The kidneys are paired organs, 11-14 cm in length in adults, 5-6 cm in width and 3-4 cm in depth. The kidneys lie retroperitoneally on either side of the vertebral column at the level of T12 to L3. The renal parenchyma comprises an outer cortex and an inner medulla. The functional unit of the kidney is the nephron of which each contains approximately one million. Each nephron is made up of a glomerulus, proximal tubule, loop of Henle, distal tubule and collecting duct. The renal capsule and ureters are innervated via T10-12 and L1 nerve roots, and renal pain is felt over the corresponding dermatomes.

Arterial blood is supplied to the kidneys via the renal arteries, which branch off the abdominal aorta, and venous blood is conveyed to the inferior vena cava via the renal veins. Approximately 25% of humans possess dual or multiple renal arteries on one or both sides. The left renal vein is longer than the right and for this reason the left kidney, where possible, is usually chosen for live donor transplant nephrectomy.

The renal artery undergoes a series of divisions within the kidney forming successively the interlobar arteries, which run radially to the corticomedullary junction, arcuate arteries, which run circumferentially along the corticomedullary junction, and interlobular arteries which run radially through the renal cortex towards the surface of the kidney. Afferent glomerular arterioles arise from the interlobular arteries to supply the glomerular capillary bed, which drains into efferent glomerular arterioles. Efferent arterioles from the outer cortical glomeruli drain into a peritubular capillary network within the renal cortex and thence into increasingly large and more proximal branches of the renal vein. By contrast, blood from the juxtamedullary glomeruli passes via the vasa recta in the medulla and then turns back towards the area of the cortex from which the vasa recta originated. Vasa recta possess fenestrated walls, which facilitates movement of diffusible substances. The collecting ducts merge in the inner medulla to form the ducts of Bellini, which empty at the apices of the papillae into the calyces. The calyces, in common with the renal pelvis, ureter and bladder are lined with transitional cell epithelium.

The glomerulus comprises four main cell types:

(1) endothelial cells which are fenestrated with 500-1000 Å pores;

(2) visceral epithelial cells (podocytes) which support the delicate glomerular basement membrane by means of an extensive trabecular network (foot processes);

(3) parietal epithelial cells which cover the Bowman’s capsule;

(4) mesangial cells. Mesangial cells are believed to be related to macrophages of the reticuloendothelial system and have a phagocytic function and contractile capabilities that can control blood flow and filtration surface area along the glomerular capillaries in response to a host of mediators. They also secrete the mesangial matrix, which provides skeletal framework for the entire glomerular capillaries. The glomerular capillary basement membrane lies between the endothelial and the visceral epithelial cells. The latter put out multiple long foot processes which interdigitate with those of adjacent epithelial cells. Together the endothelial cells, basement membrane and epithelial cells form the filtration barrier or sieve.

The renal tubules are lined by epithelial cells, which are cuboidal except in the thin limb of the loop of Henle where they are flat. Proximal tubular cells differ from other cells of the system as they have a luminal brush border. The cortical portion of the collecting ducts contains two cell types with different functions, namely principal cells and intercalated cells. Fibroblast-like cells in the renal cortical interstitium have been identified and shown to produce erythropoietin in response to hypoxia.

The juxtaglomerular apparatus comprises the macula densa, the extraglomerular mesangium and the terminal portion of the afferent glomerular arteriole (which contains renin-producing granular cells) together with the proximal portion of the efferent arteriole. The macula densa is a plaque of cells containing large, tightly packed cell nuclei (hence the name macula densa) within the thick ascending limb of the loop of Henle. This anatomical arrangement is such as to allow changes in the renal tubule to influence behaviour of the adjacent glomerulus (tubulo-glomerular feedback).

An essential feature of renal function is that a large volume of blood – 25% of cardiac output or approximately 1300 mL per minute – passes through the two million glomeruli.

