A Colour Handbook of

Renal
Medicine
ZZZPHGLOLEURVFRP
JAMES PATTISON DM FRCP
Consultant Nephrologist
Guy’s and St Thomas’ Hospital, London, UK

DAVID GOLDSMITH FRCP

Consultant Nephrologist
Guy’s and St Thomas’ Hospital, London, UK

BARRIE HARTLEY FRCPath

Consultant Renal Pathologist
St James’ University Hospital, Leeds, UK

FERNANDO C. FERVENZA MD DPhil

Assistant Professor of Medicine
Mayo Clinic, Rochester, Minnesota, USA

JOSEPH P. GRANDE MD PhD

Professor of Laboratory Medicine and Pathology
Mayo Clinic, Rochester, Minnesota, USA

MANSON
PUBLISHING
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Contents
PREFACE 5 Glomerulonephritis associated with
hepatitis C virus infection 66
ACKNOWLEDGEMENTS 5 Glomerulonephritis associated with
human immunodeficiency virus
ABBREVIATIONS 6 (HIV) 68
Miscellaneous infections and
1 ASSESSMENT OF THE PATIENT glomerulonephritis 70
WITH RENAL DISEASE 9
Introduction 10 4 TUBULOINTERSTITIAL
Symptoms of renal disease 10 DISEASES 71
Physical signs in renal disease 16 Acute interstitial nephritis (AIN) 72
Presenting symptom complexes/ Granulomatous interstitial nephritis 74
syndromes in renal disease 20 Urate nephropathy 76
Lead nephropathy 78
2 PRIMARY GLOMERULAR Lithium-induced renal disease 79
DISEASES 25 Radiation nephritis 80
Minimal change nephropathy 26
Focal segmental glomerulosclerosis 5 DISEASES AFFECTING THE
(FSGS) 28 RENAL VASCULATURE 83
Thin basement membrane Atheromatous renovascular disease 84
nephropathy 30 Fibromuscular renovascular disease 88
Membranous nephropathy 31 Cholesterol emboli 89
Membranoproliferative Essential hypertension and the kidney 90
glomerulonephritis (MPGN) 34 Scleroderma 92
Poststreptococcal glomerulonephritis Hemolytic–uremic syndrome (HUS) 94
(PSGN) 36
IgA nephropathy 38 6 RENAL INFECTIONS AND
STRUCTURAL ABNORMALITIES 97
3 SYSTEMIC DISEASES Acute pyelonephritis 98
AFFECTING THE GLOMERULI 41 Xanthogranulomatous
Diabetes mellitus 42 pyelonephritis 100
Plasma cell dyscrasias 46 Malakoplakia 101
Amyloidosis 49 Renal tuberculosis 102
Fibrillary and immunotactoid Two unusual renal infections 103
glomerulopathy 52 Vesicoureteric reflux and reflux
Systemic lupus erythematosus (SLE) 53 nephropathy 104
Primary anti-phospholipid antibody Urinary tract obstruction 106
syndrome (PAPS) 58 Congenital anomalies of the
Systemic vasculitis 60 urinary tract 108
Sickle cell anemia and Renal calculi 110
glomerulonephritis 63 Retroperitoneal fibrosis 114
Goodpasture’s disease 64 Medullary sponge kidney 115
Glomerulonephritis associated with
hepatitis B virus infection 65
7 INHERITED RENAL DISEASES 117 10 ACUTE RENAL FAILURE 161
Autosomal dominant polycystic Introduction 162
kidney disease 118 Epidemiology 162
Autosomal recessive polycystic Classification 163
kidney disease 122 Clinical assessment 172
Nephronophthisis (autosomal recessive Management and outcome 173
juvenile nephronophthisis) 124
Alport’s syndrome 126 11 CHRONIC RENAL FAILURE
Nail–patella syndrome 128 AND DIALYSIS 177
Congenital nephrotic syndrome 130 Introduction 178
Fabry disease (Anderson–Fabry Natural history 178
disease, angiokeratoma corporis Symptoms, signs, and clinical
diffusum) 132 evaluation 179
Von Hippel–Lindau disease 134 Reversible causes 179
Primary hyperoxalurias (PH) 137 Complications and consequences 180
Cystinosis 140 Clinical interventions to retard
Tuberous sclerosis complex (TSC) 142 progression to end-stage
renal failure 182
8 TUMORS OF THE RENAL Dialysis (renal replacement
PARENCHYMA AND therapy – RRT) 183
UROTHELIUM 147
Introduction 148 12 RENAL TRANSPLANTATION 213
Tumors of the renal parenchyma 149 Introduction 214
Renal urothelial tumors 154 Causes of graft dysfunction 214
Renal allograft histology 214
9 RENAL DISEASE IN Vascular and urologic complications
PREGNANCY 155 of renal transplantation 221
Normal pregnancy 156 Other complications 223
Renal diseases associated with
pregnancy 156 INDEX 229
Pre-eclampsia 156
Pregnancy in renal disease 158
Pregnancy in dialysis patients 158
Pregnancy in renal transplant
patients 158
 5

Preface
Renal medicine is one of modern medicine’s because of the increased incidence of cardio-
great success stories. Although uroscopy is an vascular and neoplastic disease in patients with
ancient art, the modern discipline of nephrology long-term renal failure.
owes its development to recent technologic The format of this book primarily reflects the
advances. The advent of the ante-mortem renal ‘stages’ of renal disease – presenting symptoms
biopsy in the early part of the last century was and syndromes, inherited renal diseases, glom-
fundamental to achieving an understanding of erular and systemic diseases, acute and chronic
the way the kidney was affected by intrinsic and renal failure, dialysis, and renal transplantation.
systemic diseases. As important was the use of This is how trainees at the resident and clinical
micropuncture techniques which unravelled fellow/senior house officer and registrar levels
some of the mysteries of renal tubular phy- – at whom this book is aimed – will see their
siology; while the development in the 1950s and patients. A short book of this nature cannot
60s of the mainstays of modern nephrology – hope to be all-embracing or comprehensive, but
dialysis and renal transplantation – depended on we hope that we have covered the main areas of
technical advances in bio-engineering, anti- interest and importance. We hope also that we
coagulation, and immunology. have shown an ‘approach’ to nephrologic prob-
More than any other subdivision of general lems which nonrenal specialist trainees will find
internal medicine, successful nephrologic prac- useful too.
tice is dependent on other specialties. This is so
for three reasons: first, the expertise needed in James Pattison
renal imaging, arterial intervention and particu- David Goldsmith
larly renal histopathologic examination; second, Barrie Hartley
because of the extent to which the kidneys are Fernando C. Fervenza
affected by so many systemic diseases; and third, Joseph P. Grande

Acknowledgements
We are very grateful to a number of colleagues Mr G. Swana, Dr B. Hunt, Dr R. Swaminathan,
for providing illustrative material. These include Dr R. Palmer, Dr G. Fogazzi, and Mr D.
Dr A. Kawashima, Dr B. King, Dr V. Torres, Spalton. We would like to thank Mr Bill
Dr J. McCarthy, Dr P. Harris, Dr G. Miller, Edwards, Keeper of the Gordon Museum, Guy’s
Dr D. Milliner, Dr N. Campeau, Dr R. Desnick, Hospital for allowing us to reproduce some of
Dr J. Berstein, Dr J. Reidy, Dr A. Saunders, the images of specimens from the Museum.
Dr J. Bingham, Dr S. Rankin, Dr G. Rottenberg, Certain figures (Chaper 5: figures 118–128)
Dr T. Gibson, Dr I. Abbs, Dr R. Hilton, Dr J. are reproduced with permission from Grainger
Cunningham, Dr D. Pennell, Dr P. Ackrill, and Allison: Diagnostic Radiology (Chapter 67:
Dr M. Venning, Dr D. Radia, Dr D. Davies, Renal arteriography, renovascular disorders and
Dr N. Roussak, Dr S. Clarke, Dr P. Hawkins, renovascular hypertension), Harcourt Health
Dr F. Tungekar, Dr J. Hextall, Dr C. Reid, Sciences, London.
6 RENAL MEDICINE

Abbreviations
AA secondary amyloidosis. DAT direct antigen testing.
ACE angiotensin converting enzyme. DIC disseminated intravascular coagulation.
ADH antidiuretic hormone. DMS diffuse mesangial sclerosis.
ADMA asymmetric dimethylarginine. DMSA dimercaptosuccinate.
ADPKD autosomal dominant polycystic (ds) DNA (double stranded)
kidney disease. deoxyribonucleic acid.
AGT alanine glyoxylate aminotransferase. DSA digital subtraction angiogram.
AIDS acquired immune deficiency syndrome. DTPA diethylenetriamine penta acetate.
AIN acute interstital nephritis. DVT deep vein thrombosis.
AL primary amyloidosis.
ANA anti-nuclear antibodies. EKG electrocardiogram.
ANCA anti-neutrophil cytoplasmic ECHO echocardiogram.
antibodies. ECV effective circulating volume.
Ang angiotensin. EDTA ethylene diamine tetra-acetic acid.
anti-Sm anti-Smith antibodies. ELISA enzyme-linked immunosorbent assay.
anti-Scl anti-scleroderma antibodies. ENT ear, nose and throat.
APD automated peritoneal dialysis. ESR erythrocyte sedimentation rate.
APS anti-phospholipid antibody syndrome. ESRD end-stage renal disease.
ARBs angiotensin receptor blockers. ESRF end-stage renal failure.
ARF acute renal failure.
ARPKD autosomal recessive polycystic FFP fresh frozen plasma.
kidney disease. FSGS focal segmental glomerulosclerosis.
AS Alport’s syndrome.
ASO antibody to streptolysin O. Gal galactose.
ATN acute tubular necrosis. GalNAc N-acetylgalactosamine.
AV arteriovenous. Gb3 galactotriosylceramide.
AVF arteriovenous fistula. GBM glomerular basement membrane.
GFR glomerular filtration rate.
BFH benign familial hematuria. GI gastrointestinal.
BK BK virus. GN glomerulonephritis.
(S, D) BP (systolic, diastolic) blood pressure.
C3 Nef C3 nephritic factors. HBcAg hepatitis B core antigen.
CABG coronary artery bypass graft. HBeAg hepatatis B e antigen.
CAD coronary artery disease. HBsAg hepatitis B surface antigen.
CAPD continuous ambulatory peritoneal HBV hepatitis B virus.
dialysis. HCV hepatitis C virus.
CAVH continuous arteriovenous filtration. HD hemodialysis.
CCB calcium channel blockers. HDL high density lipoprotein.
CLL chronic lymphatic leukemia. H+E hematoxylin and eosin stain.
CMV cytomegalovirus. HIF hypoxia-inducible factor.
CNS congenital nephrotic syndrome. HIV human immunodeficiency virus.
CREST cutaneous systemic sclerosis. HIVAN human immunodeficiency virus-
CRF chronic renal failure. associated nephropathy.
CRP c-reactive protein. HLA human leukocyte antigen.
CT computerized tomography. HUS hemolytic–uremic syndrome.
CUA calcific uremic arteriolopathy.
CVVH continuous venovenous ICU intensive care unit.
hemofiltration. IDNT Irbesartan Diabetic Nephropathy
CVVHDF continuous venovenous Trial.
hemodiafiltration. Ig (A, G, M) immunoglobulin (A, G, M).
CXR chest X-ray. IgAN IgA nephropathy.
 ABBREVIATIONS 7

INR internal normalized ratio. RTA renal tubular acidosis.

IVU intravenous urogram. RVT renal vein thrombosis.

JC JC virus. SAA serum amyloid A protein.

SAP serum amyloid P protein.
LDH lactate dehydrogenase. SLE systemic lupus erythematosus.
LDL low density lipoprotein.
LV left ventricle. TB tuberculosis.
LVF left ventricular failure. TBM tubular basement membrane.
LVH left ventricular hypertrophy. TGF transforming growth factor.
TINU tubulointerstitial nephritis–uveitis
MAP mean arterial pressure. syndrome.
MCGN mesangiocapillary TPN total parenteral nutrition.
glomerulonephritis. TSC tuberous sclerosis complex.
MCKD medullary cystic kidney disease. TTP thrombotic thrombocytopenic purpura.
MDRD modification of diet in renal disease.
MN membranous nephropathy. USRDS United States Renal Disease Service.
MPGN membranoproliferative
glomerulonephritis. VEGF vascular endothelial growth factor.
MR magnetic resonance. VHL von Hippel–Lindau.
MRA magnetic resonance angiography. VLDL very low density lipoprotein.
MRFIT The Multiple Risk Factor VUJ vesicoureteric junction.
Intervention Trial.
MRI magnetic resonance imaging. WBC white blood cell.
MS methenamine silver. WHO World Health Organization.

NO nitric oxide.
NPH nephronophthisis.
NS nephrotic syndrome.
NSAID nonsteroidal anti-inflammatory drug.

PAPS primary anti-phospholipid antibody

syndrome.
PAS periodic acid Schiff.
PCR polymerase chain reaction.
PD peritoneal dialysis.
PDGF-B platelet-derived growth factor B
chain.
PET positron emission tomography.
PH primary hyperoxalurias.
PKD polycystic kidney disease.
PTFE polytetrafluoroethylene.
PTH parathyroid hormone.
PSGN poststreptococcal glomerulonephritis.
PTLD post-transplant lymphoproliferative
disease.
PTRA percutaneous transluminal renal
angioplasty.
PTX parathyroidectomy.
PUJ pelviureteric junction.

RBC red blood cell.

(m)RNA (messenger) ribonucleic acid.
RPF retroperitoneal fibrosis.
RPGN rapidly progressive
glomerulonephritis.
RRT renal replacement therapy.
This page intentionally left blank
Chapter One
9

Assessment of
the patient with
renal disease
• Introduction

• Symptoms of renal disease

• Physical signs in renal disease

• Presenting symptom complexes/syndromes

in renal disease
10 ASSESSMENT OF THE PATIENT WITH RENAL DISEASE

Introduction

Nephrologic problems can first be discovered in herited and metabolic/storage derangements to

the context of acute emergencies with life- acquired pathologies as diverse as immunologic,
threatening potential. More often though the metabolic, neoplastic, and infective diseases. Many
symptoms and signs of more slowly progressive ‘renal’ diseases have a systemic component; this is
renal disease are occult, subtle, and too often particularly true of immunologic and metabolic
passed off as old age, fatigue, or ‘anemia’. There problems; the corollary of this is that the first
are many thousands of molecules that accumulate presentation of a problem may well be with symp-
in renal failure; ascribing individual symptoms to toms referring to another organ or system. This
any one or other of these is unnecessary (and can lead to misdiagnosis, diagnostic delay, and
impractical). Many patients on dialysis still have potential harm, e.g. a patient with epistaxis and
symptoms that first started in the predialysis phase nasal blockage may only see a generalist, or an
of their illness, as dialysis only replaces about 10% ENT specialist, so that the eventual diagnosis of
of renal function. Only successful renal trans- Wegener’s granulomatosis comes to light only
plantation can comprehensively treat the many after an episode of acute renal failure has ensued.
facets of the uremic syndrome. Screening for renal problems is in the main
Given the major reduction in projected life- relatively easily accomplished without invasive
span that ensues with the development of irre- investigation. Use of urine testing apparatus to
versible renal failure, increased emphasis on detect the presence of blood and protein in the
screening and detection of risk-associations for urine is cheap, fast, and sensitive. Equally, the
‘preventable’ renal disease, such as raised blood main blood marker of renal function, serum
pressure and diabetes, are mandatory. creatinine concentration, is a part of every bio-
Renal diseases cover the whole range, from in- chemical automated analytical profile.

Symptoms of renal disease

ASYMPTOMATIC PATIENTS ing. This is worse at night, when there is vaso-

Asymptomatic patients are typically detected after dilatation. It is multifactorial, involving altered
routine screening of urine, of blood pressure, and dermal sensation, opioid metabolism, and cal-
of excretory renal function. This is often after a cium–phosphate precipitation. Repeated scratch-
patient has moved and registered with a new ing and excoriation leads to a self-perpetuating
doctor and undergoes health screening, or in the cycle of dryness and irritation. Iron deficiency
context of a work/insurance medical examin- may exacerbate the problem. Rarely nodular
ation. Other situations include screening during prurigo is a feature. Symptomatic relief can be
pregnancy, screening due to work-related ex- obtained from menthol creams and unguents,
posure to renal toxins, or after another family from regular moisturizers, from antihistamines,
member has been diagnosed with an hereditable and in some cases, naloxone and other opioid
renal condition (e.g. polycystic kidney disease). partial agonists (1).

TIREDNESS BREATHLESSNESS
By its very nature this is a symptom that has Any one of anemia, fluid retention (pulmonary
many different causes. Most patients with sig- edema, pleural effusions), and acidosis can pro-
nificant renal impairment are tired. Anemia, duce this symptom.
now treated with erythropoietin, was the major
reason for this symptom, but many patients DISTURBED URINARY HABIT (POLYURIA,
report reduced energy levels even with normal NOCTURIA, ENURESIS, OLIGURIA, ANURIA)
hemoglobin concentrations. Hypoalbuminemia Polyuria may be due to:
is also associated with significant tiredness once • Increased water intake (e.g. compulsive poly-
plasma albumin has fallen to <30 g/l (<3g/dl). dipsia).
• Increase in osmotic load (e.g. urea in chronic
ITCHING (PRURITUS) renal failure, glucose in diabetes mellitus).
By the time GFR has fallen to <20 ml/min, • Reduced ADH secretion (e.g. head injury
many patients notice dry skin (xerosis) and itch- and central diabetes insipidus).
 SYMPTOMS OF RENAL DISEASE 11

• Renal resistance to ADH (e.g. inherited 1

nephrogenic diabetes insipidus).
• Acquired conditions (e.g. hypokalemia,
hypercalcemia, lithium toxicity).
• Reduced medullary concentrating ability
(e.g. interstitial nephritis, papillary necrosis,
nephrocalcinosis).

Polyuria is seen in the recovery phase of oliguric

acute renal failure, after renal transplantation, and
after successful angioplasty of a tight renal artery
stenosis in a single well-functioning kidney.
Loss of urinary concentrating (distal tubule
and collecting system) ability in chronic renal
failure, due to loss of functional nephrons and
refractoriness of the remnant nephrons to ADH,
is manifest by the failure of the normal physio-
logic mechanisms of decreasing urinary volume
and increasing urinary concentration; this leads
to nocturia. More observant patients may notice
that their urine is clearer, and paler, and uniformly
so, i.e. without any diurnal variation. As renal 1View of a CRF patient’s back showing a
function deteriorates nocturia worsens; many large area (accessible to scratching) of
patients need to get up three or four times at increased pigmentation and excoriation
night. Urinary stream, and bladder function, are due to uremic pruritus.
unaffected (symptomatic enquiries on this point
are crucial, as prostate and bladder problems also
of course have nocturia as part of their symptom 2
complexes). Nocturia, and reversed day–night
urine volume excretion, can be seen in the elderly
(most probably due to progressive renal impair-
ment), in diabetes mellitus and insipidus, and in
hypothyroidism.
Oliguria (less than 400 ml urine/24 h) is a
feature of acute renal failure (though many such
cases of ARF have a transient oliguric phase).
Anuria is usually due to complete urinary tract
obstruction (2–4) though more rarely seen with
acute cortical necrosis, or bilateral renal infarction.

2 Renal tract 3 4
ultrasound showing
gross hydro-
nephrosis and renal
cortical thinning in a
case of obstructive
uropathy.

3 Renal tract
ultrasound showing
normal appearance
with compact
echogenic pelvis
and clear cortico- 4 Postmortem appearance of chronic severe
medullary hydronephrosis. Note the virtual absence of
differentiation. renal cortex.
12 ASSESSMENT OF THE PATIENT WITH RENAL DISEASE

Symptoms of renal disease (continued)

BLOOD IN URINE (HEMATURIA) often associated with the development of glom-

Macroscopic hematuria (5) can be one of the erular proteinuria.
most alarming symptoms from a patient’s pers- Certain groups, such as diabetics and hyper-
pective. Pink/red/brown urine can also be seen tensives, will have their urine checked regularly
with anthocyanin ingestion (e.g. beetroot), for protein (in fact for albumin as micro-albu-
rhabdomyolysis, porphyria, alkaptonuria, rifampin minuria, or albumin excretion rate, or albu-
(rifampicin) or phenytoin therapy, and after min/creatinine ratio). The development and
phenolphthalein ingestion. Very rarely it can be persistence of this urinary abnormality im-
factitious (e.g. nucleated red blood cells seen on mediately raises the mortality risk of the indi-
urine microscopy after a patient persistently vidual (as much due to cardiovascular disease as
‘spiked’ her urine with chicken blood!). malign renal outcome).
In healthy subjects <107 red blood cells Protein in the urine can be glomerular or
(RBCs) are excreted in the urine per day. This tubular in origin. Protein is virtually excluded
equates approximately to one erythrocyte per 100% from glomerular filtrate due to poorly
microliter of urine. Only 5 ml of blood con- understood mechanisms that include pore size,
taining 25 × 109 RBCs in one liter of urine is permselectivity of the renal basement membrane,
needed to give macroscopic hematuria. Hema- and cell membrane charge. Normal protein
turia can be microscopic only, macroscopic only,
or intermittent macroscopic with persistent
microscopic. Blood can of course arise from any-
where in the urinary tract. Hemoglobinopathies Table 1 Renal causes of hematuria
such as sickle cell disease (and trait) are asso-
ciated with microscopic hematuria. Jogging and
heavy physical exercise often cause transient Coagulopathies
microscopic hematuria. Anticoagulants
Urinary testing using dipstick reagents is con- Hemophilia, sickle
venient and practical at home and in hospital
settings. These reagents detect the hemoglobin Glomerular disease
from lysed RBCs. The sensitivity of these tests is IgA nephropathy
high, and close to the normal RBC excretion rate. Alport’s syndrome
Microscopy of urine is best done with freshly- Thin membrane disease
voided acid urine (e.g. first voided after overnight Systemic vasculitis/lupus
recumbency) as this avoids premature breaking- MCGN/RPGN
up of the cell membranes. Sometimes renal hema-
turia can be so heavy that clots are seen. Table 1 Tumors
lists the major causes of hematuria. Renal cell carcinoma
Red blood cells that have traversed Bow- Transitional cell carcinoma
man’s space and the tubular system in the
nephron characteristically have abnormal shapes Stones
compared to those that arise from lower urinary Anywhere in urinary tract
tract bleeding – so called ‘dysmorphic’ RBCs. Calcium oxalate, urate
These can be recognized in freshly-voided urine
by means of urinary centrifugation and phase- Medullary/interstitial disease
contrast microscopy (6, 7). Red cells trapped in Papillary necrosis
hyaline-proteinaceous casts in the urine – red Medullary sponge kidney
cell casts – are a cardinal sign of acute glomeru- Tuberculosis
lonephritis (8).
Traumatic
PROTEINURIA Kidney, ureter
This has become a common presentation for
patients with renal disease in the era of urine Miscellaneous
screening using stick reagents. Hereditary hemorrhagic telangiectasia
Conditions such as hypertension and dia- Arteriovenous malformations
betes in which there is glomerular hypertension Loin-pain hematuria
(thereby altering glomerular permeability) are
 SYMPTOMS OF RENAL DISEASE 13

excretion is about 100 mg protein/day; over half Beta-2-microglobulin, and Tamm–Horsfall pro-
of this is albumin. The upper limit of normal for tein (secreted, and a major component of renal
protein excretion is taken as 150 mg/day. tubular casts), are two main constituents of
Experimental data suggest a heteroporous model tubular proteinuria.
to explain the development of proteinuria in Cardiac failure, heavy exercise, and orthostatic
renal disease – the development of more mem- proteinuria all need careful confirmation or
brane pores, and the appearance of larger exclusion. Young males seem most prone to
membrane pores. Glomerular proteinuria can be supine/orthostatic proteinuria (not completely
anything from 0.2–100 g/24 h. understood but perhaps an exaggerated glom-
Tubules can actively reabsorb protein. erular hemodynamic response to change in
Greater than 95% of low molecular weight posture). This condition appears to be benign.
filtered proteins are reabsorbed in the proximal A renal biopsy is indicated if there is >1 g of
tubule. Proximal tubular damage will give rise to protein loss/24 h or there is evidence of renal
‘tubular proteinuria’ which is rarely >1 g/24 h. impairment or progressive loss of renal function.

5 6 7

5 A pot of urine showing gross 6 Urine microscopy showing 7 Phase contrast urine
macroscopic hematuria. normal red blood cells in the microscopy showing cells which
urine. have irregular not smooth
outlines and are ‘dysmorphic’.

8 Urine microscopy showing a red blood cell cast (red blood

cells in the urine trapped in a hyaline cast).
14 ASSESSMENT OF THE PATIENT WITH RENAL DISEASE

Symptoms of renal disease (continued)

SWELLING (EDEMA) LOIN PAIN

Salt and water retention is one of the early mani- This is an inconsistent accompaniment to renal
festations of the acute or chronic loss of func- diseases. Patients often describe back and loin
tional nephrons. This produces symptoms and pain but mechanical back problems are more
signs depending on the location of the fluid. commonly the cause. Acute pyelonephritis is
Edema is most often first noticed as periorbital often painful; renal vein thrombosis rarely so.
puffiness on rising, and ankle edema at the end Acute IgA nephropathy and poststreptococcal
of the day (9, 10). It is of fundamental impor- glomerulonephritis can be associated with loin
tance to understand whether edema is due to aching, especially if there is significant macro-
local factors (e.g. vasodilatation or poor venous scopic hematuria.
drainage), or to systemic causes such as cardiac
or renal failure, or hypoalbuminemia. Testing IMPORTANT FACETS OF THE HISTORY
the urine for the presence of blood and protein IN RENAL DISEASE
is a cardinal investigation of edema, and should • Previous estimations of BP, urine testing, and
certainly precede the prescription of a diuretic. renal function testing.
Ascites, pleural, and pericardial effusions (11) • Childhood problems (e.g. enuresis, recurrent
can accompany severe edema such as seen in fevers).
advanced nephrotic syndrome. • Drug history (prescribed, borrowed, ‘over-
the-counter’, illicit).
LOSS OF APPETITE • Gynecological and obstetric history.
(ANOREXIA, NAUSEA) • Family history.
With advanced renal failure come anorexia, • Occupational and social histories.
nausea, and eventually vomiting. Acidemia is • Travel history.
anorectic and catabolic. Leptin retention may
play a role in anorexia; while ‘middle molecules’
are associated with the gastrointestinal symp-
toms. Well dialysed patients tend to eat better
than poorly dialysed ones, and aggressive treat-
ment of renal anemia can also improve appetite.

TWITCHING/RESTLESS LEGS
(MYOCLONUS)/NUMBNESS–BURNING
(PAR- OR DYSESTHESIA)
Middle molecule retention in advanced chronic
renal failure, or on dialysis, can lead to painful
peripheral (mainly sensory but sometimes motor
or autonomic) neuropathy. Myoclonic jerks
(restless legs) are a typical symptom, sometimes
also associated with sleep disturbance or sleep
apnea, in advanced chronic renal failure or on
dialysis. Clonazepam, diazepam, phenytoin, and
gabapentin have all been tried with some suc-
cess. Initiating dialysis, or improving solute
clearance on dialysis, may help, but the definitive
treatment remains renal transplantation.
 SYMPTOMS OF RENAL DISEASE 15

9 10

10 Abdominal CT scan showing massive sacral edema (arrow).

9 Gross edema of the lower leg in nephrotic syndrome.

11

11 CT scan of the chest showing a large pericardial

effusion (arrow).
16 ASSESSMENT OF THE PATIENT WITH RENAL DISEASE

Physical signs in renal disease

A full physical examination is an essential part 12

of a proper nephrologic diagnosis. Leuconychia
indicates chronic ill-health; a pigmented band
at the distal edge of the nail indicates chronic
uremia (12).
Inspection of the kidneys is rarely rewarding,
though occasional patients of slim physique and
with large polycystic kidneys may have obvious
abdominal distention (13).
Palpation of the lower pole of the right kid-
ney in full inspiration in a slim individual is a
normal finding. Polycystic kidneys, large solitary
lower pole cysts, and malignant tumors can all 12 Leuconychia (and jaundice).
be palpated on occasions.
General physical examination is important 13
where renal pathology has affected other organs
and systems, or in the context of a multisystem
disease. Thus, purpura can manifest Henoch–
Schöenlein purpura (14, 15), or vasculitis; but-
terfly rash and nail-fold infarcts can reveal
systemic lupus erythematosus (16); periumbilical
and genital pigmented hyperkeratotic papules are
seen in Fabry’s disease (17); peripalpebral pur-
pura (18) is a feature of extensive amyloidosis;
partial lipodystrophy (19) is most often associated
with mesangiocapillary glomerulonephritis.
Scleroderma has a characteristic appearance of the
face and hands (20, 134, 135).

14 13 Central abdominal swelling due to the

presence of grossly enlarged polycystic kidneys
in a case of autosomal dominant polycystic
kidney disease.

14, 15 Low power view of the buttocks

and extensor surface of the legs (14).
A widespread ‘vasculitic’ rash is present.
Higher power view of individual lesions (15).

15
 PHYSICAL SIGNS IN RENAL DISEASE 17

16 17

16 Butterfly rash in a patient with SLE.

17 Characteristic dermatological appearance

(angiokeratoma corporis diffusum universale)
of Fabry’s disease in a transplanted patient.
The lesions are typically in a bathing trunk
distribution.The hirsutism reflects cyclosporine
(cyclosporin) treatment.

18 19

18 Spontaneous peri-orbital palpebral (and facial) 20

purpura on the neck, due to skin chaffing from a
shirt-collar. Extensive skin amyloidosis renders skin
capillaries very fragile.

19 Partial lipodystrophy in a patient with

mesangiocapillary glomerulonephritis. Partial
lipodystrophy is also seen spontaneously, in
families, and in the context of antiviral therapy
in some HIV-positive patients.

20 Scleroderma producing swollen red featureless

fingers with ‘tight’ skin.
18 ASSESSMENT OF THE PATIENT WITH RENAL DISEASE

Physical signs in renal disease (continued)

Finger infarction, iritis, and collapse of the Fundoscopy is crucial to the diagnosis and
nasal cartilage (21–23) heralds Wegener’s granu- evaluation of hypertension and diabetes (25).
lomatosis. Gross neuropathic muscle wasting is seen in
Examination of the eye can lead to helpful severe mononeuritis multiplex in diabetes (26).
clues – hypercalcemia induces limbal calcifica- Sometimes a single investigation will yield an
tion and redness (24); vasculitis and sarcoidosis immediate diagnostic answer. Obviously this ap-
are associated with uveitis and episcleritis; plies to renal biopsy. Renal angiography can also
Alport’s syndrome is associated with lenticonus reveal a reason for renal problems, including
(194); nephronophthisis with tapetoretinal multiple microaneurysms of the renal arterial
degeneration (Senior–Loken syndrome) (192). branches in classic polyarteritis nodosa (27).

21 22

22 Acute episcleritis heralding Wegener’s granulomatosis (similar

appearances are also seen in microscopic polyangiitis and sarcoidosis).

21 Acute infarction of a digit (a very wide differential diagnosis).

23 24

24 Acute red eye of uremia. First described in the 1960s, this is due
to ectopic calcification (calcium–phosphate) in the corneal limbus
leading to local irritation.

23 Collapse of the nasal cartilage seen in Wegener’s granulomatosis

(and also in lethal medline granuloma, relapsing polychondritis, and
congenital syphilis).
 PHYSICAL SIGNS IN RENAL DISEASE 19

25 26

25 Gross proliferative diabetic retinopathy.

In type 1 diabetic patients this complication
(and neuropathy) is often seen in the context
of diabetic nephropathy.
26 Severe muscle wasting due to mononeuritis
multiplex in a poorly-controlled diabetic patient.

27

27 Renal angiogram showing multiple micro-aneurysms

(‘beads’) on renal artery branches in a case of classic
polyarteritis nodosa.
20 ASSESSMENT OF THE PATIENT WITH RENAL DISEASE

Presenting symptom complexes/syndromes

in renal disease

NEPHROTIC SYNDROME (NS) Complications of nephrotic syndrome

This is one of the best known manifestations NS can affect many other parts of the body, just
of renal disease. Its management encapsulates as uremia does. Together with the loss of albu-
many facets of the care of patients with renal min there is usually gross hepatic over-pro-
problems. If proteinuria is sufficiently severe and duction of many other proteins (not always
prolonged, nephrotic syndrome (proteinuric, albumin itself for obscure reasons).
hypoproteinemic edema) will develop.
A good working definition is edema, plasma Infections
albumin <30 g/l (3 g/dl) and >3 g of urinary Bacterial infections are more common in NS
protein loss/24 h. Edema (9) can be subtle, or and can be life-threatening. This is especially so
so severe as to be debilitating (anasarca). Neph- in adults with NS. Primary peritonitis (often
rotic syndrome is not benign, unless the under- Streptococcus pneumoniae, but also gram-nega-
lying cause can be treated and the syndrome tives and Hemophilus spp.) may present in-
brought into remission. Patients notice frothy sidiously with mild abdominal colicky pain, or
urine in heavy proteinuria (28). with circulatory collapse. Cellulitis arising from
skin splits or punctures are a risk in severely
Pathogenesis edematous limbs. Viral infections may actually
How edema develops in NS remains contro- trigger relapses in childhood NS due to minimal
versial. The old classic theory of underfilling due change nephropathy.
to reduced plasma oncotic pressure is not sup- Reasons for increased susceptibility to infec-
ported by many more recent careful investiga- tion, apart from the physical effects of edema,
tions. Plasmapheresis, which reduces plasma include hypogammaglobulinemia (reduced
albumin substantially, does not induce edema. IgG), reduced complement (factor B) system
Plasma volume measurements usually show activity, low zinc levels, and impaired T-lympho-
normality or even increase, rather than decrease. cyte function.
Sodium and water retention is somehow a con- Antibiotic and vaccine prophylaxis seem sen-
comitant of increased renal tubular protein traffic. sible measures, but rigorous evidence support-
ing their use is lacking.
Clinical features
Up to 4 liters of salt and water can remain clini- Thromboembolic disease
cally undetectable. Edema usually starts peri- Thrombosis, both venous and arterial, com-
orbitally, and can end up being severe with the monly affects severely nephrotic adults (10%)
patient 20 or more kilograms overloaded. Gross and children (2%); these problems are another
pitting skin-splitting lower leg edema, sacral and reason for the occasional fatalities seen in NS.
genital edema, pleural and pericardial effusions, There are very many abnormalities in coagu-
and ascites can all be present in severe cases. lation described in NS. Prothrombotic changes
Hyperlipidemia is a typical concomitant and include increases in Von Willebrand factor, fib-
in established persistent NS eruptive xanthomata rinogen, factor V, and protein C. Fibrinolysis is
(29) can rarely be seen. also inhibited. Platelets are reported to be hyper-
There are very many causes of NS (Table 2). coagulable. Patients with NS can be relatively
To distinguish these a renal biopsy is almost immobile. Whole blood viscosity may be in-
always indicated (the exception being children creased by hyperfibrinogenemia, by diuretics, and
aged <10 years, in whom a trial of steroids is perhaps by steroids. The most common site for
preferable, reserving biopsy for more prob- thrombosis is the deep venous system of the
lematic management cases). lower limbs; this may go undetected in warm
edematous legs until a pulmonary embolus
ensues. Renal vein thrombosis (RVT) is seen
rarely, though it is thought to be more common
in idiopathic and lupus membranous disease, and
also in amyloidosis.
 PRESENTING SYMPTOM COMPLEXES/SYNDROMES 21

28 29

28 A container of urine with an impressive ‘head’ 29 Eruptive xanthomata in a nephrotic patient

of froth. Protein in the urine significantly lowers with gross secondary hypercholesterolemia.
the surface tension of urine and with aeration
leads to bubbles. Patients often notice this frothing
(which can be mimicked by toilet cleansers).

Table 2 Common causes of nephrotic syndrome

Primary glomerular Drugs

Minimal change Gold
Mesangioproliferative, e.g. IgA Penicillamine
Membranoproliferative NSAIDs
Membranous
Focal and segmental glomerulosclerosis Miscellaneous

Secondary glomerular
Diabetes mellitus
Amyloidosis
Systemic lupus erythematosus
HIV-associated nephropathy
Hepatitis C-associated nephropathy
22 ASSESSMENT OF THE PATIENT WITH RENAL DISEASE

Presenting symptom complexes/syndromes in

renal disease (continued)
The extent and severity of venous thromboses Treatment can be effective using low-fat diets,
will depend on the investigative rigour and zeal statins, and fibrates. Reducing proteinuria (by
employed. In some series RVT can be found in whatever means) is also helpful to the dyslipidemia.
10% of NS subjects (30, 31). The classical
presentation of flank pain, deterioration of renal Loss of binding transport proteins in the urine
function, macroscopic hematuria, and ipsilateral Low concentrations of copper, zinc, and iron
testicular swelling is as rare as it is well-remem- have been noted in NS plasma. The relevant
bered. Whether it is preferable to seek out the binding proteins may be lost in the urine.
presence of RVT/DVT (using MR venography, Vitamin D concentrations can also be low in
CT scanning, or contrast venography), as op- NS. Bone disease may be more common in
posed to taking prophylactic measures for all children with protracted NS. Changes in thy-
cases of NS, remains to be established. roid-binding globulin and cortisol-binding
Arterial thrombosis is very much rarer in NS protein are clinically unimportant.
but is reported, and can be devastating. The
femoral artery is the most commonly reported Catabolism and poor nutrition
site (especially in children), but cases have been Wasting of muscle is a major problem in severe
reported for virtually every artery (32). NS. Albumin turnover is greatly increased. The
Treatment and prophylaxis are widely prac- optimal protein intake in NS remains contro-
tised, though the evidence-base is slender. Hep- versial. Cases can be made for normal or high
arin (larger doses are required in NS) and warfarin protein diets.
are the therapeutic mainstays, as well as mini-
mizing hemoconcentration, treating sepsis Acute renal failure
promptly, and encouraging mobility. The real This is a rare sequela of NS, and can happen
problems lie in deciding whom to anticoagulate, spontaneously when NS is very severe, or after
at what point in their NS, and for how long. Many excessive diuresis with loop diuretics.
authorities would advocate the use of warfarin if
plasma albumin falls to <25 g/l (2.5 g/dl), par- Treatment of nephrotic syndrome
ticularly with extensive edema. Low molecular First and foremost is the need to establish the
weight heparin, aspirin, clopidogrel, and dipyrida- underlying causation of the NS by means of a
mole are also (weaker) alternatives. careful and thorough history and then a renal
biopsy. Where there is a remediable lesion,
Dyslipidemia such as minimal change disease, then immuno-
There is often a severe secondary dyslipidemia modulatory treatment might induce a remis-
in NS. Whether or not this contributes to in- sion in days. Many cases of membranous
creased cardiovascular mortality or progressive nephropathy can remit spontaneously, or after
renal damage in NS is uncertain, but substantial prednisolone and chlorambucil/cyclophos-
sustained elevations in plasma cholesterol should phamide. In other cases though there is much
not be viewed with equanimity. Free cholesterol, less likelihood of significant remission, e.g.
cholesterol esters, and phospholipids all increase focal and segmental glomerulosclerosis, or
in NS. Triglycerides can also be elevated. LDL amyloidosis.
and VLDL concentrations are increased; HDL Sodium restriction (50 mmol/24 h
concentrations are often normal or low. Lipo- [50 mEq/24h]) and diuretics will help the
protein (a) is also increased. Lipiduria is often edema resolve. Furosemide (frusemide) by
a feature of NS. mouth may be ineffective as protein binding in
The reasons for the dyslipidemia remain to the convoluted tubule may prevent its action.
be fully elucidated but seem to include a major Thiazides are synergistic with loop diuretics in
increase in production and reduction in removal this situation. Salt-poor albumin has been widely
of lipoproteins. There is hugely increased employed in severe or diuretic-refractory, cases.
hepatic lipoprotein synthesis in rough propor- Reduction of proteinuria is the goal of
tion to protein loss and hypoalbuminemia. therapy. Leaving aside interventions to remove
Levels of important lipid regulating enzymes the cause of NS, there are several general
such as lipoprotein lipase and lecithin cholesterol measures that can be employed to reduce pro-
acyl transferase are also deranged in NS. teinuria. Most if not all depend on reducing
 PRESENTING SYMPTOM COMPLEXES/SYNDROMES 23

30

30 CT scan at the level of the kidneys showing a large blood clot in the
renal vein (arrow). RVT occurs more often in membranous nephropathy
and amyloidosis than in other causes of NS. Loin pain, hematuria, and renal
impairment are classic symptoms for a large acute thrombosis; pulmonary
emboli are not uncommon.

31 32

32 Postmortem specimen of acute renal

arterial thrombosis (arrow).

31 Postmortem specimen of an acute RVT in a

patient with renal amyloidosis (pale kidney) and
nephrotic syndrome.
24 ASSESSMENT OF THE PATIENT WITH RENAL DISEASE

Presenting symptom complexes/syndromes in renal

disease (continued)
GFR. Older measures included the use of high- UREMIC SYNDROME
dose nonsteroidal anti-inflammatory drugs Uremia can be associated with many or few
(often indomethacin), dipyridamole, or cyclo- symptoms, depending on its severity and speed
sporine (cyclosporin) (which can be an immu- of onset. The loss of excretory renal function
nomodulatory intervention in its own right in, will be manifest as fluid retention, hypertension,
e.g. steroid-resistant minimal change neph- and hyperkalemic acidosis. Plasma calcium may
ropathy, or membranous glomerulopathy). fall and phosphate rise.
NSAIDs work rapidly, but have a considerable Tiredness and lack of physical stamina are
number of unwelcome side-effects. typical – only partly explained by anemia. Loss
Use of the ACE inhibitors, alone, or in con- of mental sharpness is insidious (but commented
cert with angiotensin antagonists, are the on by some patients once renal function is
modern approach to proteinuria reduction. The restored). With severe uremia, confusion, ob-
dose response curve for proteinuria reduction is tundation, seizures, and coma are possible.
different to that of blood pressure reduction; Anorexia and nausea, with vomiting when
very high doses of these drugs can be used with severe, are associated with catabolism and loss
success. It may take many weeks for the full of muscle bulk; loss of body substance (weight)
effect of these drugs to be manifest. Sodium may be masked by fluid retention.
restriction potentiates the antiproteinuric effect Bone pain and myopathy can be seen if renal
of these drugs, as it does for their antihyper- bone pathology is present (most typically
tensive effect. It is possible to combine say secondary hyperparathyroidism).
NSAIDs with ACE inhibitors to try to induce These features will be covered in later chap-
an even larger fall in GFR. ters on acute renal failure, chronic renal failure,
Most rarely in adults, and very rarely in and dialysis.
children, NS remains severe and patients can fail
to thrive, or succumb to complications. If the
patients are refractory to several interventions
and severely incapacitated by NS, then a single,
or double, native nephrectomy can be under-
taken. The rationale is the subsequent restora-
tion of plasma albumin by supplementation, of
fluid volume control by dialysis, and then renal
transplantation. Embolization of the kidneys is
another approach to the same goal.
Chapter Two
25

Primary
glomerular
diseases
• Minimal change nephropathy

• Focal segmental glomerulosclerosis (FSGS)

• Thin basement membrane nephropathy

• Membranous nephropathy

• Membranoproliferative glomerulonephritis
(MPGN)

• Poststreptococcal glomerulonephritis (PSGN)

• IgA nephropathy
26 PRIMARY GLOMERULAR DISEASES

Minimal change nephropathy

DEFINITION mediated immunity, particularly T-lymphocytes,

Minimal change nephropathy is defined by the are involved in pathogenesis, with T-cells pro-
absence of structural glomerular abnormalities ducing a lymphokine that increases glomerular
other than the presence of epithelial cell foot permeability to protein. In a minority of
process fusion on electron microscopy in a patients, there is a clear association with drugs,
patient with proteinuria. allergy and malignancy.

EPIDEMIOLOGY AND ETIOLOGY CLINICAL HISTORY/PHYSICAL

It is the most common cause of nephrotic syn- EXAMINATION
drome in children. It is the cause of nephrotic The cardinal clinical features in children are:
syndrome in 70–90% of cases in children under abrupt onset of nephrotic syndrome, manifested
the age of 10 years, although it rarely occurs by edema, with heavy proteinuria, hypoalbu-
before the first year of life. In adolescents and minemia, and hyperlipidemia. The presence of
young adults, it is responsible for about 50% hematuria, hypertension, or impaired renal func-
cases of nephrotic syndrome, and in older adults tion is unusual in children. In adults, hyperten-
about 10–15% of cases. sion and renal insufficiency are more common.
There is geographic variation in the incidence
of minimal change nephropathy, with the DIFFERENTIAL DIAGNOSIS
disease being more common in Asia than in In children, the presence of nephrotic syndrome
North America or Europe. It is rare in African- without microscopic hematuria suggests mini-
Americans. mal change nephropathy until proven otherwise.
In children who fail to respond to steroids a renal
PATHOGENESIS biopsy is justified. In children aged <2 years,
It has been postulated that minimal change congenital nephrotic syndrome and diffuse
nephropathy results from a toxic epithelial cell mesangial sclerosis are important differential
injury, which results in foot process fusion and diagnoses. In adults, minimal change neph-
detachment of epithelial cells, with disruption ropathy accounts for <30% of the cases of
of the filtration barrier. The recognition that the patients presenting with a nephrotic syndrome,
disease often remits in children who contract and a renal biopsy is required to establish the
measles, and the association with Hodgkin’s diagnosis. The most important differential
lymphoma, suggests that abnormalities in cell- diagnoses are focal segmental glomerulosclerosis
(FSGS) and membranous nephropathy. In some
patients, minimal change nephropathy may have
a secondary cause (Table 3).
Table 3 Secondary causes of minimal
change nephropathy INVESTIGATIONS
There is usually nephrotic range proteinuria
(>3.5g/24 h in adults or *40 mg/h/m2 in
Infections children) and a low serum albumin. The ESR is
Viral (mononucleosis, HIV), parasitic raised as a consequence of hyperfibrinogenemia
and hypoalbuminemia. There are elevated total
Drugs cholesterol, LDL, and triglyceride levels. Serum
NSAID, gold, lithium, interferon alpha, IgG and IgA levels may be reduced, while serum
ampicillin, rifampin (rifampicin), trimethadione IgM levels can be mildly increased.
Urinalysis is usually normal. A few patients
Tumors (<15%) may have microscopic hematuria. Under
Hodgkin’s lymphoma, leukemia, solid tumors polarized light, oval fat bodies appear as ‘Mal-
tese crosses’.
Allergies
Food, dust, bee stings, pollen, poison ivy and
poison oak

Dermatitis herpetiformis
 MINIMAL CHANGE NEPHROPATHY 27

HISTOLOGY MANAGEMENT
Light microscopy (33) In children, high-dose steroids are the corner-
By definition there are no glomerular lesions, stone of treatment, with >90% of children going
or only minimal mesangial prominence. The into complete remission after 4–6 weeks of
tubules may show lipid droplet accumulation treatment. In adolescents and adults, the
from absorbed lipoproteins. Occasionally, find- response to therapy is still high (>80%), but in
ings consistent with acute tubular necrosis can these age groups the response is slower and some
be seen. patients may require up to 16 weeks of high-dose
steroid use before remission is achieved. Of the
Immunofluorescence microscopy patients who respond to steroid therapy, 25% will
There is no staining with antisera specific for have a long-term remission. The remaining
IgG, IgA, and complement C3, C4, or C1q. In patients will have at least one or more relapses.
same cases, mesangial IgM is present, although For patients who have frequent relapses or are
these cases may represent a different entity. resistant to steroids, alternative therapy includes
the use of cyclophosphamide, chlorambucil,
Electron microscopy (34) mycophenolate mofetil, levamisole, cyclosporine
Effacement of visceral epithelial cell foot process (cyclosporin A), and tacrolimus. More recently
is the only abnormality. However, this is a deflazacort, an oxazoline derivative of pred-
nonspecific finding and can be seen in patients nisolone but with a lower incidence of side-
with heavy proteinuria secondary to other effects, has shown promise. During relapses sup-
glomerulopathies. portive treatment of the nephrotic syndrome
should be given – diuretics, anticoagulation, and
PROGNOSIS lipid-lowering agents may be necessary.
The overall prognosis is excellent, with patients
maintaining renal function long term. The major
morbidity of minimal change nephropathy is
related to side-effects of therapy. In patients who
failed to respond to therapy or who develop
progressive renal failure, an alternative diagnosis
(such as FSGS) must be considered.

33 34

33 Normal glomerulus with mild mesangial

prominence. Light microscopy (H+E x400).

34 Electron microscopy showing diffuse effacement of visceral epithelial cell foot processes (x3400).
A continuous band of cytoplasm on the outer aspect of the basement membrane is seen (arrow).
28 PRIMARY GLOMERULAR DISEASES

Focal segmental glomerulosclerosis (FSGS)

DEFINITION INVESTIGATIONS
FSGS is a diagnostic term for a clinical– Consequences of the nephrotic syndrome are
pathologic syndrome with multiple etiologies hypoalbuminemia, reduced immunoglobulin
and pathogenic mechanisms. The ubiquitous levels, and hypercholesterolemia. Serum com-
clinical finding is nephrotic or non-nephrotic plement components are generally normal;
proteinuria, and the ubiquitous pathologic circulating immune complexes have been
feature is focal segmental glomerular consoli- detected. Serologic testing for HIV infection
dation and scarring. should be obtained.

EPIDEMIOLOGY AND ETIOLOGY HISTOLOGY

For the past 20 years, the proportion of patients This is characterized by the presence of glom-
with primary FSGS has risen from <10% to erular lesions of focal distribution affecting only
approximately 25% of adult nephropathies. some of the glomeruli. The lesions predominate
FSGS is the most common form of idiopathic in the deeper cortex mainly affecting the
nephrotic syndrome in African-Americans. juxtamedullary glomeruli. The most common
pattern is for sclerosis in the perihilar regions
PATHOGENESIS (35). The glomerular tip lesion variant, con-
FSGS may be either idiopathic or secondary to solidation confined to the segment adjacent to
a number of different causes (e.g. heroin abuse, the origin of the proximal tubule, may have a
HIV infection, sickle cell disease, obesity, reflux more benign prognosis. Another variant, col-
of urine from the bladder to the kidneys, and lapsing glomerulopathy, has segmental collapse
lesions associated with single or remnant kid- of capillaries with hypertrophy and hyperplasia
neys). As renal function declines, repeat biopsy of overlying epithelial cells. Collapsing glomeru-
specimens show more glomeruli with segmental lopathy may be idiopathic or associated with
sclerosing lesions and increased numbers of HIV infection, SLE, hepatitis C, and pamidron-
globally sclerotic glomeruli. By immuno- ate therapy.
fluorescence staining, IgM and C3 are commonly
trapped in the areas of glomerular sclerosis. PROGNOSIS
A minority of patients experience a spontaneous
CLINICAL HISTORY remission of proteinuria, and eventually most
Patients present with either asymptomatic untreated patients develop end-stage renal
proteinuria or edema. The nephrotic syndrome disease (ESRD) in 5–20 years from presen-
occurs in about two-thirds of patients at presen- tation. The degree of proteinuria is a predictor
tation, hypertension in 30–50%, and micro- for the long-term clinical outcome. Patients
scopic hematuria in about 50%; GFR is with non-nephrotic range proteinuria have a
decreased at presentation in 20–30% of patients. more favorable course with renal survival of over
Complement levels and other serologic test 80% after 10 years of follow-up, whereas the
results are normal. majority of patients excreting >10 g of protein
per day will reach end-stage renal disease
PHYSICAL EXAMINATION within 3 years.
In secondary FSGS clinical features of the One of the most useful prognostic indicators
underlying disease may be obvious. As a con- for patients with FSGS is whether or not they
sequence of the renal disease, edema, hyper- attain a remission of their nephrotic syndrome (in
tension, signs of volume overload and/or one study <15% of patients who had complete or
uremia may be present. partial remission progressed to ESRD within
5 years; up to 50% who did not attain remission
DIFFERENTIAL DIAGNOSIS progressed to ESRD within 6 years). An elevated
The differential diagnosis includes minimal entry serum creatinine is associated with a poor
change disease, membranous nephropathy, amy- long-term renal survival; serum creatinine
loidosis, diabetic nephropathy, postinfectious concentration >1.3 mg/dl (114.9 +mol/l) have
glomerulonephritis, IgA nephropathy, and a lower renal survival rate than those with better
membranoproliferative glomerulonephritis. renal function, regardless of the level of
proteinuria (10-year renal survival rate of 27%
 FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS) 29

versus 100%). Using multivariate analysis, the patients with heavy proteinuria but preserved
entry level creatinine concentration may be a renal function. ACE inhibitors may also provide
better predictor. The renal prognosis for col- a substantial reduction in proteinuria and a
lapsing glomerulopathy is particularly poor. potential long-term benefit that may be equal to
or greater than that of the immunosuppressive
MANAGEMENT therapy. During relapses supportive treatment of
The first step is to distinguish between primary the nephrotic syndrome must be given –
and secondary FSGS. Patients with secondary diuretics, antihypertensives, anticoagulation, and
FSGS have a hyperfiltration injury and should lipid-lowering agents may be necessary.
be treated with ACE inhibitors or angiotensin There is a 20–30% risk of recurrent disease
II receptor antagonists. The management of following renal transplantation. In patients with
primary FSGS remains difficult. There is recent recurrent FSGS following transplantation, the
enthusiasm for the use of high-dose, prolonged use of plasma exchange has been successful in
corticosteroid therapy. Studies in which reducing proteinuria, althought proteinuria
6–12 month courses of corticosteroids and cyto- tends to recur following discontinuation of the
toxics have been used have achieved up to a treatment. The best results have been obtained
40–60% remission rate of the nephrotic syn- when plasma exchange is initiated as soon as
drome with preservation of long-term renal proteinuria recurs. The role of plasma exchange
function. Alternatively, a trial of cyclosporine in the treatment of patients with primary FSGS
(cyclosporin)/tacrolimus may be considered for is unclear.

35

35 Glomerulus showing segmental sclerosis at the hilum (arrow).

The remaining capillary tuft is normal. Light microscopy (H+E x400).
30 PRIMARY GLOMERULAR DISEASES

Thin basement membrane nephropathy

DEFINITION DIFFERENTIAL DIAGNOSIS

Thin glomerular basement membrane (GBM) In sporadic cases, the differential diagnosis is
disease, or thin membrane nephropathy, is with other causes of isolated hematuria, mainly
characterized by isolated glomerular hematuria IgA nephropathy. The main differential
associated with a renal biopsy finding of diagnosis of BFH is with Alport’s syndrome.
excessively thin GBM. BFH is usually inherited as an autosomal domi-
nant disorder with both genders equally af-
EPIDEMIOLOGY AND ETIOLOGY fected. In patients with Alport’s syndrome,
The condition is relatively common, with some electron microscopic studies can demonstrate
authors estimating that thin GBM disease progressive thickening and multilamellation of
accounts for approximately 20–25% of patients the GBM. Early on in the disease course, how-
evaluated for persistent isolated hematuria. It ever, renal biopsy in patients with Alport’s syn-
can present sporadically, or as a familial trait. drome may show diffuse attenuation of the
When several members of the same family are GBM, making the differential diagnosis difficult.
affected, the condition is termed ‘benign familial
hematuria’ (BFH). In patients with BFH, trans- INVESTIGATION
mission follows an autosomal dominant pattern. The diagnosis of thin GBM disease can only be
made by electron microscopic examination of
PATHOGENESIS a renal biopsy.
The pathogenesis is unclear. As opposed to
patients with Alport’s syndrome, immuno- HISTOLOGY
histochemistry studies of type IV collagen in Glomeruli appear normal on light and immuno-
GBM of patients with thin GBM disease or with fluorescence microscopy. On electron micros-
BFH have shown no abnormalities in the copy, there is diffuse thinning of the lamina densa
distribution of any of the six chains. and of the GBM as a whole (36). It is important
to recognize that GBM width varies with age and
CLINICAL HISTORY gender. The thickness of the lamina densa and of
Clinical presentation is with persistent hema- the GBM increases rapidly from birth until age 2
turia, first detected in childhood. In some cases, years, and then gradually into adulthood. In
hematuria is intermittent and may not be general, values of 373 ± 42 nm and 326 ± 45 nm
manifested until adulthood. Macroscopic hema- are accepted as normal GBM thickness in adult
turia is not uncommon and may occur in asso- males and females respectively. Reported data
ciation with an upper respiratory tract infection. shows that patients with thin GBM nephropathy
When first detected in young adults, 60% have have a mean GBM thickness of 191 ± 28 nm.
a level of proteinuria <500 mg/day. The decrease in GBM thickness is invariably due
to a decrease of the lamina densa. Based on the
above data, a GBM thickness )250 nm in an
36 adult patient is considered strongly suggestive of
thin GBM disease. In children, GBM thickness
ranges from 200–250 nm.

PROGNOSIS
The vast majority of patients exhibit an excellent
prognosis with renal function preserved long
term. A very small minority of patients, how-
ever, exhibit progressive renal insufficiency,
probably due to coincidental renal disease.

