Genitourinary System

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Chapter 12 Genitourinary System

Kidney – Structure and Function 446

Glomerular Structure and Function 447

Glomerular Diseases 448

Acute Diffuse Proliferative Glomerulonephritis 449

Crescentic (Rapidly Progressive) Glomerulonephritis 450

Membranous Glomerulonephritis 451

Mesangiocapillary (Membranoproliferative) Glomerulonephritis 452

Focal Glomerulonephritis 453

IgA Nephropathy 454

Minimal Change Glomerulonephritis 454

Chronic Glomerulonephritis (GN) 455

Glomerulonephritis – Disease Mechanisms 456

Glomerular Disease in Systemic Disorders 457

The Kidney and Hypertension 458, 459

Chronic Renal Failure 460, 461

Infections of the Kidney and Urinary Tract 462

Acute Pyelonephritis 463

Chronic Pyelonephritis 464

Tuberculosis of the Kidney 465

Intercurrent Renal Conditions 466

Renal Function and Pregnancy 467

Renal Tubule – Structure and Function 468

Acute Kidney Injury (AKI) (Acute Tubular Necrosis) 469, 470

Tubulo-Interstitial Diseases 471

Metabolic Tubular Lesions 472

Thrombotic Microangiopathies (Haemolytic Uraemic Syndrome) 473

Pathological Complications of Renal Replacement Therapies 474

Congenital Disorders 475

Polycystic Kidney Disease 476

Urinary Calculi 477, 478

Tumours of the Kidney 479, 480

Diseases of the Urinary Tract 481

Urinary Tract Infection 482

Tumours of the Urothelium 483

The Prostate 484

Diseases of the Prostate 485

Adenocarcinoma of the Prostate 486

Diseases of the Penis 487

Diseases of the Testis 488

Tumours of the Testis 489, 490

Infertility 491

Kidney – Structure and Function

The kidney has several functions:

It produces several hormones:

(i) Renin, which influences vascular tone and blood pressure.

(ii) Erythropoietin, which increases red blood cell production.

(iii) 1, 25 dihydroxy Vitamin D – The active form is produced by 1α hydroxylation in the kidney. It promotes calcium absorption from the gut and is required for normal bone mineralisation.

Tests of renal function:

1. Blood analysis

Many substances will show altered values in renal failure, but the following are always elevated and are commonly used in estimating the progress of the disease.

(i) Urea – normal range 2.5–7.0mmol/l. (20–40 mg/100 ml)

(ii) Creatinine – 50–100 mmol/l. (0.6–1.2 mg/100 ml)

2. Clearance Tests (typically creatinine clearance) give an indication of glomerular filtration rate: this is not absolute since some creatinine is secreted by renal tubules. The following formula is used to calculate the volume of blood cleared:

where:

U = urinary concentration,

V = volume of urine per minute,

P = plasma concentration.

In practice renal function is now commonly assessed by estimated glomerular filtration rate (eGFR), which combines serum creatinine with the age and sex of patient.

Chronic Kidney Disease can be classified as follows:

CKD	Stage	eGFR/mL/min/1.73m²
1	with an abnormality*	>90
2	with an abnormality*	60–89
3		30–59
4		15–29
5		<15

* e.g. proteinuria

3. Urine examination

(a) Tests for the presence of protein, red cells, haemoglobin and neutrophils in the urine. Estimation of specific gravity and measurement of urinary output.

(b) Urinary casts. These are composed of foreign elements of various types which are moulded into cylindrical form by passage along tubules and are seen on microscopy.

The Kidney is divided into:

(a) glomeruli

(b) tubules

(d) vessels.

The structure and function and diseases will be discussed separately, but diseases of one may well affect others.

Glomerular Structure and Function

The glomerulus, of which there are over 600000 in the adult, consists of an invagination of a capillary network, derived from the afferent arteriole, into Bowman’s capsule – the beginning of the proximal tubule.

The glomerulus is an efficient filter due to the large surface area of the glomerular capillaries.

Ultrastructure

The barrier separating blood from the lumen of the matrix nephron consists of 3 layers:

Mesangial cells have three functions:

1. Contract and control blood flow

2. They are phagocytic cells and ingest proteins and immune complexes (p.101)

3. They form matrix and secrete inflammatory mediators.

These layers form a complicated sieve controlling glomerular permeability. Wide pores (70–100 nm) in the endothelium allow all components to reach the basement membrane.

The basement membrane produced by the endothelium and epithelium has a strong anionic (negative) charge which repels major plasma proteins (also anionic). It has a central dense layer (lamina densa).

The epithelial cells are attached to the basement membrane by foot processes, separated by ‘slit pores’ 30–60 nm in diameter.

Filtration

The glomerular filtrate is virtually protein free plasma. Its rate of production is dependent upon:

Variation in any of these factors affects the output of urine. Diminished urinary output results from a reduction in renal blood flow as in shock, from an increase in osmotic pressure as in haemoconcentration, or from obstruction to the outflow of urine.