A hydrostatic pressure gradient of approximately 10 mmHg (a capillary pressure of 45 mmHg minus 10 mmHg of pressure within Bowman’s space and 25 mmHg of plasma oncotic pressure) provides the driving force for ultrafiltration of virtually protein-free and fat-free fluid across the glomerular capillary wall into Bowman’s space and so into the renal tubule

The ultrafiltration rate (glomerular filtration rate; GFR) varies with age and sex but is approximately 120-130 mL/min per 1.73 m2 surface area in adults. This means that, each day, ultrafiltration of 170-180 L of water and unbound small-molecular-weight constituents of blood occurs. If these large volumes of ultrafiltrate were excreted unchanged as urine, it would be necessary to ingest huge amounts of water and electrolytes to stay in balance. This is avoided by the selective reabsorption of water, essential electrolytes and other blood constituents, such as glucose and amino acids, from the filtrate in transit along the nephron. Thus, 60-80% of filtered water and sodium are reabsorbed in the proximal tubule along with virtually all the potassium, bicarbonate, glucose and amino acids. Additional water and sodium chloride are reabsorbed more distally, and fine tuning of salt and water balance is achieved in the distal tubules and collecting ducts under the influence of aldosterone and antidiuretic hormone (ADH). The final urine volume is thus 1-2 L daily. Calcium, phosphate and magnesium are also selectively reabsorbed in proportion to the need to maintain a normal electrolyte composition of body fluids.

The urinary excretion of some compounds is more complicated. For example, potassium is freely filtered at the glomerulus, almost completely reabsorbed in the proximal tubule, and secreted in the distal tubule and collecting ducts. A clinical consequence of this is that the ability to eliminate unwanted potassium is less dependent on GFR than is the elimination of urea or creatinine. Other compounds filtered and reabsorbed or secreted to a variable extent include urate and many organic acids, including many drugs or their metabolic breakdown products. The more tubular secretion of a compound that occurs, the less dependent elimination is on the GFR; penicillin and cefradine are examples of compounds secreted by the tubules.

Urine concentration and the countercurrent system

Urine is concentrated by a complex interaction between the loops of Henle, the medullary interstitium, medullary blood vessels (vasa recta) and the collecting ducts. The proposed mechanism of urine concentration is termed ‘the countercurrent mechanism’. The countercurrent hypothesis states that: ‘a small difference in osmotic concentration at any point between fluid flowing in opposite directions in two parallel tubes connected in a hairpin manner is multiplied many times along the length of the tubes’. Tubular fluid moves from the renal cortex towards the papillary tip of the medulla via the proximal straight tubule and the thin descending limb of the loop of Henle, which is permeable to water and impermeable to sodium. The tubule then loops back towards the cortex so that the direction of the fluid movement is reversed in the ascending limb, which is impermeable to water but permeable to sodium. This results in a large osmolar concentration difference between the corticomedullary junction and the hairpin loop at the tip of the papilla, and hence countercurrent multiplication. There is an analogy with heat exchangers.

Since the urine that emerges from the proximal tubule is iso-osmotic, the first nephron segment actually involved in urinary concentration is the descending limb of Henle’s loop. There are two types of descending limbs. The short loops originate in superficial and midcortical glomeruli, which turn in the outer medulla. The long loops, which originate in the deep cortical and juxtamedullary glomeruli, penetrate the outer medulla up to the tip of the papilla. Approximately 15% of nephrons have long loops and the remaining 85% have short loops. Both the ascending limb in the outer and inner medulla and the first part of the distal tubule are impermeable to water and urea. Through the Na+/K+/2Cl cotransporter, the thick ascending limb actively transports sodium chloride, increasing the interstitial tonicity, resulting in tubular dilution with no net movement of water and urea on account of low permeability. The hypotonic fluid under ADH action undergoes osmotic equilibration with the interstitium in the late distal and the cortical and outer medullary collecting duct, resulting in water removal. Urea concentration in the tubular fluid rises on account of low urea permeability. At the inner medullary collecting duct, which is highly permeable to urea and water, especially in response to ADH, the urea enters the interstitium down its concentration gradient, preserving interstitial hypertonicity and generating high urea concentration in the interstitium.

The hypertonic interstitium causes abstraction of water from the descending limb of the loop of Henle, which is relatively impermeable to NaCl and urea, making the tubular fluid hypertonic with high NaCl concentration as it arrives at the bend of the loop of Henle. Urea plays a key role in the generation of medullary interstitial hypertonicity. The urea that is reabsorbed into the inner medullary stripe from the terminal inner medullary collecting duct is carried out of this region by ascending vasa recta, which deposits urea into the adjacent descending limb of both short and long loops of Henle, thus recycling the urea to the inner medullary collecting tubule. This process is facilitated by the close anatomical relationship that the hairpin loop of Henle and the vasa recta share.