MANAGEMENT
Percutaneous renal biopsy is the definitive way to
36 The thin basement membrane shows establish the diagnosis, but is not generally
attenuation down to 120 nm, but preservation of justified as these patients will usually have normal
the lamina rara externa and interna and the renal function. There is no specific treatment.
lamina densa. Electron microscopy (× 5000).
 MEMBRANOUS NEPHROPATHY 31

Membranous nephropathy

DEFINITION DIFFERENTIAL DIAGNOSIS

Membranous nephropathy is a common im- Membranous nephropathy occurs as an idiopathic
mune-mediated glomerular disease and one of (primary) or secondary disease. Secondary mem-
the leading causes of primary glomerular disease branous glomerulopathy is caused by auto-
causing nephrotic syndrome in adults. It is a immune diseases (e.g. systemic lupus erythema-
histologic diagnosis based on the presence of tosus, autoimmune thyroiditis), infection (e.g.
subepithelial deposits along the glomerular hepatitis B and C), drugs (e.g. penicillamine, gold,
basement membrane. nonsteroidal anti-inflammatory drugs), and malig-
nancies (e.g. colon cancer, lung cancer). In
EPIDEMIOLOGY AND ETIOLOGY patients over the age of 60 years, membranous
Membranous nephropathy is found in subjects nephropathy is associated with a malignancy in
of all ages, but it is most often diagnosed in 7–15% of patients.
middle-age with the peak incidence during the
fourth and fifth decades of life, followed closely INVESTIGATIONS
by the third and sixth decades. There is a 2:1 Similarly to other patients with nephrotic syn-
predominance of males to females diagnosed drome, hyperlipidemia is common. Renal impair-
with the disease. Idiopathic membranous neph- ment may be present. Lowered serum comple-
ropathy affects all races. ment levels may suggest a diagnosis of SLE.
Hepatitis B and C serology should be performed.
PATHOGENESIS
Membranous nephropathy must be diagnosed HISTOLOGY
by renal biopsy and is characterized by immune Very early on in the disease process the glomeruli
complex localization in the subepithelial zone may be normal on light microscopy, and the
of glomerular capillaries. The pathogenic mech- diagnosis can be made only by immunofluores-
anisms that cause this immune complex local- cence or electron microscopy. With more
ization and the subsequent development of advanced lesions, capillary walls are thickened
proteinuria and the nephrotic syndrome are not but capillary lumina are patent. On methena-
completely understood. The nature of the anti- mine silver stain, subepithelial projections
gen involved in the immune complex deposits (‘spikes’) are seen along the capillary walls (37).
of membranous nephropathy and its source The spikes represent deposition of new basement
remain unknown. In fact, many different membrane material along the deposits. Crescent
antigen–antibody combinations are likely to formation is rare and may be seen in association
cause membranous nephropathy. with anti-GBM antibodies. Immunohisto-
chemistry shows marked granular deposition of
CLINICAL HISTORY
At presentation, proteinuria >2.0 g/day is found
in 80–90% of patients at presentation, with
>10 g found in as many as 30%. While over 90% 37
of patients have no evidence of impaired renal
function at the time of presentation, hyper-
tension at onset is found in 13–55% of patients.
A minority will have microscopic hematuria.

PHYSICAL EXAMINATION
Findings may vary from mild peripheral edema
to full-blown nephrotic syndrome, including
ascites, pericardial, and pleural effusions.

37 Glomerulus showing capillary wall thickening

with well-developed subepithelial spike formation.
Light microscopy (MS x400).
32 PRIMARY GLOMERULAR DISEASES

Membranous nephropathy (continued)

IgG and C3 along the capillary walls (38). MANAGEMENT

Electron microscopic features have been used to Diuretics, antihypertensives, lipid lowering
classify membranous nephropathy into four drugs, and anticoagulants are often used as a
stages (39–42). In stage I, there are a few small- means of supportive care. When a secondary
size subepithelial electron-dense deposits along cause of MN is found, specific treatment of the
the capillary walls, epithelial foot process underlying lesion may lead to remission of the
effacement, but the glomeruli look normal on nephropathy. The use of immunosuppression in
light microscopy. In stage II, deposits increase the setting of idiopathic membranous glomeru-
in number and size. There is formation of sub- lopathy is controversial, especially because of the
epithelial projections of basement membrane by variable natural history of the disease and of
the side of the deposits (‘spikes’). Stage III is drug toxicity. Immunosuppression is generally
characterized by extracellular material surround- reserved for those patients with deteriorating
ing the deposits and incorporation of deposits renal function and/or heavy proteinuria.
into the capillary basement membrane. In stage Various agents have been used including corti-
IV, there is marked increase in capillary wall costeroids, cytotoxics such as cyclophospha-
thickness, with the incorporated deposits becom- mide, chlorambucil, and azathioprine or cyclo-
ing more lucent, and the spikes less apparent. sporine (cyclosporin).
The Italian Collaborative Study used
PROGNOSIS alternating monthly courses of 1) methyl-
Membranous nephropathy is considered a prednisolone 1 g intravenously daily for 3 days,
chronic disease, with the potential for spon- followed by oral prednisolone 0.5 mg/kg daily
taneous remission and relapsing episodes of the for the rest of the month, then 2) chlorambucil
nephrotic syndrome. The renal prognosis is orally in a dose of 0.2 mg/kg daily for 1 month.
variable. In an analysis of 1,189 patients with This cycle was repeated until 6 months’ treat-
membranous glomerulopathy pooled from ment had been given. After 5 years follow-up, in
across a number of clinical studies, the proba- the treated group (n=42), 14 were in remission,
bility of renal survival was 86% at 5 years, 65% four had an increased creatinine >50% above
at 10 years and 59% at 15 years. It is likely, baseline, with only one patient on dialysis. In the
however, that the prognosis is even worse in untreated group (n=39), four were in remission,
nephrotic patients, since the risk of renal failure 19 had an increased creatinine >50% above
is correlated to the severity and the duration of baseline, and four patients required dialysis. This
proteinuria. Indeed, in approximately 15% of is now a widely used if rather complicated
patients the disease has an accelerated course, regimen for MN. Recurrent disease is relatively
with end-stage renal disease reached within one rare following renal transplantation.
year from the diagnosis.

38

38 Global, granular IgG staining along the capillary walls

(which is seen as a brown reaction product).
Immunoperoxidase (anti-IgG antibody x400).
 MEMBRANOUS NEPHROPATHY 33

39 40

39 Stage I. Small electron-dense deposits are 40 Stage II. Basement membrane ‘spikes’
present along the subepithelial aspect of the separate the electron-dense deposits along
capillary loop basement membrane (arrow). the subepithelial aspect of the capillary loop
Visceral epithelial cell foot processes are diffusely basement membranes (arrows). Electron
effaced. Electron microscope appearance (x5800). microscope appearance (x5800).

41 42

41 Stage III. Electron-dense deposits are 42 Stage IV. Immune complex deposits are
completely incorporated within the thickened completely incorporated within the thickened
basement membrane (arrow). Electron capillary loop basement membranes. Most of
microscope appearance (x3400). the deposits have undergone reabsorption
and are electron lucent (arrow). Electron
microscope appearance (x7400).
34 PRIMARY GLOMERULAR DISEASES

Membranoproliferative glomerulonephritis (MPGN)

DEFINITION hypertension, and renal insufficiency. An upper

MPGN, also known as mesangiocapillary glo- respiratory tract infection often precedes the first
merulonephritis, is defined at the light micros- manifestation of the renal disease. Hypertension
copy level by the presence of diffuse mesangial is common (50–80%). In patients with cryoglobu-
proliferation and thickening of the glomerular linemia and HCV infection, clinical manifestations
capillary walls. MPGN may be primary (idio- resemble those of systemic vasculitis.
pathic) or secondary to specific diseases.
PHYSICAL EXAMINATION
EPIDEMIOLOGY AND ETIOLOGY Edema and hypertension are common. Patients
The majority of patients with idiopathic type with idiopathic MPGN type 2 may manifest
1 MPGN are children between the ages of 8 and partial lipodystrophy, usually limited to the face
16 years. It affects males and females equally. In (19) and upper body. In secondary forms there
the USA, Caucasians are relatively more affected may be signs of an associated neoplasm,
than African-Americans. Secondary forms of hereditary disease, autoimmune disease, or
type 1 MPGN tend to predominate in the adult infection. In patients with cryoglobulinemia
population. The major cause of secondary palpable purpura, arthritis, hepatomegaly, digital
MPGN is cryoglobulinemia due to HCV infec- necrosis, or vasculitic lesions may be present.
tion. Type 2 MPGN is a rare disease.
DIFFERENTIAL DIAGNOSIS
PATHOGENESIS A number of pathologic conditions may cause
Type 1 MPGN appears to be an immune- an MPGN pattern on renal biopsy. The most
mediated disease in which there is glomerular important are poststreptococcal glomerulone-
deposition of immune complexes in the mesan- phritis, thrombotic microangiopathies, parapro-
gium and subendothelial space. Immune complex teinemias, SLE, mixed cryoglobulinemia, endo-
deposition results in complement activation with carditis, and chronic liver disease. Immuno-
subsequent inflammation resulting in both fluorescence and electron microscopy studies
proliferation of mesangial and endothelial cells and together with serology and clinical history
the recruitment of inflammatory cells, including should allow the correct diagnosis to be made.
neutrophils and monocytes. MPGN type 1 is most The diagnosis of MPGN should prompt a
commonly associated with chronic immune- search for underlying bacterial or viral infections,
complex diseases like HCV, HBV, HIV, bacterial especially HCV, HBV, and HIV. The absence of
endocarditis, collagen vascular diseases, or malig- CH50 suggests an hereditary deficiency in one
nancy. The pathogenesis of type 2 MPGN is of the components of the complement cascade.
linked to the chronic activation of the alternative Low complement levels can also be found in
pathway of complement. In most cases, there is postinfectious glomerulonephritis, SLE, and
a circulating autoantibody (C3 nephritic factors; following renal cholesterol emboli.
C3Nef). This autoantibody binds to the alterna-
tive pathway C3 convertase preventing its inactiva- INVESTIGATIONS
tion, resulting in continuous complement activa- In MPGN type 1, and in cryoglobulinemic
tion and consumption. How this process results MPGN, there are low C3, C4, and CH50 levels
in the formation of characteristic ‘dense deposits’ reflecting activation of both complement path-
in the GBM is unknown. ways. In MPGN type 2 the alternative pathway
is activated, with patients having a persistently
CLINICAL HISTORY low C3 but normal C4 levels.
The clinical presentations of all forms of MPGN
are variable and include nephrotic and nephritic HISTOLOGY
features. Approximately one-third of the patients Type 1 is the most common (43). There is diffuse
present with a combination of asymptomatic global capillary wall thickening as a result of
hematuria and proteinuria. Another third will infiltrating leukocytes and intrinsic glomerular
present with nephrotic syndrome and preserved cell proliferation, leading to a lobular appearance
renal function. In about 20% of cases, patients will of the glomeruli. The proliferating mesangial cells
present with chronic renal failure. Some patients interpose their cell processes between the glom-
(~10%) will present with a nephritic syndrome erular basement membrane and the endothelium
picture, with hematuria, red blood cell casts, (‘mesangial interposition’), usually in association
 MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS (MPGN) 35

with subendothelial deposits. The production of 43

neomembrane by the endothelial cells results in
a double contour or ‘tram track’ aspect, best seen
on silver stain. Infiltrating mononuclear leuko-
cytes and neutrophils also contribute to the
glomerular hypercellularity. By immunofluor-
escence, there is granular deposition of IgG and
C3 in the mesangium and outlining the lobular
contours. IgM, IgA, C4 and C1q may also be
found, but the staining is weaker and more
variable. By electron microscopy, discrete im-
mune deposits can be seen in the subendothelial
space and in the mesangium (44).
Type 2 MPGN, also known as ‘dense deposit 43 Capillary loop lumens are compromised due
disease’, is characterized by the presence on to endocapillary proliferation, leukocyte infiltration
electron microscopy of highly electron-dense and basement membrane thickening with double-
deposits which replace the lamina densa and contouring (arrow).There is a generalized increase
produce a smooth, ribbon-like thickening (45). in mesangial cells and matrix. Light microscopy
Immunofluorescence shows intense capillary wall (PAS x400).
linear to band-like staining for C3, with little or
no staining for C4 or immunoglobulins.
Type 3 MPGN is histologically similar to 44
type 1 MPGN except that, in addition to the
subendothelial space, deposits can also be seen
within the glomerular basement membrane, and
in the subepithelial space.

PROGNOSIS
MPGN type 1 tends to run a slowly progressive
course with 40–50% of patients reaching ESRD
in 10 years. Non-nephrotic patients have a better
prognosis with 85% renal survival rate at 10 years.
In adults the prognosis is less favorable, with near
50% of the patients reaching ESRD 5 years from
diagnosis. Patients with MPGN type 2 have the
worst prognosis. In these patients clinical
remission rates are <5%. Predictors of poor out- 44 Extensive subendothelial deposits. Electron
come include impaired renal function at presen- microscopy (x12,000).
tation, nephrotic range proteinuria, hypertension,
number of crescents (>50%), and tubulointer-
stitial damage. MPGN type 1 frequently recurs 45
after transplantation, resulting in loss of the
allograft in over one-third of the patients. Recur-
rence is even more common in MPGN type 2
(80–100%), but allograft losses are less common.

MANAGEMENT
In children with idiopathic MPGN type 1, pro-
longed use of corticosteroids (up to 4 years) may
lead to partial or complete clinical remission and
stabilization of renal function. In adults, there is
less convincing evidence for a role for corti-
costeroid therapy. The use of aspirin and dipy-
ridamole is controversial. No therapy has been
shown to be efficacious in type 2 or type 3
MPGN. In secondary forms of MPGN, treatment 45 Interrupted linear, intramembranous electron-
is dependent on the underlying condition. dense deposits. Electron microscopy (x1000).
36 PRIMARY GLOMERULAR DISEASES

Poststreptococcal glomerulonephritis (PSGN)

DEFINITION dyspnea, and orthopnea. Children may also

Poststreptococcal glomerulonephritis is an acute develop fever, nausea, vomiting, abdominal pain,
glomerulonephritis that develops secondary to headache, encephalopathy, or seizures.
a pharyngitis or skin infection with specific
strains of group A ␤-hemolytic streptococci. PHYSICAL EXAMINATION
More recently, it has been shown that acute The edema is typically periorbital and is worse
glomerulonephritis also occurs with non-group in the morning. Weight gain may occur
A streptococcus, particularly group C. secondary to fluid retention. Hypertension is
usually mild to moderate and is likely to be
EPIDEMIOLOGY AND ETIOLOGY attributable to increased sodium and water
While in developed countries the incidence of retention. If fluid retention is severe, pleural
PSGN has decreased, it continues to be a effusions and pulmonary edema may develop.
significant public health problem in highly-
populated areas with low socioeconomic status DIFFERENTIAL DIAGNOSIS
and poor sanitary conditions, particularly in the Although traditionally the diagnosis of a diffuse
tropics. The disease is more common in children proliferative endocapillary GN has been asso-
between age 5 and 15 years, but it can occur ciated with streptococcal infection, similar
in all age groups. Unlike rheumatic fever, which histopathology occurs secondary to a number
can occur following a pharyngeal infection by of other infective agents (Table 4). The dif-
any group A streptococci, PSGN occurs only ferential diagnosis should also include other
with certain ‘nephritogenic’ strains of group A causes of nephritic syndrome such as IgA,
␤-hemolytic streptococci (M type 1, 3, 4, 12, Henoch–Schönlein purpura, idiopathic MPGN,
25, and 49 in pharyngitis and 2, 49, 55, 57, and and systemic vasculitis.
60 with erysipelas and impetigo).
INVESTIGATIONS
PATHOGENESIS Hematuria is present is almost all cases and may
The specific pathogenic process responsible for be macroscopic. Dysmorphic red cells (7), red
the development of PSGN is unknown. Im- cell casts (8), and white cell casts are common.
mune complex deposition, as well as autoim- Non-nephrotic proteinuria is common but it
mune reactivity, is thought to play an important may be in the nephrotic range in some cases.
role in the disease process. Circulating IgG and Normocytic normochromic anemia is usually
C3 immune complexes have been demonstrated dilutional but may reflect shortening of the red
in patients with PSGN, but also in patients with blood cells’ life-span secondary to rapid elimina-
documented streptococcal infection without tion of immune complex-coated cells. Cultures
renal compromise. It remains to be determined are usually negative but antibody titer to
whether circulating immune complexes have an streptolysin O (ASO), anti-streptokinase, anti-
increased affinity for the glomerulus or whether
streptococcal antigens can trigger the produc- Table 4 Causes of postinfectious glomerulonephritis
tion of antibodies, which cross-react against
glomerular antigens. It is also possible that Bacteria Viruses
streptococcal antigens may bind directly to Streptococcus Herpes zoster
glomerular sites forming in situ immune com- Pneumococcus Mumps
plexes that trigger an inflammatory response. Staphylococcus Hepatitis B
Klebsiella Epstein–Barr
CLINICAL HISTORY Brucella Echovirus
Onset is abrupt and is preceded by a streptococcus Treponema Coxsackie B4
infection by approximately 1–4 weeks. The typical Leptospira Influenza
presentation is with a nephritic syndrome mani- Salmonella Cytomegalovirus
fested by the presence of hematuria, oliguria, Mycoplasma
hypertension, edema, proteinuria, and azotemia. Meningococcus Parasites
Oliguria is a frequent finding, but anuria is Mycobacteria Plasmodium falciparum
uncommon and, if persistent, suggests a rapidly Gonococcus Toxoplasma
progressive glomerulonephritis. The expanded Echinococcus
extracellular fluid volume may cause cough,
 POSTSTREPTOCOCCAL GLOMERULONEPHRITIS (PSGN) 37

hyaluronidase, anti-deoxyribonuclease, and anti- 46

nicotyladenine dinucleotidase may provide
evidence of recent streptococcal infection. ASO
titers rise 10–14 days after infection and peak at
3–4 weeks with subsequent fall. Total hemolytic
(CH50) complement and C3 levels are usually
reduced, but C4 levels are normal.

HISTOLOGY
This is the classic example of an acute endocapillary
proliferative glomerulonephritis. Light microscopy
shows diffuse hypercellularity of the glomerular
tufts, with mesangial and endothelial cell prolifera-
tion and infiltration of polymorphonuclear leuko- 46 Glomerulus showing a severe increase of
cytes (thus the name exudative), mono- cellularity with numerous infiltrating polymorphs.
cytes/macrophages, and plasma cells (46). All Light microscopy (H+E x400).
glomeruli are affected in a homogeneous pattern.
Early on in the disease process, characteristic
subepithelial ‘humps’ can be detected on silver
stain. Cellular crescents are uncommon and their 47
presence is indicative of severe disease. On immu-
nohistochemistry, there is granular deposition of
IgG, C3, and occasionally IgM, distributed in
three well-described patterns: ‘starry-sky’, ‘mesan-
gial’, and ‘garland’ (47). By electron microscopy,
small immune deposits are seen in the mesangial
and subendothelial areas. Almost pathognomonic
of PSGN is the presence of large ‘humps’, which
are dome-shape subepithelial deposits in the
glomerular basement membrane (48).

PROGNOSIS
In children the prognosis is excellent with most 47 Glomerulus showing round humps of brown
patients recovering renal function within reaction product on the epithelial side of capillary
1–2 months of diagnosis. In a few patients, walls (arrow). Immunoperoxidase (anti-IgG
especially adults, microscopic hematuria, pro- antibody x350).
teinuria, hypertension, and renal dysfunction may
persist for many years. Patients presenting with a
crescentic nephritis have a poorer prognosis, with
approximately 50% developing ESRD. In contrast 48
with rheumatic fever, where the risk of recurrence
is life-long, PSGN does not recur following
subsequent streptococcal infections.

MANAGEMENT
The treatment of PSGN is supportive. Appro-
priate antibiotic therapy is indicated if there is
persistent infection. Sodium restriction and the
use of loop diuretics reduce the risk of fluid
overload and help to control hypertension. Renal
function is impaired, but only 5% of the patients
will require dialysis to control hyperkalemia or
fluid overload. The presence of crescents is an 48 Glomerular capillary tuft containing a
ominous sign. In a few case reports, the use of polymorph (arrow) and showing a subepithelial
corticosteroids, cyclophosphamide, and plasma- hump (arrow head). Electron microscopy (x4000).
pheresis improved prognosis in patients with a
crescentic glomerulonephritis.
38 PRIMARY GLOMERULAR DISEASES

IgA nephropathy

DEFINITION lating IgA. Decreased IgA1 glycosylation

IgA nephropathy (IgAN), or Berger’s disease, increases the tendency of IgA1 to aggregate and
is defined as a mesangial proliferative glomeru- form macromolecules of IgA1 complexes. In
lonephritis characterized by diffuse deposition addition, IgG antiglycan antibodies interact with
of IgA in the mesangium. hinge regions deficient in Gal and sialic acid
forming IgA–IgG immune complexes. The
EPIDEMIOLOGY AND ETIOLOGY mechanism by which IgA1 deposits in the
It is the most common primary glomerular glomeruli is unclear. Specific mesangial IgA1
disease worldwide and accounts for approxi- receptors that recognize hinge region glycans
mately 10% of patients reaching ESRD in many have been described. Changes in the carbo-
countries. The general prevalence may be as hydrate structure of immunoglobulins are
high as 1:100 people. It occurs in all age groups, known to modify interactions with cell surface
but is most commonly diagnosed in patients in receptors. Underglycosylation and desialylation
their second or third decades of life (80% of the IgA1 hinge region increases the propen-
16–35 years old). Males are more frequently sity for binding to extracellular matrix com-
affected. There is wide geographic variation. It ponents, and promotes glomerular deposition.
is the most common primary glomerular Once the aberrant IgA1 is deposited in the
diseases in Asia (30–40% cases), followed by glomeruli, it triggers traditional mediators of
Europe (20%), and North America (10%). IgAN inflammation. Deposition of C3 and properdin
is rare in central Africa and in African- without C4 suggests alternative complement
Americans. A familial form has been described. pathway activation. Interleukin-1, interleukin-
6, platelet-derived growth factor, tumor necrosis
PATHOGENESIS factor, free oxygen radicals, vascular cell ad-
The pathogenesis of IgAN is poorly understood hesion molecule-1, and membrane attack com-
but a pivotal role is played by IgA. Increase in plex (C5b-9) are a few of the factors implicated
IgA1 concentration in the serum, increase in as modulators of the disease activity.
IgA1-containing circulating immune complexes
and positive IgA–rheumatoid factor have all been CLINICAL HISTORY
described in patients with IgAN. In patients with The classical presentation is episodic macro-
IgAN, a number of studies have demonstrated scopic hematuria, usually accompanying an
abnormalities in the hinge region of the IgA1 intercurrent upper respiratory tract infection.
molecule. This region (not present in IgA2) is This typical clinical pattern occurs most fre-
composed of 18 amino acids of which five are quently in young adults in their second and
serine or threonine glycosylation sites, O-linked third decades of life. Other patients are asympto-
to N-acetylgalactosamine (GalNAc). The oligo- matic and may be identified when microscopic
saccharide chain is usually extended by addition hematuria with or without proteinuria are found
of a variable number of galactose (Gal) molecules on a routine urinalysis. Proteinuria is common
and sialic acid residues to GalNAc, resulting in but nephrotic syndrome occurs in <10% of all
several hinge region glycoforms. Both deficiency cases. Patients may present with chronic
in sialic acid with normal Gal content, or renal failure.
diminished Gal content in the IgA1 hinge
region, have been reported in patients with DIFFERENTIAL DIAGNOSIS
IgAN. Recently it has been shown that mesangial Mesangial IgA occurs in other conditions, parti-
IgA1 in IgAN exhibits aberrant O-glycosylation. cularly in a number of autoimmune and inflam-
The mechanism responsible for the abnormal matory diseases, possibly as a result of increased
glycosylation is unclear. A decrease in the activity IgA production or decreased clearance of circu-
of ␤1,3 galactosyltransferase in B-cells obtained lating IgA. The most common causes of
from patients with IgAN has been reported. secondary IgAN are: gastrointestinal diseases
There are a number of potential reasons why (alcoholic cirrhosis, inflammatory bowel diseases,
abnormalities in O-glycosylation may be celiac disease), rheumatoid diseases (Reiter’s,
pathogenic in IgAN. Hypogalactosylation of ankylosing spondylitis, psoriasis), malignancies
IgA reduces the physiologic clearance of IgA1 (carcinomas, monoclonal IgA gammopathy),
molecules by the hepatocyte asialoglycoprotein dermatitis herpetiformis, pulmonary hemo-
receptor, thus resulting in an increase in circu- siderosis, mycosis fungoides, and infections
 IGA NEPHROPATHY 39

(HIV, hepatitis B, schistosomiasis). Other con- with the degree of glomerular damage. Occa-
ditions that clinically can simulate IgAN include sionally, there is proliferation of the glomerular
thin basement membrane disease and some epithelial cells with crescent formation, but
forms of hereditary nephritis (e.g. Alport’s). circumferential crescents are rare. Acute tubular
necrosis has been documented in patients
INVESTIGATIONS developing acute renal failure during an episode
There are no specific laboratory findings for of heavy glomerular hematuria from crescentic
IgAN. Urinalysis shows persistent hematuria and IgAN. The diagnosis of IgAN requires immu-
dysmorphic red blood cells, associated with some nohistochemistry showing IgA as the pre-
degree of proteinuria. Serum IgA levels are dominant or sole immunoglobulin deposit in the
increased in up to 50% of patients, but it is not glomerular mesangium (50). In most cases, a
specific. Serum complement levels are normal. second immunoglobulin (IgG or IgM) is also
detected. Staining for C3 frequently, but not
HISTOLOGY always, coincides with the IgA deposits. Staining
Light microscopy findings are variable. The for C1q is rare and helps to distinguish IgAN
glomeruli may look normal or may show from lupus nephritis. On electron microscopy,
mesangial expansion secondary to mesangial electron-dense deposits in the mesangial and
cells proliferation, increased mesangial matrix, paramesangial areas co-localize with the immune
or both (49). The abnormalities may be global deposits (51). In some cases, there is focal thin-
or segmental. Segmental sclerosing lesions are ning, splitting, and lamination of the glomerular
common. Tubulointerstitial findings correlate basement membrane.

49 50

51
49 Glomerulus showing mild mesangial cell and
matrix expansion (arrow). Light microscopy
(PAS x200).

50 Glomerulus showing IgA deposition in

mesangial areas. Immunoperoxidase (anti-IgA
antibody x350).

51 Electron-dense deposits are identified

within mesangial regions (arrow). Electron
microscopy (x5800).
40 PRIMARY GLOMERULAR DISEASES

IgA nephropathy (continued)

PROGNOSIS troversial. In a recent trial, 6 months of

Actuarial curves of renal survival suggest 5–15% alternate-day corticosteroids in patients at risk
of patients with ESRD after 5 years from the of progression was beneficial in protecting renal
apparent onset of the disease, 10–20% after 10 function. In some series, treatment with fish oil
years, 15–30% after 15 years, and 20–50% after has also been shown to be effective in providing
20 years. Of the clinical and laboratory features long-term renal protection to patients with
included in multivariate analyses, baseline 24- proteinuria and rising serum creatinine. Cyclo-
hour proteinuria exceeding 1 g, hypertension, sporine (cyclosporin) reduces proteinuria but
impaired renal function at diagnosis, and glo- its effect is likely to be hemodynamic secondary
merular or interstitial fibrosis on renal biopsy, to reduction in GFR. Mycophenolate mofetil
are the most important predictors of a poor out- is currently undergoing clinical trials in patients
come. IgAN recurs in about 50% of patients fol- with IgAN. Patients with IgAN and concomi-
lowing renal transplantation but early loss of the tant minimal-change disease respond fully to
allograft from recurrent disease is uncommon. corticosteroids therapy. For patients with
rapidly progressive renal failure due to cres-
MANAGEMENT centic IgAN, cortiosteroids and cyclophospha-
Standard treatment includes treatment of mide with the addition of plasma exchange or
hypertension, use of ACE inhibitors and angio- pulse methylprednisolone has been tried, with
tensin II receptor antagonists, and treatment of variable results.
hyperlipidemia. Other treatments remain con-
Chapter Three
41

Systemic diseases
affecting the
glomeruli
• Diabetes mellitus
• Plasma cell dyscrasias
• Amyloidosis
• Fibrillary and immunotactoid glomerulopathy
• Systemic lupus erythematosus (SLE)
• Primary anti-phospholipid antibody syndrome
(PAPS)
• Systemic vasculitis
• Sickle cell anemia and glomerulonephritis
• Goodpasture’s disease
• Glomerulonephritis associated with hepatitis B
virus infection
• Glomerulonephritis associated with hepatitis
C virus infection
• Glomerulonephritis associated with human
immunodeficiency virus (HIV)
• Miscellaneous infections and
glomerulonephritis
42 SYSTEMIC DISEASES AFFECTING THE GLOMERULI

Diabetes mellitus

DEFINITION prognosis. Renal insufficency is generally pro-

Diabetic nephropathy is a common but not gressive, but the rate of decline varies between
invariable complication of both type 1 and 2 individual patients. As renal failure develops
diabetes mellitus. Clinically it presents with typical uremic symptoms and signs develop, and
hypertension, proteinuria, edema and progres- diabetics seem to tolerate uremia worse than
sive renal impairment. nondiabetics, developing symptoms at lower
creatinine levels. Type 2 diabetics are often
EPIDEMIOLOGY AND ETIOLOGY asymptomatic for many years before presenting
Today diabetic nephropathy is the commonest to medical attention. Therefore, when they are
cause of end-stage renal failure in the Western first seen they may already have proteinuria or
world. This is largely due to the epidemic of renal impairment.
obesity and type 2 diabetes, and better survival Symptomatic urinary tract infections are
of diabetics so that they reach end-stage renal more severe in diabetics and may be complicated
failure. The epidemiology of diabetic nephro- by papillary necrosis, acute pyelonephritis, or
pathy is easiest to study in type 1 diabetes, as perirenal abscess formation.
the time of clinical onset is generally known.
Between 25–45% of such patients will develop PHYSICAL EXAMINATION
clinically evident disease as defined by overt Type 1 diabetics with nephropathy almost invari-
proteinuria, and a further 20–30% will have ably have other signs of diabetic microvascular
subclinical microalbuminuria. The peak onset disease such as retinopathy (52, 53) and
of nephropathy is between 10–15 years after neuropathy. The relation of retinopathy to neph-
the initial presentation with diabetes. Those ropathy is not so consistent in type 2 diabetes.
individuals who do not have proteinuria at Uremic polyneuropathy is often superimposed
25 years are very unlikely to develop neph- on the diabetic neuropathy. There is a ‘glove and
ropathy subsequently. The natural history is stocking’ pattern of loss of sensation. Neuro-
probably very similar in type 2 diabetics, pathic foot lesions are due to lack of sensation
although some groups have a worse prognosis. causing recurrent trauma. Autonomic neuro-
For example, nephropathy develops in 50% of pathy is a common and troublesome problem
Pima Indians at 20 years, with 15% having affecting bowel, bladder, and sexual function.
developed end-stage renal failure by this time. The majority of patients with diabetic
Risk factors for developing diabetic neph- nephropathy will suffer from hypertension.
ropathy include a positive family history of Atherosclerosis is accelerated in uremic diabetics
diabetic nephropathy, hypertension, poor gly- and there is a very high incidence of cerebro-
cemic control, and race (increased risk especially vascular, coronary, renovascular, and peripheral
in blacks). vascular disease.

PATHOGENESIS DIFFERENTIAL DIAGNOSIS

Hyperglycemia stimulates mesangial cell matrix Since diabetes mellitus is very common, it can
production and also leads to increased glyco- co-exist with other renal diseases, especially in
sylation of proteins, leading to accumulation of the elderly. In the presence of the appropriate
advanced glyosylation end products which can clinical history and diabetic retinopathy, a renal
cross-link with collagen. Another pathway by biopsy is not usually needed. If a diabetic
which hyperglycemia may trigger damage is the has coincident microscopic hematuria, and
polyol pathway, leading to increased sorbitol especially red cell casts, it is likely that they have
concentrations. The initial physiologic abnor- concurrent nondiabetic renal disease such as
mality is glomerular hyperfiltration due to an IgA nephropathy. If renal size is asymmetric on
increase in renal volume and renal blood flow. renal ultrasound, renal arterial stenosis should
be excluded.
CLINICAL HISTORY
Type 1 diabetics normally are first noted to have
microalbuminuria and subsequently proteinuria
when they attend the diabetic clinic. The pro-
teinuria can become nephrotic range, and the
degree of proteinuria is roughly related to
 DIABETES MELLITUS 43

52

52 Left optic disk of a patient with diabetic retinopathy.There is

gross neovascularization of the disc with retinal hemorrhages and
cotton wool spots.

53

53 Left optic disc of another patient with diabetic retinopathy.There

is extensive background retinopathy with hard exudation and
hemorrhage temporal to the macula, indicating some retinal ischemia.
44 SYSTEMIC DISEASES AFFECTING THE GLOMERULI

Diabetes mellitus (continued)

INVESTIGATIONS shows a nodular appearance; these are Kimmel-

Microalbuminuria is detected by a sensitive stiel–Wilson nodules, which are pathognomonic
radioimmunoassay. Albumin excretion rate in of diabetic nephropathy, but only occur in a
normoalbuminuria is <20 µg/min, micro- minority of biopsies. Both the diffuse and nodu-
albuminuria 20–200 µg/min, and proteinuria lar mesangial expansion are composed of extra
>200 µg/min. If 24 hour urine collections are mesangial matrix, which stains positively with
performed, albumin excretion rate in normo- silver and PAS. Electron microscopy will show
albuminuria is <30 mg/24 h, micro-albu- an increase in basement membrane thickness.
minuria 30–300 mg/24 h, and proteinuria
>300 mg/24 h. There is a circadian rhythm and PROGNOSIS
considerable day-to-day variation in albumin Untreated patients with diabetic nephropathy
excretion. Therefore the diagnosis of micro- will progress to end-stage renal failure. The rate
albuminuria depends on finding increased rates of decline from developing fixed proteinuria to
of excretion in at least three collections over a end-stage renal failure varies from months to
6-month period. decades, with a mean of about 5 years.
Renal function should be measured by crea-
tinine clearance or GFR measurement. Urinaly- MANAGEMENT
sis for microscopic hematuria and red cell casts Progression of diabetic nephropathy can be
and renal ultrasonography should be performed. retarded by tight glycemic control, use of angio-
tensin-converting enzyme inhibitors or angio-
HISTOLOGY (54–57) tensin receptor antagonists and good blood
In the earliest stage of the disease there is pressure control (target 130/80 mmHg
glomerular hypertrophy and thickening of the [17.3/10.7 kPa]). Diabetics with end-stage
glomerular basement membrane. As the disease renal failure can be managed either with hemo-
progresses, these changes are followed by hya- dialysis or peritoneal dialysis. Patients who
linosis of the afferent and efferent arterioles. receive a combined kidney–pancreas transplant
Later changes include exudative lesions which have been shown to have a survival advantage
occur within the capillary loop as hyaline caps over diabetics who receive a kidney transplant,
and on the surface of Bowman’s capsule as probably due to a reduction in cardiovascular
capsular drops. There is progressive mesangial events. Islet cell transplants are currently in an
expansion causing diffuse diabetic glomeru- exciting phase of clinical development.
losclerosis. Sometimes the mesangial expansion

54

54 Arteriole showing typical ‘exuberant’ hyaline change (arrow).

Light microscopy (MS x400).
 DIABETES MELLITUS 45

55 Glomerulus showing hyaline 55

nodules in both afferent and
efferent arterioles (arrows).
Light microscopy (MS x400).

56 Glomerulus showing silver 56

positive nodular lesions (arrow)
(Kimmelstiel Wilson nodules).
Light microscopy (MS x400).

57 Glomerulus showing diffuse 57

increase of mesangial matrix
(diffuse diabetic
glomerulosclerosis) and a
capsular drop (PAS-positive
exudative lesion) (arrow).
Light microscopy (PAS x400).
46 SYSTEMIC DISEASES AFFECTING THE GLOMERULI

Plasma cell dyscrasias

DEFINITION CLINICAL HISTORY

Plasma cell dyscrasias are diseases caused by Patients with myeloma classically present with
clonal proliferation of plasma cells and their pre- skeletal pain or pathologic fractures. Hypo-
cursors, activated B-cells, which secrete unique gammaglobulinemia in these patients pre-
immunoglobulin proteins or immunoglobulin disposes them to infections. Renal disease in
light or heavy chains. Renal disease occurs com- myeloma can present as mild proteinuria with
monly in multiple myeloma, primary amy- or without hematuria, nephrotic syndrome,
loidosis, and light chain deposition disease. slowly progressive renal insufficiency, or acute
Primary amyloidosis will be discussed separately. renal failure. Renal disease is present in 50% of
patients at presentation. Most commonly renal
EPIDEMIOLOGY AND ETIOLOGY insufficiency progresses insidiously; acute renal
Myeloma has an incidence of about failure occurs in <10% of patients.
2–4/100,000 and is a disease of the elderly,
reaching a peak incidence in the eighth decade PHYSICAL EXAMINATION
in men. Immunophenotyping indicates that the Anemia is common, and there may be an en-
myeloma cells are clones of B-cells that are late hanced bleeding tendency leading to spon-
in their differentiation pathway. Chromosomal taneous bruising.
translocations affecting the immunoglobulin
heavy chain locus on the long arm of chromo- DIFFERENTIAL DIAGNOSIS
some 14 are found in 20–60% of patients; The diagnosis of multiple myeloma is made by
deletion of chromosome 13 or translocation of finding >10% plasma cells in the bone marrow,
chromosome 1q are associated with worse out- or a plasmacytoma together with one of the
come, as are mutations in ras, p53, or retino- following: a monoclonal protein in the blood or
blastoma tumor suppressor genes. It is thought urine, or lytic bone lesions. Connective tissue
that the abnormal B-cells originate in lymph diseases, metastatic cancer, lymphoma, or leu-
nodes and migrate to the bone marrow which kemia may share some clinical features with
provides a cytokine-rich microenvironment that myeloma. Multiple myeloma also needs to be
allows the cells to proliferate. distinguished from monoclonal gammopathy of
uncertain significance, smouldering multiple
PATHOGENESIS myeloma, and primary amyloidosis.
Myeloma can affect kidney function by several
mechanisms. Myeloma kidney refers to the INVESTIGATIONS
commonest type of renal injury in which large A standard myeloma workup includes a full
intratubular casts are formed. The tubular blood count, serum creatinine and calcium,
injury is caused by Bence Jones proteins. Cast serum electrophoresis and paraprotein quanti-
nephropathy only develops in some patients. fication, a 24-hour urine collection for electro-
It is thought that the physicochemic proper- phoresis and immunofixation, a bone marrow
ties of the proteins as well as host factors examination, and a skeletal survey (58). Light
explain this. chains are typically not detected by urine dip-
Bence Jones proteinuria may rarely affect sticks. They are precipitated by sulphosalicylic
proximal tubular function to cause Fanconi acid. Immunofixation is now the method of
syndrome. Hypercalcemia is common in detection for light chains. In contrast, patients
myeloma due to secretion of osteoclast activat- with primary amyloidosis will have increased
ing factor causing increased bone reabsorption. albumin excretion detected by routine urinalysis.
Hypercalcemia leads to polyuria and volume
depletion, and also causes vasoconstriction in HISTOLOGY
the renal circulation. Myeloma patients are Myeloma cast nephropathy is characterized by
particularly susceptible to radiographic contrast large, eosinophilic refractile casts that frequently
causing acute renal failure. Light chains may show fractures (so called ‘hard’ casts), which are
form nodular deposits in the glomeruli (light found mainly in the distal convoluted tubules
chain deposition disease), or be enzymatically and collecting ducts (59). The casts often incite
degraded into amyloid proteins which poly- a ‘foreign body’ giant cell reaction, and there
merize into amyloid fibrils (AL amyloid). is usually a dense interstitial cellular infiltrate
consisting of mononuclear cells and macro-
 PLASMA CELL DYSCRASIAS 47

58

58 X-ray pelvis in a patient with myeloma demonstrating multiple

lytic lesions.

59

59 Multiple myeloma. Cortical tubules contain ‘hard’ eosinophilic

casts which have fractured and incited a ‘foreign body’ giant cell
reaction (arrow). Notice the tubular epithelial cell damage and the
interstitial fibrosis. Light microscopy (H+E x350).
48 SYSTEMIC DISEASES AFFECTING THE GLOMERULI

Plasma cell dyscrasias (continued)

phages. Proximal and distal tubular cells may be PROGNOSIS

flattened with areas of necrosis and denudation Adverse prognostic factors in multiple myeloma
of the tubular basement membrane. include the presence of plasma cells in the peri-
Light chain deposition disease (60–62) is pheral blood, renal failure, infection, and increased
characterized by the finding on immuno- age. Treatment regimes include corticosteroids
histochemistry of diffuse linear staining of the and melphalan, high-dose chemotherapy, and
basement membranes of tubules, Bowman’s autologous bone marrow transplantation.
capsule, and glomerular capillaries for a single The prognosis for patients with light chain
light chain isotype. Nodular glomerulo- deposit disease depends on the severity of the
sclerosis, superficially resembling diabetic renal lesion and degree of systemic involvement,
nephropathy on light microscopy, is only with liver and heart failure common.
found in about 60% of patients. Silver staining
frequently allows these to be distinguished MANAGEMENT
because the nodules in diabetes are silver- Treatment aimed at improving renal function
positive and in light chain disease are negative. includes correction of hypovolemia, stopping
Electron microscopy will show granular nephrotoxic drugs, forced alkaline diuresis, and
electron-dense material on glomerular and reduction of light chain levels by chemotherapy
tubular basement membranes. and plasmapheresis.

60 61

62 60 Glomerulus showing silver-negative nodules

(arrow) (compare with diabetic nodules). Light
microscopy (MS x400).

61 Glomeruli from the same patient as 60 showing

positive staining (brown reaction product) of nodules
and glomerular capillary walls (arrow). Light
microscopy (Peroxidase/anti-kappa antibody x250).

62 Granular diffuse subendothelial electron-dense

material (arrow). Electron microscopy (x4000).
 AMYLOIDOSIS 49

Amyloidosis

DEFINITION CLINICAL HISTORY AND PHYSICAL

Amyloid consists of the deposition in the extra- EXAMINATION
cellular space of a waxy insoluble polymerized The most common presenting symptoms are
protein, the nature of which relates to the un- weight loss and fatigue. Symptoms and signs of
derlying etiology. Amyloid stains pink with congestive cardiac failure, nephrotic syndrome,
hematoxylin–eosin and red with Congo red, autonomic neuropathy, gastrointestinal involve-
which also shows a characteristic apple- ment, peripheral neuropathy, or carpal tunnel
green/orange birefringence when viewed with syndrome may be present. Macroglossia occurs
polarized light. Electron microscopy shows in about 10% of cases of AL amyloid. Hepato-
nonbranching fibrils. X-ray diffraction analysis splenomegaly may occur. Periorbital purpura
shows that the fibrils have a beta-pleated sheet is common.
pattern. The amyloid material that accumulates Renal involvement usually presents with
in the extracellular compartment progressively nephrotic syndrome, which persists despite
destroys the involved organ, but interestingly progression to renal insufficiency. Renal vein
does not incite an inflammatory reaction. thrombosis is a common complication.

EPIDEMIOLOGY AND ETIOLOGY DIFFERENTIAL DIAGNOSIS

Primary amyloidosis (AL) can occur in patients Although amyloid is usually deposited in multi-
without overt, underlying disease or during the ple organs it may present with single organ
course of multiple myeloma. The underlying involvement, e.g. nephrotic syndrome. A careful
disease process is the clonal proliferation of history will usually reveal an underlying cause
plasma cells in both groups, since a serum para- for AA amyloid. Tissue biopsy is necessary to
protein is found in 90% of patients in the group reach a precise diagnosis, although SAP scan-
without myeloma. The median age at presen- ning (see below) may be an alternative when
tation is 65 years, and is more common in males. biopsy is not possible. Positive immunohisto-
Secondary amyloidosis (AA) complicates chemic staining of biopsy material using anti-
chronic inflammatory conditions such as rheu- bodies to AA protein confirms AA amyloid.
matoid arthritis, ankylosing spondylitis, bron- Negative staining implies AL amyloid. This may
chiectasis, osteomyelitis, paraplegia with chronic be confirmed by demonstrating positive staining
skin ulceration, malignancies such as Hodgkin’s with either anti-kappa or lambda antibodies;
disease and renal cell carcinoma, and familial however, this is frequently unsatisfactory.
Mediterranean fever.
INVESTIGATIONS
PATHOGENESIS In AL amyloid immunoelectrophoresis and
Amyloid fibrils are composed of specific proteins immunofixation of both serum and urine will
produced in certain disease states, a serum amy- detect a monoclonal protein in 90% of cases. A
loid P protein (SAP) common to all systemic bone marrow aspiration should be done to
forms of amyloid, and small amounts of glyco- determine whether a clonal plasma cell prolifera-
saminoglycans. tion is present and to stain for amyloid. In the
For instance, in AL amyloid, which is presence of renal involvement, a renal biopsy is
associated with the production of an abnormal normally performed. Ultrasound usually shows
paraprotein, the amyloid is formed by the bilaterally enlarged kidneys. Less invasive sites
polymerizationof light chains or portions of that can be biopsied include abdominal fat pad
light chain. In this instance the amyloid is or rectum which are both positive in 80% of
unique to each patient. patients. Serum CRP or SAA concentrations can
In AA amyloid the polymerizing protein is be used to follow the activity of the underlying
identical in all patients and is serum amyloid A inflammatory process.
protein (SAA) that is produced in the liver (an Radioiodinated SAP specifically localizes to
acute phase reactant). amyloid deposits and can be used to measure
50 SYSTEMIC DISEASES AFFECTING THE GLOMERULI

Amyloidosis (continued)

the total body amyloid burden (amount and 63

organ distribution) and serial scans can be used
to follow progression or regression with treat-
ment (63). SAP is not effective for visualizing
cardiac deposits and echocardiography is needed
for this.

HISTOLOGY (64–67)
The principal site of renal involvement is quite
variable. Generally amyloid first deposits in the
glomerular mesangium and then extends out
into the capillary loops when it is associated with
a protein leak. At a later stage nodules may be
formed. It is also found along the tubular base-
ment membrane, when it may be associated
with tubular atrophy, and in the walls of
arterioles and venules. Electron microscopy
reveals regular nonbranched fibrils measuring
7.5–10 nm in width and 30–1000 nm in length.

PROGNOSIS
The median survival for AL patients is about
2 years, with adverse prognostic factors includ- 63 Serial anterior whole body I125-serum amyloid
ing cardiac failure, renal impairment, hepato- P component scintigraphy demonstrating
megaly, and diagnosis of multiple myeloma. regression of hepatic and splenic AA amyloid
Most patients with renal involvement progress deposits in a patient with rheumatoid arthritis.
to end-stage renal failure rapidly. Inflammatory disease activity was completely
suppressed by treatment with oral chlorambucil
MANAGEMENT in 1998 and the follow-up scan on the right was
The goal of treatment in AL patients is to performed 2 years later.
decrease the synthesis of the amyloidogenic light
chain. Similar approaches are used in the treat-
ment of myeloma and AL amyloid, with encour-
aging results with the use of autologous stem
cell transplantation in selected patients.
In AA amyloid, therapy is aimed at con-
trolling the underlying disease as this can lead
to stabilizationor regression of the amyloidosis.
Colchicine is used to treat familial Mediter-
ranean fever. Renal transplantation has been
performed in selected patients with AA amyloid,
as recurrence of amyloidosis tends not to cause
clinical problems until late after transplantation.
 AMYLOIDOSIS 51

64 65

64 Glomerulus showing severe eosinophilic, silver- 65 Glomerulus showing red staining of arteriole
negative mesangial expansion and capillary wall (arrow) and segmental staining of the mesangium.
thickening. Light microscopy (MS x400). Light microscopy (Congo red x350).

66

66 Similar glomerulus to 65 viewed by crossed

polarized prisms showing characteristic
green/yellow birefringence (Congo red x350).

67

67 Nonbranching fibers 12 nm in diameter.

Electron microscopy (x20,000).
52 SYSTEMIC DISEASES AFFECTING THE GLOMERULI

Fibrillary and immunotactoid glomerulopathy

DEFINITION CLINICAL HISTORY

Fibrillary glomerulonephritis is characterized by Patients with these conditions may present with
the appearance on electron microscopy in the proteinuria usually with associated microscopic
mesangium of randomly arranged fibrils that are hematuria, hypertension, or progressive renal
larger than those in amyloidosis (20–30 nm insufficiency. About 50% of patients develop
versus 10 nm in diameter) and do not stain with end-stage renal failure within 2 years.
Congo red. Immunotactoid glomerulopathy is
characterized by the formation of microtubules HISTOLOGY
(30–40 nm in diameter). The light microscopic appearances are variable
and include: mesangial hypercellularity, amor-
EPIDEMIOLOGY AND ETIOLOGY phous, eosinophilic, Congo red-negative expan-
It is controversial whether fibrillary glomeru- sion of the mesangium, sometimes showing a
lonephritis and immunotactoid glomerulopathy nodular pattern, mesangiocapillary pattern, or
are separate disorders. Fibrillary glomerulone- crescent formation. Immunohistochemistry in
phritis accounts for 85% of cases. It occurs prin- cases of fibrillary glomerulonephropathy may be
cipally in adults. In one centre’s biopsy series it positive for IgG, C3, and light chains. Electron
occurred in 1% of biopsies. microscopy (68) is required for definitive diag-
nosis and shows a fibrillar pattern, similar to
PATHOGENESIS amyloid, but usually the fibrils have a greater
Immunohistochemistry in cases of fibrillary diameter, perhaps up to 20 nm.
glomerulonephritis is characterized by IgG4
subclass deposition, suggesting this may be key PROGNOSIS
in fibril formation. Patients with immunotactoid About 50% of patients develop end-stage renal
glomerulopathy may have either a circulating failure within 2 years.
paraprotein or monoclonal immunoglobulin
deposition, and there is a disease association MANAGEMENT
with B-cell lymphoma or chronic lymphocytic There is no proven effective treatment. Although
leukemia. recurrent disease in the renal allograft is com-
mon, the rate of progression is slow, and trans-
plantation has been successful.

68

68 Nonbranching fibers. Electron microscopy (x20,000).

 SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) 53

Systemic lupus erythematosus (SLE)

DEFINITION auto-antibody formation. Auto-antibodies are

Systemic lupus erythematosus is an autoimmune formed to histones, DNA, RNA; anti-phospho-
disease characterized by autoantibody produc- lipid antibodies are found in 30% cases. Immune
tion in which renal involvement is common. complex deposition and complement activation
According to the American Rheumatism Asso- leads to glomerular damage. The type of
ciation classification, a diagnosis of SLE is made glomerular disease depends on the nature of the
if four of the following 11 criteria are present: immune complex (specificity, size, affinity,
• Malar rash. charge, ability to activate complement) and the
• Discoid rash. rate of its clearance by Fc receptors. Immune
• Photosensitivity. complexes cause damage by activating comple-
• Oral ulcers. ment, leading to chemokine production and
• Arthritis (two or more joints). recruitment of inflammatory cells.
• Pleurisy–pericarditis.
• Renal abnormalities. CLINICAL HISTORY
• Neurologic disorders (seizures, psychosis). Renal involvement usually appears after the
• Hematologic disorders (hemolytic anemia, initial presentation with SLE, and often follows
leucopenia, lymphocytopenia, thrombocyto- a chronic remitting and relapsing course. Rarely
penia). patients may present with only renal disease and
• Immunologic disorders (anti-DNA, anti-Sm, on renal biopsy have diagnostic features of lupus
positive finding of anti-phospholipid anti- nephritis. Such patients may develop clinical
bodies). symptoms or serologic tests of active lupus many
• Anti-nuclear antibody. years after the initial presentation.
Patients with World Health Organization
EPIDEMIOLOGY AND ETIOLOGY (WHO) class I and II lupus nephritis normally
SLE is about nine times more common in have mild proteinuria and a normal GFR.
females than in males. The deleterious effect of Patients with WHO class III and IV nephritis
estrogens on SLE explains the flares of disease typically have an active urinary sediment, heavier
activity with pregnancy or the use of oral contra- proteinuria, hypertension, and reduced GFR.
ception. All ages are affected but most cases Class V cases usually have nephrotic syndrome
occur between ages 16 and 55 years. There is a as the main presenting syndrome; renal vein
much higher incidence in black and Asian thrombosis and pulmonary emboli are common.
populations compared to Caucasians in the UK. Over the course of the illness, the histologic
There are certain HLA associations and some pattern may transform from one class to another
familial cases are associated with defects of the with associated changes in the clinical features of
complement pathway. Exposure to sunlight or the renal disease. Rarely patients can present with
ultraviolet light can trigger a lupus flare. oligoanuric acute renal failure, and the renal
biopsy either shows extensive crescent formation
PATHOGENESIS or glomerular capillary thrombi usually asso-
B-cell hyper-reactivity leads to the overproduc- ciated with anti-phospholipid antibodies.
tion of auto-antibodies. The primary defect is Lupus tends to flare during pregnancy and
not known, and there may be different abnor- the puerperium. The risk is less in females with
malities leading to loss of B-cell tolerance. One mild and well-controlled disease. Maternal flares
theory is that there is a genetic defect in are associated with increased prematurity and
apoptosis. Apoptotic cells express nuclear fetal mortality.
antigens on the cell surface where they trigger
54 SYSTEMIC DISEASES AFFECTING THE GLOMERULI

Systemic lupus erythematosus (SLE) (continued)

PHYSICAL EXAMINATION 69
Patients with lupus nephritis will often have
obvious physical signs of SLE, i.e. alopecia,
mouth ulcers, skin rash (69), Raynaud’s phe-
nomenon, non deforming arthritis, and retinal
cotton wool spots (70).

DIFFERENTIAL DIAGNOSIS
Mild forms of SLE may masquerade as other
diseases for many years, especially the joint or
neuropsychiatric presentations. Diseases which
may be in the differential diagnosis include
rheumatoid arthritis, subacute bacterial endo-
carditis, lymphoma, idiopathic thrombocyto-
penia, and HIV infection.

INVESTIGATIONS
Anti-nuclear antibodies (ANA) are found in 99%
of cases of SLE. They were discovered in the
1940s with the discovery of the LE cell (71).
The initial screening test for ANAs is the immu-
nofluoresence test; Hep2 cells are incubated
with patient’s serum and then fluorescein- 69 Discoid skin rash in a patient with systemic
tagged anti-human gamma globulin is added to lupus erythematosus.
produce an apple-green nuclear staining when
viewed through the fluorescent microscope. The
test is very sensitive, and the pattern of staining
may be characteristic for specific antibodies 70
(72–75). However, pattern recognition is now
replaced with specific assays to identify precisely
and quantitate antibody titers.
Anti-dsDNA antibodies are relatively specific
(95%) for SLE and often fluctuate with disease
activity. In some patients there is no correlation
with disease activity. If a patient has been
followed for several months and titers correlate
with activity, it is likely that titers will continue
to be useful for monitoring activity. Anti-
dsDNA antibodies may be measured by the Farr
assay (ammonium sulphate precipitation),
Crithidia luciliae assay (76) or ELISA. Anti-
Smith (anti-Sm) antibodies are directed against 70 Retinal cotton wool spots in a patient with
small ribonucleoproteins. They are insensitive systemic lupus erythematosus.
but highly specific for SLE, and remain so when
the disease is inactive and when anti-dsDNA
antibodies have fallen into the normal range.
They are found in 10–30% of Caucasians and Many patients with SLE have an activation of
30–40% of Asians and Afro-Caribbeans with the classic complement cascade with consump-
SLE. The presence of anti-Sm antibodies may tion of the early complement components C1q,
be associated with milder renal involvement. C4, and C3. C4 levels usually fall earlier and to
Ro/SSA and La/SSB antibodies are detected in a greater extent than C3 during a disease flare.
high frequency in the serum of patients with Renal biopsy in selected patients is necessary
Sjögren’s syndrome and subacute cutaneous to decide which patients may or may not benefit
lupus and neonatal lupus. from immunosuppression.
 SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) 55

71 Buffy coat preparation from the peripheral 71

blood of a patient with active lupus showing
nuclear material phagocytosed by polymorphs
(LE cells) (arrow). Light microscopy (MGG x1000).

72 73

74 75

72–76 Different patterns of anti-nuclear antibody 76

staining. Homogeneous staining on Hep2 cells
(x1000) (72). Speckled pattern on rat liver (x400)
(73). Nucleolar pattern on rat liver (x400) (74).
Centromere pattern (x1000) (75).

