2. It does not recur in the kidney transplant as the defect is on the cellular 

level (lysosomal storage defect).

WILSON'S DISEASE 

Characterized by accumulation of copper in renal cortex and other 

organs. Treatment is by chelating agent; namely penicillamine. 

OXALOSIS 

In the hereditary form, the basic defect is in the transaminase needed 

to convert glyoxylate to glycine resulting in an increased conversion to oxalate 

rather than glycine. 

Oxalate will be deposited in many tissues including the kidney (Fig. 8.2) 

with nephrocalcinosis and calcium oxalate stones which lead to renal failure. 

(Fig. 8.2) 


(X400) from a patient with primary 

oxalosis, examined by polarized 

light. It shows extensive oxalate 

Deposits in the renal tubules and 

interstitium. 

Etiology: 

1. Hereditary. 

2. Acquired 

• Ileal resection and ileostomy • Excessive vitamin C ingestion 

• Pyridoxine (vitamin B6) deficiency • Excessive ingestion of oxalate 

• Ethylene glycol (anti-freeze) poisoning 

• RTA 

• Liver cirrhosis 

• Sarcoidosis 


1. In the hereditary form, symptoms usually start at the age of 5-10 years 

with stone disease, infection and progressive renal failure.

2. Urinary oxalate excretion is high (oxalate/creatinine by mmol is normally 

less than 0.05). 

3. Detection of oxalate crystals in bone marrow. 

4. Sometimes oxalate in urine or tissues are equivocal especially in adult 

(acquired types). 

Treatment: 

1. Mainly by high fluid, diuretic, high magnesium, phosphate and vitamin B 6 . 

2. The disease may recur in the kidney transplant. 

BARTTER'S SYNDROME 

A syndrome characterized by: 

1. Hyperplasia of juxtaglomerular apparatus. 

2. High renin and aldosterone levels. 

3. Hypokalaemia. 

4. Metabolic alkalosis. 

5. Normal blood pressure. 

The pathogenesis of the disease is unknown. Possibly, there is a defect 

in Na + reabsorption in proximal nephron leading to sodium overloading of the 

distal nephron which impairs K + reabsorption resulting in hypokalaemia. This 

will lead to hypovolaemia. Hypokalaemia and hypovolaemia will stimulate 

aldosterone and renin secretion. 

Clinical picture is that of hypokalaemia (muscle weakness, constipation, 

polyuria). Diagnosis is by demonstrating the hypokalaemia with potassium 

wastage in urine and the presence of normal blood pressure in the presence 

of high renin and aldosterone. This will differentiate the condition from ACTHsecreting 

tumour, cathartic abuse and villous papilloma of the colon. 

VITAMIN D RESISTANT RICKETS (VDRR) 

The basic defect is in proximal tubular and jejunal phosphate 

reabsorption leading to phosphate loss. Some patients will show as well a 

defective activation of vitamin D or peripheral tissue resistance to vitamin D. 

The bone will be unmineralized with increased osteoid. 


Usually the patient presents with bone pains, fractures or 

pseudofractures, growth retardation, short stature, genu valgum or varum 

deformity. X-ray will show rackitic lesions in children and osteomalacia in 

adults.

Treatment: 

1. Vitamin D (either the active form or 500,000 units per day of the inactive 

form). 

2. Phosphate supplementation (1-4 g/d). 

PSEUDOHYPOPARATHYROIDISM 

The basic defect is renal tubular resistance to the action of PTH due to 

defect in renal adenylate cyclase system. 

Clinical features 

1. The disease is sex-linked dominantly inherited. The patient has a round 

face, depressed nasal bridge, short thick neck and short stature with 

brachydactyly. 

2. Clinical manifestations are those of hypocalcaemia with tetany, muscle 

cramps, twitching and convulsions. 

3. There is hypocalcaemia, hyperphosphataemia and high PTH. 

Treatment: 

Very high doses of vitamin D. 

FANCONI SYNDROME 

Is a complex defect of tubular functions including variable combinations 

of multiple proximal tubular abnormalities (aminoaciduria, glycosuria, 

uricosuria, phosphaturia, hypophosphataemia and distal or proximal RTA). 

Etiology: 

1. Hereditary: Primary inherited, cystinosis, Wilson's disease, Fructose 

inheritance, Tyrosinaemia, vitamin D dependent rickets and 

Galactosaemia. 

2. Acquired: Multiple myeloma, amyloidosis, Sjogren's Syndrome, nephrotic 

syndrome, kidney transplant rejection and vitamin D deficiency. 

3. Drugs: outdated tetracycline, 6-mercaptopurine, gentamycin, lead, 

mercury and cadmium. 

Clinical Features 

1. In adults and children, the presentation can be with bone pains and 

fractures due to osteomalacia or rickets. In children, growth retardation 

is also seen. 

2. Aminoaciduria, glycosuria, phosphaturia and hypophosphataemia. 

Treatment: 

1. Treat RTA 2. Phosphate and vitamin D supplementation


- Smulders YM, et al: Renal tubular acidosis. Pathophysiology and 

diagnosis. Arch Intern Med. 156 : 15, 1629-36, 1996. 

- Broyer M, et al: Management of oxalosis. Kidney Int Suppl, 53 : S93-8, 

1996. 

- Bunchman TE, et al: The infant with primary hyperoxaluria and oxalosis: 

from diagnosis to multiorgan transplantation. Adv Ren Replace Ther, 3 : 

3, 315-25, 1996. 

- Alon US: Nephrocalcinosis. Curr Opin Pediatr, 9 : 2, 160-5, 1997. 

- Lasram, et al: Ocular signs of primary hyperoxaluria type I. J Fr 

Ophtalmol, 20 : 4, 258-62, 1997. 

- Igarashi T: Renal tubular acidosis. Ryoikibetsu Shokogum Shirizu, 19 Pt 

2, 578-82, 1998. 

- Tomita K: Renal tubular acidosis. Nippon Naika Gakkai Zasshi, 87 :3, 

564-8, 1998. 

- Gregory MJ, et al: Diagnosis and treatment of renal tubular disorders. 

Semin Nephrol. 18 : 317-29, 1998. 

- Hayashi M: Physiology and pathophysiology of acid-base homeostasis in 

the kidney. Intern Med, 37 : 2, 221-5, 1998. 

- Kemper MJ, et al: Preemptive liver transplantation in primary 

hyperoxaluria type 1: timing and preliminary results. J Nephrol, 11 Suppl 

1 : 46-8, 1998. 

- McDowell GA, et al: Clinical and molecular aspects of nephropathic 

cystinosis. J Mol Med, 76 : 295-302, 1998.

TUBULAR AND INTERSTITIAL DISEASES 

Tubulointerstitial Nephritis 

Is a pathologic term describing inflammation involving the interstitium 

and renal tubules. It may be acute or chronic. 

ACUTE INTERSTITIAL NEPHRITIS (AIN) 

Etiology: 

1. Drug or Toxin induced: Antibiotics are the most commonly implicated 

drugs, in acute interstitial nephritis. Methicillin is the most frequent but 

penicillin, ampicillin, rifampicin, phenandione, sulfonamides, cotrimexazole, 

thiazides and phenytoin are frequently implicated and are 

more important clinically. Drugs that are involved but less frequently are 

non-steroidal anti-inflammatory drugs (NSAIDS), diuretics, analgesics 

and H 2 -antagonists. Toxins which can induce tubulointerstitial nephritis 

are organic solvents, ochratoxin (fungal toxin). 

2. Infection-related acute interstitial nephritis: May result from direct 

invasion of the renal interstitium by the organism (mainly the renal 

medulla which is involved with picture of acute pyelonephritis) or may 

be associated with a systemic infection without direct renal involvement 

by bacteria. The lesion will be caused by bacterial toxin or through an 

immunologic process triggered by bacterial infection. Bacterial infection 

as streptococcus, diphtheria, brucellosis, legionella, pneumococcus, 

tuberculosis, mycoplasma, virus infection as measles, cytomegalovirus, 

Hanta virus, and Epstein-Bar virus, protozoa as toxoplasmosis and 

spirochetal infection as leptospirosis are known to cause AIN. 

3. Idiopathic and immune mediated disease: Such as Sjogren's 

syndrome, SLE and transplant rejection can be associated with 

interstitial nephritis. 

Pathology: 

The mechanism of AIN is mainly immunologic reactions in response to 

exposure to drug, toxin, or infection. This is mainly a cell mediated 

immune response and to a lesser extent a humoral reaction with 

deposition of either anti-tubular basement membrane antibodies or 

immune complexes. 

Macroscopically, the kidney looks normal or increased in size. 

Microscopically, there is interstitial edema and cellular infiltrate. Tubules

may look normal or show necrosis, glomeruli; and blood vessels are 

intact. The infiltrating inflammatory cells are predominantly lymphocytes 

and plasma cells. In addition, neutrophils and eosinophils will be seen in 

drug induced AIN. 

The condition may regress completely or progress to chronic interstitial 

nephritis if the offending cause is persistent. 

Clinical Presentation: 

The disease varies from severe hypersensitivity syndrome with fever, 

rash, eosinophilia and acute renal failure to asymptomatic increase in 

plasma creatinine or abnormal urinary sediment without evidence of 

renal insufficiency. 

In cases of drug induced AIN the interval between exposure to drug and 

the onset of symptoms varies from hours to months. 

Differential diagnosis: 

This includes acute tubular necrosis, rapidly progressive 

glomerulonephritis and athero-embolic renal artery disease. 

History of drug intake or exposure to toxic substance or infection is 

important. Presence of skin rash, fever, eosinophilia, tubular proteinuria 

(usually < 1g/24 h), leucocyturia, microscopic haematuria and 

eosinophiluria are findings supporting the diagnosis of AIN. Kidney 

biopsy will settle the final diagnosis. 

N.B. Absence of eosinophilia or eosinophiluria does not exclude AIN. 

Treatment: 

1. Discontinuation of the causative drug and treatment of infection and 

supportive treatment may be sufficient to induce recovery. 

2. Steroids are sometimes given (unless there are contraindications) to 

shorten the course of illness and prevent permanent renal damage. 

CHRONIC INTERSTITIAL NEPHRITIS (CIN) 

There are many conditions that may lead to CIN. The most common 

are analgesic nephropathy, reflux nephropathy, gouty nephropathy, 

obstructive nephropathy and chronic pyelonephritis. The complete list of 

causes of CIN is in table 1. 

Pathology: 

Macroscopically, the kidney is small, atrophic. 

Microscopically, non-specific changes are seen including interstitial fibrosis, 

chronic inflammatory cellular infiltration and tubular atrophy (Figure 9.1).

(Fig. 9.1a) 

Cross section of a kidney with 

Chronic pyelonephritis, it shows 

thinning of renal parenchyma with 

Wedges-shaped subcapsular scars; 

dilated fibrosed pelvis and calyces. 


from Novartis-Switzerland) 

(Fig. 9.1b) 

Hx&E stained kidney section, it 

shows thyroid like appearance of 

renal tubules (atrophic, filled by 

eosinophilic casts) lymphocytic 

infiltration and interstitial fibrosis. 

Clinical presentation : 

1. Manifestations of the etiologic cause. 

2. Manifestations of chronic renal impairment (see page 158) which may 

progress to end stage renal disease.

Treatment: 

1. Of the etiologic cause, and 

2. Treatment of the chronic renal failure, whether conservative or with renal 

replacement therapy in advanced stages (dialysis and transplantation). 

TABLE 1 

Causes Of Chronic Interstitial Nephritis 

1. Chronic phase following acute interstitial nephritis. 

2. Drugs (analgesics, lithium). 

3. Heavy metals (cadmium, mercury, lead). 

4. Reflux nephropathy. 

5. Sickle cell disease. 

6. Medullary cystic disease. 

7. Metabolic (gout, hyperoxaluria, hypercalcaemia). 

8. Obstructive uropathy. 

9. Radiation. 

10. Infection (leprosy, syphilis, tuberculosis) 

11. Sarcoidosis. 

12. Balkan endemic nephropathy. 

13. Renal ischemia. 

14. Sjögren syndrome. 

15. Glomerulonephritis. 

16. Neoplastic disorders (multiple myeloma, leukemia, lymphoma, light chain 

nephropathy). 

17. Transplant rejection. 

RADIATION NEPHRITIS 

Occurs as a complication of irradiation when the kidney comes into the 

field of irradiation. Usually it manifests acutely 6-12 months after irradiation 

with severe hypertension and progressive uraemia. 

BALKAN ENDEMIC NEPHROPATHY 

Chronic interstitial nephritis, sometimes associated with transitional cell 

neoplasms. The disease affects people in Romania, Bulgaria and former 

Yugoslavia (Danube River) giving a history of living in endemic village. 

Recently it has been reported in Tunisia.

The etiologic cause is unknown, possibly ochratoxin (fungal toxin) or 

heavy metal poisoning. 

LITHIUM-INDUCED NEPHROPATHY 

Beside its effect on tubular functions (see page 212) some believe that 

lithium can cause interstitial nephritis and chronic renal failure with 

characteristic histologic lesions. These lesions consist of tubular dilatation, 

microcyst formation and interstitial fibrosis. 

SICKLE CELL NEPHROPATHY 

Sickling will cause occlusion of vasa recta and papillary necrosis 

occurs. Renal failure is a common cause of death in patients with sickle cell 

anaemia. 

ANALGESIC NEPHROPATHY 

Analgesic nephropathy is a chronic tubulointerstitial disease, it 

represents an important cause of end stage renal failure. Of patients under 

maintenance haemodialysis or those who have received kidney 

transplantation, 2-2.5% in North America, 9.8-16.7% in Europe and up to 21% 

in Australia are victims of analgesic nephropathy. 

Pathology: 

The following pathologic features could be seen in analgesic 

nephropathy: 

1. Renal Papillary Necrosis (RPN). 

2. Chronic Interstitial Nephritis. 

3. Vascular (Capillary) Sclerosis. 

4. Transitional Cell Carcinoma of the Urothelium. 

Macroscopic appearance: 

The kidney is small in size. The capsule is thick and adherent, with 

prominent scars and multiple small cysts seen on the surface. There may be 

a pale tumour-like nodular tissue between scars which represents hypertrophy 

of remaining nephrons in columns of Bertini. Cut surface will show the 

brownish-black necrotic shrunken papillae with atrophy of the overlying 

cortical tissue and hypertrophy of the intervening columns of Bertini (Figure 

9.2). In contrast, in diabetic nephropathy, necrotic papillae are pale and 

swollen.

Microscopic appearance: 

1. Renal papillary necrosis (RPN): Is the primary feature of analgesic 

nephropathy, resulting from medullary cytotoxicity and ischemic infarct. 

Histologically, RPN may be divided into three stages according to the 

extent of necrosis, starting by papillary tip necrosis to complete papillary 

necrosis. A striking feature is absence of inflammatory infiltrate and the 

presence of calcification of the involved papillae. Separation and loss of 

a necrotic papilla result in the formation of a cavity which becomes lined 

by fibrous tissue. Tubules of remaining viable nephron open into 

pelvicalyceal system through this cavity. 

(Fig. 9.2) 

Gross appearance of a kidney with 

Necrotizing papillitis it shows 

sloughing of the Renal papillae 


from Novartis- Switzerland 

2. Chronic interstitial nephritis: This is attributed to direct drug-related 

cytotoxicity in the renal cortex and/or secondary to tubular obstruction in 

tissue overlying the necrotic medulla. Microscopically, there is tubular 

atrophy, interstitial fibrosis and round cell infiltration. Careful 

microscopic examination may show a characteristic golden brown 

lipofuchsin-like pigment in the interstitium and tubules. The glomeruli 

may be unaffected or show secondary changes in the form of global 

sclerosis or hyalinosis, hypertrophy or focal and segmental 

glomerulosclerosis.

3. Vascular sclerosis: Affecting small arterioles, venules in the renal 

medulla and the submucosa of the renal pelvis and the urinary tract. 

There is a homogeneous thickening and sclerosis of the vessel wall 

which stain strongly with PAS stain. 

4. Transitional cell carcinoma (TCC) of urothelium: Although TCC is 

the commonest analgesic-associated tumour. However, 

hypernephroma, sarcoma and chorion epithelioma have also been 

reported. The ratio of bladder to renal pelvis tumours in analgesic 

nephropathy is 1 : 11 while in normal patients it is 15 : 1. The tumours 

may be solitary pedunculated or more commonly, broad-based solid 

infiltrating. They may be multifocal and tend to be poorly differentiated 

and more malignant. 

Pathogenesis of analgesic nephropathy: 

Aspirin, paracetamol (the metabolite of phenacetin) and other 

analgesics are concentrated in renal medulla especially renal papillae. The 

concentration is in the tubular cells, vasa recta cells and in the interstitium. 

Dehydration will increase concentration and nephrotoxicity while hydration 

protects against. Analgesic mixture is more serious than the single drug 

exposure (synergism). Cumulative dose and duration of drug intake play major 

roles in nephrotoxicity and the development of renal failure. Other factors 

which are playing a major role are hydration status, patient's sex (female > 

Male) climatic factors and genetic factor (more with HLA A 3 and B 12 ). 

At cellular level, aspirin and paracetamol will cause a lot of metabolic 

abnormalities with a release of toxic substances as reactive alkylating agents 

and glutathione depletion. This will lead to cytotoxicity and cell death. In 

addition, aspirin will block the synthesis of prostaglandins in the renal medulla 

with consequent decrease in the blood flow, renal ischaemia and tissue 

hypoxaemia which will aggravate the direct cytotoxicity. 

Clinical manifestations: 

Female to male ratio is 7 : 1, in spite of ratio of analgesic consumption 

is only 2 : 1 denoting female sex preponderance. The patient's age is usually 

40-60 years. 

Analgesic nephropathy is a part of a much wider clinical syndrome 

called the analgesic syndrome, in which there are multi-organ manifestations. 

A. Renal Manifestations: 

Analgesic nephropathy may be asymptomatic and is discovered only 

on routine medical examination.

The patient may present with manifestations of progressive renal 

impairment with more marked manifestations of tubular dysfunctions including 

more severe metabolic acidosis than expected (if we consider serum 

creatinine), early loss of concentrating ability with polyuria and nocturia, 

sodium losing state, more osteodystrophy (renal bone disease) and 

enzymuria. 

Episodes of acute-on-chronic renal failure may be precipitated by 

severe dehydration, acute haemorrhage from bleeding D.U., infection or 

ureteric obstruction. This is characterized by oliguric acute renal failure with 

severe systemic acidosis, hyperkalaemia, hypertension and volume overload 

which may result in pulmonary oedema. 

Hypertension occurs in more than 60% of cases either due to renal 

ischaemia with excess renin-angiotensin or salt and water retention due to 

nephron loss or due to loss of renal vasodilator prostaglandins. 

Gout occurs in 20% of cases. It this his is more common in males. 

Proteinuria occurs in 40% of cases, usually mixed tubular and 

glomerular (up to 3g/24h). 

Haematuria secondary to cystitis, renal calculi, malignant hypertension, 

malignancy, or less commonly of glomerular origin. 

Urinary tract infection may occur in up to 50% of cases, due to 

epithelial shedding, stones, stasis and instrumentation. Sterile pyuria is very 

common due to renal calculi or renal tubular epithelial celluria. 

Ureteric obstruction by necrotic papillary tissue, stone, tumour or 

stricture-if associated with infections-may result in a life threatening acute 

renal failure. 

b. Extra-renal manifestations of the analgesic syndrome: 

1. Gastrointestinal manifestations: Dyspepsia, gastric ulcers in 30% of cases 

(tend to be complicated and recur after surgery) abnormal liver function 

tests and relapsing pancreatitis. 

2. Haematological manifestations: Anaemia occurs in 60-90% of cases (due 

to blood loss, uraemia, paracetamol-related haemolysis), palpable 

spleen in 10% of cases. 

3. Cardiovascular manifestations: These include hypertension, premature 

atherosclerosis, more common ischemic heart, cerebral strokes, 

peripheral vascular disease, renal artery stenosis and difficult vascular 

access for dialysis. 

4. Neuropsychiatric manifestations: Including headache, personality 

inadequacies, usually are smokers, alcoholics, purgative abusers.

5. Pregnancy and gonadal manifestations: Subfertility, higher incidence of 

toxaemia of pregnancy, post maturity (due to suppression of uterine 

prostaglandins). 

6. Premature aging 

7. Pigmentation: Skin, heart, brain and joint cartilage, possibly due to 

retained phenacetin metabolites (lipofuchsin-like pigment). 

Diagnosis: 

The diagnosis is based on: 

1. History of significant analgesic abuse for long period, at least 2 kg of 

aspirin or phenacetin or analgesic mixture is required for chronic tubulointerstitial 

nephritis to occur. 

2. Demonstration of RPN which is best demonstrated by IVU or retrograde 

pyelography. If there is renal failure RPN could be illustrated by U.S. 

Pathologic examination of necrotic tissue in urine could help in 

diagnosis. 

N.B. Other causes of RPN are diabetes mellitus, sickle cell disease, 

obstructive uropathy, chronic alcoholism and renal amyloidosis. 

3. Demonstration of chronic interstitial nephritis on clinical grounds and by 

histological examination of the kidney tissue. The finding of 

characteristic capillary sclerosis and lipofuchsin-like pigment on 

examination of pathologic specimens provides a significant clue to an 

analgesic etiology. 

Management: 

1. Total avoidance of all NSAIDs is the most important therapeutic 

approach. 

2. Maintenance of a high fluid intake (greater than two liters/d). 

3. Treatment of complications e.g. hypertension, acidosis, infection. 

4. Careful long-term follow-up for early discovery of complications e.g. 

malignancy, infection, stones and renal artery stenosis. 

REFLUX NEPHROPATHY 

Vesicoureteric reflux (VUR) is the back flow of urine from the bladder to 

the ureter; and reflux nephropathy (RN) is the kidney disease characterized by 

coarse renal scars as a complication of VUR. 

Pathology: 

Macroscopically the outer surface of the kidney is irregular with scars 

which usually affect its upper or lower poles (focal RN). Sometimes scars are 

extensive and involving the whole kidney (generalized RN). The scar overlies 

a cortex with tubulo-interstitial nephritis and a scarred pyramid opposite a

clubbed calyx. In between each scar and the other, kidney tissue will show 

compensatory hypertrophy which exaggerate the irregularity of the outer 

surface of the kidney. Microscopic examination will show extensive tubular 

atrophy and interstitial fibrosis. The glomeruli may be either intact, or is 

surrounded by periglomerular fibrosis, show global sclerosis or has a focal 

and segmental glomerulosclerosis. 

Renal tissue in between scar areas will show glomerulomegaly due to 

hyperfiltration. 

Pathogenesis of Renal scarring in RN: 

Renal scars develop during infancy or during early childhood. Three 

factors are interacting to cause renal scarring. These are: 

1. Vesicoureteric reflux. 

2. Intra-renal reflux. 

3. Urinary infection. As infection reaches renal pyramids in the immature 

kidney, scars will develop. 

1. Vesicoureteric reflux (VUR): 

Normally, the ureter at the uretero-vesical junction has a long oblique 

intramural tunnel. During micturation or when the intravesical pressure is 

higher than the intraureteral pressure. This will press on the bladder wall 

closing the ureterovesical junction and urine does not reguirge up. In about 

0.5% of neoborn this mechanism is not well developed and the ureter is 

implanted less obliquely with a wider opening and a shorter junction so the 

urine may reflux up the ureter especially during voiding. By voiding 

cystourethrography VUR could be divided into five grades (Fig. 9.3). 

(Fig. 9.3): 

The grading system adopted by the International Reflux Study in Children. Contrast 

material in the collecting system is represented in black. Grade I is assigned if the 

contrast material enters the ureter, but does not enter the renal pelvis. Grade II means 

that contrast material reaches the renal pelvis, but does not distend the collecting 

system. Grade III occurs when the collecting system is filled and either the ureter or 

pelvis is distended, but the calyceal demarcations are not distorted. Grade IV is 

assigned when the dilated ureter is slightly tortuous and the calyces are blunted. Grade 

V occurs when the entire collecting system is dilated and the calyces have become 

distorted and indistinct.

VUR is genetically determined. It has an autosomal dominant mode of 

inheritance with variable penetrance. The incidence of VUR in siblings of the 

affected children is as high as 45%. 

2. Intra-renal reflux: 

This could be demonstrated in high grades of VUR using MCU, in 

which the dye will be seen in papillary ducts. In the ordinary papillae, the 

openings of the ducts are usually slit-like and non-refluxing, but in compound 

papillae (two papillae are mixed in one, about 9% of kidneys have one or more 

compound papillae which are polar), duct orifices are often gapping and 

refluxing. 

3. Urinary tract infection: 

Infection is brought to renal pyramids by reflux, local infection occurs 

repeatedly and ends by a scar formation. All renal scarring due to VUR is fully 

developed by adolescence and future progression of kidney disease is either 

due to development of FSGS in the remaining tissue or due to back pressure 

by refluxing urine on kidney tissue during micturation. 

Prevalence of RN: 

About 0.5% of neonates have VUR, but small proportion of them 

develop R.N., scarring occurs in female more than in male (5 : 1). 

1-2% of school girls have bacteruria, and of these 20-30% have VUR. 

Prevalence of RN in school girls is 0.3-0.5%. 


1. Urinary tract infections: This is the commonest presentation. In neonates 

it may present as fever and failure to thrive, in older children it is 

associated with fever, dysuria, frequency and loin pain. Usually it is 

recurrent. 

2. Hypertension: VUR is responsible for more than 60% of hypertension in 

children and 60% of adults with VUR are hypertensive. 

3. Renal failure: 10% of patients coming for dialysis have RN, usually at age 

of 30 years. Renal failure occurs due to scarring, infection, and FSGS. 

4. Other clinical presentations: As loin pain on voiding, childhood enuresis, 

renal stone, positive family history, and presence of other congenital 

anomaly as duplex ureter and posterior urethral valve.

Diagnosis: 

1. IVU will show cortical scarring and clubbing of calyx, disparity in kidney 

size and shape. 

2. Renal radionuclear imaging. Using DMSA scan to show scarring or 

area of inflammation. 

3. MCU and cystoscopy. 

4. Renal biopsy is indicated only when IVU and DMSA show no scarring. 

Early screening for reflux: 

Justified only in families with strong history of VUR. Very early 

diagnosis is important to prevent scarring. U.S. and MCU are the justified tools 

for diagnosis. 

Management of RN: 

1. Control of infection by prophylactic antibiotics which should be given 

daily (e.g. septrin once daily) till puberty or reflux disappears. If infection 

occurs it should be treated aggressively. 

2. Control of hypertension. 

3. Anti-reflux surgery: The indication of surgery in treatment of VUR is still 

controversial. Surgery will not prevent progression of renal disease. It 

may be indicated with recurrent pyelonephritis or when prophylactic 

antibiotics could not be given especially with high grade reflux. Either 

ureter is reimplanted into the bladder with special anti-reflux technique 

or cystoscopic injection of material (e.g. collagen or polytetrafluoroethylene) 

around ureteric orifice to narrow it and to prevent refluxing. 

PYELONEPHRITIS 

Is a microbial infection involving renal pelvis and renal parenchyma. 

Pyelitis means an infection mainly affecting the renal pelvis. Pyelonephritis is 

usually associated with constitutional symptoms (fever, rigors,...) due to 

parenchymatous involvement, while pyelitis like other viscous organ infection 

(e.g. cystitis and urethritis) is not. 

Pyelonephritis may be acute or chronic: 

ACUTE PYELONEPHRITIS 

Predisposing factors: 

1. Anatomical abnormalities: as vesico-ureteric reflux, ureteric stricture or 

congenital kidney disease as horse shoe kidney. 

2. Renal stones.

3. Obstruction of the urinary tract causing stasis of urine as in cases of 

senile prostatic enlargement and bladder neck obstruction. 

4. Diabetes mellitus: due to its predisposition to infection this risk will be 

magnified on presence of diabetic nephropathy. 

5. Analgesic nephropathy: due to the interstitial fibrosis and the abnormal 

urinary epithelium caused by chronic exposure to these drugs. 

6. Instrumentation: as cystoscopy which may introduce organisms into the 

urinary tract. 

7. Neurogenic bladder which leads to residual urine in the bladder and 

stasis creating a good medium for bacterial multiplication. 

8. Following primary renal disease e.g. nephrotic syndrome. 

Precipitating factors specific for female patients: 

1. Short urethra allowing easy passage of bacteria from the perineal area 

to the bladder. 

2. Trauma such as honey moon cystitis (cystitis occurring in early 

marriage). 

3. Stasis with pregnancy: due to hormones secreted during pregnancy 

causing relaxation of ureteric muscles and ureteric dilatation. 

5% of pregnant women have persistent bacilluria (bacilli in urine) and 

30-40% of these may develop acute pyelonephritis. 

1-2% of school girls may have bacilluria, 10% of them will have 

radiologic manifestation of renal scarring later on. 

Pathology of Acute Pyelonephritis: 

Gross appearance: Kidney appears enlarged, pelvic mucosa appears 

congested. In severe cases, scattered small abscesses may be seen in kidney 

tissue (Fig. 9.4a).

Surface Aspects of kidney: 

Multiple minute abscesses 

(surface may appear relatively 

normal in some cases) 

Cut section: Radiating yellowish 

gray streaks in pyramids and 

abscesses in cortex; moderate 

hydronephrosis with infection; 

blunting of calyces 

(Ascending infection) 

(Fig. 9.4a) 

Acute pyelonephritis Pathology 

(Reproduced with permission from Novartis-Switzerland) 

Microscopic appearance: Infiltration of the kidney tissue with 

polymorphonuclear leukocytes, tubules may show pus cells and leucocyte 

casts (Fig. 9.4b). 

(Fig. 9.4b) 

Acute pyelonephritis with exudate 

chiefly of polymorphonuclear 

Leukocytes in interstitium and 

collecting tubules

Symptoms: 

Fever, malaise, aches, dysuria, frequency of micturition, hematuria and 

papillae may pass in urine causing renal colic (especially in diabetic patients). 

In children, abdominal pain and screaming on micturation. 

Signs: 

Tender loin and suprapubic area and the urine may look turbid and may 

smell fishy (in Proteus infection). 

Investigations: 

1. Urine examination including: 

(a) Microscopic examination which will show pus cells and sometimes 

bacteria . 

(b) Urine culture to detect bacterial count (significant count is > 100,000 

bacteria/ml urine), for identification of type of organism, and to 

detect degree of sensitivity to antibiotics which is important for 

treatment, especially in complicated cases. 

For urine culture, the urine should be free of contamination. This could 

be achieved by using midstream urine sample in adults or suprapubic 

aspiration of urine in children. This is done by puncturing the full bladder 

by a fine needle after disinfecting the skin of suprapubic area. 

The most common organism causing acute pyelonephritis is E.coli, 

followed by coliforms bacteria. In cases with anatomic abnormality in 

urinary tract or with instrumentation the common organisms are 

pseudomonas, proteus, and k. aurogenosa. 

Causes of sterile pyuria (pus cells with negative repeated cultures) 

are: 

1. Urinary T.B. (needs special media to grow). 

2. Renal stones. 

3. Urethritis (caused by virus, fungus or chlamydia.... etc.) 

4. Analgesic nephropathy. 

5. Nonspecific inflammation of the bladder. 

2. Kidney function tests: Serum creatinine and creatinine clearance. 

Renal dysfunction could be a preceding event or a complication of 

pyelonephritis and its presence will affect the mode of treatment of 

acute pyelonephritis. 

3. Renal ultrasonography to diagnose precipitating factors as stone or 

back pressure.

4. IVP: After single attack in male and repeated attacks in females to 

diagnose stone disease or anatomic abnormality, e.g. ureteric stricture, 

back pressure changes. 

5. Kidney biopsy: Is not indicated for diagnosis as it may disseminate 

infection (Fig. 9.4b). 

Treatment: 

1. High fluid intake to induce diuresis to wash pus and bacteria out. 

2. Antimicrobial therapy: 

For first or uncomplicated infection we may start with Ampicillin, Amoxycillin 

or Septrin for 7-10 days. For resistant, recurrent or complicated infection 

antibiotic may be chosen according to urine culture and antibiotic sensitivity 

test. 

Changing urine pH is indicated with anatomic abnormalities especially 

when the sensitivity test shows garamycin as the best choice. Alkaline 

urine is needed for garamycin, sulfonamide, streptomycin. Acidic urine is 

needed for tetracycline and mandelamine. 

