Autoregulation and tubuloglomerular feedback

The JGA, situated at the hilum of the glomerulus, comprises the afferent and efferent arterioles and the modified tubular cells of the thick loop of Henle, the macula densa (Fig. 21.2), and enables autoregulation and tubuloglomerular feedback. The specialised cells of the macula densa monitor the level of chloride in the tubular luminal fluid, reflecting the amount of chloride reabsorbed by the tubule. A reduced GFR leads to a fall in the luminal chloride level. This results in dilatation of the afferent arteriole, together with constriction of the efferent arteriole, resulting from the release of renin. These two changes increase the hydrostatic pressure within the glomerular capillary and restore the GFR. Autoregulation and tubuloglomerular feedback are important for normal renal function, and are disturbed in patients with systemic hypertension due to renal artery stenosis.

Fig. 21.2 Renal tubular structure and function. Representation of a single nephron showing the function of each part of the tubule. The composition of the glomerular filtrate is modified as it flows along the tubule to form urine.

Neurohormonal factors

Neurohormonal influences operate in patients who have systemic hypotension due to heart failure, or fluid depletion in gastroenteritis.

Both angiotensin II and noradrenaline (norepinephrine) from the adrenal are involved. Angiotensin II constricts the efferent more than the afferent arteriole, and noradrenaline constricts both vessels to the same degree, which preserves the GFR. Both angiotensin II and noradrenaline stimulate prostaglandin synthesis, which by reducing arteriolar tone prevents excessive renal ischaemia. Since non-steroidal anti-inflammatory drugs inhibit the synthesis of prostaglandin, in patients who are hypoperfused they block the potential protective effect of the prostaglandins and can result in acute renal failure.

By liberating angiotensin II, renin also causes the adrenal cortex to produce aldosterone which, in turn, leads to increased reabsorption of sodium by the distal tubular epithelium.

The glomerular filtrate, which is isotonic with the plasma, has to be substantially modified osmotically so that water and electrolytes are conserved and the waste metabolites are concentrated. This occurs as the filtrate flows through the tubules (Fig. 21.2).

During pregnancy

During pregnancy the size and weight of the kidneys increases and the glomeruli enlarge. These changes are reflected in the raised GFR and renal plasma flow which reach a peak by 16 weeks and persist until the end of pregnancy.

Ageing

The size of the kidneys falls abruptly after the age of 60 years. Gradual shrinkage of the tubules commences at about 40 years. Arteries display intimal thickening, with progressive reduplication of elastic laminae. Small arteries develop medial hypertrophy and hyalinosis. The number of sclerosed or scarred glomeruli increases with age, thus reducing renal reserve. Drugs usually excreted by the kidneys must, therefore, be used cautiously in the elderly to avoid toxic accumulation.

Investigation

The investigation of patients with renal disease is multidisciplinary (Table 21.1). Urine and blood analyses are essential; imaging, biopsies and cystoscopy are optional depending on the nature of the clinical problem. Tests with the greatest general clinical utility are urine testing for glucose (to exclude uncontrolled diabetes mellitus), protein (to determine the permeability characteristics of the glomerular basement membrane), and determination of blood concentrations of urea and/or creatinine, the latter being the more reliable indicator of renal function. The GFR is an important expression of renal function and is a useful parameter for monitoring the severity and progress of renal disease.

Table 21.1 Investigation of patients with urinary tract disease

Determination of urine production rate and concentrating power of the kidneys; investigation of urinary tract infections; urinary protein indicates integrity of glomerular filter; exclusion of diabetes mellitus; investigation of glomerular or tubular lesions

Renal osteodystrophy and secondary hyperparathyroidism

Phosphate retention occurs with mild reductions of GFR and is important in CRF. Whilst calcium and phosphate are inversely related, the role of phosphate retention in CRF is pivotal. By attaching to specific receptors, calcitriol (vitamin D₃), produced predominantly by the proximal tubular epithelial cells, appears to be the main regulator of phosphate and exerts a negative feedback on the parathyroids, reducing both production and release of parathyroid hormone (PTH). In CRF, a rise in phosphate inhibiting the secretion of calcitriol may in turn reduce the inhibitory effect on PTH release. The reduced level of calcitriol continues as renal damage proceeds and GFR falls. Eventually the inhibitory effect by PTH on phosphate reabsorption by the proximal tubule will be saturated and hyperphosphataemia and hyperparathyroidism will persist, with two important clinical consequences:

The effects of hyperparathyroidism in patients with CRF can be minimised by a low phosphate diet or the administration of a phosphate-binding agent. Calcitriol is also used but is associated with hypercalcaemia due to the effect on bone. Calcimimetics, which bind to the receptors on the surface of the parathyroid cell, reduce the synthesis and release of PTH. However, oversuppression of PTH may result in adynamic bone disease.

Hypertension

Hypertension occurs in c. 90% of patients with CRF, due mostly to fluid retention; it responds to diuretics. Autoregulation in response to the reduced GFR releases renin and consequently angiotensin II. Renal scarring and subsequent focal renal ischaemia is thought to be a cause of increased renin secretion. The management of hypertension in patients with chronic renal disease is very important since persistent high blood pressure will exacerbate glomerular damage and further reduce GFR.

