Symptom or sign	Pathological basis
Proteinuria	Increased permeability of the glomerular basement membrane
Uraemia	Renal failure
Haematuria	Severe glomerular injury (red cell casts on urine microscopy) Renal tumours or trauma Bladder tumours or trauma
Urinary casts • Hyaline casts • Granular casts • Red cell casts	Formed in tubules as a result of protein loss from glomeruli Formed in tubules from aggregates of inflammatory cells Formed in tubules from red cells in filtrate from severely damaged glomeruli
Hypertension	Sodium and fluid retention (see Oedema) Renal ischaemia releasing renin in some cases (renal artery stenosis)
Oliguria or anuria	Severe renal failure (acute or chronic), obstruction or dehydration
Polyuria	Excessive fluid intake (e.g. beer) Osmotic diuresis (e.g. diabetes mellitus) Impaired tubular concentration (e.g. diabetes insipidus, recovering acute tubular necrosis)
Renal (ureteric) colic	Calculus, blood clot or tumour in ureter
Oedema	Primary renal abnormality leading to sodium and fluid retention
Dysuria	Stimulation of pain receptors in urethra due to inflammation

NORMAL STRUCTURE AND FUNCTION OF THE KIDNEYS

The kidneys contribute to the body’s biochemical homeostasis by:

• eliminating metabolic waste products

• regulating fluid and electrolyte balance

• influencing acid–base balance.

The kidneys also produce:

• prostaglandins, which affect salt and water regulation and influence vascular tone

• erythropoietin, which stimulates red cell production

• 1,25-dihydroxycholecalciferol, which enhances calcium absorption from the gut and phosphate reabsorption by the renal tubules

• renin, which acts on the angiotensin pathway to increase vascular tone and aldosterone production.

The kidneys have a large functional reserve; the loss of one kidney produces no ill-effects. However, in renal disease waste products can accumulate, causing a condition known as uraemia. If the glomerular filters become excessively leaky, large protein molecules are lost in the urine—proteinuria. If the glomeruli are severely damaged, erythrocytes pass through causing haematuria.

The basic unit of the kidney is the nephron; each nephron comprises a glomerulus connected to a tubule. Each kidney contains approximately 1 million nephrons. These form in the embryonic metanephros, after the physiological involution of the pronephros and mesonephros. The ureter, calyceal system and collecting ducts form from the ureteric bud arising from the original duct of the pronephros—the Wolffian duct.

Glomerular structure and function

The formation of urine begins in the glomeruli, where the filtration of approximately 800 litres of plasma each day results in 140–180 litres of filtrate, most of which is reabsorbed by the tubules. Each glomerulus comprises a tuft of capillaries projecting into Bowman’s space (Fig. 21.1A).

Fig. 21.1 Normal glomerulus. Each glomerulus consists of capillaries invested by epithelial cells and is surrounded by Bowman’s space. Low-power electron micrograph showing capillary loops clustered around the mesangium. The basement membrane does not surround the capillary loop completely but is reflected onto the adjacent loop in the region of the mesangium, leaving the mesangial area covered only by the endothelium. High-power electron micrograph showing ultrastructure of the glomerular capillary. The wall of each glomerular capillary comprises an inner thin layer of fenestrated vascular endothelium, the basement membrane and an outer epithelial layer characterised by cytoplasmic (‘foot’) processes. Slit diaphragms span the gap between adjacent epithelial cells. In electron micrographs the basement membrane has a central dense zone, the lamina densa, surrounded on either side by the less densely packed lamina rara interna and externa.

Blood enters and leaves the glomerular capillaries by arterioles. In contrast to all other systemic capillaries in which there is a fall in pressure towards the venous end, the hydrostatic pressure within the glomerular capillary remains high throughout its length, thus enabling efficient filtration.

The glomerular capillary comprises:

• endothelial cells

• basement membrane

• epithelial cells

All components of the capillary wall contribute to the filtration barrier, which is entirely extracellular and has two complementary aspects:

1. a charge-dependent barrier to anionic molecules, including most proteins, comprising:

• polyanionic glycosaminoglycans (e.g. heparan sulphate and sialoproteins) in the fenestrae of the endothelial cells

• proteins in the basement membrane

2. a size-dependent barrier for large molecules which are neutral or cationic, comprising

• filtration slit diaphragms between the epithelial cells

• matrix proteins of the basement membrane.