Acute Diffuse Proliferative Glomerulonephritis

This disease classically follows 2–3 weeks after an infection – usually pharyngitis due to Group A haemolytic streptococci. It is commonest in children and young adults who develop the NEPHRITIC SYNDROME: oliguria, proteinuria, haematuria (urine is smoky and dark), moderate hypertension and facial (periorbital) oedema. This disease is now uncommon in fully developed countries.

Immune complexes are identified by:

1. Electron microscopy

2. Immunofluorescence – demonstrates granular deposition of IgG and C3 (complement component 3)

The clinical findings can be correlated with pathology as follows:

Prognosis – The disease usually resolves in 1–2 weeks, particularly in children, but in adults complications are more common.

Crescentic (Rapidly Progressive) Glomerulonephritis

Without treatment, this disease progresses to end-stage renal failure in weeks or months. The histological hallmark is crescent formation in >50% of glomeruli.

Many types of glomerulonephritis can progress to crescentic GN. Examples include:

1. Goodpasture’s syndrome

In this serious disorder there is both renal and often pulmonary damage. Immunofluorescence shows the cause – an antibody to type IV collagen in the glomerular basement membrane (anti-GBM) which also damages pulmonary alveolar membranes.

IF shows linear deposits of IgG and C3 in the capillary basement membranes

RPGN may complicate:

2. Vasculitis – e.g. Wegener’s granulomatosis, microscopic polyarteritis nodosa.

3. Systemic Lupus Erythematosus.

4. Acute diffuse proliferative glomerulonephritis, especially in adults.

5. IgA nephropathy.

Prognosis – Without treatment, most patients die within 6 months.

Immunosuppressive drugs (e.g. steroids, cyclophosphamide) and plasma exchange to (remove anti-GBM antibodies) improve the prognosis but many patients require dialysis or transplantation. Hypertension is a further serious complication.

Membranous Glomerulonephritis

This accounts for around 30% of cases of the nephrotic syndrome in adults; some patients present with asymptomatic proteinuria.

Aetiology

1. Around 85% of cases are idiopathic.

2. Drugs, e.g. penicillamine – in treatment of rheumatoid arthritis.

3. Tumours, e.g. carcinoma of lung, lymphomas.

4. Infections, e.g. malaria, HIV, hepatitis B, syphylis.

5. Collagen disorders, e.g. SLE.

Pathology – There is generalised thickening of capillary basement membrane.

Tuft enlarges

Glomeruli not hypercellular

Specific silver staining of the basement membrane shows a typical pattern.

Immunofluorescence reveals deposition of IgG in the capillary walls.

Electron microscope findings explain this appearance.

In the later stages there is a massive increase in basement membrane material.

Silver staining shows

Tubular changes – In the early stages, protein droplets and lipid globules appear in the tubular epithelium. If the disease progresses there is atrophy of the tubules and interstitial fibrosis.

Prognosis – In about 25% of patients the disease remits spontaneously, the remainder continuing to have proteinuria and in 40% chronic renal failure eventually supervenes.

Mesangiocapillary (Membranoproliferative) Glomerulonephritis

In this form of glomerulonephritis there is an increase both in cells and mesangial matrix within glomeruli.

Silver staining of basement membrane

Duplication of basement membrane as in membranous glomerulonephritis, but without spikes.

These changes are due to ‘mesangial interposition’

Using electron microscopy and immunofluorescence, 2 types are identified.

Aetiology

Complement activation is a feature of both forms. In Type 1 this is due to immune complexes by the classical pathway (p.99). In Type 2 there is activation by the alternative pathway by an autoantibody which stabilises C3 converting enzyme. Serum C3 is low in both forms.

Clinical Features

Children and young adults are usually affected. They present with the nephrotic syndrome (50%), the nephritic syndrome or asymptomatic haematuria or proteinuria.

In half of patients there is progression to renal failure (with hypertension) within a decade. The disease often recurs in the subsequently transplanted kidney.

Focal Glomerulonephritis

In contrast to the glomerular diseases discussed already, focal glomerulonephritis affects only a proportion of glomeruli (focal) and only part of those glomeruli (segmental).

In some cases, part of the tuft becomes necrotic and there is related inflammation (focal segmental necrotising glomerulonephritis). Crescents are sometimes seen. This pattern is seen in:

• Systemic vasculitis, e.g. polyarteritis nodosa

• IgA nephropathy and Henoch–Schönlein purpura

• SLE (systemic lupus erythematosus)

• Some cases of Goodpasture’s syndrome

• Infective endocarditis.

The pattern is associated with haematuria or nephrotic syndrome. Segmental lesions heal by fibrosis.

Focal Segmental Glomerulosclerosis (FSGS)

In this pattern of disease, a segment of glomerulus undergoes sclerosis without inflammation, but with an increase in mesangial matrix.

Originally regarded as a variant of minimal change nephropathy, primary FSGS presents as with haematoma or nephrotic syndrome with progression to chronic renal failure. It may recur within a transplanted kidney.

Secondary FSGS may complicate a variety of preexisting conditions including those reflux nephropathy and intravenous drug use.