Anaemia

Anaemia is common in patients with CRF and accounts for their lethargy and general lack of well-being which worsen with deteriorating renal function. Anaemia results from inadequate renal production of erythropoietin (EPO). The precise site of EPO formation is uncertain but the endothelial cells of the peritubular capillaries have been suggested. Red cell survival is reduced; bleeding tendencies consequent on altered platelet function and iron deficiency are also associated with CRF.

Recombinant EPO treatment corrects most of these changes with marked symptomatic improvement. Iron supplements are required to keep pace with the red cell production as stores can become depleted. Importantly, about one-third of patients develop hypertension, which may be severe. Increased viscosity of the blood and reversal of the peripheral vasodilatory effect of the anaemia have both been implicated.

Immune glomerular injury

Immunological damage causes most human glomerular disease. There are two mechanisms:

The resulting disease is called glomerulonephritis (in some cases, glomerulopathy). Genetic factors influence susceptibility and prognosis.

Nephrotoxic antibody

In anti-GBM disease, an IgG antibody forms against the alpha-3 chain in the collagenase-resistant component of collagen IV within the basement membrane, binds to it and activates the complement cascade. Renal biopsy reveals, in glomeruli, a linear pattern of immunofluorescent staining for IgG and granular staining for C3. Polymorphs are attracted and a florid proliferative glomerulonephritis results (Fig. 21.3).

Fig. 21.3 Immunological mechanisms of glomerulonephritis. Glomerulonephritis is due to an antibody reaction to glomerular antigen (alpha-3 chain of collagen IV), to circulating immune complexes that become deposited in the glomeruli, or to antibody reacting to a foreign antigen that has become attached to the basement membrane. The final common pathway of glomerular injury is complement activation resulting in varying degrees of cell damage and inflammatory cell recruitment.

Anti-GBM disease is an uncommon cause of glomerulonephritis and in some cases is associated with pulmonary haemorrhages (Goodpasture’s syndrome), because the antigen also occurs in the alveolar basement membrane. Clinical and histological features of anti-GBM disease are discussed below.

Participation by glomerular cells in glomerular disease

Cells within the glomerulus participate in the reaction and consequently to the development of the lesion and the fate of the glomerulus. These cells produce a variety of cytokines and locally influence the coagulation cascade.

Epithelial cells overlying subepithelial deposits are stimulated to produce basement membrane material, mostly laminin. This overproduction results in irregular projections which separate and then partially surround the deposits. These projections, called ‘spikes’, are characteristic of membranous glomerulopathy. The accumulation of extracellular matrix material is an important aspect of the evolution of glomerular lesions having a wide aetiological background. This accumulation of matrix material is a balance between production, degradation and remodelling and it contributes to the development of glomerulosclerosis.

Endothelial cells lose their natural thromboresistance leading to platelet deposition on the endothelial cell surface and further damage. This is relevant in conditions such as hypertension, diabetes and the inflammatory diseases of blood vessels (vasculitis).

Mediators of glomerular damage

Glomerular cells are affected by a wide variety of substances:

The contribution of the individual mediators varies in each case.

Developmental abnormalities

Anatomical abnormalities

Ectopic kidneys form in an abnormal site, usually the pelvis, and may be associated with intestinal malrotation. They may present as a suspicious pelvic mass and there is a risk of infection due to the ureteric kinking that often accompanies this condition.

Horseshoe kidney results from fusion of the two nephrogenic blastemas during fetal life. Most are fused at the lower pole. The condition is not rare and renal function is usually normal.

Genetic abnormalities leading to enzyme abnormalities

Genetic abnormalities leading to abnormal proteins

Pathogenesis of cysts

The development of cysts is thought to involve several processes involving the development and polar differentiation of the epithelial cells. Reversal of the polarity of transporter proteins results in transport of fluid via the sodium pump into the tubular lumen which then becomes cystic. There are also changes in the primary cilia where all of the major proteins relevant to cystic disease are normally expressed.

Autosomal dominant polycystic kidney disease (ADPKD)

ADPKD is the primary renal disease in 8% of adult patients in the European Dialysis and Transplantation Registry. The condition is always bilateral; the kidneys are grossly enlarged, each commonly weighing 1000g or more (Fig. 21.4). The kidneys are distorted by numerous cysts, from a few millimetres up to c. 100 mm in diameter, with thin bands of renal parenchyma compressed between them. Most cysts contain clear fluid, but previous haemorrhage can result in the contents being brown due to haemosiderin. The cysts are formed at all levels of the nephron.

Fig. 21.4 Autosomal dominant polycystic disease (ADPKD). Both kidneys are greatly enlarged by numerous cysts of varying sizes.

ADPKD is inherited as an autosomal dominant trait with a high degree of penetrance; this is relevant to genetic counselling and screening. Most cases are linked to the alpha-globin cluster on the short arm of chromosome 16 (PKD 1) which encodes polycystin-1; the remainder are due to mutations on chromosome 4 (PKD 2) which encodes polycystin-2. This condition presents at any age from childhood to late adult life. Renal function is maintained until the enlarging cysts press on the adjacent parenchyma, causing ischaemic changes leading to hypertension or renal failure. There is an association with berry aneurysms of the circle of Willis, a frequent source of often fatal subarachnoid haemorrhage (Ch. 26). Cysts also occur within the liver, pancreas and lungs, but have no functional significance in these organs.