Relapse of infection (same organism) or reinfection (different organism) is 

usually due to wrong choice of antibiotic, inadequate dose or duration of 

treatment, female sex and anatomic abnormality. This could be managed 

through a proper vulval hygiene, long antibiotic suppressive therapy (after 

full course of antibiotic give a daily evening dose for 3-6 months) and 

correcting any anatomic abnormality. 

CHRONIC PYELONEPHRITIS 

Is believed to be the result of chronic or repeated renal bacterial 

infection. Often at presentation proof of the bacterial etiology is unavailable. 

Pathology: 

Gross Appearance: Affected kidney is decreased in size with irregular 

outline (due to underlying scars) (Fig. 9.1a). 

Microscopy: A nonspecific appearance is similar to any type of chronic 

interstitial nephritis. There is irregular, patchy, cortical infiltration with 

inflammatory cells, tubular atrophy and interstitial fibrosis (Fig. 9.1b). Vascular 

changes of hypertension may be evident (thickening of the wall with 

duplication of internal elastic lamina and narrowing of arterial lumen). 

Clinical presentation: 

1. History of recurrent episodes of urinary tract infection.

2. Hypertension. 

3. Insidious onset of renal failure. 

4. Sometimes patient may be asymptomatic with non-nephrotic 

proteinuria. 


1. Urine culture: should be repeated 3-4 times. A positive culture is 

obtained only in 30% of cases. 

2. Ultrasound and IVP: may show asymmetry in kidney size and 

distortion of calyx. 

3. GFR: may be reduced, increase in 24-hour proteinuria and 

manifestations of distal tubular dysfunction (e.g. renal tubular acidosis, 

inability to concentrate urine). 

4. Renal biopsy: is not indicated. 

Treatment: 

1. Antimicrobial therapy: according to culture and sensitivity testing and a 

long suppressive regimen is indicated. 

2. Surgical treatment for anatomic abnormality or stone disease. 

3. Treatment of hypertension. 

4. If the patient presents with chronic renal failure, treatment will be 

provided as will be described in section on chronic renal failure.

URINARY TUBERCULOSIS 

Definition: 

Urinary tuberculosis is a chronic granulomatous infection caused by 

mycobacterium tuberculosis. 

Incidence: 

age: 

- It occurs in older age in the developed countries, while it 

occurs in younger age in developing countries. 

- The disease is more common in developing countries 

e.g.: in USA the incidence is 14/100000 while in Third World 

the incidence is 400/100000 

Genitourinary tuberculosis: 

- accounts for 14% of non pulmonary tuberculosis. 

- occurs in 15-20% of patients with pulmonary tuberculosis. 

- is uncommon in children 

Epidemiology: 

- The incidence of tuberculosis is decreasing nowadays in developed 

countries due to improved environmental sanitation and improved individual 

resistance. 

- The basic methods for control of this disease include mass immunization 

with BCG vaccine, case finding and treatment as well as education. 

BCG vaccine: 

- Is an attenuated strain of mycobacterium tuberculosis 

- Its value is to prevent infection and limit mycobacterial multiplication 

- It is given as soon as possible after birth in developing countries but in the 

developed countries it is given for the older children (11-12 years) with 

negative tuberculin test. 

Drawbacks of BCG vaccine: 

- It gives protection for 15 years only. 

- It cannot to be given to the infected groups. 

- It may be followed by lymphadenitis, lupus vulgaris and BCGitis. 

Routes of urinary tuberculous infection: 

a) Blood borne : For kidneys and prostate 

b) Ascending infection : From prostate to urinary bladder 

c) Descending infection : From kidney to ureter to bladder to prostate

d) Direct infection : From epididymis to testis. 

1- The tuberculous kidney 

- The organism settles in blood vessels close to the glomeruli leading to 

inflammatory granulomatous reaction with central Langhan's giant cell 

surrounded by lymphocytes and fibroblasts (tubercle) 

- The fate of the tubercle depends on the dose of organisms, its virulence and 

the host resistance, it may either : a) stop, 

b) progress, or 

c) regress. 

- With its progression the tubercles coalesce with central area of caseous 

necrosis which then ulcerate into the pelvicalyceal system and the papillae 

that leads to the spread of infection to the ureter and bladder. 

- With regression or healing, fibrosis of the lesion is followed by calcification 

leading to stenosis of the calyces and pelviureteric junction leading to 

abscess formation or hydronephrosis. 

N.B.: (i) In duplex kidney; the disease is confined to the infected moiety. 

(ii) Renal calcification occurs in 20-60% of cases precipitated by 

recumbency, hypercalciuria, Recurrent urinary tract infection 

obstructive uropathy and high calcium intake. 

- Renal calcifications never disappear. 

- Large calcific areas or non functioning kidneys with intensive 

calcification should be removed. 

(iii) Hypertension and renal tuberculosis: 

- hypertension increases by 2 folds due to relative ischemia 

- If the tuberculous kidney will be removed, then 2/3 of cases will 

improve. 

2- The Tuberculous Ureter 

- The ureter is affected by descending infection from the kidney. 

- The commonest site to be affected is the ureterovesical junction with the 

resultant stricture and hydronephrosis. 

- The middle 1/3 of the ureter is rarely affected. 

- Fibrosis of the ureterovesical junction will be followed by shortening of the 

intramural ureter which gives the cystoscopic appearance of golf-hole 

orifice leading to reflux nephropathy. 

- Tuberculous ureter is demarcated from bilharzial ureter by the following: 

Bilharzial ureter 

Tuberculous ureter

- common - rare 

- Dilated ureter - not dilated 

- mural calcification - lumenal calcification 

3- Urinary bladder Tuberculosis 

- Urinary bladder affection is secondary to renal tuberculosis. 

- Infected material leads to vesical irritability (red, inflammed and angry 

mucosa) and granulomas with tubercle formation around the ureteric orifice. 

- The tubercles then coalesce and ulcerate (mucosal surface is irregular, 

raised and undermined). 

- With severe cases, the muscle layer is involved leading to contracted 

bladder with the resultant v-u reflux and very rarely fistula to the rectum 

may be found. 

4- Prostate and seminal vesicles tuberculosis 

- Infection is transmitted via hematogenous or direct spread. 

- On PR examination they are hard, nodular and rarely tender or enlarged. 

- Extensive involvement will lead to cavitation and perianal fistula or tissue 

destruction and decreased semen volume. 

N.B.: Transmission by sexual contact is rare. 

5- Tuberculosis of the Epididymis and testis 

- Infection is transmitted via hematogenous spread or may be a descending 

infection 

- Clinically, there is a painful inflammed scrotal swelling with discharging 

sinus. 

- Sometimes, it is difficult to diagnose (no bacilluria) 

N.B.: After 2-3 weeks of antibiotics therapy for acute epididymoorchitis has no 

response and is followed by antituberculous treatment for another 2-3 

weeks has also no response, then exploration is mandatory for possibility of 

malignancy. 

Clinical picture of genitourinary tuberculosis: 

Tuberculosis should be considered in the presence of: 

1- Chronic cystitis non responding to adequate treatment. 

2- Sterile pyuria 

3- Gross and microscopic hematuria 

4- Non tender and enlarged epididymis with beaded thick vas 

5- Chronic scrotal sinus 

6- Nodular prostate and thick seminal vesicle in young males.

Symptoms: 

1- Asymptomatic 

2- Constitutional symptoms: malaise, night fever and sweating and weight loss 

3- Symptoms related to kidney and ureter: 

- May be asymptomatic 

- Loin dull aching pain 

- Renal colic (due to blood clot, caseous material or stone) 

- Painless mass (rare). 

4- Symptoms related to the urinary bladder 

- Cystitis (burning micturition, frequency, nocturia) 

- Hematuria (gross in 10%- microscopic in 50%) 

- Suprapubic pain (due to bladder ulcers) 

- Recurrent E. Coli cystitis. 

5- Others: 

- Painless scrotal swelling or sinus 

- Haemospermia 

- Incidental discovery after TURP 

- Swollen painful inguinal lymph node in a tuberculous female may direct 

the attention to husband tuberculosis. 


Laboratory: 

1- Urine: - Persistent pyuria with sterile culture (secondary infection occurs 

in 15-20%) 

- Collection of 3-5 consecutive early morning urine for examination 

by ZN staining for detection of the acid fast bacilli (positive in 

60% of cases). 

- Urine culture for tuberculosis 

- Animal inoculation. 

2- Blood: 

- Complete blood picture, ESR, BUN, creatinine, electrolytes and 

calcium. 

- Repeating ESR after 1 month to detect the response to treatment. 

3- Tuberculin test: 

- Is a good negative test.

Radiological investigations: 

1- Plain X-ray for the abdomen usually shows: 

• Increased soft tissue shadow in one kidney 

• Obliterated renal and psoas shadow (abscess) 

• Punctate calcification (60%) 

• Stones 

• Ureteric calcification casting the ureter 

• Large prostatic calculi 

2- Intravenous urography (IVU) 

• Moth-eaten appearance of ulcerated calyces. 

• Obliterated calyces 

• Dilated calyces with narrow neck 

• Abscess cavity connected to calyces 

• Ureteric stricture 

• Straightening and shortening of the ureter 

• Non functioning kidney (autonephrectomy) 

• Small contracted bladder 

3- Retrograde study: rarely indicated. 

4- Antegrade pyelography: 

• Visualizes the non functioning kidney 

• Determines the condition above obstruction 

• Aspiration of the renal pelvis contents. 

• May inoculate chemotherapy into the cavity. 

5- Arteriography: 

• Of limited value. 

6- Radioisotope scanning: 

• May assess the response to the treatment. 

7- Ultrasound: 

• Of limited value 

• May assess the size of the cavity 

• May show contracted bladder 

8- CT: 

• can discover the incidental presence of tumour.

Cystoscopy 

- May show ulcers or contracted bladder 

- Ascending cystography: diagnose reflux 

- Help to obtain clean urine sample for culture. 

- Mucosal biopsy: Is contraindicated if acute tuberculous cystitis is suspected 

or tuberculous affection is close to ureteric orifices 

Treatment Of Genitourinary Tuberculosis 

Aim of the therapy: 

- Treating active disease 

- Making the patient non infectious as soon as possible 

- Preservation of the maximum amount of renal tissue 

Classification of antituberculous drugs: 

1- Primary: Rifampicin-isoniazid-pyrazinamide, streptomycin (bactericidal) 

2- Secondary: Ethambutol, ethionamide, cycloserine (bacteriostatic) 

3- Minor: Kanamycin, thioacetazone (bacteriostatic) 

Isoniazid (INH): 

- Interferes with nucleic acid metabolism 

- 70% excreted by kidneys 

- Penetrates caseous material and enters macrophages 

- Main side effects: 

• Neurotoxicity (lessened by pyridoxine) 

• Hepatotoxicity, lupus like disease or haemolysis with G6PD deficiency 

Rifampicin: 

- Interferes with bacterial RNA synthesis 

- Enters the macrophages 

- Its urinary excretion leads to red urine 

- Should be given before breakfast 


• Hepatotoxicity 

• Gastrointestinal 

• Hypersensitivity 

• May precipitates adrenal crisis (enzyme inducer that increases the 

metabolism of endogenous steroids).

Pyrazinamide: 

- Is a derivative of nicotinamide 

- Active against TB bacilli especially in acidic media 

- Excreted in urine 


• Hepatotoxicity 

• Precipitates gout (decreases urate secretion) 

• Gastrointestinal 

Ethambutol: 

- 80% excreted unchanged in urine within 24 hours. 


• Ocular toxicity 

• Precipitates gout 

• Idiosyncrasy 

Different drug Regimens 

6- month regimen: 

Rifampicin 600mg/day ⎫ 

⎪ 

INH 300mg/day⎬ 

2month 

⎪ 

Pyrazinamide 1gm/day ⎭ 

Followed by 

Rifampicin 

INH 

900mg/day ⎫ 

⎬ 3 times/week for 4 month 

600mg/day⎭ 

4 -month Regimen: 

Pyrazinamide 

INH 

Rifampicin 

25 mg/kg/day (maximum 2gm) ⎫ 

⎪ 

300mg/day 

⎬ 2 month 

⎪ 

450 gm/day 

⎭ 

Followed by 

INH 

Rifampicin 

600 mg thrice weekly⎫ 

⎬ for further 2 month 

900 gm/day ⎭

Rationale of short antituberculous course in urinary TB 

- Fewer organisms in genitourinary TB. 

- High concentration of INH, Rifampicin, pyrazinamide and streptomycin in 

urine 

- INH and Rifampicin pass freely into the renal cavities in high concentration. 

Some precautions for drug usage: 

- All the drugs should be administered in one dose, if they are to be divided, 

they may achieve subtherapeutic levels. 

- It is adviced to take all drugs prior to bed times. 

- Streptomycin adds nothing to the other three drugs in the initial phase, but it 

is advantageous in extensive disease with severe bladder symptoms; 

because it has a high concentration in urine. 

Patients in whom short course therapy are unsuitable: 

1- Kidney transplantation patients 

- Kidney transplant recipients should be given anti-TB drugs for 1 year or 

longer because immunosuppressive drugs may reactivate TB. 

- There is a possibility of reactivation of pulmonary and extrapulmonary foci 

with immunosuppressive treatment. 

- Rarely TB infections are acquired directly from the infected allograft from a 

donor with occult genitourinary TB. 

- Chemoprophylaxis by INH for 1 year to patients with old tuberculosis may be 

indicated. 

- Rifampicin, pyrazinamide, INH and ethambutol enhance the cyclosporine 

catabolism and decrease its level. They also enhance steroid metabolism 

2- Tuberculosis in dialysis patients: 

- Incidence: 10 folds higher than the general population. 

- There are frequently: 

• Extrapulmonary manifestations or dissemination 

• Negative tuberculin 

• Atypical presentation: Ascites, intermittent fever, hepatomegaly and 

weight loss. 

- Higher mortality 

- The diagnosis in extrapulmonary cases is achieved by demonstrating 

caseous granulomas on pleural or hepatic biopsy. 

- Streptomycin and pyrazinamide are dialyzable.

3- Bilateral renal tuberculosis 

Follow up of patients after starting antituberculous treatment 

- By investigating the patients 3, 6 and 12 months after the course of 

chemotherapy by examining 3 consecutive morning samples at each visit 

and by I.V.U. 

- If the urine showed the organism, repeat the full dose of antituberculous 

therapy. 

Use of steroids in genitourinary tuberculosis 

- May be useful in acute cystitis 

- No evidence that steroids influence the sterilizing activity of regimens that 

include INH, rifampicin and pyrazinamide. 

- Prednisolone at least 20 mg tid for 2 weeks with the 4 antituberculous 

drugs. This helps to alleviate bladder symptoms and allows an earlier 

appraisal of subsequent treatment. 

- The need for this high steroid dose is due to the fact that rifampicin reduces 

the effectiveness and the bioavailability of prednisolone by 66%. 

Topical drugs 

- 5% rifampicin + 1% INH + 10ml Iidocaine 1% + 100 ml Saline: 

• To relieve bladder symptoms 

• In closed abscess cavity after drainage 

- Cream for discharging sinus 

Some situations 

- Rifampicin and oral contraceptive pills: 

Rifampicin decreases oestrogen level so females should be advised to use 

another method for 3-4 weeks after stopping rifampicin. 

- Antituberculous drugs with pregnancy: 

Rifampicin may cause foetal limb defects; so, rifampicin should be used 

thrice weekly rather than daily in the first trimester. 

- Antituberculous drugs in lactating mothers: 

• Rifampicin has no harm 

• INH causes neurotoxicity; so pyridoxine is given to both the mother and 

her baby. 

• Ethambutol reaches the milk very little and baby ocular toxicity is 

negligible. 

- Antituberculous drugs in patients with renal impairment: 

The following table shows the different anti-TB drugs, route of elimination 

and dose adjustment with decreasing GFR and the need of supplemental 

dose after dialysis.

Drug Route of Dose in GFR GFR GFR need of 

elimination Normal 80-50 50-10 15 ml/minute 

- Augmented cystoplasty is not to be done in case of enuresis or 

incontinence 

- Diversion: incontinence and intolerable symptoms. 

Genitourinary Tuberculosis in Children: 

- Uncommon below 10 years 

- Clinically: 

• Some children have other forms of tuberculous lesions. 

• Others: - frequency, occasional hematuria 

- painful epididymal swelling 

- sterile pyuria 

• Anti tuberculous therapy should be given according to the weight and age. 

Drug resistance: 

Definition: Temporary or permanent capacity of tuberculous bacilli or their 

progeny to remain viable or multiply in the presence of the

concentration of the drug that would normally destroy or inhibit the 

growth of other cells 

Types: Primary and secondary (inadequate dose, inappropriate drugs, 

irregular courses) 

Origin of drug resistance: Adaptation or spontaneous mutation. 

Special aspects: 

• Natural resistance: Mycobacterium bovis is resistant to pyrazinamide 

• Atypical mycobacterium is resisting to most antituberculous drugs 

• Cross resistance: occur between drugs with similar structure (INH 

ethionamide) 

Management of drug resistance: 

- Avoid monotherapy 

- Adequate dose, combination, adequate duration and regular drug intake. 

- Use of drug sensitivity testing 

- Skilled psychiatrist may be required to handle the alcoholics and 

psychotics. 

- Do not use the drugs previously used except after drug sensitivity testing 

- Use of new antituberculous drugs 

• Ofloxacin, ciprofloxacin 

• Rifabutin 

• Clofazimine 

• Roxithromycin and Azithromycin 

• Methotrexate for atypical mycobacterium 

• Immunomodulators INFδ (no effect) 

TNF 

IL2 may be effective 

N.B.: Therapeutic test: use INH and Ethambutol for 4 weeks (not 

streptomycin or Rifampicin). 

Recent methods for diagnosis of tuberculosis 

(A)Bacteriologic: 

1- Polymerase chain reaction (PCR) 

Advantages: 

- Capable of detection of single organism in biological fluid 

- Can differentiate between typical and atypical mycobacteria.

Disadvantages: 

- Needs experience and equipments 

- Liable to contamination 

2- Radiometric detection method e.g. Bactec 460 system 

3- High performance liquid chromatography 

4- Mycobacteriophage typing 

5- Genetic probe technology 

6- Ligase chain reaction (LCR) 

7- Restriction fragment length pleomorphism RFLP 

8- New genotyping approach (SSCP-DNS) 

(B) Immunochemical: 

1- ELISA 

2- Adenosine deaminase activity (ADA) 

3- Tuberculostearic acid 

(C) Drug stimulating lymphocytic transformation rate.


- Friedman AL: Etiology, pathyphysiology, diagnosis, and management of 

chronic renal failure in children. Curr Opin Pediatr, 8 : 2, 148-51, 1996. 

- Ehara T, et al.: Immune complex mediated tubulo-interstitial nephritis. 

Ryoikibetsu Sjokohun Shirizu, 16 Pt 1, 284-6, 1997. 

- Bailey RR, et al: Vesicoureteric reflux and nephropathy: the Christchurch 

contribution. N Z Med, 110 : 1048, 266-9, 1997. 

- Shigematsu H: Reflux nephropathy in vesico-ureteral reflux (VUR). 

Ryoikibetsu Shokogu Shirizu, 16 Pt 1, 275-7, 1997. 

- Schwarz A, et al: Nephrotoxicity of antiinfective drugs. Int J Clin 

Pharmacol Ther, 36 : 164-7, 1998. 

- Siegert CE, et al.: Immunology in medical practice. IV. Mechanisms in 

the development of primary nephropathies. Ned Tijdschr Geneeskd, 142: 

14, 759-67, 1998.

CYSTIC RENAL DISEASES 

Renal cyst is an isolated segment of the nephron which is dilated to a 

diameter of 200 um or more. Cystic kidney is a kidney containing 3 or more 

cysts. 

Classification of Renal Cystic Disorders 

I. Polycystic kidney disease. 

• Autosomal dominant polycystic kidney disease. 

• Autosomal recessive polycystic kidney disease. 

II. Renal Medullary cysts. 

• Medullary cystic disease • Medullary sponge kidney 

• Juvenile Nephronopthisis 

III. Acquired renal cystic disease 

IV. Renal cyst in hereditary syndrome 

• Tuberous sclerosis 

• Von Hippel-Lindau disease 

• Others 

V. Simple renal cyst 

• Single 

• Multiple 

Pathogenesis: 

The pathogenesis of cyst formation is unknown. There are four major 

hypotheses: 

1. Increased compliance of the tubular basement membrane which is due 

to biochemical defect (genetic or acquired) in the basement membrane 

leading to its cystic dilatation. 

2. Intralumenal obstruction by epithelial hyperplasia and micropolyps 

formation. 

3. Abnormal epithelial cell growth and production of excessive basement 

membrane. 

4. Altered secretion: Reversal of direction of net water and solute 

movement with influx instead of efflux from affected nephrons, creating 

cysts. 

AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD) 

It is one of the most common genetic disorders and is responsible for 

approximately 10% of patients with end stage renal failure. It affects 1:400- 

1:1000 of people allover the world.

Genetics 

The disease is transmitted by autosomal dominant inheritance. So, 

50% of offsprings inherit the abnormal gene. The gene has been recently 

discovered to be on the short arm of chromosome 16 (called PKD-1 type). 

This finding can help in early diagnosis of the disease before any clinical 

manifestations even in utero. In approximately 5-10% of cases, the gene is not 

on chromosome 16 (called PKD-2 type). Cases of PKD-2 show milder disease 

with delayed renal failure. 

Clinical Features 

A. Renal Manifestations 

• Less than 5% of nephrons are involved in cyst formation. Clinically, 

most patients will have no detectable cyst at birth. Several small cysts 

will appear in childhood, and during adulthood, the cysts grow and 

kidney may be as large as 40 cm in length and over 8 kg in weight. 

• By the age of 50, nearly 30% of patients, will develop end stage renal 

failure and by the age of 73 the figure becomes nearly 50%. The bad 

signs for the development of renal failure are PKD-1 gene, fetal onset 

of the disease, male gender, hypertension and large kidney. 

Hypertension will manifest before the development of renal failure in 

60% of cases. Also, the inability to concentrate urine (polyuria and 

nocturia) and metabolic acidosis will appear earlier. Episodic dull 

aching abdominal pain which is due to cyst enlargement and 

persistent abdominal fullness by large kidneys are other common 

complaints. 

• Patients with ADPKD tend to be less anaemic with maintained 

erythropoietin secretion, more hypertensive with high renin secretion. 

• Renal complications include: 

(a) Increased incidence of renal adenoma, and renal cell carcinoma. 

(b) Haematuria which may be gross or microscopic in 50% of cases 

secondary to cyst rupture into the pelvis, infection, 

nephrolithiasis or owing to malignancy. 

(c) Infection which may be difficult to treat if involving the cysts. 

(d) Nephrolithiasis. 

(f) Non-nephrotic range proteinuria in 30% of cases. 

B. Extra-Renal Manifestations 

1. Cardiovascular involvement. 

With ADPKD, there is a higher incidence of mitral valve prolapse (30% 

while it is only 6% among normal population). In addition to aortic and

tricuspid valve incompetence and left ventricular hypertrophy that are 

most probably secondary to hypertension. 

2. Gastrointestinal involvement 

Hepatic cysts are the commonest extrarenal manifestations of ADPKD 

as they occur in 40% of cases. The incidence is higher in female and 

older patients. They may reach up to few centimeters in size, usually 

asymptomatic, but sometimes may cause dull aching abdominal pain, 

may get infected, or (rarely) may cause portal hypertension. Other 

gastrointestinal manifestations include diverticulosis (may be 

complicated by diverticulitis, abscess formation or perforation), 

pancreatic and splenic cysts and inguinal hernias. 

3. Neurological involvement 

Intracranial aneurysm occurs in 10% of cases. It is more common in 

some families than others. It may rupture leading to subarachnoid 

haemorrhage. 

Pathology. 

The two kidneys are massively enlarged (Fig. 10.1), in 80% of cases, 

the enlargement is symmetrical. Cross section will show hundreds of cysts 

occupying the cortex and medulla and compressing the normal renal tissue in 

between. 

(Fig. 10.1) 

Kidney of a patient with ADPCK, 

the renal tissue is replaced by 

i large cysts.

Diagnosis: 

1. By detecting renal cysts by US or CT scanning. Absence of cysts during 

the first 3 decades of life does not exclude the existence of the 

disease; since cysts sometimes appear later. 

2. Gene linkage analysis for the detection of responsible gene on 

chromosome 16. This test entails the presence of at least two family 

members with clinically evident disease to be used as a reference for 

the affected gene morphology. This test can diagnose the disease even 

prenatally. It is only indicated in potential related kidney donor who has 

no clinically evident disease. Also in any patient with hypertension who 

is a member of ADPKD family with history of cerebral hemorrhage (i.e. 

having intracranial aneurysm), this is important for the early diagnosis 

and management of aneurysm. 

Management: 

1. Abdominal and flank pain which is due to enlarging cyst is managed by 

non-narcotic analgesics, rarely percutaneous cyst rupture may be 

indicated for persistent severe pain. 

2. Hypertension should be treated aggressively to prevent progression of 

the kidney damage and to guard against aneurysm rupture in cases of 

families with a history of cerebral haemorrhage. 

3. Restriction of dietary protein to slow progression of kidney damage. 

4. Avoidance of urological instrumentation to prevent urinary tract 

infection. If infection occurred, give proper antibiotics, especially those 

which could penetrate into the renal cysts (trimethoprimsulphamethoxazole, 

chloramphenicol, and fluoroquinolone drugs as 

norfloxacin and ciprofloxacin). If cyst infection occurred, drainage may 

be required. 

5. Screening for intracranial aneurysm is indicated in cases with 

hypertension and positive family history for cerebral haemorrhage. CT 

scan or MRI should be done. If positive, angiography is indicated and 

elective surgical repair should be done if aneurysm is accessible and 

greater than 8-10 mm in size. 

AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY 

DISEASE (ARPKD) 

It is a disease characterized with cystic dilatation of renal collecting 

ducts with variable degrees of hepatic fibrosis. It is an autosomal recessive 

disease affecting male and female equally. The overall incidence is 1 : 10000 

to 1 : 40000 of population.

Pathology: 

1. Both kidneys are enlarged with pinpoint cysts corresponding to the ends 

of dilated cortical collecting tubules are visible on the capsular surface. 

2. Liver will show variable degrees of increase in a number of biliary ducts 

and portal fibrosis. In severe cases, portal hypertension complicated by 

splenomegaly and oesophageal varices will be seen. 

3. Infrequently, small pancreatic cysts are present. 

Clinical presentation 

The disease appears almost in infancy, but may manifest earlier (in 

utero or at birth) or later during childhood. 

The manifestations are usually renal masses, renal tubular dysfunction, 

progressive uraemia or portal hypertension. 

Diagnosis 

It is mainly diagnosis by renal ultrasonography. 

Treatment 

1. Treatment of intercurrent renal, hepatic and pulmonary infection. 

2. Treatment of RTA by oral NaHCO3. 

3. Treatment of hypertension. 

4. When renal failure develops, supportive treatment and renal 

replacement therapy should be provided.

MEDULLARY CYSTIC KIDNEY DISEASE (MCKD) 

Rare autosomal recessive disorder are most often seen in children or 

adolescents. There is a cystic dilatation of distal and collecting tubules with 

cysts involving medulla and cortico-medullary junction (Fig. 10.2a), 

progressive interstitial fibrosis, tubular atrophy and secondary 

glomerulosclerosis. The kidneys are bilaterally shrunken. The patient presents 

with manifestations of tubular dysfunction, mainly salt losing and loss of ability 

to concentrate urine. The condition inevitably progresses to end stage renal 

failure. 

(Fig. 10.2a) 

Cross section of a kidney with 

medullary cystic disease. 


from Novartis-Switzerland) 

JUVENILE NEPHRONOPHTHISIS 

It is a similar condition to MCKD. The only exception is that it is 

inherited as autosomal dominant and manifests clinically in later age. 

MEDULLARY SPONGE KIDNEY (MSK) 

There is a developmental defect leading to dilatation of collecting ducts 

in the medulla and papillae (Fig. 10.3). There is no familial, racial or sexual 

preponderance. It affects 1/5000 of general population. The disease is 

bilateral in 70% of cases.

IVU- medullary sponge kidney demonstrating 

difuse cyst formation and papillary enlargement. 

Medullary cystic disease. Ultrasound 

demonstrating medullary cysts. 

Papillary sponge kidney associated with 

Cystic kidney with acute intersttial nephritis. 

nephrolithiasis. Renal cortex and outer 

Tubular epithelium is flanttened. A large cyst 

medulla are normal. Masses of densely 

is seen filled with phagocytes and 

packed cysts are present in papilla. 

lymphocytes. Stroma evidences fibroblastic 

HE (X6) proliferation. HE (X 110) 

Fig. (10.3) 

Pathologic and Radiologic appearance of medullary sponge kidney

Clinical features 

1. Usually asymptomatic, unless complications occur. 

2. Manifestations of distal tubular disorders mainly inability to concentrate 

urine (polyuria) and distal RTA. 

3. Stone formation with recurrent colics, infection and haematuria. 

4. Ultrasonography and plain X-Ray may show an enlargement of one or 

both kidneys and variable numbers of radioopaque calculi. I.V.P may 

show radial or linear structures in papillae or cystic collection of contrast 

material in ectatic collecting ducts. 

Treatment 

1. Treatment of complications if existed (infection, stone, RTA). 

2. Prognosis is excellent. 

3. Urine analysis for diagnosis of infection and stone formation is required. 

ACQUIRED RENAL CYSTIC DISEASE 

(ARCD) 

It is a disease characterized with development of renal cysts in patient 

with other progressive renal disease without history of hereditary cystic 

disease. This is usually described in patients under maintenance dialysis 

treatment. 

Pathogenesis 

It is unknown and is most probably caused by uraemic toxins causing 

dysplastic changes in tubular epithelium followed by hyperplasia and 

adenoma formation with lumen obstruction and cyst formation. After longer 

time some cases will show carcinoma formation. In support of this hypothesis 

is the cyst involution seen in patients after successful transplantation and 

recurrence after failure of the renal transplant. 

Clinical manifestations 

1. 50-90% of patients under dialysis for more than 5 years will be affected. 

Males are more affected, also, blacks are more liable than whites. 

2. The disease may be discovered incidentally by US or CT scan imaging. 

3. Gross haematuria, flank or abdominal pain, palpable mass, fever 

(infection) or even manifestations of malignancy may be found. 

4. 5% of patients dialyzed more than 10 years may develop renal cell 

carcinoma which are bilateral and multifocal. 

5. Early, cysts will appear in small sized kidneys, but later the kidney 

becomes enlarged making it difficult to be distinguished from ADPKD.

Management 

1. Patients under dialysis treatment for more than 3 years should be 

screened annually by CT scanning. If tumour develops, nephrectomy 

should be done. 

2. After transplantation, cysts will regress quickly but not adenoma or 

carcinoma. 

TUBEROUS SCLEROSIS 

It is an autosomal dominant disease characterized with: 

1. Mental retardation and seizures. 

2. Adenoma sebaceum in the butterfly area. 

3. Renal angiomyolipomas and multiple cysts. Hypertension, renal 

impairment and renal cell carcinoma can occur. 

VON HIPPEL-LINDAU SYNDROME 

This is an autosomal dominant disease characterized with: 

1. Intracranial haemangioblastomas. 

2. Multiple systemic angiomas (especially retinal). 

3. Renal cysts, haemangiomas and renal cell carcinoma. 

4. High incidence of pheochromocytoma. 

SIMPLE RENAL CYSTS 

It is the most common cystic abnormality encountered in the human 

kidney. About 30% of patients over the age of 40 may show simple renal cyst 

which may be solitary or multiple, unilateral or bilateral, 0.5-4 cm in diameter. 

It is usually discovered by chance during routine ultrasonography. Less 

commonly it may present with mass, infection, haematuria after trauma or 

even less frequently malignant transformation.


- Popovic Rolovic M, et al: Cystic kidney disease-genetics, pathogenesis 

and clinical aspects in children. Srp Arh Gelok, Lek, 124 Suppl 1: 222- 

8, 1996. 