IgA Nephropathy

This is the commonest form of glomerulonephritis worldwide. It can present with microscopic or macroscopic haematuria or the nephrotic syndrome and may lead to chronic renal failure. It typically affects young males, who often suffer recurrent episodes after upper respiratory infections although all ages can be affected.

The serum IgA level is raised and glomerular damage is due to IgA immune complexes. Sometimes crescentic glomerulonephritis is seen.

Mechanism

IgA immune complexes in blood → Glomeruli → Often focal deposition → Activation of complement (C3) → Often focal damage

Shows deposits of IgA and C3 within the mesangium: the capillary loops are not usually affected.

Immunofluorescence

Note: The focal deposition is dependent on the molecular size of the complex and failure of mesangial clearance.

Henoch–Schönlein purpura has similar renal changes but also skin rash and gastrointestinal symptoms.

Minimal Change Glomerulonephritis

This disorder affects any age but is the major cause of nephrotic syndrome in children. It typically remits spontaneously and responds to a short course of steroids. Recurrences are quite common.

Normal

The glomeruli are histologically normal, but electron microscopy reveals fusion of podocyte foot processes. This is a finding in many causes of proteinuria. No immune complexes are found on immunofluorescence or electron microscopy.

Minimal change

Chronic Glomerulonephritis (GN)

This is the end stage of many forms of glomerulonephritis, but most patients present at this stage without a history of previous renal disease.

Pathology The kidneys are both small – granular contracted kidney.

In chronic glomerulonephritis a vicious cycle is set up.

Patients may first present with chronic renal failure, or this may develop after years of glomerulonephritis.

Glomerulonephritis – Disease Mechanisms

The mechanism in most forms of GN is:

The glomerulus is central to immune complex deposition and formation due to its fenestrated endothelium and high intraluminal pressure.

Immune complexes can occur in glomeruli as follows:

1. Deposition of circulating complex.

2. In situ formation of complexes

(a) Deposited antigens.

(b) Glomerular antigens.

Glomerular Disease in Systemic Disorders

Amyloidosis

The general features of amyloidosis have already been described (p.24). Amyloid is deposited around the capillary basement membranes of the glomeruli and in the renal vessels and interstitium.

Gross proteinuria leading to a nephrotic syndrome is common. Interstitial fibrosis results from tubular degeneration and ischaemia due to glomerular and arteriolar lesions. Chronic renal failure results.

Parasitic Glomerulopathies

The kidney and particularly the glomeruli are damaged in many parasitic infections in the tropics. Malaria and schistosomiasis are especially important.

The Kidney and Hypertension

There are two aspects to the relationship of the kidney and high blood pressure.

(a) Many renal diseases lead to hypertension (p.197).

(b) Hypertension leads to renal damage.

A vicious circle can be set up:

The renal consequences of benign and malignant hypertension differ, but in each, vascular changes are important.

Benign Hypertension

Afferent arterioles

Interlobular arteries

These arteriolar changes lead to glomerular ischaemia.

Late

These changes are patchy in distribution so that renal failure rarely occurs.

It is now thought that small emboli from atheroma of the aorta are responsible for much of the scarring in benign hypertension.

Malignant Hypertension

In this form of hypertension which may arise de novo or on a background of benign hypertension. There is often an underlying cause for the hypertension the blood pressure rises very rapidly and damages renal arteries, arterioles and glomeruli. Renal failure is common unless the disease is treated.

Afferent arterioles: the hallmark is fibrinoid necrosis.

Fibrinoid necrosis heals with the production of an ‘onion-skin’ lesion.

These changes account for the gross appearance.

Chronic Renal Failure

Progressive renal damage in many kidney diseases eventually leads to chronic renal failure. The major causes include:

(a) Chronic glomerulonephritis.

(b) Chronic pyelonephritis and interstitial nephritis.

(d) Obstructive uropathy.

(e) Polycystic kidneys.

In many cases the underlying cause cannot be determined.

The severity of renal failure is monitored by the serum urea, creatinine and by the glomerular filtration rate (GFR).

Chronic Kidney Disease

Compensatory mechanisms:

As nephrons are lost, the surviving nephrons show (1) compensatory hypertrophy and are (2) continually active with no ‘down time’. (In the normal kidney, the nephrons do not all function simultaneously.)

Effects of chronic renal failure:

1. WATER and ELECTROLYTE BALANCE

Urine concentration is lost.

2. DISTURBANCE OF ACID–BASE BALANCE

3. URAEMIA

The kidney also fails to excrete nitrogenous waste products, which accumulate. Although urea concentrations rise and are used to monitor renal function, retention of urea is not in itself harmful.

In uraemia, patients are lethargic. Anorexia, nausea and vomiting are common, with confusion, convulsions and death.

4. HORMONAL ABNORMALITIES

Three main hormones are involved: Erythropoietin, parathyroid hormone and vitamin D.