Autosomal recessive polycystic kidney disease (ARPKD)

Autosomal recessive polycystic disease (ARPKD) is a rare condition which has a recessive pattern of inheritance. All of these patients have mutations in a single gene known as the ‘polycystic kidney and hepatic disease gene 1’ (PKHD1) on chromosome 6 which encodes for the protein fibrocystin/polyductin. Fibrocystin is a transmembrane receptor located in the cilia of the renal epithelial cells and is involved in the differentiation of renal collecting ducts and bile ducts.

Clinical presentation depends on the severity of involvement and occurs in neonates, children and young adults. The antenatal or perinatal patient has the characteristic Potter facies associated with oligohydramnios and is either stillborn or develops respiratory distress soon after birth. The kidneys are enlarged and show a characteristic radial pattern of fusiform cysts which are dilated collecting ducts. The enlarged kidneys are usually palpable and may impair birth.

Patients who survive to childhood or adult life develop abnormalities of the liver, ranging from bile duct proliferation and cysts, to substantial hepatic fibrosis and cirrhosis which will eventually interfere with hepatic function and produce portal hypertension (Ch. 16). In addition, chronic lung disease, growth retardation and urinary tract infections are recorded. The median survival is 27 years for patients who survive the first month.

Renal medullary cysts

Medullary cystic diseases (nephronophthisis and medullary cystic kidney disease) have been categorised and clarified using genetic and molecular biological features. Clinical and pathological features are shared, but they have different patterns of inheritance and are associated with different extrarenal conditions. Medullary cysts develop as the diseases progress so they are not reliable early diagnostic features.

Nephronophthisis (NPH) encompasses a group of autosomal recessive inherited conditions. These are related to mutations in different NPH genes, which encode important proteins for renal development. They affect different age groups.

Medullary cystic kidney disease (MCKD) is rare, usually presents in adults and has an autosomal dominant inheritance. These patients fail to concentrate urine and lose salt, with polyuria and polydipsia in most cases. Two genes are involved: the more damaging, MCKD2, is situated on chromosome 16 and encodes for uromodulin (Tamm–Horsfall protein). Patients with this anomaly develop renal failure during the third decade of life.

Medullary sponge kidney

Medullary sponge kidney is a disease of adults resulting from dilated collecting ducts in the medulla, causing cysts mainly in the papillae. Renal function is usually normal but large calculi form within the cysts, causing pain, haematuria, infections and obstruction.

Dialysis-associated cysts

Dialysis-associated cysts occur in the kidneys of patients in chronic renal failure who have been dialysed long term. The cysts vary in size and number, frequently show intracystic haemorrhage and contain oxalate crystals. The epithelial lining forms micropapillary proliferations and c. 5% of patients with acquired cystic disease develop renal cell carcinoma; therefore patients with acquired cystic disease should be monitored.

Nomenclature of glomerular injury

Glomeruli show a limited range of reactions to injury. The following nomenclature is used to describe the pattern of injury:

Additional terms are used to describe the character of the light microscopic changes within the glomeruli:

Recognition of these changes and the use of this nomenclature have important clinical implications; for example, the presence of crescents in >50% of glomeruli corresponds to rapidly progressive glomerulonephritis, which heralds a poor prognosis unless it is treated effectively.

Morphology alone gives little indication of the precise nature of the underlying or primary abnormality. Similar morphological features occur in entirely different conditions. To establish an accurate diagnosis, immunological and ultrastructural assessment is needed.

Diffuse proliferative glomerulonephritis

Acute diffuse proliferative glomerulonephritis is one of the patterns of glomerular damage associated with a post-infective aetiology. It is usually an acute lesion following a transient infection. For many years it has been associated with a preceding beta-haemolytic streptococcal infection (post-streptococcal glomerulonephritis). However, a variety of other causative organisms produce this change, including:

Post-streptococcal glomerulonephritis

Beta-haemolytic streptococci of Lancefield group A, Griffith’s subtypes 12, 4 and 1, cause post-streptococcal glomerulonephritis. The primary infection usually causes pharyngitis but may also involve the middle ear or skin. There are considerable geographical differences in the incidence andseverity of post-streptococcal glomerulonephritis; for example, it is the commonest renal disease in India, but its incidence is falling in the UK.

Clinical features

Post-streptococcal glomerulonephritis affects all ages, but children are more commonly affected, with the onset of malaise, fever and nausea 7–14 days after a sore throat. There is oliguria (a significant reduction in urine volume), and the urine is dark or ‘smoky’ due to the presence of microscopic haematuria. Facial oedema, often periorbital, and a mild degree of hypertension are apparent on examination. A raised anti-streptolysin O (ASO) titre and a significant reduction in complement (C3) levels are present. Urine analysis reveals haematuria, together with white cells and casts, with a variable degree of proteinuria.

Histological features

The glomeruli are distended and hypercellular (Fig. 21.6A). All of the glomeruli are involved, hence the use of the term ‘diffuse’. The increase in cellularity is due to the proliferation and swelling of mesangial, endothelial and epithelial cells, together with polymorphonuclear leukocytes. Some glomeruli may show proliferation of cells lining Bowman’s capsule to form a crescent; the presence of crescents in 60% or more of the glomeruli indicates a rapidly progressive disease and heralds a poor prognosis. There is usually interstitial oedema and a variable inflammatory cell infiltrate. The tubules contain red cell casts and the tubular epithelial cells may show degenerative changes.