- Schneider MC: Advances in polycystic kidney disease. Mol Med Today, 

2 : 2, 70-5, 1996. 

- Choyke PL: Inherited cystic diseases of the kidney. Radiol Clin North 

Am., 34 : 5, 925-46, 1996. 

- Levine E: Acquired cystic kidney disease. Radiol Clin North Am, 34 : 5, 

947-64, 1996. 

- Sessa, et al: Autosomal dominant polycystic kidney disease: clinical 

and genetic aspects. J Nephrol, 10 : 6, 295-310, 1997. 

- Griffin MD, et al: Cystic kidney diseases. Curr Opin Nephrol Hypertens, 

6 : 3, 276-83, 1997.

RENAL STONE DISEASES 

Renal stone disease is a frequent illness. In the West, it is estimated 

that approximately 12% of males and 5% of females will have an episode of 

renal colic during their lifetime. In countries with hot weather as in Egypt 

higher incidence is expected especially in the presence of other predisposing 

factors as bilharziasis. 

Type of Stones: 

Stones could be classified according to their radiologic and structural 

features into: 

1. Radio opaque stones. 

• Calcium oxalate which represents 60% of renal calculi. 

• Calcium apatite or phosphates which represents 20% of renal calculi. 

2. Radiolucent stones: 

• Uric acid stones (7%) 

• Magnesium ammonium phosphate (struvit or infection) stones (7%). 

These are caused by infection with urea-splitting organisms, 

particularly proteus and pseudomonas. These produce ammonium 

and hydroxyl ions which raise urine pH. 

• Cystine stones (3%) 

Pathogenesis of renal stones: 

Always there are several factors playing together for stone formation: 

1. Supersaturation of urine by salt (e.g. calcium oxalate). 

Substances as calcium, urate, cystine, xanthine and dihydroxyadenine 

will be of high concentration in urine because of concentrated urine 

and/or increased urinary excretion of such substances (owing to 

increased intake, intestinal absorption or genetic metabolic 

abnormality). 

2. Increased urinary acidity: 

Persistently low urine pH will result in stone formation particularly 

calcium oxalate and uric acid stones. The increase in acidity occurs in 

some conditions as in gout, chronic diarrhoea, ileal resection, 

gastrectomy and ulcerative colitis. 

3. Loss of inhibitors of crystallization: 

Citrate excretion is reduced in acidosis. Deficiency of 

glycosaminoglycans (which could be familial), pyrophosphate, 

magnesium and some polypeptides promotes crystallization.

Specific factors contributing in stone formation: 

1. Hypercalciuria 

- Defined as 24 hours urinary excretion of calcium by more than 300 mg 

(7.5 mmol) or more than 0.1 mmol/kg/d. 

- This could be due to hypercalcaemia or could be with normal serum 

calcium (idiopathic hypercalciuria). 

- Idiopathic hypercalciuria may be (a) absorptive hypercalciuria because 

of the inherited abnormality of excess absorption of calcium by the 

jejunum; (b) renal hypercalcuria as a result of renal tubular defect in 

calcium reabsorption. 

2. Hyperuricosuria 

- May be endogenous over production as in (a) marrow overactivity 

secondary to myeloproliferative disorders, leukaemia or other 

neoplasms; or (b) Lesch-Nyhan Syndrome in which there is severe 

deficiency of hypoxanthine-guanine phosphoribosyl-transferase. 

- Dietary factors, food as meat, yeast products, and ethanol. 

- Hyperexcretion of urate may occur with normal or low serum urate due 

to tubular disease, uricosuric drugs, or after discontinuation of diuretic 

treatment. 

3. Hypocitraturia 

Citrate is an inhibitor of crystallization of calcium oxalate and 

phosphate. It lowers free calcium ion concentration in urine. Normal value for 

urinary citrate excretion is > 1.7 mmol/d in male, higher values are secreted in 

females which may explain lower incidences of renal stones in them. Urinary 

citrate excretion may be decreased in RTA and with chronic diarrhea. 

4. Hyperoxaluria 

It may be primary hyperoxaluria which is a rare inherited metabolic 

disease or secondary to increased colonic absorption which occurs in small 

bowel diseases, malabsorption or after jejuno-ileal bypass. 

5. Cystinuria 

There is an abnormal intestinal mucosal and renal tubular transport of 

the di-basic amino acids resulting in excessive urinary secretion of cystine. 

Normally, with usual urine pH, approximately 300 mg (1.25 mmol) of cystine 

are soluble in one litre. Homozygous cystinurics (1 per 10,000 of population) 

may excrete three times more.

6. Xanthinuria 

It is a very rare metabolic disorder characterized with gross deficiency 

of xanthine oxidase resulting in hypouricaemia and high urinary xanthine and 

hypoxanthine excretion with xanthine calculi. 

7. Inflammatory bowel diseases 

These are ulcerative colitis, Crohn's disease and ileal resection which 

may result in concentrated urine with low pH, hypocitraturia, hyperoxaluria. 

Acidic urine may promote uric acid and calcium oxalate stones. 

Clinical Manifestations of Renal Calculi: 

Renal colic is the commonest presentation. Other manifestations 

include incidental discovery (during routine X-ray), or may present by 

complications (e.g. urinary tract obstruction, hematuria, or infection). 


Not all investigations are indicated for every patient with renal stone. 

The more recurrent and aggressive the stone disease, the more the 

investigations needed. 

The investigations include: 

1. Blood tests: 

Serum creatinine (for kidney function), HCO 3 (for diagnosis of metabolic 

acidosis and RTA), uric acid (for hyperuricaemia) and serum calcium 

(for hypercalcaemia). In cases of hypercalcaemia, Vitamin D and 

parathormone (PTH) levels should be determined. 

2. Renal ultrasonography and pyelography: 

For detection of renal stones, back pressure changes, infection, kidney 

size, parenchymal echogenecity, kidney function (secretion of contrast 

media) and for diagnosis of medullary sponge kidney. 

3. Urine microscopy 

For diagnosis of infection, haematuria. The presence of calcium oxalate 

or uric acid crystals is of doubtful value since it could be detected in 

normal subjects. 

4. Urine analysis for pH, 24 hours calcium, uric acid and cystine 

excretion. 

5. Stone analysis to identify its nature. It may help in the treatment of 

stone formers.

Medical Treatment: 

1. High fluid intake to achieve a urine volume of at least 2 liters per 24 

hours. 

2. Dietary modification: Reduction of sodium, calcium, protein and oxalate: 

• Sodium restriction to 100 mmol/d since excess sodium intake 

results in excess excretion in urine which inevitably increases 

calcium urinary excretion. 

• Calcium should be restricted to 1 gm/d to decrease urinary 

calcium excretion. 

• Protein restriction is adopted because high protein diet increases 

urine acidity, uric acid and calcium excretion; and decreases 

citrate excretion. 

• Oxalate should be restricted to decrease urinary oxalate. Oxalate 

rich food as spinach, strawberry, rhubarb, tea, chocolate and 

Vitamin C. 

3. Potassium citrate increases urinary citrate, decreases urinary calcium 

and increase urine pH. 

4. Treatment of hypercalciuria: Thiazide diuretic will treat renal 

hypercalciuria (hydrochlorothiazide 50 mg twice daily). If this is proved 

ineffective cellulose phosphate will treat the absorptive hypercalciuria. 

5. Allopurinol: which may be given in a dose of 300 mg/d plus 

alkalinization of urine and restriction of dietary protein in patients with 

uric acid stones. Allopurinol has been proven effective in the syndrome 

of hyperuricosuric calcium nephrolithiasis through prevention of 

formation of uric acid nidus for calcium oxalate stone. 

6. Cystine calculi could be treated by high fluid intake, alkalinization of 

urine to pH 7-7.5 and diet low in methionine and cystine. Penicillamine 

1.5 g/d may decrease urinary cystine but with high side effects (allergic 

reactions affecting kidney, skin and bone marrow).


- Jaeger O: Genetic versus environmental factors in renal stone disease. 

Cur Opin Nephrol Hypertens5 : 4, 342-6, 1996. 

- Lingeman JE: Lithotripsy and surgery. Semin Nephrol, 16 : 5, 487-98, 

1996. 

- Pak CY: Southwestern Internal Medicine Conference: medical 

management of npehrolithiasis-a new simplified approach for general 

practice. Am J Med Sci, 313 : 4, 215-9, 1997. 

- Streem SB: Contemporary clinical practice of shock wave lithotripsy: a 

reevaluation of contraindications. J Urol, 157 : 4, 1197-203, 1997. 

- Goldfarb DS: Renal stone disease in older adults. Clin Geriatr Med, 14 : 

2, 367-81, 1998. 

- Wasserstein AG: Nephrolithiasis: acute management and prevention. 

Dis Mon, 44 : 5, 196-213, 1998. 

- Baggio B, et al: Pathogenesis of idiopathic calcium nephrolithiasis: 

update 1997. Crit Rev Clin Lab Sci, 35 : 2, 153-87, 1998. 

- Dussol B, et al: Urinary kidney stone inhibitors. What is the news Urol 

Int, 60 : 2, 69-73, 1998.

WATER AND ELECTROLYTE DISTURBANCES 

The water and solute (electrolyte) content in different body fluid 

compartments (intra & extracellular) gives its physiologic effect through 

changes in fluid osmolarity. For example, water loss with stable solutes 

(electrolytes) content will result in hyperosmolarity (hypertonicity) and the 

reverse will lead to hypoosmolarity (hypotonicity). Tonicity governs the 

movement of water across the cell membrane; so discussing osmolality will be 

a more precise way for direct expression of the changes in body water and 

electrolytes. 

I. DISORDERS OF PLASMA OSMOLALITY 

Osmolality is the force created by the presence of solutes in the 

medium pulling water from low solute to high solute concentration 

compartment. The higher the difference in solute concentrations, the higher 

the osmolality and the more the force pulling water. 

Osmolality of body fluid is vital for survival and is affected by the 

amount of body salt and water contents. Kidney and thirst mechanisms 

through adjustment of solute excretion (by the kidney) or water intake (by 

thirst center) or water and solute excretion and reabsorption (kidney, ADH) 

will control body osmolality. 

Osmolality is expressed as mosmol/litre plasma but-if expressed as 

mosmol/kg plasma-it is called osmolarity. So, the term osmolality is more 

precise to express solute status in body fluids. 

The major solute affecting body osmolality is sodium. Higher 

concentration of sodium (hypernatraemia) will result in hyperosmolality and 

lower sodium concentration (Hyponatremia) will result in hypoosmolality. Also 

excess water will dilute the salt content (dilutional hyponatremia) and will 

result in hypoosmolality. On the other hand, water loss will lead to solute 

concentration (hypernatraemia) and will result in hyperosmolality. 

Actually the clinical manifestations of hyper-and hyponatremia result 

from the concomitant hyper-and hypoosmolality. 

The main solute keeping the extracellular compartment osmolality is 

sodium; and the main solute keeping the intracellular osmolality is potassium. 

The balance between water content in the intracellular and extracellular 

compartments depends mainly on sodium concentration in body fluids. Other

solutes which could affect plasma osmolality are serum glucose, blood urea, 

plasma proteins and others. Blood urea is ineffective osmol since it passes 

freely between intra and extra cellular compartments. So, any increase in its 

concentration will be equal both intra-and extracellularly and will not affect the 

water content in these compartments. Meanwhile sodium is effective osmol 

since it will not move intracellularly. So, with hypernatraemia extracellular 

osmolality will increase and water will move from cells to the extracellular 

compartment causing cellular dehydration. The reverse will occur in 

hyponatremia which will result in cellular overhydration (oedema). 

Glucose is effective extracellular osmol; therefore, hyperglycemia will 

result in intracellular dehydration. 

The amount of total body water (TBW) equals 60% of body weight in 

male and 50% of body weight in female. Sixty percent of TBW is intracellular 

while 40% is extracellular. The extracellular water is distributed between 

intravascular (20%) and interstitial (80%) compartments. The water is kept 

intravascularly by the oncotic force of the plasma proteins. 

So, in 60 kg b.wt. male the TBW will be : 60 kg X 60 

100 

= 36,00 litres 

The intracellular water will be: 36,00 X 60 = 21,60 litres 

100 

The extracellular water will be: 36,00 X 40 = 14,40 litre 

100 

and the intravascular water will be: 14,40 X 20 = 2,88litres 

100 

The osmolality of a solute = its amount in mg .So, one mg of sodium in a solution 

its molecular weight. 

is more osmolar than one mg of glucose. 

Plasma osmolality is measured by osmometer which depends on the 

change in freezing point of plasma water caused by its solute contents. 

Normal osmolality is 270-290 osmol/L. Also, it can be calculated by the 

following equation: 

Plasma osmolality = 2 x Na + + Glucose(mg) 

18 

Effective plasma osmolality = 

+ 

2 x Na + Glucose 

18 

BUN (mg) 

2.8

• Loss of isotonic fluid e.g. diarrhea will not affect plasma osmolality, but 

if associated with fever (water loss through sweating) and acidosis 

(causing hyperventilation and water loss), it will lead to hypernatraemia 

and hyperviscosity. Water should be a part of the treatment of this case 

to achieve osmotic balance. Then isotonic saline is given to correct the 

primary (through diarrhea) defect. If the patient is suffering from 

diarrhea only, he/she should be treated by isotonic saline. Otherwise, 

the patient will be hypovolaemic but still with normal osmolality. But 

hypovolaemia will stimulate thirst center. Still, if the patient drinks water 

to correct his hypovolemia the result will be dilutional hyponatraemia 

and consequent hypoosmolality. 

• With the change in plasma osmolality, water will move between 

intracellular and extracellular compartments to induce osmotic 

equilibrium between the two compartments and a steady state is 

reached. An example of this is loss of water through hyperventilation 

and sweating in acidotic febrile patient. This will result in 

hypernatraemia and hyperosmolality of plasma. Water will move from 

intra to extracellular compartment until equilibrium is reached. Another 

example is water retention in patient with syndrome of inappropriate 

secretion of antidiuretic hormone (SIADH). This will result in dilutional 

hyponatraemia and hypoosmolality. In this condition water will move 

from extra to intracellular compartment with cellular oedema till osmotic 

equilibrium is reached. 

• In cases of hypo-or hypernatraemia our management is directed to 

treatment of hypo-or hyperosmolality. For example, in cases of 

hyperglycaemia, hyperosmolality will occur, water will move from 

intracellular to interstitial and vascular compartments. This will dilute 

plasma sodium and dilutional hyponatraemia will occur (for every 100 

mg/dl increase in plasma glucose, sodium will decrease by 1.6 

mmol/L). Here, the management is not directed to the hyponatraemia, 

but to the hyperosmolality caused by hyperglycemia. 

Regulation of Plasma Osmolality: 

1. Osmoreceptors present in the hypothalamus are sensitive to even 

minor changes (1%) in plasma osmolality. When stimulated, they will 

trigger the secretion of ADH from the posterior pituitary which will act 

on the distal nephron, and stimulate thirst center triggering water 

intake. Both will control body water.

2. Volume receptors are mainly in the right atrium. So they control urinary 

sodium excretion. With the increase in extracellular fluid volume, kidney 

will increase urinary sodium excretion while with hypovolaemic states, 

urinary sodium will decrease and it will be retained in the body. The 

mechanisms of handling sodium by the kidney were previously 

explained. 

3. Volume receptor mechanisms are more potent than the osmoreceptor 

mechanisms. So urinary sodium excretion is affected more by the 

changes in fluid volume status than by the changes in plasma 

osmolality or plasma sodium concentration. 

In SIADH where there is dilutional hyponatraemia and hypoosmolality 

state, while the fluid volume is increased due to water retention; urinary 

sodium excretion will be high (UNa > 20 mmol/L). But when there is 

hyponatraemia with hypovolaemia (e.g. long use of diuretics), urinary 

sodium will be low (UNa < 10 mmol/L). 

II. DISTURBANCES IN PLASMA SODIUM CONCENTRATION 

Sodium is the major cation (Na + ) contributing to plasma osmolality. 

Disturbances in plasma sodium concentration in most instances is due to the 

change in body water. Increase in body water will result in hyponatraemia and 

the decrease in body water will result in hypernatraemia. 

Hyponatraemia 

Definition: Hyponatraemia is a state where plasma sodium concentration is 

less than 135 mmol/L. 

Causes: Hyponatraemia is the commonest electrolyte abnormality in 

hospitalized patients. Usually this is dilutional hyponatraemia due to defective 

renal water excretion as a result of excess secretion or potentiation of ADH. 

The complete list of causes of hyponatraemia classified according to changes 

in total body water include: 

1. Hypovolaemic Hyponatraemic states: 

• Diuretic therapy. 

• Mineralocorticoid deficit (Addison's disease). 

• Salt-losing nephropathy (analgesic nephropathy, chronic tubulointerstitial 

nephritis, incomplete urinary tract obstruction, after 

recovery from acute tubular necrosis and after release of urinary 

obstruction).

• Gastrointestinal losses (diarrhea or vomiting). 

• Fluid loss in third space (peritonitis, ileus, burn or crush injury). 

In these conditions volume receptors are stimulated with secretion 

of ADH which will then stimulate water reabsorption from the distal 

nephron. This process will continue even with development of 

hyponatraemia and hypoosmolality owing to the fact that volume 

receptors are more potent than the osmoreceptors. 

2. Hypervolaemic (oedematous) Hyponatraemic states: 


• Congestive heart failure. 

• Nephrotic syndrome 

• Renal failure with water overload. 

In these conditions, although total body water is increased, the effective 

circulating blood volume is decreased as the excess fluid is 

extravascular and is interstitial. The decreased effective circulating 

volume results in excessive stimulation and secretion of ADH with more 

water retention. 

3. Euvolaemic (Normal volume) Hyponatraemic States: 

• Hormonal (Myxoedema, glucocorticoid deficiency or exogenous 

ADH vasopressin). 

• Massive water load (psychogenic polydipsia, parenteral fluid or 

excessive water absorption during bladder irrigation at transurethral 

prostatectomy). 

• Syndrome of inappropriate secretion of ADH (SIADH): 

- Drugs stimulating ADH secretion: 

Nicotine, Chlorpropamide (also increases renal sensitivity 

to ADH), Clofibrate, Vincristine, Carbamazepine 

(Tegretol) or Cyclophosphamide 

- Carcinomas (secretion of ADH-like substances). 

Lung (oat-cell), Pancreas, duodenum or bladder 

- Pulmonary disease (secretion of ADH-like substances) 

T.B., Pneumonia or abscess 

- Neurological diseases (excess ADH secretion) 

Encephalitis, Cerebral trauma, Guillian-Barré Syndrome, 

Acute psychosis. 

- Postoperative 

(post commissurotomy or pain) 

- Idiopathic

• Essential hyponatraemia: Occurs mostly with chronic illness, 

under nutrition or with T.B. There is a resetting of the osmostat 

(in the hypothalamus) for lower level of osmolality and 

consequently lower plasma sodium concentration. 

Pseudohyponatraemia: Plasma osmolality is measured by 

osmometer which depends on measuring the freezing point of 

plasma water (i.e. it is affected by number of solutes dissolved in 

plasma water and not affected by other compounds nondissolvable 

as lipids, plasma proteins and glycine used in 

bladder irrigation during TURP). So, in hyperlipidaemia and 

hyperproteinaemia the plasma sample separated by 

centrifugation of blood will contain a part of its volume as lipid or 

protein but plasma osmolality will not be affected whatever the 

changes in concentration of lipid or proteins. 

On the opposite side, measurements of plasma sodium is 

referred to as total plasma volume. So, in cases of 

hyperlipidaemia or hyperproteinaemia, although plasma water 

sodium is normal (but since a large amount of plasma volume is 

not water i.e lipid, protein or glycine) the reading of plasma 

sodium will appear low (pseudohyponatraemia). In this type of 

hyponatraemia, plasma osmolality will be normal. 

Pseudohyponatraemia should be differentiated from other 

conditions as hyperglycaemia, hypertonic mannitol infusion, 

methanol or ethanol intoxication in which these substances will 

dissolve in plasma water and will increase its osmolality with a 

consequent retention of body water to normalize plasma 

osmolality resulting in dilutional hyponatraemia. (These 

conditions are sometimes wrongly included to the list of causes 

of pseudohyponatraemia). 

Osmolal Gap: It is the difference between measured and 

calculated plasma osmolality which is usually less than 10 

mosmol/L. 

In cases of pseudohyponatraemia, osmolal gap will be > 10 

mosmol/L. 

Clinical Features of Hyponatraemia: 

• Manifestations of hyponatraemia depend greatly on the rate of its 

development. A very slowly progressive hyponatraemia can be

asymptomatic while acutely developing hyponatraemia could be very 

serious. 

• With hyponatraemia, plasma will be hypotonic while cells (especially 

brain cells) will be hypertonic. To achieve osmotic equilibrium, water 

will move from plasma to cells with a consequent cell oedema (brain 

oedema). 

• Plasma sodium concentrations above 120 mmol/L are usually well 

tolerated, while the majority of patients will have severe cerebral 

dysfunction once plasma sodium is below 110 mmol/L (lethargy, 

anorexia, nausea, vomiting, confusion, disorientation, convulsions, 

coma and even permanent brain damage). 

Diagnosis of the cause of hyponatraemia: 

Proper history, assessment of body hydration status (dehydrated, 

overloaded or normal) as well as the measurement of urinary sodium and 

blood pH will help in identifying the cause of hyponatraemia. 

A. Urinary Sodium (UNa) 

• UNa < 10 mmol/L 

- Gastrointestinal loss, third space, oedema state, long 

use of diuretics. 

• UNa > 20 mmol/L 

- With decreased effective circulating volume (dehydration): osmotic 

diuretics, early diuretic effect, adrenal insufficiency, salt losing 

nephropathy. 

- With increased effective circulating volume (oedema): SIADH, 

psychogenic polydipsia, renal failure, hypothyroidism. 

B. Blood pH 

• Hyponatraemia with normal pH: 

SIADH, psychogenic polydipsia, hypothyroidism 

• Hyponatraemia with metabolic alkalosis: 

vomiting, gastric suction, loop diuretics 

• Hyponatraemia with metabolic acidosis: 

Diarrhoea, intestinal fistula, renal failure and adrenal insufficiency. 

Treatment of Hyponatraemia: 

• In severe hyponatraemia, rapid correction with hypertonic saline is 

contraindicated as it may lead to fatal central pontine myelinolysis. It is 

wise to increase plasma sodium by only 5-10 mmol/Litre per 24 hours. 

This is achieved through the administration of loop-diuretic and normal

saline and in severe cases, small amounts (100-200 ml) of hypertonic 

(double strength i.e. 300 mmol/L) saline may be infused. 

• Correction of the underlying cause, in the overloaded patient water 

restriction can be combined with loop-diuretics as furosemide and 

sometimes salt supplements. 

• In SIADH, lithium or demeclocycline may be given to induce a renal 

concentration defect. 

Hypernatraemia 

Hypernatraemia is considered when plasma sodium is more than 145 

mmol/litre. 

Causes: 

Hypernatraemia is usually a consequence of water depletion and-to 

much lesser extent- is due to excess sodium intake. In normal situations water 

loss (renal or non-renal) or excess sodium intake will induce hyperosmolar 

state with stimulation of osmoreceptors which will lead to thirst (water intake) 

and secretion of ADH (water reabsorption from the distal nephron). Water 

gain will correct the hyperosmolar state and hypernatraemia will not persist. 

Hypernatraemia persists only when either water intake is not possible 

(unconscious, very young or very old patient unable to ask for water or absent 

water supply) or when there is a lesion affecting thirst center in the 

hypothalamus (tumour) or abnormal osmoreceptors (essential 

hypernatraemia). 

A- Renal causes of water loss: 

1. Osmotic diuresis 

• Enteral (through a nasogastric tube) or parenteral (intravenous 

hyperalimentation) feeding, usually hypertonic constituents are used. 

• Hyperglycaemia 

2. Nephrogenic diabetes insipidus (NDI) which results in renal tubular 

concentration defect. This could be due to: 

a. Toxin e.g. drug (lithium, amphotericin, demeclocycline) or Bence- 

Jones protein. 

b. Renal tubular disease as in post obstructive diuresis, recovering 

ATN, PCKD, chronic tubulointerstitial nephritis, medullary cystic 

disease and congenital NDI. 

3. Pituitary ADH deficiency (CDI) which is due to either trauma, 

neoplasm, vincristine or idiopathic (50%).

B- Non-renal causes of water loss: gastrointestinal loss. 

C- Sodium intake in excess of water. 


1- Manifestations of the etiologic cause. 

2- Polyuria, polydipsia, nocturia and functional dilatation of the bladder and 

ureters, this is seen in patients with D.I. 

3- Hypernatraemia occurs only if there is lesion in osmostat (hypothalamic 

lesion) or patients unable to drink, it manifests as muscle twitches, 

lethargy, weakness, seizures or even coma and death. 

With hypernatraemia, there is a shrinkage of brain cells and a decrease 

in brain size which if severe it may lead to rupture of blood vessels with focal 

intracerebral or subarachnoid hemorrhage. If the patient survived, brain cells 

will adapt and regain size. 

Treatment: 

1- Acute hypernatraemia could be corrected quickly but chronic 

hypernatraemia must be corrected slowly to prevent cerebral oedema 

(decrease plasma sodium by about 2 mmol/litre/hour). 

Usually the hypernatraemic patient is hypovolaemic, we can calculate the 

water deficit by the equation: 

Water deficit (litre) = 

Plasma Na 

140 

−1x (0.6 Xbody weight) 

For example, a patient of 60 kg with plasma sodium 160 mmol/L, his water 

deficit is 5.1 litre. 

The water deficit could be given orally as water or intravenous as 5% 

dextrose in water. If there is Na + loss as well give D 5%/1/2 saline (glucose 

5% in half tonic saline) is given. 

Rarely the hypernatraemic patient is hypervolaemic, in this situation we 

have to give furosemide (lasix) and compensate urine loss with either oral 

water or D 5% I.V. 

2- Treatment of the etiologic cause as DDAVP intranasally for CDI.

III. DISTURBANCES IN PLASMA POTASSIUM CONCENTRATION 

Most of body K + is intracellular. The intracellular K + is about 150 

mmol/litre, while plasma K + is only 3.5-5.5 mmol/litre. The capacity of the 

kidney to excrete K + load is large but relatively slow (> 30 min). The shift 

between intra- and extracellular compartments is quick and fast. 

Hyperkalaemia 

It is plasma K + concentration which is more than 5.5 mmol/litre. 

Causes of hyperkalaemia: 

These could be summarized as the following: 

A- Increased Potassium Intake 

• Dietary excess (Banana, citrus fruits...) 

• Intravenous load with K + containing fluids 

• Drugs containing K + e.g. potassium penicillin 

• Salt substitutes containing KCL rather than NaCL 

B- Shift of Intracellular K + to extracellular Compartment 

• Acidosis 

• Cell damage (cancer chemotherapy, crush injury, incompatible 

blood transfusion). 

• Muscle disease 

• Convulsions, myositis, periodic paralysis, suxamethonium 

anaesthesia. 

C- Decreased excretion of K + by the kidneys 

• Renal failure • mineralocorticoid deficiency 

• drug interference as ACEI, cyclosporine, NSAIDS, Tacrolimus and 

K + sparing diuretics. 

D- Factitious: 

Haemolysis of blood sample, severe leucocytosis or thrombocytosis. 

As a result of the strong defence mechanisms against hyperkalaemia, 

usually more than one factor is present for hyperkalaemia to occur. In 

practice, usually there is impaired renal excretion combined with other factor 

as drug intake e.g. ACEI. 

Normal K + homeostasis involves about 100 mmol/day oral intake and 

about 10 mmol/d faecal output and about 90 mmol/day being excreted by the 

kidney. Hyperkalaemia usually occurs only when renal failure is severe (GFR 

< 10ml/min) or when a defect in tubular excretion is present, as in saltdepletion, 

mineralocorticoid deficiency, drug interference or renal tubular 

disease.

Hyporeninaemic hypoaldosteronism is a common cause of 

hyperkalaemia in diabetics. This is seen usually in elderly diabetic with mild 

renal impairment, hyperkalaemia is mild (K= 5.5-6.5), the condition is 

aggravated by hyperglycaemia and/or salt depletion. 

Clinical features of hyperkalaemia: 

These are due to the effect of hyperkalaemia on cell membrane 

excitability especially those of the heart and the neuromuscular junctions. The 

toxic effect of K + depends on the rate of development and severity of 

hyperkalaemia. In patients with chronic renal failure, since the development is 

usually very slow, there will be a cell membrane adaptation and toxicity to 

occur needs relatively very high level in comparison with that occurring with 

acute renal failure. 

The manifestations include tingling, numbness, circumoral 

paraesthesia, muscle weakness with loss of tendon reflexes. The more 

serious, which can even be the first to appear, is the cardiac toxicity. 

ECG tracing in hyperkalaemic patient may show: 

• Tall T waves 

• Prolongation of the PR interval 

• Finally cardiac arrest in diastole 

• Widening of the QRS complex 

Treatment: 

It includes the following: 

A- Immediate correction (Emergency) of hyperkalaemia 

· 50 ml of I.V. 50% glucose + 20 units⎫ 

soluble insulin every 30 min. 

⎪ 

⎪ 

·B − adrenergic agonists 

⎪ 

(e.g. salbutamol) 

· Correct 

NaHCO 

3 

acidosis with I.V. 

8.4%(25 −100ml) 

⎬ Shift 

⎪ 

⎪ 

⎪ 

⎪⎭ 

+ 

K 

into cells 

• Caclium gluconate slow I.V. 

(5ml of 10% solution) 

} 

Physiologic anatagonist 

of K+ on cardiac 

cell membrane

B- Increase renal excretion of K + 

Diuresis with saline and furosemide 

C- Potassium exchange resin 

• Sodium phase e.g. Resonium A, kayexalate 

• Calcium phase e.g. sorbosterit 

• 25-100 g orally or by enema. 

• They will increase faecal K + . 

D- Dialysis: 

Preferably K + low Dialysate haemodialysis for patients with renal 

failure. 

The condition is considered medical emergency if ECG abnormalities 

are present. 

Beside the above therapeutic approaches, we must not forget treating 

the etiologic cause, restrict K + containing food and drugs. 

Hypokalaemia 

It is a condition of plasma potassium which is less than 3.5 mmol/litre. 

Causes: 

Causes of hypokalaemia are numerous. The more common are due to 

renal or gastrointestinal loss. Less commonly it is due to deficient intake or 

redistribution between intra and extracellular compartments. The list of causes 

includes the following: 

A- Renal K + loss 

1- Causes associated with alkalosis 

• Diuretic therapy (the commonest) 

• Primary mineralocorticoid excess (Conn's Syndrome) 

• Secondary aldosteronism (e.g. renal artery stenosis) 

• Glucocorticoid excess (Cushing's syndrome) 

• Barter syndrome 

2- Causes associated with acidosis 

• Diabetic ketoacidosis during recovery phase. 

• RTA 

• Ureterosigmoidostomy 

• Acetazolamide therapy 

3- Causes associated with polyuria 

• Recovery phase of ATN or post-obstructive ARF

• Tubulotoxicity as cisplatin, amphotericin 

• Diabetic hyperglycaemia 

B- Gastrointestinal loss 

1- Prolonged or severe diarrhoea 

2- Laxative abuse 

3- Prolonged vomiting 

4- Ileus with massive intestinal dilatation. 

C- Redistribution of K + into cells 

1- Metabolic alkalosis 

2- Periodic muscle paralysis 

3- Beta-adrenergic agonists e.g. salbutamol 

4- Insulin. 

D- Inadequate K + intake 

Intravenous fluid without K+ in patient without oral intake. 

Bartter's Syndrome is a rare disease characterized with hypokalaemic 

alkalosis, hyperreninaemic hyperaldosteronism, high urinary prostaglandin E 

and prostacyclin concentration and normal blood pressure. Kidney biopsy will 

show hypertrophied juxtaglomerular apparatus. 

In the non renal causes of hypokalaemia when the kidney is intact, it 

can decrease urinary K+ to < 20 mmol/day: 


Usually appear when plasma K+ is less than 2.5 mmol/L 

1- Muscle weakness especially proximal muscles. Tendon reflexes are 

depressed. In severe cases, muscle necrosis may occur. 

2- Gastrointestinal hypomotility up to paralytic ileus may occur with further K+ 

loss into dilated intestinal loops. 