5. HYPERTENSION – This is almost inevitable and several consequences are possible.

6. Fibrinous exudates, e.g. fibrinous pericarditis, ‘uraemic pneumonitis’ with pleural exudate.

7. Haemorrhagic ulcers of the gastro-intestinal tract.

8. Depression of immunological reaction. Infections are common and will in turn affect renal function.

Infections of the Kidney and Urinary Tract

The kidney can become infected through 2 main routes.

(1) Ascending infection usually associated with lower urinary tract infection (obstruction and/or vesico-ureteric reflux are often present). This is by far the commoner route and gives rise to pyelonephritis.

(2) Blood borne (haematogenous) infection by pyogenic organisms (e.g. from septicaemia) or in tuberculosis (the latter now uncommon).

Acute Pyelonephritis

This is an acute ascending pyogenic infection and the patient exhibits the usual general features of pyrexia, nausea, vomiting, headaches, rigors, etc., plus localising signs, e.g. frequency, dysuria, loin pain and sometimes haematuria.

Bacteriology

Large numbers of bacteria are found in the urine, several hundred thousand per ml in the acute phase.

The commonest infecting organism is Escherichia coli, but other faecal bacteria may also be found, e.g. proteus, Streptococcus faecalis.

Acute Pyelonephritis

Causes

In women, cystitis is common, particularly in the sexually active. Ascending infection is often provoked by vesico-ureteric reflux during micturition. Pyelonephritis is common in pregnancy.

In men, urinary tract obstruction is usually found, typically due to prostatic enlargement.

A number of causes of obstruction are seen in both sexes e.g. calculi or tumours in renal pelvis, tumours pressing on ureter, calculi in ureters and tumours of bladder.

Influence of Urinary Tract Obstruction

Obstruction of the urinary tract acts in 3 ways to promote infection:

1. The urine tends to stagnate and encourages growth of bacteria.

2. A tendency to vesico-ureteric reflux during micturition develops especially when cystitis occurs.

3. Catheterisation is commonly carried out in these cases and can introduce infection. In this case the infection is likely to be mixed.

Progress The possibilities are as follows:

Perinephric abscess and papillary necrosis are now rare due to specific antibiotic therapy.

Papillary necrosis (maximal at the kidney poles) is most likely to occur in cases associated with urinary obstruction, diabetes, analgesic nephropathy (e.g. aspirin), sickle cell anaemia and severe hypotension.

This can lead rapidly to renal failure.

Chronic Pyelonephritis

Chronic pyelonephritis is essentially the result of repeated attacks of inflammation and healing. Vesico-ureteric reflux in early life, often associated with congenital anomalies of the urinary tract, is now regarded as important. The process can be visualised as follows:

Kidney function may be further diminished by the onset of hypertension. In cases with urinary obstruction, the external size of the kidney may remain normal or even be increased. Those with no underlying abnormality, commoner in the female, show progressive contraction of the kidney which becomes greyish white.

Microscopically, there is interstitial fibrosis, inflammation and loss of parenchyma.

Depending on the cause, only one or both kidneys may be affected to variable degrees (c.f. chronic glomerulonephritis).

Tuberculosis of the Kidney

Uncommon in many Western countries. It is due to blood spread of infection from another site, e.g. the lungs. Even less commonly, there may be an ascending infection from some other part of the genitourinary system, e.g. epididymis.

As usual, the tuberculous process develops slowly and lesions in the lungs which are the source of infection may have healed and disappeared by the time kidney damage is clinically apparent. The disease is commonly unilateral.

Stages

Microscopically typical fibrocaseous lesions are evident and the process destroys all renal structures in its path.

Clinical Features

The patient may show the general features of tuberculous infection – fever, night sweats and loss of weight. Lumbar discomfort or pain, dysuria and haematuria can develop. Mycobacteria can usually be demonstrated in the urine either on direct microscopic examination or by culture.

Intercurrent Renal Conditions

Diabetes

Renal complications are common in diabetes. Up to 30% of diabetics develop proteinuria, usually after many years and may go on to chronic renal failure.

The renal lesion is a special form of the ‘small vessel disease’ seen systemically in insulin dependent diabetes, e.g. diabetic retinopathy. Rarely similar changes can be seen in non diabetics.

Diabetic glomerulosclerosis. This takes one of two forms:

The basement membrane thickening is due to deposition of abnormally glycosylated proteins. The nodular form is often termed the Kimmelstiel–Wilson lesion. Progressive closure of capillaries can occur together with fibrous obliteration of the capsular space and the whole glomerulus. Haemodynamic changes, especially hyperfiltration, lead to sclerosis. Secondary tubular atrophy follows.

Renal Function and Pregnancy

Four conditions affecting renal function may arise in pregnancy.

1. Acute pyelonephritis is relatively common, possibly due to (a) the effects of uterine pressure on the ureters and (b) relaxation of smooth muscle allowing ureteric dilatation and reflux.

2. Pre-eclampsia and eclampsia. This is a syndrome characterised by hypertension, increasing unselective proteinuria and oedema. Placental ischaemia with stimulation of vasoconstriction leads to disseminated intravascular coagulation (DIC). The main kidney lesion is glomerular; tubular changes are secondary.

