Kidney diseases

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Chapter 21 Kidney diseases

Common clinical problems from kidney disease 563
Pathological basis of renal symptoms and signs 563
Normal structure and function of the kidneys 564
Congenital diseases 572
Cystic disease 573
Renal disease in association with specific infections 586
Renal transplantation 587
Diseases affecting blood vessels 588

Renal disease in pregnancy 588
Commonly confused conditions and entities relating to renal and urinary tract pathology 594



Pathological basis of renal symptoms and signs

Symptom or sign Pathological basis
Proteinuria Increased permeability of the glomerular basement membrane
Uraemia Renal failure
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


Sodium and fluid retention (see Oedema)
Renal ischaemia releasing renin in some cases (renal artery stenosis)

Oliguria or anuriaSevere renal failure (acute or chronic), obstruction or dehydrationPolyuria

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) colicCalculus, blood clot or tumour in ureterOedemaPrimary renal abnormality leading to sodium and fluid retentionDysuriaStimulation of pain receptors in urethra due to inflammation


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. image Each glomerulus consists of capillaries invested by epithelial cells and is surrounded by Bowman’s space. image 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. image 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.


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.


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.


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
Specific gravity
Protein content
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

Determination of integrity of renal function; glomerular filtration rate can be calculated from urinary and plasma creatinine concentration and urine flow rate

Plain X-ray
Contrast urography

Determination of kidney size and symmetry; investigation of suspected tumours, cysts, etc.; detection of calculi; position and integrity of uretersCystoscopyInvestigation of haematuria and other symptoms; biopsy of bladder lesions

Renal biopsy
Electron microscopy

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 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


Three types of proteinuria occur in patients with renal disease emanating from:

the glomeruli
the tubules
overflow proteinuria—when excessive quantities of protein are presented to the kidney, exceeding its capacity to deal with them.

Proteinuria arising from the glomeruli implies severe damage leading to loss of the slit diaphragms and effectively reducing the filtration surface. This results in a major change in the character of the resistance to macromolecules, with ensuing substantial leakage of proteins. A degreeof vasoconstriction of the efferent arteriole occurs in response to proteinuria and this serves to increase the intraglomerular hydrostatic pressure which exacerbates the passage of protein through the wall. Therefore, reducing the hydrostatic pressure in the capillary will have a beneficial effect and rationalises the use of antihypertensive therapy in chronic renal disease. The terms selective and non-selective proteinuria refer to the degree and composition of the proteinuria which corresponds to the degree of damage to the filter. Selective proteinuria is seen mostly in minimal change disease.

The tubular epithelial cells reabsorb most of the smaller low molecular weight proteins normally escaping from the glomeruli. Tubulo-interstitial diseases therefore will impede this reabsorption and result in loss of small proteins. In patients with multiple myeloma and other plasma cell dyscrasias, excessive quantities of immunoglobulin light chains are produced and appear in the urine.

Detection of microalbuminuria is particularly important in the management of diabetes and indicates very early increases in permeability. The urinary loss of albumin in these cases amounts to 30–300 mg/day. Routine ‘dipstick’ testing of urine will not detect microalbuminaemia and is therefore unsuitable for managing diabetics.


Oedema is common in renal disease, especially in patients with the nephrotic syndrome, and also in some severe forms of nephritis. Sodium retention by the damaged kidney is the fundamental event, but the mechanism is not known. Oedema in renal disease relates therefore to sodium retention and fluid retention rather than alterations in plasma proteins and plasma osmotic pressure.

Renal failure

Renal failure, ‘impairment’ or ‘insufficiency’ are terms used when the kidneys are unable to excrete waste products and fail to manage electrolytes and water in the usual way.

Acute renal failure

Acute renal failure is said to occur when the plasma creatinine concentration has increased by at least 0.5 mg/dl within the past month. The causes of acute renal failure fall into three main groups:

pre-renal in which the kidneys are inadequately perfused
intrinsic renal disease which may be glomerular, tubulo-interstitial or vascular
post-renal or obstructive.

Chronic renal failure

Chronic renal failure (CRF) leads to clinical features often referred to as uraemia, which reflect a severe reduction in functioning renal mass. The development of the clinical changes in uraemia results from:

reduced excretion of electrolytes and water
reduced excretion of organic solutes termed uraemic toxins
impaired renal hormone synthesis.

Alterations in electrolyte excretion are minimal initially because of adaptive mechanisms involving reducing tubular reabsorption and do not become evident until the GFR reduces by c. 80%. Conversely, organic solutes are excreted primarily by glomerular filtration and will accumulate when the GFR falls. Although individual proteins and metabolites cannot be linked to specific uraemic symptoms, they are known collectively as uraemic toxins.

Hormone production by the severely damaged kidney is impaired. The consequences include renal osteodystrophy and secondary hyperparathyroidism, hypertension and anaemia.

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:

osteitis fibrosa due to the prolonged bone resorption leading to characteristic cystic changes in the bones
metastatic calcification due to calcium phosphate deposition in arteries, soft tissues and viscera.

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 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 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.


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.

Non-immunological mechanisms

Non-immunological mechanisms include:

genetic factors: defects in the genes that encode the proteins of the epithelial cell membrane result in simplification of the foot processes, leading to proteinuria
basement membrane abnormalities, as occur in hereditary nephritis
vascular lesions which result from endothelial damage and occur in hypertension and thrombotic microangiopathies
metabolic changes in basement membrane matrix materials induced by hyperglycaemia, which characterise diabetic nephropathy
accumulation of abnormal proteins in the basement membrane, e.g. amyloid.


Approximately 10% of individuals have a congenital abnormality of the urinary tract, some of which are hereditary:

developmental abnormalities related to volume of renal tissue formed or its differentiation
anatomical abnormalities including abnormal position of vascular or ureteric connections
defects in the genes encoding enzymes affecting tubular transport (e.g. cystinuria and renal tubular acidosis), proteins of the filtration slit diaphragm (e.g. congenital nephrotic syndrome) and collagen and intercellular matrix proteins (e.g. hereditary nephritis).

Developmental abnormalities

Conditions affecting the volume of renal tissue

Renal agenesis (absence of the kidney) may be unilateral or bilateral.

Bilateral agenesis results from failure of initiation of the pronephros–metanephros sequence; the ureteric bud fails to develop. It occurs in c. 0.04% of all pregnancies and is associated with a severe reduction in amniotic fluid (oligohydramnios) resulting in neonatal death due to lung hypoplasia. The majority of cases are stillborn. There are also developmental abnormalities of other tissues derived from the mesonephros, e.g. bladder and genitalia. Accompanying spinal cord abnormalities with involvement of the hind gut and fused lower extremities is termed sirenomelia (mermaid syndrome).

Unilateral agenesis of a kidney is common, affecting up to 0.1% of the population. The opposite kidney undergoes marked hypertrophy and is prone to trauma and to reflux nephropathy since it is often associated with pelvi-ureteric or ureterovesical junction obstruction. The relatively high incidence of a solitary kidney in the general population means it is imperative to confirm the presence of a second kidney before renal biopsy or nephrectomy.

Disorders of differentiation

Renal dysplasia may present in childhood as an abdominal mass simulating a tumour. It is characterised by islands of undifferentiated mesenchyme or cartilage within the parenchyma. The pathogenesis is failure of induction of both the ureteric bud and mesenchymal tissues leading to abnormal development of the collecting ducts and subsequent loss of potential nephrons with the formation of cysts. The prognosis is good if the lesion is unilateral with no obstruction.

Anatomical abnormalities

Ectopic kidneys

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