Acid-base balance

Tubular function is also critical to the control of acid-base balance. Thus, filtered bicarbonate is largely reabsorbed and hydrogen ions are excreted mainly buffered by phosphate

Table 11-1. Factors influencing serum urea levels

Production	Elimination
Increased by High-protein diet Increased catabolism Surgery Infection Trauma Corticosteroid therapy Tetracyclines Gastrointestinal bleeding Cancer Decreased by Low-protein diet Reduced catabolism, e.g. old age Liver failure	Increased by Elevated GFR, e.g. pregnancy Decreased by Glomerular disease Reduced renal blood flow Hypotension Dehydration Urinary obstruction Tubulointerstitial nephritis

The major function of the tubule is the selective reabsorption or excretion of water and various cations and anions to keep the volume and electrolyte composition of body fluid normal.

The active reabsorption from the glomerular filtrate of compounds such as glucose and amino acids also takes place. Within the normal range of blood concentrations these substances are completely reabsorbed by the proximal tubule. However, if blood levels are elevated above the normal range, the amount filtered (filtered load = GFR × plasma concentration) may exceed the maximal absorptive capacity of the tubule and the compound ’spills over’ into the urine. Examples of this occur with hyperglycaemia in diabetes mellitus or elevated plasma phenylalanine in phenylketonuria.

Conversely, inherited or acquired defects in tubular function may lead to incomplete absorption of a normal filtered load, with loss of the compound in the urine (a lowered ‘renal threshold’). This is seen in renal glycosuria, in which there is a genetically determined defect in tubular reabsorption of glucose. It is diagnosed by demonstrating glycosuria in the presence of normal blood glucose levels. Inherited or acquired defects in the tubular reabsorption of amino acids, phosphate, sodium, potassium and calcium also occur, either singly or in combination. Examples include cystinuria and the Fanconi syndrome. Tubular defects in the reabsorption of water result in nephrogenic diabetes insipidus. Under normal circumstances, antidiuretic hormone induces an increase in the permeability of water in the collecting ducts by attachment to receptors with subsequent activation of adenyl cyclase. This then activates a protein kinase, which induces preformed cytoplasmic vesicles containing water channels (termed ‘aquaporins’) to move to and insert into the tubular luminal membrane. This allows water entry into tubular cells down a favourable osmotic gradient. Water then crosses the basolateral membrane and enters the bloodstream. When the effect of ADH wears off, water channels return to the cell cytoplasm.

Various tubular mechanisms could theoretically be investigated, but, in clinical practice, tests of tubular function are required less often than glomerular function.

Twenty-four-hour sodium output may be helpful in determining whether a patient is complying with a low-salt diet and in the management of salt-losing nephropathy. Tests of proximal tubular function may be required in the diagnosis of Fanconi’s syndrome or isolated proximal tubular defects (e.g. urate clearance). Bicarbonate, glucose, phosphate and amino acid are all reabsorbed in the proximal tubule. Their presence in the urine is abnormal, and though formal methods of measuring maximal reabsorption are available, they are seldom necessary. Retinal-binding protein and β2-microglobulin are normally reabsorbed by the proximal tubule, and their urinary excretion is non-specifically increased by diseases of the proximal tubule.

Two tests of distal tubular function are commonly applied in clinical practice: measurement of urinary concentrating capacity in response to water deprivation, and measurement of urinary acidification.

The juxtaglomerular apparatus is made up of specialized arteriolar smooth muscle cells that are sited on the afferent glomerular arteriole as it enters the glomerulus. These cells synthesize prorenin, which is cleaved into the active proteolytic enzyme renin. Active renin is then stored in and released from secretary granules. Prorenin is also released in the circulation and comprises 50-90% of circulating renin, but its physiological role remains unclear as it cannot be converted into active renin in the systemic circulation. Renin converts angiotensinogen in blood to angiotensin I. Angiotensin-converting enzyme (ACE), which is located in the lung, luminal border of endothelial cells, glomeruli and other organs, converts angiotensin I (decapeptide) to angiotensin II (octapeptide). Renin release is controlled by:

• pressure changes in the afferent arteriole
• sympathetic tone
• chloride and osmotic concentration in the distal tubule via the macula densa
• local prostaglandin and nitric oxide release.