EM examination shows mesangial deposits of fibrin, fibrinogen, IgM and complement.

The lesion appears to resolve rapidly after birth.

Acute tubular necrosis, is associated with complications of pregnancy causing shock, e.g. septic abortion, retroplacental haemorrhage and postpartum haemorrhage.

In more severe cases bilateral cortical necrosis may occur especially if disseminated intravascular coagulation (DIC) is superadded.

Severe liver and cerebral damage may also occur.

Renal Tubule – Structure and Function

The renal tubules modify the glomerular filtrate. Initially isotonic and neutral, it becomes hypertonic and quite strongly acid. Within 24 hours, 180 litres of filtrate are reduced to 1.5 litres of urine. The main functions of this process are:

(a) to get rid of waste products, particularly those of protein metabolism.

(b) to aid in maintaining the normal acid–base balance.

Three mechanisms are involved:

1. Active absorption of substances from the filtrate by the tubular epithelium.

2. Passive interchange between the filtrate and the interstitial tissues to maintain osmotic equilibrium.

3. Secretion by the tubular epithelium.

Note: Active reabsorption requires energy, and there is a limit to the capacity of the process – maximal tubular capacity (Tm). When this is exceeded, the particular substance involved will appear in the urine. Glucose is an example. In diabetes, the amount of glucose in the filtrate far exceeds the absorptive capacity, and glycosuria results.

Effects of Tubular Damage

Damage to the tubules results in gross biochemical changes.

1. Loss of mechanisms controlling balance of electrolytes, water and urea.

2. Upset in acid–base balance.

3. Loss of substances in urine normally completely or almost completely reabsorbed – glucose, potassium, amino acids.

Glomerular lesions and pathological changes in the renal pelvis also upset tubular function by interfering with blood supply.

Acute Kidney Injury (Acute Tubular Necrosis)

Toxic AKI

The lesions are evenly distributed, affecting all nephrons. They are maximal in the proximal tubules and are the direct result of the toxin, the action of which is intensified by the concentrating activity of the tubule.

Clinical Effects

There are two clinical phases:

1. Oliguria

The glomerular filtration rate is greatly reduced due to reduced renal blood flow. Unselective reabsorption of the filtrate occurs through the damaged tubule. The effects are:

2. Diuresis

This occurs following healing of the lesions. The damaged tubular epithelium is replaced by a simple type which has not yet developed selective activities. Large volumes of dilute urine are passed.

The clinical results are:

The tubular epithelium has a great capacity for regeneration and ultimately regains its selective powers and the prognosis is good.

Tubulo-Interstitial Diseases

In this group of disorders there is damage to the renal tubules and to the interstitial tissues. The main forms are:

(a) Acute tubular necrosis

(b) Infection – Pyelonephritis

pages 463, 470, 471

(d) Metabolic conditions – e.g. gout, nephrocalcinosis, hypokalaemia.

(e) Myeloma cast nephropathy.

(f) Renal tubular abnormalities.

Tubulo-Interstitial Nephritis

There are two types – acute and chronic, both typically associated with an immunological reaction to drugs.

ACUTE: Symptoms develop 10–14 days after exposure to drugs e.g. methicillin and NSAIDs e.g. mefenamic acid. Patients are febrile, there is haematuria, proteinuria. Arthralgia is common. Renal impairment varies in severity – may cause ACUTE RENAL FAILURE.

Prognosis

(i) Complete remission may follow withdrawal of drug and/or treatment with steroids.

(ii) Continuing exposure → chronic renal impairment.

CHRONIC: Long-standing interstitial nephritis leads to interstitial fibrosis, inflammation and continuing tubular damage with tubular loss and atrophy. Many patients present with chronic renal failure. ‘Balkan nephropathy’ found in the river Danube valley is due to ingestion of aristolochic acid, found in herbal remedies.

Analgesic Nephropathy

This is a distinctive disorder caused by long term exposure to analgesics e.g. phenacetin (historically) and NSAIDs. Interstitial inflammation and tubular damage may proceed rapidly to papillary necrosis (p.463).

There is an associated increased risk of transitional cell carcinoma of the kidney and ureter (p.481).

Both minimal change and membranous glomerulonephritis may complicate NSAID therapy.

Metabolic Tubular Lesions

These are due to metabolic defects.

The following are some examples:

(a) Hypercalcaemic nephritis

Calcium is deposited in tubular epithelial cells with subsequent fibrosis and calcification – nephrocalcinosis.

The usual causes of hypercalcaemia are malignant tumours, primary hyperparathyroidism, hypervitaminosis D and sarcoidosis.

(b) Urate nephropathy occurs in patients with long standing hyperuricaemia and gout.

Increased primary secretion of uric acid leads to uric acid crystal formation in the acid environment of the distal tubule. Renal uric acid stones can occur.

This is dealt with on pages 433 and 434.

Renal Tubular Acidosis

The tubules, either due to an inherited defect or to damage secondary to other renal diseases, are unable to produce an acid urine.