Fig. 21.6 Diffuse proliferative glomerulonephritis. The glomerular injury in this case, characterised by hypercellularity owing to cellular proliferation and acute inflammatory cell infiltration, is due to immune complex deposition. Ultrastructure of diffuse proliferative glomerulonephritis. The principal abnormality is the presence of electron-dense immune complexes deposited between the epithelial cells and the basement membrane. The cells with the granular cytoplasm in the lumen are neutrophil polymorphs attracted by the activation of complement in the loose subendothelial material.

Using immunofluorescence techniques, granular deposits of IgG and C3 are identified on the peripheral basement membranes. Ultrastructurally, subepithelial deposits correspond to the granular IgG and C3 demonstrated by the immunological techniques (Fig. 21.6B).

Pathogenesis

The precise streptococcal antigen is not yet known—one is antigenically similar to streptokinase, others are cationic: streptococcal M protein, for example, cross-reacts with basement membrane antigens. Current evidence suggests an in-situ antigen–antibody reaction in post-streptococcal glomerulonephritis.

Prognosis

This is good in children, but only 60% of adults recover fully. Acute post-streptococcal glomerulonephritis is usually treated conservatively; renal biopsy is not usual unless the anticipated improvement fails to occur. In most cases the characteristic morphological changes will have resolved by 6–8 weeks after the onset of the illness. All that remains is mild mesangial hypercellularity, which may persist for many months or even years. The relationship between post-streptococcal glomerulonephritis and subsequent chronic glomerulonephritis remains controversial.

Focal proliferative glomerulonephritis

‘Focal’ implies uneven involvement of the glomeruli with some affected and the majority normal. In addition, involvement of only parts of individual glomeruli is usual, and the term ‘segmental’ is also appropriate. Thus, focal and segmental lesions are often found together. A focal glomerulonephritis is a fairly common pattern of reaction which is found in a variety of systemic diseases including:

The unqualified term ‘focal glomerulonephritis’ is not helpful clinically. The immunological and ultrastructural profile of the glomerular lesion in the renal biopsy must be ascertained for a more precise diagnosis.

There is one significant condition having a focal pattern that affects the kidney primarily: IgA disease. IgA deposition also occurs systemically, giving rise to Henoch–Schönlein purpura, a systemic vasculitis with involvement of the kidney.

Membranous glomerulopathy

Membranous glomerulopathy (membranous glomerulonephritis, MGN), a chronic immune complex-mediated disorder, has a distinctive histological picture but many causes. It is an important cause of nephrotic syndrome.

Aetiology

In approximately 85% of patients with membranous glomerulopathy there is no identifiable cause; it is idiopathic. Other cases have an identifiable cause; these are secondary membranous glomerulopathies:

• infective—syphilis, malaria, hepatitis B

• drugs—penicillamine, gold, mercury, heroin

• tumours—lymphomas, melanomas, carcinoma of the breast and bronchus.

These patients are important to identify because the renal lesions may subside when the causative factor is removed. Approximately 10% of patients with systemic lupus erythematosus have membranous change.

Clinical features and prognosis

MGN affects all ages, but more commonly adults, with the highest incidence in the fifth to seventh decades. Males are affected more frequently. The presenting feature is either proteinuria or nephrotic syndrome. Hypertension occurs in about half of the patients. Treatment is controversial; most cases are unresponsive to steroids. Adult patients progress over a variable and unpredictable period; the 10-year survival is c. 75% and c. 30% will develop CRF due to glomerulosclerosis. The prognosis in children is much better, particularly when there is proteinuria alone. In these cases, only 10% develop renal failure, and some 50% remit.

Histological features

Capillary wall thickening, without proliferation or inflammation, and characteristic spikes occur in all glomeruli (Fig. 21.7). There are granular immune deposits of IgG and C3 in the thickened capillary walls. Electron microscopy reveals immune complexes deposited on the outer aspect of the basement membrane beneath the epithelial cells and there is effacement of the foot processes. The epithelial cells overlying the deposits produce new basement membrane, forming the spikes seen light microscopically; this encircles the deposits which undergo degradation and lysis. Eventually the affected glomeruli become sclerosed.

Fig. 21.7 Membranous glomerulopathy. Membranous glomerulopathy is characterised by thickened glomerular capillary walls. Histological staining by a silver impregnation method reveals minute ‘spikes’ on the outer aspects of the capillary wall. An electron micrograph shows the capillary wall to be thickened by the deposition of electron-dense deposits beneath the epithelial cells and between them new basement membrane corresponding to the ‘spikes’ seen histologically. Immunofluorescence microscopy reveals granular deposition of IgG in the glomerular basement membranes, corresponding to the electron-dense deposits ultrastructurally.

Pathogenesis

The features of membranous glomerulopathy suggest a chronic immune complex disease, but the precise molecular target is still debated. Possibilities include glycoproteins (megalin) on the surface of the epithelial cells.