3- In chronic hypokalaemia, renal tubular damage with chronic 

tubulointerstitial nephritis may occur (Fig. 12.1). 

4- With severe hypokalaemia fatal cardiac arrhythmia may cause death. 

ECG will show the following: 

• Depressed T waves and S-T segments 

• Appearance of U waves 

• Widening of the QRS 

• Finally, ventricular ectopics and fibrillation may occur.

(Fig. 12.1) 

Extensive vacuolization of renal 

tubules in hypokalemic nephropathy 

(H. and E. Stain, X 250). 

Treatment: 

1- Treatment of the etiology 

2- Potassium supplement either oral or parenteral according to the severity of 

hypokalaemia. As a rule, we have not to give KCL intravenous more than 

10 mmol/hour. 

IV. Disorders of Plasma Calcium 

Concentration 

Generally, the kidney, the gastrointestinal tract and the skeleton play a 

key role in body calcium and phosphate homeostasis. 

The contribution of the kidney in calcium and phosphate metabolism 

includes: 

1- Synthesis of 1,25 dihydroxycholecalciferol 

Inactive vitamin D (cholecalciferol) is activated in the liver by hydroxylation 

to 25, hydroxycholecalciferol, the second step of its activation is in the 

kidney to be 1, 25, dihydroxycholecalciferol. The active vitamin D 

promotes the gut calcium absorption and the normal calcification of bone. 

2- Renal excretion of calcium

85-90% of the filtered Ca 2+ is reabsorbed by the PCT while the rest is 

reabsorbed by the DCT, under the influence of PTH, only

3- Gastrointestinal manifestations 

• Nausea and vomiting which are central effects of hypercalcaemia. These 

may aggravate dehydration induced by polyuria 

• Peptic ulcer disease 

• Pancreatitis 

4- Nervous system 

Nausea, vomiting, malaise, fatigue, and even psychosis are all central 

effects of hypercalcaemia. 

5- Tissue deposition of calcium may lead to nephrocalcinosis, vascular 

calcification, pruritus, conjunctival calcification (red-eye) and band 

keratopathy. 

Treatment: 

A- Treatment of the etiologic cause 

B- Treatment of hypercalcaemia 

1- Saline diuresis in patients with reasonable kidney function. If there is no 

response we can inforce diuresis by furosemide and intravenous saline. 

Loop diuretics in contrary to thiazide diuretics increase urinary calcium 

excretion. 

2- Glucocorticoids are effective in all conditions other than 

hyperparathyroidism. In sarcoidosis and Vit. D intoxication 10 mg 

prednisolone may be sufficient while in malignancy doses up to 60 mg/d 

may be required. 

3- Others: 

• Methramycin is particularly useful in malignancy related 

hypercalcaemia, a dose of 20-30 ug/kg may induce fall in serum Ca 2+ 

within hours and last for few days. 

• Calcitonin 50-100 units S.C. 

• Phosphate oral or intravenous, but carries the risk of metastatic 

calcification. 

• Diphosphonate will suppresses hypercalcaemia in hyperparathyroidism 

4- Dialysis in renal failure especially on using low Ca 2+ dialysate will be 

very effective in decreasing serum calcium. 

Hypocalcaemia 

It is plasma calcium concentration less than 2.20 mmol/litre (8.5 mg/dl). 

Causes of hypocalcaemia 

1- Renal failure 

2- Hypoparathyroidism

(surgical, idiopathic, pseudohypoparathyroidism) 

3- Vitamin D deficiency 

4- Hypoalbuminaemia 

5- Acute pancreatitis 

In renal failure, hypocalcaemia is due to the lack of activation of vitamin 

D and to the hyperphosphataemia which will cause drop of serum calcium. 

The presence of acidosis will delay the manifestations of hypocalcaemia by 

increasing serum ionised calcium. 

Vitamin D deficiency may be due to decreased intake, decreased 

exposure to sun light, defective gut absorption or lack of its activation. 

Hypovitaminosis D is characterized with hypocalcaemia, hypophosphataemia 

and hyperparathyroidism. 

Clinical features of hypocalcaemia 

1- Manifestations of the etiologic cause. 

2- Neuromuscular; in acute hypocalcaemia takes the form of tetany, tingling, 

numbness, parasthaesia, even convulsions. While in chronic 

hypocalcaemia the main features are depression, irritability, intracarnial 

calcification. 

3- Bone disease as osteomalacia in vitamin D deficiency and renal failure and 

hyperparathyroid disease in hyperparathyroidism 

4- Cataract may be seen with chronic hypocalcemia 

Treatment: 

1- Treatment of the cause 

2- Calcium and vitamin D supplementation 


- Ando K, et al: Emergency therapy of acute kidney failure and waterelectrolyte 

imbalance. Nippon Naika Gakkai Zasshi, 84 : 11, 1852-7, 

1995. 

- Vamvakas S, et al: Alcohol abuse: potential role in electrolyte 

disturbances and kidney diseases. Clin Nephrol, 49 : 4, 205-13, 1998. 

- Cserhalmi L: Effect pf combined captopril-spironolactone therapy of 

cardiac insufficiency on kidney function and serum electrolyte values. 

Orv Hetil, 139 : 63-6, 1998.

DISORDERS OF ACID-BASE BALANCE 

Physiology Of The Acid-Base System: 

The bicarbonate (HCO 3 

- )- and Carbonic acid (H2 CO 3 ) pair is the major 

physiologically active buffer system in the extracellular fluids (ECF). 

HCO 

- 

According to the equation (pH = PK + log 

3 

), the 

H 2 

Co 3 

or α X PCo 2 

HCo 3 

- and PCo 2 are the major determinants of blood pH. 

(where pH is the - log of H + concentration, K is 6.1 and α is solubility constant of 

CO 2 which equals 0.03). 

When there is influx of acid or alkali into body fluid the first line of 

defence will be the extra cellular buffer system (HCO 3 

- ) followed by the 

intracellular buffer system, (proteins and hemoglobin and phosphates). In the 

condition of excess acid load, i.e. accumulation of H+ ions in blood, H+ will 

combine with plasma HCo 3 

- to form H 2 Co 3 which dissociates quickly into H 2 o 

and Co 2 which could be removed by lungs through ventilation. But in case of 

excess alkali load as HCo 3 

- , this will be buffered by plasma H + to form 

H 2 Co 3 . These reactions occur according to the equation (Co 2 + H 2 O × 

H 2 Co 3 × HCo 3 

- + H+). Normally H 2 Co 3 is present in blood in very low 

concentrations as it is very unstable. 

The second line of defense against acid-base disorders is the lung and 

kidneys. The lung through hyperventilation will wash Co 2 in states of acid load 

and through hypoventilation will lead to accumulation of Co 2 in states of 

alkalosis. Retained CO 2 will react with H 2 O resulting in generation of H 2 Co 3 

which will dissociate into H+ and HCo 3 

- . The respiratory defence mechanism 

is rapid in the contrary to renal defence mechanisms which are slow. 

The renal defence mechanisms involve the adjustment of the 

reabsorption of the filtered HCo 3 

- and the secretion of H + . In states of acid 

load, the kidney increases the proximal tubular HCo 3 

- reabsorption (H + + 

HCo 3 

-∅ H 2 Co 3 ∅ H 2 O+ Co 2 , and excrete more H + through more titratable 

acids excretion (e.g. phosphates and sulfates through the glomerular filtration) 

and through increasing the rate of formation of ammonia (NH 2 + H + ∅ NH 4 by 

the renal tubules). The reverse will occur in states of alkali load, i.e. less 

HCO 3 

- reabsorption with bicarbonaturia, less titratable acid excretion and less 

ammonia formation.

Daily, as a result of the normal metabolic process, there is 1- a release 

of 40-60 mmol (1 mmol/kg/d) of H + (mainly from protein metabolism) into the 

extracellular fluids. These hydrogen ions are removed through the lungs and 

the kidneys after being dealt with by the first line of defense; and 2- a release 

of 13,000-15,000 mmol of Co2 (mainly of carbohydrate source). This is mainly 

dealt with through the respiratory system. 

Plasma pH is normally 7.35-7.45 which represents a H + concentration 

of 36-44 mmol/litre. The normal plasma HCo 3 

- concentration is 20 to 30 

mmol/litre. The lowest urinary pH is 4.5 units (with severe metabolic acidosis 

in presence of normal kidneys) and the highest urinary pH is 10 units (with 

severe metabolic alkalosis). 

Metabolic Acidosis 

Metabolic acidosis can result from the generation or the ingestion of 

acid; or from the loss of bicarbonate ions with consequent accumulation of H+ 

in the circulation. 

This will be compensated for by the increase in ventilation with a 

consequent drop in the level of Co 2 and HCo 3 

-. 

The term acidaemia is sometimes used when compensatory 

mechanisms fail to maintain the pH level within the normal range. But in 

practice, the term acidosis is usually used whether the pH level is within the 

normal range or lower. 

Features of metabolic acidosis: 

• Low plasma HCo 3 

- concentration (< 20 mmol/litre). 

• Low arterial Co 2 concentration (< 40 mmol/litre). 

• Low plasma pH (< 7.35) 

Causes of metabolic acidosis: 

First we have to know about the concept of anion gap which is the 

difference between plasma concentration of Na + and the sum of chloride and 

bicarbonate [Na + - (CL + HCo 3 

- ) = 6-16 mmol]. This gap represents 

substances which combine with Na + other than CL - and HCo 3 

- which are not 

measured in routine chemistry such as amino acids. 

We may classify metabolic acidosis into those with high anion gap [Na + 

- (CL + HCo 3 

- ) > 16 mmol] and those with normal anion gap: 

I- Metabolic acidosis with high anion gap: 

The high anion gap is due to the addition into the circulation of anionic 

toxic substances which combine with Na+ at the expense of chloride and

HCo 3 

-. Since these substances are not measured the anion gap will be 

high. 

Causes of metabolic acidosis with high anion gap are: 

• Lactic acidosis; the anion toxic substance here is lactate 

• Diabetic ketoacidosis with accumulation of acetoacetic acid; B- 

hydroxybuteric acid 

• Intoxication with methyl alcohol; Ethylene glycol, paraldehyde and 

salicylates. 

• Renal failure with accumulation of sulfates; phosphates and phenols. 

II- Metabolic acidosis with normal anion gap (hyperchloraemic metabolic 

acidosis). 

This could be due to renal, gastrointestinal or other defects. 

A. Renal causes of metabolic acidosis with normal Anion gap: 

1- Diamox, a diuretic which causes bicarbonate wastage (bicarbonaturia). 

2- Renal tubular acidosis (RTA); resulting from either: 

a. Type I, classic (Distal) RTA: In this condition, there is inability to 

secrete H+ load. 

b. Type II, proximal RTA: In this condition, the PCT is unable to 

reabsorb HCo 3 

- as there is a set up of HCo 3 

- Tm at low level e.g. 

HCo 3 

- Tm of 16 mmol/l, so any HCo 3 

-. Above this concentration will 

be a loss in urine. 

c. Type III RTA: There is both inability to secrete H+ load and proximal 

HCo 3 

- wastage. 

d. Type IV RTA: There is hyperkalaemic hyperchloraemic metabolic 

acidosis with hyporeninaemic hypoaldosteronism. This is usually 

seen in diabetics with mild renal impairment. 

Causes of classic (Distal) RTA: 


• Hyperthyroidism 

• Hyperparathyroidism with nephrocalcinosis 

• Hypergammaglobulinaemia (e.g. SLE. Cryoglobulinaemia, T.B., Sjogren's 

syndrome, Hodgkin lymphoma). 

• Medullary sponge kidney 


• Drugs intoxication as amiloride, vitamin D, amphotericin B 

• Chronic kidney graft rejection, chronic pyelonephritis 

• Genetic diseases as galactosaemia, Fructose intolerance, Ehlar-Danlos 

syndrome and Elliptocytosis

Causes of proximal RTA 

• Fanconi's syndrome 

• Hereditary fructose intolerance 

• N.S. 

• Graft rejection 

• Wilson's disease 

• heavy metal poisoning, tetracycline 

• multiple myeloma 


Diagnosis of RTA: 

1- NaHCo 3 test: Urinary minus blood Co 2 content is less than 10 mmol/l in 

distal RTA and more than 20 mmol/L proximal RTA. 

2- Ammonium chloride (NH 3 cL) test: Loading with NH 3 CL till blood HCo 3 

- is 

less than 15 mmol/L. In normal persons and in cases with proximal RTA 

urinary pH is 5.4. 

In hepatic patient as NH 3 cL is contraindicated, CaCl 2 could be used 

instead. 

3- As a screening test, we can look for the morning urine pH (which is the 

lowest pH along the 24 hrs) if it is > 6 we may consider Distal RTA. 

Distal 

Proximal 

(type 1) (type 2) 

Hypokalemia Severe Mild-moderate 

Response to K+ therapy Good Poor 

Bicarbonate Tm Normal Decreased 

Bicarbonate loss in urine Small Large 

Serum bicarbonate concentration May be very Usually >16-18 

low ( 20 mEq/L > 5.5 > 5.5 

< 15 mEq/L > 5.5 May be 5mEq/kg/day 

correct acidosis 

Response to alkali therapy Good Poor 

Glycosuria Absent Often present 

Aminoaciduria Absent Often present 

Hypercalciuria Often present Usually absent 

Urinary citrate Low Normal 

Fanconi's syndrome No Yes 

Nephrocalcinosis Often present Rare 

Nephrolithiasis Often present Absent 

Renal insufficiency Often present Absent 

Bone disease Often present Absent

B- Gastrointestinal causes of metabolic acidosis with normal anion gap: 

1- Diarrhoea; There is loss of K + and HCo 3 

- , every litre of diarrhoea fluid 

contains 30-50 mmol of HCo 3 

- . 

2- Fistula or tube drainage: Each litre of the small intestinal fluid contains 60 

mmol HCo 3 

- while pancreatic fluid contains 120 mmol/litre. 

3- Ureterosigmoid or ileal loop urine diversion: In these conditions there is 

loss of mucosal HCo 3 

- (normally present in high concentration in intestinal 

mucous) in exchange with the urinary CL - (hyperchloraemia). 

4- Anion exchange (CL - versus HCo 3 

- ) as with the use of cholestyramine. 

5- Ingestion of Ca and Mg chlorides. 

C- Other causes of metabolic acidosis with normal Anion gap: 

1- Hyperalimentation using formulas rich in cationic aminoacids and chlorides. 

This does not occur with formulas containing aminoacids and organic 

anions. 

2- Use of Hcl, arginine chloride or lysine chloride 

3- Dilution with chloride solution. 

NB: Causes of Metabolic acidosis with low or even negative anion gap include bromide 

intoxication and dysproteinaemia. 

Treatment of metabolic acidosis: 

1- Treatment of the cause and compensate for the deficit 

2- In distal RTA, NaHCo 3 should be provided 1-3 mmol/kg/d, sometimes K+ 

supplementation is required. In children NaHCo 3 will be provided in a dose 

of 5-15 mmol/kg/d. 

3- In proximal RTA large amounts of alkali are provided (10-25 mmol/kg/d) 

and K+ supplementation. 

Respiratory Acidosis 

In respiratory acidosis, Co 2 retention occurs and the reaction Co 2 + 

H 2 O ∅ H 2 Co 3 ∅ H + + HCo3 - results in accumulation of H + in circulation and 

acidosis. The kidney compensates by the secretion of H + and reabsorption of 

HCo3 - . 

In acute respiratory acidosis blood Hco 3 

- increases by 1 mmol/L for 

every 10 mmHg increase in PCo 2 while in chronic respiratory acidosis HCo3 - 

increases by 3.5 mmol for very 10 mmHg increase in PCo 2 . 

Features of respiratory acidosis: 

• high PCo 2

• low pH 

• high HCo 3 

- 

• urine pH is low 30 mmol/litre) 

• High plasma pH (pH > 7.45) 

• High Pco 2 , for every 1 mmol/litre increase in plasma HCo 3 

- there will be a 

0.6-0.7 increase in Pco 2 . Hypoxaemia stands as a limiting factor for the 

respiratory compensation. So, if it exists, we have to give oxygen support. 

• Chloride and K + are also usually low. K + is low as a result of the renal loss 

and the intracellular shift. 

Causes: 

A- Renal: 

1- Adrenocorticoid and adrenocorticoid-like effect (HCo 3 

- retention with K + 

and H+ excretion). 

• Secondary aldosteronism (e.g. cirrhosis) 

• Primary aldosteronism

• Cushing's syndrome 

• Bartter's syndrome 

• Liquorice ingestion 

2- Volume depletion (Cl - depletion and HCo 3 

- reabsorption) 

• diuretics • diarrhea • cirrhosis 

B- Gastrointestinal loss of acid: 

• Vomiting 

• Gastric aspiration 

C- Ingestion of alkali: 

• NaHCo 3 

• Milk-alkali syndrome 

Hyperaldosteronism stands as a common mediator in metabolic 

alkalosis as it lead to enhanced K + and H + excretion, with sodium and 

bicarbonate retention (hypokalaemic alkalosis). Diuretic therapy, secondary 

aldosteronism in cirrhotics and severe vomiting are the common causes of 

metabolic alkalosis. 


1- Manifestations of the cause 

2- Manifestations of neuromuscular irritability owing to the decreased ionized 

calcium. 

Treatment: 

1- Of the cause 

2- Support respiratory and renal compensatory mechanisms. 

3- If there is renal failure with severe metabolic alkalosis, dialysis may be 

provided. 

Respiratory Alkalosis 

Excessive pulmonary wash of Co 2 will result in alkalosis owing to 

directing the reaction (H 2 O + Co 2 × H 2 CO 3 × H + HCo 3 

-) to the left with 

consequent reduction in H + . 

The renal defence mechanism will include the increase in HCo 3 

- 

secretion and retention of H + . This mechanism is relatively slow. It needs 24 

hours to be established. 

For each 10 mmHg ↓ in PCo 2 , there is a 2.5 mmol/L ↓ in plasma HCo 3 . 

Features: 

• ↓ PCo2 

• ↓ pH 

• ↓ HCo 3

Causes of respiratory Alkalosis: 

1- Iatrogenic in patients under ventilatory support. 

2- Liver cirrhosis, salicylate intoxication, exercise and hypotension. 

3- Hyperventilation syndrome in neurotic patients 

4- Cerebral hypoxia and intracranial disease 


1- Manifestations of the cause 

2- Parasthesia, tinnitus, neuromuscular irritability and/or cerebral 

vasoconstriction 

Treatment: 

1- Of the cause 

2- Breathing into a mask (rebreathing of expired air with its high level of Co 2 ). 


- Hanna JD, et al: The kidney in acid-base balance. Pediatr Clin North 

Am, 42 : 6, 1365-95, 1995. 

- Hüssinger D: Liver and kidney in acid-base regulation. Nephrol Dial 

Transplant, 10 : 9, 1536, 1995. 

- Hayashi M: Disorders of body water regulation and the therapy-acid 

base equilibrium in the kidney and disorders. Nippon Naika Gakkai 

Zasshi, 86 : 9, 1665-9, 1997. 

- Hayashi M: Physiology and pathophysiology of acid-base homeostasis 

in the kidney. Inter Med, 37 : 221-5, 1998.

HYPERTENSION AND THE KIDNEY 

The values of systolic and diastolic blood pressures which are accepted 

as normal are derived from statistical analysis of the values obtained from 

large population groups. 

The level above which blood pressure is considered high 

(hypertension). Consequently, the patient requires treatment; as this level is 

associated with risk of morbidity is still debatable. 

Most physicians, consider the blood pressure above 140/90 mmHg in 

patients under the age of 50 years as hypertension thus deserves treatment. 

It was believed that diastolic blood pressure was the more important as 

it represents a more constant stress on the arterial wall. Recently, based on 

large-scale epidemiological studies it was demonstrated that systolic pressure 

predicts more accurately the cardiovascular pathologic changes. 

Etiology And Classification Of Hypertension: 

Hypertension, according to severity and target organ damage (of retina, 

kidney, heart) could be classified into benign or malignant. Etiologically, 

hypertension may be classified as essential (primary) or secondary. 

Secondary hypertension may be: 

1- Renal: 

a- Renovascular hypertension: 

• Renal artery stenosis 

• Polyarteritis nodosa 

• Renal artery aneurysm 

• Renal artery malformation 

b- Renoparenchymal: 

• Glomerulonephritis 

• Polycystic kidney disease 

• Analgesic nephropathy 

• Renal tumour as Wilms' tumour 

• Other renal parenchymal diseases 

2- Endocrinal: 

a. Adrenal cortex: 

• Cushing's syndrome 

• Conn's syndrome

- Adrenal medulla and splanchnic sympathetic chain: 

• Pheochromocytoma 

c- Others: 

• Acromegaly 

• Hyperparathyroidism 

3- Iatrogenic: 

• Oral contraceptives 

• Sympathomimetic amines 

(nasal decongestants and bronchodilators) 

• Corticosteroids 

• Cyclosporine 

• Nonsteroidal anti-inflammatory drugs (NSAIDs) 

• Tricyclic antidepressants 

• Liquorice 

• Pregnancy-associated hypertension 

• Acute intermittent porphyria 

Essential Hypertension 

Pathogenesis Of Essential Hypertension 

In normal situation, the blood pressure is controlled via central and 

renal mechanisms. The central (nervous) mechanism is achieved through the 

autonomic nervous system which controls the cardiac output and the 

peripheral vascular resistance. 

The renal mechanism depends on handling of sodium and water 

reabsorption which will control the intravascular volume. 

The pathogenesis of essential hypertension is still speculative. There 

are two major proposed mechanisms. These are the genetically determined; 

and the behaviorally and dietary determined mechanisms. 

The genetically determined mechanisms: 

There are many theories which try to explain essential hypertension on 

genetic basis. Most of these theories come to the conclusions that essential 

hypertension is due to: 

1- Abnormal renal handling of sodium with consequent increased 

intravascular volume, increased cardiac output and increased tone of 

peripheral blood vessels (peripheral resistance).

2- Secretion of hormone which causes arteriolar constriction and 

excretion of retained sodium. This hormone is most probably secreted by the 

hypothalamus or the adrenal glands. It is Na-K-ATPase inhibitor, probably 

related to the cardiac glycoside ouabain. 

3- Hyperinsulinism with decreased sensitivity of non-oxidative glucose 

transport. Insulin would raise blood pressure by its action on central nervous 

system receptors (increasing sympathetic outflow) and on renal tubular 

receptors (sodium retention). This is consistent with the common finding in 

hypertensive patients of impaired glucose homeostasis, 

hypercholesterolaemia and increased coronary artery disease. 

4- Abnormalities in atrial natriuretic peptide (ANP), prostaglandins and 

vascular endothelial factors (Nitric oxide, endothelins). 

The Behavioural and Dietary Factors: 

These factors will interact strongly with the genetic predisposition to 

produce hypertension. These factors include obesity, dietary sodium, alcohol 

and sedentary life. 

• Obesity: 

There is a strong association between obesity, hypertension and 

cardiovascular morbidity. This is most probably due to insulin resistance. 

• Sedentary life: 

Beside contributing to obesity, sedentary low exercise life style appears 

to be associated with an increased sympathetic outflow; and the increasing 

exercise has been shown to reduce high blood pressure. 

Histopathologic changes with essential hypertension: 

1- Changes in blood vessels: These involve all blood vessels with 

arteriosclerosis, thickening of the wall, duplication of elastic lamina and 

degeneration of the media. The arterial lumen will be narrow with a 

consequent ischaemic changes in organs as the brain, the kidney and the 

heart. Weakness in the media; as a result of the degenerative changes; 

may result in aneurysm formation; as in cerebral vessels. This may rupture 

with catastrophic sequelae. 

2- Target organ damage: 

• The kidney will be affected by the long term hypertension owing to 

chronic ischaemia. Kidney biopsy will show nephrosclerosis. In early 

phases there will be wrinkling of the glomerular basement membrane; due 

to renal ischaemia; and hyaline changes in the afferent arterioles. In the

late phases there will be extensive glomerulosclerosis, tubular atrophy and 

interstitial fibrosis (Fig. 1). In benign hypertension these changes need a 

longer time (more than 15 years duration) to appear. Black Africans are 

more liable to these complications. 

(Fig. 14.1) 

PAS stained kidney section (X 100) 

of a case of benign nephroscleroris, 

it shows sclerosis of glomerular tufts, 

tubular atrophy and marked 

thickening of a small artery. 


from IGAKU-SHOIN Ltd, Japan 

In malignant hypertension renal changes occur very quickly. There is a 

marked arteriolar intimal proliferation which is sometimes severe enough to 

cause occlusion of the arteriolar lumen. Fibrinoid necrosis will affect the 

arteriolar smooth muscles and adventitia will show fibrosis. The glomeruli 

will be damaged by the severe ischaemia as a result of the arteriolar 

occlusion (Fig. 14.2). 

(Fig. 14.2a) 

PAS stained section (X260) of a 

case with malignant hypertension, 

It shows a striking "onion peel" 

thickening of the intinsa of a small 

Artery with marked narrowing of 

the lumen. 

• The brain, myocardium and retina are other organs (Target organs) which 

are affected by benign and malignant essential hypertension.

(Fig. 14.2b) 

Hx&E stained kidney section from a 

Patient with malignant hypertension 

(X26), it shows fibrinoid necrosis of 

an arteriole at the glomerular hilus. 


from IGAKU SHOIN Ltd, Japan). 

Clinical Manifestations of Essential Hypertension: 

1- Hypertension may be discovered by chance e.g. during routine medical 

examination (i.e. asymptomatic). 

2- Vague constitutional symptoms, especially dizziness, fatigue and morning 

bilateral occipital headache. 

3- Manifestations of target organ damage as cerebral stroke, myocardial 

infarction, left ventricular failure or retinal artery or vein occlusion. Renal 

wise, hypertension may cause proteinuria or microhematuria; and long 

standing hypertension may present with chronic renal failure due to 

nephrosclerosis. Malignant hypertension will present with acute or RPGN. 

4- Fundus examination will show changes in retinal vessels which resemble 

those in other organs. These changes are mainly in the form of thickening 

of the media and narrowing of the arteriolar lumen. Retinal arterioles will 

show silver wire appearance and at site of arterioles crossing veins will 

show arteriovenous nipping. In severe forms of hypertension with 

endothelial damage, permeation of plasma and blood outside the retinal 

vessels will show exudates and areas of circumscribed hemorrhages, also 

ischaemic changes in optic nerve appearing as blurring of the disc 

margins; a picture which could be confused with papilloedema (Fig. 14.3). 

5- Hyperlipidemia, glucose intolerance, obesity and smoking are more 

common in hypertensive patients than in general population. These 

together will significantly magnify the risk of the target organ damage.

(Fig. 14.3) 

Appearance of the optic 

fundus in a patient with 

malignant hypertension. 

There are linear of 

Flame – shaped retinal 

haemorrhage and 

papilloedema. For 

clinical diagnosis of 

malignant hypertension, 

haemorrhage must be 

present in both eyes. 

Diagnosis of Essential Hypertension: 

1- As a large proportion of patients are asymptomatic at diagnosis, most of 

population especially those at risk should be subjected to blood pressure 

assessment at least once yearly. 

2- White-coat hypertension (i.e. hypertension occurring only during medical 

assessment is due to patient's anxiety) should be suspected especially if 

the patient is asymptomatic with no manifestation of target organs 

involvement. 

3- For the diagnosis of labile hypertension or to confirm a mild hypertension or 

white coat hypertension, we have to frequently measure blood pressure 

(e.g. 3 times/week), home blood pressure measurement using electronic 

sphygmomanometer or to do a 24-hour continuous monitoring. 

4- Diagnosis of Hypertension is considered final with no need for further 

confirmation in patient with moderate or severe hypertension (≥ 180/110), 

with long standing symptoms, or with the presence of target organs 

affection e.g. fundus changes or proteinuria. 

5- Mercury column sphygmomanometer is the standard and electronic devices 

need to be periodically checked. 

The cuff should be comfortably surrounding the arm without being loose or 

pressing firmly, the tubes should be medial and the air bag should be 

centered over the brachial vessels with the cubital fossa uncovered for 

palpation of the brachial pulse. Air is pushed into the bag and the mercury 

column is raised quickly till brachial artery pulsation is not felt then

pressure is released gradually (2cm/beat). The first sound (phase I 

Korotkoff-sounds) is the systolic blood pressure. This is followed by silence 

(Phase 2 Korotkoff) which is sometimes called latent period which is 

responsible for improper measurement if palpation method was not 

followed. This is followed with reappearance of sound (phase 3 Korotkoff) 

which can be mistaken as phase 1 Korotkoff if palpation of brachial pulse is 

not used. This is followed by a sudden decrease in sound intensity 

(muffling) which is called phase 4 Korotkoff and is considered by some 

authorities as the diastolic blood pressure in normal persons. In patients 

with hyperdynamic circulation (Severe anaemia, Aortic reguirge, 

thyrotoxicosis....) all authorities consider phase 4 Korotkoff as the diastolic 

blood pressure. Muffling of sound is followed with the disappearance of 

sound (phase 5 Korotkoff), which is considered as the diastolic blood 

pressure by some authorities. 

On the first time to measure blood pressure for a patient we have to do this 

for the two arms and the higher one (usually the dominant arm) unless 

there is anatomic or pathologic abnormalities. It is considered for future 

assessment of blood pressure for this patient. Blood pressure should be 

measured in lying and standing positions for the diagnosis of postural 

hypotension. On standing position, systolic blood pressure fall should not 

be more than 15 mmHg. 

Investigations For Hypertension: 

As more than 90% of hypertension is idiopathic, not all hypertensive 

patients have to be subjected to intensive investigations to identify the 

etiologic cause. Yet, all the hypertensive patients should be investigated for 

other risk factors as plasma lipids and glucose tolerance test and serum uric 

acid. 

Indications for the investigations of the etiologic causes of 

hypertension: 

1- Absence of family history of hypertension. 

2- Age below 30 or above 60 years. 

3- Loss or failure to control blood pressure despite use of combination 

therapy. 

4- Presence of symptoms or signs suspecting secondary hypertension as 

cushingoid features, periodic paralysis, epigastric bruit, symptoms of 

catecholamine release, episodic hypertension, clinical or laboratory 

evidence of renal disease as proteinuria.

According to the manifestations associated with hypertension one may plan 

for investigative priorities. For example paroxysmal hypertension will be an 

indication for the investigation of pheochromocytoma. In absence of 

manifestations suggestive of endocrine involvement, one has to start with 

the investigations for renal etiology being the commonest among the 

causes of secondary hypertension. 

Treatment Of Essential Hypertension: 

A- Non-pharmacologic treatment: 

It includes weight loss, low salt diet, physical exercise, giving up 

smoking, reduction of alcohol intake, Yoga and similar biofeedback 

techniques. This is indicated and may be the only approach required in 

patients with mild hypertension (BP < 160/105) especially obese and high salt 

users. 

The non-pharmacologic treatment should be kept as a background 

treatment for those with more severe hypertension. 

B- Pharmacologic treatment: 

1- Diuretics: 

Loop diuretics (Furosemide, bumetanide and ethacrynic acid) which are 

potent diuretics acting on loop of Henle are not used in the treatment of 

benign hypertension. They are used only in patients with renal impairment, 

patients with marked salt and water load and in severe uncontrollable 

hypertension usually in combination with minoxidil or ACEI. 

Thiazides as hydrochlorothiazide are the commonly used diuretics in 

hypertensive patients. They act on proximal and distal convoluted tubules. 

They may be used singly (25 mg/d) or in combination with other diuretic 

(potassium sparing diuretic triamterine or amiloride) or with other hypotensive 

drug commonly ACEI and B-blockers. The mechanism of the hypotensive 

action of diuretics is unknown, but mostly through the depletion of body 

sodium content. 

The side effects of thiazide diuretics include: 

• Male impotence 

• Skin rash 

• Thrombocytopenia 

• Insulin resistance and hyperglycemia 

• Hyperuricaemia 

• hypokalaemia 

• Hypertriglyceridaemia and decreased high density lipoproteins 

• Hypercalcaemia.

2- Vasodilators: 

This group includes Hydralazine, minoxidil, diazoxide and sodium 

nitroprusside. 