There are 2 main forms:

1. In Type I the defect is in the distal tubule.

2. In Type II the function of the proximal tubule is abnormal and there are usually other abnormalities in addition to acidosis, e.g. in the Fanconi syndrome there is aminoaciduria, glycosuria and hypophosphataemia.

Thrombotic Microangiopathies (Haemolytic Uraemic Syndrome)

This is a rare complication of many conditions.

The renal lesions are similar to those seen in malignant hypertension. There is fibrinoid necrosis of the afferent arterioles and capillaries of the glomeruli, resulting in tubular necrosis. In the most extreme cases, bilateral cortical necrosis of the kidneys may occur. Clinical manifestations include renal failure, haemolytic anaemia, hypertension, and sometimes purpura with thrombocytopenia.

Aetiology

Activation of the clotting system can occur in many widespread circumstances:

1. In children there is a close association with alimentary infections: particularly by E. coli 0157 which produces a verocytotoxin.

2. Shock, e.g. following abruptio placentae in pregnancy, endotoxic shock.

3. Malignant hypertension.

4. Drugs, e.g. immunosuppressives.

Pathological Complications of Renal Replacement Therapies

The prognosis of end-stage renal failure has been greatly improved by (1) Dialysis and (2) Renal Transplantation. The following possible pathological complications are important:

1. Dialysis

(a) Haemodialysis

(i) Local – infection and thrombosis at site of vessel access.

(ii) Systemic – aluminium toxicity: historically, severe dementia or severe osteomalacia was caused by using water containing excess aluminium. Aluminium and other impurities are now removed.

Amyloidosis largely affecting osteoarticular tissues (e.g. carpal tunnel syndrome: joint stiffness bone cysts) due to raised circulating β₂ microglobulin. Visceral involvement is rare and late.

(b) Continuous Ambulatory Peritoneal Dialysis (CAPD) – infective peritonitis: especially due to Staphylococci, Gram –ve organisms and fungi.

Sclerosing peritonitis is a non-infective complication with fibrous thickening of the peritoneum; this may result in small bowel obstruction or necrosis.

2. Renal transplantation

Rejection is the main complication, depending on the extent of HLA matching between donor and recipient. The Banff classification is used to type rejection of which there are four forms:

(a) Hyperacute rejection – within minutes or hours

Pre-existing antibodies against donor HLA or ABO → Binding to endothelial cells → Thrombosis and necrosis

(b) Acute cellular rejection – within days to months

Cell mediated response against donor cells → Interstitial lymphocytic infiltrate and ‘tubulitis’ → Tubular destruction

Cell mediated immune response to epithelial cells → Infiltration of vessel wall by lymphocytes ‘endotheliitis’ → Thrombosis and necrosis

(d) Chronic rejection – months to years

Continuation of immune attack → Vascular occlusion, glomerular sclerosis → Ischaemia and renal failure

Other Complications

1. Cyclosporin and tacrolimus toxicity

2. Opportunistic infections

3. Increased incidence of tumours, particularly LYMPHOMAS

4. Recurrence of original renal disease, e.g. IgA nephropathy in transplanted kidney.

Associated with therapeutic immuno-suppression.

Note: Many lymphoproliferative disorders are due to Epstein–Barr virus infection and some respond to reduction in immuno-suppressive therapy.

Congenital Disorders

There are many forms of malpositions and malformations of the kidney:

1. Ectopic kidney (pelvic kidney)

One or both kidneys fail to reach the normal adult position. The condition causes difficulty:

(a) During childbirth

(b) In differential diagnosis of pelvic neoplasms and infections

2. Fusion of kidneys

This is usually partial, producing the so-called ‘horse-shoe’ kidney. The ureters may be partially obstructed leading to hydronephrosis, infection and stones.

3. Single kidney

This may be a form of fusion and there may be two ureters. In other cases, there is absence (agenesis) of one kidney, usually the left. There is no interference with renal function unless, of course, the single kidney becomes diseased.

4. Bilateral agenesis (Potter’s syndrome)

This is incompatible with life. The affected infants have a distinctive appearance, with low set ears, receding chin, parrot beak nose and wide set eyes.

Polycystic Kidney Disease

This occurs in two main forms:

1. Autosomal Dominant Polycystic Kidney Disease (ADPKD)

This is relatively common, and accounts for 5–10% of cases of chronic renal failure. The kidneys are converted into a mass of cysts with loss of renal parenchyma.

It is an inherited autosomal dominant trait due to two genes, PKD-1 (85% of cases) which encodes a protein polycystin-1, and PKD-2 (15%) associated with milder disease.

The precise defect is unclear but defects of the cilia of tubular epithelial cells appear responsible. There is cyst formation in some of the collecting tubules, causing a mixture of normal and abnormal nephrons. Cystic change develops after birth and is progressive, resulting in atrophy of normal nephrons by pressure.

Cysts also occur in the liver. Death from cerebral haemorrhage is more frequent than expected, partly due to the hypertension secondary to the kidney disorder and in some cases to Berry aneurysms of cerebral arteries.

It is usually discovered during 3rd and 4th decades.