76 Immunofluoresence staining of Crithidia lucillae.

This trypanosome contains a kinetoplast circular
DNA which is double stranded.
56 SYSTEMIC DISEASES AFFECTING THE GLOMERULI

Systemic lupus erythematosus (SLE) (continued)

HISTOLOGY (77–84) Class IV Diffuse proliferative glomerulonephritis

There is hypercellularity of the glomerular tuft, Class V Membranous glomerulonephritis
which can be segmental or global, focal or dif-
fuse, and may include polymorphs. In active Crescents are commonly found in classes III
disease there may be foci of fibrinoid tuft and IV lupus nephritis. Interstitial nephritis is
necrosis, nuclear fragmentation, wire-loops, common and rarely may occur without glom-
hyaline thrombi, and crescent formation. Hema- erular involvement. A thrombotic microangi-
toxylin bodies formed from digested nuclear opathy may occur in association with anti-
material may be found in areas of necrosis. phospholipid antibodies.
Immune deposits are the hallmark of lupus Activity indices based on the features men-
nephritis. A ‘full house’ of staining for IgG, IgM, tioned above, and chronicity indices, based on
IgA, C3, C1q, and C4 is characteristic of lupus features such as glomerular sclerosis, tubular
nephritis. Mesangial deposits are found even in atrophy, and interstitial fibrosis, are also useful
patients without overt renal disease. in guiding treatment.
Capillary wall deposits, which are charac-
teristically subendothelial when seen in electron PROGNOSIS
microscopy, cause the thickened, rigid, and refrac- Patient survival has improved in lupus patients
tile capillary wall known as the classic ‘wire-loop’. over the past few decades. The results from two
There will often also be subepithelial and intra- prospective cohorts of 1000 European and 644
membranous deposits, which may be an aid to Canadian patients with lupus found 95% and
diagnosis. The so-called ‘hyaline thrombi’ seen in 93% 5-year survival rates, respectively. Most
light microscopy are in fact huge subendothelial deaths are caused by active SLE, thrombosis, or
electron-dense deposits that bulge out into the infection. Renal survival has also improved with
lumen, sometimes causing occlusion of the glom- the use of cytotoxic drugs.
erular capillary lumen. True thrombi may be seen
in the anti-phospholipid syndrome. Rarely, a MANAGEMENT
fingerprint-like pattern or tubuloreticular inclu- The management of lupus nephritis is complex.
sions may be seen in the electron-dense deposits. Corticosteroids and azathioprine are used for
The WHO classification is widely used by patients with mild renal involvement. For
nephrologists and renal pathologists: patients with severe lupus nephritis, intravenous
Class I Normal methylprednisolone and cyclophosphamide are
Class IIA Mesangial deposits necessary but have undesirable side-effects.
Class IIB Mesangial hypercellularity There is increasing experience with myco-
Class III Focal, segmental proliferative phenolate mofetil in the treatment of lupus
glomerulonephritis

77 78

77 Glomerulus from a case of focal proliferative 78 Glomerulus from a case of diffuse proliferative
lupus nephritis (WHO class III) showing a lupus nephritis (WHO class IV) showing increased
segmental area of consolidation and necrosis cellularity, wire-loop thickening of capillary walls
(arrow). Note the uninvolved tuft is normal. (arrow head) and hyaline ‘thrombi’ (arrow). Light
Light microscopy (H+E x350). microscopy (H+E x400).
 SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) 57

nephritis. Other drugs that have been trialled synthetase inhibitor, anti-CD40 ligand, and
for lupus nephritis include cyclosporine anti-interleukin-10. Lupus nephritis recurs
(cyclosporin), tacrolimus, a thromboxane A2 infrequently after transplantation.

79 80

79 Diffuse proliferative lupus nephritis showing IgG 80 Lupus nephritis showing focal IgG staining on
localizing on glomerular capillary walls and segmentally tubular basement membranes (brown reaction
in mesangial areas (brown reaction product). product, arrow). Immunoperoxidase (anti-IgG
Immunoperoxidase (anti-IgG antibody x400). antibody x400).

81 82

81 Hematoxylin body (arrow). Light 82 Subepithelial (arrow) and subendothelial deposits

microscopy (H+E x1000). (arrow head). Electron microscopy (x4000).

83 84

83 Very large subendothelial electron-dense 84 High magnification of deposits from the same
deposits from the same case as 82, that would case as 82, showing the fingerprint pattern
equate to the hyaline thrombi seen in light (arrows). Electron microscopy (x10,000).
microscopy. Electron microscopy (x5000).
58 SYSTEMIC DISEASES AFFECTING THE GLOMERULI

Primary anti-phospholipid antibody syndrome (PAPS)

DEFINITION DIFFERENTIAL DIAGNOSIS

Since the first description of the syndrome in Systemic lupus erythematosus with associated
1981 its protean clinical and laboratory features anti-phospholipid antibodies is excluded by the
have been defined. For a positive diagnosis there clinical history and a negative ANA. Other
must be radiologic or histologic evidence of thrombophiliac conditions such as Protein C
arterial or venous thrombosis, or recurrent and S deficiency and factor V deficiency should
miscarriages, and the presence of medium or be excluded.
high titers of IgM or IgG anti-cardiolipin anti-
bodies or lupus anticoagulant on two occasions INVESTIGATIONS
at least 6 weeks apart. This disorder is referred The activated partial thromoboplastin time is
to as the primary APS when it occurs alone; prolonged and is not normalized when the
however, it can also be found in association with patient’s plasma is diluted 1:1 with normal
SLE, or with certain infections and drugs. platelet-free plasma (lupus anticoagulant
activity). IgG or IgM anti-cardiolipin antibody
CLINICAL HISTORY titers are measured by a standardized ELISA
Patients usually have a history of a major technique. In patients with neurologic involve-
thrombotic event such as a deep vein thrombo- ment there may be multiple, small, high-density
sis or pulmonay emboli. There may be multiple lesions on MRI (85).
miscarriages or severe pre-eclampsia due to small
vessel thrombosis and placental insufficiency. HISTOLOGY
There may be a history of arterial thromboses The characterisic pathologic change is a
affecting the cerebral or coronary circulation. thrombotic microangiopathy with minimal
Other manifestations include livedo reticularis, perivascular inflammation (86). Renal histo-
hemolytic anemia, thrombocytopenia, neuro- logical changes include small vessel vaso-occlu-
logic dysfunction, pulmonary hypertension, sive lesions associated with fibrous intimal
avascular necrosis, and adrenal failure. Rarely, hyperplasia of interlobular arteries, and focal
primary APS can cause multiorgan failure due cortical atrophy.
to multiple small vessel occlusion. Renal involve-
ment may present with hypertension, pro- PROGNOSIS
teinuria, renal impairment, or acute renal failure. The renal prognosis is variable but generally the
Renal arterial and venous thromboses have been thrombotic microangiopathy leads to progres-
reported. There is an association with renal sive renal destruction causing end-stage renal
artery stenosis. failure and can recur in renal allografts.

PHYSICAL EXAMINATION MANAGEMENT

A variety of cutaneous abnormalities may be Patients with renal involvement must be antico-
seen, including livedo reticularis, digital gan- agulated to keep the INR >3. Selected patients
grene, and Degos’ disease (malignant atrophic with acute renal failure may respond to plasma
papulosis). A major thrombotic event may cause exchange and/or immunosuppression.
obvious clinical signs.
PRIMARY ANTI-PHOSPHOLIPID ANTIBODY SYNDROME (PAPS) 59

85

85 MRI scan in a patient with primary anti-phospholipid antibody

syndrome demonstrating periventricular white matter lesions.

86

86 Primary anti-phospholipid antibody syndrome.Thrombosis

is present within the glomerular tuft and afferent vessels
(arrow). Light microscopy (H+E x200).
60 SYSTEMIC DISEASES AFFECTING THE GLOMERULI

Systemic vasculitis

DEFINITION Table 5 Classification of vasculitis

The vasculitides can be classified using only two
criteria: the size of the vessel involved and the
Granulomas
presence or absence of granuloma formation Size of Yes No
(Table 5). vessel
Large vessel vasculitis is only rarely com-
plicated by glomerulonephritis, and polyarteritis Small Wegener’s Microscopic
nodosa may cause renal infarction. In renal units granulomatosis polyarteritis
Henoch–Schönlein
small vessel vasculitides are by far the most purpura
common type, causing a pauci-immune focal
necrotizing and crescentic glomerulonephritis. Medium Churg–Strauss Polyarteritis nodosa

EPIDEMIOLOGY AND ETIOLOGY Large Giant cell arteritis

Small vessel vasculitis is characteristically a Takayasu’s syndrome
disease of middle-aged and elderly patients, with Kawasaki disease
a slight preponderance of males. It can however
present in childhood. It is rare in Afro-Carib-
bean patients. The etiology of systemic vasculitis
remains obscure, although a minority of patients DIFFERENTIAL DIAGNOSIS
may have a bacterial infection, commonly Differential diagnoses include atheroembolic
staphylococcal, as a trigger. disease, infective endocarditis, SLE, and other
pulmonary renal syndromes, especially Good-
PATHOGENESIS pasture’s disease. Patients with the latter condi-
Immune complexes are not found in the glom- tion do not have a skin rash and often do not
eruli or vessels of patients with small vessel have the prodromal illness of fever, weight loss,
vasculitis. Cell-mediated immunity involving T- and myalgia that is typical of vasculitis.
lymphocytes and monocytes is probably critical,
as these cells are the predominant types found INVESTIGATIONS
histologically. The pathogenic role of anti- A normochromic anemia is common, and the
neutrophil cytoplasmic antibodies (ANCA) platelet count is usually raised. The ESR is
remains controversial. invariably raised. Serum albumin is reduced.
Microscopic hematuria, proteinuria, and a raised
CLINICAL HISTORY creatinine are usual. The renal function may
Patients usually present with fever, malaise, and decline rapidly. Urine microscopy will demon-
weight loss. Skin, joints, lungs, eyes, and nervous strate red cell casts. Serum immunoglobulin and
system are commonly affected along with the complement concentrations are normal. ANCA
kidney. Vasculitis may be limited to the kidney; (91, 92) are found in about 90% of untreated
alternatively, in some patients renal involvement cases of small vessel vasculitis. In Wegener’s
may never occur. A diagnosis of Wegener’s granulomatosis the target is usually a neutrophil
granulomatosis requires the presence of at least granular enzyme proteinase 3 and on immuno-
two of the following four criteria: renal involve- fluorescence study of ethanol-fixed neutrophils
ment, a histologic diagnosis of granulomatous shows a diffuse cytoplasmic staining (c-ANCA
arteritis, an abnormal chest radiograph (87), and pattern). Patients with microscopic polyarteritis
nasal or oral inflammation. generally have p-ANCA which has a perinuclear
pattern of staining. The target of p-ANCA is
PHYSICAL EXAMINATION principally myeloperoxidase. ANCA titers can be
Arthritis, purpura (88), scleritis (89), or uveitis used to monitor disease activity over time. A renal
may be present. Vasculitic infarcts may be seen biopsy is necessary to assess the severity of renal
commonly in the nail folds, finger pulps, and involvement in small vessel vasculitis and thus
fundi. Collapse of the bridge of the nose may guide treatment. The value of renal or visceral
occur in Wegener’s granulomatosis (90). Severe angiography is minimal in small vessel vasculitis,
hypertension is uncommon. but diagnostic in cases of large vessel vasculitis.
 SYSTEMIC VASCULITIS 61

87 88

87 Chest radiograph in a patient who presented with ANCA-positive vasculitis, presenting with acute renal
failure due to a severe necrotizing glomerulonephritis.The patient subsequently became acutely short of
breath with associated hemoptysis.The radiograph shows bilateral diffuse alveolar shadowing due to
pulmonary hemorrhage.

88 Vasculitic rash in a patient with rapidly progressive glomerulonephritis (ANCA-positive).

89 90

89 Acute focal anterior scleritis in a patient with 90 A patient with Wegener’s granulomatosis
Wegener’s granulomatosis. showing depression of the bridge of the nose
because of involvement of cartilage; the
differential diagnosis is relapsing polychondritis.

91 92

91 Immunofluorescence staining of alcohol-fixed 92 Immunofluorescence staining of alcohol-fixed

normal human neutrophils. Cytoplasmic normal human neutrophils. Perinuclear (p-ANCA)
(c-ANCA) staining (x1000). staining (x1000).
62 SYSTEMIC DISEASES AFFECTING THE GLOMERULI

Systemic vasculitis (continued)

HISTOLOGY (93–95) 93
The typical appearances are dependent on the
severity and the length of time the disease has
been active. This may be a focal segmental
necrotizing glomerulonephritis, with crescent
formation or a diffuse global process with 100%
crescents. Immunohistochemistry is negative or
shows nonspecific segmental localizationof IgM
and complement in areas of chronic damage.
Fresh necrotizing lesions will show fibrin.
Interstitial mononuclear infiltration is common
and may be severe, but granulomata are rarely
seen in needle biopsies, even in unequivocal
clinical Wegener’s. Extraglomerular vasculitis is 93 A glomerular tuft showing fibrinoid necrosis
only seen in vessels in a minority of biopsies. and surrounded by a circumferential crescent
(arrow). Light microscopy (H+E x400).
PROGNOSIS
The prognosis for small vessel vasculitis affecting
the kidney has improved from almost inevitable 94
death 30 years ago to about 70% 5-year survival
currently, with the advent of successful immu-
nosuppressive regimens.

MANAGEMENT
Standard induction treatment involves intra-
venous methylprednisolone and oral cyclophos-
phamide. In cases with rapidly deteriorating
renal function, plasma exchange is generally
used. In resistant cases intravenous immuno-
globulin may be used. Maintenance treatment
consists of corticosteroids and cyclophospha-
mide or azathioprine. There is increasing evi- 94 Vasculitis in an interlobular artery cut
dence for the use of mycophenolate mofetil as longitudinally.There is a dense local mononuclear
an alternative maintenance agent. cell infiltrate. Light microscopy (H+E x400).

95

95 A glomerulus showing fibrinoid necrosis of the

arteriole at the hilum (arrow head) and an adjacent
granuloma (arrow) in a patient with Wegener’s
granulomatosis. Light microscopy (H+E x350).
 SICKLE CELL ANEMIA AND GLOMERULONEPHRITIS 63

Sickle cell anemia and glomerulonephritis

DEFINITION leads to the increased glomerular size, and later

Sickle cell disease (homozygous hemoglobin SS) to focal and segmental glomerulosclerosis. Other
and sickle cell trait (heterozygous hemoglobin factors may play a role including iron overload,
SA) are associated with a variety of renal abnor- debris from erythrocytes phagocytosed by
malities including impaired concentration of the glomeruli, and immune complexes. Medullary
urine leading to polyuria, hematuria, papillary hypoxia leads to sickling and damage to the
necrosis, acute renal failure related to multiple urine-concentrating mechanism.
organ failure during a sickle cell crisis, and
glomerulonephritis causing nephrotic syndrome HISTOLOGY
and end-stage renal failure. Focal and segmental glomerulosclerosis is the
commonest lesion. A mesangiocapillary glom-
EPIDEMIOLOGY AND ETIOLOGY erulonephritis can also occur (96).
The incidence of proteinuria in patients with
sickle cell disease is common. End-stage renal PROGNOSIS
disease has been reported in 10–20% of adults Patients with glomerulosclerosis progress over
with sickle cell disease. This proportion is likely months or years to end-stage renal failure.
to increase with improved survival due to better
medical treatment of other complications of MANAGEMENT
this condition. ACE inhibitors may prolong renal survival.
Renal transplantation has been performed suc-
PATHOGENESIS cessfully in this condition.
The chronic anemia leads to increased renal
blood flow and glomerular filtration rate. This

96

96 Sickle cell nephropathy. Glomerular capillary wall shows

double-contouring (arrow). Light microscopy (MS x250).
64 SYSTEMIC DISEASES AFFECTING THE GLOMERULI

Goodpasture’s disease

DEFINITION DIFFERENTIAL DIAGNOSIS

Goodpasture’s disease is caused by anti-basement The other principal causes of rapidly progressive
membrane antibody production, leading to glom- glomerulonephritis with alveolar hemorrhage
erular and pulmonary injury. Patients may have include systemic vasculitis and SLE. The main
severe pulmonary hemorrhage and only minor differential diagnoses of acute renal and respira-
renal involvement; alternatively, they may have tory failure are pulmonary edema due to fluid
severe renal involvement and no lung involvement, overload in acute renal failure, opportunistic
or severe pulmonary and renal disease. infections in patients with rapidly progressive
glomerulonephritis who have been heavily im-
EPIDEMIOLOGY AND ETIOLOGY munosuppressed, severe cardiac failure, and
Goodpasture’s disease is a rare disease occurring paraquat poisoning.
in about 0.5 cases/million/year. It is associated
with HLA-DR2. Cigarette smoking and INVESTIGATIONS
exposure to organic solvents and hydrocarbons Anti-GBM IgG auto-antibodies are detected by
have been implicated with cases of this disease. ELISA, radioimmunoassay, or indirect immuno-
There have been case reports of the condition fluorescence. Monitoring anti-GBM levels is
associated with membranous glomerulone- helpful in guiding the intensity of treatment. In
phritis, lymphoma, and lithotripsy. about 10% of cases ANCA titers are positive and
these patients tend to have features of systemic
PATHOGENESIS vasculitis. Measurement of the rate of carbon
The pathogenic anti-glomerular basement monoxide uptake by the lung (KCO) is helpful
membrane antibody (anti-GBM) is directed in distinguishing between pulmonary hemorr-
against the noncollagenous NC1 domain of the hage and pulmonary edema.
␣3(IV)-chain of basement membrane collagen.
Although this is the archetypal antibody- HISTOLOGY (97, 98)
mediated disease, there is also clear involvement A renal biopsy is essential for prognostic
of T-cells in its pathogenesis. purposes. In cases with severe renal involvement
there is a diffuse, extracapillary, proliferative
CLINICAL HISTORY glomerulonephritis, with necrosis and extensive
The prodromal symptoms of malaise, weight crescent formation. There may be rupture of
loss, and arthralgia are less marked than in Bowman’s capsule. There is usually an interstitial
systemic vasculitis. Renal impairment at presen- nephritis. Immunohistochemistry shows linear
tation is usually severe, and deteriorates rapidly. localization of IgG and frequently C3 on the
Macroscopic hematuria and loin pain may occur. glomerular capillary basement membrane.
Pulmonary hemorrhage occurs in about two-
thirds of patients. The amount of hemoptysis PROGNOSIS
correlates poorly with the severity of hemorr- Patients with severe renal impairment (>70%
hage. Pulmonary hemorrhage can remit and crescents and plasma creatinine >600 ␮mol/l
relapse and there may be a history of episodic [6.8 mg/dl]) have a poor renal prognosis.
breathlessness over the previous months. Patients with less severe disease may respond to
immunosuppression. Recurrence of renal or
PHYSICAL EXAMINATION respiratory disease is a rare but recognized
It may be difficult to distinguish clinically and phenomenon. Renal transplantation should be
radiologically between respiratory failure due to postponed until at least 6 months after the dis-
pulmonary edema secondary to renal failure and appearance of circulating anti-GBM antibodies.
pulmonary hemorrhage.
MANAGEMENT
Induction treatment consists of plasma
exchange to remove the pathogenic antibody
and immunosuppression with corticosteroids
and cyclophosphamide. Immunosuppression
can usually be stopped after 3 months.
 GLOMERULONEPHRITIS ASSOCIATED WITH HEPATITIS B VIRUS 65

97 98

97 Two glomeruli in anti-GBM disease showing 98 Linear staining of the glomerular capillary walls
occlusive cellular crescents.The residual silver with IgG (brown reaction product).
positive glomerular tuft is shown (arrow). Light Immunoperoxidase (anti-IgG antibody x400).
microscopy (MS x250).

Glomerulonephritis associated with

hepatitis B virus infection

DEFINITION HISTOLOGY
Hepatitis B virus infection is associated with two The light microscopic appearances are similar to
major forms of renal involvement: polyarteritis idiopathic membranous glomerulonephritis,
nodosa and membranous glomerulonephritis. except there may be more mesangial cell pro-
liferation and there may be areas of focal
PATHOGENESIS mesangiocapillary change in some of the
Hepatitis B-associated membranous glomerulo- capillary loops. All cases stain for IgG, and most
nephritis is probably immune complex- for IgM and complement. A subset of patients
mediated. HBsAg, HBcAg and HBeAg have all have mesangial IgA deposits. HBsAg and
been identified in the glomeruli, but it is HBcAg are found inconsistently in the glom-
thought that the HBeAg or antigen–antibody eruli, whereas HBeAg is commonly found in
complex are the appropriate size and charge to subepithelial deposits.
cross the glomerular basement membrane and
deposit in the subepithelial space. PROGNOSIS
Most children clear HBsAg from the blood with
CLINICAL HISTORY resolution of proteinuria without residual renal
Patients with hepatitis B-associated mem- impairment. This course is rare in adults and
branous glomerulonephritis usually present with there is usually progression to renal failure over
nephrotic syndrome. At presentation most months to years.
patients have a normal serum creatinine but
often massive proteinuria. Liver involvement is MANAGEMENT
usually mild at the time of renal presentation, Symptoms associated with nephrotic syndrome
with a normal bilirubin and modestly raised are treated with salt restriction, diuretics, and
values for serum alanine aminotransferase levels. lipid lowering agents. Corticosteroids may
Liver biopsy usually shows mild chronic active enhance viral replication and worsen the liver
hepatitis rather than cirrhosis. and renal disease. Interferon has been successful
at reducing viral replication, clearing HBsAg
from the blood, and reducing proteinuria in
some patients.
66 SYSTEMIC DISEASES AFFECTING THE GLOMERULI

Glomerulonephritis associated with

hepatitis C virus infection

DEFINITION HISTOLOGY (100–102)

Patients with hepatitis C infection may develop The light microscopic appearances are of
mesangiocapillary glomerulonephritis or cryo- diffuse intracapillary hypercellularity, often
globulinemic glomerulonephritis. severe enough to occlude the capillary lumina.
The hypercellularity consists of a mixture of
EPIDEMIOLOGY AND ETIOLOGY resident glomerular cells, and migrating neu-
Hepatitis C is a blood-borne virus transmitted trophils, T-cells and especially monocytes.
sexually, by blood transfusion, and by sharing Eosinophilic thrombi are often found in the
needles for intravenous drug use or tattooing. capillary lumina and consist of cryoprecipitable
Areas of high prevalence of infection include immunoglobulins. Immunohistochemistry
North America, southern Europe, and the shows localization of IgG and IgM in these
Indian subcontinent. areas. Electron microscopy shows dense sub-
endothelial deposits which may occlude the
PATHOGENESIS glomerular capillary. High magnification often
Hepatitis C infection can lead to chronic active reveals a microtubular appearance which may
hepatitis, cirrhosis, and hepatoma. Mixed essen- show a curved annular and cylindric con-
tial cryoglobulins are commonly found and figuration. Vasculitis affecting small or medium
contain HCV RNA and anti-HCV IgG. The sized arteries may be seen in patients with an
mechanisms that trigger precipitation of cryo- acute clinical picture.
globulins within the glomeruli are not known,
but once in the glomeruli they bind comple- PROGNOSIS
ment and induce chemokine production leading The clinical course is very variable but progres-
to inflammatory cell recruitment. sion to end-stage renal failure is rare. Death is
more commonly due to nonrenal complications
CLINICAL HISTORY AND PHYSICAL such as vasculitis, hypertension, and infections.
EXAMINATION
Patients usually have symptoms and signs of MANAGEMENT
chronic liver disease. The renal disease may Combination treatment with interferon and
present with proteinuria, microscopic hema- ribavirin can clear the virus from the circulation,
turia, nephrotic syndrome, or renal impairment. although replication often recurs after stopping
Patients may develop a purpuric rash (99) or the antiviral agents. Antiviral drugs have been
arthralgias. Hypertension may be severe. shown to improve liver histology. Plasma ex-
change may be used if there is evidence of severe
DIFFERENTIAL DIAGNOSIS acute nephritis or evidence of a systemic vasculitis.
ANCA-positive vasculitis presenting with a rash
and renal impairment is distinguished by the
presence of ANCA serologically and renal
biopsy appearances. Type 1 cryoglobulins are
monoclonal immunoglobulins found in multiple
myeloma, Waldenstrom’s macroglobulinemia,
or benign monoclonal gammopathy.

INVESTIGATIONS
Cryoglobulinemia is usually associated with low
C3 and C4 levels. Cryocrits are variable and
correlate poorly with the disease activity. Anti-
HCV IgG is detected by ELISA and HCV RNA
by PCR.
 GLOMERULONEPHRITIS ASSOCIATED WITH HEPATITIS C VIRUS 67

99 100

100 Glomerulus showing global increase of cellularity, mesangial

expansion, and an eosinophilic ‘thrombus’ (arrow). Light
microscopy (MS x250).

101
99 Purpuric rash in a patient
with chronic hepatitis C infection
and cryoglobulinemia.

101 Glomerulus showing

peripheral capillary wall
localization of IgM (brown
reaction product).
Immunoperoxidase
(anti-IgM antibody x250).

102

102 Microtubule formation.

Electron microscopy (x10,000).
68 SYSTEMIC DISEASES AFFECTING THE GLOMERULI

Glomerulonephritis associated with human

immunodeficiency virus (HIV)

DEFINITION INVESTIGATIONS
HIV infection can cause renal complications in Renal ultrasound in HIVAN characteristically
many ways. Electrolyte, acid–base disorders and shows abnormally large echo-bright kidneys
acute renal failure may occur, often due to sepsis (103). HIV serology is positive and there is
from opportunistic infections or related to usually a reduction in the CD4 count.
chemotherapy for neoplasia. HUS/TTP is a
recognized complication of HIV infection. HISTOLOGY (104–106)
Almost all types of glomerular lesions have been There are a number of different renal histologi-
reported in HIV-seropositive patients. However, cal characteristic changes in the glomeruli and
the characteristic glomerular lesion is a collaps- tubules. There may be a focal and segmental
ing form of focal and segmental glomeru- collapsing glomerulopathy with shrinkage and
lonephritis. This human immunodeficiency sclerosis of the entire glomerulus, leaving Bow-
virus-associated nephropathy (HIVAN) is the man’s space empty or filled with acidophilic
subject of this section. proteinaceous material. There may alternatively
be a marked proliferation of glomerular epi-
EPIDEMIOLOGY AND ETIOLOGY thelial cells such that the appearances mimic a
HIVAN is much more common in blacks than cellular crescent. Another form of renal involve-
whites (about 10:1). The reasons for this are not ment is a striking focal microcystic dilatation
known, although an increased susceptibility of of renal tubules which are filled with casts.
blacks to renal disease is seen with the increased There may also be an interstitial nephritis.
frequency in blacks of hypertensive nephro- Immunohistochemistry may show nonspecific
sclerosis, diabetic renal disease, and idiopathic localizationof IgM and C3 in the mesangium
focal and segmental glomerulosclerosis. HIVAN and sclerotic areas. Electron-dense deposits
can present before there has been any other may be found in the mesangium. Tubuloreticu-
AIDS-defining illness. lar inclusions are commonly found in endo-
thelial cells.
PATHOGENESIS
Experiments using transgenic mice expressing PROGNOSIS
certain HIV proteins provide strong evidence Untreated, there is rapid progression to end-stage
that direct infection of renal cells by the virus renal failure over a matter of weeks or months.
leads to production of inflammatory cytokines,
thus leading to development of HIVAN. Host MANAGEMENT
genetic factors are also important. ACE inhibitors reduce proteinuria and slow the
progression to end-stage renal failure. Treat-
CLINICAL HISTORY AND PHYSICAL ment with combination antiretroviral therapy
EXAMINATION has led to stabilization or improvement in renal
Patients usually present with nephrotic range function in patients with HIVAN. It is thus
proteinuria and renal impairment. The presence important to make a diagnosis of HIVAN as
of hypertension is variable. Edema is often progression to renal failure can be stopped with
minimal. There may be physical signs suggesting antiviral drugs.
HIV infection, e.g. hairy leucoplakia, herpetic
lesions, or Kaposi’s sarcoma.

DIFFERENTIAL DIAGNOSIS
Patients with heroin-associated nephropathy
usually have small kidneys on ultrasound, a
noncollapsing focal and segmental glomeru-
lonephritis, and a slow progression to end-stage
renal failure.
 GLOMERULONEPHRITIS ASSOCIATED WITH HIV 69

103

103 Ultrasound demonstrating large echogenic kidneys.

104 105

104 Glomerulus showing collapsed shrunken tuft 106

(collapsing FSGS). Light microscopy (MS x400).

105 Glomerulus showing severe proliferation of

epithelial cells in Bowman’s space mimicking a
crescent (arrow). Light microscopy (MS x400).

106 Cortical tubules showing focal cystic

dilatation with eosinophilic casts. Light
microscopy (PAS x150).
70 SYSTEMIC DISEASES AFFECTING THE GLOMERULI

Miscellaneous infections and glomerulonephritis

SYPHILIS common cause of nephrotic syndrome in west

The commonest glomerular lesion is mem- and east Africa. The patient may present with
branous nephropathy. Fine granular deposits of mild proteinuria or nephrotic syndrome with
IgG, IgM, and C3 are found in the capillary wall massive edema and ascites. The disease pro-
and mesangium. Spirochetes may be seen on gresses slowly, leading to hypertension and renal
light microscopy in the interstitium and tubules. failure within 3–5 years. The renal disease does
Treponemal antigen and antibody have been not respond to steroids or antimalarial treat-
found and it is thought to be an immune ment. In early cases there is focal and segmental
complex nephropathy. Proteinuria usually thickening of the capillary walls, which may be
resolves after penicillin treatment. double-contoured (107). Later the capillary
walls become occluded and there is diffuse
LEPROSY mesangial sclerosis. There are granular deposits
The major renal lesions are glomerulonephritis of IgG and IgM along the capillary walls.
and secondary amyloidosis. Morphologically,
the commonest types of glomerular lesions are MALIGNANCY AND
mesangial proliferative and diffuse proliferative GLOMERULONEPHRITIS
glomerulonephritis. Granular deposits of IgG Neoplastic disorders can affect the kidneys in
and C3 are seen in the mesangium and capillary various ways. Leukemia or lymphoma can cause
wall. Electron microscopy demonstrates subepi- diffuse infiltration of both kidneys causing acute
thelial and subendothelial deposits. Amyloidosis renal failure. Malignancy in the retroperitoneum
is much more common in lepromatous than or lower urinary tract can cause obstructive
tuberculoid leprosy. There is no convincing uropathy. However, tumors are also associated
evidence that antileprosy drugs alter the course with various forms of glomerulonephritis which
of the glomerular lesions. resolve on eradication of the tumor. Lymphoma
can be associated with minimal change disease.
SCHISTOSOMIASIS Membranous glomerulonephritis is associated
Schistosoma hematobium which is widely preva- with carcinomas of the lung, stomach, breast,
lent in the Middle East and Africa does not ovary, cervix, and thyroid. Crescentic glomeru-
cause glomerulonephritis but affects the ureters lonephritis can occur rarely in patients with
and bladder which can lead to obstructive malignancy. Secondary amyloidosis can be
uropathy. Schistosoma mansoni which is preva- associated with renal cell carcinoma.
lent in Brazil, Egypt, and east Africa causes an
immune complex-mediated disease. It usually
presents in patients with hepatosplenic disease
with nephrotic syndrome. Serum complement
levels are low and circulating immune complexes
may be found. In early disease mesangial pro-
liferation or mesangiocapillary nephropathy are 107
found. Focal and segmental glomerulosclerosis
and amyloid deposits may also be found. IgG,
IgE, IgM, and less often IgA and C3 are found
in the capillary walls and mesangium. Progres-
sion to end-stage renal failure is over several
years, and is not affected by antiparasitic drugs
or immunosuppression.

MALARIA
Plasmodium falciparum can cause a mild mesan-
gial proliferative glomerulonephritis which
completely resolves after antimalarial treatment.
Severe falciparum malaria is associated with 107 Plasmodium malariae. Glomerulus shows
intravascular hemolysis and acute renal failure mesangial sclerosis and segmental double-
(blackwater fever), with acute tubular necrosis. contouring of the capillary wall (arrow). Light
Plasmodium malariae (quartan malaria) is a microscopy (PAS x400).
Chapter Four
71

Tubulointerstitial
diseases
• Acute interstitial nephritis (AIN)

• Granulomatous interstitial nephritis

• Urate nephropathy

• Lead nephropathy

• Lithium-induced renal disease

• Radiation nephritis
72 TUBULOINTERSTITIAL DISEASES

Acute interstitial nephritis (AIN)

DEFINITION Table 6 Common causes of acute

AIN is an acute, usually reversible, inflammatory interstitial nephritis
disease, characterized by the presence of a
mononuclear cellular infiltrate within the renal Drugs
interstitium. • Antibiotics: penicillin G, ampicillin, methicillin,
rifampin (rifampicin), ciprofloxacin,
EPIDEMIOLOGY AND ETIOLOGY sulfonamides (sulphonamides), trimethoprim
AIN is a relatively common cause of acute renal + sulfamethoxazole (co-trimoxazole)
dysfunction comprising approximately 10–15% • Nonsteroidal anti-inflammatory drugs
of cases of acute renal failure in large reported • Phenytoin
series. It can occur in any age group, but is rare • Allopurinol
in children. AIN is most frequently associated • Diuretics (thiazides, furosemide [frusemide])
with drugs, particularly antibiotic, or nonsteroidal • Cimetidine, ranitidine
anti-inflammatory drugs. Infections are the • Propylthiouracil
second most common cause of AIN. AIN also • Phenindione
occurs in association with selected autoimmune
systemic diseases, and malignancies. In 10–20% Infectious agents
of cases, AIN is idiopathic (Table 6). • Bacteria: Legionella, Brucella, Streptococcus,
Staphylococcus, Pneumococcus
PATHOGENESIS • Virus: Epstein–Barr, CMV, Hanta virus, HIV,
AIN is considered an immune-mediated allergic hepatitis B, polyoma virus
reaction triggered against an inciting (renal or • Fungal: Candida, Histoplasma
extrarenal) antigen. Potential mechanisms include • Parasites: malaria, Toxoplasma, Schistosoma,
binding of the antigen to kidney membranes, Leishmania
acting as haptens, or formation of circulating
immune complexes with deposition in the kidney. Systemic diseases
In humans, a T-cell-mediated mechanism is sug- • Systemic lupus erythematosus
gested by the predominance of T-cell lympho- • Sjögren’s syndrome
cytes in the interstitial infiltrates, and the general • Sarcoidosis
absence of antibody deposition in tubules or • Mixed cryoglobulinemia
interstitium. T-cell reactivity against the antigen • Wegener’s granulomatosis
(drug) has been demonstrated in vitro, using
standard lymphocyte stimulation assays. An Others
antibody-mediated mechanism cannot, however, • Herbal medicines (aristolochia fangchi)
be excluded. In some patients with drug-induced
AIN, renal biopsies will show IgG and comple- Idiopathic
ment deposition along the tubular basement
membrane. Anti-tubular basement membrane
antibody is also present in some cases. In addi-
tion, IgE antibodies to the drug have been 50% of the cases. Hematuria is common but is
demonstrated in several patients. It is possible that rarely macroscopic. Renal impairment can vary
different immunologic mechanisms operate to from a mild elevation in serum creatinine to
varying degrees in different patients. When AIN severe acute renal failure requiring dialysis.
is secondary to a drug, the response is idiosyn- Tubular damage can impair the urinary concen-
cratic and unrelated to drug dosage. tration mechanism and result in the develop-
ment of polyuria. Tubular dysfunction can be
CLINICAL HISTORY also manifested by the development of a renal
Presentation is acute, with oliguria present in tubular acidosis (RTA) with both type I (distal)
approximately 40% of cases. In patients with and type II (proximal) RTA occurring.
drug-induced AIN, systemic manifestations of
a hypersensitivity reaction include fever (50%), PHYSICAL EXAMINATION
maculopapular rash (40%), and arthralgias Low-grade fever and a maculopapular rash may
(10%). Flank pain is secondary to distension of be present. Mild arthralgias are common, but
the renal capsule and occurs in approximately arthritis is unusual.
 ACUTE INTERSTITIAL NEPHRITIS (AIN) 73

DIFFERENTIAL DIAGNOSIS PROGNOSIS

The presence of an intense infiltrate of lympho- Historically, drug-induced AIN has been con-
cytes and eosinophils clearly distinguishes AIN sidered a reversible process with renal function
from acute ischemic or nephrotoxic injury. returning to baseline in the majority of patients.
Fever, lumbar pain, and leukocyturia are seen However, recent studies have shown that
in patients with acute pyelonephritis, but in this impaired renal function can persist long-term in
condition bacteriuria and leukocytosis are also up to 40% of the patients. Predictors of poor
present, and renal biopsy will show focal areas outcome include the presence of diffuse infil-
of infiltrating neutrophils. In chronic forms of trates, interstitial fibrosis, tubular atrophy, and
interstitial nephritis secondary to drugs (anal- granuloma formation on renal biopsy. Addi-
gesic nephropathy, lithium, gold), interstitial tional factors that correlate with a poor outcome
fibrosis and tubular atrophy are prominent, with include pre-existing impaired renal failure and
fewer eosinophils present. Sarcoidosis, Sjögren’s persistence of oliguria (>3 weeks).
syndrome, systemic lupus erythematosus, and
mixed cryoglobulinemia may all present as AIN, MANAGEMENT
and need to be considered in the diagnosis. Therapy is primarily supportive. The likely
Interstitial infiltrates by atypical and monomor- inciting factor(s) need to be identified and
phic cells can be seen in leukemia or lymphoma. eliminated. In patients with drug-induced AIN,
available data from small, uncontrolled, retro-
INVESTIGATIONS spective series suggest that treatment with
Eosinophilia is common (40%). Urinalysis corticosteroids may hasten the recovery of renal
demonstrates hematuria, sterile pyuria, and function, and may be of benefit in patients who
white blood cell casts in over 75% of the cases. fail to regain renal function within 1 week of
Rarely, red blood cell casts can be seen in the stopping the offending agent. To date, no
urinary sediment. The presence of eosinophiluria prospective, randomized, well-controlled clinical
(>1%), observed better with Hansel’s stain, is trial has assessed the role of corticosteroid
suggestive of AIN but is also seen in other therapy in patients with drug-induced AIN.
unrelated renal pathologies. The absence of Corticosteroids are not indicated in infection-
eosinophiluria should never discourage the diag- related AIN. In patients with AIN associated
nosis. Proteinuria is generally mild (<1 g/24 h). with autoimmune systemic diseases, steroid
Serologic markers are usually normal except treatment may result in dramatic improvement
when AIN is part of a systemic autoimmune of renal function.
process (e.g. SLE). On ultrasound, kidneys
appear normal or slightly increased in size.

HISTOLOGY
Because of the poor predictive value of clinical
criteria, the diagnosis of AIN requires a renal
biopsy. On light microscopy, there is a marked
inflammatory interstitial infiltrate and interstitial
edema, most commonly involving the deep
cortex and outer medulla (108). The interstitial 108
infiltrate is predominantly made up of CD4+ T-
cell lymphocytes, but monocytes, eosinophils,
and plasma cells can also be present. In severe
cases, there is disruption of the tubular base-
ment membrane and the presence of tubulitis.
Glomeruli and vessels are usually spared. Glom-
erular involvement producing a minimal change
lesion is seen with the use of NSAIDs. Occa-
sionally, interstitial granulomas can be seen,
especially in cases of drug-induced AIN. Both
immunofluorescence and electron microscopy
are usually negative. Occasionally, a linear or
granular staining for IgG or complement may 108 Acute interstitial nephritis with mononuclear
be seen along the tubular basement membrane. cells infiltrating tubules (arrow). Light microscopy
(H+E x150).
74 TUBULOINTERSTITIAL DISEASES

Granulomatous interstitial nephritis

DEFINITION Drug reactions are the most likely cause of

Granulomatous interstitial nephritis encom- acute granulomatous interstitial nephritis. Drugs
passes a subset of cases of acute interstitial most commonly associated with causing granu-
nephritis in which granulomas are present in lomatous interstitial nephritis are antibiotics,
the interstitium. A granuloma is an inflamma- nonsteroidal anti-inflammatory agents, and
tory reaction characterized by the accumulation diuretics. Besides drugs, other agents or disease
and proliferation of various cell types, but processes recognized in association with granu-
mainly macrophages. Giant cells are often lomatous interstitial nephritis include infections,
found as well. autoimmune diseases and foreign body reactions.
In some instances, no etiologic factor can be
EPIDEMIOLOGY AND ETIOLOGY identified and the condition is called idiopathic.
The presence of granulomas in renal biopsies is
rare. In large renal biopsy series in which PATHOGENESIS
interstitial nephritis is the predominant change, The pathogenic mechanism is poorly under-
granulomas are found in only 1–5% of cases. stood. Proposed immunologic mechanisms
include: T-cell-mediated delayed hypersensi-
tivity, anti-tubular basement membrane anti-
bodies, and reaginic antibodies.
Table 7 Recognized causes of granulomatous
interstitial nephritis CLINICAL HISTORY
The great majority of patients present with acute
renal failure. Anuria is not uncommon. As with
Drugs other patients with an AIN, a maculopapular
• Antibiotics: penicillin G, ampicillin, methicillin, rash may be present, accompanied by eosino-
oxacillin, ciprofloxacin, rifampin (rifampicin), philia. Other signs and symptoms may reflect
nitrofurantoin, sulfonamides (sulphonamides), the underlying pathogenic process.
trimethoprim + sulfamethoxazole (co-
trimoxazole), spiramycin PHYSICAL EXAMINATION
• Nonsteroidal anti-inflammatory drugs As with patients with AIN, low-grade fever and
• Anticonvulsants: phenytoin, lamotrigine, a maculopapular rash may be present. Patients
carbamazepine with granulomatous interstitial nephritis second-
• Diuretics: furosemide (frusemide), ary to a systemic illness may have characteristic
hydrochlorothiazide, triamterene signs of the disease (e.g. erythema nodosum in
• Others: allopurinol, glafenine (glafenin), a patient with sarcoidosis).
captopril, cimetidine, fenofibrate,
phenindione, acyclovir (aciclovir) DIFFERENTIAL DIAGNOSIS
Granulomatous interstitial nephritis has been
Infections described in association with a number of clini-
• Bacteria: Mycobacteria (tuberculosis, kansasii, cal conditions as listed in Table 7.
leprae), Brucella, Salmonella,Whipple’s
• Virus: Epstein–Barr INVESTIGATIONS
• Fungi: Histoplasma, Candida In cases of sarcoidosis, serum angiotensin con-
• Parasites: Toxoplasma, Schistosoma verting enzyme (ACE) levels are usually raised,
Foreign body reaction and a gallium scan will characteristically show
• Oxalate, uric acid increased uptake in the parotid glands, hilar
regions of the lungs, and the kidneys.
TINU (tubulointerstitial nephritis–uveitis syndrome)
HISTOLOGY (109, 110)
Others The number of interstitial granulomas varies
• Crohn’s, sarcoidosis,Wegener’s greatly from case to case. Typically, granulomas
granulomatosis, heroin use form a nodular infiltrate comparable in size to a
glomerulus. The cellular infiltrate is formed
Idiopathic mainly of mononuclear cells. Macrophages are
the principal elements in a granuloma, but
 GRANULOMATOUS INTERSTITIAL NEPHRITIS 75

lymphocytes, plasma cells, and fibroblasts are also MANAGEMENT

found. Epithelioid cells tend to cluster together Treatment will depend on the causative factor.
at the periphery of the nodule. Giant multinuclear In patients with a drug-induced nephritis,
cells are occasionally observed. Necrosis may removal of the inciting agent is imperative.
occur at the center of the granuloma, depending Corticosteroids are commonly used and may
on its cause (e.g. tuberculosis). Granulomas are hasten the recovery of renal function. Corti-
accompanied by an intense lymphocytic interstitial costeroids are indicated in cases where granulo-
infiltrate. Immunofluorescence shows no deposi- matous interstitial nephritis is associated with
tion of immunoglobulins or complement. systemic diseases (e.g. sarcoidosis). In infec-
tion-associated cases, treatment is targeted to
PROGNOSIS the underlying infection. In patients with
In patients with acute granulomatous interstitial tuberculosis-induced granulomatous interstitial
nephritis, prognosis is usually good. In some nephritis, there have been reports of successful
cases, renal function will recover slowly over a treatment with combined antituberculous
period of months, while others will have persis- drugs and corticosteroids.
tent renal insufficiency long term.

109, 110 Interstitial nephritis 109

(carbamazepine-induced)
showing a granuloma with
associated mononuclear cells
and a multinucleate giant cell
(arrow). Light microscopy. Low
power (H+E x100) (109). High
power (H+E x250) (110).

110
76 TUBULOINTERSTITIAL DISEASES

Urate nephropathy

DEFINITION Chronic uric acid nephropathy

There are mainly three forms of renal presentation Chronic uric acid nephropathy is thought to result
by which pathologic alterations in uric acid meta- from the deposition of monosodium urate crystals
bolism or excretion may occur: acute uric acid in the renal interstitium, but its pathogenesis is
nephropathy, chronic uric acid nephropathy, and controversial. The frequent co-existence of hyper-
uric acid stones. tension, hyperlipidemia, atherosclerotic vascular
disease, and diabetes (all conditions that by
EPIDEMIOLOGY AND ETIOLOGY themselves can cause renal injury) in patients with
Until approximately 40 years ago, renal failure gout has led some investigators to suggest that the
appeared to have been a common complication of progressive renal failure seen in these patients is
middle-aged males with gout. Nowadays, how- primarily a result of the above conditions, rather
ever, the presence of renal failure in patients with than secondary to abnormalities in uric acid
‘primary’ or classic gout is rare. Relatively recent handling. How the uric acid crystals reach the renal
studies have shown that, in patients with gout, interstitium is equally controversial. In experi-
renal function is almost always normal for their age mental models of crystal-induced nephropathies,
and in the absence of hypertension remains stable the initial event includes damage to the tubular
over time. The reason for this historic discrepancy epithelium, disruption of the basement membrane,
is unclear, but it may reflect better control of hyper- with migration of crystals into the interstitium.
uricemia after introduction of allopurinol. This is followed by phagocytosis of uric acid
crystals by polymorphonuclear leukocytes, leuko-
PATHOGENESIS cyte degranulation, and lysis of adjacent cellular
Uric acid is the final degradation product of purine components, resulting in the formation of renal
metabolism in humans. Approximately two-thirds microtophi and development of an inflammatory
of the daily turnover of uric acid is excreted in the response in the form of a chronic interstitial
urine through a complex process involving glom- nephritis. Urate crystal may also injure cells directly
erular filtration, proximal tubule absorption and by forming hydrogen bonds with the cellular
secretion, and further reabsorption along the membrane. In these experiments, even short
proximal renal tubule. Urate clearance is affected periods of crystal deposition resulted in severe renal
by a number of factors including the extracellular damage. Although deposited crystals eventually
volume, urinary flow rate, acid–base balance, disappear, progressive renal failure continues.
urinary pH, and plasma urate levels.
CLINICAL HISTORY
Acute hyperuricemic nephropathy Acute hyperuricemic nephropathy classically
Acute hyperuricemic nephropathy is an important occurs in the setting of a ‘tumor lysis syndrome’.
cause of oliguric acute renal failure. It is said to occur It typically presents with a history of acute
in up to 5% of patients with myeloproliferative dis- oliguria in a patient with leukemia or lymphoma
orders or neoplasias, especially while undergoing who has recently (within 48 hours) been treated
chemotherapy or radiation (tumor lysis syndrome). with cytotoxic therapy. In this situation, massive
Other conditions associated with sudden cell lysis cell lysis results in hyperkalemia, hyperphos-
and rapid increase in serum uric acid levels include phatemia, hypocalcemia, and acidosis. Metabolic
hemolysis and rhabdomyolysis. These pathologic abnormalities develop quickly, and uric acid levels
situations are usually associated with an increase in can rise to 15–20 mg/dl (0.9–1.2 mmol/l), with
purine catabolism, resulting in markedly increased massive uricosuria. In the acidic milieu of the
uric acid levels in the serum and massive uricosuria. collecting tubules, uric acid crystallizes, causing
Risk factors for acute hyperuricemic nephropathy acute tubular obstruction, oliguria, and azotemia.
include dehydration, low urinary volume, high serum Chronic uric acid nephropathy (or ‘gouty
uric acid levels, urinary pH <5.0, rapid response to nephropathy’) should be thought of as a potential
chemotherapy, pre-existing renal failure, and use of cause of chronic renal failure in a patient with
radiocontrast dye, all of which markedly increase uric repeated episodes of gout. Renal function is
acid excretion. In these settings, uric acid levels reach generally mildly impaired and slowly progressive.
supersaturation values in the urine and uric acid
crystallizes within the tubular lumen. Crystallization PHYSICAL EXAMINATION
occurs predominantly in the medullary collecting Patients with chronic uric acid nephropathy may
ducts, resulting in the development of tubular present with the classical gouty monoarticular
obstruction and acute renal failure. arthritis. The affected joint will show signs of
 URATE NEPHROPATHY 77

intense inflammation: swelling, erythema, warmth, tubular lumen of collecting ducts. However, the
and exquisite tenderness. Low-grade fever may be absence of crystal does not rule out uric acid
present. The skin may show nodular soft tissue nephropathy as the initial cause.
prominences in and around the joints (tophi). In
advanced cases, joint deformities, secondary to des- PROGNOSIS
truction of cartilages and bone are clearly present. With proper prophylaxis, acute nephropathy is rare.
For those patients who develop acute renal failure,
DIFFERENTIAL DIAGNOSIS prognosis is usually good and renal function
In patients presenting with a compatible clinical typically returns to baseline in 7–10 days. Chronic
history, the differential diagnosis of acute uric acid urate nephropathy is a slowly progressive disease.
nephropathy should not pose difficulties. On the
other hand, the diagnosis of chronic uric acid MANAGEMENT
nephropathy requires that other causes of chronic The best treatment for acute hyperuricemic
renal failure are ruled out first. The differential nephropathy is prevention. Allopurinol, a com-
diagnosis includes causes of secondary gout, petitive inhibitor of xanthine oxidase, decreases
especially chronic lead nephropathy (saturnine uric acid production within 48 hours and its use
gout). Primary gout is predominantly a male is indicated in patients undergoing chemotherapy.
disease, whereas saturnine gout has an equal The dose needs to be adjusted for renal function.
male:female prevalence. Chronic lead poisoning Forced diuresis helps to maintain a good urine
should be especially suspected in female patients output and reduces tubular concentration of uric
with renal failure and gout. Elevated uric acid acid. In patients developing oliguria, rapid
levels can also cause renal failure in patients with expansion of the extracellular fluid volume and
inherited disorders of purine metabolism (i.e. use of diuretics may reverse the acute situation.
Lesch–Nyhan syndrome). In addition, urinary alkalinization increases uric
acid solubility in the urine. Caution should be
INVESTIGATIONS taken when alkalinizing the urine when the phos-
In acute hyperuricemic nephropathy laboratory phorus is >7 mg/dl (>2.3 mmol/l) because it can
abnormalities include hyperkalemia, hyper- precipitate calcium phosphate crystals and
phosphatemia, hypocalcemia, and acidosis. exacerbate intraluminal obstruction. For patients
Urinalysis usually shows massive amounts of uric with established acute renal failure, hemodialysis
acid or urate crystals in the sediment. In patients provides an effective clearance of uric acid.
with chronic uric acid nephropathy the diagnosis Apart from the general recommendations
may be suggested by the presence of hyper- regarding the management of patients with
uricemia that is disproportional to the degree of chronic renal failure, such as treating hyper-
renal impairment. Urinalysis is unremarkable tension, hyperlipidemia, and restriction of pro-
except for mild proteinuria. tein intake, there is no specific treatment for
chronic uric acid nephropathy, except the use of
HISTOLOGY allopurinol to control hyperuricemia.
Acute hyperuricemic nephropathy is characterized
by intraluminal precipitation of uric acid crystals,
tubular obstruction, and minimal interstitial 111
cellular infiltration. Crystallization is seen pre-
dominantly in the medullary collecting ducts.
Chronic uric acid nephropathy is charac-
terized by tubulointerstitial fibrosis. Uric acid
crystals (microtophus) can be seen precipitated
inside the tubules in the medulla and renal
papilla, which gives the appearance of yellow-
white nodules or streaks. If tubular disruption
occurs, crystals may be seen in the interstitium
where they trigger a focal granulomatous inter-
stitial nephritis, consisting of macrophages,
multinucleated giant cells, and lymphocytes
(111). Ultimately, progressive interstitial fibrosis,
arteriolar nephrosclerosis, and glomerulosclerosis
develop. Crystals are characteristically needle- 111 Urate nephropathy.Tophus containing uric
shaped and are birefringent under polarized acid crystals is surrounded by macrophages. Light
light. Crystalline material can be seen within the microscopy (H+E x400).
78 TUBULOINTERSTITIAL DISEASES

Lead nephropathy

DEFINITION urate secretion by the impaired proximal tubules.

Lead nephropathy is a chronic interstitial neph- In adults, the best screening tests for lead exposure
ritis secondary to heavy exposure to lead over are lead levels in the blood and erythrocyte
a number of years. protoporphyrin. In children, where significant lead
toxicity can occur with low-level exposure,
EPIDEMIOLOGY AND ETIOLOGY measurement of blood lead levels is the primary
Certain professions like miners, painters, screening method. In addition, determination of
plumbers, and workers involved in the manufac- urinary lead excretion after administration of a lead
turing of batteries, pottery and pewter are chelator such as calcium disodium salt of ethylene
examples of occupational exposure to lead. En- diamine tetra-acetic acid (EDTA) can be used to
vironmental contamination also occurs by inges- document excessive lead absorption in patients
tion of lead-contaminated food or water. Child- with chronic low levels of lead exposure.
ren under the age of 6 years are at increased risk
of lead toxicity in comparison to adults, because HISTOLOGY
of their increased capacity for lead absorption. In acute lead nephropathy renal biopsy shows
Other factors that increase the susceptibility to proximal tubular injury, with intranuclear
lead toxicity include the amount of calcium and inclusion bodies composed of a lead–protein
vitamin D in the diet, and iron stores. complex. With chronic lead nephropathy kid-
neys are shrunken (112). On histology there is
PATHOGENESIS a nonspecific interstitial nephritis and tubular
Lead present in the glomerular ultrafiltrate is atrophy that is indistinguishable from other
reabsorbed in the proximal tubule where its forms of nephrosclerosis.
accumulation is likely to mediate the pathologic
process of lead toxicity, although the precise PROGNOSIS
mechanism is unknown. In patients in whom the main manifestation of
lead nephrotoxicity is abnormal proximal tubu-
CLINICAL HISTORY AND PHYSICAL lar function, prognosis is good and usually
EXAMINATION reversible. Chronic lead nephropathy is con-
The two main forms of presentation are: sidered to be irreversible, with patients slowly
• As part of an acute lead intoxication syn- progressing to end-stage renal disease.
drome, with abdominal pain, hemolytic
anemia, peripheral neuropathy, encepha- MANAGEMENT
lopathy, and proximal tubular dysfunction Preventive measures, such removal of lead from
manifested either as proximal renal tubular gasoline and paint, have reduced the risk of lead
acidosis or Fanconi’s syndrome, with amino- toxicity in the general population. Initial treatment
aciduria, phosphaturia, and glycosuria. involves removal of the source of lead. Blood lead
• Chronic lead nephropathy. These patients levels *45 ␮g/dl (2.2 +mol/l) in children, and
present similarly to patients with chronic renal *70 ␮g/dl (3.4 +mol/l) in adults, are an indi-
failure from other etiologies. Hypertension is cation for chelation therapy.
usually present. Proteinuria tends to be low
(<1g/24 h). Chronic lead toxicity is associated
with saturnine gout and renal adenocarcinoma. 112

DIFFERENTIAL DIAGNOSIS
The main differential diagnosis is with chronic urate
nephropathy. A history of occupational lead
exposure or presence of urate deposits (tophi) in
renal biopsy help in making the correct diagnosis.