Membrano-proliferative glomerulonephritis

Membrano-proliferative glomerulonephritis (MPGN), a glomerular lesion with many causes, features both membrane thickening and proliferation (Fig. 21.8A). In addition, there is accentuation of the lobular architecture of the glomerulus. The thickened capillary walls, which have a duplicated ‘tram track’ appearance of the basement membrane revealed by silver staining (Fig. 21.8B), prompt the alternative name of mesangiocapillary glomerulonephritis (MCGN). This duplication is due to a new layer of basement membrane laid down by cell processes interposed between the endothelium and the basement membrane (Fig. 21.8C). Two main types are recognised.

Fig. 21.8 Membrano-proliferative glomerulonephritis. The combination of mesangial cell proliferation and basement membrane thickening exaggerates the lobular architecture of the glomerulus. MST stain shows the new layer of basement membrane giving rise to the reduplicated peripheral profiles characteristic of mesangiocapillary glomerulonephritis. Electron microscopy shows the wall between the capillary lumen and urinary space to be thickened by the interposition of cellular processes and electron-dense deposits in relation to them.

Type II MPGN

Type II MPGN is characterised by markedly thickened capillary walls expanded by a discontinuous linear deposition of altered basement membrane material and C3. Ultrastructurally, large electron-dense ribbon-like deposits give rise to the preferable alternative name—dense deposit disease (Fig. 21.9).

Fig. 21.9 Dense deposit disease. Electron micrograph showing the irregular ribbon-like deposits in dense deposit disease.

The lesion results from self-perpetuating activation of the alternative pathway of the complement cascade by a C3 nephritic factor (C3NeF), now termed NeFa, and explains the hypocomplementaemia.

Crescentic glomerulonephritis

Crescentic glomerulonephritis, which equates clinically to rapidly progressive glomerulonephritis (RPGN), is a manifestation of severe glomerular damage characterised by the presence of >50% cellular crescents that eventually compress the glomeruli (Fig. 21.10). There is a florid necrotising glomerulonephritis with fibrinoid necrosis and breaks in the basement membrane.

Fig. 21.10 Crescentic glomerulonephritis, in this case due to pauci-immune ANCA-associated glomerulonephritis. The glomerulus, which is partially necrotic, is surrounded by an exuberant crescent. Silver stains emphasise the disruption of the Bowman’s capsule and the compression of the glomerulus by the crescent.

Crescentic glomerulonephritis may be limited to the kidneys or be part of a systemic small vessel vasculitis. Three main categories lead to this histological appearance:

Immune complex-mediated represents a heterogeneous group in which crescentic nephritis complicates a known form of glomerulonephritis, e.g. IgA, Henoch–Schönlein purpura (HSP), lupus nephritis, MPGN, etc.

Pauci-immune glomerulonephritis is characterised by few or no immunoreactants on immunofluorescent staining. Some 85% of these patients have demonstrable antineutrophil cytoplasmic antibody (ANCA). ANCA has been shown to damage the glomerular capillaries and small renal vessels by interacting with and activating neutrophils.

Anti-GBM disease has already been discussed (p. 577). In c. 50% of cases the lesion is restricted to the kidneys. When the renal disease is accompanied by haemoptysis and pulmonary haemorrhages it is part of the pulmonary–renal (Goodpasture’s) syndrome, which accounts for the remainder. This disease is commoner in young men; the causative factor is unknown although both a recent flu-like illness and exposure to hydrocarbons feature in the clinical history in some patients.

Anti-GBM disease is the most aggressive lesion and requires vigorous immunosuppression augmented by plasma exchange (plasmapheresis) at a very early stage. Nevertheless, there is a high risk of permanent scarring of the kidney with subsequent hypertension.

Minimal change disease

Minimal change disease (MCD) is an important cause of nephrotic syndrome, particularly in children. With a light microscope the glomeruli are normal; the extensive effacement of the epithelial foot processes is evident only by electron microscopy.

Focal glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is an important cause of nephrotic syndrome; the incidence is increasing in adults. It accounts for c. 10% of children with nephrotic syndrome. This pattern of glomerular damage results from a variety of pathogenic and aetiological factors such as in diabetic nephropathy, HIV infection, heroin abuse and reflux nephropathy. It occurs not uncommonly in the late stages of immune complex-induced lesions, e.g. IgA nephropathy.

Systemic lupus erythematosus

Renal involvement occurs in about 70% of lupus patients. The lesions are varied and represent a spectrum with increasing degrees of damage. The glomeruli contain granular immune deposits typically comprising all of the immunoglobulins (IgG, IgM, IgA) with C3 and C1q. A diffuse proliferative glomerular reaction is the most frequently occurring histological picture. Membranous change occurs in c. 20% of cases and is associated with marked proteinuria or nephrotic syndrome.

Henoch–Schönlein purpura

Henoch–Schönlein purpura (HSP) is a systemic vasculitis affecting the skin, joints, intestine and kidneys and occurs most commonly in childhood before the age of 10 years. A purpuric rash typically affects the extensor aspects of the arms and legs and buttocks. This is due to leukocytoclastic angiitis in the dermal capillaries and is related to IgA deposits within them. Joint pains and abdominal pains, with or without intestinal haemorrhage, are also related to involvement of small blood vessels. Most patients with HSP have one episode which completely resolves. However, recurrences occur but are usually milder and shorter than the initial episode.