The integrity of the filtration barrier is disturbed in glomerular disease.

The attenuated endothelial cytoplasm lining the luminal aspect of the glomerular capillary has numerous holes or fenestrae, 70–100 nm diameter. Functionally the endothelial cells:

• play an important role in the charge-dependent filtration barrier. The cell surfaces, covered by podocalyxin and other polyanionic sialoproteins and glycosaminoglycans, will repel anionic molecules such as albumin. In addition the fenestrae are filled with polyanionic glycoproteins and represent the first channel through which plasma components must pass in the process of ultrafiltration

• synthesise, release and bind coagulation factors

• participate in antigen presentation along with monocytes and macrophages by expressing class II histocompatibility antigens on their surface

• synthesise and release a relaxing factor.

The basement membrane is a mesh of filamentous matrix proteins, including collagen IV, laminin and fibronectin, many of which are anionic, through which the ultrafiltate must pass.

The external aspect of the basement membrane bears epithelial cells with complex interdigitating cellular processes, termed foot processes, enveloping the capillary loops. Modified adherens-type junctions (filtration slit diaphragms) occur where the foot processes meet and are essential to the function of the epithelial cell (Fig. 21.1C). The integrity of the slit diaphragm is maintained by the complex inter-relationship of numerous proteins including nephrin, podocin and CD2-associated protein (CD2AP). Other proteins, such as integrins, span the membrane and anchor the actin cytoskeleton to the collagen IV in the lamina rara externa of the basement membrane. Therefore, changes in these proteins modify the configuration of the foot process, and defects in the genes encoding these proteins result in simplification of the foot processes.

The glomerular capillary tufts are supported centrally by mesangial cells, which proliferate and become more prominent in some diseases. Surrounded by a loose network of fibrillary material — the mesangial matrix — the mesangial cells comprise two types. One type of mesangial cell contains actin filaments and is contractile. They attach to the capillary basement membrane at the point where it is reflected over the mesangial matrix, thus anchoring the capillary to the central structure. Contraction of these cells therefore pulls on the glomerular basement membrane and will alter the shape and calibre of the capillary. Damage to this area reduces the strength of the capillary with the formation of a micro-aneurysm. The other type of mesangial cell resembles a monocyte and is analogous to a tissue macrophage. Both types of cell are involved in the mesangial reaction in glomerular disease by synthesising new matrix material and secreting cytokines responsible for cell proliferation and attraction of inflammatory cells.

The basement membrane is reflected over the mesangial area to extend onto the adjacent capillary, which means endothelium is attached to the mesangial matrix in the central core area (Fig. 21.1B). This allows access of immune complexes to the mesangium and the ability of mesangial cells to probe the capillary lumen.

Glomerular filtration rate

Blood flow through the kidneys produces 130–180 l/day of ultrafiltrate which is termed the glomerular filtration rate (GFR). The GFR reflects the permeability of the capillary wall, together with the hydrostatic and osmotic gradients between the capillary lumen and the Bowman’s capsular fluid. The hydrostatic pressure within the glomerular capillary is determined by the calibres of the feeder afferent and draining efferent arterioles.

The GFR is modified by three important mechanisms, all of which are closely inter-related and involve the juxtaglomerular apparatus (JGA):

• autoregulation within the glomerulus

• tubuloglomerular feedback

• neurohormonal influences.

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).

Tubular structure and function

Epithelial cells modify the filtrate by transferring electrolytes and solutes aided by a series of carrier proteins or transporters within the apical (luminal) cell membrane. Transfer from the cytoplasm to the interstitial and peritubular fluid is performed by an energy-dependent ATPase pump situated on the basolateral membrane of the cell. The epithelial cells are separated from each other by tight junctions that contain claudins, membrane proteins that prevent the unregulated passage of electrolytes, water and solutes through the epithelial layer between the cells.