2. Autosomal Recessive polycystic kidney disease

This is a rare condition, which may present in the perinatal period or later in childhood.

The nephrons are said to be normal in number and formation. Cystic dilatation is situated in the terminal branches of the collecting tubules. The disease, if severe, is incompatible with life, and death occurs shortly after birth. It is an autosomal recessive trait due to mutations of the PKHD-1 gene. Congenital hepatic fibrosis often dominates in children who survive infancy.

Urinary Calculi

Stones may form in the renal pelvis, ureter or bladder.

Commonly the stones are mixed.

Mode of formation. There are two steps – nucleation followed by aggregation:

Predisposing Factors

1. Urinary pH. Urate and oxalate stones form in an acid urine; phosphate stones in alkaline urine.

2. Dehydration – causing increased urinary concentration.

3. Stasis. Obstruction to urine flow encourages salt precipitation.

4. Infection is one of the most important factors.

Effects

This can lead to:

• Renal colic

• Hydronephrosis

• Infection, e.g. pyelonephritis.

With the development of stasis and infection, further stone formation is encourgaged:

Staghorn Calculus

This large single stone is associated with suppuration and ulceration of the pelvis and calyces. It is composed mainly of phosphates.

Stones and infection in the pelvis can lead to squamous metaplasia of the epithelium. In a few instances this may develop into squamous carcinoma.

Bladder Calculi

These may have passed down the ureter. In the bladder they can increase greatly in size, due to the deposition of phospates. Cystitis is common. Stones may actually form in the bladder when there is urethral obstruction and chronic cystitis.

Tumours of the Kidney

Malignant Tumours

Three are of importance: renal cell carcinoma, transitional cell carcinoma and nephroblastoma.

Renal Cell Carcinoma

This is the commonest (90%) primary malignant renal tumour and arises from tubular epithelium. It has a typical appearance.

Aetiology: Renal cell carcinoma is associated with:

(a) Cigarette smoking,

(b) Obesity,

(d) Genetic predisposition, e.g. the von Hippel–Lindau syndrome (renal cysts, cerebellar haemangioblastoma) – associated with a gene on chromosome 3.

Systemic Effects

Patients with renal carcinoma may have:

(i) Hypercalcaemia – parathyroid related hormone peptide production (PTHrP).

(ii) Hypertension – increased renin production by tumour or in adjacent kidney.

(iii) Polycythaemia – increased erythropoietin.

Transitional cell carcinoma of the renal pelvis is discussed on p.483.

Nephroblastoma (Wilms’ Tumour)

This is one of the commonest malignant tumours of childhood usually presenting between 2 to 5 years. About 10% are bilateral. It is an embryonic type of tumour derived from ‘nephrogenic rests’, and forms a large well-circumscribed growth which rapidly invades blood vessels, giving rise to pulmonary secondaries. With modern therapy 90% long-term survival rates are achieved.

Mutation of the Wilms’ tumour gene (WT-1) on chromosome 11 and a variety of other genes appear to be responsible for the development of this tumour.

Benign Tumours

1. Oncocytoma. This benign epithelial tumour accounts for 5% of surgically removed tumours. It arises from cells of the collecting ducts. The cells are large with eosinophilic nuclei due to many mitochondria.

2. Papillary adenoma. This is a small (< 5 mm) nodular proliferation of tubular type epithelium.

3. Angiomyolipoma. This mass of fat, blood vessels and smooth muscle may occur sporadically or in tuberous sclerosis.

Diseases of the Urinary Tract

The urinary tract is a collecting and discharge system. There are 4 main pathological processes affecting its function: (1) obstruction, (2) infection, (3) calculus formation and (4) neoplastic disease.

Obstruction

Acute obstruction, if complete, causes rapid cessation of urine production. If both kidneys are involved, renal failure quickly follows. Chronic obstruction is more common and leads to anatomical changes, with sequels.

Hydronephrosis

This is a dilatation of the renal pelvis and calyces, due to chronic incomplete or intermittent obstruction.

Microscopically, there is tubular atrophy and glomerular scarring. Superimposed infection is common and aggravates the renal damage.

Urinary Tract Infection

Acute Cystitis

The bladder shows the usual signs of inflammation. Small haemorrhages are common in the oedematous mucosa. The causes have already been discussed.

Chronic Cystitis

This is the result of repeated attacks of acute cystitis, but it is usually associated with obstruction of the urethra causing stasis of urine.

Mixed infection including B. proteus is common and, together with urea-splitting organisms forming ammonia, result in an alkaline urine. Phosphates precipitate and can form crumbling whitish calculi.

Interstitial Cystitis

This disorder usually affects women who complain of intermittent pain, frequency and dysuria without bacterial infection.

Mast cells are commonly seen in the mucosa which may show typical ulcers (Hunner ulcers). The cause is unknown.

Tuberculous Cystitis

This is always secondary to a tuberculous infection elsewhere, usually in the kidney. Less commonly, the epididymis is the source of infection. Small tubercles form in the submucous layer, usually at the bladder base. These ulcerate and secondary infection is common.