The proportion of patients with renal involvement is difficult to assess. Significant renal damage occurs in over one-third of cases, ranging from proteinuria with nephrotic syndrome, to rapidly progressive glomerulonephritis.

Infective endocarditis

Renal complications of infective endocarditis (Ch. 13) are:

The last two complications are due to immune complex deposition.

In cases with a focal and segmental glomerulonephritis the kidney shows multiple haemorrhagic foci throughout the cortex and beneath the capsule; it is one of the causes of a ‘flea-bitten’ kidney. The renal lesions subside when the bacterial source of the antigen is removed by intensive antibiotic therapy or removal of the valve.

Diabetes mellitus

Diabetes mellitus is associated with damage to large and small vessels throughout the body. Severe atheroma involving the renal artery may cause renal ischaemic lesions and hypertension. Involvement of the microcirculation, in addition to causing lesions in the retina, nerves and skin, significantly affects the kidneys, leading to glomerulopathy, arteriolar hyalinosis and tubulo-interstitial lesions. The combination of changes that occur in individual cases is varied and referred to collectively as diabetic nephropathy.

Diabetic glomerulopathy

Glomerular disease in diabetics causes proteinuria, which becomes heavier as the disease progresses, leading to nephrotic syndrome and chronic renal failure. The clinical importance of diabetic glomerulopathy is exemplified by the fact that diabetes is the commonest cause of end-stage renal failure in the United States, Europe and Japan. In comparison to patients with insulin-dependent diabetes (type 1), those with non-insulin-dependent diabetes (type 2) have a shorter course to end-stage renal failure and a higher mortality. Being older they have more cardiovascular disease—myocardial infarcts and congestive cardiac failure. In contrast, patients with type 1 diabetes have a higher incidence of microvascular lesions causing retinopathy and neuropathy.

Histologically, three types of glomerular lesion occur—a spectrum of increasing severity:

• Capillary wall thickening is the initial change.

• Mesangial matrix expansion encroaches on the capillaries, causing diffuse diabetic glomerulosclerosis.

• Nodular expansion of the mesangium, beginning in the centre of the mesangium and encroaching on the capillaries, causes nodular glomerular sclerosis or Kimmelstiel–Wilson lesion (Fig. 21.11).

Fig. 21.11 Diabetic glomerulopathy (nodular glomerulosclerosis). This lesion features hyaline sclerotic nodules, thickened capillary walls and hyaline arteriolar change. An electron micrograph shows an early mesangial nodule and the thickened basement membrane characteristic of this condition.

The glomerular lesions are accompanied by arteriolar hyalinosis affecting both the afferent and efferent arterioles. Tubular basement membrane thickening, analagous to the glomerular changes with tubular atrophy and interstitial fibrosis, completes the picture of diabetic nephropathy.

Pathogenesis of diabetic nephropathy

Hyperglycaemia has a central role in the pathogenesis of diabetic nephropathy and is prominent when control is poor. The effects of hyperglycaemia are mediated by several metabolic pathways, the most important of which are the accumulation of advanced glycation end products (AGEs) and increased glucose flux through changes in the polyol–inositol pathway. Hyperglycaemia thereby induces morphological changes and matrix protein production. The resultant imbalance between synthesis and degradation explains the accumulation of matrix material. The basement membrane becomes more permeable.

Accumulation of abnormal proteins in the basement membrane

Thrombotic microangiopathies

Thrombotic microangiopathies are characterised by the deposition of thrombi within the capillaries, arterioles and small arteries of a variety of organs. There are two major conditions in this group: haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura, with considerable clinical overlap.

The extensive deposition of thrombi within the microvasculature leads a microangiopathic haemolytic anaemia. The circulating erythrocytes are deformed and fragmented (helmet cells, burr cells, schistocytes) by the strands of fibrin. The haemolytic anaemia is accompanied by a thrombocytopenia due in part to the excessive deposition of platelets, but damage to the platelets also occurs.

Disseminated intravascular coagulation

Disseminated intravascular coagulation (DIC) (Ch. 23) is a systemic problem involving activation of the coagulation cascade by a variety of extraneous factors.

Fibrin thrombi are identified within the glomerular capillaries, but the condition is characterised by a marked reduction in the levels of fibrinogen and factors V and VII, and is termed a consumptive coagulopathy, in contrast with the thrombotic microangiopathies where endothelial damage is the initiating factor.

Changes resulting from procedural events

Events during the process of renal transplantation can lead to delayed graft function. Preservation injury results from renal anoxia during harvesting or transport. Perfusion injury occurs as a result of the graft being perfused with storage solution which is too cold during preparation; this causes endothelial damage and consequent microthrombi form in the glomerular capillaries and small arteries.

Allograft rejection

Two distinct types of graft rejection can damage the kidney during the first days or weeks after transplantation. Both are immunologically mediated and involve different aspects of the immune system: acute cellular rejection involves the cell-mediated system and features a T-cell response; acute antibody-mediated rejection involves activation of the complement cascade.

Chronic allograft rejection—seen after some years and responsible for long-term graft loss—involves both mechanisms.

Graft rejection must be distinguished from graft ischaemia (e.g. due to stenosed or occluded vascular anastomosis) and from drug-induced pathology (e.g. due to immunosuppressive agents such as ciclosporin and tacrolimus).