INVESTIGATIONS
Urinalysis shows proteinuria, mainly due to low-
molecular weight proteins such as ␤2-micro-
globulin or retinol-binding protein. Anemia is 112 Macroscopic appearance of lead
characterized by the presence of ‘basophilic nephropathy.The kidney is small secondary to
stippling’. Hyperuricemia is secondary to reduced cortical loss and has a smooth outer surface.
 LITHIUM-INDUCED RENAL DISEASE 79

Lithium-induced renal disease

DEFINITION HISTOLOGY
Lithium is an effective drug in the control of Lithium-induced ATN is characterized by cell
bipolar affective disorders. However long-term ballooning, swelling, and vacuolation mostly
use is frequently complicated by nephrotoxicity. seen in the distal convoluted tubules. In patients
with chronic lithium nephropathy biopsies show
EPIDEMIOLOGY a focal chronic interstitial nephropathy, with
Patients with severe unipolar and bipolar affective interstitial fibrosis, tubular atrophy, and glom-
disorders are at increased risk of lithium toxicity. erular sclerosis (113). Characteristically there is
cystic dilatation of the distal tubules.
PATHOGENESIS
Lithium is freely filtered at the glomerulus with PROGNOSIS
re-absorption occurring at several places along the Nephrogenic diabetes insipidus is usually reversi-
nephron. In the renal medulla, lithium transport ble once lithium intake has been discontinued,
into the collecting tubule cells occurs via sodium although in some cases abnormaliies in urinary
channels in the luminal membrane. In this neph- concentration may persist for many months.
ron segment, lithium accumulation interferes with Patients with a clinical history complicated by
the ability of vasopressin to increase water re- repeated episodes of lithium intoxication may
absorption by at least two mechanisms: show a sustained increase in serum creatinine.
• Direct inhibition of the adenylate cyclase system. However, the role of lithium in causing end-
• Inhibition of transepithelial water movement by stage renal failure is controversial.
down-regulating the expression of aquaporin 2.
MANAGEMENT
CLINICAL HISTORY AND PHYSICAL For patients with mild lithium intoxication, treat-
EXAMINATION ment of acute lithium intoxication includes admit-
The renal manifestations of lithium toxicity ting the patient to the hospital, discontinuation of
include: the drug, and vigorous restoration of extracellular
• Nephrogenic diabetes insipidus. volume depletion. For patients with severe lithium
• Type 1 (distal) renal tubular acidosis (RTA). intoxication, hemodialysis is the treatment of
• Nephrotic syndrome. choice. Lithium levels may rebound following
• Acute tubular necrosis (ATN). dialysis. Thiazide diuretics should be avoided in
• Chronic interstitial nephritis. patients on lithium therapy because the volume
contraction can result in an increase in proximal
Nephrogenic diabetes is suggested by the tubule reabsorption of sodium and lithium that
presence of polyuria and polydipsia in up to 40% together can precipitate an episode of acute lithium
of patients. RTA is incomplete and rarely of clinical intoxication. Patient on long-term lithium therapy
significance. Nephrotic syndrome is secondary to should have their renal function checked at least
minimal change nephropathy and remits upon once a year. Lithium therapy should be discon-
lithium withdrawal. ATN may be the presenting tinued if there is evidence of progressive renal
feature following acute lithium intoxication. In function decline.
patients with lithium-induced chronic interstitial
nephritis, GFR is usually modestly reduced.
Physical examination is unrevealing. 113 Lithium- 113
induced renal
DIFFERENTIAL DIAGNOSIS disease. Extensive
The differential diagnosis includes other causes interstitial fibrosis
of polyuria and mild renal failure such as and tubular
diabetes mellitus, chronic interstitial nephritis, atrophy is seen
and Fanconi syndrome. with a chronic
lymphocytic
INVESTIGATIONS inflammatory
Investigations include a determination of infiltrate. Light
lithium levels and estimation of the glomerular microscopy
filtration rate and of the 24-hour urine volume. (H+E x100).
In patients with elevated creatinine a renal
biopsy should be considered.
80 TUBULOINTERSTITIAL DISEASES

Radiation nephritis

DEFINITION CLINICAL HISTORY AND PHYSICAL

Radiation nephritis is an inflammatory, throm- EXAMINATION
botic and degenerative disorder of the kidney that There are four clinical syndromes associated with
is secondary to the effects of ionizing radiation. renal irradiation in excess of 20 Gy (2000 rads):
• Acute radiation nephritis: occurs in 40% of
EPIDEMIOLOGY patients after a latency of 6–12 months.
In general, direct exposure of >50% of the Patients typically present with abrupt onset
kidney to 20–30 Gy (2000–3000 rad) during of hypertension, proteinuria, edema, and
a period of 5 weeks or less will result in nephritis. progressive renal failure.
Minimizing the total dose of irradiation to • Chronic radiation nephritis: usually mani-
<20–30 Gy (2000–3000 rads), proper shielding fested by insidious onset of hypertension and
of the kidneys, and/or fractionation of the total proteinuria that develops in a patient *1 year
body irradiation into several small doses over after irradiation. There is gradual loss of renal
several days has resulted in the virtual disap- function.
pearance of radiation nephritis. • Benign hypertension: may occur *2 years
after exposure to radiation. Hypertension is
PATHOGENESIS associated with variable proteinuria and
In experimental models, direct irradiation of normal renal function, a good long-term
the kidney results in degeneration of the prognosis.
glomerular tuft and tubular epithelial cells, • Malignant hypertension: can present months
associated with inflammatory interstitial infil- to years after radiation. Patients in this group
trates. With time, there is progressive glom- have a poor prognosis.
erular sclerosis, tubular atrophy, and interstitial
fibrosis. Renal endothelial cells appear to be DIFFERENTIAL DIAGNOSIS
the initial target of ionizing radiation. There is Because of morphologic similarities, the main
a suggestion that endothelial cell injury may differential diagnoses are hemolytic uremic syn-
be mediated by the generation of oxygen free drome and thrombocytopenic purpura.
radicals, formed by radiation-induced enzyme
activation. The sensitivity of the endothelial INVESTIGATIONS
cells to radiation is increased by some anti- Laboratory abnormalities include proteinuria
neoplastic medications. Increased sensitivity of (may be nephrotic), little or no hematuria,
the kidney to radiation has been noted with anemia, and elevated creatinine.
use of actinomycin-D, bleomycin, vinblastine,
and cyclophosphamide.
 RADIATION NEPHRITIS 81

HISTOLOGY PROGNOSIS
Histologic features may vary, depending on the Acute radiation nephritis may resolve spon-
dose of radiation administered and the time of taneously in some cases. More frequently, it
the biopsy. In mild cases, glomeruli show progresses to chronic radiation nephritis. Malig-
mesangial cell proliferation and matrix expan- nant hypertension and impaired renal function
sion, with occasional areas of mesangiolysis. early on presentation indicate a poor prognosis.
Typically the capillary walls appear thickened
and show ‘splitting’. In severe cases, glomeruli MANAGEMENT
may show fibrinoid necrosis and thrombosis, Treatment is supportive, with care taken to
and epithelial crescents are not unusual. Larger control blood pressure and risk factors for renal
vessels may be normal or show patchy intimal disease progression. In experimental models,
proliferation with increased thickness, intimal ACE inhibitors have been shown to reduce the
fibrosis, or fibrinoid necrosis (114). The inter- progression of renal disease and improve
stitium may show interstitial infiltrates, tubular survival. As in many other conditions, the best
atrophy, and interstitial fibrosis. Interstitial treatment is prevention. The risk of developing
changes may occur in the absence of glomerular radiation nephritis may be reduced by keeping
abnormalities. On immunofluorescence, immu- the total dose of radiation to the kidney to
noglobulins and fibrin may be seen deposited <20–30 Gy (2000–3000 rads), fractionating the
along the capillary walls. Electron microscopy total dose into several small doses over several
shows splitting of the capillary wall due to inter- days, and proper shielding of the kidneys.
position of mesangial matrix between the glom-
erular basement membrane and the endothelial
cells. The subendothelial space is widened by
deposition of a nondescript amorphous material.

114

114 Focal medial hypertrophy of interstitial arteries.These vessels

(arrows) show endothelial cell swelling, subintimal deposition of
basophilic material, severe interstitial fibrosis, and tubular atrophy.
Light microscopy (H+E x200).
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Chapter Five
83

Diseases affecting
the renal
vasculature
• Atheromatous renovascular disease

• Fibromuscular renovascular disease

• Cholesterol emboli

• Essential hypertension and the kidney

• Scleroderma

• Hemolytic–uremic syndrome (HUS)

84 DISEASES AFFECTING THE RENAL VASCULATURE

Atheromatous renovascular disease

DEFINITION the aorta in association with neurofibromatosis are

Atheroma of the renal arteries can cause stenosis important causes (115). Large or medium vessel
or occlusion of the vessels leading to hyperten- vasculitides such as polyarteritis nodosa, giant cell
sion or renal impairment. It is the commonest arteritis, syphilis, and Takayasu’s arteritis can cause
cause of renovascular disease. Atherosclerotic renal artery stenosis (116). Renal or adrenal
lesions of the renal artery typically occur in the tumors or even large simple renal cysts may
ostium or proximal renal artery and are eccentric compress the renal artery, producing hypertension.
rather than concentric in nature. Lesions are
commonly bilateral. The natural history is of INVESTIGATIONS
progressive narrowing of the stenosis leading Ultrasound is a useful initial imaging technique
eventually to occlusion. because the presence of asymmetric kidneys in a
patient with other evidence of vascular disease is
EPIDEMIOLOGY AND ETIOLOGY very suggestive of renal arterial disease. Renal
Atheromatous renovascular disease is extremely angiography (117) is the gold standard investiga-
common in patients who have evidence of tion but is invasive and the dye is potentially
generalized atherosclerosis. If hypertensive nephrotoxic. Pressure gradients can be measured
patients with coronary artery disease or peripheral at the time of angiography if it is not certain from
vascular disease are screened by renal angiography, the images obtained whether the stenosis is critical.
30–50% will be found to have a renal artery Various noninvasive tests can be of use. Captopril-
stenosis. Advanced age, diabetes mellitus, hyper- DTPA scans can be useful functional tests of the
tension, hypercholesterolemia, and smoking are significance of a renal artery stenosis. The func-
risk factors. It is a common cause of end-stage tionality of a significant unilateral renal artery
renal failure in the elderly population. stenosis is demonstrated by a fall in the single kidney
GFR after ACE I administration, relative to that of
PATHOGENESIS the contralateral kidney (118, 119). Duplex
If a unilateral stenosis is severe there may be Doppler ultrasound is not a reliable screening
tubular atrophy and interstitial fibrosis on the investigation in most centers. Magnetic resonance
side ipsilateral to the stenosis due to long-stand- angiography (MRA) is becoming a reliable non-
ing ischemia, and possibly cholesterol emboliza- invasive alternative to conventional angiography. It
tion. The ischemic kidney secretes renin which does not require arterial catheterization or adminis-
leads to increased angiotensin II production. tration of nephrotoxic drugs (120, 121).
The resultant hypertension may in time cause
nephrosclerosis in the contralateral kidney.
115
CLINICAL HISTORY
Patients with atheromatous renovasular disease
usually present with hypertension and/or renal
impairment. Sometimes the deterioration in renal
function follows commencement of an ACE
inhibitor. Another classic presentation is with
recurrent pulmonary edema, usually in patients
with bilateral disease. Proteinuria is common and
occasionally may be in the nephrotic range.

PHYSICAL EXAMINATION
Renal artery bruits may be audible. There is com-
monly evidence of generalized atherosclerosis,
e.g. absent foot pulses, carotid artery bruits. 115 Middle aortic syndrome. Aortogram of a 17-
year-old male with severe hypertension showing
DIFFERENTIAL DIAGNOSIS typical feature of the middle aortic syndrome.
Although atheroma is the commonest cause of Note the severe tubular stenosis involving most
renal artery stenosis, other conditions can cause it. of the abdominal aorta.There are multiple renal
The commonest is fibromuscular dysplasia. In arteries that are stenosed.The superior
children, coarctation of the aorta or narrowing of mesenteric artery is also severely stenosed.
 ATHEROMATOUS RENOVASCULAR DISEASE 85

116 117

116 Polyarteritis nodosa. A selective injection 117 Intra-arterial digital subtraction angiogram
of a lower pole branch artery shows typical (DSA) showing normal renal arteries.
microaneurysms.

100
118 100
119

50 50

0 0
0 5 10 15 20 0 5 10 15 20
Minutes Minutes

118 Precaptopril renogram in a patient with 119 Postcaptopril renogram showing delayed
bilateral renal artery stenosis.Transit time: right transit times bilaterally.Transit time: right kidney
kidney 198 s, left kidney 177 s. 398 s, left kidney 377 s.

120 Magnetic resonance 120 121

angiogram showing total
occlusion of the right renal
artery and stenosis of the
proximal left renal artery.

121 Corresponding DSA.

86 DISEASES AFFECTING THE RENAL VASCULATURE

Atheromatous renovascular disease (continued)

Renal artery occlusion may occur spon- Renal artery aneurysms (124, 125) are
taneously due to thrombosis or embolism (122) usually due to atherosclerosis but can be caused
or as a result of trauma. Trauma can cause renal by any of the above mentioned diseases. Com-
artery occlusion by raising an intimal flap or plications include rupture, thrombosis, hyper-
causing a dissection of the renal artery (123). tension, distal embolization, and formation of
Causes of traumatic renal artery thrombosis an arteriovenous fistula.
include blunt trauma, or iatrogenic trauma com-
plicating such procedures as nephrolithotomy, PROGNOSIS
nephrostomy, renal biopsy or, most commonly, Atheromatous renovascular disease is progres-
percutaneous transluminal renal angioplasty sive so stenoses tend to become more critical
(PTRA). Acute renal artery occlusion in a pre- and eventually occlude. It is also common for
viously normal artery leads rapidly to infarction the disease to become bilateral over time. Reno-
presenting as loin pain, fever, and vomiting. vascular disease is part of a generalized process
Thrombosis of a solitary kidney or bilateral renal and patients often die from coronary or cerebro-
artery thrombosis will cause anuric acute renal vascular disease before they develop end-stage
failure. More commonly thrombosis is superi- renal failure.
mposed on a pre-existing progressive renal
artery stenosis. The ischemic kidney will have MANAGEMENT
developed an extensive collateral circulation Medical management consists of optimizing
from intercostal, lumbar, adrenal, gonadal, and blood pressure control, and lowering serum
ureteric vessels. As a result infarction does not cholesterol levels. The role of PTRA and surgery
occur and the occlusion is usually asymptomatic, remains controversial. Most centers will use
although there may be worsening of hyperten- PTRA rather than surgery as it is much less inva-
sion and renal function. sive in often elderly high-risk patients. Stenting

122 123

123 Traumatic occlusion of the left renal artery

following a road traffic accident. On enhanced
CT note the absence of contrast medium in the
left renal artery and the lack of enhancement of
the kidney (arrow).
122 Renal artery embolism. On an earlier
aortogram the whole of the right renal artery
was demonstrated. On this subsequent study the
middle branch is occluded with a sharp cut-off.
These appearances are typical of embolism.
 ATHEROMATOUS RENOVASCULAR DISEASE 87

is now often performed following angioplasty. in renal function and a >9 cm (3.5 in) in length
PTRA has been shown to improve blood pres- kidney beyond the stenosis (126, 127). Surgery
sure control in a proportion of patients but its is indicated in patients unsuitable for PTRA,
effect on renal function may be to worsen or where the aorta needs to be reconstructed, and in
improve it. patients with an occluded renal artery but evi-
Patients most likely to benefit from PTRA are dence of good collateral blood flow and evidence
those with very severe stenoses, rapid deterioration of a viable kidney.

124 125

124, 125 Renal artery aneurysm. A 60-yearold female presented with severe hypertension. An
aneurysm measuring 3 cm (1.2 in) in diameter is demonstrated at the renal hilum with a relatively
narrow neck (124). It was possible to place coils safely within the aneurysm.The final postembolization
procedure shows that the arterial supply to the kidney is unaffected (125).

126 127

126, 127 Renal artery stenting. Aortography shows diffuse aortic disease with an occluded right renal
artery and a severe proximal stenosis on the left (126). Primary stenting was performed. A follow-up
study 27 months later demonstrates a satisfactory angiographic appearance with the stent just
protruding into the aorta (127).
88 DISEASES AFFECTING THE RENAL VASCULATURE

Fibromuscular renovascular disease

DEFINITION CLINICAL HISTORY AND PHYSICAL

Fibromuscular disease typically affects the mid- EXAMINATION
dle or distal portions of the renal arteries. It may Fibromuscular disease should be considered in
affect other vessels most commonly the carotid patients, typically females, who present with
arteries, but also the subclavian, coronary, hypertension before the age of 25 years in the
mesenteric, and iliac arteries. Most commonly absence of a strong family history of essential
it affects the medial muscular layer with medial hypertension.
fibroplasia in 85% and medial hyperplasia in
10%. Typically lesions are multiple and stenotic INVESTIGATIONS
segments are linked by aneurysmal areas, giving Diagnosis is made by renal angiography (128).
a strings-of-beads appearance on angiography.
PROGNOSIS
EPIDEMIOLOGY AND ETIOLOGY The natural history of untreated fibromuscular
Fibromuscular disease is the commonest form dysplasia is not well-described, especially as most
of renovascular disease in young adults. It is cases are now treated by PTRA. A proportion
about six times more common in females than of cases can progress to occlusion.
males. It is rare in blacks.
MANAGEMENT
PATHOGENESIS PTRA is more successful in patients with
The pathogenesis of fibromuscular dysplasia is fibromuscular disease than atheromatous reno-
unknown. vascular disease at curing or improving hyper-
tension. Re-stenosis is also less likely. PTRA is
thus the treatment of choice, allowing the
patient a chance of discontinuing antihyper-
tensive medication.

128

128 Fibromuscular dysplasia. Saccular dilatations

and web-like stenoses are seen affecting the distal
right renal artery.
 CHOLESTEROL EMBOLI 89

Cholesterol emboli

DEFINITION PHYSICAL EXAMINATION

Cholesterol crystals that embolize to the renal Common findings are livedo reticularis and
circulation lodge in the small arteries or afferent gangrene of the toes, often with normal pedal
arterioles and set up an inflammatory reaction pulses (trash feet). Fundoscopy may show
which compromises renal function. emboli lodged at branch points in the retinal
arterioles (Hollenhorst plaques) (129).
EPIDEMIOLOGY AND ETIOLOGY
Cholesterol embolization occurs in elderly INVESTIGATIONS
patients with generalized atherosclerosis. It may Typically the ESR is raised, there is eosinophilia
occur spontaneously from ruptured aortic and serum complement levels are depressed.
atheromatous plaques but more commonly
occurs after interventional procedures which HISTOLOGY
dislodge cholesterol from the aortic wall, or after Sites of emboli are recognized by cleft or needle-
anticoagulation or thrombolysis which lead to like spaces usually within the interlobular and
hemorrhage into a plaque with subsequent arcuate vessels (130), but may also be seen in
dislodgement of cholesterol crystals. Cholesterol glomerular capillaries. The presence of choles-
emboli may also be found downstream of a terol rapidly incites a foreign body giant cell
significant renal artery stenosis. reaction. The vessels will usually show intimal
thickening and fibrosis. Rarely, a crescentic
PATHOGENESIS glomerulonephritis can occur.
Cholesterol crystals cause vascular occlusion and
incite a foreign body giant cell reaction with a PROGNOSIS
mononuclear cell infiltrate which leads to inter- The outcome for these patients is generally poor
stitial fibrosis, tubular atrophy, and intravascular and is determined by the severity of the vascular
fibrosis. disease and degree of embolization that has occur-
red. Renal function usually declines progressively.
CLINICAL HISTORY
Patients may present with oliguric acute renal MANAGEMENT
failure or slowly progressive renal insufficiency. Interventional vascular procedures and anti-
Microscopic hematuria and minor proteinuria coagulation are contra-indicated. There have
may be present. Patients often have symptoms of been reports of renal function stabilizing in
other organ involvement if cholesterol emboli patients treated aggressively with statins to lower
have showered into other circulations. There may the serum cholesterol levels.
be an acute confusional state or focal neurologic
deficits, pancreatitis, or gastrointestinal bleeding.

129 130

130 Cholesterol emboli. Interlobular artery

129 A cholesterol embolus (Hollenhorst plaque) shows complete occlusion with large cholesterol
(arrow) can be seen lodged at the bifurcation of clefts. Light microscopy (MS x250).
the inferior branch retinal artery.
90 DISEASES AFFECTING THE RENAL VASCULATURE

Essential hypertension and the kidney

DEFINITION PHYSICAL EXAMINATION

Renal function and blood pressure are intimately Patients with essential hypertension may have
linked: primary renal disease causes hyperten- clinical signs of left ventricular hypertension.
sion, and hypertension impairs renal function. Accelerated hypertension causes loss of auto-
In the absence of primary renal disease, essential regulation in the retinal vessels leading to hard
hypertension can cause structural changes in the exudates formed by constituents of plasma and
kidney which are at their most florid in accel- hemorrhage (131). Soft exudates (cotton wool
erated hypertension. spots) are caused by ischemic infarction of nerve
fibers. Papilloedema is a swelling of the optic
EPIDEMIOLOGY AND ETIOLOGY disk with loss of the disk margins.
In whites it is debated whether essential hyper-
tension, without an accelerated phase, can cause INVESTIGATIONS
end-stage renal failure. In the European Dialysis Essential hypertension over time leads to left
and Transplantation Association Registry in ventricular hypertrophy which is seen on
1986, hypertension was documented as the echocardiography. Accelerated hypertension
cause of renal failure in 6.1% of patients. Blacks leads to elevated renin and aldosterone levels
seem to be much more likely to develop renal which lead to a hypokalemic metabolic alkalosis.
failure as a consequence of hypertension.
HISTOLOGY
PATHOGENESIS The effects of essential hypertension in stable
The morphologic effects of hypertension on the phase on the kidney have traditionally been
kidney can be studied in the Goldblatt rat model termed nephrosclerosis. There is segmental
of two-kidney, one-clip hypertension, by exam- hyalinization of interlobular arteries and afferent
ining renal histology in the kidney contralateral arterioles, which leads to ischemic collapse of
to the renal clip. The changes seen in the kidney the glomerular tuft and focal glomerulosclerosis.
are similar to those seen in humans with essen- There will then be atrophy of the tubules related
tial hypertension. The initial change is medial to that glomerulus (individual nephron dam-
hypertrophy of the intrarenal arterial and age). This will eventually lead on to cortical
arteriolar wall, followed by segmental hyalinosis atrophy and renal failure. In accelerated hyper-
of the vessel wall, probably due to breakdown tension there is a proliferative intimal arteritis of
of autoregulation and intrusion of blood vessel the interlobular arteries, leading to almost
constituents into the vessel wall. At a later stage complete occlusion of the lumen with the so-
focal and segmental glomerulosclerosis with called onion skin lesion (132, 133). There is
tubular atrophy develops. The final stage also fibrinoid necrosis of the afferent arterioles
involves severe concentric intimal fibrosis of the which may extend into the glomerular tuft to
interlobular arteries. If the clip is removed after cause focal and segmental necrosis, sometimes
one year, the blood pressure decreases tem- with crescent formation.
porarily and then, after 1 week, returns to the
hypertensive levels. Normotension is regained PROGNOSIS
if the previously untouched kidney is removed, Patients with accelerated hypertension and acute
indicating the importance of the hypertension- renal failure with no pre-existing renal disease
induced structural changes in maintaining the will often recover significant renal function after
hypertensive state. blood pressure is brought under control.

CLINICAL HISTORY MANAGEMENT

Usually hypertension is asymptomatic until it Optimal control of essential hypertension is
reaches the accelerated phase. important to prevent the development of
Then patients may complain of headache, atherosclerosis leading especially to coronary
visual disturbance, or symptoms of heart failure. and cerebrovascular disease.
In accelerated hypertension proteinuria is com-
monly present, and may reach nephrotic
range, and largely resolves after treatment of the
hypertension.
 ESSENTIAL HYPERTENSION AND THE KIDNEY 91

131 Superficial and deep retinal 131

hemorrhages are seen in a patient with
accelerated hypertension.There is
comparatively little change in the retinal
arteries themselves, indicating that the
hypertension is of relatively acute onset.

132 Essential hypertension. Large 132

interlobular artery showing extensive
reduplication of the internal elastic
lamina. Light microscopy (MS x250).

133 Accelerated hypertension. Small 133

interlobular artery is shown in which
there is onion skin proliferation (arrow)
and fibrinoid necrosis (arrow head) of
the arteriole at the hilum. Light
microscopy (MS x250).
92 DISEASES AFFECTING THE RENAL VASCULATURE

Scleroderma

DEFINITION CLINICAL HISTORY

Scleroderma is a disease characterized by pro- Renal disease may present with hypertension,
gressive and irreversible accumulation of con- proteinuria, and slowly progressive renal impair-
nective tissue in the skin and often in visceral ment. Scleroderma renal crisis tends to occur in
organs, together with structural changes in the patients with rapidly progressive and diffuse
microvasculature. The disease varies in severity cutaneous systemic sclerosis. Patients usually
and extent from patches of hard skin have accelerated hypertension often with
(morphoea) to life-threatening systemic illness. headaches, confusion, and visual impairment,
Generalized scleroderma can be divided into and become oligoanuric rapidly. Scleroderma
three subgroups. renal crisis can be triggered by cold weather,
pregnancy, or by corticosteroids.
Subgroup one:
• Diffuse cutaneous systemic sclerosis. PHYSICAL EXAMINATION
• Onset of Raynaud’s phenomenon within Patients with scleroderma renal crisis may have
1 year of onset of skin changes. signs of accelerated hypertension. They usually
• Truncal and acral skin involvement. exhibit Raynaud’s phenomenon and diffuse
• Early and severe incidence of interstitial lung scleroderma (134, 135).
disease, renal failure, gastrointestinal disease,
and myocardial disease. INVESTIGATIONS
• Absence of anti-centromere antibodies. Renal size on ultrasound is usually normal. In
diffuse cutaneous systemic sclerosis anti-centro-
Subgroup two: mere antibodies are usually absent. Anti-Scl 70
• Limited cutaneous systemic sclerosis antibodies are found in 30–60% of cases.
(CREST syndrome).
• Isolated Raynaud’s phenomenon for years. HISTOLOGY
• Scleroderma limited to hands and feet. The earliest changes in the arcuate and inter-
• Late incidence of pulmonary hypertension, lobular arteries are of intimal proliferation and
skin calcinosis, and telangiectasia. edema, followed by perivascular fibrosis. There
• High incidence of anti-centromere antibodies. may be fibrinoid necrosis affecting the small
arteries and arterioles indistinguishable from the
Subgroup three: changes of acclerated hypertension. The glom-
• Scleroderma sine scleroderma. erular changes are secondary to ischemia.
• Visceral disease without cutaneous involve-
ment. PROGNOSIS
Scleroderma renal crisis, untreated, will lead to
EPIDEMIOLOGY end-stage renal failure and death from accel-
In the US the incidence is about 10 new erated hypertension. However, treatment with
cases/million/year. The average age of onset ACE inhibitors can lead to recovery of renal
is 30–50 years, and is much more common in function even after dialysis has been initiated.
females. There is an association with HLA DR3,
DR5 and C4 null alleles. MANAGEMENT
Avoidance of cold and calcium channel blockers
ETIOLOGY AND PATHOGENESIS is useful for managing Raynaud’s phenomenon.
The etiology of scleroderma is poorly under- Patients with diffuse cutaneous systemic sclerosis
stood. One interesting hypothesis is that in should have their blood pressure and creatinine
some women it may be triggered by fetal cells clearance measured regularly for any sign
causing a graft versus host type disease. What- of deterioration. Various immunosuppressive
ever initiates the process there is overactivity of agents have been tried and much current
fibroblasts and endothelial cells leading to interest is focussed on mycophenolate mofetil
increased production of connective tissue. and sirolimus.
Scleroderma renal crisis is probably caused when
a Raynaud’s type renal vasoconstriction is
superimposed on more chronic structural
changes to the vessels.
 SCLERODERMA 93

134

134 Scleroderma of the face.

135

135 Scleroderma of the hands.

94 DISEASES AFFECTING THE RENAL VASCULATURE

Hemolytic–uremic syndrome (HUS)

DEFINITION INVESTIGATIONS
Most patients with HUS have different clinical Thrombocytopenia and hemolytic anemia are
features from patients with thrombotic throm- found. Fragmented red blood cells, schistocytes,
bocytopenic purpura (TTP), although some are found in the peripheral blood film (136).
patients may be difficult to differentiate. Both Markers of hemolysis include elevated lactate
conditions cause a microangiopathic hemolytic dehyrogenase (LDH), unconjugated bilirubin
anemia and thrombocytopenia, with HUS more levels and reticulocyte levels, and low hapto-
commonly causing renal failure and TTP neuro- globin levels.
logic symptoms. HUS is classified into typical
diarrhea associated D+, or atypical D- forms. HISTOLOGY
HUS/TTP cause thrombosis of intrarenal
EPIDEMIOLOGY AND ETIOLOGY vessels in the absence of cellular inflammation.
D+ HUS occurs mainly in young children, but In D+ HUS there is mainly glomerular capillary
can occur in adults. It is usually caused by thrombosis, whereas in other forms there is
ingestion of meat containing E. coli 0157:H7. predominant involvement of the small arteries
This produces shiga-like toxins which bind to with a florid intimal mucoid proliferation of
a glycolipid receptor, galactotriosylceramide arteries and arterioles with onion-skinning and
(Gb3) on renal endothelial cells, and trigger thrombosis (137–139). Acute tubular necrosis
endothelial damage. D- HUS may be inherited occurs in proportion to the vascular pathology.
or associated with Streptococcus pneumoniae Immunohistochemistry shows fibrin in areas of
infection, HIV, pregnancy, oral contraceptives, thrombus formation, but no immunoglobulin
systemic lupus erythematosus especially with deposition. Electron microscopy shows a charac-
anti-phospholipid antibodies, cyclosporine teristic area of electron lucency between the
(cyclosporin) and tacrolimus, mucin-secreting basement membrane and the swollen endo-
carcinoma, and mitomycin-C. TTP is now thelium (140).
thought to be due either to a genetic deficency
of von Willebrand factor converting enzyme or PROGNOSIS
to auto-antibody production directed against D+ HUS has a current mortality of 6%, and
this enzyme, possibly triggered by infection. complete recovery of renal function normally
occurs within 2 or 3 weeks. In adults with HUS,
PATHOGENESIS prognosis is worse. Older age is associated with
Endothelial injury leads to a prothrombotic increased mortality in the acute phase, whereas
state by a variety of mechanisms, including severe renal involvement at the onset of disease
reduced prostacyclin and nitric oxide produc- is associated with an unfavorable long-term
tion and increased release of von Willebrand renal prognosis.
factor multimers by endothelial cells.
MANAGEMENT
CLINICAL HISTORY AND PHYSICAL Anemia is managed by blood transfusion and
EXAMINATION renal failure by dialysis if necessary. D+ HUS
D+ HUS often occurs after bloody diarrhea has does not respond to FFP or plasma exchange,
started to improve. It presents as weakness, whereas D- HUS should be managed by
pallor, and purpura. Oligoanuria may develop treating any underlying disease and with plasma
together with hypertension and signs of fluid exchange. Platelet transfusions should be
overload. Uremia and hyponatremia may avoided unless there is active bleeding, because
cause neurologic symptoms such as confusion there is a risk of accelerating the process.
and seizures. Familial HUS recurs commonly after renal
transplantation.
 HEMOLYTIC–UREMIC SYNDROME (HUS) 95

136 137

136 Blood film showing fragmented red cells 137 Occlusive mucoid intimal proliferation in an
(under oil immersion x500). interlobular artery. Light microscopy (MS x250).

138 139

138 Glomerulus showing arteriolar thrombus 139 Thrombotic thrombocytopenic purpura.

(arrow). Light microscopy (MS x400). Glomerulus showing arteriolar (arrow) and
capillary tuft thrombus (arrow head). Light
microscopy (MS x400).

140

140 Glomerular capillary showing a wide area of

subendothelial lucency (arrow). Electron
microscopy (x5000).
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Chapter Six
97

Renal infections
and structural
abnormalities
• Acute pyelonephritis

• Xanthogranulomatous pyelonephritis

• Malakoplakia

• Renal tuberculosis

• Two unusual renal infections

• Vesicoureteric reflux and reflux nephropathy

• Urinary tract obstruction

• Congenital anomalies of the urinary tract

• Renal calculi

• Retroperitoneal fibrosis

• Medullary sponge kidney

98 RENAL INFECTIONS AND STRUCTURAL ABNORMALITIES

Acute pyelonephritis

DEFINITION immersion field on a Gram-stained field of

Acute pyelonephritis is an infection of the renal uncentrifuged urine), and the presence of white
parenchyma usually by bacteria which have blood cell or bacterial casts confirms renal
ascended the urinary tract. Renal abscesses are parenchymal invasion (141). Urinalysis sticks
usually caused by hematogenous spread to detect white cells by measuring leucocyte
the kidney. esterase, and bacteriuria by the demonstration
of nitrites produced by the bacterial reduction
EPIDEMIOLOGY AND ETIOLOGY of nitrate normally present in urine. Blood and
Acute pyelonephritis, like acute cystitis, is much urine cultures must be performed. Significant
more common in females than in males. Risk bacteriuria is conventionally defined as the
factors include sexual intercourse, instrumenta- presence of 105 or more of the same organism
tion of the urinary tract, structural abnormalities per ml. However, many patients are sympto-
of the urinary tract including obstruction and vesi- matic with lower bacterial counts.
coureteric reflux, pregnancy, diabetes mellitus, and Ultrasound shows renal enlargement and is
asymptomatic bacteriuria. Urinary tract infections mainly useful at excluding obstruction. Intra-
usually occur in males aged over 40 years and are venous urography is indicated after acute pye-
often associated with prostatic disease or urinary lonephritis has been treated if the episode has been
tract calculi. The most common pathogens are severe, slow to resolve, or relapsing. It provides
organisms that are normal bowel flora, Escherichia excellent imaging of the calyces, pelvis, and ureter.
coli, Proteus, Pseudomonas and Klebsiella species. Intravenous urography is good at detecting
Approximately 10–15% of infections are due to obstruction, stones, papillary necrosis, or stones.
Gram-positive organisms, mainly staphylococcal In severe cases there may be a solid inflam-
species and Enterococcus fecalis. matory mass without drainable pus, termed
acute focal bacterial pyelonephritis, which can
PATHOGENESIS progress to intrarenal and perirenal abscess
The first step is colonization of the lower vagina formation which is best imaged by CT.
and periurethral area with uropathogenic bacteria Emphysematous pyelonephritis is a rare form
originating from the gut flora, followed by trans- of acute pyelonephritis, found most often in
urethral passage of the bacteria and bladder diabetics and alcoholics, that is best imaged by
infection. Whether bacteria ascend the urinary tract CT (142).
to cause acute pyelonephritis is due to a poorly-
understood interplay between host defences and HISTOLOGY
bacterial virulence. The renal medulla is the first Renal biopsy is rarely indicated in acute pye-
area of renal parenchyma to be infected. lonephritis. Histologic appearances are of pus-
filled abscesses within the cortex and medulla.
CLINICAL HISTORY AND PHYSICAL If associated with an ascending infection, pus
EXAMINATION will be seen radiating up from the pelvis within
Patients usually present with high fever, rigors, collecting ducts and tubules.
loin pain and usually lower tract symptoms of
dysuria, urgency, and frequency. Bacteremia and PROGNOSIS
septic shock may develop, usually in association Acute pyelonephritis in patients with normal
with obstruction or immunosuppression. upper tracts is usually easily treated and leaves
no permanent structural or functional damage.
DIFFERENTIAL DIAGNOSIS Renal infection associated with obstruction or
The symptoms and signs of acute pyelonephritis stones may lead to irreversible renal damage.
may be mimicked by obstructive uropathy, acute
glomerulonephritis, renal infarction, pneu- MANAGEMENT
monia, acute pancreatitis, and other intra- Parenteral antibiotics are needed for patients
abdominal conditions. with obstruction or stones, and in older patients
in whom sepsis is more common. Obstruction
INVESTIGATIONS must be dealt with as a medical emergency. Oral
Urine microscopy reveals pyuria (more than five antibiotics can be given to younger patients who
white blood cells/high-powered field) and have no evidence of systemic sepsis and no
bacteriuria (one or more bacterium per oil complicating factors.
 ACUTE PYELONEPHRITIS 99

141

141 Urine microscopy demonstrating a white cell cast.

142

142 CT scan in a patient with bilateral emphysematous

pyelonephritis demonstrating grossly enlarged kidneys with
air within the parenchyma (arrows).
100 RENAL INFECTIONS AND STRUCTURAL ABNORMALITIES

Xanthogranulomatous pyelonephritis

DEFINITION INVESTIGATIONS
Xanthogranulomatous pyelonephritis is charac- Urinalysis shows pyuria and microscopic hema-
terized by chronic granulomatous infiltration turia. Urine culture is usually positive. Anemia,
of the kidney with prominent collections of leucocytosis and abnormal liver function tests
foam cells. are often found. Intravenous urography shows
an enlarged kidney usually associated wiith
EPIDEMIOLOGY AND ETIOLOGY calculi; the kidney is usually nonfunctional, but
It mainly affects females and is most common calyceal distortion may be evident. CT demon-
in the elderly. strates multiple low attenuation areas of soft
tissue density within the kidney surrounded by
PATHOGENESIS thickened parenchyma (143). Biopsy and cul-
Most often, infection is caused by Proteus ture may be necessary to confirm the diagnosis.
mirabilis, but other bacteria may also be present
so that the typical histology is not related to any HISTOLOGY
specific organism. The kidney is enlarged. The cut surface appears
yellow and there may be multiple abscesses.
CLINICAL HISTORY AND PHYSICAL There is inflammation around the kidney. The
EXAMINATION yellow areas consist of sheets of large foamy
Xanthogranulomatous pyelonephritis usually lipid-containing macrophages, neutrophils,
presents with loin pain, fever, weight loss, and plasma cells, and necrotic debris (144).
general malaise. A renal mass may be palpable.
PROGNOSIS AND MANAGEMENT
DIFFERENTIAL DIAGNOSIS Usually irreversible renal damage has been done
Renal cell carcinoma and renal tuberculosis are by the time of diagnosis and nephrectomy is the
the main differential diagnoses. treatment of choice. Fortunately subsequent
involvement of the contralateral kidney does not
seem to occur.

143 144

143 CT scan in a patient with xanthogranulo- 144 Xanthogranulomatous pyelonephritis. Large

matous pyelonephritis affecting the left kidney. numbers of foamy lipid laden macrophages
There is a calculus in the lower pole of the left (arrow). Light microscopy (H+E x400).
kidney (arrow) with a soft tissue inflammatory
mass surrounding the posterior aspect of the
left lower pole (arrowheads). Also note the
low-density lipid (open arrows) replacing the
parenchyma of the left kidney.
 MALAKOPLAKIA 101

Malakoplakia

DEFINITION HISTOLOGY (145–147)

Malakoplakia is a rare condition which usually The renal parenchyma is replaced by collections
affects the bladder but can affect the ureters and of large macrophages. These may contain
kidneys. It is characterized by aggregates of round, laminated, basophilic bodies termed
macrophages containing inclusion bodies. Michaelis–Gutman bodies.

EPIDEMIOLOGY AND ETIOLOGY PROGNOSIS

It is more common in females and the elderly. Untreated renal impairment will progress, but
after treatment with antibiotics renal function
PATHOGENESIS will stabilize or improve.
Malakoplakia is usually associated with E.coli
infection, and is thought to be a result of a MANAGEMENT
defect in bactericidal function of macrophages. Treatment is with a 6-week course of antibiotics
followed by low-dose prophylaxis for at least
CLINICAL HISTORY AND PHYSICAL 12 months. There is some evidence for Vitamin
EXAMINATION C and cholinergic agents being of benefit.
Lower urinary tract malakoplakia usually pre-
sents with urinary frequency, urgency or hema-
turia. Renal malakoplakia may present with renal
impairment and fever. 145

DIFFERENTIAL DIAGNOSIS
This is similar to xanthogranulomatous pyelone-
phritis.

INVESTIGATIONS
Renal imaging will often show enlarged kidneys.
Histology is necessary to make a diagnosis.

145 Gross specimen of malakoplakia.The cut

surface contains cream-colored nodules surrounded
by normal parenchyma. Microscopy of the nodules
shows malakoplakia.

146 147

146 A relatively normal glomerulus is seen top 147 High power micrograph showing numerous
right; tubules are replaced by a dense Michaelis–Gutman bodies (arrow). Light
mononuclear cell infiltrate, rich in plasma cells. microscopy (PAS x1000).
Light microscopy (H+E x250).
102 RENAL INFECTIONS AND STRUCTURAL ABNORMALITIES

Renal tuberculosis

DEFINITION 148
About 20% of all cases of extrapulmonary tuber-
culosis involve the genitourinary tract. In the
West, most cases are due to Mycobacterium
tuberculosis.

EPIDEMIOLOGY AND ETIOLOGY

Renal tuberculosis is more common in men, and
has a peak incidence in the fifth decade. There
is a latent period of months to decades between
the primary infection and diagnosis of renal
tuberculosis. Since the 1980s the incidence has
been increasing, partly due to the AIDS
epidemic. About 4–8% of patients with pul-
monary tuberculosis will develop genitourinary
tuberculosis.

PATHOGENESIS
Following the transmission of tuberculous
infection by inhalation or ingestion, a primary
focus develops which usually heals spon-
taneously. However, the primary infection often
causes a silent bacillemia which seeds to the INVESTIGATIONS
kidneys amongst other organs, leading to Urinalysis shows sterile pyuria and microscopic
bilateral granulomatous glomerular involve- hematuria. Renal impairment is rare unless there
ment. As delayed hypersensitivity develops, is bilateral ureteric stricturing. The key test is
these lesions may resolve or progress slowly by urine culture of early-morning urine samples.
rupturing into the tubular lumen and causing Abdominal X-ray may show renal calcification.
medullary granulomas. These lesions caseate Intravenous urography at an early stage of
producing tumor-like masses called tubercu- disease shows calyceal blunting, and at a later
lomas, cavitating lesions and calyceal amputation stage destruction of the papillae and multiple
(148). Seeding of the urine may result in in- ureteric strictures. CT is useful in the investi-
volvement of the urothelium of the renal pelvis, gation of a nonfunctioning kidney. Renal biopsy
ureter, and bladder as well as the genital organs. is not usually indicated, but histology will show
a caseating interstitial nephritis (149, 150).
CLINICAL HISTORY AND PHYSICAL
EXAMINATION PROGNOSIS
Considerable tissue destruction may have occur- Complications include formation of abscess
red before symptoms develop. Some patients are cavities which may become secondarily infected
asymptomatic and are diagnosed during the with pyogenic organisms, hemorrhage, and
investigation of sterile pyuria. In symptomatic fistula formation. Renal failure may result from
patients, the commonest symptoms are fre- bilateral obstruction. Hypertension may be
quency, dysuria, loin pain, and hematuria. Con- caused by a nonfunctioning kidney.
stitutional symptoms are usually slight. Physical
examination is often unremarkable. MANAGEMENT
Genitourinary infections by sensitive organisms
DIFFERENTIAL DIAGNOSIS are treated with 6 months of isoniazid and
The differential diagnosis of the symptoms of rifampin (rifampicin), and pyrazinamide for the
lower urinary tract disease includes acute bac- first 2 months. If the organism is isoniazid
terial infections and neoplasia. The differential resistant, at least four drugs are given. Progressive
of a renal mass includes renal cell carcinoma and ureteric strictures require reconstructive surgery.
xanthogranulomatous pyelonephritis. Nephrectomy may be indicated for sepsis, hemorr-
hage, intractable pain, inability to sterilize the urine
with drugs, and new onset severe hypertension.
 TWO UNUSUAL RENAL INFECTIONS 103

148 Opposite. Late caseous and ulcerative 149

tuberculosis. Cut surface shows middle calyceal
system completely replaced by a tuberculous
abscess containing chalky caseous pus.The upper
pole shows scarring and cavitation.The ureter is
distended with a stricture at the lower end.

149 Tuberculosis showing widespread tubular

destruction with a caseating granuloma and a
Langerhans giant cell (arrow). Light microscopy
(H+E x150).

150 Ziehl-Neelsen stained section showing 150

acid fast bacilli (arrows). Light microscopy
(Ziehl-Neelson x400).

Two unusual renal infections

SYPHILITIC GUMMA OF KIDNEY (151) HYDATID CYST OF KIDNEY (152)

151 152

151 The kidney is occupied by a massive gumma

in which irregular caseous zones of gummatous
necrosis lie embedded in dense scar tissue. 152 Half the kidney is occupied by a large,
Microscopy shows necrosis with infiltrating opened leathery cyst, the external capsule, from
lymphocytes and macrophages. which the internal hydatid has been removed.
104 RENAL INFECTIONS AND STRUCTURAL ABNORMALITIES

Vesicoureteric reflux and reflux nephropathy

DEFINITION INVESTIGATIONS
Primary vesicoureteric reflux is a common con- Fetal ultrasonography can detect hydronephro-
genital condition with a probable autosomal sis in utero and neonates who have persistent
dominant inheritance with variable penetrance. upper tract dilatation should have micturating
The end result is reflux nephropathy which may cystourethography performed. This can be per-
present with urinary tract infections, hyper- formed with radiologic contrast (153) or radio-
tension, proteinuria, or renal impairment. nuclides. These techniques allow assessment of
Reflux nephropathy has replaced the term the severity of reflux. Intravenous urography is
‘chronic nonobstructive atrophic pyelonephritis’ the traditional method for imaging reflux
to describe the small, irregularly-scarred kidney nephropathy. There is usually reduced renal size,
which occurs in this condition. This is a better and localized thinning of the renal parenchyma
name because it recognizes the importance of associated with clubbing and dilatation of the
vesicoureteric reflux, and does not imply bac- directly underlying calyx due to contraction of
terial infection, the role of which is controversial. the renal papilla (154). DMSA scans are very
sensitive for detecting scars and also reliably
EPIDEMIOLOGY AND ETIOLOGY measure single kidney function (155).
Studies of affected families suggest a single
autosomal dominant gene to be reponsible for HISTOLOGY
vesicoureteric reflux. The gene for this condition The macroscopic features are of coarse seg-
remains to be discovered. The prevalence of mental scarring (156), most prominent at the
primary vesicoureteric reflux is uncertain. poles. The scars are related to the dilated calyx.
Studies vary from 0.4–9.0% of the otherwise In the scarred areas there is tubulointerstitial
normal infant population. Reflux nephropathy fibrosis and often a lymphocytic infiltrate. In
is probably responsible for about 10% of patients other areas there may be appearances of focal
reaching end-stage renal failure. These patients and segmental glomerulosclerosis which is a
usually require renal replacement therapy in the result of glomerular hyperfiltration in the rem-
second or third decade. nant nephrons.

PATHOGENESIS PROGNOSIS
Primary vesicoureteric reflux is the backflow of Some kidneys subjected to vesicoureteric reflux
urine through the vesicoureteric junction (VUJ) will become progressively damaged, whereas
due to shortness of the submucosal segment of others will be unaffected. The severity of reflux
ureter, probably as a result of congenital lateral is the major risk factor for renal parenchy-
ectopia of the ureteric orifice. As a child grows mal damage.
the intravesical ureter lengthens and reflux
decreases with age. Renal damage is associated MANAGEMENT
with intrarenal reflux; urine under high pressure Children with vesicoureteric reflux should be
is forced back up the collecting ducts. This may placed on long-term antibiotic prophylaxis as
be sufficient to initiate the scarring process. this has been shown to reduce progression to
Bacterial infection probably accelerates the renal failure. In general surgery has not been
scarring. Much of the damage caused by reflux shown to be of benefit except in the most severe
occurs in utero or in the first months of life. grades of reflux. Siblings of affected children
Another theory is that the abnormal renal should be screened for the condition.
development is a form of renal dysplasia.

CLINICAL HISTORY AND PHYSICAL

EXAMINATION
Reflux nephropathy may present with recurrent
urinary tract infections, nocturnal enuresis,
hypertension, proteinuria, renal impairment, or
with asymmetric kidneys on renal imaging.
 VESICOURETERIC REFLUX AND REFLUX NEPHROPATHY 105

153 154

153 Micturating cystourethrogram showing gross 154 Intravenous pyelogram of a 9-year-old female
unilateral reflux. presenting with recurrent urinary tract infections.
Bilateral vesicoureteric reflux is present, with
cortical scarring and calyceal dilatation.

155 DMSA scan showing bilateral severe renal 155

scarring.

Posterior view
Individual functions
Left 78% Right 22%

156 Chronic pyelonephritis.The kidneys are 156

unequal in size, with scarring of the cortex.
106 RENAL INFECTIONS AND STRUCTURAL ABNORMALITIES

Urinary tract obstruction

DEFINITION present with renal failure. Repeated urinary tract

Obstructive uropathy describes the structural infections, especially in a male, should raise the
changes in the urinary tract that impair outflow possibility of obstruction. Hypertension is com-
of urine. Obstructive nephropathy refers to the mon in acute and chronic obstruction.
renal disease that results from impaired flow of
urine. Hydronephrosis refers to dilatation of the DIFFERENTIAL DIAGNOSIS
renal pelvis; it may occur in the absence of The differential of complete anuria includes
obstruction, for example in vesicoureteric reflux severe acute glomerulonephritis and bilateral
or pregnancy. Obstruction may be acute, for renal arterial occlusion.
example due to a stone, or sloughed papilla or
chronic, e.g. due to congenital conditions. INVESTIGATIONS
Obstruction as a cause of acute renal failure Ultrasound is the first-line investigation as it is
(ARF) is covered in Chapter 10, p. 170. noninvasive and will detect dilatation of the
renal pelvis (157). It does not distinguish
EPIDEMIOLOGY AND ETIOLOGY between dilated obstructed systems and
Obstructive uropathy is most common at the nonobstructed distended systems. Furthermore,
extremes of life. In early childhood it is a result not all cases of acute obstruction will have
of congenital abnormalities of the urinary tract. dilated systems.
In elderly men it is usually due to prostatic Plain abdominal X-rays with tomograms will
disease. Obstruction may be caused by lesions detect radio-opaque stones (90%). Intravenous
within the lumen or the wall of the urinary tract urography may help to define the site, degree,
or by extrinsic compression (Table 8). and cause of obstruction (158) but care needs
to be taken in patients with renal impairment,
PATHOGENESIS myeloma, and diabetes mellitus because of the
Acute obstruction leads to increased ureteric nephrotoxicity of radiocontrast dye. In cases of
pressure, and briefly increased renal blood flow acute obstruction the obstructed kidney is
before this declines. The kidney becomes enlarged and smooth in outline, the nephro-
edematous and hemorrhagic. Histologically gram is delayed and dense, and the ureter may
there is tubular dilatation. Chronic obstruction be dilated down to the level of obstruction. In
causes thinning of the renal parenchyma prob- long-standing obstruction there is generalized
ably as a result of raised back-pressure and renal thinning of the renal parenchyma and calyceal
ischemia, and dilatation of the renal pelvis. His- dilatation. Spiral CT is sensitive for detection of
tologically there is tubulointerstitial fibrosis, renal calculi and CT is necessary to define retro-
dilated tubules, and global sclerosis of some peritoneal and pelvic lesions.
glomeruli. If bacterial infection is present rapid Furosemide (frusemide) renography is help-
destruction of the renal substance can occur. ful in distinguishing between a nonobstructed
dilated collecting system and true obstruction
CLINICAL HISTORY AND PHYSICAL (159, 160).
EXAMINATION
Acute upper tract obstruction causes pain in the PROGNOSIS
loin which typically radiates to the groin. Pain This clearly depends on the site, duration and
is exacerbated by a high fluid intake, alcohol, or cause of obstruction. Infection will rapidly
diuretics. In children the kidney may be palp- destroy the renal parenchyma.
able. In the presence of infection there is fever
and increased loin tenderness. Complete anuria MANAGEMENT
develops only if there is complete bilateral If infection is present, obstruction must be
obstruction of a single functioning kidney. If relieved immediately, usually by the insertion of
obstruction is incomplete there may be polyuria. a percutaneous antegrade nephrostomy, and
In the presence of intermittent obstruction broad-spectrum antibiotics. Stones of <5 mm
there may be alternating polyuria and anuria. (0.2 in) usually pass spontaneously. About 50%
Lower tract obstruction usually causes hesitancy of 5–7 mm (0.2–0.3 in) stones will pass. Larger
in starting urination, weak stream, terminal stones require intervention either by lithotripsy
dribbling, and acute urinary retention. Chronic or endourological techniques. Patients with PUJ
obstruction may be asymptomatic and patients obstruction are treated by Anderson Hynes
 URINARY TRACT OBSTRUCTION 107

pyeloplasty. In patients with malignant 157

disease, decisions are made on an indi-
vidual basis about the appropriateness
of intervention.

Table 8 Causes of urinary obstruction

Within the lumen

Calculus
Sloughed papilla
Blood clot
Fungus balls

Within the wall

PUJ obstruction
157 Ultrasound. 158
VUJ obstruction
Hydronephrosis is
Strictures (TB, calculi)
seen with echogenic
Ureteric, bladder tumors
fungal balls within the
Neurogenic bladder
dilated calyces.
Posterior urethral valves
Ureterocele
Urethral stricture
158 Papillary
necrosis (from
Extrinsic compression
analgesic abuse).
Retroperitoneal fibrosis
Intravenous urogram
Retroperitoneal tumors
reveals small
Iatrogenic (ligation)
collections of
Prostatic disease
contrast material of
Cervical carcinoma
various sizes in the
Crohn’s disease
papillae of the right
kidney.

159 160
Right Right

Left Left

0 10 20 0 10 20
Minutes Minutes

Right

Right

Left Left

0 10 20 0 10 20
Minutes Minutes

159 Furosemide- (frusemide-) DTPA renogram 160 Furosemide- (frusemide-) DTPA renogram
demonstrating right pelviureteric junction demonstrating a baggy but nonobstructed right
obstruction.The upper panel pre-frusemide, renal pelvis.The upper panel pre-frusemide, and
and the lower panel post-frusemide.There is the lower panel post-frusemide.
no drainage from the right renal pelvis.
108 RENAL INFECTIONS AND STRUCTURAL ABNORMALITIES

Congenital anomalies of the urinary tract

Malformations of the urinary tract are among the most com- 161
mon of all congenital anomalies. They vary in severity from
noncompatability with life, e.g. bilateral renal agenesis, to
often asymptomatic anomalies, e.g. horseshoe kidney. Con-
genital abnormalities of the kidney and urinary tract are
listed (Table 9), and certain types are illustrated in 161–168.

162

161 Pelvic ectopia. A 163 164

portion of the trunk
of a fetus dissected to
show the right kidney
lying upon the
vertebral column at
the pelvic brim.The
ureter arises from the
anterior aspect of the
organ.The left kidney
and adrenal gland are
in normal position.
Most pelvic kidneys
are asymptomatic, but
may develop
pyelonephritis or be
the cause of an
obstructed delivery.

162 Horseshoe
kidney, present in 1:500 autopsies.The total amount of renal substance is within normal limits, but there
is continuity between the lower poles of each kidney anterior to the aorta.The pelvis looks directly
forward and ureters pass superficial to the median communicating bridge of renal tissue.

163 Unilateral renal dysplasia in a 1-month-old child. Kidney is occupied by large numbers of translucent,
variably sized cysts. Unilateral renal dysplasia is the commonest abnormal abdominal mass palpable in
neonates.There is no mature renal tissue. It is comprised of undifferentiated mesenchyme from which
abortive tubules and primitive glomeruli are formed. Some tubules show cystic dilatation. Nodules of
cartilage and bone may be present.

164 Intravenous pyelogram showing left pelviureteric junction obstruction.

 CONGENITAL ANOMALIES OF THE URINARY TRACT 109

165 Duplex pelvis and kidney. 165 166

Bisected adult kidney of normal size
with separate pelvicalyceal systems
at each pole, each draining via a
separate ureter which fuse later in
the course.The single ureter enters
the bladder normally. Duplex
pelvis/ureter is the commonest
congenital abnormality of the renal
collecting system with some degree
of duplication found in 4–6%
autopsies. It varies from mere
extrarenal bifurcation of the pelvis,
to replication of the entire course of
the ureter with two openings into
the bladder.

166 Posterior urethral valves. Both

kidneys are massively enlarged and
hydronephrotic.The bladder and
ureters are distended
with almost complete 167 168
obstruction of the
membranous urethra.

167 Prune belly

syndrome: baby
showing lack of
abdominal
musculature.

168 Micturating
cystourethrogram in
the same child as
167 showing
megaureters and
megacystis.

Table 9 Congenital abnormalities of the kidney and urinary tract

Renal abnormalities Bladder abnormalities

Agenesis (unilateral or bilateral) Urachus
Hypoplasia (oligomeganephronia, Exstrophy
segmental [Ask–Upmark kidney])
Urethral abnormalities
Ectopia (simple, crossed, horseshoe)
Valves
Dysplasia
Hypospadias
Ureteric abnormalities
Atresia
Duplication
Ectopic
Ureterocoele
Vesicoureteric reflux
110 RENAL INFECTIONS AND STRUCTURAL ABNORMALITIES

Renal calculi

Renal calculi may occur in 12% of the popula- intoxication, immobilization, milk-alkali syn-
tion. They are more common in males, and the drome, and medullary sponge kidney. The
highest incidence is seen in the fifth and sixth majority of stones are idiopathic. Hyperoxaluria
decades. Sixty to seventy per cent of stones seems to be a more important risk factor than
consist of calcium oxalate alone or calcium hypercalciuria. Recurrent stones are common.
oxalate together with calcium phosphate. Pure
calcium phosphate stones occur in about 7%. Pathogenesis
About 10–20% of stones are made of mag- The initial stage is crystal formation due to
nesium ammonium phosphate hexahydrate supersaturation of the urine. Calcium phosphate
(struvite) together with carbonate apatite and may form a nucleus for calcium oxalate crystal-
are a result of urinary infection by bacteria lization. Stones may become anchored at the
producing urease which alkalinize the urine. calyceal tip of renal papillae allowing the stones
Uric acid stones make up 5–10% of all stones to grow.
and cystine stones 1–2%.
Stones may be asymptomatic and discovered Clinical history
by chance when renal imaging is performed. Calcium stones may be asymptomatic and dis-
Renal colic occurs when the stone passes down covered only on coincidental imaging, or may pre-
the ureter. The pain resolves immediately the sent with the passage of a single stone or gravel
stone passes. Loin pain and fever occur when every few days, or with ureteral obstruction.
there is obstruction and infection.
Investigations
CALCIUM STONE DISEASE Radiodense stones are seen on X-ray and spiral
Definition CT (169). Calcium oxalate/phosphate crystals
Calcium-containing stones are the commonest may be seen in the sediment from fresh warm
renal calculi. urine (170). A 24-hour urinary collection
should be performed and volume, calcium,
Epidemiology and etiology creatinine, urate, and oxalate measured.
The main risk factors in calcium stone disease are
a low urinary volume and low pH, a high excre- Management
tion of calcium, oxalate, and uric acid, and a low Patients are advised to drink enough fluid to
level of inhibitors of crystal formation. Underlying allow a urine flow of >3 l of urine per day. Foods
diseases which predispose to stone formation rich in oxalate should be avoided (rhubarb, nuts,
include primary hyperparathyroidism, enteric strawberries, raspberries, tea, and chocolate).
hyperoxaluria, primary hyperoxaluria, renal Thiazides lower urinary calcium excretion.
tubular acidosis, Cushing’s syndrome, vitamin D

169 170

169 Spiral CT showing a calcium-containing renal 170 Urine microscopy showing calcium oxalate
calculus (arrow). crystals (x400).
 RENAL CALCULI 111

INFECTION STONES Management

Definition Treatment is with surgery or shock-wave lithotripsy
The typical infection stone contains magnesium to eliminate the stones and correct any anatomic
ammonium phosphate (struvite) and calcium abnormality. Appropriate antibiotic coverage must
phosphate in roughly equal amounts, together be given. When stone fragments remain, infection
with carbonate. persists and new stones are frequent.