Hydralazine is mainly used in hypertension with pregnancy. It carries 

the risk of the development of lupus erythematosus like syndrome especially 

when large dose is used or in slow acetylators which metabolize the drug very 

slowly. 

Minoxidil is the most potent hypotensive drug. It is administrated as last 

resort when all drugs fail to control blood pressure. The main side effects of 

minoxidil are oedema, palpitation, hirsutism and pericarditis; so it should be 

given in combination with B-blocker and diuretic. 

Diazoxide is given as intravenous bolus mainly in hypertensive 

emergencies. 

3- Centrally Acting Hypotensives: 

These mainly include clonidine (catapress) and α-methyl DOPA 

(Aldomet). Beside the central action, Aldomet acts also through formation of a 

false neurotransmitter in peripheral nerves. 

The main side effects of this group are drowsiness and male 

impotence. Moreover, Clonidine, causes depression and increased thirst. 

Aldomet may trigger autoimmune disease causing haemolytic anaemia and 

hepatic fibrosis. 

Since the introduction of B-blockers in practice, the use of centrally 

acting hypotensive drugs has been much reduced. Aldomet is still the drug of 

choice in hypertension with pregnancy. 

4- α-Adrenergic blockers: 

Prazosin (Minipress) is the main currently available drug among this 

group. 

Centrally acting drugs have a peripheral α-adrenergic inhibitory effect 

through stimulation of CNS α-adrenergic receptors and consequent reduction 

of outgoing sympathetic nerve traffic. 

Longer-acting α-adrenergic blocking agents are becoming available as 

doxazosin, terazosin and trimazon. 

α-adrenergic blockers inhibit the sympathetic venoconstrictor response 

to upright posture so postural hypotension is a predictable adverse effect. This 

problem occurs mainly with first dose, in elderly and when big dose is used. 

To avoid this adverse effect we have to start with smaller doses. The first dose 

should be given immediately before the patient goes to bed.

α-adrenergic blocker are mildly hypocholesterolaemic and may have an 

inhibitory effect on cell growth (similar to ACEI); so, this group of drugs may 

be of special privilege in the presence of hypercholesterolaemia and left 

ventricular hypertrophy. 

5- B-Adrenergic Blockers: 

The non-selective B-adrenergic blockers (propranolol) is rarely used 

now as hypotensive drugs due to their many side effects. 

The cardioselective B-adrenergic blockers (e.g. Atenolol and 

Metoprolol) are widely used as hypotensives although are not purely selective. 

Several effective compounds have been synthesized. They have B- 

adrenergic blocking activity and another property such as labitalol (Trandat) 

which has both α and B-adrenergic blocking activity; carvedilol (Dilatrend) 

which has both α and B-adrenergic blocking effects as well as an anti oxidant 

properties, and celiprolol which has both B-blocking and smooth muscle 

relaxing action. 

B-adrenergic blockers are of choice in hypertensive patients with 

anxiety, arrhythmia, left ventricular diastolic dysfunction or with ischaemic 

heart disease. 

B-blockers (even cardio-selective) are better avoided in hypertensive 

patients with bronchospasm, diabetes mellitus, peripheral vascular disease, 

conduction defect; or with systolic dysfunction. Fatigue and bronchospasm are 

the major causes of conversion from B-blocker to other drug groups. 

6- Calcium channel blockers: 

This group of drugs block cellular calcium traffic essential for the 

calcium dependent phase of action potential causing a direct smooth muscle 

relaxation and consequent arteriolar vasodilatation. Beside peripheral vessels, 

these drugs may affect cardiac contractility (negative inotropic) and 

conducting system of the heart (negative chronotropic) as with verapamil and 

diltiazem, or may cause coronary vasodilatation as with Nifedipine or mainly 

peripheral vasodilator with non-significant cardiac effect as Amlodipine. 

These drugs may cause unwanted effects such as: 

• Flushing, headache or oedema lower limbs (mainly nifidipine) 

• Systolic dysfunction and bradycardia (mainly verapamil) 

7- Angiotensin-converting enzyme inhibitors (ACEI): 

ACEI are group of drugs introduced to the medical practice so as to 

control blood pressure through the interference with the vasopressor action of

the angiotensin II. There are three generations of these drugs, the first is the 

short acting captopril and most of the second generation are long acting drugs 

as fosinopril, Ramipril and quanipril. These two generations achieve their 

action through the inhibition of the angiotensin I converting enzyme. The third 

generation of these drugs e.g. valsertan (tareg) are not ACEI, rather they are 

blockers of the angiotensin II receptor sites. As angiotensin converting 

enzyme is originally classified as kininase II degrading many small 

physiologically active peptides including bradykinin. The first two generations 

of ACEI extend their hypotensive action through this mechanism while the 

third generation drugs are specific in their action as blockers of angiotensin II 

receptor site. 

Initially, ACEIs exert their hypotensive action through an action on 

circulating angiotensin II, but later, this is extended to pulmonary tissue and 

arterial wall renin-angiotensin system. 

ACEI are the drug of choice in the presence of proteinuria (especially in 

diabetics), congestive heart failure, and in the presence of peripheral vascular 

disease (unless there is concomitant renal artery stenosis). 

ACEI, are better not to be given with B-blockers or Aldosterone 

antagonist for the risk of hyperkalaemia. 

ACEIs cause systemic arteriolar vasodilatation, inhibit the synthesis of 

aldosterone and reduce α-adrenergic supply to arterioles, the proximal tubule 

sodium absorption and suppression of thirst. 

ACEI may block the vasoconstrictor action of angiotensin II on the 

glomerular efferent arterioles decreasing the intraglomerular pressure. This 

action could be one of the mechanisms of the anti-proteinuric action of ACEIs. 

Adverse effects of ACEI include: 

1- Renal impairment resulting from loss of the compensatory efferent arteriolar 

vasoconstriction which is an important mechanism maintaining the GFR in 

situations as in renal artery stenosis and in congestive heart failure 

especially when diuretics are used. 

Renal failure may be severe with renal artery stenosis but gradual and 

partial with CHF. With RAS, renal failure will be manifest only if it is 

bilateral. Otherwise the unilaterally involved kidney will be lost unnoticed. 

2- Cough is a major disadvantage of an unknown mechanism encountered in 

up to 15% of cases. It is claimed that this adverse effect is not observed 

with the third generation ACEI drugs. 

3- Neutropenia is a class effect observed mainly in patients with renal 

impairment.

4- ACEI with sulfhydryl groups may cause proteinuria and membranous 

nephropathy. 

5- Loss of taste, abnormal taste sensation or scalded mouth are observed in 

minority of cases due to abnormal metabolism of some peptides as 

substance P. 

6- Hyperkalaemia as a result of the effect of ACEIs on aldosterone. 

Treatment Strategies of Essential Hypertension: 

• The treating physician has to develop a skill in the use of one or two 

members of each drug group. 

• There is no fixed treatment protocol for hypertension; and the treatment 

should be tailored to individual patients. 

• Patient economic status, compliance potentials and the presence of comorbid 

condition are of value in drug selection. The same hypotensive 

effect obtained by expensive drug could be obtained by a cheaper one. 

Long acting hypotensive drugs with single daily dose are preferable in 

poor compliant patients. ACEIs are preferable when avoiding impotence is 

in mind. For hypertensive patients with concomitant heart failure diuretic 

and ACEIs are preferable. The patient with arrhythmia or ischaemic heart 

disease B-blockers may be of choice. ACEIs are preferably avoided with 

hyperkalaemia and B-blocker avoided with bronchospasm and with 

diabetics liable to hypoglycaemic attacks. 

• Patients presenting with severe hypertension with true hypertensive 

emergency as acute left ventricular failure and pulmonary oedema, 

intracarnial haemorrhage or encephalopathy, central retinal artery 

occlusion or intraocular haemorrhage or in patients with eclampsia. In 

such patients blood pressure should be dropped rapidly. This could be 

achieved either by oral or intravenous drugs. Oral drugs include Nifidepine 

sublingual (or the capsule could be crushed orally then swallowed), 

sublingual ACEI or large doses of labitalol (400 mg), prazosin or 

amlodipine. Intravenous drugs include diazoxide in 15 mg boluses at 1-5 

min. intervals, or sodium nitroprusside intravenous infusion. 

• In patients presenting with severe hypertension of 180/120 or above with 

only severe headache, dizziness, blurring of vision or nausea, abrupt 

reduction of blood pressure may cause cerebral stroke and blood pressure 

should be decreased steadily, i.e. over 6-8 hours.

Secondary Hypertension 

A- Renal Hypertension: 

Renal hypertension is the commonest type of secondary hypertension. 

This may be due to diseases of the renal artery as renal artery stenosis 

(renovascular hypertension) or disease of the renal parenchyma as 

glomerulonephritis (Renoparenchymal hypertension). 

Pathogenesis: 

Hypertension may develop owing to either: 

• Excess secretion of renin with a consequent more angiotensin II activity. 

Angiotensin II has a vasopressor activity and stimulates Aldosterone which 

causes salt and water retention. 

Excess renin release may occur mainly with renal artery stenosis. 

However, this will occur in some types of renoparenchymal hypertension 

due to kink or distortion of intrarenal vessels as in case of renal cyst in 

PCKD or by scar in reflux nephropathy and analgesic nephropathy. 

• Vasopressor substances as Endothelin will be released by the diseased 

kidney. Endothelins are cyclic peptides released by arteriolar endothelium. 

They may have a vasoconstrictor action and strong platelet activation. 

• Failure to secrete salt and water load because of the decreased nephron 

mass. This will lead to the expansion of the extracellular volume and 

hypertension. 

• Failure to secrete vasodilator substances such as prostaglandins, platelet 

activating factor and kinins due to decreased nephron mass. 

Treatment: 

1- Treatment of renal disease as renal artery stenosis by balloon dilatation or 

bypass surgery and SLE by steroids and immunosuppressive drugs. 

2- Control of hypertension in renal patients may be a part of the treatment of 

the renal disease as it is known that uncontrolled hypertension is one of 

the major factors causing progression of renal damage and scarring. 

3- Any drug which controls hypertension will be valuable but it seems that, in 

the presence of significant proteinuria, ACEIs may be superior in the 

prevention of glomerular scarring. On the contrary, in the presence of renal 

artery stenosis this group of drugs are contraindicated.

Renovascular Hypertension (RVH) 

Renal artery stenosis (RAS) is the most common cause of potentially 

curable secondary hypertension. It has been reported to occur in 0.5% of 

hypertensive population. The prevelance may be much higher among 

selected a group of patients, e.g. elderly with severe hypertension and high 

serum creatinine. In such a group of patients a prevelance up to 70% of RAS 

has been reported. 

Pathogenesis of Renovascular Hypertension: 

For better understanding of the pathogenesis of renovascular 

hypertension, we have to go through the experimental models of RVH. 

Goldblatt experimental model of Renovascular hypertension (Fig. 14.4): 

Goldblatt and his colleagues induced hypertension in dogs by putting a 

clip around the renal artery causing renal artery stenosis with 75% reduction 

of the arterial lumen. Two experimental models have been described. They 

have comparable clinical situations, the first is called two kidney on clip 

(2k/1C) and the second is either two kidney, two clip (2K/2C) or one kidney, 

one clip (1K/1C). 

2K/1C 2K/2C 1K/1C 

Unilateral Bilateral RAS RAS in a solitary 

RAS 

kidney 

(Fig. 14.4 ) 

Different experimental models of renovascular hypertension and their corresponding clinical examples.

A-Two-kidney-one-clip (2K/1C) model for renovascular hypertension : 

In this model, renal artery stenosis is induced in one kidney and the 

contralateral kidney is left intact. In the early phase of this model, it is 

observed that: 

1- In the ischaemic side : 

• The kidney secretes more renin; and more angiotensin II is formed 

causing systemic hypertension. 

• As this kidney is hypoperfused, excess sodium and water are 

reabsorbed by the renal tubules. Consequently, the urinary Na + is 

low, urine volume is low and urine osmolarity is high. 

2- In the contralateral side. 

• There is a suppression of renin activity by the excess circulating 

angiotensin II. 

• There is a decreased tubular reabsorption of water and sodium in 

addition to increased urine volume; as a reaction to the extracellular 

fluid volume expansion induced by the ischaemic kidney. 

• The changes in this side are attempts by the healthy kidney to 

compensate for the changes in the ischaemic side. 

3- Systemic hypertension in this phase is renin dependent and shows a good 

response to ACE inhibitors or releasing the arterial clip while no response 

will occur to diuretic therapy. 

In a late phase (long time after induction) of this model, it is observed that: 

1- In the contralateral kidney, the long standing hypertension will cause 

structural changes in its vascular bed and it will become ischaemic as well 

with failure of its capacity to compensate for the changes occurring in the 

side of RAS. Consequently, there will be no compensatory natriuresis or 

suppression of its renin activity. 

2- There will be extracellular fluid volume expansion which will suppress renin 

secretion; and angiotensin II level will go down. 

3- Hypertension in this phase is mainly volume dependent with no response to 

ACEIs or to releasing the arterial clip. Diuretics may decrease the blood 

pressure, but the dog will always be hypertensive because of the 

irreversible changes in the systemic vascular bed induced by the long 

standing hypertension.

B-One-kidney-one clip (1K/1C) and two-kidney-two clip models of RVH : 

In the very early phase of these models, the hypertension is renindependent 

but by time-as the salt and water retention induced by the renal 

hypoperfusion is progressive-the animal will be volume expanded and 

hypertension will be volume dependent. 

In the late phase of 2K/1C, 1K/1C and 2K/2C models, if there is no 

systemic vascular bed damage, diuretics if given will render these models 

renin dependent. 

Etiology of Renovascular Hypertension : 

The two most common causes of RAS are atherosclerotic RAS and 

fibromuscular dysplasia of renal artery. 

Atheromatous RAS is more common in males than it is in females (2 : 

1) with a peak age of incidence of 60 years. The disease usually starts 

unilateral but may extend to be bilateral. It usually involves the proximal part 

of the vessels and is a part of systemic disease with a concomitant coronary, 

mesenteric and peripheral vascular involvement. In 20% of cases RAS may 

occur without other major vessels affection. Usually the obstruction involves 

the proximal part of the renal artery. Not uncommonly the lesion may be 

osteal (i.e. in the aorta or at the origin of the renal artery). 

Fibromuscular dysphasia (hyperplasia) is more common in middleaged 

females, the disease starts in the middle of the renal artery and extends 

distally to its main branches. The disease is multifocal, giving the renal artery 

the beaded appearance (Fig. 14.5). It starts unilateral and may progress to 

be bilateral, but the total arterial occlusion is much less common than it is in 

the atheromatous renal artery disease. 

Screening for renal artery stenosis : 

The criteria of patients in whom RAS should be suspected, and 

consequently have to be subjected to aggressive investigations are the 

following:- 

1- Those with hypertension starting at age below 30 years. 

2- Those with abrupt onset of hypertension. 

3- Those with a definite worsening of previously well-controlled hypertension. 

4- Presence of epigastric bruit (Systolic and diastolic). 

5- Hypertension resistant to triple therapy which includes a diuretic, especially 

in atherosclerotic patient.

(Fig. 14.5 ) 

An angiogram showing a renal 

Artery stenosis due to fibromuscular 

dysplasia. There are alternating 

areas of constricition and dilatation 

-the so-called "beaded" appearance. 

6- Deterioration of the kidney function, especially with the use of ACE 

inhibitors. 

7- Patient with peripheral vascular disease as gangrene, claudications or 

vasculitic-like rash. 

Diagnosis of Renal Artery Stenosis: 

Renal artery stenosis can exist incidentally in patient with essential 

hypertension. In this situation, intervention (surgical or with PTCA) is of no 

clinical value. 

The tests used for the diagnosis of RAS include: 

1- Ultrasonography 2- Echo-Doppler renal vessels 

3- Rapid sequence urography (IVP) 4- Isotope Renogram 

5- Angiography 6- C-T (spiral, Digital, 3 dimensional) 

7- MR angiography 

For more details see chapter-1 (Radiologic Investigations) 

The ideal test for diagnosis of RAS is the one which will not only 

diagnose the anatomic abnormality, but also predicts the functional 

significance of the RAS; and the also least invasive.

Renal angiography is currently the best test for the diagnosis of RAS 

but it carries the disadvantage of being invasive and of less predictive value 

as regards the response to treatment. 

Use of captopril will increase the sensitivity and the predictive value of 

isotope renogram and Doppler ultrasonography. These two tests have the 

advantage of being non-invasive, but require experienced hand. 

Assessment of renal vein renin (RVR) will help in predicting the 

outcome after interference (PTCA or surgical). This is achieved by obtaining 

venous samples from the renal vein of the stenosis side, renal vein of the 

contralateral side and from the vena cava inferior to the renal veins. The best 

response to PTCA or surgery will be obtained when the RVR of the ischaemic 

kidney is higher than that of the vena cava renin and both are higher than that 

from the contralateral kidney (local suppression). Also, the higher the ratio of 

RVR of the ischaemic to the contralateral side (> 1.5 : 1) the better is the 

response to the interventional treatment. 

Ultrasonographic finding of a unilateral smaller sized kidney may be 

suggestive of RAS and may indicate further investigations. 

Treatment of Renal Artery Stenosis: 

The target of treatment of RAS is to achieve both the proper control of 

hypertension and the prevention of ischaemic kidney damage (ischaemic 

nephropathy). 

The small sized kidney will not recover after revascularization. So we 

have to treat RAS early so as to conserve the kidney tissue and function. 

Collateral circulation may maintain the renal blood supply till a reduction of 

renal artery lumen by RAS up to 50-60%. More reduction will be followed by 

significant renal ischaemia with a consequent hypertension and ischaemic 

nephropathy. 

The treatment options are either medical, percutaneous i.e. 

translumenal angioplasty (PTCA- balloon dilatation with or without stenting), 

or surgical treatment (bypass, endartrectomy....). 

The decision regarding the type of treatment depends on :- 

1- Local experience and facilities available. 

2- Patient's age. 

3- Degree of control of blood pressure. 

4- State of kidney function. 

5- Site of arterial stenosis.

PTCA will be tried as example in young patient with accessible renal 

artery stenosis caused by fibromuscular dysplasia. Successful correction in 

these cases could reach up to 90%; and the cure from hypertension could be 

achieved in 60% (i.e. in 30% of cases hypertension may persist despite 

successful dilatation). After dilatation of the renal artery a stainless-steel stent 

will be left in place to prevent re-stenosis. 

Balloon dilatation carries the risk of recurrence, vessel trauma 

haemorrhage, cholesterol emboli and even the kidney loss. 

Atherosclerotic patient with uncontrollable hypertension or with a failing 

kidney function should be treated either by angioplasty or by surgical 

correction. 

Medical treatment is the best choice in patients who are responsive to 

hypotensive drugs, with stable kidney function; or when PTCA or surgical 

interference are risky or unavailable. Medical treatment includes giving up 

smoking, the treatment of hyperlipidaemia and hypotensive drugs (other than 

ACEI). In future, laser will be routinely applicable for vessel dilatation, 

especially in atherosclerotic RAS. 

Ischaemic Nephropathy 

Ischaemic nephropathy is a progressive kidney damage resulting from 

a progressive decrease of the renal artery lumen. At least 75% loss of arterial 

lumen is required for the ischaemic renal damage to occur. Development of 

collaterals may help in slowing or minimizing the kidney damage induced by 

RAS. If the renal artery stenosis is unilateral, it will manifest as hypertension. 

But if it is bilateral, it will manifest by both hypertension and progressive loss 

of kidney function. 

Angioplasty is indicated in patients with ischaemic nephropathy even 

when hypertension is not severe and responding to medical treatment. Good 

response is obtained when serum creatinine is less than 4 mg/dl. 

Ischaemic nephropathy is usually suspected in patient with advanced 

atherosclerosis presenting with hypertension and serum creatinine is > 1.5 

mg/dl. In such cases, urine sediment is normal and renal U.S. shows no 

urinary tract obstruction but may show that one of the two kidneys smaller 

than the other. Further investigations as Echo-Doppler will show the bilateral 

renal artery stenosis.

B- Conn's Syndrome-Primary hyperaldosteronism: 

This is characterized with excess aldosterone which is due to excess 

secretion by adenoma or hyperplasia of the zona glomerulosa of the adrenal 

cortex. This will result in hypokalaemia and metabolic alkalosis. Plasma 

sodium will be high and bicarbonate will be above 30 mmol/L, also plasma 

renin will be low. Patients with Conn's syndrome usually present with muscle 

weakness and mild hypertension. In few cases with Conn's syndrome, the 

course of this disease will be marked with malignant hypertension and stroke. 

Treatment depends mainly on surgical excision and in bilateral cases 

steroid replacement may be needed. 

C- Pheochromocytoma: 

This is a tumour of chromaffin cells occurring in all age stages. In 

children, the tumour is always highly malignant (neuroblastoma and 

medulloblastoma), while in adults the tumour is always benign. Yet, 

hypertension will have a sinister prognosis if untreated properly. 

In 90% of cases the tumours is in adrenal medulla while in 10% the 

tumour is extra-adrenal affecting the sympathetic chain. It could be multiple 

and malignant. The extra-adrenal tumour could be abdominal or even 

thoracic. 

Beside the clinical criteria of this tumour, serum and urinary 

catecholamine assay will confirm the diagnosis. 

Localization of tumour site is mandatory for surgical excision. This is 

usually carried out by isotope scanning using the tracer meta-iodo 

benzaguanin (MIBG). The tumour is extremely sensitive to X-ray contrast 

media, on exposure it will secrete a huge amount of catecholamine with fatal 

outcome. So, in hypertensive patient if pheochromocytoma is expected, this 

should be excluded first; by catecholamine assay before the patient is 

subjected to the contrast media. 

Treatment is by hypotensive drugs having α and B-adrenergic blocking 

properties as labetalol and carvedilol. They are the drug of choice. The 

definitive treatment is surgical excision.


- Stanley JC: David M. Hume memorial lecture. Surgical treatment of 

renovascular hypertension. Am J Surg, 174 : 2, 102-10, 1997. 

- Ram CV: Renovascular hypertension. Curr Opin Nephrol Hypertens, 6 : 

6, 575-9, 1997. 

- Tikkanen T, et al: Diagnosis and therapy of renovascular hypertension. 

Duodecim, 111 : 15, 1453-60, 1995. 

- Koomans HA, et al: Tony Raine Memorial Lecture. Hypertension and the 

kidney: culprit and victim. Nephrol Dial Transplant, 11 : 10, 1961-6, 1996. 

- Rodicio JL: Does antihypertensive therapy protect the kidney in essential 

hypertension J Hypertens Suppl, S69-75; Discussion S75-6, 1996. 

- Cowley AW, Jr, et al: The role of the kidney in hypertension. JAMA, 275 : 

20, 1581-9, 1996. 

- Perazella MA: Lead and the kidney: nephropathy, hypertension, and 

gout. Conn Med, 60 : 9, 521-6, 1996. 

- Chapman AB, et al: Hypertension in autosomal dominant polycystic 

kidney disease. Kidney Int Suppl, 61 : S71-3, 1997. 

- Zucchelli P, et al: The kidney as a victim of essential hypertension. J 

Nephrol, 10 : 4, 203-6, 1997. 

- Navar LG: The kidney in blood pressure regulation and development of 

hypertension. Med Clin North AM, 81 : 5, 1165-98, 1997. 

- Whelton PK, et al: Kidney damage in 'benign' essential hypertension. 

Curr Opin Nephrol Hypertens, 6 : 2, 177-83, 1997. 

- Ram CV, et al: Renovascular hypertension. Semin Nephrol, 15 : 2, 152- 

74, 1995.

- Stanley JC: Renovascular hypertension in women. Semin Vasc Surg, 4, 

306-16, 1995. 

- Aurell M, et al: Treatment of renovascular hypertension (editorial). 

Nephron, 75 : 3, 373-83, 1997. 

- Romero JC, et al: New insights into the pathophysiology of renovascular 

hypertension. Mayo Clin Proc, 72 : 3, 251-60, 1997. 

- Tesar V: Hypertension in kidney failure and its treatment. Cas Lek Cesk, 

137 : 14, 438-41, 1998. 

- Tesar V: Hypertension in diseases of the kidney. Pathogenesis and 

therapy. Cas Lek Cesk, 29 : 137-13, 410-4, 1998.

MISCELLANEOUS 

PROTEINURIA 

Proteinuria is a rare presenting complaint of patients. Yet, when severe 

enough, it may cause hypoalbuminaemia and oedema. As protein in urine 

decreases the surface tension, it causes frothy urine which may be observed 

by some patients (bile salts and detergents used in toilets do the same). 

Abnormal protein excretion is usually albumin, small molecular weight 

proteins, immunoglobulins and Bence Jones protein. 

The urine is tested for proteinuria by dip stick test. Dipstick is a plastic 

strip, attached to it is a paper impregnated with chemical substance 

(tetrabromophenol) which is normally yellow in colour and changes according 

to amount of protein in urine (0, +, ++, +++). It can detect a protein down to a 

concentration of 300 mg/l. Proteinuria detected by dip stick test should be 

confirmed by collecting the 24 hours urine and testing for quantity of 

proteinuria using chemical methods. 

Definitions: 

• Proteinuria is a secretion of an abnormal amount of protein in urine. 

Normal protein excretion per 24 hours in adults is less than 200 mg. Most 

of this protein is albumin and Tamm Horsfall protein with smaller amounts 

of immunoglobulins. 

• False positive proteinuria by dip stick occurs mainly when urine is alkaline 

and very concentrated; or if the stick test is left in urine for long time. 

False negative proteinuria is observed when protein excretion is mainly 

Bence Jones proteinuria and when urine is very diluted. 

• Bence Jones protein which is the light chain fraction of immunoglobulin 

appears in abnormal amounts in urine in cases of multiple myeloma, clots 

at temperature 45-55°C, above and below that range it dissolves in urine. 

Presence of Bence Jones proteinuria should be confirmed by 

immunoelectrophoresis. 

• The causes of Bence Jone's proteinuria include: multiple myeloma, 

amyloidosis, adult Fanconi syndrome, benign monoclonal gammopathy 

and hyperparathyroidism. 

• Microalbuminuria is defined as an abnormal amount of urine (> 200 

mg/24hr) but below the sensitivity of dipstick (< 300 mg/l). It could be 

detected by sensitive methods e.g. Radioimmunoassay or ELISA. In 

diabetic patients the presence of microalbuminuria means that the patient 

may develop frank diabetic nephropathy within few years.

• Orthostatic proteinuria means proteinuria related to posture. The first 

voided urine in the morning is free of protein, but at the end of the day the 

urine will contain abnormal amount of protein, it is very common in the 

young, being present in about 30% of children, but only 5% of young 

adults. The mechanism is unknown. Possibly, the lordotic position of 

vertebral column encroaches upon the venous return from the kidney 

causing proteinuria. 

• Tubular proteinuria means proteinuria of tubular origin (i.e. due to tubular 

disease), usually it is of low molecular weight e.g. B 2 -microglobulin and 

less than 2 grams/day. 

• Glomerular proteinuria means proteinuria of glomerular origin (i.e. due to 

glomerular disease). Usually it is albumin and globulins and more than 2 

grams/day. 

• Selectivity of proteinuria If the abnormal protein excreted is mainly albumin 

(> 85%). It is called selective proteinuria. If both albumin (low molecular 

weight protein) and globulins (large molecular weight protein) are nearly 

equal it is called non-selective proteinuria. Proteinuria in minimal change 

nephritis is highly selective while that in bad prognostic lesions as 

mesangiocapillary glomerulonephritis is poorly (or non-) selective. 

Mechanism of proteinuria: 

There are four known mechanisms for proteinuria. These are: 

1. Abnormality in permeability of the glomerular basement membrane 

because of glomerular disease or abnormal glomerular 

hemodynamics. 

2. Increased concentration of small molecular weight protein in blood 

(MW 60000- 70000) e.g. hemoglobin, myoglobin and 

immunoglobulin light chains. These will pass easily through the 

normal GBM 

3. Tubular disease with inadequate reabsorption of normally filtered 

proteins of MW

a. Strenuous exercise 

b. Fever 

c. Orthostatic proteinuria 

d. Miscellaneous 

(Thyrotoxicosis, severe anaemia, CNS lesions) 

II. 

Patients with proteinuria of 0.5-3.5 gm/d: 

a. Acute interstitial nephritis. 

b. Chronic interstitial nephritis such as bacterial (pyelonephritis), gouty 

nephropathy, analgesic nephropathy or nephrolithiasis. 

c. Tubular proteinuria such as Fanconi syndrome, heavy metal 

intoxication (lead, cadmium), multiple myeloma, hypokalaemic 

nephropathy, polycystic kidney disease and medullary cystic kidney 

disease. 

III. 

Patients with proteinuria of more than 3.5 gm/d: 

Usually caused by glomerular disease. 

a. Primary glomerular disease: refers to all types previously discussed 

under glomerulonephritis. 

b. Secondary glomerular disease is Previously discussed under 


Investigations of a case of proteinuria: 

1. Characterization of proteinuria: After diagnosis of proteinuria by dip 

stick test, it should be confirmed by quantitative estimation of 24 hours 

proteinuria. Further assessment may include electrophoresis or 

immunoelectrophoresis to determine the type of abnormal protein 

excreted. 

2. Urine analysis: For pus cells (to diagnose U.T. infection), RBCs and 

casts (to diagnose glomerular disease), also urine volume (oliguria or 

polyuria), pH of urine, specific gravity and test for glycosuria; and 

aminoaciduria and B 2 microglobulin (may help in the diagnosis of tubular 

disease). 

3. Blood and serologic examination: 

a. Kidney function tests: serum creatinine, creatinine clearance, 

electrolytes (Na, K, Ca, Po 4 ). 

b. Total protein, albumin, cholesterol to diagnose nephrotic syndrome. 

c. Serologic examination e.g. for anti-DNA and complement 

component C 3 and C 4 for diagnosis of lupus erythematosus.

4. Radiologic assessment including: 

a. Examination of the kidney for its size, state of parenchyma, the 

presence of stone, back pressure change or pyelonephritic 

changes. It is achieved through ultrasound examination, plain X- 

ray, and IVP (if the kidney function is normal). 

b. Investigations to discover malignancy which could be the 

etiologic cause of proteinuria e.g. skeletal survey for multiple 

myeloma, X-ray chest and bronchogram or CT scan for 

bronchogenic carcinoma. 

5. Renal biopsy will give the final answer for the diagnosis of the kidney 

lesion causing proteinuria. 

HAEMATURIA 

Definitions 

• Normally the number of RBC's in urine should not be more than 5 

RBCs/high power field on microscopic examination of fresh centrifuged 

urine sample. So, haematuria is defined as a secretion of more than 5 

RBCs/HPF in urine. 

• Haematuria may be the only symptom or associated with other 

symptoms, according to the etiologic cause e.g. loin pain and fever with 

infection and renal colic with renal stones. 

• Haematuria could be gross (causing red-coloured urine) or microscopic 

(urine appears normal. But RBCs are seen on microscopic 

examination). 

In gross hematuria, urine looks red if alkaline, but brown or coca-cola 

like if urine is acidic due to denaturation of the hemoglobin. 

• Also, hematuria could be glomerular (because of glomerular disease, 

sometimes called medical); or non glomerular (sometimes called 

surgical). Glomerular could be differentiated from non glomerular 

haematuria by: 

1. The shape of RBCs in urine is dysmorphic in cases with glomerular 

haematuria while it will be normal in case of non glomerular 

haematuria. 

2. The size of RBCs whose mean corpuscular volume in urine of patient 

with glomerular haematuria which is smaller than it is in peripheral 

blood. But in non glomerular cases it is equal. 

3. Proteinuria is present in most cases of glomerular hematuria but not in 

cases of non glomerular hematuria.

4. Casts such as proteinuria. 

5. Blood clots indicate non-glomerular bleeding and can be associated 

with pain & colic. 

Differential Diagnosis of Hematuria: 

A. First, hematuria should be differentiated from other causes of red or 

brownish urine: 

- Microscopy will show RBC's only with hematuria. 

- Dipsticks (Hemastix) will be positive with hemoglobinuria (hemolysis) 

and myoglobinuria (muscle damage) but negative with other causes 

e.g. porphyrins (in porphyria), bile (in jaundice), melanin (in 

melanoma), alkaptonuria, food dyes and drugs as PAS or 

phenylphthalein. 