In the proximal tubule approximately 50–55% of the sodium in the filtrate is reabsorbed through selective sodium transporters, together with specific transmembrane co-transporters linked separately to glucose, phosphate or amino acids. In this way nearly all of the glucose, phosphate and amino acids are reabsorbed by the proximal tubule, thus altering the osmolality of the tubular fluid and causing water to flow into the cytoplasm through specialised water channels termed aquaporins. Some of the sodium transporters are linked with hydrogen exchange, whereby sodium is reabsorbed and hydrogen is excreted. Consequently, c. 80% of all the bicarbonate filtered is reabsorbed by the proximal tubules.

The loop of Henle, situated in the medulla and doubling back on itself, is the next part of the nephron through which the now reduced volume of the filtrate must pass. The two limbs have quite different physiological properties. The descending loop is permeable to water but not to ions, whereas the ascending limb is permeable to ions but, lacking aquaporins, is impermeable to water. Thus, the interstitium of the medulla becomes hypertonic. The filtrate in the loop lumen equilibrates with this, because of the permeability to water in the descending limb.

The distal tubule is continuous with the ascending limb of the loop of Henle. The epithelial cells of this segment lack aquaporins, making this segment impermeable to water. Sodium and chloride are reabsorbed by a co-transporter, the activity of which is governed by the concentration of chloride in the luminal fluid. Transport of sodium and chloride in the loop of Henle and distal convoluted tubule is flow-dependent, an important concept in the context of understanding the action of loop diuretics which tend to increase the rate of flow. Calcium transport, under the influence of parathyroid hormone and 1,25-dihydroxycholecalciferol (vitamin D₃), occurs in the distal convoluted tubule and adjacent segments.

The distal convoluted tubule continues into the collecting duct. Two main cell types are present:

• principal cells fund mainly in the cortical collecting duct and inner medullary collecting duct are concerned with sodium and water reabsorption, both of which are influenced by hormones

• intercalated cells are found in the cortex and outer medulla and are involved with acid–base balance.

Aldosterone increases the number of open sodium channels, thus increasing the reabsorption of sodium in the event of volume depletion. The principal cells of the collecting ducts are relatively impermeable to water due to the paucity of aquaporins on the apical membrane. However, under the influence of antidiuretic hormone (ADH) produced by the pituitary, a complex sequence of changes occurs within the cell. This culminates in the fusion of intracytoplasmic vesicles containing preformed aquaporins with the apical membrane so that water can be cleared into the circulation.

The intercalated cells are concerned with hydrogen ion excretion. The excreted hydrogen combines with ammonia in the lumen to form ammonium. Ammonia, formed in the proximal tubule by the metabolism of glutamine and by diffusion from the interstitial fluid, is freely diffusible in contrast to ammonium which is lipid insoluble and cannot pass back into the tubular cytoplasm.

The vasa recta is the delicate meshwork of capillaries that invests the tubules and is derived from the efferent glomerular arteriole. The configuration of the vascular network complements that of the tubule and plays an integral role in the functioning of the countercurrent mechanism.

Countercurrent mechanism

The countercurrent mechanism ensures urine of variable osmolarity forms in response to a variable water intake. The hairpin configuration of the loop of Henle, the complementary vasa recta, coupled with the selective permeabilities to ions and water of the different segments of the loop, the distal tubule and collecting tubules, are all pivotal to the countercurrent mechanism. The active transport of sodium by the thick ascending limb increases the osmolarity of the interstitium. As a result of this, water diffuses from the filtrate in the lumen of the descending limb, which is permeable to water but not to ions. With progress towards the tip of the loop, osmolarity of the filtrate and interstitium increases, particularly in the longer loops derived from the juxtamedullary glomeruli. The principal cells of the collecting tubules display a variable permeability to water under the influence of ADH, achieving urine of variable osmolarity by passing through this hyperosmolar environment on the way to the papillae.

Tamm–Horsfall protein (uromodulin) is a large mucoprotein produced exclusively by the cells of the thick ascending limb of the loop of Henle. It is the main constituent of all tubular casts and may help prevent infections of the urinary tract, but other functions are uncertain. Mutations in the gene encoding this protein are associated with medullary cysts, hyperuricaemia and progressive renal failure.