Acute cellular rejection (ACR)

A gradual rise in the serum creatinine, weight gain, fever and tenderness over the grafted kidney alert to acute cellular rejection, the most common form of rejection, usually in the first 6 weeks. The interstitium, tubules, arteries and glomeruli are all affected. A brisk interstitial infiltrate of activated lymphoblasts and T-cells features most frequently in ACR (Fig. 21.13). Damage to arterial and arteriolar endothelium occurs in more severe cases. In most cases, glomerular damage is minimal and limited to occasional segmental mononuclear cells. The T-cell infiltrate is thought to be promoted by a concurrent cytomegalovirus infection. Acute cellular rejection usually responds to pulses of steroids, ciclosporin or OKT3 treatment.

Fig. 21.12 Renal papillary necrosis. The renal papillae in this diabetic patient’s kidney appear yellow and structureless due to necrosis. Necrotic papillae may detach and cause ureteric colic or obstruction.

Fig. 21.13 Acute cellular rejection in a renal transplant. The renal architecture is overwhelmed by infiltrating T-cells which also infiltrate the tubules (tubulitis).

Banff classification

Transplant rejection is classified according to two working schemes, the first devised internationally at Banff, the second the Collaborative Clinical Trials in Transplantation. The two are congruent and seek to grade each histological aspect of rejection. Adoption of these schemes aims to improve the consistency of reporting between centres and thus enable more meaningful conclusions on a larger group of patients, particularly in the context of multicentre therapeutic trials.

Recurrent disease

Recurrent disease is seen more frequently in transplants for:

Embolic infarction

Most renal infarcts result from embolisation of:

Many renal infarcts are clinically silent, but some result in haematuria and loin pain.

Renal infarcts are pale or white, and have a characteristic wedge shape with the apex directed towards the hilum.

Diffuse cortical necrosis

Diffuse cortical necrosis is a rare condition complicating pregnancy or trauma associated with severe haemorrhage or severe sepsis. Profound hypotension occurs in these situations, but there is considerable controversy relating to the pathogenesis of this condition. Vasoconstriction is important because infarction can be avoided by the use of angiotensin antagonists.

Diffuse cortical necrosis is a cause of acute anuric renal failure. The prognosis is poor when the infarction is generalised, but is less ominous when the infarction is focal.

Macroscopically, the appearance is striking: the external surface bears irregular yellowish areas with intervening congestion and haemorrhage. The cut surface shows the infarction to be confined to the cortex.

Infection

Infection is the most frequent urinary tract abnormality in pregnant women and is usually detected on routine antenatal urine testing. Asymptomatic bacteriuria occurs in up to 10% of pregnant women, and such patients are at risk of acute pyelonephritis. Prompt diagnosis and early treatment are essential. Renal abnormalities such as the coarse polar scarring of vesico-ureteric reflux are detected radiologically in a high proportion of these patients. In addition, physiological changes occur in the smooth muscle cells of the lower urinary tract in pregnancy, with slower ureteric peristaltic activity and pelvi-ureteric dilatation. This leads to stasis which, combined with infection, particularly with urea-splitting organisms, predisposes to stone formation; existing stones may enlarge considerably during pregnancy.

Hypertension

Hypertension is an important complication of pregnancy. The patient may have latent essential hypertension or concurrent renal disease. Alternatively, pre-eclampsia or eclampsia may be present. Pre-eclampsia is characterised by hypertension, proteinuria and oedema; eclampsia supervenes when fits occur. In severe cases the glomeruli are large and relatively bloodless due to marked swelling of the endothelial and mesangial cells. Arteries and arterioles display endothelial swelling and myointimal proliferation. The vascular and glomerular lesions are reversible when the hypertension has been corrected. However, a thrombotic microangiopathy may be superimposed during the course of pre-eclampsia, and persistent hypertension may ensue when fibrinoid necrosis of the arterioles has occurred.

Acute interstitial nephritis

Acute interstitial nephritis is an important cause of acute renal failure which is often oliguric; c. 60% require dialysis initially. Acute interstitial nephritis is a complication of severe systemic bacterial infections. Most cases of acute renal failure due to acute interstitial nephritis are due to drugs, most commonly penicillins, sulphonamides and non-steroidal anti-inflammatory drugs (NSAIDs). The kidneys are large and swollen due to oedema. The interstitium is oedematous and infiltrated by lymphocytes, macrophages and eosinophils with infiltration of the tubules (tubulitis). This explains the urinary finding of white cell casts in these cases. The renal changes will resolve completely if the drug is discontinued, often with little lasting damage. The reaction is idiosyncratic and not dose-related, but will recur if the patient is re-exposed to the offending drug.

Chronic interstitial nephritis

Patients with chronic interstitial nephritis present in chronic renal failure; establishing a cause is often difficult.

Hypokalaemic nephropathy

Persistently low plasma levels of potassium occur in:

Hypokalaemia causes coarse vacuolation of the tubular epithelial cells principally in the proximal tubules, but in severe states those of the distal tubules are also involved; the medullary tubules are spared.