B. Hematuria may be of renal, ureteral, bladder or urethral origin. 

I. Haematuria of renal origin: 

a. Glomerular haematuria: Either primary glomerular disease (e.g. IgA 

nephropathy, mesangial proliferative glomerulonephritis or crescentic 

glomerulonephritis); or secondary glomerulonephritis i.e. renal 

involvement is a part of systemic disease (e.g. post-streptococcal 

glomerulonephritis, Henoch-Schönlein purpura, SLE, polyarteritis 

nodosa). 

b. Renal infection: Pyelonephritis (especially with papillary necrosis) or 

renal tuberculosis. 

c. Renal neoplastic disease: Renal cell carcinoma, transitional cell 

carcinoma of the renal pelvis and others. 

d. Hereditary renal disease: Medullary sponge kidney or polycystic 

kidney disease. 

e. Coagulation defect: Use of anticoagulant, liver disease and 

thrombocytopaenia. 

f. Renal vascular disease: Renal infarction, renal vein thrombosis or 

malignant hypertension. 

g. Exertional haematuria. 

II. Hematuria of ureteral origin: 

a. Malignancy. 

b. Nephrolithiasis

c. Ureteral inflammatory condition secondary to nearby inflammation e.g. 

diverticulitis, appendicitis or salpingitis. 

d. Ureteral trauma e.g. during ureteroscopy. 

III. Hematuria of bladder origin: 

a. Infection: schistosoma, viral or bacterial cystitis. 

b. Neoplasms. 

c. Foreign body in the bladder e.g. stones. 

d. Trauma: During instrumentation or accidental. 

e. Drug: e.g. cyclophosphamide induced haemorrhagic cystitis. 

IV. Hematuria of urethral or associated structures: 

a. Prostate: acute prostatitis, benign prostatic hypertrophy. 

b. Urethritis, foreign body or local trauma to the urethra. 

Investigations of a case of hematuria: 

1. First exclude haemoglobinuria and myoglobinuria since both of them can 

also cause positive dipstick test for haematuria. This is done by 

microscopic examination of fresh urine sample. In case of haematuria, 

RBCs could be seen while in the other two conditions no RBC's could be 

seen. 

In case of myoglobinuria, clinical examination may show manifestations of 

muscle disease and the examination of urine by immunoelectrophoresis 

may show myoglobin. In case of haemoglobinuria, manifestations of 

haemolysis may be evident. 

2. Examination of urine for proteinuria and casts (to diagnose glomerular 

disease), pus cells and urine culture (for diagnosis of infection), Zeil- 

Nelson stain and specific media (for diagnosis of T.B.). 

3. Plain X-ray, I.V.P. (if serum creatinine is normal), ultrasound and 

possibly angiography, for the diagnosis of surgical diseases e.g. stone, 

malignancy or infection. 

4. RBCs in urine could be examined for its shape to differentiate glomerular 

from non glomerular causes (by phase contrast microscopy). 

5. Kidney function tests. 

6. Specific investigations for diagnosis of systemic diseases causing 

haematuria e.g. SLE. 

7. Kidney biopsy for glomerular haematuria.

VALUE OF URINE EXAMINATION IN MEDICAL DIAGNOSIS 

Normal Urine Characters: 

1. Volume is 600-2500 ml/24 h (average is 1200 ml/24 h). 

2. Colour is umber yellow. 

3. Specific gravity is 1003-1030 (represents amount of solids in urine). 

4. pH is 4.6-8.8 (average 6.0) 

5. Protein: The amount as detected by semiqualitative methods is 

0.0-0.1 gm/24 hr urine. 

6. Cells and casts: 

- R.B.C.s and W.B.C.s. < 5 by H.P.F. 

- Hyaline casts occasionally present (protein collected in the renal 

tubules taking a cylinderical shape producing occasional hyaline casts). 

7. Glucose: should be negative. 

8. Some other substances may be present e.g.: 

- Calcium < 150 mg/24 hr. 

- Phosphate : 1mg/24 h. 

- Amylase: 260-950 mg/24h. 

- Creatinine: 1.6 gm/24 h (15-25 mg/kg/24h). 

- Porphyrin: 50-300 mg/24h. 

- Ketones: qualitative amounts. 

How to examine urine: 

We have to comment on the following items: 

- Volume/24 h 

- Specific gravity (osmolality) 

- Colour of urine 

- Dip stick examination of urine 

- Microscopic examination. 

1. Volume of urine: 

Changes in urine volume may be oliguria or polyuria: 

Polyuria: 

(Urine volume > 2500 ml/day) may occur with: 

- Diuretics 

- Excessive water intake (within the normal range). 

- Compulsive water drinking in psychological cases (psychogenic 

polydepsia). 

- Uncontrolled D.M.

- Diabetes insipidus which may be central or nephrogenic. 

• In central D.I. there is a decreased A.D.H. secretion. 

• In nephrogenic D.I. the renal response to A.D.H. is defective as 

in analgesic nephropathy and medullary cystic kidney disease. 

- Early stage of chronic renal failure. 

- Diuretic phase of acute renal failure. 

(for more details see chapter on hypernatraemia) 

Oliguria: 

(Urine volume < 600 ml/day), may occur with: 

i. Obstructive causes: 

Mainly produce anuria i.e. no urine at all, should be differentiated 

from urine retention by detecting urine in the bladder (suprapubic 

dullness, by U.S., or by urethral catheter). 

- Removal of solitary functioning kidney. 

- Bilateral ureteric obstruction (or unilateral ureteric obstruction of 

a solitary functioning kidney). 

- Retro-peritoneal fibrosis blocking ureteric flow. 

ii. 

iii. 

Nonobstructive causes: 

Mainly produce oliguria: 

- Inadequate renal perfusion e.g. with vomiting, or diarrhea will 

cause depletion of body salts and fluids. 

- Intravascular volume depletion e.g. with internal haemorrhage 

or rapidly developing ascites. 

Oliguria with intrinsic renal disease: 

- Oliguric phase of acute tubular necrosis. 

- Rapidly progressive glomerulonephritis. 

- Bilateral cortical necrosis. 

- End stage renal failure. 

- Acute nephritic syndrome. 

- Nephrotic syndrome. 

2. Specific gravity: 

Specific gravity represents the amount of solids in urine: 

- Specific gravity is measured by urinometer or by another special 

complicated apparatus which is more perfect (osmometer). 

- Specific gravity is one of the kidney function tests. In D.I. repeated 

measurement of urine specific gravity in face of water deprivation and 

after vasopressin administration is mandatory for proper diagnosis.

3. Colour: 

- Normal: umber yellow 

- Examples of colour changes of urine: 

• Red urine: with hematuria, myoglobinuria and haemoglobulinuria 

(with haemoglobinuria the colour is red brown). 

• Pink: with rifampicin. 

• Orange: concentrated normal urine, urobilin, bilirubin, 

• Deep yellow: Mepacrine. 

• Milky: Chyluria. 

• Smoky: acute glomerulonephritis. 

4. Dip stick examination of urine: 

- Dip stick is a plastic strip with squares of paper impregnated with 

enzymes which change in colour on exposure to target chemicals. 

- Dip stick is used for detection of protein, ketones, glucose, pH, 

haemoglobin, bile, bacteria, pus cells and leucocytes.... 

i. Proteinuria: 

- Normal protein in urine (by quantitative assessment) is

• Drug intoxication, it is advised give alkalies in acidic drug 

intoxication as salicylates and acids in alkaline drug 

intoxication as pethidine. 

• Increase potency of some antibiotics in urinary tract 

infection, alkalies with aminoglycosides and acids with 

tetracyclines are given. 

iii. Haemoglobinuria: 

- Haemoglobin may be present in urine in haemoglubinuria or 

haematuria (differentiated by presence of R.B.C.s in case of 

haematuria). 

- RBCs may rupture in cases of hypotonic urine but RBCs ghosts 

could still be seen. 

- Ascorbic acid may produce false test for haemoglobinuria. 

Causes of Haemoglobinuria 

• Intravascular haemolysis e.g. in severe exercises or severe burns. 

• Chemicals e.g. naphthalene and hydroquinone derivatives. 

• Mismatched blood transfusion. 

• Black water fever. 

• Paroxysmal cold Haemoglobulinuria. 

• Paroxysmal nocturnal Haemoglobulinuria. 

• Snake bites. 

• Vegetable toxins e.g. mushroom poisoning. 

• False Haemoglobinuria. 

• Trans-urethral prostatectomy with post operative washing with 

water, which when absorped cause hypotenicity of blood with 

consequent haemolysis. 

iv. Bacteruria: 

• To collect a urine sample one of the following methods should be 

used: 

- Cleaning of the area around the urethra and a midstream 

urine is collected. 

- Urine specimen may be obtained by a urethral catheter 

(especially in females). 

- Supra-pubic puncture in children. 

• Detection of bacteruria is by colony count what is significant if 

>100,000/ml (indicate infection). False low count may occur with 

high urine flow, antibiotic treatment or contaminated container.

• Direct microscopic examination of urine (stained or unstained) 

has the reliability of about 85-90% of colony count. 

• Microscopic detection of pus cells in urine is less sensitive and 

produces more negative results. 

• Bacteruria may occur in: 

• 10% of pregnant ladies. 

• 15% of diabetic patients. 

• 20% of patients with prostatic enlargement. 

• 95% of patients with catheter for more than 2 days without 

prophylactic antibiotics. 

v. Glycosuria: 

May occur in: 

- Hyperglycaemia which may be endocrinal (e.g. in D.M.) or non 

endocrinal (as liver disease) or due to administration of 

hormones (e.g. corticosteroids, A.C.T.H., thyroid and adrenaline 

drugs). 

- In renal tubular defects e.g. renal diabetes, heavy metal 

poisoning or Fanconi syndrome. 

N.B. 

In renal glycosuria, hypoglycaemic attacks may occur. At the same 

time someone may wrongly give hypoglycaemic drugs which are 

dangerous in such cases so caution should be taken on diet and 

treatment of glycosuria. 

Concomitant hyperglycaemia should be detected before giving 

hypoglycaemic drugs. 

5. Microscopic examination of urine: 

- For cells (type and count). 

- For casts (type and count). Casts may be: 

• Fine granular casts (in chronic renal disease). 

• Hyaline casts (in chronic renal disease). 

• RBCs casts (acute nephritic syndrome). 

• WBCs casts (in U.T.I.). 

• Fat casts (in nephrotic syndrome).

6. Crystals (Fig.1): 

- Crystals mainly appear in alkaline urine e.g. urate, phosphate 

(Treatment depends on the acidification of urine by vitamin C 

then follow up of pH by dip sticks). 

- Crystals in acidic urine e.g. oxalate or uric acid. 

(Fig. 15.1a) 

Shows different crystals 

which could be seen by 

microscopy of urine with 

alkaline pH. 

(Fig. 15.1b) 

Shows different crystals 

which could be seen by 

microscopy of urine with 

acidic pH.

7. Chemicals: 

Determination of 24 hours urine of some chemical substances e.g. 

- Calcium: Increases in hyper-parathyroidism, Vitamin D intoxication. 

ecreases in hypo-parathyroidism, rickets. 

- Porphyrin: Increases in lead poisoning, liver cirrhosis or infective 

hepatitis. 

- Urinary L.D.H. (lactic dehydrogenase): increases in carcinoma of the 

kidney, prostate and bladder, glomerular disease or myocardial 

infarction. 

- Urine catecholamine : Increase in pheochromocytoma (also increases 

level of V.M.A.) and neuroblastoma.


- Ishida M: Approach to proteinuria. Nippon Naika Gakkai Zasshi, 85 : 9, 

1534-9, 1996. 

- Roy S: Proteinuria. Pediatr Ann, 25 : 5, 277-8, 281-2, 1996. 

- Harris KP, et al: Proteinuria: a mediatro of interstitial fibrosis. Contrib 

Nephrol, 118 : 173-9, 1996. 

- Jerums G, et al: Why is proteinuria such an important factor for 

progression in clinical trials Kidney Int Suppl, 63 : S87-92, 1997. 

- Mahan JD: Evaluation of hematuria, proteinuria, and hypertension in 

adolscents. Pediatr Clin North Am, 44 : 6, 1573-89, 1997. 

- Chen L, et al: Proteinuria and tubulointerstitial injury. Kidney Inst Suppl, 

61 : S60-2, 1997. 

- Ahmed Z, et al: Asymptomatic urinary abnormalities. hematuria and 

proteinuria. Med Clin North Am, 81 : 3, 641-52, 1997.

RENAL MANIFESTATIONS OF SYSTEMIC DISEASES 

Systemic diseases which may involve the kidney include the following 

groups: 

1- Systemic lupus erythematosis. 

2- Systemic vasculitis 

• Polyarteritis nodosa. 

• Wegener's granulomatosus 

• Henoch-Schönlein purpura 

• Churg-Strauss disease. 

• Giant cell arteritis 

3- Anti-GBM disease. 

4- Thrombotic Microangiopathy 

• Haemolytic uraemic syndrome. 

• Thrombotic thrombocytopaenic purpura. 

• Postpartum renal failure. 

5- Connective tissue diseases. 

• Rheumatoid arthritis. 

• Sjogren's syndrome. 

• Behcet's diseases 

• Rieter's syndrome 

• Systemic sclerosis (scleroderma). 

• Mixed connective tissue disease 

6- Metabolic diseases. 

• Diabetes mellitus. 

• Amyloidosis. 

• Gout. 

• Abuse of NSAID's. 

• Nail-patella disease 

• Fabry's disease. 

7- Haematologic diseases. 

• Cryoglobulinaemia. 

• Sickle cell anaemia. 

• Leukemia and lymphoma. 

• Multiple myeloma. 

• Paraproteinaemias.

8- Malignancy. 

9- Systemic infections as 

• Tuberculosis. 

• Schistosomiasis. 

• Malaria. 

• Hepatitis virus infections. 

• HIV infection (AIDS). 

Most of these diseases are described in details in this book. In this 

chapter we will give some details on the remaining disease of clinical 

importance. 

Rheumatoid Arthritis And The Kidney 

Renal involvement in patients with rheumatoid arthritis are almost due 

to toxicity of drugs used in its treatment. 

The list of causes of renal disease in rheumatoid arthritis are : 

1- Drug-related (NSAIDs, Gold, Penicillamine). 

2- Secondary to amyloidosis occurring as a result of long standing rheumatoid 

arthritis. 

3- Vasculitis. 

4- Renal disease secondary to the disease itself. 

Histopathologically, the disease may show any of the following forms : 

1- Interstitial nephritis (acute and chronic, induced by NSAIDs). 

2- Minimal change nephritis (NSAIDs-induced). 

3- Renal amyloidosis. 

4- Membranous glomerulonephritis (gold or penicillamine induced). 

5- Mesangial proliferative or focal proliferative glomerulonephritis which is due 

to rheumatoid arthritis or as a part of systemic vasculitis. 

Amyloidosis 

Amyloidosis may be primary or secondary to the following : 

1- Familial mediterranean fever (FMF). 

2- Rheumatoid arthritis. 

3- Tuberculosis. 

4- Multiple myeloma. 

5- Chronic sepsis as empyema and osteomyelitis. 

Amyloid material may be deposited in the renal glomeruli, tubules, 

blood vessels and interstitium. Renal manifestations of amyloidosis may 

include :- 

1- Nephrotic syndrome.

2- Nephrogenic diabetes insipidus. 

3- Renal tubular acidosis, and 

4- Retroperitoneal fibrosis. 

Nephrotic syndrome is the commonest clinical presentation. 

Hypertension is uncommon finding. 

When the disease progresses it may lead to chronic renal failure. 

By U.S., the kidney size may look normal or even enlarged unless the disease 

is far advanced when the kidney may look decreased in size. 

Amyloid protein in primary amyloidosis and in cases with multiple 

myeloma is formed of immunoglobulin (condensation of light chain fragments 

of immunoglobulin and is called AL protein) while in that of the secondary 

amyloidosis; it is formed of a protein which is similar to the one present in 

plasma (serum amyloid A protein and is celled AA protein). 

Amyloidosis may involve different organs with different systemic 

manifestations as : 

1- Gastrointestinal tract with malabsorption, chronic diarrhoea and motility 

disorders. 

2- Cardio-vascular system with hypertension and cardiomyopathy. 

3- Neurologic with neuropathy (sensory, motor, and autonomic). 

4- Cutaneous with skin rash. 

Diagnosis 

Diagnosis is settled by the demonstration of amyloid material in tissue 

biopsy (kidney, liver, gum, rectal mucosa or subcutaneous fat). Biopsy is 

stained by Congo-red and amyloid. When seen by light microscopy, it should 

be confirmed by polarized light microscopy (Fig 15.2). 

(Fig. 15.2a) 

Cong-red stained kidney section 

(X250), it shows amyloid deposits in 

the glomeruli, and the arterioles.

(Fig. 15.2b) 

The same section examined by 

polarized light, it shows applegreen 

birefringence which is 

specific for amyloid. 

(Fig. 15.2c) 

Electron micrograph of a kidney 

section from the same case, it shows 

subendothelial amyloid fibrils. 

Treatment 

1- Mainly prophylactic by early eradication of the cause. In patients with FMF, 

colchicine will abort the attacks and will prevent amyloidosis. 

2- Symptomatic and supportive treatment when the disease is settled (as 

diuretic in NS and sodium bicarbonate in RTA). 

3- In primary amyloidosis with renal involvement, melphalan, steroid and 

colchicine have been used with limited response. So, they could be used in 

some selected cases.

Gout and Kidney 

Patient with gout may suffer from renal disease through the following 

mechanisms : 

1- Chronic interstitial nephritis which is due to deposition of urate crystals in 

the interstitium. 

2- Uric acid stones which may lead to obstructive uropathy. 

3- Chronic pyelonephritis triggered by renal stones. 

4- Nephrotoxicity by NSAIDs drugs. 

Proper control of hyperuricaemia by diet control and the use of 

Allopurinol, giving colchicine rather than NSAIDs for control of joint pain, and 

the alkalinization of urine to prevent crystallization and stone formation are all 

mandatory to prevent renal disease in gouty patients. 

Sickle Cell Anemia and the Kidney 

Sickle cell disease (SS haemoglobin) and sickle cell trait (SA 

haemoglobin) may cause kidney disease. It is commonly a tubular disorder 

(Nephrogenic diabetes insipidus or RTA) which is due to sickling of the red 

cells in the hypertonic renal medulla leading to papillary necrosis and 

sclerosis. Less commonly sickle cell anemia may be complicated by 

glomerular disease with proteinuria and nephrotic syndrome. It is caused 

either directly or through a concomitantly acquired HCV or HBV infection 

(through blood transfusion). Histologically, the glomerular lesions are either 

membranous or memberano- proliferative. 

The renal disease (tubular or glomerular) may progress to chronic renal 

failure. 

Mixed Connective Tissue Disease 

Mixed connective tissue disease is a mixture of features of 

scleroderma, polymyositis and SLE associated with a pronounced 

autoantibody response to a saline-extractable nuclear RNP antigen. The 

serum complement component concentrations are typically normal. 

Renal disease usually involves 25% of the cases with mixed C.T. 

diseases. It usually takes the form of proteinuria or nephrotic syndrome. 

Histologically, there is membranous or MPGN, it seldom progresses to renal 

failure and is steroid responsive. 

Sjogren's Syndrome 

This syndrome is characterized with a triad of xerostomia (dry mouth), 

keratoconjunctivitis sicca (dry eye) and a connective tissue disorders.

The systemic manifestations are: 

1- Oral: dry mouth, difficult mustication, dental caries and episodes of bilateral 

painful enlarged parotid glands. 

2- Ophthalmic: burning eyes and photosensitivity. 

3- Joints: manifestations similar to rheumatoid arthritis, even subcutaneous 

nodules. 

4- Renal manifestations: mainly of tubulointerstitial disease including 

inability to concentrate urine (polyuria) and metabolic acidosis (RTA). 

5- Other manifestations: nasal dryness, crusting, otitis media, upper 

respiratory infection hoarseness, pleurisy, atelectasis, and pericarditis. 

Investigations for Sjogren's Syndrome include: 

1- Schimer's test, in which a filter paper when put in the conjunctival sac, it 

shows no tear production. 

2- Biopsy from mucous membrane of the lip which when examined by light 

microscopy it shows infiltration of the minor salivary glands by lymphocytes. 

3- Hypergammaglobulinaemia (especially IgG). 

4- Parotid sialogram shows a dilatation of parotid duct. 

Treatment of Sjogren's Syndrome: 

Is by methyl cellulose eye drops (artificial tears), glycerin for dry mouth. 

Steroids and possibly cyclophosphamide may be used, according to 

the severity of the disease.

RENAL DISEASES IN HEPATIC PATIENTS 

There are many renal disorders which are known to occur in cirrhotic 

patients. These are : 

1- Hepatorenal syndrome 

2- Cirrhotic glomerulopathy 

3- Glomerulopathy induced by infection common in cirrhotic patients such as: 

• Malaria 

• Bilharziasis 

• HBV 

• HCV 

4- Tubulointerstitial disorders that are due to: 

• Infection (brucellosis, mononucleosis, tuberculosis) 

• Systemic disease (sarcoidosis, Sjogren's syndrome, lymphoma) 

• Drugs (methicillin, ampicillin, penicillin, sulfonamides, rifampicin, 

acetaminophen, Allopurinol). 

5- Drugs and toxins producing combined Hepatic and Renal damage. 

A- Drugs causing hepatic injury and acute tubular necrosis: 

• Hallogenated hydrocarbons as carbon tetrachloride, chloroform and 

chlorethylene 

• Hallogenated anaesthetics as Halothane and Methoxyflurane 

• Tetracycline 

• Sulfonamides 

• Rifampicin 

• Acetaminophen 

• Methotrexate 

• Arsenic 

• Copper sulphate 

B- Hepatic injury and acute interstitial nephritis 

• Sulfonamides 

• Phenindione 

• Rifampicin 

• Allopurinol 

Hepatorenal Syndrome (HRS) 

Definitions :- 

HRS is an unexplained, functional renal failure occurring in patients 

with advanced liver disease. The diagnosis of HRS is considered when there 

is no laboratory or anatomic evidence of other known cause of renal failure. 

HRS occurs in patients with cirrhosis, acute hepatitis, fulminant hepatic 

failure and with hepatic malignancy.

Cirrhotic patient may have a reduced GFR before coming to medical 

attention. That is, the kidney of cirrhotic patient is always vulnerable to renal 

failure whether functional or ischaemic acute tubular necrosis. 

Etiology :- 

HRS usually develops in hospitalized patient, indicating that iatrogenic 

factors are playing important role in the pathogenesis of this disorder. 

Abdominal paracentesis, vigorous diuretic therapy and bleedingespecially 

gastrointestinal-are known precipitating factors. Sometimes HRS is 

idiopathic. 

Pathogenesis of HRS: 

1- HRS is a functional renal failure, the arguments supporting this concept 

are: 

• Pathological abnormalities in renal specimens obtained from patients 

with HRS are minimal and inconsistent. 

• Tubular functional integrity is maintained. Sodium reabsorptive 

capacity and concentration ability are relatively unimpaired. 

• Kidneys from patient with HRS will show immediate diuresis when 

transplanted in uraemic patient. 

• When a cirrhotic patient with HRS receives a liver transplant, his 

kidney recovers immediately. 

• Postmortem renal angiography in patients died with HRS discloses a 

striking reversal of all the intrarenal vascular abnormalities. 

2- There is renal hypoperfusion with preferential cortical ischaemia. 

• The effective circulating volume is decreased as a result of ascites 

and oedema formation. 

• There is peripheral arterial vasodilatation 

3- HRS constitutes an extreme extension of underfilling of the arterial 

circulation with the most extreme elevation of vasoactive hormones, 

including plasma renin activity, vasopressin, with a maximum degree of 

renal vasoconstriction. 

4- Hormonal changes contributing in the pathogenesis of HRS are : 

• Activation of the renin-angiotensin system: an increase in plasma renin 

activity due to renal hypoperfusion, decrease hepatic synthesis of α2- 

globulin, the renin substrate. This will contribute to renal vasoconstriction. 

• Alterations in renal eicosanoids, there is decrease in the vasodilator 

prostaglandins and increase in the vasoconstrictor thromboxanes.

• Elevated plasma endothelin (E) levels (E-1, E-3) which are renal 

vasoconstrictors. 

• Enhanced Nitric Oxide (NO) synthesis in peripheral vessels (by endotoxins) 

which results in an intense peripheral V.D. and renal hypoperfusion. 

• Relative impairment of renal kallikrein production 

• There is glomerulopressin deficiency 

5- The role of systemic endotoxaemia and HRS 

• Endotoxins are lipopolysaccharide constituents of the cell wall of 

certain bacteria. They are potent renal V.C. and may produce V.D. of 

other vascular beds. 

• Enteric endotoxins are liberated into the systemic circulation through 

the porto-systemic shunts, thus bypassing the hepatic kupffer cells. 

6- Neural and haemodynamic factors in HRS 

• There is increase in sympathetic nervous system activity in cirrhosis 

with renal V.C. and sodium retention. Also there is an alteration in 

the intrarenal blood flow distribution. 

Clinical features of HRS 

The patient usually presents with manifestations of advanced liver 

disease and on development of HRS. There will be further progression of the 

bad general condition, disturbance of consciousness, mental concentration, 

increase in oedema, ascites and progressive oliguria and even anuria. 

Laboratory assessment will show a progressive increase in serum creatinine 

and blood urea. 

Differential Diagnosis: 

HRS should be differentiated from other causes of azotaemia in patient 

with advanced liver disease especially prerenal azotaemia and acute tubular 

necrosis. The following table presents the important differentiating points. 

Pre renal Hepatorenal Acute tubular 

azotemia syndrome necrosis 

Urinary sodium(mmol/L) 30/1 >20/1 200 higher relatively similar 

(mosmol/l) than plasma than plasma to plasma (isothenuric) 

Urine sediment Normal Unremarkable Casts, cellular debris

Treatment of Hepatorenal Syndrome 

• Treatment of HRS is largely supportive. 

• Prevention is more important. Toxic agents as NSAIDs, demeclocycline, 

aggressive diuresis or aggressive paracentesis have to be avoided. 

• If azotaemia is discovered in hepatic patient, the precipitating factor as 

volume contraction, cardiac decompensation and urinary tract obstruction 

have to be discovered and promptly treated. 

• If prerenal azotemia is possible we have to give a volume expander (colloid 

as albumin or crystalloid as saline). 

• Abdominal paracentesis with plasma volume expansion (e.g. by salt free 

albumin) may decrease the intra-abdominal pressure, decrease inferior vena 

cava obstruction and may increase the cardiac output and the renal 

perfusion. 

• Dialysis may be indicated in selected patients with HRS. Mainly those with 

potentially reversible acute liver disease and those awaiting orthotopic liver 

transplantation. 

The purpose of dialysis is to: 1- keep the biochemical profile in best possible 

shape, 2- remove excess fluid; and 3- allow giving required fluid or 

hyperalimentation. 

The technique of dialysis suitable for patient with HRS is either the 

conventional haemodialysis or continuous arteriovenous haemofiltration 

(CAVH). The former is employed in patients with stable cardiovascular 

system while the later is used in hypotensive patient or in those with 

significant cardiac disease. 

• Peritoneovenous shunt (e.g. Le Veen Shunt) which is a synthetic tube 

shunting fluid from the peritoneal cavity to the venous system (subclavian 

vein) has been used in patients with HRS. 

Initial reports on this line of treatment demonstrate stabilization of renal 

function but with no prolongation of patient's survival. 

• Transjagular intrahepatic portosystemic shunt. The retionale for this 

procedure is similar to that for the establishment of a side-to-side portocaval 

shunt (to decompress the portocaval system). Preliminary reports on the use 

of this technique in patients with HRS are successful, but they are few and 

anecdotal.

• Orthotopic liver transplantation is the definitive line of treatment in patients 

with end stage liver disease and HRS. The renal function is resumed 

immediately after transplantation. 

• New experimental trials for the treatment of HRS include: 

1- The use of renal dose dopamine (i.v. 1-2 ug/kg/min) 

2- Misoprostol (PGE1 analogue) 0.4 mg orally four times daily plus albumin 

infusion. 

3- Thromboxane-receptor antagonist (ONO-3708)


- Pol S: Hepatitis C virus infection in hemodialyzed patients and kidney 

allograft recipients. Adv Nephrol Necker Hosp, 24 : 315-30, 1995. 

- Martin P: Chronic viral hepatitis and the management of chronic renal 

failure. Kidney Int, 47 : 5, 1231-41, 1995. 

- Räz HR, et al: Acute kidney insufficiency in an alcoholic patient with liver 

cirrhosis (clinical conference). Schweiz Med Wochenschr, 126 : 1306-13, 

1996. 

- Praditpornsilpa K, et al: Hepatitis virus and kidney. Singapore, 37 : 6, 

639-44, 1996. 

- Zeniya M, et al: Kidney in chronic active hepatitis. Roikibetsu Shokogun 

Shirizum 17 Pt 2, 471-4, 1997.

MALIGNANCY AND THE KIDNEY 

The spectrum of renal involvement in malignancy includes the 

following: 

1- Renal and urothelial tumours. 

2- Renal and urinary tract metastatic involvement. 

3- Renal involvement in multiple myelomatosis. 

4- Renal infiltration by haematologic malignancy (lymphomas and 

leukemias). 

5- Renal complications as a result of alterations induced by cancer as: 

• Glomerulonephritis. 

• Vasculitis. 


• Hemolytic uraemic syndrome. 

• Fluid and electrolyte disorders as hypercalcaemia, hypocalcaemia, 

hyponatraemia, hypernatraemia, hypophosphataemia hypokalaemia. 

• Tumour lysis syndrome. 

6- Renal complications induced by cytotoxic drugs. 

7- Malignancy in patients under renal replacement therapy. 

(1) Renal and urothelial tumours 

Renal and urothelial tumours include the following types: 

a- Renal cell carcinoma (Hypernephroma) 

b- Nephroblastoma (Wilms' tumour) 

c- Urothelial tumours such as squamous cell carcinoma of the bladder 

and transitional cell carcinoma of the urinary tract. 

d- Sarcoma 

(2) Renal and urinary tract involvement by metastasis 

It is usually due to carcinoma metastasizing into retroperitoneal lymph 

nodes with a consequent ureteric obstruction and hydronephrosis. 

(3) Renal involvement in multiple myelomatosis 

Multiple myelomatosis may affect the kidney through one or more of 

the following mechanisms:

1- Deposition of amyloid (AL amyloid), light chain, uric acid, or calcium 

into the kidney tissue . 

2- Hyperviscosity and dehydration. 

3- Renal infiltration by plasma cells. 

4- Nephrotoxicity by drugs used for diagnosis or treatment of multiple 

myelomatosis. 

5- Depression of immunity leading to pyelonephritis. 

This may manifest clinically by one or more of the following syndromes 

(Fig. 15.3): 

1- Glomerulopathy (Amyloid, fibrillary....) 

2- Tubulointerstitial diseases as Fanconi's Syndrome, mostly due to the 

toxic effect of light chain on proximal convoluted tubules. 

3- Acute tubular necrosis which is either: 

• Ischaemic (dehydration, hyperviscosity), or 

• Toxic (uric acid, drugs as NSAIDs, cytotoxic and contrast media). 

4- Myeloma cast nephropathy. 

5- Polyuria (hypercalcaemia) 

6- Pyelonephritis. 

Myeloma cast Nephropathy: 

It is characterized with casts mainly of light chain protein and Tamm- 

Horsfall protein occupying the distal convoluted tubules and collecting ducts. 

These sometimes may be seen in the proximal convoluted tubules and even 

in the urinary space of the glomeruli. 

Myeloma cast nephropathy is the most frequent lesion seen in 

myeloma patients (45%) and is the major cause of the renal failure among 

them. 

Pathologically, the casts may be seen in the DCT with tubular atrophy. 

The casts look hard and sometimes look fractured, associated with crystal 

deposition and surrounded by inflammatory mononuclear cells and giant cells. 

Interstitium will show the fibrosis and infiltration by mononuclear cells.

Multiple myeloma. Case of light chain 

Multiple myeloma. Light chain disease. 

disease. Glomerulus showing homogenous Proliferative glomerulonephritis with 

mesangial nodules with a few cell nuclei 

a fibroepithelial crescent. 

along the periphery. These nodules H & E stain. X 260. 

stronghly resemble nodular diabetic 

glomerulosclerosis. PAS stain. X 260. 