Renal papillae and urinary reflux

The collecting ducts open onto the surface of the renal papillae projecting into the calyces. The shape of the duct orifice is relevant to the development of reflux and pyelonephritis. Two patterns have been described:

• In the mid-zone papillae, the ducts open obliquely onto the surface. In the event of urinary reflux from the bladder, these duct orifices will close under the increased pressure in the pelvicalyceal system, acting effectively as a one-way valve.

• In contrast, the polar papillae are more frequently compound. These are formed as a result of fusion of lobes of renal parenchyma during fetal development. They have a flattened or slightly depressed summit (see Fig. 21.14). The collecting ducts in this central area open vertically onto the surface of the papilla; they have no valve effect and remain widely patent, thus allowing the refluxed urine and any bacteria within it to flow into the kidney.

Physiological changes

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.

RENAL DISEASE

Clinicopathological features

Diseases of the kidney can present with a variety of features, alone or in combination. As the kidneys are so often affected by a primary disease elsewhere in the body, a simple urine examination (e.g. colour, glucose, protein, haemoglobin) is routine practice in patients being investigated for a variety of disorders.

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

Investigation	Diagnostic utility
Urine analysis Volume Specific gravity Culture Protein content Glucose Haemoglobin Microscopy (casts, etc.)	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
Blood analysis Urea Creatinine Electrolytes	Determination of integrity of renal function; glomerular filtration rate can be calculated from urinary and plasma creatinine concentration and urine flow rate
Imaging Plain X-ray Ultrasound Contrast urography Angiography	Determination of kidney size and symmetry; investigation of suspected tumours, cysts, etc.; detection of calculi; position and integrity of ureters
Cystoscopy	Investigation of haematuria and other symptoms; biopsy of bladder lesions
Renal biopsy Histology Electron microscopy Immunofluorescence	Diagnosis of glomerular, tubular and interstitial renal diseases

Renal biopsy is performed only when clinically justified, because of the risk of haemorrhage. The biopsy is examined by light microscopy with additional information revealed by immunofluorescence and electron microscopy in some cases.

Accurate information about the incidence of diseases of the urinary tract is available from transplant and dialysis registries. However, two important factors conspire to make the true incidence of renal disease almost impossible to ascertain. First, not all countries have registries for the accurate recording of cases. Second, transplantation and dialysis registries record severe and end-stage disease only, making no allowance for mild and subliminal disease. Clinical experience suggests that the prevalence of post-infectious glomerulonephritis is much higher in Africa and India than in Europe and North America.

Pathophysiological basis of renal disease

Two main clinical syndromes occur in renal disease: nephritis (also referred to as the nephritic syndrome) and the nephrotic syndrome. As part of these, patients present with either acute or chronic renal failure.

Nephritis

Nephritis is characterised by an ‘active’ urinary sediment comprising red cells, white cells and urinary casts. The clinical manifestations are variable depending on the degree of damage ranging between intermittent painless (asymptomatic) haematuria, acute renal failure and rapidly progressive glomerulonephritis. The unifying feature of the diseases that cause nephritis is endothelial damage and inflammation. In cases of severe nephritis where the inflammatory infiltrate is intense and widespread (i.e. diffuse), there is a substantial reduction in the GFR. The diseases causing nephritis fall into three broad groups:

• immune complex deposition as in post-infective glomerulonephritis or lupus nephritis

• antibodies against the glomerular basement membrane, anti-GBM disease

• systemic vasculitis in which antibodies against neutrophil cytoplasmic antigens (ANCA) are identified.