Epidemiology and etiology URIC ACID STONES

The most usual organisms are Proteus mirabilis, Definition
Escherischia coli, or Klebsiella. These bacteria Uric acid stones are formed as a result of either
split urea to ammonia and carbon dioxide which uric acid overproduction and hyperuricosuria
leads to alkaline urine leading to precipitation (>4.5 mmol [75.6 mg.dl]/day), a low urine
of calcium phosphate and magnesium am- volume (<1 l) or a persistently acidic urine
monium phosphate. These stones are more (<pH 5.5).
common in females and patients with struc-
turally abnormal urinary tracts in whom urinary Epidemiology and etiology
infections are more common. Very large stones Uric acid stones occur most frequently in mid-
may be formed and have the shape of the renal dle-aged males. Most cases are idiopathic asso-
pelvis and calyces (staghorn calculi) (171). ciated with low urinary pH. Uric acid stones are
These stones harbor infection and lead to pye- most common in Western populations who have
lonephritis and renal damage. a high purine intake. Uric acid stones may occur
in patients with gout and patients who develop
Clinical history hyperuricemia following chemotherapy. Patients
Most patients have recurrent urinary tract infec- with diarrheal diseases or an ileostomy have
tions. The stones may be asymptomatic or cause a metabolic acidosis which predisposes to
recurrent loin pain and fever. stone formation.

Investigations Clinical history

The urine is alkaline and there is minor pro- Symptoms vary from the occasional passage of
teinuria. White cells, bacilli, and struvite crystals gravel to acute ureteral obstruction.
are found on urine microscopy. Urine culture is
usually positive. Plain radiographs demonstrate
the stones.

171

171 Anterior half of kidney has been removed to

display a large staghorn calculus which has
destroyed most of the kidney.
112 RENAL INFECTIONS AND STRUCTURAL ABNORMALITIES

172 Renal calculi (continued)

Investigations
Urine pH is usually <5.5, and uric acid crystals
are seen in a fresh urine sample (172). The
stones are radiolucent on intravenous urography,
but are detected by ultrasound (173, 174).

Management
High water intake together with alkali and
allopurinol is effective not only in preventing new
stone formation but also in dissolving stones.

172 Urine microscopy containing uric acid CYSTINURIA

crystals (x200). Definition
Cystinuria is a hereditary disorder of cystine and
dibasic amino acid (lysine, ornithine, arginine)
transport resulting in formation of cystine stones.
173
Epidemiology and etiology
The disease is inherited as autosomal recessive.
The incidence varies from 1:15,000 in the US
to 1:2500 in Libyan Jews. It affects both
genders with equal frequency, but is more severe
in males. Cystine urolithiasis accounts for 1% to
2% of patients with renal calculi in the US. Two
cystinuria genes have been identified. The rBAT
gene has been mapped to chromosome 2p21.
rBAT expression is present in the straight (S3)
portion of the renal proximal tubule and small
intestine. Over 30 distinct rBAT mutations have
been described and account for patients with
type I cystinuria (fully recessive). The second
cystinuria gene (SLC7A9) has been localized on
chromosome 19q. Mutations in SLC7A9
account for the incompletely recessive forms of
cystinuria (types II and III).
173 Echogenic shadows caused by uric acid
stones (arrow). Pathogenesis
In humans, 99% of cystine in the glomerular
filtrate is normally reabsorbed by transporters
located in the luminal brush border membrane
174 of cells of the proximal tubule. In patients with
cystinuria, a defect of the transepithelial trans-
port of cystine and dibasic amino acids in the
proximal renal tubule results in urinary
excretion of cystine which usually exceeds
400 mg/24 h (>50–200% the normal filtered
load). Cystine is the least soluble of all amino
acids. At a urinary pH between 5.0 and 7.0,
cystine precipitates in the urine when con-
centration levels increase above 300 mg/l.
Current evidence suggests that the SLC7A9
gene encodes for a transmembrane channel
protein that mediates cystine and dibasic amino
174 Urate stones. acids uptake at the luminal surface. The smaller
rBAT protein forms a heterodimeric complex
 RENAL CALCULI 113

with this channel and appears critical for its highly-soluble disulfide compound decreasing
targeting to the luminal membrane. the excretion of cystine. Because of their toxicity
profile, these agents should be reserved for
Clinical history patients in whom increased fluid intake and
The disease is usually first manifested by the urinary alkalinization are insufficient to prevent
development of symptomatic urolithiasis in a formation of new or dissolution of pre-existing
teenager or young adult. However, there have stones. Frequent clinical, radiological, and
been reports of infants and octogenarians pre- laboratory surveillance are important to identify
senting with cystine calculi. Patients commonly complications (e.g. obstruction), and to keep
have multiple cystine calculi or large staghorn patients motivated and maintain long-term com-
calculi. Urinary tract obstruction and infection pliance with therapy. Cystine stones are poorly
are a common association and the causes of fragmented by extracorporeal shock-wave litho-
chronic renal failure in these patients. tripsy. Relief of urinary tract obstruction fre-
quently requires surgical manipulation.
Differential diagnosis
The differential diagnosis is with other causes of Prognosis
stone formation. Cystinuria has also been The prognosis is usually good for patients com-
described to occur as part of a syndrome asso- pliant with a high fluid intake and urine alkalin-
ciated with hyperuricemia and uric acid stones. ization. However, recurrent urinary tract ob-
The diagnosis of urolithiasis in a child or history struction and infection will result in some
of recurrent urolithiasis should prompt the patients developing end-stage renal failure. For
evaluation for cystinuria. these patients, renal transplantation is the treat-
ment of choice.
Investigations
Examination of acid urine shows the typical
cystine crystals, which appear as hexagonal, flat 175
structures (175). Pure cystine stones appear
yellow-brown to sand-colored and granular.
Because of their high sulfur content, pure cys-
tine stones are radiopaque (176). Frequently,
however, cystine stones undergo calcium oxa-
late, calcium phosphate, and magnesium ammo-
nium phosphate deposition. Urine electro-
phoresis or chromatography can be used to
identify lysine, arginine, and ornithine in in-
creased quantities in the urine.
175 Urine microscopy showing cystine
Management stones (x200).
The goal of therapy is to reduce the concentra-
tion of cystine in the urine below supersatura-
tion levels to prevent precipitation, and stone 176
formation. The solubility of cystine is constant
within the range of urinary pH 5.0–7.0 (250
mg/l), but increases significantly at urinary pH
above 7.5 (500 mg/l). Thus, increasing fluid
intake and alkalinization of the urine are the
major therapeutic maneuvers. Fluid intake large
enough to maintain a daily urine volume of >3
l requires overnight hydration, but is essential
for therapeutic success. For alkalinizing the
urine, potassium citrate supplements, rather than
sodium bicarbonate, should be used since
sodium restriction lowers urinary cystine con-
tent. Administration of thiol derivates such as D-
penicillamine and ␣-mercaptopropionylglycine,
cleave cystine into 2 cysteine moieties and 176 Abdominal X-ray showing a large
combine with a molecule of cysteine to form a cystine stone.
114 RENAL INFECTIONS AND STRUCTURAL ABNORMALITIES

Retroperitoneal fibrosis

DEFINITION DIFFERENTIAL DIAGNOSIS

Idiopathic retroperitoneal fibrosis (RPF) is a rare The differential of a retroperitoneal mass caus-
condition in which the ureters in their middle ing ureteric obstruction includes lymphoma and
thirds become embedded in dense fibrous carcinoma. A biopsy of the mass is necessary
tissue, pulled towards the midline and extrinsic to make a definitive diagnosis.
obstruction occurs.
INVESTIGATIONS
EPIDEMIOLOGY AND ETIOLOGY The ESR is usually raised and there is often a
The condition is three times more common in normochromic normocytic anemia. CT will
males than in females. Peak incidence is in the define the peri-aortic mass (177). Biopsy is
fifth decade. Some cases may be related to inflam- usually done at the time of ureterolysis, or
matory abdominal aortic aneurysms. There is a under CT guidance.
rare association with mediastinal fibrosis. Certain
drugs such as methysergide, beta-blockers, and PROGNOSIS
methyldopa have been implicated. Renal prognosis is worse in cases of bilateral
obstruction, which present with advanced
PATHOGENESIS renal failure.
The periaortic fibrosis may represent an
autoimmune response to leakage of material MANAGEMENT
from atheromatous plaques in the diseased Surgical treatment is by ureterolysis. Corti-
aorta. costeroids will cause the peri-aortic mass to
shrink. Relapse is possible after stopping steroid
CLINICAL HISTORY AND EXAMINATION therapy. Life-long follow-up is necessary.
Patients may complain of loin or back pain
(269, 270). The patient is often hypertensive
with significant renal impairment. A hydrocele
is found in 10% of patients.

177

177 Retroperitoneal fibrosis. CT showing an inflammatory

aortic aneurysm causing bilateral ureteric obstruction.
 MEDULLARY SPONGE KIDNEY 115

Medullary sponge kidney

DEFINITION DIFFERENTIAL DIAGNOSIS

Medullary sponge kidney is due to dilatation of This includes nephrocalcinosis, renal tubercu-
the inner medullary collecting ducts with losis, papillary necrosis, and medullary cystic
enlargement of the pyramids, giving a spongy disease.
appearance to the kidney (178).
INVESTIGATIONS
EPIDEMIOLOGY AND ETIOLOGY Intravenous urography is the diagnostic pro-
A few cases are familial but most cases are cedure. In florid cases there is cystic dilatation
sporadic. There is a definite association with of the collecting ducts, giving the ‘bunch of
congenital hemihypertrophy. The pathogenesis grapes’ appearance. There may be stones in the
is unknown. It affects both sexes and presents enlarged papillae (179). Ultrasound will show
usually between 20–45 years. renal calcification.

CLINICAL HISTORY PROGNOSIS

Medullary sponge kidney usually presents as a Progression to end-stage renal failure is rare.
result of urinary tract infection or calcium stone However, some patients may suffer considerable
formation. Renal colic and macroscopic hema- morbidity from the continuous passage of stones
turia are common. Renal function is normal and may become dependent on analgesics.
although there may be decreased urinary con-
centrating ability and distal renal tubular acidosis. MANAGEMENT
A high fluid intake and thiazides for patients
with hypercalciuria are recommended.

178 179

178 Medullary sponge kidney. One-half of

each kidney is shown. Marked scarring of the
subcapsular surface is present. Multiple minute
cysts in the medullary pyramids give the cut
surface the appearance of a sponge.

179 Intravenous pyelogram of a medullary

sponge kidney.
This page intentionally left blank
Chapter Seven
117

Inherited renal
diseases
• Autosomal dominant polycystic kidney disease

• Autosomal recessive polycystic kidney disease

• Nephronophthisis (autosomal recessive

juvenile nephronophthisis)

• Alport’s syndrome

• Nail–patella syndrome

• Congenital nephrotic syndrome

• Fabry disease (Anderson–Fabry disease,

angiokeratoma corporis diffusum)

• Von Hippel–Lindau disease

• Primary hyperoxalurias (PH)

• Cystinosis

• Tuberous sclerosis complex (TSC)

118 INHERITED RENAL DISEASES

Autosomal dominant polycystic kidney disease

DEFINITION tensin II, epidermal growth factor, osteopontin,

Autosomal dominant polycystic kidney disease transforming growth factor-`), resulting in
(ADPKD) is a genetically inherited systemic dis- interstitial inflammation and fibrosis.
order characterized by multiple, bilateral renal
cysts (180) associated with cysts in other organs CLINICAL HISTORY
such as liver and pancreas. The disease is characterized by multiple renal and
extrarenal manifestations, but there is significant
EPIDEMIOLOGY AND ETIOLOGY variability in the clinical presentation. Renal size
ADPKD is a common disease with an incidence increases with age with renal enlargement occur-
of 1:1,000 to 1:400. In the US alone there are ring in virtually all patients (182–184). Manifes-
approximately 400,000 patients with ADPKD tations of renal involvement include pain, hema-
and it is estimated that the disease is present in turia, hypertension, and renal insufficiency. Acute
over 10 million patients worldwide. Both gen- flank pain may occur as a result of cyst hemorr-
ders are affected. Mutations in at least two genes hage, infection, or stone. Macroscopic hematuria
give rise to the disease. The PKD1 gene is on occurs in over 40% of patients with ADPKD and
the short arm of chromosome 16 and is respon- may be the presenting symptom. Cyst hemorr-
sible for 85–90% of cases of ADPKD. The hage is frequent. It can present as macroscopic
PKD2 gene maps to the long arm of chromo- hematuria, or with pain and fever simulating
some 4. A third gene for ADPKD exists but its infection of the cyst. In the majority of patients,
location is still unknown. symptoms resolve within 1 week. Persistence of
hematuria, especially if the initial episode occurs
PATHOGENESIS after age 50 years, should prompt exclusion of
The PKD1 and PKD2 genes encode for two underlying neoplasm. Urinary tract infection may
distinct proteins named polycystin 1 and poly- present as cystitis, pyelonephritis, cyst infection,
cystin 2, respectively. The PKD1 gene is a very or a perinephric abscess. If cyst infection is sus-
large gene with 46 exons coding for 4302 amino pected, cyst aspiration under ultrasound or CT
acids. Computer modeling of polycystin 1 predicts guidance may need to be undertaken to confirm
a large extracellular N-terminal domain, multiple the diagnosis and guide selection of appropriate
transmembrane loops, and a C-terminal intracellu- antimicrobial therapy.
lar tail (181). This structure suggests that poly- Renal stones occur in approximately 20% of
cystin 1 may function as a cell membrane receptor patients with ADPKD. In the majority of cases,
involved in cell–cell or cell–matrix interactions. the stones are composed of uric acid and/or
The PKD2 gene contains 15 exons that code for calcium oxalate. CT scan is the procedure of
968 amino acids. Polycystin 2 contains an N- choice to detect radiolucent stones and for
terminal cytoplasmic domain, six transmembrane differentiating stones from tumor or clots. An
domains, and a C-terminal cytoplasmic tail. The important complication of ADPKD is the
resulting protein has similarities to a voltage- development of hypertension. Hypertension
activated calcium channel. It has been experi- precedes the development of renal failure. The
mentally demonstrated that a tail-to-tail inter- prevalence of hypertension increases with age,
action may occur between polycystin 1 and poly- affecting virtually all patients by the time renal
cystin 2, suggesting that the two proteins may failure develops. Patients with ADPKD are at an
function through a common signaling pathway. increased risk for early development of left
Although ADPKD is caused by an inherited ventricular hypertrophy and, therefore, are at
germline mutation, only ~1% of nephrons will increased risk for cardiovascular complications.
develop cysts. A two-hit hypothesis, in which a The most common extrarenal manifestation
somatic mutation is superimposed on a germline of ADPKD is polycystic liver disease (185).
mutation, has been postulated as the mechanism Multiple cysts result in hepatomegaly. Despite
of cystogenesis in ADPKD. this, liver function is preserved. Females are
The mechanism by which ADPKD causes more affected than males, particularly women
renal failure is not clearly understood. It is likely who have had multiple pregnancies, suggesting
to involve several mechanisms including com- that hepatic cyst growth is affected by estrogen.
pression of normal parenchyma by the cysts, Massive liver enlargement can cause symptoms
hypertension, and production of inflammatory by compressing surrounding structures and
factors and growth factors by the cysts (angio- include hepatic venous flow obstruction, inferior
 AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE 119

180 Signal sequence

181
WSC domain
C-type lectin
REJ module
Transmembrane region
G-protein binding
Voltage activated/TRP
channel homology
Leucine rich repeats
PKD repeat
LDL-A related
GPS domain
PLAT – lipid bonding?
Coiled coil
180 Autosomal dominant polycystic kidney
EF hand
disease. Gross specimen of a polycystic kidney.

181 Structural features of polycystin 1 and

polycystin 2 molecules, and possible interaction COOH COOH NH2
of the molecules.

182 183

182 Autosomal dominant polycystic kidney 183 Autosomal dominant polycystic kidney
disease. Ultrasound showing multiple cysts of disease. CT showing asymmetrically enlarged
different sizes. kidneys and polycystic liver.

184 185

184 Autosomal dominant polycystic kidney 185 Large polycystic liver.

disease. Renal MRI.
120 INHERITED RENAL DISEASES

Autosomal dominant polycystic kidney disease (continued)

vena cava compression, and portal vein or bile often asymptomatic and are found incidentally
duct compression. Treatment options to relieve on radiologic studies. Simple renal cysts must
the obstruction include aspiration of the cyst be distinguished from renal cell carcinoma.
and alcohol sclerosis, laparoscopic fenestration, Multiple bilateral renal cysts are uncommon,
or combined hepatic resection and cyst fenestra- and suggest an underlying inherited disease.
tion. Other complications include cyst hemorr-
hage, infection, and rarely cyst rupture. INVESTIGATIONS
Another important extrarenal manifestation In patients with a family history of ADPKD the
of ADPKD is the development of intracranial diagnosis can be established using the renal
aneurysms. The incidence of the aneurysms ultrasonography criteria described above. Link-
varies according to the family history, occurring age genetic analysis can establish the diagnosis
in approximately 5% of patients with a negative at the molecular level but requires other family
family history and 22% of those with a positive members to be available for testing. It can also
family history. The risk of rupture depends on be used for prenatal diagnosis. Direct mutation
the size of the aneurysm, being minimal for analysis is possible in most families with PKD2.
aneurysms <5 mm (0.2 in) in diameter but high In patients with PKD1, direct mutation analysis
for aneurysms >10 mm (0.4 in) in diameter. In is difficult because of the larger size of the gene
addition to intracranial aneurysms, patients with and due to the fact that approximately 75% of
ADPKD can present with other vascular abnor- the PKD1 gene is duplicated at least three times
malities such as aneurysms of the thoracic aorta on chromosome 16.
and coronary artery aneurysms. Other asso-
ciated conditions include valvular heart abnor- HISTOLOGY
malities, most commonly mitral valve prolapse, On gross examination, kidneys are enlarged and
pancreatic cysts, arachnoid cysts, spinal menin- diffusely cystic. Microscopically, there is marked
geal diverticula, and hernias. sclerosis of preglomerular vessels, interstitial
fibrosis, and tubular epithelial hyperplasia (186).
PHYSICAL EXAMINATION Interstitial fibrosis is an early finding, and is
Hypertension is common. Renal size increases present even in patients with normal renal
with age and kidneys become palpable in most function. Microdissection studies demonstrate
cases. Liver enlargement, especially in women, cysts arising from focal dilatation of renal
may be found. Mitral or aortic regurgitation tubules anywhere along the nephron. Epithelial
murmurs are commonly heard. Inguinal and cells lining the cysts are characterized by an
umbilical hernias may be demonstrated. increased nuclear to cytoplasmic ratio, decreased
microvilli on the apical surface, reduced baso-
DIFFERENTIAL DIAGNOSIS lateral folding, and persistent expression of
The diagnosis is relatively straightforward in proteins present in earlier stages of development
patients with a family history of ADPKD. In such as vimentin, clusterin, and PAX2. Micro-
these patients, sonographic diagnostic criteria scopic adenomas have also been described.
include two cysts arising unilaterally or bilat-
erally for individuals <30 years of age, two cysts PROGNOSIS
in each kidney for individuals aged 30–59 years, There is significant variability in the rate of
and at least four cysts in each kidney for those progression of the renal disease, even within
over the age of 60 years. Presymptomatic members of the same family. In approximately
screening by ultrasound before age 20 years is 50% of patients, end-stage renal failure occurs
not recommended because results may not be by the age of 55–75 years. Genetic and environ-
conclusive. In patients without a family history mental factors appear to modulate the rate of
the diagnosis is more difficult because of the progression of renal failure. The disease is
variable clinical phenotype associated with usually milder in patients with mutations in the
ADPKD and because renal cystic disease can PKD2 gene than in patients with mutations in
occur in other systemic diseases such as tuberous the PKD1 gene, who have an earlier onset of
sclerosis complex, von Hippel–Lindau, and hypertension and progression to renal failure.
orofaciodigital syndrome type 1. Simple renal Risk factors associated with progressive renal
cysts are common, especially after the age of failure include PKD1 genotype, male gender,
50 years. Typically, these cysts are unilocular, African-American background, early age at diag-
and located in the renal cortex. Simple cysts are nosis (<30 years), and onset of hypertension
 AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE 121

before age 35 years. Actuarial data indicate that 186

ADPKD patients have a better dialysis outcome
when compared with patients with end-stage
renal failure from other causes.

MANAGEMENT
There is no specific treatment for patients with
ADPKD. Current therapy is directed to control-
ling the renal and extrarenal complications of
the disease. Uncontrolled hypertension accel-
erates the decline in renal function. Hyper-
tension also aggravates target-organ damage,
particularly left ventricular hypertrophy, and
therefore should be tightly controlled. In some
patients, large renal or liver cysts may require
decompression, in order to control pain or com-
plications from local compression (187, 188).
Decompression of renal cysts does not affect the 186 Autosomal dominant polycystic kidney
rate of progression to end-stage renal failure. disease. Light microscopy showing marked cystic
Urinary tract infections or asymptomatic bac- dilatation of the tubules with severe interstitial
teriuria should be treated to prevent retrograde fibrosis and tubular atrophy (H+E x100).
infection of the kidney. Infected cysts may
require percutaneous or surgical drainage.
Screening for intracranial aneurysms is indi- 187
cated in patients with a family history of aneur-
ysm rupture, patients with a previous rupture,
patients with high-risk occupations (e.g. pilots),
development of symptoms, and patients who
need reassurance. Magnetic resonance angio-
graphy is the screening method of choice.
Surgical intervention is indicated for aneurysms
*10 mm (0.4 in) in diameter. Hypertension,
hyperlipidemia, and smoking are risk factors for
rupture of intracranial aneurysm. Transplan-
tation is the treatment of choice for patients
who develop end-stage renal disease.

187 CT scan showing a large left renal cyst.

188

188 Same patient as 187, post-cyst aspiration and

ethanol ablation.
122 INHERITED RENAL DISEASES

Autosomal recessive polycystic kidney disease

DEFINITION decrease in glomerular filtration rate, which starts

Autosomal recessive polycystic kidney disease at the same time as hypertension.
(ARPKD) is an inherited disease characterized by With progression of renal disease, kidneys tend
the association of polycystic kidneys with a biliary to regress in size, and older patients may present
dysgenesis known as ‘congenital hepatic fibrosis’. with relatively small kidneys. Occasionally, large
abdominal mass, oligohydramnios, and pulmonary
EPIDEMIOLOGY AND ETIOLOGY hypoplasia (Potter syndrome) may be present at
ARPKD has an estimated incidence of 1:20,000 birth. Respiratory failure is the immediate cause
live births. The genetic mutation has been map- of death in these patients. Liver involvement is a
ped to the short arm of chromosome 6 (6p21- constant finding in patients with ARPKD. In
22). The polycystic kidney and hepatic disease contrast to the kidneys, liver cysts are not an impor-
1 gene is a complex gene containing 67 exons, tant or common feature of ARPKD. Instead,
with several mRNAs generated by alternative hepatic involvement is secondary to fibrosis of the
splicing. The protein product (fibrocystin) is portal tracts and biliary dysgenesis. Hepatic involve-
massive, containing 4074 amino acids (189). It ment is clinically manifested by the signs of portal
contains a large highly glycosylated extracellular hypertension, usually occurring between 5 and 10
region, a single transmembrane domain and a years of age. Hepatosplenomegaly, as well as hyper-
short cytoplasmic tail containing potential phos- splenism, is usually found in these patients. In some
phorylation sites. It is expressed in the collecting cases, gross cystic dilatations of the intrahepatic
ducts of kidneys, bile ducts, and pancreas. biliary tree can simulate Caroli’s disease. These
patients are at increased risk of recurrent cholangitis.
PATHOGENESIS
The biliary lesion is considered to be the result of PHYSICAL EXAMINATION
an arrest in the normal organogenesis of the intra- In neonates and young infants, palpable ab-
hepatic bile ducts, an abnormality termed ductal dominal masses and hypertension are the signs
plate malformation. As a result, bile ducts persist that most often lead to the diagnosis. In older
in an embryonic form, the portal vein branches children and adolescents, hepatosplenomegaly
abnormally, and progressive portal fibrosis evolves. and signs of portal hypertension predominate.
A similar maturational arrest mechanism has been
postulated to occur in the kidney. DIFFERENTIAL DIAGNOSIS
Although unusual, autosomal dominant polycystic
CLINICAL HISTORY kidney disease (ADPKD) can occur in infants and
ARPKD affects both the kidneys and the liver. children, posing a diagnostic problem, especially
However, clinical presentation is extremely vari- in neonates. Family history, coupled with renal
able, even among members of the same family. ultrasound of the parents, can help to establish the
The majority of patients present with large kidneys correct diagnosis. Other cystic diseases in children
at birth or soon after (190). While cysts are include renal cystic dysplasia, renal cysts asso-
present in 60–90% of their nephrons, liver involve- ciated with multiple malformation syndromes
ment is mild. In other patients, the diagnosis is such as Meckel syndrome, Zellweger syndrome,
not made until after the third to the sixth month Laurence–Moon–Biedl syndrome, several
of life and can be as late as 1–5 years of age. In chromosomal disorders (trisomy 9, 13, 18, and
these patients, renal cysts involve only 10–25% 21), and the contiguous PKD1/TSC2 syndrome.
of their nephrons, but hepatic fibrosis is severe.
Occasionally, ARPKD can be diagnosed for the INVESTIGATIONS
first time in a young adult. In neonates and young Ultrasonography is the method of choice for initial
children, clinical manifestations that suggest the screening. In neonates, renal ultrasound shows
diagnosis include palpable abdominal masses, enlarged, hyperechogenic kidneys, with multiple
hypertension, and urinary tract infections. In older small cysts in the cortex and in the medulla. In
children, signs of hepatic involvement and portal older children, larger cysts alter the renal contour
hypertension predominate. Hypertension devel- and may simulate ADPKD. Ultrasound of the
ops in over two-thirds of the patients. It usually liver shows dilatation of the biliary ducts and signs
begins within the first year of life, and can be of portal hypertension, but no cysts. Ultrasono-
severe. Abnormalities in urinary concentration are graphy has also been used for antenatal screening.
usually present but rarely cause clinical problems. In severe cases, the use of this technique can lead
The majority of patients have a slowly progressive to the diagnosis as early as week 16 of gestation.
 AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY DISEASE 123

However, mild forms may be missed. In families survive the neonatal period usually have initially
with other affected members, genetic linkage relatively well-preserved renal function. After the
analysis can be used for prenatal diagnosis. first few months, the course is variable. Some
children will continue to have adequate renal
HISTOLOGY function, while others will progress to end-stage
The macroscopic appearance will depend on age renal failure. In general, progression of renal failure
at diagnosis. When ARPKD is diagnosed in the is slow and fewer than one-third of cases reach
neonatal period, kidneys can have as much as ten end-stage renal failure before adulthood. For
times their expected weight. Despite their size, children who survive the first year of life, recent
normal kidney shape is symmetrically main- series show a 60–80% probability of renal survival
tained. Multiple 1–2 mm (0.04–0.08 in) cysts at 15 years. The prognosis for the liver involve-
are visible at the tip of large cylindric or fusiform ment is related to the complications of portal
tubule channels that radiate from the calyxes hypertension since hepatocellular function remains
through the entire cortical thickness. Dilated normal long term. Effective management of portal
tubules are also seen in the medulla. In older hypertension, coupled with the widespread use of
patients (>1 year of age) the appearance of the renal and liver transplantation, has resulted in
kidneys changes. Fewer but larger cysts are significant improvement in long-term survival.
present, giving the kidneys an overall bumpy and
irregular appearance that may be indistinguish- MANAGEMENT
able from the pattern in ADPKD. Microscopi- Therapy is supportive and includes careful
cally, neonatal kidneys are composed almost control of blood pressure. Renal transplantation
entirely of cystic tubules (191). There is strong is indicated for patients who develop end-stage
evidence that the cysts originate from collecting renal disease. Portal hypertension needs close
ducts. Later on, the extent of cystic involvement monitoring by serial ultrasound and Doppler
decreases, but progressive glomerular sclerosis, flow studies. Esophageal varices may require
tubular atrophy, and interstitial fibrosis develops. banding or sclerotherapy. In some patients,
portocaval or splenorenal shunt surgery is
PROGNOSIS indicated. Patients with end-stage renal disease
Neonates with severe disease usually die soon after and severe portal hypertension are candidates for
birth from pulmonary insufficiency. Patients who combined kidney and liver transplantation.

189 190

Signal peptide
TIG domain
TIG-like
TMEM2 homology
DKFZ homology
Transmembrane
domain

191

189 Structural features of fibrocystin, the autosomal

recessive polycystic kidney disease molecule.

190 ARPKD.T2-weighted MRI of a 1-year old

child showing massively enlarged kidneys.

191 ARPKD. Light microscopy showing cystic

dilatation of the tubules (H+E x100).
124 INHERITED RENAL DISEASES

Nephronophthisis (autosomal recessive

juvenile nephronophthisis)

DEFINITION undetected until end-stage renal failure has

Juvenile nephronophthisis (NPH), also called developed.
nephronophthisis type 1 (NPH1), is an auto-
somal recessive disorder characterized by PHYSICAL EXAMINATION
chronic tubulointerstitial nephritis and cysts at Apart from growth retardation and pallor
the corticomedullary border of the kidneys. (anemia), which are out of proportion to the
degree of renal insufficiency, the physical
EPIDEMIOLOGY AND ETIOLOGY examination in patients with juvenile nephro-
At least three different loci for the disease have nophthisis is unremarkable.
been identified, NPH1, NPH2, and NPH3,
which correspond to three different forms of DIFFERENTIAL DIAGNOSIS
clinical presentation: juvenile, infantile, and Histopathologically, NPH is similar to medul-
adolescent respectively. NPH1 accounts for lary cystic kidney disease (MCKD). However,
approximately 85% of cases of NPH, and is MCKD is associated with hyperuricemia and
considered the most frequent genetic cause of gout and with a much later age of onset of
end-stage renal disease in children and young ESRD. While patients with ADPKD or ARPKD
adults. The genetic mutation has been mapped usually have significant renal enlargement, with
to chromosome 2q12-q13. In >80% of children cysts distributed uniformly over the entire
with NPH1, the disease is due to a homozygous organ, in NPH cysts occur primarily at the renal
deletion of the gene. Other patients carry a corticomedullary junction, with kidneys typically
point mutation in combination with hetero- maintaining a normal size. NPH1 has been
zygous deletion. The genes for NPH2, and reported to occur in association with nystagmus,
NPH3 have been mapped to chromosomes 9 retinitis pigmentosa and blindness (Senior–
and 3 respectively. Sporadic mutations account Loken syndrome), ocular motor apraxia and
for about one-sixth of cases. retinal degeneration (Cogan syndrome), con-
genital liver fibrosis, and bone abnormalities,
PATHOGENESIS particularly with cone-shaped epiphyses.
The product of the NPH1 gene is a protein of
unknown function that contains a src-homology INVESTIGATIONS
3 domain called nephrocystin. Because src- Urinalysis is normal and proteinuria is usually
homology 3-containing proteins are part of focal absent. On renal ultrasound kidneys appear nor-
adhesion signaling complexes, it has been mal or reduced in size, with loss of cortico-medul-
suggested that the pathogenesis of NPH might lary differentiation. Thin-section CT scan or MRI
be related to abnormalities in signaling processes examination may detect cysts in the medulla or
at the level of cell–matrix or cell–cell interactions. corticomedullary junction (192). As a consequence
The gene products and the type of genetic of the identification of the NPH1 gene, the
mutations for NPH2 and NPH3 are unknown. molecular diagnosis of patients with NPH1 is now
possible. The presence of a homozygous deletion
CLINICAL HISTORY of the NPH1 gene is diagnostic for the disease.
Children usually present with polyuria, poly- Heterozygous deletion can be detected by
dipsia, and nocturnal enuresis reflecting abnor- fluorescence in situ hybridization, and the specific
malities in the urinary-concentrating mechanism mutation identified by direct sequencing of all
with a salt-wasting nephropathy present in the 20 NPH1 exons. If these tests are unavailable, renal
majority of patients. The onset of the clinical biopsy should make the diagnosis.
manifestations is usually after age 2 years but it
can occur as early as the first few months of life HISTOLOGY
in children with NPH2. Males and females are Histologic findings are similar among the dif-
equally affected. In up to 30% of patients, ferent forms of NPH. Macroscopically, cut sec-
anemia precedes the development of renal fail- tions show a variable number (5–50) of small (up
ure. Similarly, growth retardation that is dispro- to 2 cm [0.8 in] in diameter), spherical, thin-
portional to the degree of renal impairment is walled cysts irregularly distributed along the
common. Hypertension is uncommon. Progres- corticomedullary junction. Similar cysts may also
sive renal failure is insidious, and may remain occur in the deeper medulla and papillae. No
 NEPHRONOPHTHISIS 125

cysts are detected in up to 25% of cases. Micro- PROGNOSIS

scopic examination is characterized by disintegra- NPH commonly results in progressive decline
tion of the tubular basement membrane, tubular in renal function but the median age for reach-
atrophy, and interstitial fibrosis, usually without ing end-stage renal failure varies among the
interstitial cell infiltration. Typically, atrophic different forms of the disease. Patients with
tubules with thickened basement membranes are NPH2 reach end-stage renal disease between
clustered next to areas of viable tubules showing 1–3 years of age, while the age for NPH1 and
dilatation or marked compensatory hypertrophy NPH3 has been determined to be 13 years and
(193). Glomeruli may appear normal or globally 19 years of age, respectively. The clinical course
sclerosed. On microdissection, cysts appear to is similar among members of the same family.
originate from cells of the loop of Henle, distal
convoluted tubules, and collecting ducts. On MANAGEMENT
electron microscopy, the tubular basement mem- Therapy is supportive. Excessive sodium losses
brane appears irregularly thickened. Some may cause orthostatic hypotension and require
tubules may exhibit an abrupt transition from sodium supplementation. Patients who reach
thick to thin basement membrane, a feature that end-stage renal failure are candidates for dialysis
is characteristic of NPH and rarely seen in and transplantation.
other conditions.

192 Juvenile nephronophthisis. Renal 192

MRI. Kidneys are relatively normal in size
and only 2–3 cysts are clearly visible in
each kidney, the largest of which is in
the right kidney and measures 1.5 cm
(0.6 in) in diameter. The remainder of
the cysts are tiny and are localized in
the medulla, while others are peripheral
near the renal capsule.

193 Juvenile nephronophthisis. Light 193

microscopy showing markedly dilated
medullary tubules (H+E x200).
126 INHERITED RENAL DISEASES

Alport’s syndrome

DEFINITION gresses with age, becoming nephrotic in approxi-

Alport’s syndrome (AS) is an inherited disorder mately 30% of patients. Hypertension occurs late
of basement membranes, arising from mutations in the course. Like proteinuria, hypertension is
in type IV collagen. It is characterized by a pro- more common in homozygous males than in
gressive nephritis manifested by hematuria, heterozygous females, but affects both genders
frequently associated with a sensorineural hear- equally in patients with the autosomal recessive
ing loss and ocular abnormalities. form. In males, virtually all progress to ESRD,
often by age 16–35 years. The disease is usually
EPIDEMIOLOGY AND ETIOLOGY mild in heterozygous females but some will
The worldwide incidence is approximately develop end-stage renal failure, usually after the
1:10,000, accounting for up to 2% of children age of 50 years. The rate of progression to end-
with end-stage renal disease. It is seen in all races stage renal failure is fairly constant among
and geographic areas. In at least 80% of the affected males within individual families, but
patients the disease is X-linked. In approximately varies significantly from family to family.
5% of cases, an autosomal recessive pattern of High frequency sensorineural hearing loss
inheritance is found. In a few kindreds, the is present in 30–50% of patients, mainly males.
disease follows an autosomal dominant pattern. Progressive renal failure does occur in patients
without overt hearing loss. Ocular disorders
PATHOGENESIS accompany 15–30% of cases. Of the lens abnor-
In over half of the patients the disease results malities, anterior lenticonus (194) is both the
from a mutation in the COL4A5 gene on the X most frequent and specific. Lenticonus is charac-
chromosome. This gene codes for the _5 chain terized by thinning of the lens capsule resulting
of type IV collagen _5 (IV). A variety of muta- in bulging of the lens substance into the anterior
tions have been described including deletions, chamber, as a result of the defective type IV
point mutations, and splicing errors. Although collagen forming the anterior lens capsule.
the primary molecular defect in AS most Progression of the lenticonus results in increas-
commonly involves the _5 (IV) chain, faulty ing protrusion of the cone into the anterior
assembly of the _3, 4, 5 heterotrimer produces chamber and increasing myopia. Anterior
similar pathologic changes. Failure of normal lenticonus is diagnosed by the characteristic ‘oil
heterotrimer formation is illustrated by the droplet in water’ effect: a dark disk is seen in the
absence of demonstrable _3 chain of type IV center of the pupillary region on indirect
collagen in the glomerular basement membrane fundoscopy. Other ocular lesions said to be
in many patients whose genetic defect is in the characteristic of AS are macular and mid-peri-
gene coding for the _5(IV) chain. In autosomal pheral retinal flecks. Macular flecks are round
recessive AS, homozygous or mixed hetero- whitish or yellowish granulations surrounding
zygous mutations of COL4A3 or COL4A4 the foveal area. In the periphery of the retina
have been described. Mutations causing auto- flecks tend to merge and form larger, irregular,
somal dominant disease have not yet been iden- circular forms. These changes are not associated
tified. Concomitant deletions in parts of the with visual impairment.
COL4A5 and COL4A6 genes occur in familiar
forms of esophageal and genital leiomyomatosis. PHYSICAL EXAMINATION
Overt hearing loss is present in many but not all
CLINICAL HISTORY patients. Anterior lenticonus and retinal flecks
The basis for diagnosis is the presence of progres- are present in a minority of patients.
sive renal disease in a patient with hematuria,
sensorineural hearing loss, and family history for DIFFERENTIAL DIAGNOSIS
AS. Persistent or intermittent microscopic hema- The differential diagnosis involves excluding
turia, with episodes of gross hematuria, is present other causes of microscopic hematuria including
in virtually all affected males. Hematuria may be renal tumors and structural abnormalities of the
exacerbated by exercise or upper respiratory urinary tract. Immunofluorescence studies of
infection. Microscopic hematuria is also common renal biopsies should rule out IgA nephropathy,
in heterozygous females. Dysmorphic red blood membranoproliferative glomerulonephritis, and
cells and red cells casts are commonly seen. Mild other immune complex-mediated glomeru-
proteinuria is present in most cases and pro- lonephritis. Once these have been excluded, the
 ALPORT’S SYNDROME 127

main differential diagnosis is with familial glom- HISTOLOGY (195–197)

erular syndromes, in particular thin basement On light microscopy lesions are nonspecific.
membrane disease. Glomeruli may appear normal or exhibit
thickening of capillary walls along with an
INVESTIGATIONS increase in mesangial matrix. An increased
Absence of the _3 (IV), _4(IV), and _5(IV) number of fetal glomeruli may be present. Foam
chains from GBM and distal TBM occur only in cells may be seen in the interstitium. As the
patients with AS, and are a diagnostic finding on disease progresses, progressive glomerular
renal biopsy. Patients with AS frequently lack sclerosis and interstitial fibrosis develop. Routine
staining with fluoresceine labelled anti-GBM immunofluorescence staining is usually negative.
antibody, and this unique abnormality can be of Diagnostic features are usually seen on electron
help in establishing the diagnosis. In families with microscopy. At an early stage, thinning of the
a previously defined mutation, molecular diagnosis GBM may be the only visible abnormality, and
of affected males or gene-carrying females is may suggest thin basement membrane disease.
possible. In families where mutations have not With time, there is thickening of the GBM with
been defined, genetic linkage analysis can deter- splitting of the lamina densa into several irregular
mine whether an at-risk individual carries the layers that may branch and rejoin, giving a
mutant gene, provided there are at least two other characteristic ‘basket weave’ appearance. The
affected members available for testing. capillary walls show foot processes effacement in
variable degrees. Not all patients with AS have
these characteristic electron microscopic features.

194 195

194 Lenticonus. 195 Large red cell cast (arrow) within a cortical
tubule. Light microscopy (MS x200).

196 197

196 Interstitial foam cells. Light microscopy 197 Splitting and lamellation of the lamina densa
(PAS x250). of the basement membrane (arrow). Electron
microscopy (x2000).
128 INHERITED RENAL DISEASES

Alport’s syndrome (continued)

PROGNOSIS MANAGEMENT
Virtually all as affected males progress to end- There is no specific treatment for AS. Retinal
stage renal disease. In heterozygous females, lesions do not affect vision and required no
the prognosis is usually benign, with most treatment. Lenticonus or cataracts are best
maintaining preserved renal function long treated by removal of the lens with implantation
term. Heterozygous females with a history of of an intraocular lens. Hearing loss is improved
macroscopic hematuria and nephrotic range by the use of hearing aids. Tinnitus is generally
proteinuria are likely to develop progressive unresponsive to any form of therapy. Tight
renal disease. Sensorineural deafness and control of blood pressure and moderate protein
anterior lenticonus are also predictors of poor restriction is recommended to retard the pro-
outcome in affected women. Patients with gression of renal disease, but the benefit is un-
autosomal recessive AS, regardless of sex, tend proven. Peritoneal dialysis, hemodialysis, and
to progress to end-stage renal failure during the renal transplant are used successfully. Trans-
second or third decade of life. planted patients frequently develop anti-GBM
antibodies but the risk of developing an anti-
GBM crescentic nephritis is lower (5–10%).
Alport’s patients who have already lost a graft
due to anti-GBM-mediated nephritis are at very
high risk for recurrence if re-transplanted.

Nail–patella syndrome

DEFINITION clude abnormal pigmentation of the iris, micro-

The nail–patella syndrome is a rare (~1:50,000) cornea, congenital glaucoma, strabismus, or
autosomal dominant disorder characterized by ptosis. Renal involvement is clinically manifested
dystrophic nails, absence or hypoplasia of the in fewer than half of the patients. Proteinuria
patella, skeletal deformities, ocular abnormali- and microscopic hematuria are the most com-
ties, and renal disease. mon findings. Proteinuria is usually low grade
(<3 g/24 h) but it can be nephrotic. Approxi-
ETIOLOGY AND PATHOGENESIS mately 50% of the patients have impaired ability
The syndrome has been linked to mutations in in concentrating and acidifying the urine. Some
the LMX1B gene on chromosome 9. The patients develop mild hypertension.
LMX1B gene appears to be important for
normal skeletal and renal development, but the PHYSICAL EXAMINATION
precise mechanisms for the renal effects of the Nail dysplasia and patellar aplasia or hypoplasia are
LMX1B mutations remains unknown. essential features for diagnosis. The presence of
triangular nail lunulae is a pathognomonic sign.
CLINICAL HISTORY Iliac horns are triangular bony protruberances of
Clinical features include osseous abnormalities, the posterior ilium and may be palpable.
of which the most classical is the absence or
hypoplasia of the patella (198) (60%), nail DIFFERENTIAL DIAGNOSIS
changes (80–90%), ocular changes, and renal The typical ultrastructural changes of the GBM
manifestations (30–40%). The patellae, when of nail–patella syndrome have also been
present, are subject to recurrent dislocation, and described in a new type of genetic GBM disease
can be associated with effusions and osteo- named collagen III glomerulopathy.
arthritis of the knees. Nail changes are bilateral
and symmetric with fingernails, specially the INVESTIGATIONS
thumbs, more commonly affected than toenails. The most common radiologic findings are bilateral
Nails changes include discoloration, koilonychia, iliac horns (199) and hypoplasia or absence of the
absent or dystrophic nails, V-shaped lunulae, or patellae. Humeral and radial abnormalities have
longitudinal ridges. Ocular abnormalities in- also been described including aplasia, hypoplasia,
 NAIL–PATELLA SYNDROME 129

and posterior processes at the distal end of the lucent areas can also be seen in the mesangium.
humerus and hypoplasia of the proximal radial Sometimes, the lucent spaces are found to con-
heads. Iliac horns (osseous spurs extending pos- tain coarse fibrillar densities with the appearance
teriorly from the iliac wings) occur in approxi- and periodicity of collagen, which are better seen
mately 80% of patients and are considered after staining the sections with phosphotungstic
pathognomonic for the disease. Radiologic exam- acid. The fibrils, usually clustered in small collec-
inations have also detected a number of renal and tions, have not been found in any other basement
urinary tract structural abnormalities including membranes except the kidneys. The visceral
dilated calyces and cortical scarring, unilateral renal epithelial foot processes are usually effaced.
atrophy, bifid ureter, unilateral hypoplasia and
contralateral double kidney, duplication of right PROGNOSIS
pyelocalyceal system, and renal stones. Despite proteinuria, renal function is usually
preserved in these patients. However, a few patients
HISTOLOGY (10%) will develop progressive renal failure.
There are no specific features of nail–patella syn-
drome on light or immunofluorescence micros- MANAGEMENT
copy. On electron microscopy, the glomerular There is no specific available treatment for this
basement membrane is irregularly thickened and disease, except for the usual recommendations
contains multiple areas of increased lucency for management of chronic renal failure, and
(described as a ‘moth-eaten’ appearance). These surgical correction of bone deformities.

198 Absent patella in nail–patella 198

syndrome.

199 Pelvis X-ray showing 199

bilateral iliac horns.
130 INHERITED RENAL DISEASES

Congenital nephrotic syndrome

DEFINITION Table 10 Causes of congenital nephrotic

Congenital nephrotic syndrome (CNS) is defined syndrome
as the presence of nephrotic syndrome at the time
of birth or within the first 3 months of life.
• 'Classic' or Finnish type
EPIDEMIOLOGY AND ETIOLOGY • Diffuse mesangial sclerosis (DMS)
CNS can occur as a manifestation of a number • Idiopathic
of disorders (Table 10). The ‘classic’ or Finnish • Denys–Drash syndrome (DMS, male
type is the most common and best known of all pseudohermaphroditism, and
the types of CNS. It is inherited as an autosomal Wilms tumor)
recessive trait, with an incidence of 1:8000 births • Galloway–Mowat syndrome (DMS,
in Finland. The incidence is significantly lower microcephaly, gyral abnormalities, and
in other countries. The disease is caused by developmental delay)
mutation on a novel 29-exon gene (the NPHS1 • Idiopathic focal and segmental
gene) localized to chromosome 19q13.1, coding glomerulosclerosis (FSGS)
for a transmembrane 1241 amino acid protein • Genetic disorders
of the immunoglobulin superfamily termed • Mucopolysaccharidosis
nephrin. The two most common mutations in • Infantile sialic acid storage
the NPHS1 gene have been named Fin-major • Carbohydrate-deficient-glycoprotein
and Fin-minor. The Fin-major is a frameshift syndrome
mutation resulting in a truncated protein of only • Nail–patella syndrome
90 amino acids. Fin-minor mutation is a non- • Lowe’s syndrome
sense mutation leading to a truncated 1109- • Congenital infections
residue protein. Sixty-five per cent of the Finnish • Syphilis
patients have been found to be homozygous for • Cytomegalovirus
the Fin-major mutation, while 8% are homo- • Toxoplasmosis
zygous for Fin-minor. A number of other muta- • Mercury
tions, including insertions, deletions, nonsense • Infantile systemic lupus erythematosus
and missense mutations have been described in
non-Finnish patients.

PATHOGENESIS Due to the severity of the nephrotic syndrome,

Nephrin is produced by glomerular podocytes infections are common, and account for up to
and it is localized at the slit diaphragm. Electron one-third of the overall mortality. Thrombo-
microscopy studies of kidney samples obtained embolic complications are also frequent.
from patients with Fin-major and Fin-minor
mutations show abnormalities of the slit dia- PHYSICAL EXAMINATION
phragm. This suggests that nephrin is an impor- Edema and abdominal distension, mainly caused
tant component of the slit diaphragm and plays by ascites, is present at birth in 25% of cases.
a crucial role in maintaining glomerular perm- These signs develop in an additional 25% of
selectivity. Recent studies suggest that nephrin cases during the first week of life, and full-blown
is also involved in the development of pro- nephrotic syndrome is manifested in all patients
teinuria in other glomerular disease. by the age of 3 months. With time, reduced
subcutaneous tissue and muscular wasting is
CLINICAL HISTORY clearly visible.
The classic findings in CNS of the Finnish type
include prematurity, large placenta, and pro- DIFFERENTIAL DIAGNOSIS
teinuria, which already begins in utero. Due to The main differential diagnosis is with diffuse
the large placenta, difficulties at delivery are mesangial sclerosis (DMS) and FSGS. In patients
common, including postural deformities and with DMS, nephrotic syndrome usually manifests
malpresentation. Progressive ascites refractory after the second month of life. Progression to end-
to diuretics develops and interferes with feeding, stage renal failure with hypertension by the age of
resulting in severe growth failure and develop- 2 years is usual. The pathology may be associated
mental delay. Umbilical hernias are common. with male pseudohermaphroditism (Denys–Drash
 CONGENITAL NEPHROTIC SYNDROME 131

syndrome) and microcephaly (Galloway–Mowat PROGNOSIS

syndrome). FSGS is the most common histo- Without active treatment, prognosis is poor.
pathologic finding in children with steroid- Before the end of their first year 75% of children
resistant nephrotic syndrome. In some cases, with Finnish type CNS have died; only 3% have
proteinuria may be present at birth. A hetero- lived to the age of 2 years; and none has reach
geneous group of disorders accounts for the rest 4 years of age. With transplantation, there may
of cases of CNS (Table 10). be a remarkable catch-up growth and develop-
mental progress.
INVESTIGATIONS
Nephrotic range proteinuria and low serum MANAGEMENT
albumin levels are usually present immediately Current treatment of children with CNS in-
after birth. Microscopic hematuria and leuko- cludes active protein and nutritional support,
cyturia are also common. Serum creatinine and including albumin and immunoglobulin infu-
glomerular filtration rate are usually within sion, high-protein low-salt diet, diuretics, and
normal limits during the first 3 months of life antibiotic prophylaxis. During the nephrotic
but renal function decreases slowly thereafter. state, prophylactic anticoagulation is recom-
Serum albumin levels are significantly reduced, mended to reduce the risk of thromboembolic
with a mean value <0.5 g/dl (5 g/l). Raised _- complications. Some children will require thy-
fetoprotein levels are present in the amniotic roid hormone replacement therapy. Classic CNS
fluid, and sometimes in the maternal plasma, (Finnish type) patients usually do not respond
which may indicate the development of CNS to the use of ACE inhibitors or indomethacin,
in utero. although anecdotal cases have been reported.
Similarly, corticosteroids and immunosuppres-
HISTOLOGY sive drugs are also ineffective. Conservative
Histopathologic examination shows mesangial therapy should be followed with bilateral neph-
hypercellularity, hyper lobulated capillary tufts, rectomy and dialysis, prior to undergoing renal
and some scarring. Proximal and distal tubuli transplantation. Renal replacement therapy is
may show microcystic dilatation. Scattered effectively achieved with peritoneal dialysis.
inflammation and fibrosis can be observed in the Several months on this treatment are required
interstitium. Electron microscopy shows glom- in order to allow the patient to recover from the
erular podocyte fusion (200). Immunohisto- severity of the nephrotic syndrome, and renal
chemistry studies can confirm the absence of transplantation is most commonly delayed
nephrin on the podocyte surface. Later, diffuse until the child reaches 8–9 kg (18–20 lb) of
mesangial sclerosis and significant interstitial body weight (usually in the second or third
fibrosis are present in the cortex. year of life).

200 Congenital Finnish nephrosis. Electron 200

microscopy showing diffuse effacement of
visceral epithelial foot processes with
microvillous transformation.Visceral epithelial
cells are vacuolated (x3400).
132 INHERITED RENAL DISEASES

Fabry disease (Anderson–Fabry disease,

angiokeratoma corporis diffusum)

DEFINITION also vary from a few microns to several milli-

Fabry disease is the clinical and pathologic mani- meters. On histology, angiokeratoma consists of
festations of an inborn error of glycosphingolipid small upper dermal dilated veins, covered by a
metabolism, secondary to deficiency of the hyperkeratotic epidermis. Other skin manifesta-
lysosomal enzyme alpha-galactosidase A (_GalA). tions include palmar erythema, telangiectasias and
subungual splinter hemorrhages. Neurologic
EPIDEMIOLOGY AND ETIOLOGY compromise is characterized by peripheral and
Fabry disease is a rare (1:40,000) X-linked dis- autonomic neuropathy, and cerebrovascular com-
order linked to mutations in the gene encoding plications. Autonomic neuropathy is manifested
for _GalA, which is located on chromosome X, by acral paresthesias, which are exacerbated by
Xq22>q24. The disease is more common in fever or exercise, hypohydrosis, impaired pupillary
whites, but it has been reported in other races. constriction, and abnormal intestinal motility.
It characteristically affects males. Heterozygous Temperature sensation may be impaired reflect-
females may have mild manifestations of the ing peripheral nerve involvement.
disease but severe Fabry disease has been Cerebrovascular disease can present as seizures,
documented in females who have inactivation transient ischemic attacks, or completed strokes.
of the normal _GalA allele. The specific muta- The vertebrobasilar circulation is most frequently
tions vary between individuals and accounts affected and disease can be manifested by vertigo,
for the variable clinical expression of the enzy- nausea, vomiting, nystagmus, diplopia, and ataxia.
matic defect. Repeated strokes can lead to significant memory
loss or dementia. Corneal opacities are seen in
PATHOGENESIS virtually all patients and in the majority of
The lysosomal enzyme _GalA is responsible for heterozygous carriers. By slit-lamp examination,
the hydrolysis of ceramide to sphingosine and they appear as whorls of whitish discoloration that
free fatty acid. Deficiency of _GalA results in radiate from the center to the periphery of the
intracellular accumulation of neutral glyco- cornea. Other ocular findings include posterior
sphingolipids, predominantly ceramide trihexo- capsular cataracts, retina and eyelid edema, and
side, in tissues throughout the body. Blood vessel retinal and conjunctival telangiectasias. Heart
cells, renal epithelium, corneal epithelium, myo- involvement can be manifested by development
cardium, and ganglion cells of the autonomic of angina, myocardial infarction, or conges-
nervous system are primarily affected, but gly- tive heart failure. Finally, generalized lymph-
cosphingolipid accumulation occurs in virtually adenopathy, hepatosplenomegaly, myopathy, and
every organ of the body. With time, this process aseptic necrosis of the femoral and humeral heads
leads to a multisystem dysfunction. Because of have been described to occur in some patients.
the accumulation of B-specific glycosphingo-
lipids, patients with blood types B and AB have DIFFERENTIAL DIAGNOSIS
earlier and more severe clinical presentations. Fabry disease should be considered in the dif-
ferential diagnosis of stroke or renal disease of
CLINICAL HISTORY AND PHYSICAL unknown etiology, or fever, pain, and skin lesions
EXAMINATION of unknown origin. Potential misdiagnoses include
Fabry disease is a multisystem disorder affecting rheumatoid or juvenile arthritis, rheumatic fever,
the skin, heart, peripheral and central nervous SLE, and multiple sclerosis (stroke-like events).
systems, and the kidneys. Renal involvement is
common and is manifested by hematuria and INVESTIGATIONS
proteinuria (<3 g/24 h) beginning in the third The diagnosis can be confirmed by demonstrating
decade of life, with gradual progression to end- reduced activity of _GalA in peripheral blood
stage renal failure in the fourth or fifth decades. leukocytes. In homozygote males there is almost
Skin involvement is characterized by the presence no enzyme activity. Female heterozygotes have
of angiokeratomas (201) which appear as red- enzyme levels that are intermediate between
purple macules or papules typically located in the normal and homozygote patients. Carriers for the
lower abdomen, buttocks, hips, genitalia, or disease can be identified by measuring ceramide
upper thighs. The number of lesions varies from digalactoside and trihexoside levels in the urine.
20–40, but they may be few or absent. Size can During childhood, birefringent lipid globules with
 FABRY DISEASE 133

a characteristic ‘Maltese cross’ shape can be in size, shape, number, and location, according to
observed in the urine by polarization microscopy. the different cells. They are typically round and are
composed of concentric layers of dense material
HISTOLOGY separated by clear spaces giving an ‘onion skin’
The glomerular visceral epithelial cell is the primary appearance (‘myelin figures’), or may have an ovoid
site of glycosphingolipid accumulation. On light shape with the dense layers arranged in parallel
microscopy these cells appear enlarged and (‘zebra bodies’). Inclusions are also seen in hetero-
vacuolated. The vacuoles, which represent lipid zygous females although to a lesser degree.
material that has been extracted during processing,
are small, uniformly distributed, and have a foamy PROGNOSIS
or ‘honeycomb’ appearance. Similar vacuolated cells The survival rate for patients on dialysis is
are also present in epithelial cells of distal con- approximately 40% at 5 years. Neurologic and
voluted tubules and loop of Henle, but are rarely cardiovascular complications account for the
seen in the mesangium or proximal tubules. increased mortality in these patients.
Extensive vacuolation is also seen in the arterial
vessels. Progressive renal involvement results in the MANAGEMENT
development of segmental and global glomeru- Recombinant _-galactosidase A is available as
losclerosis. Immunofluorescence microscopy is infusion therapy. It has been shown to stabilize
typically negative, except for areas of advanced glomerular filtration rate, reduce pain, improve
sclerosis where IgM and complement may be cardiac conduction, and reverse cardiomyop-
present. On electron microscopy cellular inclusions athy. Patients with end-stage renal failure can be
are localized almost entirely within lysosomes treated by dialysis, or by renal transplantation.
(202). The inclusions are present in all cells, Renal transplantation does not affect the extra-
regardless of the light microscopy features, and vary renal manifestations.