Urate (gouty) nephropathy

Renal damage due to elevated levels of uric acid in the blood occurs in gout (Ch. 7). Additionally, patients with chronic renal damage due to pyelonephritis or glomerulonephritis have impaired filtration and reduced tubular secretion of uric acid; this leads to retention of uric acid and its subsequent deposition in the kidney. Uric acid crystallises in an acid environment such as that found in the distal tubules, collecting ducts and interstitium of the papillae.

Hypercalcaemic nephropathy (nephrocalcinosis)

Calcium deposition in the kidneys occurs when there is hypercalcaemia: this is ‘metastatic’ calcification (Ch. 7). The onset of renal symptoms is insidious; the tubular disturbance results in an inability to concentrate urine, with consequent polyuria often causing the patient to complain of nocturia. The kidney is often scarred and focally calcified. The cut surface of the kidneys reveals stones within the pelvicalyceal system, and linear white streaks and flecks. There is interstitial fibrosis, a non-specific inflammatory infiltrate and tubular atrophy in relation to the calcification.

Oxalate nephropathy

Calcium oxalate deposition occurs systemically in the tissues when blood levels are high. Increased urinary excretion of oxalate also occurs and the kidneys may be damaged. Hyperoxalaemia and the resulting hyperoxaluria are either primary or secondary. The primary form is due to deficiencies of hepatic enzymes, which are concerned with the decarboxylation of glyoxylate, which accumulates and is oxidised by an alternative pathway to oxalate. Hepatic together with renal transplantation are required to replace the deficient hepatic enzyme. Oxalate accumulates in many tissues (e.g. myocardium), causing systemic problems after the onset of renal failure, and transplantation before that stage is recommended. Secondary hyperoxaluria is seen in poisoning with ethylene glycol (antifreeze) or the anaesthetic agent methoxyflurane, and in pyridoxine (vitamin B₆) deficiency. Oxalate deposition is also seen in the kidneys in a variety of chronic renal disorders.

In advanced cases, the kidneys are small, granular and scarred, the thinned cortex reflecting the fibrosis and tubular disruption that occurs with the deposition of oxalate. Stones are often present in the pelvis and calyceal system.

Obstructive uropathy

Obstructive uropathy is an important cause of interstitial nephritis; the causes include:

Clinical features

The signs, symptoms and prognosis depend on the level of the obstruction. Thus, a renal calculus or a fragment of sloughed papilla will cause renal colic, whereas obstruction due to carcinoma of the bladder or benign prostatic hyperplasia will be accompanied by bladder symptoms. Acute obstruction in the lower urinary tract will result in anuria and pain, and if not relieved is incompatible with survival.

Pathogenesis

The pelvis and calyceal system become dilated due to back pressure; the dilatation is mild in cases of acute obstruction. The peristaltic activity of the ureters is increased in obstruction; this raises the intrapelvic pressure, which in turn is transmitted into the renal parenchyma. Initially, the filtrate formed is reabsorbed through lymphatic and vascular channels. The continued rapid rise in pressure, however, reduces glomerular and medullary blood flow and eventually impairs glomerular filtration.

Gross dilatation occurs as a result of prolonged back pressure. The kidney becomes a dilated sac-like structure: this is hydronephrosis (Fig. 21.15).

Fig. 21.15 Hydronephrosis. The renal pelvis and calyces are grossly dilated, causing compression atrophy of the renal tissue. In this case, hydronephrosis is due to blockage of the ureter by a stone.

Acute pyelonephritis

Acute pyelonephritis, due to infection of the kidney by pyogenic organisms, presents with malaise and fever, and pain and tenderness in the loins. Dysuria and urgency of micturition indicate an associated infection in the lower urinary tract. Finding pus cells in the urine (pyuria) is helpful, but white cell casts provide unequivocal evidence of pyelonephritis. Urine culture in suspected cases is imperative, but bacteriuria is regarded as significant only when in excess of 10⁵ culture-forming units/ml; this result eliminates cases of extraneous bacterial contamination.

Morphology

There are either abscesses throughout the cortex and medulla or wedge-shaped confluent areas of suppuration. Minute abscesses are randomly distributed when the infection is blood-borne, but tend to be located at the upper and lower poles when associated with urinary reflux. A lower urinary tract infection may be associated with inflammation of the pelvic and calyceal mucosa, and pus may be present in the pelvis.

Histology reveals intratubular polymorphs together with interstitial oedema and inflammation (Fig. 21.16). These white cell ‘granular’ casts pass into the bladder and are evident on microscopy of the urine. With healing, fibrosis occurs in the interstitium and the inflammatory infiltrate becomes dominated by lymphocytes and plasma cells.

Fig. 21.16 Acute pyelonephritis. The tubules contain casts consisting of neutro-phil polymorphs; the intertubular connective tissue is oedematous and infiltrated by inflammatory cells.

Chronic pyelonephritis

Chronic pyelonephritis is associated with obstruction developing during adulthood, the site of which determines whether or not one or both kidneys are involved. In contrast to reflux nephropathy, the obstruction leads to dilatation of the renal pelvis and calyceal system with widespread atrophy of the overlying parenchyma. The papillae are stretched and distorted, enabling intraparenchymal reflux to occur. Histologically, atrophic changes with ‘thyroidisation’ are seen together with inflammatory cells. Obstruction is the predominant aetiological factor together with persistent bacteria and an altered host response.