(Fig. 15.3) 

MULTIPLE MYELOMATOSIS WITH RENAL INVOLVEMENT

The glomeruli may be normal, show secondary sclerotic changes or 

may show glomerulopathy. 

Fanconi's syndrome: 

Usually, the diagnosis of Fanconi's syndrome precedes that of plasma 

cell dyscrasia (smoldering myeloma). 

Pathologically, proximal convoluted tubules may show crystal 

deposition and degenerative changes. 

Monoclonal immunoglobulin deposition disease (light chain deposition 

disease): 

This constitutes a systemic disease due to deposition of light chain 

proteins in different organs including the kidney, liver, heart, nerve fibers, 

choroid plexus, lymph nodes, bone marrow and spleen. 

In the kidney, the light chain proteins are deposited in the renal 

glomeruli and tubules. Light microscopy shows: 

• Tubules and interstitium: There is deposition of refractile, eosinophilic 

PAS positive, ribbon-like materials along the outer part of the tubular 

basement membrane with variable degrees of tubular atrophy and interstitial 

fibrosis. 

• Glomeruli: The most characteristic lesion is nodular 

glomerulosclerosis and resembling nodular diabetic glomerulosclerosis, but 

the distribution of the nodules here is fairly regular in a given glomerulus. In 

mild forms, the mesangium looks thickened. 

Immunofluorescent microscopy is the key step for the diagnosis of light 

chain deposition disease. It may show light chain deposits in the tubular and 

the glomerular capillary basement membrane. Electron microscopy may show 

the electron dense deposits on the outer surface of the tubular and glomerular 

capillary basement membrane. 

Amyloidosis: 

Beside renal involvement, other clinical features which strongly suggest 

AL amyloid may appear as: 

• Cutaneous purpura (non-thrombocytopaenic) 

• Macroglossia 

• Capral tunnel syndrome 

• Peripheral and autonomic neuropathy

POEMS Syndrome 

(P= polyneuropathy, O= organomegaly, E= Endocrinopathy, M= M 

protein, S= Skin changes) 

This is a rare multi-systemic disorder of an unknown origin occurring in 

association with plasma cell dyscriasias including the non-malignant 

monoclonal gammopathy and multiple myelomatosis. 

POEMS syndrome may involve the kidney (but uncommonly) with 

proteinuria, microscopic hematuria or with renal failure. 

Histopathologically, there will be interstitial nephritis, mesangiocapillary 

glomerulonephritis or any form of myeloma kidney. 

Treatment is by steroids especially if the renal failure occurs. 

Treatment of Myeloma kidney: 

1- To prevent deposition of light chain and renal failure. 

• Proper hydration 

• Alkalinization of urine 

• Treatment of hypercalcaemia 

• Avoid nephrotoxic drugs as NSAIDs and contrast media 

• Treatment of infection 

2- Treatment of multiple myelomatosis: 

• Alkylating agents (as Melphalan) and corticosteroids (prednisolone) 

• Vincristine and Doxorubicin (especially with hypercalcaemia or ARF) 

3- Plasma exchange 

Especially with hyperviscosity, hypercalcaemia and ARF. Usually in 

conjunction with the other measures. 

(4) Renal infiltration in Hematologic Malignancy 

Generally, the renal involvement in haematologic malignancy takes one 

of the following forms: 

1- Obstructive uropathy (mass effect) 

2- Infiltration of the renal parenchyma, urinary tract or blood vessels 

3- Urate nephropathy 

4- Glomerulopathy 

5- Therapy-related kidney damage 

6- Amyloidosis 

7- DIC

Renal involvement with lymphoma: 

• Renal failure develops in up to 20% of lymphoma patients. It usually 

occurs through bilateral ureteric obstruction, renal vein thrombosis or the 

compression of the renal arteries. 

• Renal parenchymal infiltration occurs in 50% of lymphoma patients. 

This manifests as a renal mass which is palpable clinically or is detected only 

by ultrasound. Histopathologically, diffuse lymphoid cells may be seen 

infiltrating the kidney tissue. 

• Minimal change nephritis may occur especially with Hodgkin's 

lymphoma. This is most probably due to an increase in release of proteases 

or lymphokines by T-cells which increases the glomerular permeability to 

protein. Renal failure may occur with lymphoma or leukaemia due to 

infiltration. 

Renal involvement in leukaemia 

• Renal invasion was found at autopsy in 50-60% of patients who died 

from leukaemia. The infiltration is always bilateral and may be nodular or 

diffuse. 

• Acute renal failure is common in acute leukaemia, while chronic renal 

impairment occurs in 1% of patients. 

(5) Renal complications by alterations induced by cancer 

A- Malignancy-related glomerulopathy 

The occurrence of massive proteinuria in association with malignant 

neoplasia is uncommon, but highly instructive event. The renal lesions may 

antedate the discovery of tumour in two thirds of cases. This is usually 

encountered in patients above the age of 50 years. 

Type of malignancy: 

Glomerular diseases, principally manifested as heavy proteinuria or 

progressive renal failure, have been observed to occur in association with 

carcinoma such as carcinoma of the lung, breast, stomach and colon in 

addition to pheochromocytoma, Wilms' tumor, Hodgkin's disease, Burkitt's 

lymphoma and chronic lymphatic leukemia. 

Histopathology: 

Glomerular diseases complicating cancer usually present with the 

following histologic features: 

1- Membranous glomerulonephritis (mainly with solid tumours)

2- Minimal change glomerulonephritis (Hodgkin's disease, pancreatic 

carcinoma, malignant mesothelioma, renal cell carcinoma and prostatic 

cancer). 

3- Other lesions may occur as mesangiocapillary and crescentic 


Pathogenesis of malignancy-related glomerulopathy: 

Glomerulopathy in cancer patient may be induced by cytokines 

released from abnormal T-cells or by released tumour antigens which may 

trigger immune complex mechanism for glomerular disease. 

Evidence of causal relationship: 

- Close temporal relationship between the clinical appearance of the renal 

lesion and of the tumour. 

- Remission or complete removal of tumour should be associated with 

remission of nephropathy. 

- Recurrence of tumour would be accompanied with the recurrence of 

nephropathy. 

N.B.: patients over the age of fifty presenting with nephrotic syndrome should 

be thoroughly investigated for malignancy. 

B- Malignancy-related vasculitis: 

Systemic vasculitis and Henoch-Schönlein purpura have been reported 

in patients with haematologic malignancies and carcinoma. In these 

conditions, malignant neoplasia might act as an immunologic stimulus with the 

formation of immune complexes. 

C- Malignancy-related amyloidosis 

Renal amyloidosis has been reported in patients with multiple 

myelomatosis, lymphoma and carcinoma. 

D- Malignancy-related hemolytic uraemic syndrome: 

This has been observed with disseminated cancer and may be 

complicated with renal failure. 

E- Malignancy-related fluid and electrolyte disorders. 

1- Hypercalcaemia: 

Malignant tumours are the single most common cause of 

hypercalcaemia. This may be mediated through release of PTH-like 

substance, PGE, transforming growth factors, interleukin, or 1.25 (oH) 2 Vit D.

2- hypocalcaemia: 

It is very rare, but may occur in diffuse bone forming metastasis as in 

cancer prostate and cancer breast. Also, it may occur after extensive neck 

surgery for cancer thyroid with a damage of the parathyroid glands. 

3- Hypophosphataemia: 

It may result in what is called oncogeneous osteomalacia which is 

characterized by bone pains, muscle weakness, and pathological fractures. 

Biochemically, it is characterized by hyperphosphaturia, hypophosphataemia, 

high alkaline phosphatase, low 1, 25 (oH) 2 Vit. D and normal PTH 

levels. Starvation, malnutrition, vomiting, diarrhoea, use of AL (OH) 3 and 

parenteral hyperalimentation without phosphate supplementation may lead to 

hypophosphataemia. 

4- Hyponatraemia: 

It is common with malignancy. It may be due to gastrointestinal losses, 

heart failure, liver cell failure or due to SIADH. 

5- Hypernatraemia 

It may be due to craniopharyngioma or metastasis leading to the loss 

of secretion of ADH with CDI or due to hypothalamic tumours damaging the 

thirst center. 

6- Hypokalaemia 

This is mostly due to GIT losses as in villous adenoma or 

adenocarcinoma of the pancreas; or due to tumour secreting ACTH, renin or 

Aldosterone. 

F- Acute tumour lysis syndrome:- 

It occurs in patients with rapidly growing haematopoietic or lymphopoietic 

tumour (high turnover tumours) that are responsive to therapy. The massive 

cytolysis caused by anti-neoplastic agents or radiation therapy generates high 

levels of uric acid, potassium, phosphates and xanthine that cause acute renal 

dysfunction. 

Acute hyperuricemic nephropathy is due to precipitation of urate crystals 

in the tubules. 

Severe hyperkalaemia that may result from cell lysis with acute renal 

failure may result in lethal cardiac arrhythmias. 

Hyperphosphatemia may precipitate calcium and phosphate in the kidney 

tissue leading to ARF

Prevention of tumour lysis syndrome is achieved by good hydration, use 

of allopurinol before chemotherapy and intensive monitoring of uric acid level 

and kidney function. When severe hyperuricaemia and ARF occur, dialysis 

prevents further kidney damage and promotes recovery of renal function. 

(6) Renal complications of anti-neoplastic treatment 

Anti-neoplastic drugs may be nephrotoxic. This is favored by 

dehydration, use of NSAIDs, aminoglycosides and amphotericin B. 

• Cisplatin:- 

- Produces dose-related nephrotoxicity. 

- Pathologically, there are PCT dilatation, vacuolization, and hydropic 

degeneration. 

- Adequate hydration, alkalinization of urine and forced diuresis with 

furosemide will decrease the risk of ARF 

• Methotrexate:- 

- High dose (1gm/m 2 ) causes increase in serum creatinine 

- The cause of toxicity is precipitation of the drug in the renal tubules 

• Mitomycin:- 

- It may induce HUS 

• Methramycin:- 

- This agent produces cumulative and persistent renal toxicity. 

- Acute rise in serum creatinine can occur after a single dose therapy. 

• Interferon:- 

- May rarely induce proteinuria, increase in serum creatinine and ARF. 

- This may be due to development of autoantibodies that trigger 

interstitial nephritis or glomerular abnormalities. 

• Radiation nephritis:- 

- It may occur when the kidneys are included in the field of therapeutic 

irradiation. 

- It is now uncommon due to the development of advanced techniques 

for localized irradiation. 

(7) Neoplasia as a complication of chronic renal disease 

Uraemic patients are known to be at more risk to develop malignancy. 

This is even more pronounced in the following circumstances: 

A- Analgesic-induced renal disease:- 

Transitional cell carcinoma has high incidence in the patients with 

analgesic nephropathy.

B- Auto-immune renal diseases:- 

• There is an increase in the incidence of cancer in SLE and in patients with 

primary GN. 

• Auto immune diseases lead to functional defect in T cells (that normally 

limits the extent of B cell reaction). This may favour B cell hyperplasia in 

response to self antigens or viral infections in patients who are genetically 

predisposed. This uncontrolled B cell reaction progresses from hyperplasia 

to neoplasia. 

• Immunosuppressive therapy can also predispose to neoplasia. 

• Acute leukemia is the most frequent cancer induced by alkylating agents 

- Cyclophosphamide increases the risk of urinary bladder cancer. 

- Cyclophosphamide predisposes to malignancy after a cumulative dose of 

80gm with a mean duration of 50 months. 

C- Dialysis patients:- 

• Dialysis patients have a greater incidence of cancer than general population. 

• Pathogenesis 1- original kidney disease. 

• Autoimmune disease. 

• Analgesic nephropathy. 

• Previous immunosuppressive therapy. 

2- Altered immune system by uraemia 

3- Dialysis itself has a carcinogenic potential due to the 

exposure to substances such as ethylene oxide, 

nitrosamine in haemodialysis and glutamic acid 

products in peritoneal dialysis. 

4- Acquired renal cyst may be complicated by renal 

carcinoma. 

• Dialysis patients should be carefully monitored for the early diagnosis and 

the treatment of cancers. 

D- Renal transplant recipients 

• Renal transplant patients have an increased risk of cancer. 

• The incidence of tumours in transplant patients ranges from 1-18% 

• Cancer accounts for 26% of deaths in patients who have received 

transplantation for 10 years or more. 

• Tumour may develop at any age with a mean age of 40 years. 

• The pattern of tumours is radically different from that of the general 

population where the more frequent types are lip cancer, carcinoma of 

uterine cervix, hepatoma, carcinoma of the vulva and anus and skin cancer 

(squamous cell carcinoma)

• Non Hodgkin's lymphoma, and Kaposi's sarcoma have the greatest 

incidence in the transplanted patients. 

• There is a strong association between EPV infection and post transplant 

malignancy, it has a poor prognosis with mortality rate up to 80%. 

• Kaposi's sarcoma accounts for more than 6% of cancers in transplant 

recipients (frequently in mediterranean area). 

• The mean interval of development of cancer is 22 months for Kaposi's 

sarcoma and 65 months for other tumours. 

(8) Renal replacement therapy in patients with cancer 

Dialysis: 

- Generally dialysis therapy is provided only to patients with operable, chemo, 

or radiosensitive cancer. 

- The 5-year actuarial survival of patients submitted to bilateral nephrectomy 

and dialysis because of bilateral renal cell cancer is 44% and the quality of 

life for them is similar to that of the overall dialysis population. 

- In multiple myeloma complicated with irreversible renal failure, the bad 

prognostic criteria include large tumour mass, extensive osteolysis, severe 

hypercalcaemia and bone narrow hypoplasia. 

Renal transplantation 

The risk of tumour recurrence after transplantation is as follows: 

1- Nil: In incidentally discovered renal neoplasms 

2- Low (3-18%): In testicular carcinoma and insitu uterine carcinoma, 

3- Intermediate (11-25%): In cancer body of uterus, Wilms' tumour, 

cancer colon, prostate and breast. 

4- High (>25%): In cancer urinary bladder, sarcoma, melanoma, multiple 

myeloma symptomatic renal carcinoma and in non melanoma skin 

cancer. 

2 years wait is recommended for most cancers but a longer period (5- 

year or more) is needed for colorectal, breast, prostatic cancer and in 

melanoma.


- Dagher F, et al: Renal transplantation in multiple myeloma. Case report 

and review of the literature. Transplantation, 62 : 11, 1577-80, 1996. 

- Kamaeva OI: Multiple myeloma and the kidneys. Ter Arkh, 69 : 6, 73-5, 

1997. 

- Gordeev AV, et al: Kidneys involvement in multiple myeloma. 

Therapeutic issues. Klin Med (Mosk), 75 : 8, 60-2, 1997. 

- Ozu H, et al: Multiple myeloma. Ryoikibetsu Shokogun Shirizu, 17 Pt 2, 

340-2, 1997.

DRUGS AND THE KIDNEY 

In this chapter we will discuss the following items: 

1- Drug-induced kidney diseases 

2- Drug handling in renal diseases, and 

3- The clinical use of diuretics 

I. Drug induced kidney diseases 

The following kidney lesions may be drugs induced: 

(A) Glomerular lesions: 

1- Minimal change nephrotic syndrome may occur with NSAIDS 

2- Membranous nephropathy may occur with gold, penicillamine, capoten, 

phenytoin and propenicid. 

3- Acute nephritis may occur with penicillin, sulfa and amphetamines. 

(B) Interstitial lesions: 

- Chronic interstitial nephritis may occur with the long term use of NSAIDS 

- Acute interstitial nephritis may occur with lasix, methicillin, thiazides and 

Rifampicin. 

(C) Tubular lesion 

- A.T.N. may occur with aminoglycosides, cephalosporins, outdated 

tetracycline, polymyxin and contrast media. 

Renal Tubular Acidosis (RTA): Proximal RTA may occur with Tetracycline and 

heavy metals, while, Distal RTA may occur with vit. D toxicity and 

amphotericin B. 

- Nephrogenic D.I.: May occur with Vincristine, lithium and colchicine. 

(D) Obstructive uropathy: 

• Nephrocalcinosis e.g calciferol toxicity 

• Extrarenal by retroperitoneal fibrosis e.g methergide, methyl dopa and 

hydralazine. 

• Intrarenal deposits as with urate and Dextran. 

II. Drug handling in kidney diseases 

Although renal impairment has its most important effect on drug 

excretion, other aspects of pharmacokinetics and pharmacodynamics may be 

affected. Here, we consider the basic pharmacokinetic changes that occur in 

the presence of renal impairment and how they affect drug usage.

(A) Drug Absorption: 

1- Gastrointestinal Absorption: 

• Ammonia produced in chronic renal failure buffers Hcl of stomach 

∅ ⎯⎯ gastric Hcl ∅ ¬¬ absorption of drugs that need low PH such 

as: Ferrous sulfate, chlorpropamide, folic acid, and cloxacillin. 

• Aluminium OH used as phasphate binder for several drugs as iron, 

aspirin and ciprofloxacin. 

• Diuretic resistance is reported in some nephrotics and is most 

probably due to binding of the drug in the tubular lumen and not due 

to poor absorption from edematous intestine because the addition of 

oral thiazide overcomes this resistance. 

2- peritoneal absorption: 

• Peritoneum is an absorptive surface during peritoneal dialysis. 

• Absorption of gentamycin is unidirectional to the plasma. 

• With peritonitis, insulin requirement may decrease as absorption 

increases with the mesothelial damage. 

3- Subcutaneous and intramuscular routes of absorption: 

The absorption of drugs from these sites is impaired in critically ill patients. 

(B) Drug Distribution: 

• Renal impairment increases acidic components that compete for 

binding sites on albumin decreasing drug protein binding 

• Hypoalbuminaemia in nephrotics, elderly, cachectics lead to: 

1- The decrease of binding sites for drugs; and 

2- Free drug/bound drug ratio increases, this leads to great 

fluctuations in the free drug concentration following each dose. 

• Binding of phenytion to plasma protein is decreased in direct 

proportion to the decrease in GFR, and the free fraction can be 

removed by dialysis. 

• Tissue binding of digoxin decreases in renal failure and smaller 

loading dose is needed. Also, the maintenance dose is smaller. 

(C) Drug Metabolism: 

• uremia affects drug metabolism and reduces non-renal clearance of drugs 

as: 

acyclovir (zovirax) captopril (capoten) 

aztereonam (azactam) cimetidine (tagamet) 

cefotaxime (claforan) metoclopromide (primperan)

• Uremia may reduce drug metabolism e.g. the activation of sulindac to active 

sulfide metabolite is reduced in uremia. Also, vit. D activation is impaired in 

uremia. 

• First pass metabolism by the liver of some drugs such as inderal or 

cimetidine may be reduced in renal impairment. 

(D) Renal drug excretion: 

⎧ Filteration 

⎪ 

It depends on ⎨ Active tubular secretion/reabsorption 

⎪ 

⎩ Passive diffusion. 

• Drugs of MW < 60,000 Dalton are filtered through the glomerulus. 

• Lipid soluble drugs that diffuse readily across tubular cells whereas water 

soluble compounds do not. 

• Organic acids e.g (penicillins, cephalosporins, aspirin, frusemide and 

thiazide) and organic bases as (amiloride, procainamide) have active tubular 

secretion. Some drugs decrease such secretion as probenicid. 

• Drugs present in tubular fluid may affect excretion of other compounds such 

as: 

- Aspirin decreases excretion of methotrexate. 

- Low protein diet increases urine pH which leads to reabsorption of 

oxpurinol (metabolite of allopurinol) with more adverse reactions. 

• Factors affecting clearance of drugs by haemodialysis or haemofilteration: 

• Properties of the drug 

⎧ MW 

⎪ 

⎨ protein binding 

⎪ 

⎩ volume of distribution 

• Delivery of the drug to the filters 

⎧ Blood flow to filter 

⎨ 

⎩ Blood flow within filter 

• Properties of the filter 

⎧ pore size 

⎪ 

⎨ surface area 

⎪ 

⎩ Duration of use

Drug prescription in renal impairment 

The dose can be adjusted in two main ways: 

(1) The size of dose can be reduced. Or 

(2) The frequency of administration is reduced. 

1- Antibacterials: 

Most of antimicrobials have a wide therapeutic index and require no 

dose adjustment [except aminoglycosides and vancomycin] untill GFR is < 20 

ml / min. 

- Penicillins: 

• Both piperacillin and augmentin require the addition of half dose post 

hemodialysis 

• Piperacilin should be given in half dose when GFR 20 -50 and 1/3 - 1/2 dose 

if GFR

• It's usual dose is 1gm / 8hrs. 

• The loading dose is 250 mg / 8hrs when GFR < 10 ml / min. 

• It is dialyzable, half dose is given after each dialysis session. 

- Imipenem / cilastatin: 

• It is a broad spectrum antibiotic except against pseudomonas. 

• Cilastatin is dipeptidase inhibitor. 

• The dose is 0.5 - 1gm /6hrs, reduced to 0.5 gm / 12hrs with renal impairment. 

- Erythromycin: 

• It is used in upper respiratory tract infection especially legionnaire's disease. 

• It is not dialyzable 

• It inhibits metabolism of cyclosporin 

N.B. clindamycin is used with usual dosage while clarithromycin is usually 

used in half dose (0.5 gm / 12h). 

- Tetracyclins: 

• All are excreted renally except doxycycline and minocyclin 

• They are contraindicated in renal disease except doxycycline 

• They are not dialyzable 

• Demeclocycline is vasopressin antagonist used in treatment of SIADH. 

- Sulfonamides 

• Eliminated by acetylation, excreted by kidneys, cause crystalluria and 

tubular damage 

• Alkaline urine promotes sulfamethoxazole excretion, acidic urine promotes 

trimethoprim excretion. 

• Half the dose is used if GFR = 20 ml /min, supplemented after dialysis. 

• Are used in p.carinii infection ∅ side effects, being balanced against 

seriousness of the condition. 

2- Antiviral drugs: 

• Acyclovir: 5gm / kg /8hrs In uremia ∅ 2.5 mg / kg / day. 

• Amantadine: 200 mg /day In uremia∅200 mg every other day. 

• Foscarnit: 90 mg/kg/day I.V. In uremia∅ unknown. 

• Gancuclovir: 5 mg / kg /12 hrs In uremia∅ 1.25 mg/kg /24 hrs. 

3- Antifungal drugs: 

• Amphotericin B: 

- Nephrotoxic; newer preparation encapsulated in liposomes avoids 

much of toxicity (liposomal amphotericin B).

- Protein bound & dialyzable, dialysis patients should receive the drug 

after dialysis. 

• Imidazoles (ketoconazole, miconazole): 

- Extensively metabolized by liver (used in the usual dose) 

- When given with CsA, it increases its blood level 

• Fluconazole: 

- Used in candida, and cryptococcal infection 

- Give half the dose if GFR < 50 ml / min., first, give loading dose of 

400mg then, 200 mg / day 

• Griseofulvin: 

- usual dosage does not interfere with CsA 

4- C.N.S. drugs: 

- Antidepressants: 

• Tricyclics can be used in usual dosage. 

- Tranquilizers: 

• Major tranquilizers require no adjustment. 

• Minor tranquilizers: 

- Benzodiazepines used in usual dose 

- Midazolam, cases with renal impairment are more sensitive, dose is 

reduced to between 1/4-1/3 when GFR is < 10 ml /min. 

- Anticonvulsants: 

• Phenytion and valproic acid are highly protein-bound and the binding 

declines in proportion to the G.F.R. 

Neither of them is dialyzable. They are used in the usual dosage. 

• Also carbamazepine is used in the usual dosage. 

• All anticonvulsants other than Na+ valproate and vigabatrin are potent 

inducers of cytochrome P 450. 

5- Antihistaminics: 

• Both terfenadine and prochlorperazine are used in usual dosage 

6- Cardiovascular drugs: 

- Antiarrhythmics 

• Most antiarrhythmics are used without modification e.g. lignocaine, 

amiodarone, flecainide, verapamil, sotalol; except digoxin which must be 

reduced to 0.125 mg / day depending on serum level (0.7 - 2 ng /ml), and 

venticular response

• Digoxin is not dialyzable 

• Quinidine can be used in the usual dosage. 

- Antiangina: 

• Nitrates given in the usual dose 

• Ca ++ channel blockers are given in the usual dose 

• Atenolol is dialyzable, requires supplemental 1/2 dose after dialysis,unlike 

other beta blockers propranolol, metoprolol, oxprenolol, pindolol. 

- Diuretics: 

• Thiazides lose their potency when GFR is < 25 ml / min 

• Increasing doses of loop diuretics may be needed as GFR declines. 

• All potassium sparing diuretics should be avoided in renal impairment. 

- ACEI : 

• All this class of drugs should be started at low dosage and the dose is 

increased slowly with the careful monitoring of serum creatinine and 

potassium. 

• Avoid its combination with k+ sparing diuretics. 

• ACEIs are dialyzable. 

- losartan: 

• Angiotensin II receptor blocker. 

• Starting dose is 25 mg daily (1/2 dose if GFR is < 20). 

- Vasodilators: 

• Alpha (1) blockers (prazosin), Ca++ channel blockers, minoxidil are all used 

by the usual dosage 

• Minoxidil is dialyzable 

- Centrally acting agents: 

- Alpha methyl dopa & clonidine are given in the usual dose 

7- Endocrine drugs: 

- Insulin : 

• Its requirements decrease with declining renal function (acute or 

chronic). 

• Intraperitoneal requirement is 50% of the I.V. one 

- Oral hypoglycaemic agents: 

• Gliclazide (Diamicron) is of choice in renal impairment with a dose range of 

40-320 mg /day.

• Metformin should be avoided when GFR < 20 ml / min to avoid metformin - 

induced lactic acidosis (can be treated by dialysis). 

- Thyroid drugs: 

Thyroxine and antithyroid drugs are given in their usual doses. 

- Allopurinol: 

• It is metabolized to oxypurinol which is responsible for its side effects. 

• When GFR < 20 ml /min, the dose should not exceed 100 mg / day. 

• It is given cautiously in transplant cases, as it interferes with imuran. This 

may result in leukopenia. When given together, the dose of imuran should 

be decreased to one third. 

8- Antiasthma: 

B- agonists by inhalation, oral or by I.V. routes require no adjustment of the 

dose. 

9- G.I.T drugs: 

• H 2 receptor blockers: 

- Ranitidine is the preferable drug with renal impairment. 

- It interferes with creatinine secretion with consequent increase in serum 

creatinine. 

- The dose must be halved when GFR < 10 ml / min. 

- It is dialyzable, supplemental dose is needed after dialysis. 

- In peritoneal dialysis, a dose of 150 mg /12 hrs is given safely. 

• Omeprazole 

- It is given in the usual dose (20 -40 mg / day). 

• Misoprostol: 

- It is a prostaglandin analogue 

- It is given in a dose of 200 mg / day in renal impariment alone or with 

NSAIDS. 

• Bismuth : 

- It is avoided in renal impairment. 

• Prokinetic drugs: 

- loperamide, lomotil Metoclopromide and Domperidone (motilium) are given 

in their usual doses. 

10- NSAIDs 

• They suppress prostaglandin synthesis by inhibiting cyclo-oxygenase 

enzyme.

• Renal prostaglandins (PGE 2 , PGI 2 ) are mainly renal vasodilators and 

natriuretic. 

• When NSAIDs are given in cases with heart failure, nephrotic syndrome, and 

liver disease, they may lead to 

(1) ¬ GFR 

(2) fluid retention 

(3) Hyperkalaemia 

• They are not dialyzable 

11- Corticosteroids and immunosuppressive agents: 

• Prednisone and prednisolone are not cleared by the kidneys but the dose 

must be reduced in dialysis patients as uremia may reduce their clearance 

by the liver. Normal doses can be used in nephrotics. 

• Methylprednisolone is cleared by dialysis, so it should be given after dialysis 

• Azathioprine should be reduced in renal impairment to a maximum of 1mg 

/kg /day if GFR is < 10 ml /min 

• Cyclosporin A is metabolized by the liver via cytochrome P 450 

Drugs affecting cytochrome P.450. 

Inhibitors 

Inducers 

ketoconazole 

Rifampin 

Erythromycin 

Phenytoin 

Oral pills 

Phenobarbitone 

Verapamil 

Depakine 

Amiodarone 

Tegretol 

Quinidine 

Omeprazole 

• Cyclophosphamide dose should be reduced in renal impairment 

• Melphalan : 

- is used in M.myeloma 

- half the dose if GFR is < 25 ml /min. 

12- Vaccines: 

• Live attenuated vaccines are contraindicated in immunocompromized 

patients. 

• Repeated doses of vaccine to produce seroconversion is usually needed e.g 

for HBV. 

III. Clinical use of diuretics 

Diuretics are of clinical value in the following conditions: (A) Arterial 

hypertension, (B) Congestive heart failure, (C) Liver cirrhosis and ascites, (D) 

Nephrotic syndrome, (E) Acute renal failure, (F) Others.

(A) Arterial hypertension: 

• Despite the introduction of new hypotensive drugs as ACEIs and calcium 

channel blockers, diuretics remain the corner stone in the treatment of 

hypertension. 

• Their B.P. lowering effect is pronounced in the elderly, those with systolic 

hypertension, those with low renin states and those with volume dependent 

hypertension. 

• Thiazide diuretics are more effective antihypertensives than are the loop 

diuretics except in renal impairment. 

• They are useful as second antihypertensive agents. 

• They are essential in overcoming Na + -retaining effect of other vasodilators 

as minoxidil. 

• Mechanisms of their antihypertensive action: 

(1) Normalization of enhanced intracellular Na+, and Ca++ concentration. 

(2) Decrease vascular response to vasoconstrictor agents as angiotensin 

ΙΙ and noradrenaline. 

(3) Increase formation of vasodilator prostaglandins. 

(4) Decrease endogenous digitalis-like Natriuretic hormone which is 

vasopressor. 

(5) Potassium channel opening effect in resistance arteries. 

(B) Treatment of congestive heart failure: 

• In cases with acute myocardial infarction or chronic heart failure, loop 

diuretics have immediate action in reducing pulmonary wedge pressure, 

decreasing cardiac index and increasing systemic vascular resistance. Left 

ventricular end diastolic pressure is decreased due to decreased preload. 

• Metolazone (a thiazide diuretic) is effective in inducing diuresis in loop 

diuretic resistant cases. If the case is resistant to the combined loop and 

thiazide diuretic then continuous infusion of frusemide becomes successful. 

(C) Diuretic in liver cirrhosis and ascites: 

Aldosterone antagonists are more frequently used because of the high 

blood level of aldosterone in these cases. If the response is not satisfactory 

loop diuretics may be added. 

In cirrhotic patients diuretics are used to treat ascites and to decrease 

portal hypertension.

(D) Diuretic treatment of nephrotic edema: 

If the GFR is in within normal, thiazide diuretics with or without 

aldosterone antagonists may be used. 

When renal function is impaired, thiazides will be ineffective and loop 

diuretic are indicated. Furosemide (Lasix) is given orally in a variable dose 

according to the response. The dose may be increased up to 120 mg/d. If 

there is no response, the drug may be given intravenously and a thiazide as 

metolazone (Metinix) may be added. 

If the response is still poor, salt free human albumin and I.V. loop 

diuretic are indicated. 

In cases of severe intractable oedema not responding to the above 

mentioned measures, ultrafiltration (using haemodialysis machine) and I.V. 

human albumin may be useful. 

The resistance to loop diuretics in renal failure is due to 

pharmacokinetic and pharmacodynamic causes. 

a) Pharmacokinetic causes: 

This is mainly due to the decrease in drug delivery to loop of Henle as a 

result of: 

• Decrease renal perfusion 

• Decrease volume of distribution 

• Decrease diuretic secretion in tubule resulting from the competition with 

organic acids. 

• Binding of diuretic to filtered albumin. 

b) Pharmacodynamic causes 

This is mainly due to the decrease in the number of functioning 

nephrons with a consequent decrease in Na filtered load . 

Loop diuretics in hemodialysis patients may have a role - by large 

doses - in controlling the fluid balance in selected patients. 

(E) Diuretics in Acute Renal Failure (ARF) 

(1) Mannitol: 

• Its infusion during early stages of AFR may prevent the loss of renal 

function. Yet, this statement is still debatable. 