201 Angiokeratoma located on the 201

umbilicus.

202 Electron microscopy demonstrating 202

‘myelin figures’ (arrow) within the
lysosomes in visceral epithelial and
endothelial cells (x8000).
134 INHERITED RENAL DISEASES

Von Hippel–Lindau disease

DEFINITION sive renal failure. In patients with VHL there is an

Von Hippel–Lindau (VHL) disease is an auto- increased incidence of renal cell carcinomas.
somal dominant cancer syndrome characterized Tumors are often bilateral. Thirty to fifty percent
by the presence of benign and malignant of patients with symptomatic renal carcinoma will
tumors. Hallmark lesions include retinal have metastatic disease. In patients with VHL,
angiomas, hemangioblastomas of the central pheochromocytomas differ from those in sporadic
nervous system, renal cell carcinomas, and cases in that they occur in younger patients, and
pheochromocytomas. are often bilateral, multiple, and extra-adrenal.
They are often asymptomatic and rarely meta-
EPIDEMIOLOGY AND ETIOLOGY stasize. Patients with VHL and pheochromo-
The disease occurs in all ethnic groups and cytomas cluster in families. Angiomatous or cystic
affects both sexes equally. It has an estimated lesions may also occur in the pancreas and
incidence of approximately 1:40,000 births. the epididymis.
Diagnosis is usually made in the third or fourth Central nervous system hemangioblastomas
decade but increases with age. Penetrance has occur more frequently in the cerebellum fol-
been estimated at 80–90% by age 65 years, lowed by the spine and the brain stem (204,
although expression is highly variable. All 205). Tumors are often multiple and occur at a
patients with this disease harbor a germ line younger age than in patients with sporadic cases.
mutation of the VHL gene located on chromo- The hemangioblastomas are benign, but they
some 3p25. Tumor development is linked to may produce symptoms, including nausea,
loss or inactivation of the remaining wild-type vomiting, headache, and vertigo, depending on
VHL allele. their number, size, and site. In over 50% of the
patients angiomas (hemangioblastomas) are
PATHOGENESIS present in the retina (206). Tumors are often
The product of the VHL gene, pVHL, is impor- multiple, bilateral, and recurrent. The most
tant in the regulation of a transcription factor serious complications are retinal hemorrhage and
called hypoxia-inducible factor (HIF). In the retinal detachment that may lead to blindness.
presence of oxygen, pVHL polyubiquitinates
HIF_ subunits which targets HIF for proteo- PHYSICAL EXAMINATION
somal degradation. In the absence of pVHL, Signs of central nervous system involvement
HIF_ subunits cannot be degraded and conse- include papilledema, ataxia, slurred speech, and
quently will overstimulate HIF target genes. nystagmus. Retinal angiomas appear as reddish
Among these are genes implicated in angio- spherical tumors of variable size with a dilated
genesis, such as VEGF (vascular endothelial feeding artery and a draining vein.
growth factor) and PDGF-B (platelet-derived
growth factor B chain). Thus, the vascular nature DIFFERENTIAL DIAGNOSIS
of VHL-associated tumors is explained by the The differential diagnosis of renal lesions in
overproduction of angiogenic factors encoded VHL includes ADPKD and tuberous sclerosis
by HIF-stimulated genes. In this sense, the VHL complex (TSC). Patients with VHL are usually
gene behaves as a tumor suppressor gene. normotensive, have normal renal function, and
have fewer and smaller renal cysts than patients
CLINICAL HISTORY with ADPKD. Renal cell carcinomas are uncom-
There are several characteristic features of VHL. mon in ADPKD. Liver cysts are common in
The renal lesions in VHL include both cysts and ADPKD but are rarely seen in VHL. In both
carcinomas (203). Renal cysts are present in over TSC and VHL multiple renal cysts and tumors
half of the patient. They may be solitary, but most occur. However, renal tumors in TSC are usually
frequently are bilateral and multiple and occasion- angiomyolipomas and the extrarenal manifesta-
ally can mimic autosomal dominant polycystic tions help to differentiate TSC from VHL.
kidney disease (ADPKD). Unlike ADPKD, renal
cysts in VHL rarely cause hypertension or progres-
 VON HIPPEL–LINDAU DISEASE 135

203 204

203 CT scan showing bilateral solid and cystic

renal masses.

204 MRI showing cerebellar hemangioblastoma

(arrow).

205 206

206 Retinal angioma.

205 T2-MRI sagittal image of the cervical spine showing a

partially cystic intramedullary neoplasm expanding the spinal
cord. Note the dilated pial vascularity (arrows).
136 INHERITED RENAL DISEASES

Von Hippel–Lindau disease (continued)

INVESTIGATIONS MANAGEMENT
Detection of central nervous system hemangio- In patients who develop central nervous system
blastomas has improved substantially with the symptoms secondary to a tumor-mass effect,
use of gadolinium-enhanced magnetic reson- surgical resection of hemangioblastomas often
ance imaging. Genetic testing can be used to provides excellent results. Regular ophthal-
identify carriers of VHL gene mutations. mologic examinations are an essential compo-
Mutations can be detected in over 80% of nent of the preventive screening. Retinal angi-
families with VHL. In the remaining patients, omas can be treated by laser and cryotherapy.
genetic linkage analysis can help to identify Early intervention is recommended to ensure
individuals carrying a mutant VHL gene pro- preservation of vision. Annual surveillance with
vided that there are at least two other affected CT, ultrasonography, or both is indicated for
members available for testing. early detection of renal cell carcinomas. Treat-
ment of solid lesions is by parenchymal-sparing
HISTOLOGY surgery whenever possible, in order to avoid or
Microscopically, kidneys from patients with delay the need for dialysis or transplantation.
VHL may contain numerous small neoplasms. Repeated surgical intervention is usually required
Cysts are lined by a flattened, nondescriptive or as tumors continue to develop. Symptomatic
cuboidal clear cell epithelium that may appear pheochromocytomas must be removed surgi-
as focal nodular hyperplasia, or intracystic renal cally. It is important to attempt to localize extra-
cell carcinomas. In patients with renal cell adrenal tumors pre-operatively in order to
tumors, the predominant histologic finding is a prevent life-threatening complications during
clear cell carcinoma. surgery, because of unexpected tumor mani-
pulation. Because of the increased risk of cancer,
PROGNOSIS family screening is imperative, including analysis
The development of multiple central nervous of mutations. Patients who did not inherit the
system tumors is still a major problem, and central mutant gene do not need further evaluation.
nervous system involvement is an important cause Patients who are carriers for a VHL mutation or
of morbidity and mortality in these patients. at-risk individuals in whom the presence of a
Patients with VHL have a lifetime risk >70% for mutation cannot be determined need periodic
developing a renal cell carcinoma, and these screening for occult disease manifestation.
tumors cause death in up to 50% of VHL patients.
In patients with VHL, early cancer screening
beginning in childhood with ophthalmoscopy and
magnetic resonance imaging of brain, spine, and
abdomen, has a direct beneficial impact on the
long-term prognosis.
 PRIMARY HYPEROXALURIAS (PH) 137

Primary hyperoxalurias (PH)

DEFINITION ruvate reductase results in failure of glyoxalate

PHs are autosomal recessive disorders charac- reduction to glycolate, but the cause of
terized by metabolic overproduction of oxalate increased oxalate production is unclear. In the
resulting in urolithiasis, nephrocalcinosis, and kidney, oxalate is freely filtered by the glom-
accumulation of insoluble oxalate throughout erulus and then undergoes a complex absorp-
the body. tion and secretion process. The upper limit for
renal excretion is approximately 40 mg/24 h.
EPIDEMIOLOGY AND ETIOLOGY Excessive ingestion of oxalate in the diet can
There are two types of PH that result from result in increased urinary oxalate, but rarely
different enzymatic defects in the hepatic exceeds 60 mg/24 h. In PH, however, urinary
glyoxalate pathway. In type I PH the defective oxalate levels may range from 80–300 mg/24
enzyme is alanine glyoxylate aminotransferase h. Within the kidney, crystal deposition results
(AGT). In humans the AGT gene is encoded on in intratubular obstruction. Rupture of the
chromosome 2q36-37. Differences in the type tubular epithelial allows oxalate to migrate to
of mutation results in a varied pattern in AGT the interstitium where it triggers a severe
enzyme expression: total absence (~30% of inflammatory response. With time, the chronic
patients), presence of an inactive enzyme interstitial process will result in progressive loss
(~25%), or selective mistargeting of the enzyme of renal function.
from peroxisomes to the mitochondria (~40%).
PHs are rare disorders. Type I PH occurs in ~ CLINICAL HISTORY AND PHYSICAL
1:120,000 live births, but incidence is much EXAMINATION
more frequent when parental consanguinity is In either, type I or II PH, the disease is most
present. Type II PH is an even rarer disorder often manifested during the first or second
that is due to deficiency of hepatic hydroxy- decade of life with symptoms related to the
pyruvate reductase. The gene encoding for this urinary tract: loin pain, hematuria, urinary tract
enzyme is localized on chromosome 9 and infections, or passage of a renal stone. In some
specific mutations have been described in a small patients, the disease may remain unrecognized
number of patients. until well into adulthood. Some patients may
present with end-stage renal failure without a
PATHOGENESIS preceding history of urolithiasis. In patients with
Oxalate is a poorly soluble end product of preserved renal function, plasma oxalate levels
metabolism. In humans, oxalate excretion is remain close to normal, with the main clinical
mainly renal, although there is increasing problem being urolithiasis. With time, the
evidence that the gastrointestinal tract, mainly increased renal deposition of oxalate and stone
the colon, also plays a role. Approximately formation will result in variable degrees of
80–90% of the daily oxalate excreted in the urine obstruction, progressive renal interstitial fibrosis,
is produced endogenously, with only 10–20% and renal failure. Once glomerular filtration rate
being of dietary origin. Dietary oxalate falls below 30 ml/min, continued overproduc-
originates mainly from fruits and vegetables. tion of oxalate by the liver along with reduced
Absorption occurs throughout the entire renal oxalate excretion results in increasing
intestine, but mostly in the small bowel. Total oxalate deposition in many organs. The major
colectomy does not appear to alter oxalate compartment of the insoluble oxalate pool is
absorption, but increased colonic absorption bone, and therefore bone disease is the most
occurs in patients with enteric hyperoxaluria. disabling complication of oxalosis. Along with
Formation of oxalate occurs in the liver through the skeleton, systemic involvement includes: the
a partially understood metabolic pathway. cardiovascular system (cardiomyopathy, conduc-
Hepatic peroxisomal AGT and hydroxypyruvate tion defects, disseminated vascular occlusive
reductase are key enzymes in this pathway. AGT lesions), nerves (peripheral neuropathy, mono-
is needed for converting glyoxylate to glycine, neuritis multiplex), joints (synovitis), skin (cal-
thus diverting glyoxylate from being oxidized cinosis, livedo reticularis), soft tissues, liver,
to oxalate. Pyridoxine is a co-factor in the AGT and retina.
pathway. In type II, deficiency in hydroxypy-
138 INHERITED RENAL DISEASES

Primary hyperoxalurias (PH) (continued)

DIFFERENTIAL DIAGNOSIS PROGNOSIS

Other causes of hyperoxaluria include intestinal PH is associated with serious morbidity and
(hyperabsorptive) hyperoxaluria, enteric hyper- mortality. Without aggressive treatment, includ-
absorption (e.g. ileal resection, pancreatic insuf- ing transplantation, the majority of patients will
ficiency, Crohn’s disease, malabsorption), exces- die before the third decade of life. The earlier
sive dietary ingestion of substances containing the diagnosis, the better the chance of improv-
oxalic acid (e.g. cocoa, tea, spinach, nuts), or ing the prognosis and quality of life in patients.
poisoning (e.g. ethylene glycol). High plasma Aggressive conservative treatment and pre-emp-
oxalate levels also occur in patients with chronic tive transplantation have significantly improved
renal failure due to other causes. the long-term outcome.

INVESTIGATIONS MANAGEMENT
The diagnosis of a type I PH is strongly sug- The main goal of treatment is to increase oxalate
gested in a patient with a marked increase in solubility and decrease production. A high uri-
urinary oxalate excretion (usually >100 mg/24 h) nary output is crucial and patients are required
and an elevated urine glycolate, and these findings to drink a fluid load large enough to maintain a
may be sufficient to establish the diagnosis in urinary volume of at least 3 l/24 h. In patients
patients with typical clinical features. However, with type I PH, treatment with pyridoxine
up to 25% of patients with type I PH will have (vitamin B6) may reduce oxalate production to
urinary glycolate levels within the normal range, normal or near normal in up to 30% of cases.
and may require a liver biopsy for AGT analysis Urine alkalinization (target pH >6.5) will
to confirm the diagnosis. Nephrocalcinosis, best increase the solubility of calcium and oxalate.
demonstrated by ultrasound, is present on plain Magnesium also inhibits urinary stone forma-
abdominal radiograph in patients with advanced tion and can be given orally either as magnesium
stages of the disease (207). Linkage studies or gluconate or as magnesium oxide. Orthophos-
direct detection of mutation are useful diagnostic phate is also effective in decreasing calcium
tools but, at present, <50% of cases can be diag- oxalate supersaturation and inhibiting urinary
nosed by DNA testing. In patients with chronic calcium precipitation and can be used safely in
renal failure, urinary oxalate and glycolate excre- patients with preserved renal function (clearance
tion may be normal. In this situation, plasma >30 ml/min). Low oxalate diet is of limited
oxalate and plasma glycolate will be markedly value in patients with PH.
elevated. Interpretation of plasma oxalate levels To remove sufficient oxalate, daily hemo-
in patients on dialysis is difficult because most dialysis, with 6–8 hours per session, is required.
patients with end-stage renal failure from other The only curative treatment is liver transplanta-
causes will have elevated plasma oxalate levels. In tion to replace the defective liver enzyme. In
patients with type II PH, the diagnosis is selected patients, isolated liver transplant is the
suggested by the findings of marked urinary oxa- therapy of choice and should be performed
late, urine glycerate, and normal urine glycolate. before chronic renal failure onset. Combined
kidney and liver transplantation is indicated for
HISTOLOGY patients with advanced renal failure. Following
Macroscopically, calculi are commonly seen combined kidney and liver transplant, care
within the pelvis and calyceal system. Micro- should be taken to protect the kidney against
scopically, the hallmark of the renal disease is the the damage that can be induced by the heavy
presence of abundant calcium oxalate deposits oxalate load that results from the rapid mobiliz-
within the nephron associated with chronic ation of oxalate accumulated in the tissues.
tubulointerstitial nephritis (208). The glomeruli
may appear normal or focally sclerosed. Inter-
stitial lesions include giant cell formation, lym-
phocytic infiltration, and interstitial fibrosis.
Crystals vary in shape from round to elongate,
often fan-shaped, and are birefringent.
 PRIMARY HYPEROXALURIAS (PH) 139

207

207 Plain abdominal radiograph showing dense

nephrocalcinosis and characteristic bone changes in
a patient with primary hyperoxaluria and end-stage
renal failure.

208

208 Calcium oxalate crystals within renal tubules under cross-

polarized light. Light microscopy (H+E x250).
140 INHERITED RENAL DISEASES

Cystinosis

DEFINITION CLINICAL HISTORY AND PHYSICAL

Cystinosis is a metabolic disease characterized EXAMINATION
by excessive intracellular accumulation, particu- Three different clinical forms of cystinosis can
larly in lysosomes, of the amino acid cystine. be distinguished based on the clinical course and
the intracellular cystine content: infantile (or
EPIDEMIOLOGY AND ETIOLOGY nephropathic) cystinosis, adolescent or late-
The disease is inherited as an autosomal reces- onset cystinosis, and benign or adult cystinosis.
sive trait. It has an estimated incidence of Infantile cystinosis is the most common form.
1:200,000 live births. The cause is a defect in a The disease is usually diagnosed between 6 and
gene mapped to chromosome 17p13, coding 18 months of age with symptoms of excessive
for an integral lysosomal membrane protein, thirst and urination, failure to thrive, rickets
cystostatin, responsible for transporting cystine (209), and frequent episodes of dehydration.
out of the lysosome. The disease is more com- These findings are a result of a Fanconi syn-
mon in Caucasians but other races are affected. drome. Subtle abnormalities of tubular function
can be demonstrated earlier in families with
PATHOGENESIS other affected children, but they are not present
In cystinosis, the defect in the lysosome trans- at birth. Children with cystinosis also develop
porter for cystine results in cystinotic cells accumu- cystine crystals in the cornea (after the first year
lating 50–100 times the normal cystine values. of life) (210). Photophobia is common and is
The low solubility of cystine results in crystal progressive, but visual impairment and blindness
formation within lysosomes. How crystal forma- are rare. A few patients have developed renal
tion results in cellular injury is unclear. It has been calculi. Without specific treatment, patients
postulated that accumulated intracellular cystine develop end-stage renal failure by late childhood
may interact with sulphydryl groups disrupting (7–10 years of age). Late complications include
sulphydryl-dependent enzyme systems. muscle wasting, difficulty swallowing, diabetes,

209 210

210 Corneal cystine crystals.

209 A patient with cystinosis (left) is shown alongside

a normal boy of the same age.The renal rickets is
secondary to the amino acid loss and defective
calcium and phosphate reabsorption.
 CYSTINOSIS 141

hypothyroidism, hepatomegaly and spleno- PROGNOSIS

megaly, corneal ulcerations, and decreased visual The renal prognosis has improved with cys-
acuity. In patients with benign or adult cystino- teamine treatment. It remains to be determined
sis, intracellular cystine levels are mildly elevated whether children treated with cysteamine from
with cystine crystals present in the cornea and infancy will be spared from the other compli-
bone marrow only. These patients do not cations of cystinosis.
develop renal failure. Patients with the ado-
lescent form have intracellular cystine levels that MANAGEMENT
are intermediate between those of the infantile Treatment of the Fanconi syndrome involves
and adult forms. replacement of the urinary losses of water,
electrolytes, bicarbonate, and minerals. Some
DIFFERENTIAL DIAGNOSIS patients also need vitamin D therapy. The use
Childhood Fanconi syndrome is most com- of indomethacin may be of benefit in patients
monly the result of cystinosis. Other causes of with severe polyuria. Cysteamine treatment has
Fanconi syndrome include nephrotoxicity from proven effective in reducing cystine accumu-
heavy metals (cadmium, lead) and systemic lation within the cells and delaying the decline
diseases (myeloma, fructose intolerance, galac- in GFR, especially if started earlier in the course
tosemia, and Wilson disease). of the disease. Cysteamine is easily transported
inside lysosomes where it combines with cystine,
INVESTIGATIONS forming cysteine and a mixed disulfide cys-
The diagnosis is based on detecting increased teamine–cysteine compound. Both cysteine and
intracellular cystine levels in white blood cells the disulfide compound exit the lysosome via
or skin fibroblasts. Normal cells contain transport mechanisms other than the cystine
<0.3 nmol half cystine/mg protein. Carriers of carrier. Cysteamine also improves the growth of
cystinosis have levels between 0.3 and 1.0 nmol cystinosis children, although it does not lessen
half cystine/mg protein while those affected the severity of the Fanconi syndrome. Treat-
with cystinosis have levels above this range. ment should be started as soon as the diagnosis
Prenatal diagnosis can be made by measuring is made with low doses of cysteamine bitartrate.
cystine levels in cells obtained by chorionic villus Side-effects of cysteamine therapy include
sampling or amniocentesis in families where nausea, vomiting, and a foul odor and taste.
there is a known risk of cystinosis. Chorionic Leukocyte cysteine levels should be checked
villus sampling is performed at 8–9 weeks of every 3–4 months and therapy adjusted to
gestation; amniocentesis can be performed at maintaining cysteine levels below 1.0 nmol half
14–16 weeks of gestation. cystine/mg protein. Renal transplantation is the
treatment of choice for patients who develop
HISTOLOGY end-stage renal failure, as the disease does
Histologic findings vary with the stage of the not recur in the allograft. Renal transplantation
disease. Early findings include cystine crystal does not improve the extrarenal manifestations
deposition in tubular epithelial and interstitial of cystinosis.
cells, but rarely in glomerular epithelial cells
(211). By nephron microdissection, a shorten-
ing and swan-neck deformity of the initial
portion of the proximal tubules has been 211
described, but this finding is not specific for
cystinosis. Later in the disease, there is progres-
sive interstitial fibrosis, periglomerular fibrosis,
and glomerulosclerosis. Abundant deposition of
small, brick-shaped, hexagonal, or needle-
shaped birefringent crystals is found with multi-
nucleated, giant cell formation in the glomeruli
visceral epithelium and atrophic proximal
tubules. On electron microscopy, crystalline
inclusions can be seen inside the cells.

211 Renal biopsy viewed under birefringent light

showing interstitial cystine crystals (x100).
142 INHERITED RENAL DISEASES

Tuberous sclerosis complex (TSC)

DEFINITION PATHOGENESIS
TSC is an autosomal dominant disorder in Both TSC1 and TSC2 genes have been identified
which patients develop hamartomatous lesions and sequenced. The protein product of TSC1 is
in many different organs, most commonly in the called hamartin. TSC2 produces a 5.5kb tran-
brain, heart, kidney, and skin. script whose protein has been named tuberin.
Both are tumor suppressor genes involved in
EPIDEMIOLOGY AND ETIOLOGY regulation of cell growth and differentiation. The
TSC has an estimated prevalence of 1:10,000. precise mechanism of hamartomatous growth is
It affects both sexes equally, with no race not completely understood.
predilection. Mean age at diagnosis is the third
decade. The disease is caused by mutations in CLINICAL HISTORY AND PHYSICAL
two different genes, which are located on EXAMINATION
chromosomes 9q32p34 (TSC1) and 16p13 In this disease, multiple hamartomatous tumors
(TSC2). There is a high frequency of spon- develop in multiple organs, including the skin
taneous mutations with sporadic forms account- (212–214), brain, retina (215), liver, bone,
ing for approximately 60% of newly diagnosed heart, lung, and kidney. The most common
cases. There is great variability in the disease clinical manifestations are related to the skin and
penetrance and clinical presentation, with only central nervous system. Skin manifestations
50% of patients having a positive family history. include facial angiofibromas (adenoma seb-

212 213

213 Periungual fibroma.

212 Facial angiofibroma.

 TUBEROUS SCLEROSIS COMPLEX (TSC) 143

214

214 Hypomelanotic macule.

215

215 Retinal hamartoma.

144 INHERITED RENAL DISEASES

Tuberous sclerosis complex (TSC) (continued)

aceum), ungual fibromas (Koenen tumors), INVESTIGATIONS

hypomelanotic macules (ash-leaf spots), and Ultrasonography, CT, and arteriography are the
shagreen patches. Central nervous system mainstay for the diagnosis and are helpful in
involvement is manifested by the development distinguishing angiomyolipomas from renal
of seizures and mental retardation. Many cysts or tumors.
patients are neurologically normal despite
radiographic evidence of typical brain lesions HISTOLOGY
such as subependymal calcifications (216). Renal angiomyolipomas are hamartomas formed
Renal involvement occurs frequently in TSC by atypical blood vessels, smooth muscle-like
(217, 218). It is manifested by the presence of cells, and adipose tissue. Cysts originate from any
hypertension, angiomyolipomas, and renal cysts. nephron segment. The epithelium lining of the
Angiomyolipomas are the main form of cysts exhibits marked cellular hypertrophy
hamartomas in TSC. They are multiple and and hyperplasia.
usually bilateral. An important aspect of angio-
myolipomas is their potential for bleeding that PROGNOSIS
can be manifested as macroscopic hematuria or Affected patients frequently have early onset of
retroperitoneal hemorrhage. Bilateral renal severe hypertension and chronic renal failure
angiomyolipomas may also cause chronic renal that progress to end-stage renal failure in the
failure. Angiomyolipomas are larger in females second or third decade of life. Patients who
than in males, suggesting a sex hormone effect. develop end-stage renal failure are candidates
Cysts are usually numerous and small, but large for renal transplantation. Immunosuppressive
cysts do occur and may be confused with poly- therapy does not worsen the course of TSC.
cystic kidney disease. Cysts and angiomyo-
lipomas may be present in combination or only MANAGEMENT
one type may be present. The CT finding of Renal angiomyolipomas are usually asympto-
angiomyolipomas and cysts occurring together matic and require no treatment. Aggressive con-
is strongly suggestive of TSC. An association trol of blood pressure may slow renal disease
with renal carcinomas has also been described. progression. Patients with TSC are at increased
Carcinomas are frequently bilateral. Some risk for developing renal tumors and need to
malignant tumors are now recognized as malig- be followed on a yearly basis with a CT or
nant epithelioid angiomyolipomas. renal ultrasound.
The diagnosis is based on clinical, radiologic,
and biopsy findings. The disease however
presents great phenotypic variability with size,
number, and location of lesions differing signi-
ficantly among patients, even in members of the
same family. Specific clinical criteria have been
defined for the diagnosis of TSC (Table 11).

DIFFERENTIAL DIAGNOSIS
Renal cysts and angiomyolipomas can occur as
sporadic lesions in individuals not affected by
TSC. Sometimes, renal imaging can mimic
autosomal dominant polycystic kidney disease.
The TSC2 gene is positioned next to the PKD1
gene, and a contiguous TSC2/PKD1 gene syn-
drome, secondary to deletions affecting both
genes, has been described. These patients are
characterized by severe early onset of polycystic
kidney disease.
 TUBEROUS SCLEROSIS COMPLEX (TSC) 145

Table 11 NIH consensus panel for TSC diagnostic criteria

Major features Minor features (continued)

• Facial angiofibromas • Dental enamel pits
• Periungual fibroma • Confetti macules
• Ash-leaf spots (>3)
• Shagreen patch Definite diagnosis: either 2 major feature or
• Retinal hamartomas 1 major feature with 2 minor features.
• Subependymal nodule Probable diagnosis: 1 major feature and
• Giant cell astrocytoma 1 minor feature
• Cardiac rhabdomyoma Possible diagnosis: either 1 major or 2 more
• Cortical tuber† minor features
• Lymphangiomyomatosis‡ † Cortical dysplasia and cerebral white matter
• Renal angiomyolipomas‡ migration occurring together should be counted
Minor features as 1 rather than 2 features of TSC.
• Gingival fibromas ‡ Simultaneous occurrence of lymphangiomyo-
• Nonrenal hamartomas matosis and renal angiomyolipomas requires
• Multiple renal cysts§ other features of TSC to be present before a
• Bone cysts!! definitive diagnosis is assigned.
• Hamartomatous rectal polyps§ § Histologic confirmation is recommended
• Cerebral white matter migration lines†!! !! Radiologic confirmation is sufficient

216 217

218

216 Head CT without contrast showing calcified

subependymal nodules and a cortical/subcortical
tuber in the right frontal lobe (arrow).

217 Multiple angiomyolipomas.

218 Markedly distended kidneys due to multiple

angiomyolipomas.
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Chapter Eight
147

Tumors of the
renal parenchyma
and urothelium

• Introduction

• Tumors of the renal parenchyma

• Renal urothelial tumors

148 TUMORS OF THE RENAL PARENCHYMA AND UROTHELIUM

Introduction

Most renal tumors are malignant in childhood primary tumor include ultrasound, CT, MRI,
and adult life. Benign simple cysts of the renal angiography, and retrograde ureteroscopy.
parenchyma are seen with increasing frequency Metastatic spread to lung, bone, and lymph
over the age of 50 years (219). Macroscopic nodes is commonplace. Direct spread into
hematuria, pain, and weight loss are the three surrounding tissues, or invasion into the renal
commonest symptoms experienced in cases of vein (and even into the right atrium) is a
renal malignancy. Imaging techniques for the predilection shown by renal cell carcinoma.

219

219 CT scan of the kidneys with contrast.The antero-lateral border

of the right kidney is distorted by the presence of a large single
simple renal cyst with a calcified wall.
 TUMORS OF THE RENAL PARENCHYMA 149

Tumors of the renal parenchyma

CHILDHOOD TUMORS scopy (221, 222). Radiotherapy and chemo-

Wilm’s tumor (nephroblastoma) therapy are extremely important adjunctive
The peak age incidence for this tumor is 2 years, therapies. The cure rate in specialized centers is
but onset from age 1–10 years is not unusual currently 80–90%.
(220). The overall incidence world-wide is
about 5 per million children under the age of Mesoblastic nephroma
15 years. Presenting features include a vis- These tumors typically occur within the first
ible/palpable mass, hematuria, and weight loss 6 months of life and are very rare after 12 months.
(or failure to grow). Surgery to remove the Their cut surface is whorled like a uterine fibroid.
tumor is the definitive treatment. The tumor is Surgery alone usually lead to a cure.
usually large by the time it presents and has a
pale firm cut surface (with islands of darker Multicystic nephroma
hemorrhage and necrosis). There is an immature This presents as a very well-defined multicystic
spindle-cell stroma which surrounds primitive mass involving one but not both kidneys in early
tubular and glomerular structures on micro- childhood. Surgery alone will effect a cure.

220 221

221 Histology of a Wilm’s tumor showing an immature

spindle-cell stroma (arrow) which surrounds primitive
tubular and glomerular structures (arrow head) on
microscopy (H+E x200).

222
220 Postmortem specimen of Wilm’s
tumor in a child.The tumor is usually
large by the time it presents and has a
pale firm cut surface (with islands of
darker hemorrhage and necrosis).

222 Histology of a Wilm’s tumor

showing muscle differentiation (with
cross striations visible at the arrow)
(H+E x400).
150 TUMORS OF THE RENAL PARENCHYMA AND UROTHELIUM

Tumors of the renal parenchyma (continued)

ADULT TUMORS Ultrasound, CT and MRI scanning, and

Renal cell carcinoma (hypernephroma) arteriography help to delineate the size and
This is the commonest renal tumor with an disposition of the primary tumor (225), and
annual incidence of 5/100,000 population. The local spread including invasion of the inferior
cut surface of a renal cell tumor is pale yellow vena cava by extension along the renal vein
with black areas of hemorrhage (223, 224). It (226). A chest film and CT (227, 228) are
is commonest between the fifth and seventh important as one-third of tumors have already
decades of life, but can occur earlier, especially metastasized by diagnosis; distant metastases are
in the clinical context of von Hippel–Lindau common, and often involve the skin and bones
disease (see Chapter 7). Presentation with renal (229, 230). Bleeding, pathologic fracture, and
cell carcinoma is most often with frank hema- pain are features of distant metastatic disease
turia, flank pain, and weight loss. Metabolic (231, 232).
consequences of the tumor such as hyper-
calcemia, fever, or polycythemia are well-recog-
nized but rare.

223 224 223 Postmortem

specimens of a
‘hypernephroma’
(clear cell renal
carcinoma) arising
from the upper
renal pole.

224 ‘Hyper-
nephroma’ arising
from the lower
renal pole.

225 226

225 Magnetic resonance image of an upper-pole 226 CT scan of a clear cell renal carcinoma
renal cell carcinoma. (occupying most of the enlarged single kidney)
showing invasion of the inferior vena cava.
 TUMORS OF THE RENAL PARENCHYMA 151

227 228

227 CT scan of thorax 229 230

showing a large soft tissue
mass eroding through ribs and
emerging onto the chest wall.

228 Plain CXR showing hugely

enlarged hilar lymph nodes.

229 AP plain radiograph of

lumbar spine showing a missing
vertebral pedicle (arrow).

230 MRI of lumbar spine

showing vertebral body
destruction by metastatic
renal cell carcinoma (arrow).

231 232

231, 232 Pathological tumor deposit expanding

the cortex of the lower tibia (231). Postmortem
histology (232) from the bone marrow showing
diffuse infiltration by monomorphic malignant cells
(renal cell carcinoma) (H+E x100).
152 TUMORS OF THE RENAL PARENCHYMA AND UROTHELIUM

Tumors of the renal parenchyma (continued)

A single tumor can show marked variation in 233

histology (233) from papillary growth pattern
to anaplastic sarcoma-like stroma.
The standard surgical intervention is radical
nephrectomy (removing kidney, adrenal, upper
ureter and perirenal fascial/fat planes). Adjunc-
tive chemotherapy and radiotherapy (the latter
especially for distant metastases to control pain)
are palliative.
Progesterone therapy is only modestly effec-
tive in slowing tumor growth in some patients.
Interferon therapy, and removing the primary
tumor, may be more effective. The tumor can
be very slow growing. 233 Histology of a ‘clear cell’ renal carcinoma
showing tumor cells with abundant clear
Renal cell adenoma cytoplasm (containing fat) (H+E x400).
These are small tumors that resemble renal cell
carcinomas, but have a consistent histologic
pattern, e.g. papillary. These are often inci- 234
dentally located, or removed with a nephrec-
tomy. They have very little malignant potential.

Renal oncocytoma
Oncocytes are cells with an eosinophilic granular
cytoplasm. These tumors can grow to a large
size but rarely metastasize (234, 235).

Angiomyolipomata
These tumors are highly vascular but also
contain smooth muscle and fat components as
well as those from blood vessels (236, 237).
There is a strong association with tuberous 234 Postmortem specimen of a renal
sclerosis (and see Chapter 7). These tumors can oncocytoma.The huge tumor has virtually
grow large enough to be palpable and present replaced the normal renal tissue.
as a mass. Hemorrhage into these vascular
tumors, with pain and anemia, is common as
these tumors exceed 5 cm (2 in) in diameter. 235
Nephron-sparing surgery can be undertaken
successfully.

Renal lymphoma/leukemia
A primary renal lymphoma (usually B-cell) is
exceptionally rare. Lymphomatous or leuke-
matous involvement of the kidneys is rare but
not so uncommon in chronic lymphatic leu-
kemia (up to 20% of CLL cases at postmortem
can have renal deposits) (238–241). Post-
transplantation lymphoproliferative disease (see
Chapter 12) can affect the allograft.
235 Histology of a renal oncocytoma showing
eosinophilic granular cytoplasm (H+E x400).
 TUMORS OF THE RENAL PARENCHYMA 153

236 237

237 Histology of a renal angiomyolipoma. Abundant

fat (clear areas) can be seen (H+E x200).

236 Postmortem specimen of a large angiomyolipoma

(a tumor composed of blood vessel, muscle, and fat)
seen particularly in tuberous sclerosis.

238 239

239 Histology of a primary renal lymphoma

(consisting of an infiltrate of mononuclear
lymphoid series cells) (H+E x400).

238 Postmortem specimen of a kidney infiltrated

(white areas) by metastatic lymphoma.

240 241

241 Histology of kidney infiltrated by acute

lymphoblastic leukemia (H+E x400).

240 Postmortem specimen of a kidney diffusely infiltrated

(hemorrhagic areas) by acute lymphoblastic leukemia.
154 TUMORS OF THE RENAL PARENCHYMA AND UROTHELIUM

Renal urothelial tumors

The urothelium is a transitional epithelium from 242

the renal papillae down to the urethra. Chemical
carcinogens (rubber and aniline dye workers;
cyclophosphamide therapy; phenacetin; thoro-
trast) and chronic inflammation (e.g. bilharzia,
Chapter 6) are the main predisposing factors.
About 10% of urothelial tumors occur in the
upper tracts (renal pelvis and ureters)
(242–245). They can present with hematuria,
or obstruction. Malignant cells are seen on
cytologic examination of the urine. Uretero-
scopy and biopsy are also used in the diagnosis
of upper tract tumors.
Removal of as much of the urothelium as
possible is required, as the scope for future
malignancy is very great.

242 Postmortem appearance of a large tumor

arising from the transitional epithelium in the
renal pelvis.

243 244

243 CT scan appearance of a large tumor arising

from the transitional epithelium in the renal pelvis.

244 IVU appearance of a pelvic transitional cell 245

carcinoma in the left kidney.The right kidney's
pelvis and proximal ureter are full of radio-opaque
contrast material. On the left there is virtually no
contrast in the pelvis (a little is seen in the
proximal ureter) which is radiolucent.The upper
pole has significant patchy parenchymal contrast
retention (arrow) compared to the lower pole
and the contralateral kidney, due to partial
obstruction at the level of the renal pelvis.

245 Histology of a transitional cell renal tumor

showing malignant urothelial cells (H+E x400).
Chapter Nine
155

Renal disease
in pregnancy
• Normal pregnancy

• Renal diseases associated with pregnancy

• Pre-eclampsia

• Pregnancy in renal disease

• Pregnancy in dialysis patients

• Pregnancy in renal transplant patients

156 RENAL DISEASE IN PREGNANCY

Normal pregnancy

During a normal gestation the kidneys enlarge level until delivery, thus lowering serum urea
in size and the renal calyces, pelves, and ureters and creatinine levels. Blood pressure decreases
become dilated due to hormonal effects on early in pregnancy so that the diastolic pressure
smooth muscle and possibly compression by falls by 10–15 mmHg (1.3–2 kPa) by the 20th
the uterus. The right ureter is usually more week, before slowly rising during the second
dilated than the left. GFR increases by about half of pregnancy to approach prepregnancy
50% in the first trimester and remains at this levels at term.

Renal diseases associated with pregnancy

Urinary tract infections are common in preg- of acute renal failure are due to amniotic fluid
nancy. Women with asymptomatic bacteriuria embolism, acute fatty liver of pregnancy, and
are likely to develop symptomatic infections in postpartum hemolytic uremic syndrome. Ob-
pregnancy, and should be treated with a course stetric complications are the most common causes
of antibiotics. Acute pyelonephritis in pregnancy of acute cortical necrosis, the most severe out-
is a serious complication and should be managed come of acute renal failure (246). Acute cortical
aggressively, in hospital with a prolonged course necrosis is most common in the last trimester,
of antibiotics. most frequently after placental abruption and less
Acute renal failure in pregnancy may occur commonly following prolonged intra-uterine
due to septic shock complicating acute pyelo- death or with pre-eclampsia. It may involve the
nephritis or septic abortions, or following entire renal cortex with irreversible renal failure,
hemorrhage or severe pre-eclampsia. Rare cases or be patchy with some return of renal function.

Pre-eclampsia

DEFINITION CLINICAL HISTORY

Pre-eclampsia is characterized by hypertension, Pre-eclampsia may develop slowly or present
proteinuria, edema and, sometimes, liver func- abruptly. It occurs most commonly in the last
tion and coagulation abnormalities. It usually trimester but may occasionally occur as early as
occurs in the last trimester. Eclampsia is 20 weeks. Edema with nephrotic range pro-
characterized by grand-mal seizures. teinuria is common. Headaches, epigastric pain,
and vomiting often precede eclamptic fits.
EPIDEMIOLOGY AND ETIOLOGY
Pre-eclampsia occurs in 5–10% of all pregnancies INVESTIGATIONS
and is most common in women having their first Hyperuricemia, deranged liver function tests,
pregnancy. Other risk factors include a previous thombocytopenia, and coagulation disturbances
pregnancy complicated by pre-eclampsia, ma- may be seen. Renal biopsy is occasionally indi-
ternal age >35 years, twin pregnancy, diabetes cated in women with nephrotic syndrome when
mellitus, and pre-existing renal impairment it is impossible clinically to distinguish between
(serum creatinine >1.5 mg/dl [133 +mol/l]). pre-eclampsia and a primary renal disease.
Uterine artery Doppler ultrasound is useful in
PATHOGENESIS predicting women at risk of developing pre-
Uteroplacental ischemia due to abnormal tro- eclampsia (247).
phoblast implantation is thought to be the
primary abnormality. There is increased per- HISTOLOGY (248)
ipheral resistance due to vasoconstriction, in part The glomeruli are enlarged due to swelling of
due to reduced prostacyclin production. glomerular endothelial cells (‘glomerular endo-
theliosis’). The epithelial cells are normal.
Deposits of IgM and fibrin are found. These
changes reverse rapidly after delivery.
 PRE-ECLAMPSIA 157

246 Acute cortical necrosis. 246

Hemorrhagic zone can be seen
affecting the outer 3–5 mm
(0.1–0.2 in) of the renal cortex.

247

247 Normal (left) and abnormal (right) uterine artery Doppler ultrasound waveforms.

PROGNOSIS 248
Pre-eclampsia rapidly resolves after delivery. It
is still the major cause of maternal death in the
UK, with cerebral hemorrhage, pulmonary
edema, and hepatic necrosis major causes of
death. Pre-eclampsia is associated with fetal
growth retardation, prematurity, miscarriage,
and neurodevelopmental abnormalities.

MANAGEMENT
Definitive treatment is by delivery. Magnesium
sulfate is the treatment of choice for seizures.
Methyldopa, labetalol and hydralazine are effec-
tive antihypertensive agents in this condition. 248 Pre-eclampsia. Light microscopy showing
Aspirin and possibly antioxidant vitamins C and occlusion of glomerular capillary lumen by swelling
E may be useful prophylactic agents. of glomerular endothelial cells (H+E x400).
158 RENAL DISEASE IN PREGNANCY

Pregnancy in renal disease

Pre-existing renal disease can affect the outcome complex clinical problems. Pregnancy may be
of pregnancy and pregnancy can alter the course associated with disease flares especially in the
of renal disease. Hypertension, heavy protein- puerperium. Women with active SLE are advised
uria, and impaired renal function all predispose not to conceive until the disease is under
to pre-eclampsia and prematurity. Pregnancy can control. Mycophenolate mofetil is showing
accelerate the progression of renal failure, increasing promise in the treatment of lupus
especially in patients with a creatinine nephritis, but women are currently advised not
>2.0 mg/dl (177 +mol/l) prior to pregnancy. to conceive whilst taking this drug because of
In patients with chronic glomerulonephritis, concerns about teratogenicity. Anti-phospho-
pregnancy does not seem to worsen renal lipid antibodies are associated with fetal loss in
outcome if pre-existing renal function is good. all three trimesters and with pre-eclampsia.
The normal physiologic changes of pregnancy Prepregnancy counseling is essential to
will increase the degree of proteinuria. Systemic explain the risks of pregnancy in patients with
lupus erythematosus commonly affects women renal disease.
of childbearing age, and pregnancy can cause

Pregnancy in dialysis patients

Pregnancy is rare in dialysis patients because of and fetus is required, with aggressive dialysis
reduced libido and impaired fertility. The risks essential (Table 12). Dialysis aims to keep blood
need to be carefully explained to the parents: urea below 15 mmol/l (90 mg/dl), control
maternal hypertension, pre-eclampsia, pre- hypertension, and minimize hypotension during
maturity, and intra-uterine growth retardation. dialysis which could reduce placental blood flow.
If the parents decide to proceed with the Therefore daily hemodialysis is optimal.
pregnancy very careful monitoring of mother

Pregnancy in renal transplant patients

The outcome is excellent for pregnancy in Women with impaired graft function are
women with stable and good renal transplant at increased risk of pre-eclampsia and
function. Women with chronic renal failure worsening renal function with pregnancy.The
should thus be advised to defer pregnancy until guidelines for preconception counseling for
they have been successfully transplanted. renal transplant patients are listed in Table 13.
 PREGNANCY IN RENAL TRANSPLANT PATIENTS 159

Table 12 Guidelines to optimize pregnancy outcome in the dialysis patient

• Prophylactic dialysis: urea <15 mmol/l (90 mg/dl) to avoid polyhydramnios

• HD: 5–7 sessions/week, bicarbonate, minimal heparin, slow ultrafiltration
• PD: decrease volumes and increase frequency
• Adequate supply of calories and protein
Protein intake 1 g/kg/day + 20 g/day for fetal growth
Water soluble vitamins/zinc
• Tight BP control with methyldopa and beta blockers
• Correction of anemia
Hb 10–11; erythropoietin, iron, and folic acid
• Prevention of metabolic acidosis
• Prevention of hypocalcemia with calcium carbonate
• Treatment of premature labor
Use beta agonist; avoid NSAIDs
• Regular fetal monitoring

Table 13 Guidelines for preconception counseling in renal transplant recipients

• Wait at least 1 year post-transplant

• Stable good renal function
• No recent rejection
• Minimal proteinuria
• Absence of pelvicalyceal distension
• Easily managed hypertension
• Drug therapy reduced to maintenance levels
• Avoid mycophenolate mofetil, sirolimus
This page intentionally left blank
Chapter Ten
161

Acute renal failure

• Introduction

• Epidemiology

• Classification

• Clinical assessment

• Management and outcome

162 ACUTE RENAL FAILURE

Introduction Epidemiology

Acute renal failure (ARF) is a medical emer- The lack of a precise consensus definition of
gency which taxes both the patient and the ARF makes for difficulties comparing epi-
physician alike. ARF is likely to be encountered demiologic ARF series. If one includes any case
in the community and in hospital wards and of minor reversible alteration in renal function
intensive care units, with input from generalists, – seen by any physician, not necessarily dialysed
internal medicine specialists, cardiologists, – the incidence is probably 200–300 cases per
diabetologists, infectious disease specialists, million population per year; the figure is about
gerentologists, general, orthopedic, vascular and 50 cases for those requiring dialysis. In major
cardiothoracic surgeons, and obstetricians – and tertiary hospitals 5% of inpatients may develop
of course, nephrologists. ARF (reflecting the types of surgery and medi-
ARF is not one disease, but a stereotyped cine practiced, e.g. coronary interventions, vas-
renal response to myriad different renal insults, cular surgery).
with different pathophysiologic mechanisms. The incidence of ARF rises very steeply with
ARF can arise alone, or in the context of two, age for three reasons. First, older patients have a
three, or four organ failures (249, 250). Many greater number of comorbidities, whose treatment
of the renal insults that end up causing ARF are may well be the cause of ARF: second, because
the result of modern medicine and surgery – natural defence mechanisms, such as cardiovas-
there is some opportunity for prediction and cular reflexes, autoregulation, and anti-bacterial
prevention (not always grasped). Equally, and anti-oxidant systems are less effective: and
prompt detection and diagnosis of ARF can third, because from the age of 40 years GFR
arrest an otherwise inevitable cycle of events that declines by about 9 ml/min/decade – a subject
leads to protracted renal shut-down and the aged 80 years will have about 50% of the renal
need for dialysis, with the attendant increase in function of someone 50 years or so younger.
mortality. In the hospital setting acute tubular necrosis
is by far the commonest cause of ARF (roughly
DEFINITION OF ARF evenly divided between sepsis and ischemia) but,
Arbitrarily ARF is defined as a rapid and in the community, prostatic obstruction and
substantial decline in excretory renal function drugs are the main causes of ARF. The increas-
(i.e. sudden fall in GFR) leading to accumu- ing use of nonsteroidal anti-inflammatories, and
lation of nitrogenous waste products and elec- ACE inhibitors and angiotensin receptor
trolytes. There is no broadly-accepted definition blockers, often in an aging population, is a
of the degree of renal impairment (i.e. rise in major factor in community-acquired ARF.
urea or creatinine), nor its rapidity of onset. In developing countries, obstetric, infective
and toxic causes of ARF predominate.

249 250

249, 250 Patients in an intensive care setting with multiple organ failure after trauma or surgery.
Acute renal failure is common. 249 shows a wide defect in the anterior abdominal wall after
surgery for necrotising fasciitis. 250 shows a road traffic accident victim.
 CLASSIFICATION 163

Classification

Traditionally and usefully ARF is classified into framework for the understanding of ARF and
prerenal (hemodynamic), renal, and postrenal its management. Table 14 lists the major causa-
causes. This classification provides a conceptual tions arranged logically and mechanistically.

Table 14 Classification of causes of acute renal failure

ARF classification Mechanism Example

Prerenal Reduced effective GI bleed

circulating blood volume Pancreatitis
Hypotension
Sepsis

Renal Renal arterial occlusion Thrombosis

Embolism
Ligation

Small vessel disease Vasculitis

HUS/TTP
Embolic
Hypertension
Scleroderma

Interstitial disease Drugs

Autoimmune
Infection
Malignancy

Glomerulonephritis Lupus
Rapidly progressive glomerulonephritis

Ischemic ATN Many

Maintained prerenal

Toxic ATN: endogenous Rhabdomyolysis

Bilirubin
Hemoglobin
Light chains

Toxic ATN: exogenous Drugs

Contrast media

Intratubular blockage Casts

Crystals

Renal vein occlusion Nephrotic syndrome

Postrenal Obstruction Prostate

Ureter
164 ACUTE RENAL FAILURE

Classification (continued) abrupt change in GFR is seen only with a severe

stenosis affecting a single functional kidney, or
PRERENAL ARF with bilateral stenoses. GFR can be rapidly
Pathophysiology of prerenal ARF restored to normal by withdrawl of the drug,
The fundamental change is a marked reduction though rarely thrombosis of the renal artery can
in glomerular perfusion. Decreased effective occur in a low-blood flow/acute illness setting.
circulating blood volume is the major reason for Nonsteroidal anti-inflammatories (NSAIDs)
this. A number of factors can cause this change profoundly inhibit prostaglandin synthesis. In a
– the most common is hypovolemia which itself variable but small number of people renal blood
has many causations. Congestive cardiac failure, flow is exquisitely dependent on endothelially-
cirrhosis, sepsis, and severe nephrotic syndrome derived renal prostanoids. In a setting of low
can act similarly. effective circulating volume (e.g. sepsis, diar-
Normally baroreceptors and baroreflexes act rhea), or with other nephrotoxic drugs,
to maintain perfusion pressures. As these are NSAIDS can cause ARF.
activated, the renin–angiotensin and sym- Cyclosporine (cyclosporin) usually causes
pathetic nervous systems are activated, and intense afferent arteriolar vasoconstriction and
ADH released. Systemic vasoconstriction occurs leads to a fall in GFR. The vasoconstriction
but renal arterial resistance rises to a lesser seems to be multifactorial and related to reduced
extent. Renal blood flow is highly regulated to NO production, to greater endothelin and
achieve constancy by autoregulation (myogenic thromboxane production, and activation of the
reflex) across the mean arterial pressure range renin–angiotensin and sympathetic nervous
of 60–160 mmHg (8–21.3 kPa) in health. As systems. Early withdrawal of cyclosporine (cyclo-
well as this autoregulation the kidney can auto- sporin) leads to rapid GFR recovery; later, inter-
regulate GFR and blood flow simultaneously; stitial fibrosis leads to long-term loss of GFR.
this is achieved by having independent
mechanisms to control the tone of the afferent RENAL/PARENCHYMAL ARF
and efferent arterioles. Angiotensin, prosta- Acute tubular necrosis (ATN)
glandins, nitric oxide, and other vascular media- Pathophysiology of ATN
tors have crucial roles in these tasks. ATN describes the injury to the renal paren-
All of the above devices and mechanisms chyma that occurs following prolonged renal
have limits beyond which renal injury cannot be ischemia or exposure to nephrotoxins. The term
prevented. Once efferent arterioles start to con- ATN is of course histologic but typically
strict (e.g. with very profound sympathetic inferential – ironically it is this type of patient
nervous system activation), renal blood flow and who is least likely to undergo renal biopsy as
GFR fall and renal failure ensues. potentially ATN is recoverable; the acute
necrosis of renal tubular epithelial cells is
Causes of prerenal ARF followed by tubular regeneration.
These include hypovolemia (blood or urine or The proximal tubule and the medullary thick
fluid loss) and contributions from inadequate ascending loop of Henle are the most sus-
salt and water intake. Left ventricular failure ceptible areas to injury. In part this is because
(LVF) is a cause of prerenal ARF, as is over- the renal medulla is intensely metabolically
zealous use of diuretics or ACE inhibitors to active (the S3 tubular segments especially so),
treat LVF. Cirrhosis of the liver is associated receives only 20% of renal blood flow (normal
with systemic and intrarenal hemodynamic renal blood flow is 1200 ml/min), and is
derangements – in part because of abnormal incipiently hypoxic even in health (oxygen
prostanoid generation and handling. Hypo- tension is typically 3–4 kPa [22.5– 30 mmHg]).
albuminemia may also play a role, as it more Decreased oxygenation or increased metabolic
clearly does in the ARF seen rarely in severe demand can lead to hypoxic damage.
nephrotic syndrome. ACE inhibitors and Necrosis and apoptosis are seen in the
angiotensin receptor blockers can induce ARF tubules as lethal cell changes (251–256). Less
in patients whose GFR is maintained only by severe damage causes cell swelling, vacuolation,
angiotensin-II-mediated efferent arteriolar vaso- disruption of the tubular cell cytoskeleton,
constriction. This is seen especially with a dissolution of the integrin-dependent cell matrix
hemodynamically significant renal artery adhesion, loss of cell surface brush border, and
stenosis (stenosis >80%, see Chapter 5), but can cell desquamation into the tubular lumen. Thus
also be seen in cirrhosis and heart failure. The cellular debris is shed into the proximal renal
 CLASSIFICATION 165

251 252

251 Histology of normal renal tubules. Note 252 Acute tubular necrosis. Desquamated
‘back-to-back’ renal tubules with plump epithelial epithelial cells causes tubular blockage (arrow)
cells (H+E x150). (H+E x200).

253 254

253 Acute tubular necrosis. Electron micrograph 254 Histology of severe acute tubular necrosis.
of a proximal tubule showing blockage with Electron micrograph of a tubule showing
cellular debris. rupture/destruction of the delicate brush border.