Urethritis

Acute inflammation of the urethra is commonly due to the gonococcus, but another form is now more common in Western countries: so-called non-specific urethritis is often due to chlamydia infection.

In Reiter’s syndrome, in addition to urethritis, there is arthritis and conjunctivitis.

Schistosomiasis

Infection of the bladder with Schistosoma haematobium results in chronic granulomatous inflammation with urinary obstruction and haematuria. There is a strong association with the development of squamous cell carcinoma of the bladder.

Tumours of the Urothelium

Transitional Cell Carcinoma

This tumour arises from the epithelium of the renal pelvis and is similar to the commoner transitional cell carcinoma of the bladder, with which it shares aetiological factors.

Patients usually present with haematuria.

Transitional cell carcinomas occur in the bladder, ureters and renal pelvis. They arise from the stratified transitional epithelium lining the tract and are all considered to be carcinomas but show a wide spectrum of malignant potential. They are graded I to III as follows, according to the World Health Organisation (WHO) classification. They can be papillary or solid in growth pattern.

GRADE I – These are usually Papillary Tumours with uniform, well-differentiated epithelial covering showing no mitotic activity, a slender stalk and delicate branching fronds. Haemorrhage is common.

GRADE II – These also are mainly Papillary. The epithelial cells show mitoses and nuclear pleomorphism.

GRADE III are often solid sessile tumours. They show marked nuclear pleomorphism, mitotic activity and aggressive growth. Ulceration and necrosis are common: invasion into the bladder muscle and lymphatic invasion are usual.

Squamous carcinoma and adenocarcinoma are rare tumours. Rhabdomyosarcoma may occur in the bladder in children.

(i) Urothelial tumours are often multiple and recurrence is common: long term surveillance is important.

(ii) Progression from a low grade to higher grades is frequent.

Aetiology

Smoking and analgesic abuse are important risk factors as is industrial exposure, e.g. rubber and dye industries. Infections with Schistosoma haematobium is associated with squamous carcinoma in the Middle East. Bladder carcinomas are an industrial hazard:

(a) In aniline dye manufacture due to beta-naphthylamine

(b) In the rubber industry

The Prostate

The prostate surrounds the bladder neck and urethra. Although traditionally divided into five lobes, it is now regarded as having four major zones, which tend to be affected by different disorders.

There are three main disorders of the prostate:

1. Prostatitis

2. Benign prostatic hyperplasia

3. Prostatic carcinoma.

Prostatitis

There are three forms:

1. Acute bacterial prostatitis – associated with urinary tract infections – usually by Gram negative bacilli such as E. coli. Instrumentation, e.g. catheterisation may provoke the episode.

2. Chronic bacterial prostatitis – due to repeated urinary tract infections, usually by the same group of organisms.

3. Chronic abacterial prostatitis – the cause of this is unknown. The patient complains of urinary symptoms such as dysuria and frequency, low back pain and perineal discomfort.

4. Granulomatous prostatitis – can be seen in a variety of set ups, e.g. TB and following BCG therapy for bladder cancer. Ruptured ducts and acini may stimulate a granulomatous reaction which can simulate cancer.

Diseases of the Prostate

Benign Prostatic Hyperplasia

This is an extremely common finding in over 70% of men over 60 years. The prostate is enlarged often over 100 g (normal prostate 20 g). The transitional and periurethral zones are most affected.

Aetiology

Androgens are responsible for prostatic proliferation with conversion of testosterone to dihydrotestosterone by the enzyme 5α-reductase, found mainly in prostatic stromal cells.

Use of 5α-reductase inhibitors is effective treatment in many cases; often combined with α adrenergic blockers.

Adenocarcinoma of the Prostate

This is now the commonest cancer in men in the UK and a significant cause of cancer death. It is rare below the age of 40 and rises to very high prevalence in men over 80.

Histological grading:

The GLEASON system (Grades 2 through 10) indicates the degree of differentiation from (2) very well differentiated to (10) aggressive anaplastic tumours. Grading correlates well with prognosis.

Spread

1. Direct spread occurs throughout the prostate and outwards to the pelviprostatic tissue.

2. Lymphatic spread is the main mode of extension. There is a rich lymphatic plexus and the perineural lymphatics are particularly affected. The pelvic nodes are invaded and subsequently the abdominal chain.

3. Bone metastases tend to be common, especially in the vertebrae. This is due to retrograde spread from the prostatic venous plexus to the vertebral veins. These secondaries are often characterised by the formation of new dense bone around them (osteosclerosis).

Biochemical Tests

1. Prostatic specific antigen (PSA) measured in the blood is a useful diagnostic marker.

2. These tumours produce prostatic acid phosphatase and, when metastases are present, an increased level may be found in the blood. When bones are invaded, blood alkaline phosphatase may also rise due to osteoblastic activity.

Prostatic intraepithelial neoplasia (PIN), analogous to CIN (p.503), has been recognised as a pre-invasive stage of the disease. High grade PIN is strongly associated with development of invasive cancer.