• The probable mechanisms of actions: 

1- Increase intratubular flow rate which prevent obstruction by debris, and 

proteins. 

2- Decrease endothelial and epithelial cell swelling. 

3- Protect mitochondrial function.

4- Decrease O2 free radicals. 

5- Renal V.D. (due to increase in prostaglandin, and decrease in renin) 

(2) loop diuretics: 

• Debatable 

• Its use with renal dose dopamine in incipient ARF is the treatment of choice 

in many centers, although this approach is still empirical. 

• Possible mechanisms : 

(1) Decrease transport activity of loop of Henle. 

(2) Remove obstructing casts. 

(3) renal V.D. by increasing prostaglandin. 

(F) Other indications of diuretics: 

(1) glaucoma 

(2) urine alkalinization 

(3) Calcium nephrolithiasis 

(4) Treatment of hypercalcaemia 

(5) Treatment of toxicity of aspirin and phenobarbitone.

KIDNEY AND THE HEART 

This issue could be discussed by covering the following items: 

1- Effects of cardio-vascular diseases on the kidney. 

2- Effects of renal diseases on the heart. 

3- Diseases affecting both organs. 

4- Cardiac drug modification in renal diseases. 

Effects of Cardiovascular Diseases on the Kidney 

The following are some of the effects on the kidney which may be 

induced by cardiovascular diseases. 

1- Heart failure, affects the kidney through the backward and the forward 

failure effects. 

a- systemic venous congestion 

This results in an increase in the capillary pressure, transudation into 

interstitial spaces with decrease in effective circulating volume. This will 

be aggravated by the presence of forward failure and decrease in 

perfusion of the vital organs including the kidney. 

The result is oliguria; and in severe cases it may lead to prerenal failure. 

Increase in right atrial pressure and systemic congestion will increase 

secretion of ANP. 

b- Decreased cardiac output. 

This results in a decrease in the renal perfusion with: 

• Renal vasoconstriction 

• Increased secretion of renin, angiotensin, aldosterone with consequent 

salt and water retention. 

• Increased secretion of ADH with consequent water retention. 

2- Infective endocarditis: This may result in glomerulonephritis, embolic 

renal disease and renal impairment. 

3- Cardiogenic shock: This may result in either pre-renal failure or acute 

tubular necrosis; according to the severity and the duration of the condition. 

4- Atrial fibrillation may lead to thromboembolic disease involving the 

kidney. 

5- Hypertension may result in nephrosclerosis. 

6- Dissecting aortic aneurysm may extend to affect the renal vessels with 

consequent ischaemic renal disease.

Effects of the Kidney on the Cardiovascular System 

1- Hyperlipidaemia may complicate renal disease as nephrotic syndrome and 

chronic renal failure. This may play a major role in the pathogenesis of 

systemic atherosclerosis and coronary artery disease. 

2- Renal hypertension may perpetuate atherosclerosis, coronary artery 

disease and may lead to hypertensive heart failure. 

3- Hypervolaemia of renal failure may result in pulmonary oedema. 

4- Hypovolaemia of nephrotic syndrome may result in postural hypotension. 

5- Deep vein thrombosis as a known complication of nephrotic syndrome 

which may result in pulmonary embolism. 

6- Chronic renal failure may result in pericarditis, uraemic cardiomyopathy, 

pulmonary oedema or coronary artery disease. 

7- Anaemia due to renal failure may result in heart failure and anginal pain. 

8- Electrolyte and acid-base disorders resulting from renal diseases may have 

cardiac manifestations as arrhythmia and intractable heart failure. 

Diseases Affecting Both Organs 

Many diseases may affect the heart and kidney such as: 

1- Viral infection which may cause myocarditis and interstitial nephritis. 

2- Parasitic diseases as schistosoma that may lead to corpulmonale and 

schistosomal nephropathy. 

3- Autoimmune diseases as SLE which may cause cardiomyopathy and lupus 

nephritis. 

4- Systemic vasculitis that may affect the heart and the kidney. 

5- Systemic amyloidosis that may lead to cardiomyopathy and nephropathy. 

6- Metabolic diseases as diabetes mellitus and hyperparathyroidism may 

affect both systems. 

7- Toxic substances as NSAIDS heavy metals as lead may affect both 

systems. 

Modification of cardiac drugs in renal disease 

See the chapter on drugs and kidney (Page 383).


- Leschke M, et al: Coronary heart disease in patients with end-stage 

kidney failure. Dtsch Med Wochenschr, 133 : 31-32, 967-82, 1997. 

- Bellomo R, et al: The kidney in heart failure. Kidney Int Suppl, 66 : S58- 

61, 1998.

KIDNEY AND THE LUNG 

The interaction between the kidney and the lung is enormous. The 

following are examples of this relationship: 

1- Renal disease may result in pulmonary disease such as: 

• Hypercoagulable state in nephrotic syndrome that may be complicated by 

DVT which may result in pulmonary embolism. 

• Pulmonary oedema may complicate fluid overload or severe hypertension 

secondary to a renal disease as acute nephritis and chronic renal failure. 

2- Pulmonary disease may be complicated with renal disease such as: 

• Bacterial pneumonia and upper respiratory infection may lead to acute 

nephritis. 

• Pulmonary TB and empyema may lead to renal amyloidosis. 

3- A systemic disease may effect both organs as SLE, Good pasture's 

syndrome and cryoglobulinaemia. 

RENAL DISEASES IN THE ELDERLY 

As a result of improvement of quality of medical service and nutritional 

status, there is an increase of longevity with a consequent increase in elderly 

population. 

Kidney wise, there are structural and functional changes which take 

place in the kidney with age. These changes have an impact on the 

management of these patients. 

The renal structural and functional changes with aging are as the 

following: 

1- Structural changes: 

Macroscopically, there is a reported decrease in the kidney size 

which may reach up to 20-40% (on comparing ages of 30 to 90 years). This 

reduction in renal mass is most probably related to the reduction in body 

mass. 

Microscopically, with age the following microscopic findings could be 

observed: 

• There is an increasing reduction in the number of glomeruli and there is an 

increase in glomerular sclerosis. Also, there is an increase in the GBM 

thickness. 

• Renal tubules show an irregular thickening of the basement membrane 

especially in the DCT. The overall tubular mass is decreased. The 

interstitium may show areas of tubular atrophy and interstitial fibrosis.

• The renal vessels may show intimal thickening and reduplication of the 

elastic lamina. 

• These structural renal changes may start as early as the age of 30 years. 

2- Functional changes: 

There is an age-related reduction in both renal plasma flow and 

glomerular filtration rate. The renal plasma flow declines at approximately 

10% per decade from about the age of 30 years. 

The renal plasma flow decreases by 10ml/min every decade of life and 

the glomerular filtration rate declines with age at a decremental rate of 0.75 

ml/min/year. The cortical blood flow is reduced to a greater extent than the 

medullary flow. 

As there is a reduction in muscle mass and body weight with age, the 

reduction in GFR is not associated with comparable changes in serum 

creatinine because of the decrease in endogenous creatinine production. So, 

for proper assessment of the kidney function in elderly, creatinine clearance 

with 24 hours urine collection is mandatory. Equations relying on body weight 

for calculation of GFR are misleading in the elderly. 

Tubular function seems to be little influenced by age, although it is 

recognized that the ability to concentrate and dilute urine is impaired. In 

addition, there is a reduction in the ability of the nephron to conserve sodium. 

Glomerular Diseases in The Elderly: 

Some forms, particularly membranous nephropathy, may be more 

common in elderly. This may be linked to the increased incidence of 

malignancy among this group of patients. 

Elderly patients often have multiple pathology such as hypertension, 

diabetes and atherosclerotic changes. Any of these may be a cause or 

associated with primary glomerular disease. 

Tubulointerstitial diseases in the Elderly: 

Patients are more at the risk of having tubulointerstitial nephritis than 

younger patients are. This is most probably due to:- 

• Elderly use drugs more commonly than young; especially NSAIDS. 

• Diminished drug clearance, due to decreased GFR. 

• Presence of co-morbid conditions, making them more vulnerable to drug 

nephrotoxicity (as DM, heart failure). 

Renovascular Disease: 

Elderly are the main victims of renovascular hypertension and 

ischaemic nephropathy.

End-stage renal disease in the Elderly: 

Dialysis: 

There is a growing trend that there should be no age limit for the 

acceptance to dialysis therapy so far the patient could benefit from treatment. 

This decision should be taken after careful consideration of the patient's 

general and psychological health as well as his or her family circumstances. 

Haemodialysis is always confronted with the following difficulties: 

• Vascular access problems. 

• Cardiac insufficiency and vascular instability during dialysis. 

• Tolerance of interdialysis fluid gain is always poor. 

However, in view of the availability of advanced dialysis facilities and 

experienced physicians and nursing staff, many elderly patients can achieve 

a satisfactory degree of rehabilitation by haemodialysis. 

Peritoneal dialysis is always well tolerated by elderly patients. 

Transplantation: 

Elderly are less tolerable to immunosuppression and corticosteroid 

therapy. 

Previous cerebrovascular disease seems to be of particular poor 

prognostic significance. 

If there is no comorbid condition, transplantation is still the best 

therapeutic option with better patient survival.


- Lindeman RD, Tobin J, Shock NW: Longitudinal studies on the rate of 

decline in renal function with age. J Am Geriatr Soc 1985; 33 : 278-285. 

- Abrass CK: Glomerulonephritis in the elderly. Am J Nephrol 1985; 5 : 

409-418. 

- Lamy PP: Renal effects of nonsteroidal antiinflammatory drugs: 

Heightened risk in the elderly J Am Geriatr Soc 1986; 34 : 361-367. 

- Kasiske BL: Relationship between vascular disease and age-associated 

changes in the human kidney. Kidney Int 1987; 31 : 1153 : 1159. 

- Gourtsagiannis N, Prassopoulos P, Cavouras D, Pantelidis N: The 

thickness of the renal parenchyma decreases with age: A CT study of 

360 patients. AJR 1990; 155 : 541-544. 

- Röhrich B, Asmus G, Von Herrath D, Schaefer K: Is it worth performing 

kidney replacement therapy on patients aged over 80 Nephrol Dial 

Transplant. 1996; 11 : 2412-2413. 

- A. Davison. Renal diseases in elderly. Nephron 1998, 80 : 6-16.

KIDNEY AND PREGNANCY 

This chapter on kidney and pregnancy will shed the light on the 

following items: 

1- Renal physiological changes during pregnancy 

2- Renal alterations in Toxemia of pregnancy 

3- Obstetric-related acute renal failure 

4- Some specific renal diseases in relation to pregnancy. 

1- Renal Physiologic changes during pregnancy: 

• The blood pressure decreases in early phases of normal pregnancy due to 

the reduction in systemic vascular resistance. As pregnancy approaches full 

term, these changes become attenuated and blood pressure returns 

towards normal. 

• There is extracellular fluid volume expansion as a result of augmentation in 

renal tubular salt and water reabsorption induced by the excess oestrogen 

and aldosterone and fall in blood pressure. 

• There is increase in the cardiac output and in the renal perfusion. 

• GFR increases in the first trimester and reaches a peak (about 50% above 

the non pregnancy level) and serum creatinine decreases to about 0.3-0.5 

mg/dl by the beginning of second trimester 

• GFR returns towards baseline during 9th month of gestation. 

2- Toxaemia Of Pregnancy (Preeclampsia and Eclampsia) 

Definition: 

Preeclampsia is characterized with gradual onset of hypertension, 

proteinuria and edema which usually manifest after the 20th week of 

gestation. In severe cases, this may progress to a convulsive phase which is 

then called eclampsia. 

Incidence: 5-10% of all pregnancies are complicated with toxaemia. 

Pathogenesis: 

There is a uteroplacental ischemia due to vasoconstriction of the 

placental vessels. This is mediated by abnormal prostaglandin metabolism 

which results in the increase in thromboxane level and activation of 

coagulation system. This leads to obliteration of the placental vessels by 

platelets and fibrin. Ischemic placental degeneration occurs, this may result in 

the release of thromboplastins into the systemic circulation leading to fibrin 

deposition in the kidney and other organs.


Glomeruli show swelling and ballooning of the endothelial and mesangial cells 

leading to the narrowing of the glomerular capillary lumens (Fig. 15.4a). This 

characteristic ballooning of endothelial cells may be related to fibrin deposition 

(Fig. 15.4b) and is called glomerular endotheliosis. 

(Fig. 15.4a) 

H & E stained kidney section (X 360) of a case with 

preeclamptic toxaemia of pregnancy. It shows minimal 

increase in cellularity and occlusion or extreme 

narrowing of capillary lumina. The glomerulus appears 

uniformly "Solid" 

(Fig. 15.4b) 

The same case examined by immunofluorescence 

microscopy (X 260), it shows deposits of fibrinogen 

along the capillary walls and in the mesangium. 

Electron microscopy shows widening of the glomerular basement membrane 

by fibrin deposits. 

Immunofluorescence microscopy shows deposits which are mainly of 

fibrinogen along the capillary walls and the mesangium (Fig. 15.4b). 

After termination of pregnancy, these changes resolve within 2-3 weeks. 

In severe preeclampsia, there may be extensive glomerular deposition 

of fibrin and platelets which may be associated with cortical necrosis or 

delayed and incomplete recovery of renal damage.

Management: 

• Close monitoring of pregnancy 

• Use of prophylactic low dose aspirin in high risk patients. 

Category of patients at risk of toxaemia of pregnancy includes: 

- Diabetics 

- Hypertensives 

- Those with laboratory risk factors such as hyperuricaemia and 

hypocalciuria. These are due to increased tubular reabsorption 

of uric acid and calcium. 

• Patients prone to develop toxaemia of pregnancy characteristically 

demonstrate increased blood pressure response to infusion of angiotensin 

II at as early as 24th week of pregnancy. Also, in these patients there is 

exaggerated blood pressure response to changes in posture with more 

increase in supine position. In these patients, the percentage of 

development of hypertension or preeclampsia is 45% while only 5% of non 

responders develop these complications. 

• The definitive treatment of toxaemia of pregnancy is the delivery of the fetus 

and placenta. The only reason to delay delivery in established preeclampsia 

is evidence of fetal immaturity. In this setting bed rest in lateral 

recumbent position and antihypertensive agents should be used until 

delivery is safely performed. However, delivery should not be delayed if 

there are signs indicating that the mother is at risk of progression to 

eclampsia. These include uncontrollable hypertension, visual disturbance, 

seizures, HELLP syndrome (hemolysis, elevated liver enzymes and low 

platelet count) or D.I.C. 

• We have to use safe antihypertensive drugs during pregnancy including α 

methyldopa, atenolol, and hydralazine 

• ACEI and diuretics are contraindicated during pregnancy. 

3- Obstetric-Related Acute Renal Failure: 

Acute renal failure can occur during pregnancy in a variety of situations 

similar to those causing sudden renal dysfunction in nonpregnant patients. 

However, pathology peculiar to pregnancy must always be considered. 

Acute fatty liver of pregnancy can be complicated by renal failure and 

its early recognition with prompt treatment reduces fetal and maternal 

mortality rates. Hemolytic-uremic syndrome is also associated with high 

morbidity and mortality rates.

- Treatment of sudden acute renal failure resembles that in non pregnant 

populations and aims at retarding the appearance of uremic syndrome, 

acid-base and electrolyte disturbances and volume problems (i.e. 

overhydration when the patient is oliguric and dehydration during the 

polyuric phase). 

• Infection problems should be taken seriously. 

• Some of the problems can be dealt with judious conservative management, 

but if such an approach is unsuccessful, dialysis must be used promptly. 

• Urea, creatinine and a variety of metabolic waste products cross the 

placenta. Then, "prophylactic" dialysis could be more compelling in a 

pregnant woman with an immature fetus and in whom temporization is 

desired. 

• The method of dialysis (peritoneal or hemodialysis) should be dictated by 

facilities available and by clinical circumstances. 

• Peritoneal dialysis is effective and safe as long as the catheter is inserted 

high in the abdomen under direct vision through a small incision. It probably 

minimizes the rapid metabolic perturbation which occurs with 

haemodialysis and provides another route for drug administration. 

• Controlled anticoagulation with heparin during hemodialysis should be 

similar to that used in non pregnant patients. 

• Great care should be given to avoid significant volume shifts during 

hemodialysis to avoid impairment of uteroplacental blood flow. 

• Early delivery (as dictated by fetal maturity) should be undertaken. 

• Blood losses at or after delivery should be corrected. 

• The neonate can be subject to rapid dehydration because of increased 

concentrations of urea and other solutes within the fetal circulation which 

precipitates an osmotic diuresis shortly after birth. 

• Once the patient has recovered from acute renal failure, she should have no 

difficulty in conceiving or carrying another pregnancy to term.

4- Specific kidney diseases and pregnancy 

Renal disease 

Chronic glomerulonephritis 

IgA nephropathy 

Pyelonephritis 

Reflux nephropathy 

Urolithiasis 

Polycystic disease 

Diabetic nephropathy 

Systemic lupus erythematosus 

Polyarteritis nodosa 

Scleroderma 

Previous urinary tract surgery 

After nephrectomy, solitary kidney 

and pelvic kidney 

Wegener's granulomatosis 

Renal artery stenosis 

Effects and outcome 

Usually no adverse effect in the absence of hypertension. 

One view is that glomerulonephritis is adversely affected by 

the coagulation changes of pregnancy. Urinary tract 

infections may occur more frequently 

Risks as uncontrolled and/or sudden escalating hypertension 

and worsening of renal function 

Bacteriuria in pregnancy can lead to exacerbation. Multiple 

organ system derangements may ensue, including adult 

respiratory distress syndrome 

Risks of sudden escalating hypertension and worsening of 

renal function 

Infections can be more frequent, but ureteral dilatation and 

stasis do not seem to affect natural history. Limited data on 

lithotripsy, thus best avoided. 

Functional impairment and hypertension are usually minimal 

in childbearing years 

Usually no adverse effect on the renal lesion, but there is 

increased frequency of infection, oedema, and/or preeclampsia 

Controversial; prognosis most favorable if disease is in 

remission >6 months prior to conception. Steroid dosage 

should be increased postpartum 

Fetal prognosis is dismal and maternal death often occurs 

If onset during pregnancy then there can be a rapid over all 

deterioration. Reactivation of quiescent scleroderma may 

occur postpartum 

Might be associated with other malformations of the 

urogenital tract. Urinary tract infection is common during 

pregnancy. Renal function may undergo reversible decrease. 

No significant obstructive problem but Caesarean section 

often needed for abnormal presentation and/or to avoid 

disruption of the continence mechanism if an artificial 

sphincter is present 

Might be associated with other malformations of the 

urogenital tract. Pregnancy is well tolerated. Dystocia rarely 

occurs with pelvic kidney. 

Limited information. Proteinuria (+hypertension) is common 

from early in pregnancy. Immunosuppressives are safe but 

cytotoxic drugs are better avoided 

May present as chronic hypertension or as recurrent isolated 

pre-eclampsia. If diagnosed then transluminal angioplasty 

can be undertaken in pregnancy if appropriate.

Pregnancy In Dialysis Patients: 

• These patients are usually infertile but contraception should not be 

neglected. 

• The live birth outcome at best is 36%. Realistically, these women should not 

take any health risks. 

• Early diagnosis of pregnancy in dialysis patients is difficult because the 

symptoms of early pregnancy may look like uremic symptoms, urine 

pregnancy test is unreliable. So if pregnancy is suspected ultrasound is the 

method of choice. 

Pregnancy in kidney transplant patients 

- Is not free of risk to both foetus and the mother. 

- Neonatal problems in offsprings of renal transplant patients include 

• Pre-term delivery, offspring is always small for gestational age 

• Respiratory distress syndrome is more common 

• Lymphoid-thymic hypoplasia is more common 

• Adrenocortical insufficiency is more common 

• CMV, HBV and HCV hepatitis are more common. 

• Congenital anomalies. 

- Criteria for the reduction of post transplant pregnancy risks are the following: 

1- Pregnancy occurring 11/2-2 years post-transplant. 

2- Patients with reasonable graft function 

Serum creatinine < 2 mg/dl 

Preferably < 1.5 mg/dl 

3- Patients with no recent episode of rejection 

4- Normotensives or those using minimal antihypertensive drugs 

5- Patients with minimal or no proteinuria 

6- Patients with normal graft ultrasound 

7- Patients with Prednisone < 15 mg/day, 

Azathioprine < 2 mg/kg/day, and 

Cyclosporine within the therapeutic window. 

Important remarks: 

- In perinatal period, steroid dose should be augmented to cover the stress of 

labour and to prevent precipitation of rejection. 

- Breast feeding should be discouraged. 

- Great care should be taken to the graft function during the 3 months 

postpartum.


- Marwah D, et al: Renal disease in pregnancy. Curr Opin Nephrol 

Hypertens, 5 : 2, 147-50, 1996. 

- Jungers P, et al: Pregnancy in renal diseases. Kidney Int, 52 : 4, 871- 

85, 1997. 

- Bernheim J: Hypertension in pregnancy (clinical conference). Nephron, 

76 : 3, 254-63, 1997. 

- Suzuki S, et al: Postpartum renal lesions in women with pre-eclampsia. 

Nephrol Dial Transplant, 12 : 12, 2488-93, 1997. 

- Hussey MJ, et al: Obstetric care for renal allograft recipients or for 

women treated with hemodialysis or peritoneal dialysis during 

pregnancy. Adv Ren Replace Ther, 5 : 1, 3-13, 1998. 

- Hou S, et al: Management of the pregnant dialysis patient. Adv Ren 

Replace Ther, 5 : 1, 24-30, 1998. 

- Schmidt RJ: Fertility and contraception in end-stage renal disease. Adv 

Ren Replace Ther, 5 : 1, 38-44, 1998. 

- Paller MS: Hypertension in pregnancy. J Am Soc Nephrol, 9 : 2, 314- 

21, 1998.

ENVIRONMENTALLY-INDUCED KIDNEY DISEASES 

The extent of the contribution of environment in causing renal disease 

is unknown. This is largely due to the following: 1- The fact that multiple 

environmental factors could be working together, 2- Difficulty in confirming 

and quantifying the exposure to a certain environmental toxin; and 3- The lack 

of specific clinical or pathologic presentation of different environmental toxin. 

In the USA, 19% of patients with end stage renal failure have disease 

of unknown cause and in 30 per cent of those presenting with 

glomerulonephritis the aetiology is unrecognized, possibly environmental 

toxins are responsible at least in part for these cases. 

The kidney is more prone to environmental toxins for the following 

reasons: 

1- The kidney is the principal organ for excretion of different toxins; 

2- High renal blood flow; 

3- Extensive surface of endothelial contact with toxins; 

4- Positive intraglomerular hydrostatic pressure; 

5- The medullary counter-current multiplier system leading to more 

accumulation of toxic agents and their metabolites in the renal medulla. 

The environmentally-induced renal injury may be tubulo-interstitial, 

glomerular or combined. Tubulo-interstitial lesions may be in the form of acute 

tubular necrosis (such as exposure to high concentration of mercury) or 

chronic tubulointerstitial nephritis (such as chronic exposure to low doses of 

lead). Glomerular lesions may be due to direct toxicity (such as deposition of 

gold in basement membrane and silica in the mesangium) or immunologicallyinduced 

(for example immune complex disease in chronic exposure to 

hydrocarbons). 

Environmental chemicals with nephrotoxicity includes solvents, 

hydrocarbons, heavy metals and fungal toxins. Other environmental 

nephrotoxins include physical agents (e.g. radiation injury) and biological (e.g. 

parasite as bilharziasis and malaria). 

Volatile Hydrocarbons (Organic Solvents) As Environmental 

Nephrotoxins 

Types of exposure include: 

• Ingestion or inhalation of carbon tetrachloride;

• Intentional sniffing of cleaning fluid (toluene-containing glues, 

trichlorethylene, 1,1,1,-trichloroethane); 

• Suicide attempts by ingestion of tetralin; 

• Occupational exposure (inhalation of trichloroethylene, diesel fuel and 

toluene, paints, glue, degreasing solvents); 

• Washing hands and hair with diesel fuel; 

• Domestic solvent inhalation. 

Kidney lesions induced by organic solvents include: 

• Acute tubular necrosis owing to exposure to high doses of organic solvent; 

• Chronic tubulo-interstitial nephritis as a consequence of acute exposure; 

• Glomerulonephritis owing to chronic exposure with possibly genetic 

predisposition, which may result in either anti-GBM glomerulonephritis, 

membranous glomerulonephritis or proliferative glomerulonephritis. 

• Clinically, renal lesions may present as acute renal failure, chronic renal 

failure or nephrotic syndrome; and neoplasia especially renal cell 

carcinoma. 

Heavy Metals As Environmental Nephrotoxins 

These include lead, cadmium, mercury, uranium and arsenic. 

Moreover, addition, therapeutic forms of gold, bismuth and platinum can 

cause nephrotoxicity. Silicon, beryllium, lithium, barium and selenium are not 

heavy metals (specific gravity

Lead containing inclusion bodies will be detected in renal tubular cells, 

urine, liver, neural tissue and osteoblasts. 

Good responses can be achieved by chelation therapy (EDTA, BAL 

and Penicillamine). 

Chronic lead nephropathy: 

Histologically, it will appear as a slowly progressive tubulointerstitial 

nephritis. Clinically, this manifests as chronic renal failure, hypertension, 

hyperuricaemia and gout. These manifestations are associated with others, 

including gastrointestinal, haematologic and neurologic. The diagnosis is 

confirmed with the detection of an abnormal body lead level >80 ug/L and 

positive EDTA lead chelation test. In the hypertensive gouty patient with 

chronic renal failure and without stone disease, chelation test may detect an 

unrecognized lead exposure. 

Chronic lead nephropathy, especially if diagnosed and treated early 

could be arrested or its progression is retarded. 

Ca Na2 EDTA is given in combination with BAL for symptomatic cases. 

Cadmium nephropathy: 

Source of exposure: Cadmium is a component of metal alloys, in the 

manufacture of electrical conductors, electroplating storage batteries, aircraft 

industries, as a by-product of iron smelting, as a pigment, in ceramics, glass, 

in plastic stabilizer, in photographic developer, rubber or dental prosthetics. 

Also, the burning of coal, oil and cigarettes. 

Cadmium toxicity: The acute absorption of as little as 10 mg of dust or 

fumes will cause severe gastrointestinal symptoms; and 12 hours later, 

pulmonary oedema. Chronic low dose exposure will cause emphysema, 

anosmia and renal disease. Early renal manifestations are those of adult 

Fanconi syndrome, tubular proteinuria and renal tubular acidosis. Urinary 

calculi are detected in 40 per cent of cases. In late phases chronic renal 

failure appears. 

Treatment: Ca Na2 EDTA is of little value after cadmium has fixed in tissues. 

Vitamin D and calcium may be of help for bone disease, but may aggravate 

renal disease (by more stone formation). 

Mercury nephrotoxicity: 

Mercury toxicity depends on its chemical form and route of 

administration. Elemental mercury is harmless when ingested but when its 

vapour is inhaled will be very toxic. Environmentally, mercury is either organic

or inorganic salt. Toxicity is usually caused by methyl, ethyl, or phenoxyethyl 

organic salts and the chloride salt. 

Acute mercury nephrotoxicity will manifest as acute renal failure due to 

acute tubular necrosis associated with erosive gastritis, haematemesis and 

melena. 

Chronic mercury nephrotoxicity will manifest as tubulo-interstitial nephritis 

or nephrotic syndrome (due to membranous nephropathy or nil-change 

disease or less commonly anti-GBM disease) which is associated with 

neurologic deficits. 

Treatment: Acute toxicity is treated with BAL and chronic toxicity by removal 

from the source of exposure. 

Arsenic nephrotoxicity: 

Elemental arsenic is not toxic, but the pentavalent, trivalent salts and 

arsine gas (Arsine) are very toxic. 

Exposure: 

• Industry: glass, pigment, bronze plating or metal alloys. 

• Wood preservation, veterinary medicine, herbicides, insecticides and 

rodenticides. 

• Certain herbal preparations, burning of arsenic-treated wood or arsenic 

containing prescription medicines. 

• Arsine can be released from sewage plants. 

Clinical manifestations of arsenic nephrotoxicity: 

a) Acute exposure (for example arsine gas): Acute renal failure (ATN), 

haemolytic anemia, cardiomyopathy, encephalopathy, epigastric pain, 

vomiting and explosive diarrhoea. This is usually fatal and those who 

recover develop chronic renal failure. 

b) Chronic exposure: slowly progressive renal failure, encephalopathy, 

polyneuropathy, cardiomyopathy, anemia, liver cirrhosis, abdominal 

cramps, diarrhoea and vomiting and hyperpigmentation. 

Diagnosis and treatment: 

Arsenic may be detected in urine, blood, hair and nail. Treatment is 

with BAL, exchange transfusion or haemodialysis which should be performed 

within 24 hours of exposure.

Radiation injury 

It may be defined as any somatic or genetic disruption of function or 

form caused by electromagnetic waves or accelerated particles. These could 

be ultraviolet radiation, microwave radiation, high intensity ultrasound and 

ionized radiation from natural or man made sources. 

Exposure: 

a) Medical: Staff or the public may be affected by a malfunction or during 

repair of machinery in radiotherapy departments. Patients subjected to 

radiotherapy may be affected and can be a source of irradiation to others. 

b) Industrial and military: atomic weapon testing, catastrophes (such as 

Chernobyl reactor), industrial and laboratory exposure. This could be 

through ingestion or inhalation of long-lived isotopes (such as radium and 

plutonium). 

Radiobiology of kidney tissue: 

After exposure to a dose of radiation of 10 Gray (GY) or more, the 

renal tubular cells are reduced in number, exhibiting flattening in the tubule 

lining. Whole nephrons are lost over 4-18 months after exposure. 

Radiation Nephrotoxicity: 

a) Immediate: decreased renal blood flow and glomerular filtration rate. 

b) Early: acute nephritis 

c) Late: chronic nephritis, obstructive uropathy, urinary fistula and fluid and 

electrolyte depletion. 

Infective (biological) environmental risk factors 

a) Parasitic: for example malaria, schistosoma and hydatid disease. 

b) Bacterial: for example tuberculosis. 

c) Viral: for example viral hepatitis and HIV. 

d) Fungal toxins: especially ochratoxin and aflatoxin. 

Ocratoxins arise from fungus Aspergillus ochraceus, discovered in the 

mid 1960s during a search for new toxic substances from moulds. It was 

discovered to be a natural contaminant of maize (Fig. 15.5), and to be the 

cause of porcine nephropathy in Scandinavia by 1978. It is established as 

grain contaminant and a cause of porcine nephropathy in Europe and USA.

(Fig.15.5) 

Normal and fungus- invaded 

Kernels of maize. The later, 

as other funguscontaminated 

grains, could 

produce nephropathy in 

animals and human. 

Ochratoxin nephrotoxicity 

• Ocratoxins induce nephropathy and kidney tumours in rodents, dogs, pigs 

and birds. 

• It induces endemic porcine nephropathy in central and northern European 

countries. 

• It most probably has a major role in the aetiology of Balkan endemic 

nephropathy which is characterised by chronic tubulo-interstitial disease 

(Fig. 15.6) progressing to end stage renal failure and urethral tumours, a 

picture similar to porcine nephropathy. 

• Recently it has been reported to be responsible for nephropathy in Tunisia 

and possibly in Egypt. 

(Fig. 15.6) 

Kidney section of case with 

chronic tubulointerstitial 

nephritis, most probably 

produced by ochratoxicosis

Suggested Reading: 

- Sobh M: Environmental pollution is increasing the incidence of chronic 

renal failure. J Toxicol-Toxin Reviews, 15 (3), 199-205, 1996. 

- Maaroufi K, et al: Human nephropathy related to ochratoxin A in 

Tunisia. J Toxicol-Toxin Reviews, 15 (3), 223-237, 1996. 

- Simon P: Ochratoxin and kidney disease in human. J Toxicol-Toxin 

Reviews, 15 (3), 239-249, 1996. 

- Badria D: A multidisciplinary study to monitor mycotoxins in Egypt. J 

Toxicol-Toxin Reviews, 15 (3), 251-272, 1996.

Essentials of Clinical Nephrology (Shorouk Press, Cairo, 2000, ISBN ...

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