255 256

255 Histology of severe acute tubular necrosis, 256 Histology of milder/recovering ATN.Tubular
with widespread renal tubular epithelial cell epithelial cell regeneration is seen (mitotic figures)
attenuation (H+E x250). (arrow) (H+E x400).
166 ACUTE RENAL FAILURE

Classification (continued) absorbed in the proximal tubule but in gross

excess these defences are overwhelmed and a
tubules and this debris can block the distal great load of myoglobin is received in the distal
tubules once it has combined with the viscid tubule, where it precipitates to block the tubule
Tamm–Horsfall protein secreted there. Light (particularly in acid urine [260]) and causes
chains in myeloma (59) or myoglobin in rhado- oxidative damage (the heme scavenges NO).
myolysis form ‘hard’ casts which plug distal Rhabdomyolysis patients often have severe
tubules, and may excite an inflammatory reac- volume depletion (as their muscles are grossly
tion in surrounding parenchyma. edematous). This is an example of several
Recovery of ATN requires tubular regenera- mechanisms combining to produce renal injury.
tion and luminal patency. Understanding how Trauma remains an important etiology, but
to manipulate these processes may one day reap muscle damage from pressure (e.g. alcoholic
rich clinical dividends. stupor, or coma) is more common. Status
epilepticus or neuroleptic malignant syndrome
ACUTE CORTICAL NECROSIS can also induce severe muscle damage. Mara-
Unlike ATN, cortical necrosis (246) is virtually thon running in an undertrained dehydrated
impossible to recover from. There is micro- individual is another risk for this type of
vascular and glomerular thrombosis and cortical problem. Drug reactions (e.g. statins, fibrates)
infarction. Medullary blood supply can be are seen rarely; rhabdomyolysis is seen in <0.1%
maintained (but to no useful purpose). Obstet- patients on statins. Intense myositis (viral,
ric emergencies (abruptio placentae), endo- immune) or inherited muscle enzyme defects
toxinemia and DIC are typical causes of this very such as McCardle’s syndrome (myophosphory-
rare outcome to acute renal injury. Why some lase deficiency) or carnitine palmityl transferase
patients develop ATN and not cortical necrosis deficiency complete the picture.
or vice versa is not clear. Children seem more Muscles are usually swollen, painful, and
prone to cortical necrosis than do adults. tender – indeed fasciotomies may be needed
Though the classical appearance of tram-line quickly if a limb is to retain viability (261).
renal cortical calcification is well-known (and Urine is chocolate-brown in color (262). The
can also be seen on CT scanning) (257–259), urine dipstick shows intense heme reaction, but
in practice this is unusual, and renal biopsy is a microscopy does not show any red blood cells.
more reliable way to determine its presence. The urine myoglobin should be measured, as
should plasma creatine phosphokinase (in-
RAPIDLY PROGRESSIVE variably elevated >5000 U/ml). Creatinine, uric
GLOMERULONEPHRITIS (RPGN) acid, phosphate, potassium, and acid moieties
Particularly out of hospital this can be an are all released from dead muscle. Hypocalcemia
important cause of ARF and must be diagnosed in the acute phase is common; hypercalcemia in
in time for treatment to be effective. Red cell the recovery phase is rarer.
casts in the urine are pathognomonic, but not Treatment is by means of adequate hydration
totally specific (8). Typically RPGN is due to by intravenous infusion of saline and dilute
renal or systemic vasculitis; often auto-anti- bicarbonate. Dialysis or filtration may be needed
bodies or signs of inflammation are present. The to prevent lethal hyperkalemia, or to remove a
urine tests strongly positive for blood and causative factor, e.g. theophylline leading to
protein and the urinary sediment contains red status epilepticus and muscle damage. Recovery
cell casts. Renal biopsy is the best way to achieve is usual within 3 weeks; there are no long-term
a diagnosis. Treatment is typically with pred- renal sequelae.
nisolone, cyclophosphamide, and plasma ex- Hemoglobinuric-ATN is seen in the context
change in some cases (Chapter 3). of massive intravascular hemolysis, e.g. glucose-
6-phosphate deficiency, paroxysmal nocturnal
ENDOGENOUS NEPHROTOXINS hemoglobinuria, blood transfusion reaction,
Myoglobinuria and acute myoglobinuric renal malaria, drugs, venoms, and prosthetic heart
failure were first described in the context of air- valves. Hemoglobin being much larger than
raid bomb damage victims. Rhabdomyolysis is myoglobin is much less well-filtered, and is less
a fairly common cause of ATN, seen in 5–10% tubularly toxic.
of hospitalized cases. The plasma is typically pink in hemoglo-
Myoglobin is a freely-filtered 17 kDa heme- binuria; the urine can often be a normal color
protein which is normally endocytically re- (though it is black when severe). Hydration and
 CLASSIFICATION 167

257 258

257 CT scan of a renal transplant showing diffuse 258 Histology of acute cortical necrosis
calcification of a much-thinned renal cortex.The showing pallor/infarction of tubules and
graft had been ‘lost’ many years before following glomeruli (H+E x10).
DIC secondary to severe bacterial sepsis.

259 260

259 Histology of acute cortical necrosis 260 Myoglobin cast (chocolate-brown color) in
showing survival of some endothelial cells urine (H+E x300).
(H+E x250).

261 Muscle 261 262

fasciotomy to
prevent acute
compartment
syndrome in a
case of acute
rhabdomyolysis
(following a
prolonged
stupor after
alcohol excess).

262 Chocolate-brown colored, thick urine in the

catheter bag. Leg redness and edema can also be
seen in this elderly female who fell at home and
lay helpless for 48 hours on the floor.
168 ACUTE RENAL FAILURE

Classification (continued) Alcohol, bicarbonate, and fomeprizole are treat-

ments for this potentially lethal poisoning.
urine alkalinization are recommended; obviously Contrast media are known for their nephro-
removing the cause of hemolysis is paramount. toxicity despite the introduction over the last
Bilirubin causes ATN only when there is two decades of non-ionic media, which are
additional renal injury, e.g. sepsis – so ascending substantially less toxic. However, many older
cholangitis would be a prime example. Relief of subjects are undergoing studies involving the
biliary obstruction, hydration, and vigorous use of these agents. Age, diabetes, myeloma, use
treatment of sepsis are indicated (263, 264). of metformin, and pre-existing renal failure are
Some light chains are directly nephrotoxic; risk factors for renal damage.
acute renal failure is a rare but important presen- The media are significantly hyperosmolar and
tation of acute myeloma. Cast nephropathy can impose an oxidative stress on tubules. Acute
occur which evinces a brisk inflammatory oliguria is unusual – more often there is gradual
reaction in the renal interstitium. Myeloma casts oliguria and renal impairment over 3–7 days
tend to be dense, fractured, and associated with postcontrast load. If there has been an aortogram
a giant cell reaction (59). or a cardiac catheter, atheroembolism from the
Crystals can be seen in acute elevation of uric vascular catheter in an atherosclerotic aorta, as
acid levels, e.g. after chemotherapy in tumor- well as contrast nephrotoxicity, can induce renal
lysis syndrome. Urine alkalinization and allo- failure. Adequate hydration and N-acetyl cysteine
purinol are needed urgently. Hypercalcemia can are potential preventative measures.
also cause intratubular crystal deposition. Drugs are a very important cause of nephro-
toxicity by a number of different mechanisms.
EXOGENOUS NEPHROTOXINS Some drugs compromise the hemodynamic
Ethylene glycol (antifreeze) is readily metabol- response to renal injury, other cause crystalluria,
ized by alcohol dehydrogenase to glycolic acid, others cause acute renal parenchymal injury, e.g.
which is a tubular toxin, glyoaxalic, and oxalic acute interstitial nephritis (108). Reactions can
acids. Oxaluria ensues with a metabolic acidosis. be dose-dependent or idiosyncratic. Table 15
Oxalate crystals may precipitate intratubularly. lists the most important nephrotoxic drugs.

263 264

264 Deep-green jaundice, and deep-green

peritoneal dialysate, from a patient in acute renal
failure following acute, severe, drug-induced
hemolytic anemia.

263 Pigmented bilirubin cast in free (green-

colored) urine following acute severe drug-
induced hemolytic anemia.
 CLASSIFICATION 169

POSTRENAL ARF 265

By definition this is a urologic area. Pelvi-
ureteric, ureteric, vesico-ureteric, bladder, pros-
tate, and urethral obstruction can give rise to
ARF. Prolonged obstruction leads to severe
cortical thinning (265) and loss of renal
function, so that relief of obstruction may not
then be accompanied by worthwhile renal
functional recovery.

265 Ultrasound scan showing gross hydro-

nephrosis and severe cortical thinning (2–4).

Table 15 Nephrotoxic drugs

Classification/mechanism Example

Intrarenal vascular
Thrombotic microangiopathy Cyclosporine (cyclosporin), tacrolimus, mitomycin C,
oral contraceptive pill
Vasculitis Amphetamines

Toxic ATN
Antimicrobials Aminoglycosides Amphotericin
Vancomycin Pentamidine
Foscarnet

Chemotherapy Cisplatin 5-fluoruracil

Ifosfamide Cytarabine
Mithramycin

Miscellaneous Lithium
Paracetamol (acetaminophen)

Recreational drugs Ecstasy Amphetamines

Interstitial nephritis Antibiotics NSAIDs

Urinary tract obstruction

Papillary necrosis Analgesic, NSAIDs

Crystals Aciclovir (acyclovir) Triamterine

Methotrexate Indinavir
Sulfonamides

Retroperitoneal fibrosis Ergotamine

170 ACUTE RENAL FAILURE

Classification (continued) 266

Cases of obstruction can be much more
subtle (266–271) (see also urinary tract obstruc-
tion in Chapter 6, p. 106). As an initial approach
a nephrostomy can be inserted into a dilated
pelvicalyceal system (the puncture can reveal pus
or blood and not just urine). Urinary tract
stenting may be needed. As well as relieving
obstruction a nephrostomy can allow investiga-
tion of its causation (272–274). Dialysis sessions
may still be needed for a while as accompany-
ing ATN is common, especially if there have
been nephrotoxic drugs in use, or sepsis. Team-
work between urologic and nephrologic special-
ists is essential. 266 Ultrasound scan showing mild hydro-
nephrosis and dilatation of the proximal ureter.

267 268

267 CT scan of the pelvis showing a large

gynecological mass.This was responsible for acute
renal failure in a 90-year-old female (same patient 268 CT scan of the kidneys showing mild bilateral
as 265, 266). hydronephrosis.

269, 270 IVU from a 269 270

female discovered to be
in acute renal failure (and
with anemia, back pain,
and an ESR of
>120 mm/first hour).
Early phase (269) shows
relatively normal
nephrogram and
pyelogram for the left
kidney, but with medial
indrawing of the left
ureter. Right kidney is
obstructed. Later phase
(270) shows late
retention of contrast in a
dilated right renal pelvis,
and marked proximal
right ureteric medial indrawing. A case of retroperitoneal fibrosis.
 CLASSIFICATION 171

271 272

271 CT scan showing bilateral severe 272 Abdominal CT scan showing a small right
hydronephrosis, worse on the right. A large kidney, a normal left kidney, and two percutaneous
soft tissue mass is present between the nephrostomies.
kidneys arising from the retroperitoneum.
Biopsy disclosed B-cell lymphoma.

273 An antegrade 273 274

contrast study
(antegrade
pyelography)
where contrast is
injected down the
nephrostomy tube
into the renal
pelvis.The contrast
in this case
terminates abruptly
at the lower ureter
near the
vesicoureteric
junction.This is a
typical site for
tumors.

274 A nephrostomy can be seen entering the renal pelvis,

and then a ureteric stent can be seen from renal pelvis down
the ureter to the bladder.
172 ACUTE RENAL FAILURE

Clinical assessment (Table 16)

As there are so many different causes of ARF, The assessment of the patient must be
there needs to be a logical exercise in informa- thorough enough to answer all of these points.
tion and evidence gathering, assimilating diverse Thus, most of the following are often needed:
information, then answering some basic funda- • Complete physical examination (volume,
mental questions, the answers to which give in- icterus, ascites, bruits).
sight into causation and appropriate intervention: • Careful scrutiny of old notes, drug and fluid
• Is this acute renal failure (i.e. was there charts, computer records.
normal or abnormal renal function before)? • Urinalysis, urine volume, biochemistry.
• Is there evidence of reduction in circulating • Blood tests (renal, liver, immunologic, hema-
blood volume? tologic).
• Has there been a major vascular occlusion? • Renal tract imaging – plain film, ultrasound,
• Are there clearly identifiable nephrotoxins? CT scan, nuclear medicine.
• Is there parenchymal disease other than ATN? • Renal angiography.
• Is there any evidence of renal tract obstruction? • Renal biopsy.

Table 16 Differentiating features of investigations into ARF

Assessment Prerenal ATN Acute GN Interstitial Atheroembolic Obstruction

Clinical Hypovolemia Ischemic Rare anuria Drugs, rash Vasculopathy Pain, anuria
toxin eosinophils

Urea/creatinine High Medium Medium Medium Medium High

ratio

Urinary sodium* <10 >50 <10 10–100 >50 <20

(mmol/l [mEq/l])

Urinalysis Normal Casts +++ bld +bld Normal Normal

+++ prot +prot
WBC
eosinophils

Urine osmolality* >500 <350 300–500 300–500 <350 >500

(mmol/kg
[mOsm/kg] H2O)

Ultrasound size Normal Normal Enlarged Normal Scars/small Pelvis and

calcyces
dilated

*Urine osmolality and electrolyte data are uninterpretable in the presence of loop diuretics
 MANAGEMENT AND OUTCOME 173

Management and outcome

PRERENAL ARF of claims for nephroprotective/renal tubular

To restore depleted intravascular volume the regenerating compounds).
choice is between blood and isotonic solutions
(saline or Ringer’s). Colloid versus crystalloid COMPLICATIONS OF ATN ARF
has been a recently controversial question – there Euvolemia is hard to maintain in this setting, and
seem to be few real advantages to the more most patients become severely salt and water
expensive colloids. Patients can often have salt overloaded. Loop diuretics (intravenously in
and water overload (extracellular salt and water difficult cases or where plasma albumin is low,
excess) while being intravascularly volume thereby increasing gut edema and reducing drug
depleted. Salt and water diuresis must be absorption) with or without thiazides are the
matched by movement from the extracellular to mainstay of therapy. Hyponatremia is common
the intravascular spaces, otherwise further as free water excretion in ATN is impaired.
volume depletion will occur. Loop diuretics, as Careful fluid replacement (intravenous or
either a bolus or an infusion, with, in refractory nasogastric/feed) can prevent or overcome this.
cases, salt-poor albumin, can be effective. Im- Hyperkalemia is very common in ARF; in
proving heart failure-induced ARF involves a noncatabolic patients plasma potassium rises by
twin strategy of increasing cardiac output and 0.5 mmol/day, and can rise by five times this in
reducing cardiac afterload, e.g. inotropes and very catabolic patients or patients with a large
nitrates. Noradrenaline (norepinephrine) to amount of damaged tissue (e.g. rhabdomyo-
‘tighten’ the excessively vasodilated systemic lysis). Potassium supplements and retaining-
circulation can be effective in ‘sepsis’ ARF (but drugs must obviously be stopped. Dietary/feed-
needs careful monitoring of cardiac output and ing advice is important. In mild cases calcium
systemic vascular resistance). Dopamine has been resonium by mouth or rectum can be effective
in vogue (whether at high dose as an alpha in the short term. If there is urine being pro-
agonist or at so-called ‘low dose’ as a renal vaso- duced, loop diuretics are kaliuretic. More severe
dilator) for three decades. Sadly there never has cases required insulin and dextrose, more rarely
been any evidence that using dopamine is help- hypertonic saline or bicarbonate, with emergency
ful; there is quite a lot of evidence that it is intervention with boluses of 10% calcium glu-
potentially harmful (arrhythmias and adverse conate. These bolus maneuvers merely ‘hide’
metabolic sequelae). Prevention of prerenal ARF potassium in cells, and this strategy is doomed
by careful patient selection and supervision, and to failure unless the excess potassium is actually
rapid response to altered hemodynamic status excreted from the body. If this is not possible,
and oliguria, can help to reduce the amount of dialysis is needed.
dialysis-requiring ATN in hospital. The use of hypertonic intravenous sodium
bicarbonate acutely to correct acidoses (diabetic
ATN ARF ketoacidotic, lactic, renal failure) has fallen into
Prerenal ARF and ischemic ATN are part of a opprobrium – this relates to the osmolar,
spectrum of renal responses to renal hypo- sodium, and fluid loads imposed, and the fact
perfusion. Prevention of contrast nephropathy that bicarbonate on dissociation is a carbon
is best achieved by identification of ‘at-risk’ dioxide donor. Oral sodium bicarbonate is often
subjects (older, diabetic, myeloma, metformin), used slowly to correct mild metabolic acidosis.
achievement of adequate hydration and urine Hyperphosphatemia, hypocalcemia, and
output (using 0.45% or 0.9% saline intra- hyperuricemia are further potential metabolic
venously), and possibly by N-acetyl cysteine for complications.
48 hours before and after contrast. Reducing Nutrition needs active management during
the amount of injected contrast to the bare ARF. Catabolism may be net 200 g protein/day.
minimum in ‘at-risk’ cases is sensible. Some Adequate calories are needed, without excessive
drug toxicities can be avoided, especially where protein, sodium, or potassium.
concentrations can be measured (lithium, genta- Bleeding is a significant issue in ARF. Sites
micin, vancomycin), hydration ensured (aciclo- include gastrointestinal tract, and sites of trauma,
vir [acyclovir]), or less nephrotoxic variants used line insertion, and operations. Prophylactic
(e.g. lipid-soluble amphotericin). measures against peptic ulceration are very sen-
There is as yet no widely-accepted specific sible (e.g. proton pump inhibitors). Uremia is
treatment of established ATN (but no shortage associated with an acquired platelet functional
174 ACUTE RENAL FAILURE

Management and outcome (continued)

defect (reduced aggregability and reduced activa- associated with a better ARF recovery rate.
tion) which can be measured as a prolonged Dialysate needs to have a bicarbonate-based
bleeding time. Dialysis best deals with this, but buffering system. Anticoagulation should be
transfusion to a hemoglobin of >10 g/l (1 g/dl) minimized to low-dose heparin, or heparin-
also helps. Clearly careful thought needs to be free dialysis should be attempted (high flow,
given to the continued use of antiplatelet agents saline flushes).
and other anticoagulants in ARF. Uremic bleed-
ing can be treated with 1-deamino-8-D-arginine CONTINUOUS
vasopressin (an analogue of ADH) which HEMOFILTRATION/DIAFILTRATION
transiently releases endogenous endothelial cell Many of the sickest patients with ARF, e.g.
stores of factor VIII–von Willebrand factor com- those with several organ failure, are hemody-
plexes; these increase platelet adhesion to the namically unstable and hypercatabolic. Attempts
vessel wall. The effect of this intervention is rapid to use intermittent HD usually result in circu-
(within minutes) but wanes rapidly and there is latory collapse. It is much preferable to use
tachyphylaxis. Cryoprecipitate can also be helpful, continuous convective-based renal replacement
but takes 8–24 hours to work. therapies in this setting. Continuous veno-
venous filtration (CVVH) and continuous
DIALYSIS IN ARF arteriovenous filtration (CAVH) rely on convec-
The absolute indications for dialysis are the tive clearance of solute across a porous dialysis
development of the uremic syndrome or irre- membrane with fluid replacement with physio-
mediable and life-threatening hyperkalemia logic solutions. Diffusive and convective clear-
(275–277), acidosis, or pulmonary edema ance can usefully be combined in CVVHDF
(278). If recovery is not imminent, most neph- (279). Bicarbonate-based buffers are used in
rologists would commence dialysis with a plasma severe catabolism or liver failure. In all of these
creatinine >7.0 mg/dl (619 +mol/l). If the techniques one has the potential to control fluid
patient is not in a medical facility where some balance, plasma ionic composition, and remove
sort of dialysis is available, the patient needs to toxins with as little hemodynamic disturbance
be made safe to transfer to a suitable facility; in as possible.
practice hyperkalemia and pulmonary edema are
the two risks for sudden deterioration. Emerg- PERITONEAL DIALYSIS
ency hemofiltration on the ICU at a referring This is a useful therapy for children and adults
hospital is safer than a long risky journey with a where more expensive therapies (see above) are
hypoxic hyperkalemic patient. not provided. Although ‘gentle’ this therapy is
What type of renal replacement therapy to very limited in its applicability to a septic unwell
institute depends in part on local factors such as patient, and there are risks from the insertion of
facilities and expertise. The options include the peritoneal catheter (as, to be fair, there are
peritoneal dialysis, intermittent hemodialysis, for venous access). Peritonitis is another risk
and continuous therapies. There is evidence (and again, vascular catheter-related sepsis is a
though that continuous convective-based ther- major problem in ICU).
apies are superior (in outcome terms) for sepsis-
and ischemia-induced ATN; in part this is due OUTCOME IN ARF
to better removal of circulating cytokines, and The mortality of ARF is about 40% – ranging
also because of the avoidance of further hemo- from 10% for uncomplicated easily reversible
dynamic instability that can be seen when ATN to 80%+ for ICU-based multiple-organ
using intermittent hemodialysis in an acutely failure patients. The age and comorbidities of
unwell patient. the typical ARF patient may explain this high
mortality rate; most deaths are due now to the
INTERMITTENT HD underlying cause and not the renal failure per se
This is performed 3–5 times a week, depend- (but sometimes due to complications arising
ing on the fluid removal and catabolism issues. from its treatment).
Vascular access is by means of a cuffed double- Patients who survive an ARF episode general-
lumen catheter in a great vein. Use of a bio- ly recover sufficiently to live a normal life span.
compatible membrane (e.g. polysulfone, poly- ARF can be irreversible, or only partly reversible,
carbonate, polyamide, polyacrilonitrile) is in the elderly with pre-existing renal damage.
 MANAGEMENT AND OUTCOME 175

275

276

277

275–277 EKG traces showing the effect of potassium. Gross

conduction defects (275) due to hyperkalemia (potassium 8.6 mmol/l
[mEq/l]). Emergency treatment with 10 ml intravenous 10% calcium
gluconate allowed dialysis to start.Tall peaked T-waves (276) and some
QRS prolongation (potassium 6.6 mmol/l [mEq/l]). After 4 hours'
dialysis a normal EKG tracing (277) with plasma potassium of
4.0 mmol/l (mEq/l).

278 279

278 Chest X-ray showing acute pulmonary 279 Continuous hemofiltration

edema which required emergency hemodialysis. machine.
This page intentionally left blank
Chapter Eleven
177

Chronic renal failure

and dialysis

• Introduction

• Natural history

• Symptoms, signs, and clinical evaluation

• Reversible causes

• Complications and consequences

• Clinical interventions to retard progression to

end-stage renal failure

• Dialysis (renal replacement therapy – RRT)

178 CHRONIC RENAL FAILURE AND DIALYSIS

Introduction

The progression of chronic renal failure (CRF) patients in the UK and >300,000 in the USA.
leads in time to end-stage renal failure, at which The UK Renal Registry is beginning to hold
stage renal replacement therapies (dialysis) need epidemiologic and clinical audit data, mirroring
to be considered. In the UK about 110 patients the efforts of the United States Renal Data
per million population are currently accepted Service (USRDS).
for dialysis each year (i.e. about 5500–6000 Although in absolute terms the numbers of
patients); this compares with 270 patients per patients with severe CRF going onto dialysis are
million in the USA in 1996. The incidence of modest (especially compared to cardiac or can-
CRF rises very steeply with age, and is much cer patients), there is a disproportionate financial
greater in African-American or Asian popula- cost – a typical dialysis patient’s health care will
tions than in Caucasians. The prevalence of ‘cost’ at least £20,000 (US $30,000) per annum
patients with significantly elevated plasma to deliver. Presently 30–40% of all new dialysis
creatinine values cannot precisely be estimated, patients have diabetes as the underlying causa-
but it might be 2000–3000 per million popula- tive factor for CRF. As populations have grown
tion. Only a minority of these patients will have more obese, there has been a huge increase in
seen, or be under the active management of, a type II diabetes and its attendant complications.
nephrologist. Many of the complications that Such patients, if they live to enter a dialysis
dialysis patients suffer have their origins in the programme, are typically 60–70 years of age,
pre-ESRF CRF phase; familiarity with these, and with cardiovascular morbidities, and are very
with preventive strategies, mandates a liaison rarely suitable for renal transplantation. Thus
with nephrology specialists. Dialysis patient only about one in four current dialysis patients
numbers run at about 5–8 times the incidence; can hope to receive a renal transplant.
there are about 30,000 dialysis and transplanted

Natural history

Renal functional decline can often be found to ACE genotype, aldose reductase, TGF-beta);
be a linear event when plotted as reciprocal diabetic and nondiabetic nephropathies cluster
creatinine versus time. Variations around this in families. Proteinuria is emerging as a prime
linearity are, though, common, e.g. intercurrent risk factor for renal decline (and also for cardio-
illnesses, dehydration, drugs. The rate of renal vascular mortality in hypertensive and diabetic
functional decline depends on many factors – populations). The Modification of Diet in Renal
these include the etiology of the underlying Disease (MDRD) study shows baseline pro-
nephropathy, the quality of blood pressure teinuria is a strong predictor of future renal
control, and factors specific to individual decline. Increasing evidence is also incriminating
patients. Chronic glomerulonephritis causes a dyslipidemia.
faster decline in renal function than is seen in The strongest association of all, however,
chronic interstitial nephritis. between a risk factor for nephropathy and a
Various factors affect the progression of CRF. prime mover in renal functional decline, is
Age is relevant as the incidence of ARF and CRF hypertension and renal disease. The rate of
rises steeply with age. The etiology of CRF is functional decline can vary 10-fold depending
very different for aged patients (hypertension, on prevalent blood pressure levels. The MDRD
type 2 diabetes, renovascular and prostatic study showed the great relevance of blood
diseases). Male gender has long been known to pressure to renal functional decline in the
be a risk factor for a more rapid decline in renal presence of significant proteinuria (>3 g/24 h).
function; renal diseases are also more common There is clear evidence that smoking cigarettes
in males. Race is also an important risk factor contributes to adverse renal outcomes.
for CRF, in part because diabetes and hyperten-
sion are more common in African-Americans MECHANISMS OF CRF PROGRESSION
and Asians. There are clearly many genetic Much information has been derived from a
factors in the susceptibility to nephropathy (e.g. variety of animal models of human uremia. These
 REVERSIBLE CAUSES 179

include 5/6 nephrectomy, puromycin neph- this resolution is not accompanied by any scar-
ropathy, and mercuric chloride nephropathy. The ring; in others, scarring is severe.
progression of CRF is associated with a stereo- Tubulointerstitial scarring is an extremely
typed renal structural reponse, as the kidney has important feature of progressive renal problems.
a limited repertoire of reponses to diverse in- Indeed, the severity of tubulointerstitial scarring
jurious insults. Progressive sclerosis and fibrosis correlates much better with renal function, and
of the glomeruli – glomerulosclerosis – is a car- future renal functional predictions, than does
dinal feature of all chronic renal disease. the state of the glomeruli. Once again, there is
Initial glomerular endothelial cell injury is injury, reponse with inflammation, proliferation
followed by inflammation, endothelial cell of fibroblasts, excessive extracellular matrix
proliferation, then fibrosis. The endothelial cells deposition (collagen types I and III), and scar-
have a phenotypic shift from their constitutive ring/fibrosis. Angiotensin (Ang) II is an impor-
antithrombotic, antiproliferative, and antimi- tant player in this process – the kidney has most
totic functions, to prothrombotic, proliferative, of its angiotensin in the Ang II form (unlike any
and mitogenic characteristics. A wide variety of other organ where Ang I predominates).
cytokines and chemokines has been linked with Vascular sclerosis is another important feature
these fundamental changes. The similarity with of the structural changes seen in CRF. Renal
endothelial response to injury in an artery, and arteriolar hyalinosis, in the absence of elevated
subsequent atherosclerosis, is telling. How acute blood pressure, is an early feature. Hyalinosis of
glomerular injury then resolves is an issue of the afferent and efferent arterioles is a characteristic
greatest importance; clearly in some situations of diabetes.

Symptoms, signs, and clinical evaluation

Patients with CRF can present ‘gradually’ i.e. mortality, and protracted anemia, fluid overload,
with modest or no symptoms or with a fully- and hypertension will have damaged the left
fledged uremic emergency. Unfortunately, a ventricle. As important, an elective planned start
substantial proportion (about one-third) of to dialysis means the patient is motivated,
patients with CRF only present as they require educated, and involved in his or her health care;
dialysis (either soon, or immediately). As hyper- as the care of the dialysis patient is best as a
tension and diabetes form about 50–60% of the partnership, not a dictatorship, those patients
current reasons for ESRF, this is disturbing. denied the chance for physical and mental
The consequences of late referral can be planning of their renal replacement therapy tend
severe – the uremic emergency has a significant to fare less well.

Reversible causes

It is very important to hold in mind that, culminating in a renal biopsy in many cases
although many CRF etiologies are irreversible (except where the cause is obvious for other
(e.g. diabetes, except with pancreatic transplan- reasons or the kidneys too contracted to permit
tation), many are eminently reversible, e.g. renal biopsy safely). As it is, many patients enter dialy-
tract obstruction, analgesic nephropathy, lupus, sis programmes without a clear-cut diagnosis,
vasculitis, membranous glomerulopathy, amy- with a bland urinary deposit, small scarred kid-
loidosis (rarely), and renal tuberculosis, familial neys, and negative auto-antibody screens. Such
juvenile hyperuricemic nephropathy. Establish- patients could have had interstitial nephritis,
ing the cause for CRF is important therefore, hypertension, glomerulonephritis, renal tuber-
and requires a full history, examination, and a culosis, or sarcoidosis.
battery of laboratory and imaging investigations,
180 CHRONIC RENAL FAILURE AND DIALYSIS

Complications and consequences

CARDIOVASCULAR DISEASE CRF, patients are told to avoid eating many

Cardiovascular disease is 3–5-fold increased in different foodstuffs (to avoid excess sodium,
patients with chronic renal failure. Even micro- potassium, calcium, phosphate, protein); too
albuminuria significantly increases cardiovascular often this results in poor calorie intake. Prob-
risk. The reasons include the high prevalence of lems with sodium, potassium, and water balance
diabetes, hypertension, and dyslipidemia, but are typically seen when GFR falls below
also less ‘conventional’ factors such as hyper- 15–20 ml/min. A low-salt diet is helpful in
homocysteinemia, increased oxidative stress, preventing fluid overload, e.g. 50 mmol (mEq)
progressive malnutrition, and ‘micro-inflam- sodium/day. Water intake must be modulated
mation’. too. Potassium excess is seen as the need for
dialysis gets greater; hyporeninemic hypo-
ANEMIA aldosteronism (so called ‘type IV’ renal tubular
Anemia is very common in CRF (most ADPKD acidosis seen typically in type II diabetics), and
patients are spared this) due to a reduction in the use of ACE inhibitors and angiotensin
circulating erythropoietin and some bone receptor blockers contribute to this problem.
marrow resistance to its action. Human recom- Beta-blockers are also associated with hyper-
binant erythropoietin at about 80–120 IU/kg kalemia in CRF. CRF patients misdiagnosed
will restore hemoglobin concentrations (the with heart failure, and placed on ACE inhibi-
target level is controversial, but 12–13 g/dl tors, beta-blockers, and spironolactone, are
[120–130 g/l] seems ideal). Left ventricular size guaranteed to run into potassium problems.
decreases and function improves in virtually all
patients, though BP control may need inten- SKIN PROBLEMS
sification in about one-quarter of patients. Skin problems include excoriations, xerosis,
nodular prurigo (280), pseudomyxedamatous
RENAL BONE DISEASE scleroderma, diffuse brown pigmentation, ‘half-
Renal bone disease is a composite of high- and and-half ’ nails (281), and bullous eruptions
low-turnover bone diseases. In uremia there is (282) (these are due either to large doses of
skeletal resistance to the action of circulating furosemide [frusemide] as a photosensitivity
PTH, and often incipient vitamin D deficiency fixed drug eruption, or more rarely as a result
(through loss of tubular 1-alphahydroxylase of pseudoporphyria).
activity). Early symptoms are very rare, so
biochemical and radiologic analysis is required. ENDOCRINE ABNORMALITIES
Control of plasma phosphate (dietary com- Endocrine abnormalities include of course the
pliance, phosphate binders), correction of meta- dysregulation of vitamin D, and lack of erythro-
bolic acidosis (using oral sodium bicarbonate), poietin. In addition, increased reversed fT3
and judicious use of vitamin D analogues (e.g. conversion is seen. Reduced insulin degradation
1-alfacalcidol in the UK, calcitriol in the USA) by renal tubules is a feature of a GFR
are required. Over-enthusiasm however can <40 ml/min; this, and decreased calorie intake,
induce low-turnover bone, with problems of may substantially reduce insulin or oral hypo-
increased fracture rate, and increased soft tissue glycemic agent requirements in CRF. Insulin
metastatic calcification. (See later discussion in resistance, however, also rises with falling GFR,
the context of dialysis patients.) so the relationship between food intake, fasting
insulin, glucose, and glucose-altering medica-
MALNUTRITION tions is complex. Testosterone levels are often
Malnutrition is too common in CRF especially low in male dialysis patients; prolactin elevation
as renal function deteriorates to GFR levels of can contribute to gynecomastia. Erectile dys-
10–20 ml/min. Clues to this problem include function is common (and helped by sildenafil,
low/falling cholesterol and falling plasma testosterone, and erythropoietin). Most female
albumin and plasma creatinine (reflecting loss dialysis patients are amenorrheic; pregnancy
of muscle bulk, and capable of misinterpretation with advanced CRF or on dialysis is highly
as renal functional improvement by the un- unusual and rarely successful (see Chapter 9).
initiated). Body weight may not alter much;
fluid retention/edema dilute its usefulness. In
 COMPLICATIONS AND CONSEQUENCES 181

INFECTION RATES AND IMMUNE PSYCHIATRIC PROBLEMS

SYSTEM FUNCTION Psychiatric problems are much more common in
Infection rates and immune system function are CRF and dialysis patients. These range from
often abnormal in CRF. Infection is a common depression, anxiety, and phobias, to full-blown
cause of death and morbidity. T-cell function psychosis. Sympathy, realism, education, and
is defective, as is neutrophil activity against bac- counseling are all important. Rarely formal psy-
teria. Patients are notoriously hard to immunize. chiatric review and therapy are needed. Patients
with severe mental illness such as schizophrenia,
MALIGNANCY or with profound personality disorders, are
Malignancy is more common in CRF and on especially challenging to manage on dialysis.
dialysis. Multicystic kidneys are one reason, but Though unusual, where patients are rude and
increased rates of primary liver and thyroid unco-operative with the dialysis team, this leads
cancers and lymphoma are reported. The reason to dialysis staff (typically health-care assistants and
may relate to impaired immune surveillance, and nurses) becoming heavily stressed. Even more
T-cell function. One ‘advantage’ of the relative rarely, violence can make dialysis very difficult.
immunosuppression of uremia is the usual Lack of understanding, fear, and drug abuse, or
behavior of most lupus and vasculitis cases – it undiagnosed physical and mental illnesses, can
is unusual for such patients on dialysis to suffer explain these occurrences in some cases.
full-blown relapses, and the intensity of immu-
nosuppression can safely be reduced.

280 281

280 Nodular prurigo as a manifestation of skin 281 Hands showing diffuse lemon-brown
disorders in chronic renal failure.The skin is pigmentation of chronic uremia, and also showing
diffusely hyperpigmented in areas of intense leuconychia with typical ‘half-and-half ’ nails
excoriation. (proximal pallor, distal pigmentation) of chronic
renal failure. Also note gross shortening of distal
phalanges (as renal pseudoclubbing – a sign of
severe hyperparathyroidism. See 344, 345).

282 Bulla on a finger (skin 282

photosensitivity reaction to
furosemide [frusemide]). Nails
also show the proximal pallor
and distal rim of pigmentation.
182 CHRONIC RENAL FAILURE AND DIALYSIS

Clinical interventions to retard progression to

end-stage renal failure

Dietary manipulation has long been advocated and are accompanied by little or no reduction in
as a means of retarding CRF. Low protein low micro-albuminuria/proteinuria. However, CCBs
phosphate diets in 5/6 nephrectomized rats are are very effective antihypertensives, and using them
very effective. The data in human subjects, how- in concert with an ACE inhibitor/ARB is highly
ever, are muddled and confusing. Many trials effective and confers nephroprotection.
exist. The largest of them, the MDRD study, It is surprising how often it is forgotten that
followed 840 patients over 3 years and was not a 10–15% fall in GFR is often seen on the
able to show a difference in renal functional administration of an ACE inhibitor/ARB. The
decline between patients with and without dietary small and nonprogressive rise in plasma
restriction. Re-analysis, and meta-analysis, can creatinine should be monitored carefully, but is
provide some suggestions that for severe renal not a reason to withdraw the drugs. Indeed,
impairment, severe protein restriction can retard there is some evidence that patients who show
GFR decline. However, the practicalities are more this hemodynamic response fare best in the
complex. First, because of the anorectic effect of longer term. Of course, in the presence of severe
uremia, many patients self-restrict their total renal artery stenosis, where glomerular filtration
calorie (and hence protein) intake. Second, there is dependent exclusively on angiotensin II-
are real dangers in further restricting food intake mediated efferent arteriolar vasoconstriction,
in patients already proscribed a great deal. Unless the administration of an ACE inhibitor/ARB
there is an intense degree of dietary supervision can lead to a disastrous GFR reduction (Chapter
there is a real danger of inducing malnutrition in 5). Hyperkalemia after ACE inhibition is seen
a cohort of patients, with attendant risks when in about 5–10% of patients with CRF; this is
these patients reach ESRF. contrasted with about 1–2% with an ARB.
Blood pressure control by contrast is accepted There is growing evidence to support the
universally as being of paramount importance. use of statin-based lipid lowering therapy to help
Data from the MRFIT study showed a graded retard progressive renal functional decline,
relationship between SBP and DBP and ESRD. especially in proteinuric renal disease. Finally,
The Helsinki Heart Study renal subgroup careful supervision and follow-up of CRF
showed similar findings, with an interaction patients is vital to success – these patients and
between BP and lipids. The MDRD study their generalist physicians must know that they
provided further evidence, and suggested that should not take NSAIDs, tetracyclines, or other
a lower BP target (mean arterial pressure [MAP] potentially nephrotoxic drugs.
92 mmHg [12.3 kPa]) was more appropriate for
patients with heavy (>3 g/24 h) proteinuria than TRANSITION FROM PREDIALYSIS TO RRT
for patients with lesser proteinuria (MAP One of the prime reasons for timely nephrologic
98 mmHg [13.1 kPa]). A recent study of poly- referral of a patient with declining renal function
cystic kidney patients, however, could not show is to facilitate an orderly start of renal replace-
a relationship between achieved BP control and ment therapy. Amongst the goals to be achieved
future renal functional deterioration. in this setting, uppermost are reducing the rate
Recent meta-analyses for the period 1977–99 of renal functional decline to a minimum,
have suggested that ACE inhibitors provide unique reversing/preventing the complications of renal
nephroprotection, over and above that expected disease at this stage (e.g. renal bone disease,
from BP reduction. This is a very controversial anemia, acidosis, left ventricular hypertrophy),
area. ACE inhibitors in type 1 diabetic neph- formation of dialysis access (e.g. arteriovenous
ropathy, and angiotensin receptor blockers (ARBs) fistula) in good time, and allowing the patient
in type 2 diabetic nephropathy, are the gold and carers to be educated about renal disease,
standard BP reducing agents. In nondiabetic CRF, its implications, and treatments.
ACE inhibitors reduce the risk of ESRF by 31% There can be no precise creatinine value or
compared to placebo or other BP reducing agents. GFR at which dialysis must be started. With
From the African-American Study, and from the careful attention to detail many patients can
IDNT study, there are now data to suggest that function well even with GFR values <10 ml/min.
monotherapy with dihydropyridine calcium In certain cases, fluid overload or hyperkalemia
channel blockers (CCB) are not ideal – these mandate a sudden start of RRT. In other cases,
agents cause afferent arteriolar vasodilatation, thus loss of appetite/nausea or falling albumin or body
may raise intraglomerular pressure not reduce it, weight are signs that dialysis should be started.
 DIALYSIS (RENAL REPLACEMENT THERAPY – RRT) 183

Dialysis (renal replacement therapy – RRT)

INTRODUCTION medically-dependent patients). Blood access is

Hemodialysis (HD) has evolved from decidedly best achieved using an arteriovenous fistula
primitive physical arrangements to a computer- (283); these depend on arterialization of peri-
ized, mechanized maneuver. This ‘advance’ pheral veins in the upper or lower arm due to
however is not what it seems – the principles exposure of veins to arterial pressure. This pro-
of dialysis four decades ago were substantially cess can take 4–8 weeks to occur (and is charac-
similar to those in use now. Blood needs to be terized by marked vessel wall thickening thus
withdrawn from the circulation in a sterile way permitting large needle (14 or 15 French
without clotting, to bathe one side of a semi- Guage) insertion. Gortex/PTFE grafts are alter-
permeable membrane, across which counter- natives. Short- and long-term tunnelled venous
flows preprepared dialysate, and then be catheters, single- or double-lumen, are further
returned safely to the patient. Cannulae, antico- alternatives (284). Anticoagulation is achieved
agulation, sterility, air embolism – all of these typically with a bolus and then an infusion of
were major impedimenta in the early days – now intravenous heparin. Treatment duration is
solved by technologic advances. Initially all typically for 4 hours, thrice-weekly, with arterial
dialysis was seen as a ‘bridge’ to renal recovery blood flow of 250–300 ml/min and dialysate
from injury, or until renal transplantation could flow of 500–600 ml/min. The dialysate is
take place (rather like a left ventricular assist bicarbonate-buffered, and potassium, calcium,
device might now be viewed). Gradually it was and magnesium concentrations can be varied.
the case that more and more patients were
dialysed for longer, and the idea of a chronic
RRT service developed. Initially the acceptance
criteria for such programmes were both strict
and paternalistic. As time has progressed there
are fewer bars to providing long-term RRT. 283
A 16-station hemodialysis unit, operating
three shifts/day and 6 days/week dialysing
patients thrice-weekly, will perform 15,000
hemodialyses per annum – and >99% of these
sessions will take place as scheduled.
Peritoneal dialysis (e.g. CAPD) has had a
shorter history (starting 1975) as a chronic RRT.
There were, as for HD, many technical problems
in its initial use. Long-term technique survival is
rarer for CAPD than for HD. Initial survival rates 283 A mature arteriovenous fistula (radial
are comparable. In a civilized society, patients anastomosis).
should be encouraged to exercise choice about
how they dialyse; this helps to involve the patient
in his own long-term care. The techniques HD 284
and CAPD are often regrettably seen as mutually
exclusive – most patients will require some time
on each of these dialysis modalities. Many
patients do not have the physical or mental
attributes to permit self-dialysis; in these cases,
unit-based HD is preferred unless relatives or
carers can be trained to do CAPD.

HEMODIALYSIS
Modern HD can take place at home, in a dialysis
center away from a main hospital (‘satellite
dialysis unit’) or at a main hospital site (for more

284 Plain chest X-ray showing a tunnelled left

internal jugular ‘Permcath’.
184 CHRONIC RENAL FAILURE AND DIALYSIS

Dialysis (RRT) (continued) Similar reactions in patients on ACE in-

hibitors using AN69 membranes have been
The typical modern dialysis machine (285) can recorded (due to bradykinin release).
vary dialysis bicarbonate, sodium, and dialysate Iron dextran infusions can also induce
temperature in sophisticated ways. anaphylactoid reactions on dialysis.
There is increasing interest in daily HD, with
short treatment times (e.g. 2 hours). By this Early (30–60 minutes)
means several significant complications of HD This is a mild reaction, with fever due to activation
(e.g. hypertension, left ventricular hypertrophy, of white cells and platelets by the dialysis mem-
and hyperphosphatemia) can be avoided. brane. This was more often seen with so-called
bioincompatible dialysis membranes (e.g. cupro-
Complications of acute hemodialysis phane), which have largely been superseded by
There are many complications that can arise be- more expensive biocompatible materials.
cause of HD. We shall consider these first as those
arising during, or as a direct result of, the hemo- Any time
dialysis session. The other main group of compli- Pyrogen reactions are due to contamination of
cations is as a result of being on dialysis for some dialysis fluid by bacteria or bacterial endotoxins.
time (and overlaps substantially with complications The very highest standards of water preparation
seen in long-term CAPD patients); this will be (ionic and microbiologic) are mandatory
discussed at the end of this chapter as a result. (but expensive).
There are various adverse reactions that can
occur as a result of the passage of patients’ blood HEMODYNAMIC COMPLICATIONS
over the surface components of the extracorporeal The next group of complications arises from the
circuit. These can be grouped by time of onset: hemodynamic effects that dialysis has, and the
circulatory response mediated by baroreceptors
Immediate (i.e. within the first 30 minutes) and the autonomic and sympathetic nervous
Anaphylaxis is rare, mediated by IgE, and reflects systems.
exposure of blood to ethylene oxide, glutaralde-
hyde, or renalin (used in sterilizing dialysers). Dialysis hypotension
Treatment involves stopping HD, avoiding Symptomatic intradialytic hypotension occurs
blood return to the patient, and any/all of anti- in 10–30% of dialysis treatments. It can shorten
histamines, corticosteroids, and epinephrine dialysis times, result in hypertension as a con-
(adrenaline). Alternative sterilization techniques sequence of maneuvers to avoid hypotension,
(e.g. irradiation), and increased predialysis and may possibly have deleterious effects on
dialyser flushing , are helpful. brain and cardiac perfusion if severe, prolonged,
or repeated.
The etiopathogenesis is complex and multi-
285 factorial – including autonomic neuropathy,
antihypertensive medications, sepsis, blood-
pooling, increased body core temperature,
hypoalbuminemia, and anemia. Acetate-buf-
fered dialysis (rare in the developed world), and
low sodium and calcium dialysate concentra-
tions, also are risk factors.
Treatment is by temporary cessation of
dialysis, reverse Trendelenburg position, and by
saline infusions. Prevention is by attending to as
many risk factors as possible. Sodium profiling,
cooled dialysate, and on-line biofeedback ultra-
filtration monitoring may all help. Midodrine (an
alpha-agonist) has also been successfully used.

Dialysis hypertension
BP control in dialysis patients is rarely optimal or
optimizable. Large doses of several antihyper-
tensives may control BP to a degree between
285 A typical modern hemodialysis machine. dialysis sessions, but brings with it a large risk of
 DIALYSIS (RENAL REPLACEMENT THERAPY – RRT) 185

intradialytic BP instability. Many patients show Restless legs can occur on dialysis, or be-
clear volume dependency in their BP. In others tween sessions. The legs either twitch (myo-
the relationship is more subtle. Increased sympa- clonus) or the patient experiences an irresistible
thetic drive, accumulation of pressor compounds, desire to move their legs because of dysesthesiae.
defective nitric oxide synthase/ endogenous Co-existing iron deficiency anemia and vascular
inhibitors of nitric oxide synthase (e.g. asymmetric insufficiency may exacerbate these problems.
dimethylarginine [ADMA]), and erythropoietin Clonazepam, phenytoin, L-DOPA and gaba-
are other reasons for dialysis patients to be pentin may all help.
hypertensive. Diurnal BP rhythm is generally very Dialysis disequilibration syndrome is for-
deranged in dialysis patients, with many showing tunately rare. Risk factors are more aggressive
a rise in BP with recumbency (286). Autonomic dialysis techniques (greater solute removal per
dysfunction is likely to be a major reason for this, unit time) and intercurrent illnesses. Restlessness,
which has prognostic implications. For many agitation, headache, nausea, vomiting, blurred
patients, the price paid for short dialysis sessions vision, seizures, and coma are seen. It may result
and excessive sodium dialysate concentrations from transient osmotic disquilibrium in neurons;
(which engineer some cardiovascular stability), is cerebral imaging shows cerebral edema. When
chronic salt and water overload, and chronic mild the syndrome is rapidly reversible. Short,
refractory hypertension. It has been known for 40 gentle dialysis sessions minimize risk.
years that long, slow dialysis, or, more recently, Seizures are rare on dialysis – their causation
daily dialysis, can normalize BP without the use is multifactorial, including hypoxia, hyperten-
of antihypertensives. Some patients show a sion, disequilibrium, metabolic (low calcium,
vigorous end-of-dialysis BP surge – this is as a magnesium, blood glucose), or removal of anti-
result of hypokalemia/hypovolemia stimulation convulsants by HD.
of an intact renin–angiotensin system. This can be
blocked by angiotensin antagonists. Technical mishaps and disasters
Over the 40 years of regular HD many different
Arrhythmias and sudden death catastrophes have been recorded. Only the more
Sudden death rates (more often after than before common are described.
or during HD) are vastly increased in dialysis Hemorrhage/circuit blood loss is still a
patients (mainly but not exclusively HD). This is feared but very rare occurrence: large bore
especially the case for type 1 diabetics on HD. needles in arterialized veins, with a uremic
Eighty per cent of these sudden deaths are as a platelet defect, and systemic anticoagulation +/-
result of ventricular fibrillation. End-of-dialysis antiplatelet drugs are the reasons. Dialysis
hypokalemia, hypocalcemia, and hypomag- machines respond to a fall in pressure (such as
nesemia, and mild intradialytic hypoxemia are occurs with hemorrhage) by automatically
partly to blame, as are malignant ventricular re- ceasing dialysis and by sounding alarms.
entrant arrythmias resulting from a combination Air embolism (split lines, or bubble forma-
of coronary artery disease, inter-cardiomyocyte tion) can be lethal. Clinical manifestations
fibrosis seen in the uremic myocardium, and from
left ventricular hypertrophy. Pericarditis and
conducting system calcification are also respon- 240
286
200
sible for arrhythmias on dialysis. Prevention is by
BP (mmHg)

160
scrupulous attention to postdialysis electrolyte 120
concentrations, by avoiding digoxin use where 80
possible, and by prompt diagnosis and treatment 40

of ischemic heart disease. 0

200
Hear rate (bpm)

MISCELLANEOUS COMPLICATIONS 150

Neuromuscular complications 100

Up to 25% of patients can report muscle cramps, 50

usually in the legs, towards the end of dialysis 0

– this seems to be related to incipient or real 10 11 12 13 14 15 16 17 18 19 20 21 22 23 0 1 2 3 4 5 6 7 8 9 10
Time (hours)
hypovolemia, and also low calcium and mag-
nesium concentrations. Quinine, diazepam, and 286 Diurnal BP rhythm is abnormal in uremia – in
less aggressive dialysis schedules may relieve the this tracing it can clearly be seen that BP rises
symptoms, which, when severe, are a cause of during the sleep period (marked by the green
premature dialysis session discontinuation. hatched area on the BP tracing).
186 CHRONIC RENAL FAILURE AND DIALYSIS

Dialysis (RRT) (continued) 287

depend on the amount of air, how it is
introduced, how quickly, and the patient’s
position. Emboli in the cerebral circulation can
be manifest as seizure and coma. Air in the right
ventricle causes cardiovascular collapse. Initial
management is to clamp all lines, stop the
pumps, and place the patient in the left Tren-
delenburg position, followed by oxygen, intu-
bation and ventilation. Air can be aspirated from
the right ventricle. 287 Local aneurysmal dilatation of an
Incorrect dialysate composition is rare but arteriovenous fistula due to an upper arm
possible, as the only practical safeguard is dialy- fistula stenosis.
sate electrical conductivity monitoring. Thus
deviations in dialysate sodium will be picked up,
but not bicarbonate or calcium problems. Hypo- 288
natremia, hypernatremia, hypocalcemia, hyper-
calcemia, metabolic acidosis, and alkalosis can all
be manufactured by faulty dialysis circuits.

Access-related problems
Arteriovenous fistulae are robust and by far the
most reliable form of dialysis access. Infection is
rare. Stenosis at the site of arteriovenous anas-
tomosis can occur early, and prevent maturation
(angioplasty may help this). Other typical sites
for fistula stenosis relate to needle-sites, or
previous central vein cannulation. Clues to the
presence of stenoses include local aneurysmal
dilatation (287), increasing venous pressure,
and reduced dialysis solute clearances. Angio-
plasty can resolve these difficulties (288, 289).
ACE inhibition may reduce the tendency to
fistula stenosis; poor calcium–phosphate control
may contribute to it. Fistula occlusion by 288 Angiogram showing tight stenosis at a
thrombosis rarely occurs except when there are needling site of an AVF.
adverse factors such as hypercoagulability, low
blood pressure, or flow, e.g. with a severe
stenosis. A good fistula can provide excellent 289
dialysis for two decades. Central venous lines are
a poor (but in some patients necessary) sub-
stitute for a fistula. Infection and thrombosis are
the chief complications. The presence of the line
can cause stenosis/thrombosis of central veins
(290–294).

289 Angiogram showing the result of balloon

angioplasty – an improved appearance. Blood
flows were higher, venous pressures lower, and
dialysis clearances improved.These problems
though can recur and require repeated treatment
or stenting/operative revision.
 DIALYSIS (RENAL REPLACEMENT THERAPY – RRT) 187

290 291

290 Distended veins on the surface of the upper

arm and chest herald central venous obstruction 292
and collateral formation.

291 An MR image of the shoulder showing huge

collateral venous channels.

292 A venogram for the patient shown in (290)

revealing central venous obstruction and multiple
collateral channels.

293 294

293 Angiogram showing a severe stenosis of the 294 Post angioplasty/stent appearance for venous
innominate vein secondary to long-term use of a stenosis shown in (293).
central venous dialysis catheter for dialysis.
188 CHRONIC RENAL FAILURE AND DIALYSIS

Dialysis (RRT) (continued) chambers have been developed). The osmotic

agent is glucose – all PD fluid is grossly hyper-
Rarely, a right atrial thrombus can form osmolar, and, at pH 5.2, hardly physiological.
(295) on long-term cannula that enter the right Other fluids are now available, e.g. a glucose
atrium (which can lead to sepsis/pulmonary polymer Icodextrin as a 7.5% solution which works
emboli). Incorrect cannula placement can be by colloid osmosis, and a 1.1% amino acid mixture.
life-threatening (296, 297). To check that enough solute clearance is
taking place a 24-hour collection of spent
PERITONEAL DIALYSIS dialysate can be undertaken. Also a peritoneal
The peritoneal membrane is semi-permeable equilibration test can be performed (using 2.27%
and therefore permits dialysis if a sterile dialysate glucose dwelling for 4 hours). Results are
is placed into the abdominal cavity. Some solute expressed as the ratio of dialysate to plasma
is also removed by convection and by solute creatinine. Ultrafiltration (water removal) can be
drag. Transport across the peritoneal membrane assessed by examining the patients’ daily records,
is linked to vascular surface area and to intrinsic including body weights. Residual renal function
peritoneal permeability. is important to assess; indeed, for many patients,
There are many different designs of peritoneal the gradual loss of residual renal function over
catheter now available. There are usually one or time on dialysis eventually undermines their
two cuffs to provoke subcutaneous fibrosis ability to continue with peritoneal dialysis.
(helping to anchor the catheter and to reduce How much PD is ‘necessary’ is a vexed ques-
the risk of infection tracking back alongside the tion not completely answered by trials. The recent
catheter). Insertion methods vary from direct CANUSA trial (suggesting that achieving and
vision under general anesthesia, to ‘blind’ inser- maintaining as much solute clearance as possible
tion using the Seldinger technique in a conscious is best) seems to have been contradicted by a
patient. The latter method results in a greater larger Mexican (ADEMEX) trial. Increasing solute
complication rate, including hematoma forma- clearance can be brought about by increasing the
tion (298) or perforation of abdominal viscera. number, or volume, of exchanges – at the expense
Peritoneal dialysis (PD) involves filling the of quality of life and an increased risk of compli-
abdominal cavity with dialysis fluid, allowing this cations. As residual renal function declines,
fluid to ‘dwell’ for a while, then draining it out patients can experience progressive problems
to be replaced with fresh dialysate. This takes maintaining fluid balance, BP control, and
place (as CAPD) typically using 2–2.5 liter adequate solute clearance – in part because with
volumes, four to five times daily, 7 days a week. time and constant exposure to unphysiologic solu-
Machines can perform overnight dialysis using tions, the peritoneal membrane structure changes
a rapid sequence of exchanges (automated and function deteriorates. Anuric patients are
peritoneal dialysis, APD). challenging to maintain long-term on PD.
All PD fluids contain sodium, calcium, mag- There are many complications that arise as a
nesium, and chloride. Lactate is the usual buffer result of continued PD. These can be classified
(recently bicarbonate bags with two/three into infectious and noninfectious.

295

295 Cardiac magnetic resonance appearance of a right atrial thrombus (arrows) arising from
a dialysis cannula.
 DIALYSIS (RENAL REPLACEMENT THERAPY – RRT) 189

296

296 CT scan of thorax showing a dialysis cannula (arrow) traversing

the mediastinum and peri-aortic hematoma.

297

297 CT scan of thorax showing a dialysis cannula traversing the

mediastinum.The tip is in the pericardial space.

298

298 Anterior abdominal wall hematoma after peritoneal dialysis

cannula insertion.
190 CHRONIC RENAL FAILURE AND DIALYSIS

Dialysis (RRT) (continued) eosinophilic or not, is rarely seen, and should not
constitute >10% of all peritonitis episodes – it is
INFECTIOUS COMPLICATIONS a composite of chemical irritation, drug/fluid
Without doubt the most important complication allergic reaction, and failure to culture micro-
of PD is infection in the peritoneal cavity. organisms with fastitidious growth requirements.
Infection can be virtually asymptomatic or cause In a well-run unit, infection rates of about 1–2
severe systemic upset. Usually colicky abdominal per 24 patient therapy months should be
pain and cloudy effluent (white cell content of expected. Repeated cycles of peritoneal infection
>100 white cells/mm3 (108/l) [299]) are the can damage peritoneal membrane structure
clues. Fever and raised CRP are typical. Empiri- irreparably. Persistent fever and raised inflamma-
cal antibiotics are started (as either intravenous tory markers for many days or weeks after a severe
or intraperitoneal boluses, then added to the peritonitis episode should alert the nephrologist
bags) and then changed as appropriate once PD to the possibilities of localized infected collections
fluid cultures have been analyzed. The com- in the abdomen (301), peritoneal tuberculosis,
monest infection is with Staphylococcus spp. or sclerosing peritonitis (see below).
Culture of a mixed growth, particularly Gram- Infection of the exit site or subcutaneous
negatives and anerobes, strongly suggests catheter tunnel (302, 303) are serious and in
abdominal viscus perforation or abscess. Failure time can lead to peritonitis. Topical (and nasal)
to respond to antibiotics is an indication for treatments can help eradication and prevent
catheter removal +/- laparotomy. Fungal infec- reinfection. Systemic antibiotics are often
tions, though rare, invariably require catheter required, and refractory cases require catheter
removal for recovery (300). Sterile peritonitis, removal.