Nephrotic syndrome

The nephrotic syndrome is due to excessive leakiness of the glomerular filter and comprises:

The unifying abnormality in patients with the nephrotic syndrome is damage to the epithelial cells resulting in ‘effacement’, ‘fusion’ or ‘simplification’ of the foot processes. It results from molecular alterations at the base of the cells and the filtration slit diaphragms. Nephrin and podocin, amongst other proteins, span the cell membrane and effectively hold the cells together in the region of the filtration slit diaphragm. Similarly, integrins anchor the cell surface to the underlying lamina rara externa of the basement membrane, and these proteins in turn connect to the actin-based cytoskeleton of the cell. Thus, when these proteins are altered, through either mutation or damage, the cell cytoplasm retracts, resulting in simplification or effacement, and leading in some cases to focal epithelial separation from the basement membrane.

Diseases causing the nephrotic syndrome fall into four broad groups:

• damage to the integrity of the epithelial cells, as in minimal change disease or focal segmental glomerulosclerosis

• damage to the integrity of the basement membrane by excessive accumulation of abnormal membrane-like material, as in diabetes mellitus

• immune deposition within the capillary wall, as in membranous glomerulonephritis

• deposition of extraneous substances within the wall, as in amyloid deposition.

Proteinuria and oedema

MECHANISMS OF GLOMERULAR DAMAGE

Glomeruli can be damaged by immunological or non-immunological mechanisms.

Immunological mechanisms

Immune glomerular injury

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

• nephrotoxic antibody, as in anti-glomerular basement membrane (anti-GBM) disease

• immune complex deposition/activation.

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.

Immune complex deposition/activation

An immune complex develops when an antibody binds to its soluble specific antigen. The antigen may be extrinsic, e.g. derived from an infective agent, or endogenous, e.g. DNA in lupus; the latter is said to be autoimmune. Some immune complexes form large lattice structures within the circulation and are eliminated by the reticuloendothelial system; others are smaller and initiate glomerular damage by either deposition or in-situ formation (Fig. 21.3). The complexes seen in the glomeruli are termed ‘deposits’. The glomeruli are vulnerable because the kidneys filter large volumes of blood. Immune complex damage occurs by:

• entrapment of antigen or complexes, leading to mesangial and subendothelial deposits, or subendothelial deposits

• in-situ formation, following antigen binding to glomerular proteins or by antigenic cross-reaction with basement membrane constituents.

The interaction of antigen and antibody within the deposit activates the complement cascade with the production of the C5b-9 membrane attack complex. In addition, C3a and C5a are chemotactic and recruit polymorphonuclear leukocytes, macrophages and monocytes.

The site of the interaction determines the type of glomerular lesion and the clinical features. Thus, deposits within the mesangium or subendothelial lamina rara interna have access to the circulating blood, and complement activation elicits a proliferative reaction and an active nephritis with haematuria. Both membrano-proliferative glomerulonephritis and IgA disease have this pattern.

In contrast, deposits within the subepithelial lamina rara externa will also activate complement, but the reactants are sequestered from the circulation by the basement membrane. There is therefore no evidence of inflammatory reaction; an example of this pattern is seen in membranous glomerulonephritis (glomerulopathy).

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:

• Complement activation (Ch. 9) has a major role in glomerulonephritis of both anti-GBM and immune complex types. All complement pathways activate C3 and yield C5b-9, the membrane attack complex.

• Nephritic factors (NeFs) or C3 nephritic factors (C3Nefs) are immunoglobulins that inactivate inhibitors of the converting enzymes of the complement cascade. Consequently, the breakdown of C3 remains unchecked, resulting in the depletion of C3 from the plasma, a situation termed hypocomplementaemia.

• Polymorphonuclear leukocytes are attracted by C3a and C5a. The polymorphs bind to the immune complexes by their C3 and Fc receptors. They release their lysosomal enzymes in the vicinity of the complexes, augmenting the damage to the glomerular basement membrane.

• Reactive oxygen species derived from recruited leukocytes and native glomerular cells enhance degradation of the basement membrane and influence arachidonic acid metabolism, thus promoting thrombus formation within the glomerulus.

• Clotting factors also mediate glomerular damage. Fibrin entraps platelets which, because of their C3 and Fc receptors, form microthrombi, degranulate and release their vasoactive peptides, thereby increasing vascular permeability. Platelet-derived growth factor encourages mesangial migration, proliferation, matrix production and thus glomerulosclerosis.

The contribution of the individual mediators varies in each case.