299

299 PD fluid is normally perfectly clear (PD bag right of

picture). In peritonitis the fluid becomes turbid (left of
picture) due to white blood cells and fibrin.

300

300 Fungal hyphae growing along the PD cannula.This is one of the

later signs of fungal peritonitis. It is virtually impossible to eradicate
fungal infections without cannula removal.
 DIALYSIS (RENAL REPLACEMENT THERAPY – RRT) 191

301 After some episodes of 301

severe peritonitis, especially if the
PD cannula is removed without
a laparotomy and wash-out,
residual ‘puddles’ of infected PD
fluid remain and can form
infected collections/abscesses.
CT scan of the abdomen
showing an anterior abdominal
wall infected collection (arrow)
that required percutaneous
drainage and prolonged
antibiotics.

302 There was an associated 302

leak of peritoneal dialysis fluid
(as shown by the contouring of
the anterior abdominal wall in
this thin patient [see 304, 305]).

303 Red swollen ‘exit-site’ where 303

the cannula emerges from its
long subcutaneous tunnel.This
was due to Pseudomonas
aeruginosa infection.The redness
extends along the proximal part
of the tunnel (so this was also a
tunnel infection).
192 CHRONIC RENAL FAILURE AND DIALYSIS

Dialysis (RRT) (continued) change in the peritoneum – sclerosing (encapsu-

lating) peritonitis is a very serious complication.
NONINFECTIOUS COMPLICATIONS The peritoneal membrane becomes very
Catheter migration/omental capture can mean thickened, with loss of ultrafiltration and small
the end of the catheter is enmeshed in exuberant solute clearance typical. This happens to about
omentum, preventing drainage. Re-implanta- 20% of patients continuously exposed to PD
tion and omentectomy are helpful. Constipation solutions for 8 years or more (and to 50% of
(very common on PD) can cause catheter dis- those on PD for >12 years). It can be triggered
placement (304, 305). by peritonitis or after a series of severe peritonitis
A peritoneal leak (306, 307) can occur early episodes. Reactions to acetate, to chlorhexidine
after insertion of the catheter if healing is and, probably, to glucose degradation products
delayed, or intra-abdominal pressure high. (formed in the manufacture of PD fluid) are
Treatment is by resting from PD, or the use of likely causes. In some cases the peritoneal
very small exchange volumes. Refractory cases membrane becomes grossly thickened and starts
will need surgical repair with a mesh. Herniae to ‘invade’ the bowel wall (308–316). This
are common with longer-term PD, polycystic causes nausea, vomiting, small bowel obstruc-
kidney disease, and large exchange volumes. tion, malabsorption, and death. Careful entero-
Again, repair is needed, and recurrences are clysis may help, as may TPN and immuno-
common. Fluid can escape across the diaphragm suppressive drugs (prednisolone and azathio-
to cause hydrothorax. prine). Transplantation is the definitive therapy.
Failure of ultrafiltration can occur when the An aggressive calcific sclerosing peritonitis
osmotic (glucose) gradient collapses (type I can occur with a bloody effluent, abdominal
failure) – use of shorter exchange dwell times, pain and calcified bowel loops grinding against
or an alternative osmotic agent (icodextrin) one another with peristalsis (317–319).
help. Type II failure occurs with a structural

304 305

304, 305 The tip of the peritoneal dialysis cannula should lie near the midline (arrow) in the true pelvis
(304). In this case (305) it is grossly displaced to the right (arrow) and superior to where it should lie.
Erratic and poor drianage of PD fluid is what the patient notices. In this case severe constipation has
caused the migration, which can be treated. Omental capture, another cause of catheter malposition,
requires exploration, omentectomy, and resuturing of the catheter in its correct position.
 DIALYSIS (RENAL REPLACEMENT THERAPY – RRT) 193

306 307

306 Abdominal swelling, and peau d’orange 307 CT scan appearance of a subcutaneous leak of
appearance of skin in a subcutaneous leak of PD fluid (arrow).
PD fluid.

308

308 Postmortem appearance of grossly wrinkled and

thickened parietal peritoneum in a case of sclerosing
encapsulating peritonitis.

309 310

309, 310 Sclerosing peritonitis at laparotomy. Initial site once peritoneum incised (309): instead of
peritoneal space and free bowel loops, a large inflammatory pannus is present which completely binds
together all bowel loops. No anatomic planes for dissection are visible. 310 After 6 hours' painstaking
dissection, and many inevitable serosal lesions and some full thickness bowel perforations, the small
bowel has been dissected out and freed from the fibrosis.
194 CHRONIC RENAL FAILURE AND DIALYSIS

311 312

313 311, 312 Plain X-ray (311) of the

abdomen showing linear peritoneal
calcification, heralding sclerosing
peritonitis, often most visible in the
pelvis. Dilated small bowel loops are
visible too. Barium study (312):
24 hours after ingesting barium
there is stasis in the mid-small bowel,
no barium in the pelvis, but intense
pelvic calcification.

313 CT scan of the abdomen in a

case of sclerosing encapsulating
peritonitis.Thickened parietal
peritoneum is visible (with many
areas of calcification), particularly
intense around the spleen.

314
314 The small bowel loops are
focally dilated and thick-
walled/matted together centrally due
to the multiple adhesions.There is
plentiful ascites (the patient was no
longer on peritoneal dialysis).
 DIALYSIS (RENAL REPLACEMENT THERAPY – RRT) 195

315 316

315 The strands of fibrous tissue ‘invade’ the 316 Histology of sclerosing encapsulating
muscularis mucosa of the large bowel leading to peritonitis.Thickened peritoneum, a band of
atony/obstruction (H+E x100). amorphous fibrous tissue, and diabetiform
changes in the peritoneal blood vessels are seen
(H+E x250).

317 318

318 CT scan of the abdomen in the same case as shown in

311, 312. Heavy calcification is present on the
antimesenteric border of many small bowel loops.

319
317 Plain X-ray of abdomen showing
remarkable series of curvilinear
calcifications in a case of calcific
sclerosing peritonitis.

319 Postmortem appearance of intense calcification on the

antimesenteric side of small bowel loops, giving rise to the
CT scan appearances in 313, 314.
196 CHRONIC RENAL FAILURE AND DIALYSIS

Dialysis (RRT) (continued) to succeed. Coronary artery angioplasty, rota-

tional atherectomy, followed by stenting (perhaps
LONGER-TERM COMPLICATIONS OF using stents impregnated with the immuno-
(ALL) DIALYSIS modulatory drug sirolimus) are effective
There are inevitable consequences of relying on maneuvers in experienced centers. The mortality
renal replacement therapy for a protracted and morbidity from CABG is greater (by about
period. In the simplest terms, expected life-span 3–5-fold) than is the case for nonuremic subjects
is much reduced – someone aged 20 years – but if successful the long-term results are much
starting dialysis can expect at most 20–25 more better than, e.g. for coronary angioplasty (where
years of life on dialysis; someone starting dialysis recurrence rates of 80% have been reported at 12
aged 70 years can expect only 4–6 years. As a months). Peripheral vascular disease (small vessel,
rule of thumb, patients can only expect 50% of heavily-calcified, ‘diabetiform’ in behavior) is also
the actuarially-calculated life-span remaining, a problem seen with increased exposure to
and much less than even this if there are dialysis. The calcification, both medial and
significant co-morbidities at the time dialysis intimal, once again reduces the effectiveness of
begins, e.g. active ischemic heart disease. angioplasty, and significantly increases the risks
of attempted reconstructive arterial surgery.
Coronary artery disease (CAD)
CAD is much more prevalent in dialysis patients. Ectopic calcification
The prevalence varies from 10–15% in young The vascular calcification referred to above is an
subjects to >80% of type 1 diabetics over 50 years example of a very widespread problem for dialysis
of age. The risk factors are similar to the non- patients, namely ectopic calcification, which we
uremic population, with smoking exerting a are now seeing with increased frequency. The
particularly malign influence. Symptoms are often etiology is complex and reflects, first, elevated cal-
more subtle, or absent, due to a more sedentary cium–phosphate product; second, the reduced
life-style, and autonomic neuropathy. Screening buffering capacity of the skeleton (which can be
procedures (EKG, stress-EKG, biochemical due to leaching out of calcium and phosphate by
markers, e.g. troponin-I, troponin-T, soluble PTH in hyperparathyoidism exacerbated by
FAS, nuclear scintigraphy [320], electron-beam excess use of vitamin D analogues, and also where
CT scanning [321]) are all of some use, but their overuse of calcium salts and vitamin D analogues
specificity and sensitivity are both significantly less have produced a low-turnover bone state); and,
than is the case for nonuremic cohorts. Thus finally, the absence of a renal route of excretion
coronary angiography (322) is often the only way of excess calcium and phosphate. Calcification
effectively to screen for the presence of significant can take place in skin (and be a cause of nodular
CAD. CAD in uremia is often more distal, more prurigo), in the joints as peri-articular tumoral
calcified, and more diffuse – all of these features masses (323) giving rise to pain, immobility, joint
make interventions more complex and less likely hemorrhage, and infection), in the lungs and

320 320 Adenosine-myoview scan of the

myocardial blood flow patterns in an
asymptomatic diabetic dialysis patient
being investigated for potential
transplantation.The resting scan
shows normal blood distribution, but
after adenosine (a vasodilator) is
injected there is reduced blood flow
to the anterior wall of the left
ventricle, indicating obstructive
coronary artery disease in the left
coronary artery.
 DIALYSIS (RENAL REPLACEMENT THERAPY – RRT) 197

321 An electron-beam (ultrafast) CT scan 321

of the heart of a long-term dialysis patient
showing gross calcification of the left
coronary artery.

322 A coronary angiogram showing a 322

tight proximal stenosis of the left anterior
descending coronary artery.

323 X-ray of right shoulder showing a huge 323

‘tumoral’ calcific mass (arrow) in/around the
shoulder joint.
198 CHRONIC RENAL FAILURE AND DIALYSIS

Dialysis (RRT) (continued) which is where most vascular calcification is seen

in nonuremic subjects, i.e. as part of com-
myocardium giving rise to dyspnea, respiratory plex/mature atheroma. Atheroma is calcified
failure, LV dysfunction and conduction defects much more early and to a greater extent than in
(324), and in the great arteries – aorta (325, nonuremic subjects. Ectopic calcification can also
326), iliacs (327), and smaller, e.g. digital arteries affect the aortic and mitral valves, leading to
(328, 329). The calcification is, as in diabetes, in stenosis, regurgitation, and endocarditis (330,
the medial layer of the vessel wall (like Monke- 331). The commonest organism responsible for
berg’s medial sclerosis, as in 328, 329), but endocarditis in dialysis patients is Staphylococcus
calcification can also be abluminal and intimal, aureus (mortality is greatly in excess of 50%).

324 324 Diffuse myocardial calcification

(shown post mortem).

325 325 Aortic calcification.Thoracic CT

scan showing several discrete patches
of aortic arch wall calcification in a
dialysis patient.

326 326 Abdominal CT scan of the same

patient as 325 showing heavy concentric
aortic wall calcification.
 DIALYSIS (RENAL REPLACEMENT THERAPY – RRT) 199

327 328

329

327 Plain X-ray of a long-term dialysis 330

patient showing ‘pipe-stem’ arterial
calcification of both abdominal aorta
and iliac arteries.

328 Mammogram showing a skein of

‘tram-line’ calcifications, with fractures, in
the small arteries of the breast in a
long-term, diabetic dialysis patient.

329 Hand X-ray showing digital arterial

calcification.

331
330 Postmortem view of calcification of
the leaflets of the aortic valve (arrow).

331 Gross destruction of aortic valve

by staphylococcal endocarditis and
aortic root abscess.
200 CHRONIC RENAL FAILURE AND DIALYSIS

Dialysis (RRT) (continued) cidol (calcitriol), ACE inhibition, and renal

transplantation. After many years of concentric
Left ventricular changes LVH the LV can progressively dilate (334) – this
Left ventricular changes are virtually ubiquitous is often accompanied by hypotension and ‘heart
in chronic renal failure and dialysis. Left ven- failure’ and has a very poor prognosis.
tricular hypertrophy (LVH) (332) can be shown
to develop relatively early with declining renal Dialysis-related amyloidosis
function, and LV mass increases pari passu with Dialysis-related amyloidosis (beta-2-
renal impairment. Concentric LVH is the com- microglobulin amyloidosis) is seen in any subject
monest pattern; some have reported asymmetric exposed to dialysis for long enough. Younger
LVH in long-term hemodialysis patients. By the subjects typically take 10–20 years to develop
time dialysis has started about 50–60% of patients this complication, and, as technique longevity
have LVH. This proportion rises rapidly to on CAPD is much poorer than is the case for
become 70–90% of longer-term dialysis patients. HD, it is associated with the latter dialysis
The reasons are multi-factorial, and include modality (but is really only a function of dialysis
increased large artery stiffening and abnormal and time). Beta-2-microglobulin levels are
hemodynamics, sleep apnea (inducing repeated elevated (by lack of renal metabolism and
sympathetic nervous system stimulation during excretion) in CRF and dialysis (indeed it can be
sleep [333]), increased systemic BP (including used to model larger molecular weight solute
nocturnal hypertension), anemia, fluid overload, dialysis clearances). Its production is stimulated
the presence of an AV fistula, and hyperpara- also by the use of less than ideally pure dialysis
thyroidism. Histologically there has been demon- water in HD, and by the contact of blood with
strated a remarkable degree of intercardiomyo- bioincompatible membranes. It may be that the
cyte fibrosis with relative paucity of capillaries (as use of hemodiafiltration with these desirable
well as the expected changes in cardiomyocytes), characteristics will delay the onset of this
which most likely contributes to the arrhythmo- condition. Symptoms usually start in the hands
genicity of dialysis and the incidence of sudden as carpal tunnel syndrome; carpal tunnel release
cardiac death in dialysis patients. is helpful (and the histology shows amyloid
LVH is associated with reduced survival on deposits in many but not all cases). If dialysis is
dialysis, even after renal transplantation. Methods prolonged further, recurrence is typical,
to reduce LV mass include daily short-hours sometimes with large amyloid deposits (335);
hemodialysis, erythropoietin, intravenous alfacal- some patients need repeated carpal tunnel

332

332 Magnetic resonance image of the heart showing severe

concentric left ventricular hypertrophy.
 DIALYSIS (RENAL REPLACEMENT THERAPY – RRT) 201

333 Output from a 333

sleep apnea study.
Oxygen saturation
is shown in red in
the upper tracing
(numerous ‘dips’ are
seen) and pulse rate
in blue showing
acute rises in heart
rate which
accompany the falls
in oxygen
saturation.The
yellow symbols on
the bottom of the
figure show number
and severity of
apnea episodes.

334

334 Nuclear
scintigraphy scan
showing (left side)
thick wall and tiny
LV cavity. Right-sided
images show gross
LV dilatation.

335 Wrist of a long-term dialysis 335

patient.There is already a scar from a
previous surgical carpal tunnel release.
There is recurrent amyloid tissue
(swelling).
202 CHRONIC RENAL FAILURE AND DIALYSIS

Dialysis (RRT) (continued) 336

surgery. The hands become markedly deformed
and the range of finger movement much
reduced (336). Carpal cysts are seen on plain
X-ray (337, 338). The shoulders, hips (339,
340), and knees can also be affected with severe
pain and aching particularly on dialysis; some-
times there can be pathologic fractures. The
cervical spine can be involved in an erosive/des-
tructive spondylolisthesis (341, 342). Dynamic
amyloid scanning can show the amyloid deposits
clearly. The deposits in bone are associated with
advanced glycation end-product deposition.
Regression may occur after successful renal
transplantation (and symptomatic relief is
obtained quickly on account of the steroids
used). There is another rarer form of non-
amyloid long-term dialysis small-joint destruc-
tive arthropathy (343).

336 Hands (prayer sign) from a long-term dialysis

patient with beta-2-microglobulin amyloidosis.

337 338

337, 338 Radiologic appearance (337) from same patient as 336 with extensive carpal bone cyst
formation. Apple-green birefringence (338) under cross-polarized light of excised material.
 DIALYSIS (RENAL REPLACEMENT THERAPY – RRT) 203

339 340

339 Plain X-ray of the pelvis from a patient on 340 MR of the hips from the same patient
dialysis for 26 years and a painful left hip. A large as 339.The bone cyst in the left hip is well
subcapital bone cyst (beta-2-microglobulin shown (arrow).
amyloid) is seen.

341 342

343

341, 342 Plain cervical spine X-ray (341) and

cervical vertebral tomography (342) showing
erosive/destructive cervical spine
spondyloarthropathy (arrow).

343 Plain X-ray of the hands showing the rare

nonamyloid small-joint destructive arthropathy.
Amyloid bone cysts in the carpal bones are also
demonstrated.
204 CHRONIC RENAL FAILURE AND DIALYSIS

Dialysis (RRT) (continued) 344

Renal bone disease
Renal bone disease (excluding amyloidosis) is
invariable in subjects with chronic uremia or
dialysis. It can start with mild chronic renal
failure as there is some mild phosphate reten-
tion. Hyperparathyroidism, osteomalacia, ady-
namic bone syndrome (aluminium- and non-
aluminium-related), mixed osteodsytrophy and
osteopenia are different patterns of skeletal
response to chronic uremia, depending on 344 Renal pseudo-clubbing indicating terminal
patient population and dialysis treatments. digital osteolysis.
There are characteristic radiologic and histologic
(bone biopsy) changes (344–355).

345 346 347

348 349 345 Radiologic appearance of

the hands in severe renal (tertiary)
hyperparathyroidism – vascular
calcification, osteopenia, gross
trabecular pattern loss, periosteal
cysts, and bone resorption.

346 Magnified view of a digit

from 345. Gross osteopenia,
trabecular loss, medial erosions
are present, all indicating severe
hyperparathyroidism.

347 Lower leg X-ray showing

cortical tibial cyst (arrow) – a
‘brown’ tumor of
hyperparathyroidism.
348, 349 A bone scan (348) showing radio-isotope avidity (arrow)
indicating metabolic over-activity, and a lateral X-ray (349) of the
lumbar spine showing ‘rugger-jersey’ changes of hyperparathyroidism.
 DIALYSIS (RENAL REPLACEMENT THERAPY – RRT) 205

350 351

350 Pelvic X-ray showing fractures of the pubic

rami (arrow) – Looser's zones, as seen in
osteomalacia or the fracturing osteodystrophy 351 Bone biopsy (Girschman trichrome). Normal
caused by skeletal aluminium toxicity. bone – mineralized osteoid is blue, noncalcified
osteoid is red.

352 353

352 Bone biopsy (Girschman trichrome).This 353 Bone biopsy (fluorescence double labeling
shows much increased noncalcified osteoid and [tetracycline given as two oral doses 10 days
is indicative of a mineralization problem, in this apart]). Gross increase in uptake, and a large gap
case osteomalacia. between the two parallel lines of fluorescence are
seen indicating high turn-over bone disease, in this
case hyperparathyroidism.

354 355

354 Bone biopsy (fluorescence double labeling 355 Bone biopsy. Faint red staining at the
[tetracycline given as two oral doses 10 days ossification front is aluminium, in this case of
apart]).Virtually no fluoresence, and no double- aluminium osteodystrophy. Aluminium is one
line is seen.This indicates no bone turnover or cause of adynamic bone syndrome (giving rise
adynamic bone syndrome. Few patients are now to fracturing microcytic anemia).
exposed to aluminium (355) – modern causes of
adynamic bone are overtreatment of
hyperparathyroidism with calcium-containing
phosphate binders and vitamin D metabolites.
206 CHRONIC RENAL FAILURE AND DIALYSIS

Dialysis (RRT) (continued) 356 357

Parathyroidectomy (PTX)
PTX is required for the majority of patients who
have been on dialysis for >10 years. Initial milder
forms of hyperparathyroidism can be controlled
by prevention or reversal of plasma phosphate
elevation, judicious manipulation of dialysate
calcium concentrations, and use of vitamin D
preparations. If the parathyroid glands become
too large, their behavior becomes autonomous
and largely refractory to normal physiologic
stimuli or pharmacologic manipulation.
Ectopic calcification in skin, muscle, joint or
soft tissues, calcific uremic arteriolopathy (calci-
phylaxis), hypercalcemia, myopathy, tendon
rupture, or bone fracture are all indications for
surgical parathyroidectomy. Many of the
radiologic changes of hyperparathyroidism can
reverse/normalize after PTX (356, 357).
Elevated calcium, phosphate, bone-specific
alkaline phosphatase, and PTH are typical.
Parathyroid uptake scans show diffusely enlarged
overactive glands (358) – it is not usually useful
to locate glands before a first parathyroidectomy; 356, 357 Plain X-ray of a digit (356) just
these glands are often >1 cm3 when removed. before surgical parathyroidectomy. Severe
The histology of removed glands usually shows changes of hyperparathyroidism can be seen,
nodular hyperplasia (359); very rarely para- including ectopic calcification. Six months after
thyroid carcinoma is found (360). the parathyroidectomy (357) there has been
If the patient remains on dialysis for 5 years improvement in many of these abnormal
or more after an initial parathyroidectomy there appearances.
is a high rate of recurrent/relapsing hyperpara-
thyroidism if a remnant gland was left behind
(deliberately or accidentally) or autotransplanted
at the initial parathyroidectomy (361). Rarely 358
this parathyroid tissue can behave pseudo-
malignantly as parathymatosis. In these cases
preoperative localization of all residual para-
thyroid tissue in the neck, mediastinum, or limbs
is important (it can be done by ultrasound, CT,
MR, or by venous-PTH sampling maps).

358 Thallium-technetium subtraction scan to

visualize abnormal (hypervascular) parathyroid
glands.The four white circular areas are the four
overactive parathyroid glands in a dialysis patient
with hyperparathyroidism.
 DIALYSIS (RENAL REPLACEMENT THERAPY – RRT) 207

359 Histology of a parathyroid 359

gland removed at
parathyroidectomy. Multiple
nodules of hyperplastic
parathyroid tissue can be seen
(H+E x30).

360 Histology of a parathyroid 360

gland removed at
parathyroidectomy showing
parathyroid carcinoma (islands of
malignant cells in vessels in the
stroma around the gland). Only
18 cases of this very rare
condition have been reported in
dialysis patients.

361 A thallium scan showing 361

extensive metabolic activity in a
parathyroid autograft in the left
deltoid muscle.
208 CHRONIC RENAL FAILURE AND DIALYSIS

Dialysis (RRT) (continued) imposed endovascular fibrosis was found to be

the most common lesion seen in the biopsy
Calcific uremic arteriolopathy (CUA, material, and was much more frequent than two
Seyle’s calciphylaxis) and calcinosis other lesions proposed to cause the ischemia
CUA and calcinosis are both rare and fascinating (thrombosis and global calcific obliteration
conditions. CUA is most commonly seen in [365]). The calcified stenotic vessels averaged
patients on dialysis, though can rarely occur in 100 µm in diameter (i.e. small arterioles) and
chronic renal failure or after successful renal the calcification could also be seen even at
transplantation. capillary level (and clearly therefore adversely
There is evidence that it is increasing in affecting tissue oxygenation). Calcification
incidence, though in part this will represent preceded the endovascular fibrosis. Vessels with
better diagnosis and investigation. Recent early endovascular fibroblastic activation were
evidence about the regulation of calcification (in found statistically to be strongly associated with
orthodox and heterodox locations) – which is the presence of a giant cell reaction. Proximal
by means of a wide variety of calcification regu- locations of necrosis (thighs, buttocks, trunk)
lating proteins – has suggested a role for carried a more unfavorable prognosis compared
warfarin in inducing metastatic calcifications. to distal locations (calves, forearms, fingers, toes,
This is controversial and obviously has signifi- penis). Diabetics with chronic renal failure had
cant implications for dialysis patients. It is clear acral gangrene in 61% compared to 34% of the
that in man there are two distinct clinical syn- nondiabetic calciphylaxis patients.
dromes (but with uniform histologic findings). In general therapies for this distressing
The first of these is symmetric ascending acral condition are few in number and ineffective.
gangrene, often with painful plaques of skin on Hyperbaric oxygen therapy (which would
the shins (362, 363). The second is a destruc- counter the severe hypoxia and reduced tissue
tive necrotic calcifying panniculitis, affecting the viability) warrants further study. Parathyroidec-
pannus typically in poorly-nourished, obese, tomy in the context of obvious biochemi-
white, diabetic females (364). One of the chief cal–clinical hyperparathyroidism is associated
problems, apart from diagnostic suspicion, is the with a favorable outcome.
wide differential diagnosis – this must include Calcinosis refers to the deposition of cal-
emboli, cholesterol embolisation syndrome, cium–phosphate in the skin but without necrosis.
systemic vasculitis, cryoglobulinemia, cryo- It is seen in some patients after prolonged
fibrinogenemia, and systemic oxalosis. exposure to excessive calcium and especially
Careful histochemical analysis of a few cases phosphate. Large, almost tumoral, masses can
has been performed. A distinctive and previously develop, and strict control of calcium and
described small vessel calcification with super- phosphate balance is mandatory to aid recovery.

362

362 Calcific uremic arteriolopathy (Seyle's calciphylaxis). Extensive acral

ascending gangrene of the hands.
 DIALYSIS (RENAL REPLACEMENT THERAPY – RRT) 209

363 Same patient as 362. 363

Extensive acral ascending
gangrene of the feet.

364 Extensive infected gangrene 364

of the pressure areas over the
buttocks and thighs.

365 Histology of skin shows 365

extensive abnormality including
intense medial calcification
(arrow) of small arterioles and
capillaries, with intense intimal
proliferation and thrombosis.
210 CHRONIC RENAL FAILURE AND DIALYSIS

Dialysis (RRT) (continued) advocated using ultrasound, CT scanning, or

MR scanning on a regular basis, but this is
Acquired cystic disease of native kidneys not (yet) routine practice. Regression of these
Patients who spend many years in significant cysts can occur slowly after successful renal
renal failure, and particularly on dialysis, transplantation.
develop shrunken native kidneys with large
numbers of cortical cysts (366). Very rarely Diabetic muscle infarction
these can enlarge massively. These can give rise Diabetic patients with advanced renal impair-
to retroperitoneal or perirenal hemorrhage ment, or on dialysis, are prone to this compli-
(367). Renal cell carcinoma can also arise from cation. Patients notice muscle weakness (usually
these cysts – loss of erythropoeitin requirement thigh) which can be painful accompanied by
(due to tumor-related polycythemia) is rare elevated temperature, inflammatory markers,
(368, 369). Screening for these cysts has been and muscle enzyme levels (370).

366

366 Ultrasound of the kidneys in a long-term dialysis patient,

showing multiple small cysts uniformly distributed in an otherwise
echogenic small kidney.

367

367 CT scan of the abdomen showing a massive

retroperitoneal/pararenal hematoma (arrow) in a long-term
dialysis patient.The tiny native kidney is hard to distinguish.
 DIALYSIS (RENAL REPLACEMENT THERAPY – RRT) 211

368 Renal cell carcinoma arising 368

from acquired renal cystic
disease. CT scan of the abdomen
to investigate weight loss and
reduced erythropoetin
requirements in a long-term
dialysis patient, showing a right
renal mass (and biopsy needle).

369 Nephrectomy specimen 369

from the same patient as 368
showing multiple small cortical
cysts and large renal cell
carcinoma.

370

370 MRI scan of the thigh of a patient with acute diabetic muscle infarction. Increased muscle signal is
due to increased water content.
212 CHRONIC RENAL FAILURE AND DIALYSIS

Dialysis (RRT) (continued) long-term antibiotics and often surgery. Renal

patients are also more prone to Clostridium
Infections difficile diarrhea and pseudomembranous colitis
Renal patients are much more prone to infec- (373, 374). Tuberculosis is also more common
tions, and sepsis is a major cause of morbidity in both hemodialysis and also peritoneal
and mortality on dialysis. Renal patients, dialysis patients.
especially using dialysis cannulae, repeatedly get
bacteremias. These are a major cause of endo- Malignancy on dialysis
carditis. In addition, there is a greatly increased There is a small but significant increase in the
incidence of staphylococcal (and other organ- incidence of solid-organ and bone-marrow
ism) vertebral diskitis (371, 372), which require tumors in dialysis patients.

371 372

372 CT scan of the lumbar vertebrae. A

paravertebral abscess (arrows) and facet joint
infection are shown (this was staphylococcal
in origin).

371 MRI scan of the cervical vertebrae. A

paravertebral abscess and cervical diskitis are
shown (arrow).This was ‘sterile’ on aspiration,
biopsy, and culture but settled on antibiotics.

373 374

373, 374 CT scan of the abdomen (373) with bowel

and intravenous contrast showing the grossly
thickened/edematous rectal wall (arrow), and sigmoidoscopic appearances (374) showing gross edema
and pseudomembrane formation.
Chapter Twelve
213

Renal
transplantation
• Introduction

• Causes of graft dysfunction

• Renal allograft histology

• Vascular and urologic complications

of renal transplantation

• Other complications
214 RENAL TRANSPLANTATION

Introduction

Renal transplantation is now the treatment of However, graft survival is improving; the pro-
choice for most patients with end-stage renal jected half-lives of grafts performed in 1995 in
failure. Transplantation has been shown to the USA were 21.6 years for recipients of living
improve long-term survival and quality of life donor grafts, and 13.8 years for cadaveric grafts.
compared to patients who remain on dialysis. The improvements are due to increased experi-
Combined kidney–pancreas transplantation is the ence of transplant teams, better HLA matching,
optimal treatment for selected type 1 diabetics. and newer immunosuppressive agents and anti-
Patient and graft survival at one year is viral drugs.
excellent, although graft loss from chronic In this chapter, we will highlight some of the
allograft nephropathy remains a major problem. clinical problems after renal transplantation.

Causes of graft dysfunction

When renal allograft dysfunction occurs it is logic complications. Imaging is initially per-
necessary to find the cause. Common reasons formed by ultrasound which will detect trans-
are hypovolemia, acute pyelonephritis, drug plant hydronephrosis or a lymphocele. Subse-
toxicity, acute or chronic rejection, recurrent or quently, renal biopsy is often essential to define
de novo glomerular disease, or vascular and uro- cause of graft dysfunction and guide therapy.

Renal allograft histology

Following renal transplantation, there are three Acute tubular necrosis

major periods: delayed graft function, early dys- The pathologic appearances of acute tubular
function, and late dysfunction. necrosis vary greatly in degree, from incipient
infarction to mild and focal attenuation of
DELAYED GRAFT FUNCTION tubular epithelial cells (Chapter 10). This process
This refers to failure of the graft to function may be accompanied by a variable degree of
from the moment that the clamps are removed interstitial edema but is not associated with
from the renal vessels and may last for a very cellular infiltration. There is a notoriously poor
variable period, usually only for a few hours or correlation between the pathologic changes and
days, but on occasion for several weeks, with the degree of dysfunction, and it is unreliable to
eventual onset of adequate function. Manage- predict the speed of recovery from the severity
ment of the patient during this period requires of the appearances. Sometimes it may take weeks
regular renal biopsies to exclude rejection. for the onset of renal function. High levels of
Delayed graft function may be associated calcineurin inhibitors may prolong the process.
with a variety of processes, and these include:
• Acute tubular necrosis. Accidents to the vascular or ureteric
• Accidents to the vascular or ureteric anasto- anastomosis
mosis. There are no reliable pathologic features to
• Perfusion injury. diagnose or exclude these possibilities. Throm-
• Hyperacute rejection. bosis of the main renal artery will give rise
to nonhemorrhagic infarction, whereas throm-
bosis of the main renal vein will cause hemor-
rhagic infaction.
 RENAL ALLOGRAFT HISTOLOGY 215

Perfusion injury The pathologic appearances of hyperacute

There may be obvious damage to endothelial rejection are of platelet thrombi in the micro-
cells, or in extreme cases changes in the wall of circulation, with margination of polymorphs,
arteries indistinguishable from fibrinoid necro- proceeding to hemorrhage and necrosis.
sis. These appearances may also be seen in non-
heart beating donors, and can cause the path- EARLY GRAFT DYSFUNCTION
ologist a serious diagnostic dilemma in making This may be defined as the onset of dysfunction
a distinction from vascular rejection. The after a period of adequate function, and may
diagnosis may only be revealed by time, in that start within a few days to a few months after
recovery is unlikely in vascular rejection, but transplantation. It is in this period that acute
function may ensue after perfusion injury. Per- rejection becomes one of the most important
fusion injury may be accompanied by a fall in possibilities to exclude, because early and effec-
the platelet count, which may help to dis- tive treatment will be necessary to limit the
tinguish these conditions. degree of irreversible damage and give the
greatest chance of prolonged good function.
Hyperacute rejection During this period, therefore, the possible
Hyperacute rejection is seen very occasionally diagnoses include:
(375, 376). It is caused by the presence of • Acute tubular necrosis.
circulating antibodies from previous sensitiza- • Acute cellular rejection.
tion of the recipient, which react with antigens • Accidents to the vascular or ureteric
that are present in the donor kidney. These are anastomoses.
most commonly ABO or HLA Class I antigens. • Calcineurin inhibitor toxicity.
A negative cross-match between donor lympho- • Acute vascular rejection.
cytes and recipient serum guards against such • Infection, including pyelonephritis, cyto-
an event. However, accidents can occur – e.g. megalovirus, polyoma virus.
if the cross-match sample predates sensitization
caused by a blood transfusion. A situation Acute cellular rejection
mimicking hyperacute rejection can be caused Acute cellular rejection may be seen as early as the
by cold-reacting IgM antibodies. This can be fifth day after transplantation, but is more com-
avoided by ensuring that the donor organ is at monly seen after one week. It becomes decreasing-
body temperature before the clamps are ly common as each week passes, but may occa-
removed from the vascular anastomosis. sionally be seen years after transplantation, usually

375 376

375 Photograph of a kidney that has undergone 376 Hyperacute rejection, with transmural arterial
hyperacute rejection. infarction, fibrin thrombus in afferent arteriole
(arrow), death of tubules, and peritubular
hemorrhage. Light microscopy (MS x250).
216 RENAL TRANSPLANTATION

Renal allograft histology 377

(continued)

in association with noncompliance with medi-

cation. Cellular rejection accounts for approxi-
mately 90% of acute rejection episodes.
The microscopic features are very similar to
an acute tubulointerstitial nephritis of any cause,
for example drug sensitivity. There is a diffuse
interstitial cellular infiltrate composed mainly of
T-lymphocytes and macrophages, and these cells
characteristically infiltrate the tubular epi-
thelium, causing destruction of the epithelial
cells and the tubular basement membrane (377, 377 Acute cellular rejection showing tubules
378). There may be associated hemorrhage and intimately mixed with mononuclear cells. It is
edema. The earliest cellular infiltration is seen difficult to detect tubulitis without a basement
around the interlobular veins. Natural killer cells membrane stain. Light microscopy (H+E x250).
and plasma cells are only seen in small numbers.
Occasionally there are significant numbers of
eosinophils. It is important to remember that
the renal medulla is not usually involved, even Early recognition of vascular rejection may be
in severe cellular rejection. This means that if aided by staining of the biopsy with antibodies
the biopsy core does not include cortex, acute to C4d. Positivity will be seen in peritubular
cellular rejection cannot be reliably excluded. capillaries. This apperance occurs before the
more serious features listed above, and will allow
Acute vascular rejection (379–381) appropriate treatment to be started sooner.
There are a variety of factors involved in this
process. These include circulating antibodies Calcineurin inhibitor toxicity
directed at various sites such as the endothelium The appearances in cyclosporine (cyclosporin)
or the muscle cells of the vessel wall, or the toxicity are identical to those in tacrolimus
direct cytotoxic effect of specific T-lymphocytes. toxicity. The following three features, although
It is sometimes possible to demonstrate the not specific to calcineurin inhibitor toxicity, if
presence of anti-HLA antibodies in the recipi- taken with the appropriate clinical picture, i.e.
ent’s serum; however, vascular rejection may be graft dysfunction with high drug levels, will help
seen in the absence of recognizable antibodies. in making the diagnosis:
From a practical point of view it is possible to • The presence of hyaline lesions in arterioles
distinguish a process that mainly affects capillary (382). The interpretation of these appear-
size vessels, as opposed to larger vessels such as ances has to be taken with caution because
arterioles and arteries. In rejection of the kidney, many donors are hypertensive and it is dif-
veins do not appear to have a significant role ficult to be certain that such changes did not
other than allowing lymphoid cells access to the come with the kidney from the donor.
renal parenchyma. When capillary-sized vessels • Isometric vacuolation in tubular epithelium
are involved, the result is interstitial hemorrhage (383). This is the presence of multiple small
due to damage to peritubular capillaries. When clear vacuoles of similar size. This appearance
large vessels are principally involved, they may is only infrequently present, and is often only
show a variety of changes such as: limited to occasional tubules, but when
• Endothelial cell swelling or necrosis which present is a very useful diagnostic feature.
can result in thrombosis. • Peritubular and glomerular capillary thrombi,
• Margination and infiltration by mononuclear although not specific, are a useful feature.
cells (intimal arteritis).
• Fibrinoid necrosis of the vessel wall.
• Mucoid intimal proliferation (similar to that
seen in HUS).
 RENAL ALLOGRAFT HISTOLOGY 217

378 379

378 Acute cellular rejection showing mono- 379 Acute vascular rejection. Interlobular artery
nuclear cells infiltrating into the tubular epithelium showing intimal arteritis. Light microscopy
(tubulitis) with destruction of the basement (H+E x250).
membrane (arrow). Light microscopy (MS x400).

380 381

380 Acute vascular rejection. Interlobular artery 381 Acute vascular rejection. Interlobular artery
showing intimal arteritis and fibrinoid necrosis of showing mucoid intimal proliferation (arrow).
the vessel wall (arrow). Light microscopy Light microscopy (H+E x250).
(H+E x250).

382 383

382 Calcineurin inhibitor toxicity. Arteriole 383 Calcineurin inhibitor toxicity.Tubules from a
showing hyaline change (arrow). Light child on cyclosporine (cyclosporin) for a liver
microscopy (MS x400). transplant showing isometric vacuolation (arrow).
Light microscopy (H+E x250).
218 RENAL TRANSPLANTATION

Renal allograft histology (continued)

Infection arrived at by a wide variety of pathologic proces-

The main infective processes affecting the renal ses which may include: recurrent episodes of
transplant are: cellular or vascular rejection, reflux nephropathy,
• Acute pyelonephritis. or graft ischemia. It is not generally possible to
• Cytomegalovirus infection. distinguish between these etiologies by the
• Polyoma viruses including BK and JC. pathologic appearances.

Dysfunction may be attributable directly to Chronic allograft nephropathy

the infective process or as a result of the infec- It is more appropriate to consider all of the
tion inducing an episode of acute rejection. chronic changes that occur in the transplant
The diagnosis of acute pyelonephritis will under this heading, rather than chronic rejec-
usually be made on account of pain, pyrexia, and tion, and to include the specific glomerular
pyuria. Occasionally the presence of large num- appearances of transplant glomerulopathy.
bers of polymorph casts within tubules in Transplant glomerulopathy (387, 388) is
the renal biopsy can be the first indication generally associated with the onset of significant
of infection. proteinuria, which may reach nephrotic levels.
Cytomegalovirus infection is sometimes asso- There are characteristic pathologic appearances
ciated with graft dysfunction without rejection. which include glomerular hypercellularity,
A biopsy taken under these circumstances may endothelial swelling, and double-contouring of
occasionally show the characteristic inclusions in the glomerular capillary walls. Immunohisto-
tubular epithelial cells or glomeruli (384). chemistry usually shows little immunoglobulin
More recently infection with polyoma or complement deposition, although sometimes
viruses, including BK and JC, have been recog- there may be capillary wall localization of IgM,
nized. These infections are associated with a making distinction from membranoproliferative
gradual decline in graft function often many glomerulonephritis difficult. Electron micros-
months after transplantation. It is recognized copy will show an electron-lucent subendo-
that these infections are more common with thelial zone in allograft glomerulopathy, whereas
intensive immunosuppression. The initial poor electron-dense deposits are expected in mem-
prognosis has improved with the strategy of branoproliferative lesions.
reducing immunosuppression and use of the
antiviral drug cidofovir. The biopsy shows Chronic calcineurin inhibitor toxicity
chronic tubular damage associated with charac- Chronic toxicity causes tubular damage and
teristic nuclear and cytoplasmic changes in the interstitial fibrosis. Sometimes the pattern of
tubular epithelium (385). Urine cytology will damage gives rise to bands of fibrous scarring
show ‘decoy cells’ consisting of sloughed-off alternating with relatively well-preserved tubules.
renal tubular cells with inclusion bodies (386). This is known as striped fibrosis.

LATE GRAFT DYSFUNCTION Recurrent and de novo glomerular

This clinical period extends from several months disease
to years after transplantation. Some of the Some glomerular diseases are particularly prone
conditions encountered during this period are to recur in grafts and cause graft loss, especially
listed below: focal and segmental glomerulosclerosis, mem-
• Chronic rejection. branoproliferative glomerulonephritis, and fam-
• Chronic allograft nephropathy. ilial hemolytic–uremic syndrome. IgA neph-
• Chronic calcineurin inhibitor toxicity. ropathy frequently recurs but rarely causes early
• Recurrent glomerular disease. graft loss.
• De novo glomerular disease. Any form of glomerular disease may occur de
• Post-transplant lymphoproliferative disorder. novo in a renal graft. The presenting symptoms
will be the same as in native kidneys. The
Chronic rejection pathologic appearances may be more difficult to
This term is an attempt to link an etiologic assign because of the potential similarities
process with a pathologic appearance which between allograft glomerulopathy and mem-
includes chronic glomerular, interstitial, and branoproliferative glomerulopathy, HUS, and
vascular damage. These appearances may be accelerated phase hypertension.
 RENAL ALLOGRAFT HISTOLOGY 219

384 385

384 CMV.Tubular cells contain ‘owl-eyes’ 385 BK nephropathy with intranuclear inclusions
intranuclear inclusions (arrow). Light microscopy within renal tubular cells (arrow). Light microscopy
(H+E x250). (H+E x400).

386 387

386 BK nephropathy. Urinary cytology showing 387 Transplant glomerulopathy showing double-
decoy cells. contouring of the capillary walls (arrow). Light
microscopy (MS x400).

388

388 Transplant glomerulopathy with wide sub-

endothelial electron-lucent zone (arrow). Electron
microscopy (x5000).
220 RENAL TRANSPLANTATION

Renal allograft histology (continued)

Post-transplant lymphoproliferative Table 17 The Banff 97 schema

disorder
There is a spectrum of proliferative disorders of
lymphoid cells that may occur in transplant Normal
recipients. Generally these are B-cells and are of
Antibody-mediated rejection
host origin, and are most commonly associated
with Epstein–Barr virus. At one end of this Borderline changes,‘suspicious of acute
spectrum, there is a polyclonal B-cell prolifera- rejection’.This shows mild tubulitis, but no
tion that presents as an infectious monucleosis vascular changes
type of illness, and will respond to reduction
Acute rejection
or withdrawal of immunosuppression, while at
Type:
the other there is an aggressive monoclonal
IA Significant interstitial mononuclear
proliferation that behaves like a high-grade lym-
infiltration, but only moderate tubulitis
phoma, requiring treatment with chemotherapy
IB Significant interstitial mononuclear
and anti-B-cell monoclonal antibodies.
infiltration, with severe tubulitis
About half of patients with PTLD present
IIA Mild to moderate intimal arteritis.
with extranodal disease, and about one-quarter
IIB Severe intimal arteritis
show involvement of the graft kidney, which
III Transmural arteritis and/or arterial
may result in dysfunction. Distinction from
fibrinoid change
cellular rejection may require immunopheno-
typing (389, 390). Rejection is associated with Chronic allograft nephropathy
T-cell infiltration while PTLD is usually asso- Grade I: mild interstitial fibrosis and tubular
ciated with B-cells. It is also possible to demon- atrophy
strate EBV in a proportion of the cells in PTLD Grade II: moderate interstitial fibrosis and
by in situ hybridization. tubular atrophy
Grade III: severe interstitial fibrosis and tubular
Banff classification of renal allograft atrophy
pathology
Changes not considered to be due to
This is a continually evolving international con-
rejection
sensus amongst pathologists who are involved
with the interpretation of renal allograft bi-
opsies. The purpose is to standardize the inter-
pretation of allograft biopsies in order to guide The Banff 97 schema includes six diagnostic
therapy and give an objective end point for categories, which are presented in a simplified
clinical trials. form in Table 17.

389 390

389 Post-transplant lymphoproliferative disease. 390 The same case as 389 showing cells staining
High power view showing pleomorphic positively with antibody to EBV Light microscopy
lymphoblastic infiltrate in an aggressive PTLD. (immunoperoxidase x400).
Light microscopy (H+E x400).
 VASCULAR AND UROLOGIC COMPLICATIONS 221

Vascular and urologic complications

of renal transplantation

LYMPHOCELE Differential diagnosis

Definition The principal differential diagnosis is a pyogenic
Lymphoceles are collections of lymph around collection. There is usually a raised white cell
the renal transplant. count and CRP; aspiration will confirm infection.

Epidemiology and etiology Investigations (391)

Up to 50% of renal allograft may have lympho- Ultrasound is the easiest method of imaging.
celes detectable on ultrasound. Most resolve Lymphoceles are characteristically homogeneous
spontaneously, and intervention is required only and lie between the kidney and the bladder.
in the minority.
Prognosis
Pathogenesis Small lymphoceles resolve spontaneously, where-
Most lymphoceles arise from leakage of un- as larger ones require intervention. Complica-
ligated iliac vessel lymphatics of the recipient, tions include infection of the collection and deep
rather than from the graft itself. The incidence venous thrombosis.
of clinically significant lymphoceles appears
higher in patients receiving sirolimus therapy, Management
because sirolimus slows wound healing. Intervention usually initially involves percu-
taneous drainage which may need repeating.
Clinical history and physical examination However, lymph may continue to drain and
Most lymphoceles are clinically silent. Larger surgery may be required. The technique termed
lymphoceles can present with swelling around fenestration involves creating a window between
the graft, leg swelling, worsening renal function, the collection and the peritoneum.
and deep vein thrombosis. Most present within
2 weeks to 6 months after transplantation, with
a peak incidence at 6 weeks.

391

391 Ultrasound demonstrating a large lymphocele.

222 RENAL TRANSPLANTATION

Vascular and urologic complications of renal

transplantation (continued)

RENAL ARTERY STENOSIS 392

Definition
Whereas renal artery or vein thrombosis (31,
32) are the commonest causes of immediate
graft loss after transplantation, renal artery
stenosis is an important late complication.

Epidemiology and etiology

The incidence varies in different series (1–12%)
and partly depends on the rigour of the screen-
ing policy adopted by individual units. The
causes are probably multifactorial involving
atheroma in the donor vessels, technical errors,
chronic immune damage, and CMV infection.
The peak time of presentation is 3 months to
2 years after transplantation.
393
Clinical history
Patients may present with a rising creatinine or
with worsening hypertension. A substantial rise
in creatinine after initiation of ACE inhibitors
is a characteristic presentation. Flash pulmonary
edema may also occur. A bruit may be audible.

Differential diagnosis
A critical stenosis of the proximal iliac vessels
may mimic renal artery stenosis.

Investigations
Noninvasive methods of screening include
power Doppler ultrasound (392, 393) and
magnetic resonance angiography (394). These 392, 393 Color Doppler ultrasound (392) and
have the advantage of avoiding nephrotoxic power Doppler ultrasound (393) of a normal
contrast. Digital subtraction angiography renal transplant.
remains the gold standard, and if doubt remains
the pressure gradient across the stenosis can be
measured (>20mmHg [2.7 kPa] is significant).
394
Prognosis
If a critical stenosis is left untreated the graft
function and hypertension will usually deterior-
ate. Re-stenosis may occur postangioplasty.

Management
Percutaneous transluminal renal angioplasty is
the treatment of choice for most functionally
significant lesions. There is a small risk of arterial
occlusion with graft loss. Re-stenosis should be
suspected clinically, and power Doppler can be
used as a sensitive screening technique.
394 Magnetic resonance angiogram of a renal
transplant (normal study).
 OTHER COMPLICATIONS 223

URETERAL OBSTRUCTION Other complications

Definition
Ureteral obstruction is an important cause of
impaired or deteriorating graft function. CARDIOVASCULAR
Cardiovascular disease is the commonest cause of
Epidemiology and etiology death after renal transplantation, and is a major
It may occur early or late after transplantation. It target of intervention. Coronary artery disease
may be caused by extrinsic compression of the and left ventricular hypertrophy are prevalent in
ureter by a lymphocele or hematoma, or by a patients with chronic renal failure (Chapter 11).
hematoma or calculus within the lumen. Ischemia The hypertension and dyslipidemia induced by
may also cause stricturing of the ureter. steroids and calcineurin inhibitors are risk factors
for accelerating atherosclerosis. Aggressive con-
Clinical history trol of blood pressure and lipids is vital in the
The transplant kidney is not innervated and management of post-transplant patients.
therefore obstruction is usually painless. There
is usually a rise in creatinine. MUSCULOSKELETAL
Bone disease is a major complication of renal
Investigations transplantation, especially in postmenopausal
Ultrasound will in most cases show hydrone- woman who already may have pre-existing
phrosis. Antegrade pyelogram will demonstrate osteoporosis. Patients will have pre-existing
the site of obstruction as well as relieving obstruc- renal bone disease from their chronic renal
tion (395). Furosemide (frusemide) renography failure (Chapter 11). After transplantation
can help to distinguish between true obstruction patients may lose 10–15% of their bone density
and a large floppy pelvicalyceal collecting system. in the first few months due to initial immobiliza-
tion and high doses of steroids used. Thereafter
Prognosis bone density stabilizes or even rises. The inci-
This depends on the cause of the obstruction. dence of vertebral and hip fractures is greatly
Ischemic strictures need surgical intervention. increased. Modern immunosuppressive regi-
mens involve minimizing corticosteroids. Bi-
Management sphosphonates may be useful in preventing post-
Obstruction can be temporarily relieved by transplant osteoporosis.
insertion of a nephrostomy or stent. Urinary Avascular necrosis of the hip (396) was a
tract infections should be treated. Surgery may particularly common complication in the pre-
be required for definitive treatment. cyclosporine (cyclosporin) era because larger
doses of corticosteroids were given. Treatment
requires hip replacement.

395 396

395 Nephrostogram demonstrating

hydronephrosis in a renal transplant.
396 MRI scan showing avascular necrosis of
the hips.
224 RENAL TRANSPLANTATION

Other complications (continued)

NEUROLOGIC tion). Viruses, mycobacteria, protozoa, and

Immunosuppression can lead to unusual central certain fungi are important potential pathogens
nervous system infections by organisms such as in transplant recipients.
Cryptococcus, Aspergillus, Nocardia, and Listeria.
Calcineurin inhibitors cause a tremor in a dose- Viruses
related fashion. Rarely, they can cause reversible Viral pathogens that definitely cause disease in
posterior leucoencephalopathy syndrome: this transplant recipients are listed in Table 18.
may present with blindness, fits, and decreased
conscious level (397, 398). Cytomegalovirus (CMV)
This is probably the most important viral
INFECTION pathogen affecting renal transplant recipients.
Renal transplant recipients are susceptible to It may be either transmitted by the graft or
pyogenic bacterial infections in the first few days reactivated in the recipient by immunosuppres-
and weeks after transplantation. This is because sion. The most severe infections tend to occur
of the immunosuppression caused by the uremic in patients who have a primary infection at the
state as well as the immunosuppressive drugs time of transplantation. Without antiviral
used. Host defences are breached by central prophylaxis, symptoms and signs of infection
lines, urinary catheters, and sometimes by con- begin 4–8 weeks after transplantation. Usually
taminated organs. Wound, pulmonary, and there is fever, leucopenia, and thrombocyto-
urinary infections are common. penia. Tissue-invasive disease can affect the
Thereafter opportunistic infections become esophagus, colon, liver, lungs, and retina (397).
a more serious problem. Calcineurin inhibitors Various techniques have been available to
selectively inhibit T-cell function, and so the monitor CMV infection, but direct antigen
infections that are controlled by cell-mediated testing (DAT) and CMV PCR are the most
immunity tend to predominate (as in HIV infec- widely used. Prophylaxis is now given to high-

397 398

397 MRI scan in a man who developed reversible 398 A follow-up scan in the same patient as 397
blindness secondary to cyclosporine (cyclosporin) – after a full recovery following discontinuation of
‘reversible posterior leucoencephalopathy syndrome’. cyclosporine (cyclosporin).
The scan shows lesions in the occipital cortex.
 OTHER COMPLICATIONS 225

risk recipients by using ganciclovir or valacy- ciclovir. A rare complication of prolonged gan-
clovir (valaciclovir). Treatment involves reduc- ciclovir usage is the development of ganciclovir-
ing immunosuppression and intravenous gan- resistant mutant strains.

Table 18 Viral pathogens that definitely cause disease in transplant recipients

Virus Clinical manifestation

Herpes simplex Cold sore (399)
Herpes zoster Chickenpox/shingles (400)
Cytomegalovirus Fever, leucopenia, pneumonitis, hepatitis, colitis, retinitis
Epstein–Barr virus Post-transplant lymphoproliferative disease
Human herpes virus-8 Kaposi's sarcoma
Hepatitis B and C Hepatitis, cirrhosis
HIV Immune deficiency
Polyomaviruses
BK Interstitial nephritis, ureteric stenosis, cystitis
JC Progressive multifocal leucoencephalopathy
Papillomavirus Warts, squamous cell carcinoma

399 Herpes simplex infection 399

on the lip.

400 Herpes zoster infection on 400

the buttock.
226 RENAL TRANSPLANTATION

Other complications (continued)

Opportunistic pathogens Skin tumors

Important nonviral opportunistic pathogens are Skin tumors are the commonest malignancy in
listed below: transplant recipients. They are particularly
• Bacteria: Legionella, Nocardia (401), Myco- prevalent in areas of the world where sun
bacteria. exposure is great. In a study from Queensland
• Fungi: Pneumocystis (402), Candida, Asper- in Australia, the cumulative incidence of basal
gillus (403), Cryptococcus, Mucormycosis; cell and/or squamous cell carcinoma rose from
Coccidiomycosis and histoplasmosis in en- 7% at 1 year to 45% at 11 years and 70% at
demic areas. 20 years following transplantation. Squamous
• Parasitic: Strongyloides, toxoplasmosis. cell carcinomas (405) occur with a greater
incidence than basal carcinoma which is a
NEOPLASIA reverse of the incidence in nonimmunosup-
There is an increased incidence of certain malig- pressed individuals. Squamous cell carcinoma
nancies in the transplant population due to the tend to be multiple, recur and metastasize more
long-term effects of immunosuppressive drugs readily than in the normal population. In the
reducing tumor surveillance, activating onco- Australian population malignant melanoma
genic viruses, and increasing production of pro- (406) was four times more prevalent in the
proliferative cytokines such as TGF-`. Lym- transplant population.
phomas (399, 404), cervical carcinoma, and Kaposi’s sarcoma (407) is found most com-
skin malignancies are particularly found in the monly in transplant patients of Arabic, African,
transplant population. or Mediterranean origin. Human herpesvirus-8
is implicated in its pathogenesis. The tumors may
appear on the skin as purple macules or in the
mouth, respiratory, or gastrointestinal tract. They
may regress after reduction in immunosup-
pression and may respond to local radiotherapy.

401 402

401 MRI brain scan in a renal transplant patient 402 CXR of a patient with Pneumocystis carinii
with cerebral nocardiosis (arrow). pneumonia.
 OTHER COMPLICATIONS 227

403 404

403 CT scan demonstrating an aspergilloma in a

renal transplant patient.

404 PET scan demonstrating increased uptake in the

cervical glands (arrows) in a patient with post-
transplant lymphoproliferative disease.

405 406

407

405 Squamous cell carcinoma on the ear.

406 Malignant melanoma.

407 Multiple cutaneous Kaposi sarcoma lesions.

228 RENAL TRANSPLANTATION

Other complications (continued)

COSMETIC offending drugs are discontinued. Cyclosporine

Immunosuppressive drugs can cause undesirable (cyclosporin) may also cause severe hyper-
cosmetic side-effects. trichosis within the first 6 months of treatment
Steroids cause an increase in appetite and a (410). Tacrolimus does not cause either of these
change in body fat distribution causing ‘moon- side-effects.
like’ facies, truncal obesity, and striae formation. Viral warts (411) are very common in transplant
Steroids also induce acne mainly over the face, recipients. They correlate with the degree of sun
upper trunk, and upper arms (408). exposure and duration of immunosuppression.
Cyclosporine (cyclosporin) causes marked They may be multiple and difficult to distinguish
gingival hyperplasia (409) especially when used from squamous cell carcinomas. They may cause
in conjunction with the antihypertensive drugs much cosmetic surgery. Treatment involves mini-
nifedipine or amlodipine. The gum hypertrophy mizing immunosuppression, cryosurgery, and
may be very severe, but will regress if the topical or systemic retinoids.

408 409

408 Severe steroid-induced acne. 409 Cyclosporine (cyclosporin)-induced gingival

hyperplasia.

410 411

410 Severe hypertrichosis in a female induced by 411 Multiple viral warts.

cyclosporin (ciclosporin).