Angiotensin II has two major systemic effects: systemic vasoconstriction and sodium and water retention. Both of these actions will tend to reverse the hypovolaemia or hypotension that is usually responsible for the stimulation of renin release. Angiotensin II promotes renal NaCl and water absorption by direct stimulation of Na+ reabsorption in the early proximal tubule and by increased adrenal aldosterone secretion which enhances Na+ transport in the collecting duct. In addition to influencing systemic haemodynamics, angiotensin II also regulates GFR. Although it constricts both afferent and efferent arterioles, vasoconstriction of efferent arterioles is three times greater than that of afferent, resulting in increase of glomerular capillary pressure and maintenance of GFR. In addition, angiotensin II constricts mesangial cells, reducing the filtration surface area, and sensitizes the afferent arteriole to the constricting signal of tubuloglomerular feedback. The net result is that angiotensin II has opposing effects on the regulation of GFR: (a) an increase in glomerular pressure and consequent rise in GFR; (b) reduction in renal blood flow and mesangial cell contraction, reducing filtration. In renal artery stenosis with resultant low perfusion pressure, angiotensin II maintains GFR. However, in cardiac failure and hypertension, GFR may be reduced by angiotensin II.

Erythropoietin is the major stimulus for erythropoiesis. It is a glycoprotein produced principally by fibroblast-like cells in the renal interstitium. Under hypoxic conditions both the alpha and beta subunits of hypoxia inducible factor 1 (HIF-1) are expressed, leading to subsequent erythropoietin gene transcription via the combined effects of hepatic nuclear factor 4 (HNF-4), and HIF-1-alpha and -beta. Erythropoietin, once formed, binds to its receptors on erythroid precursor cells. Under normal oxygen conditions, only the HIF-1-beta subunit is expressed. The alpha subunit undergoes proline hydroxylation in the presence of iron and oxygen by prolyl hydoxylase. The hydroxylated HIF-1-alpha subunit binds to von Hippel-Lindau protein and a ubiquitin ligase complex is activated. This leads to ubiquitination and subsequent degradation of HIF-1-alpha via proteosomes so that no erythropoietin is transcribed.

Loss of renal substance, with decreased erythropoietin production, results in a normochromic, normocytic anaemia. Conversely, erythropoietin secretion may be increased, with resultant polycythaemia, in patients with polycystic renal disease, benign renal cysts or renal cell carcinoma. Recombinant human erythropoietin has been biosynthesized and is available for clinical use, particularly in patients with renal failure.

Naturally occurring vitamin D (cholecalciferol) requires hydroxylation in the liver at position 25 and again by a 1α-hydroxylase enzyme (mitochondrial cytochrome P450) mainly in the distal convoluted tubule, the cortical and inner medullary part of the collecting ducts and the papillary epithelia of the kidney to produce the powerfully metabolically active 1,25-dihydroxycholecalciferol (1,25-(OH)2D3). The 1α-hydroxylase activity is increased by high plasma levels of parathyroid hormone (PTH), low phosphate and low 1,25-(OH)2D3. 1,25-Dihydroxycholecalciferol and 25-hydroxycholecalciferol are degraded in part by being hydroxylated at position 24 by 24-hydroxylase. The activity of this enzyme is reduced by PTH and increased by 1,25-(OH)2D3 (which therefore promotes its own inactivation).

Reduced 1α-hydroxylase activity in diseased kidneys results in relative deficiency of 1,25-(OH)2D3. As a result, gastrointestinal calcium and to a lesser extent phosphate absorption is reduced and bone mineralization impaired. Receptors for 1,25-(OH)2D3 exist in the parathyroid glands, and reduced occupancy of the receptors by the vitamin alters the set-point for release of PTH in response to a given decrement in plasma calcium concentration. Gut calcium malabsorption, which induces a tendency to hypocalcaemia, and relative lack of 1,25-(OH)2D3, contribute therefore to the hyperparathyroidism seen regularly in patients with renal impairment, even of modest degree.

Endothelins

The endothelins ET-1, ET-2 and ET-3 are a family of similar potent vasoactive peptides that also influence cell proliferation and epithelial solute transport. They do not circulate but act locally. ETs are produced by most types of cells in the kidney. The vascular actions are mediated by two receptors, with ETA (specific for ET-1) mediating vasoconstriction and ETB (responsive to all ETs) causing vasodilatation. Endothelins inhibit sodium and water absorption by suppressing Na+/K+-ATPase and Na+/H+ antiporter activity in the proximal tubule and antagonizing the action of ADH and aldosterone in the collecting duct. Tubular transport actions are mediated by ETB. Endothelins, through vasoconstriction by ETA and salt and water retention via ETB receptors, cause hypertension. Endothelins, mainly through ETA receptors, can also alter cell proliferation and matrix accumulation by increasing tissue inhibitor of metalloproteinase, cytokines, fibronectin and collagen. These peptides also stimulate the proliferation of a variety of renal cell types.

Prostaglandins

Prostaglandins are unsaturated, oxygenated fatty acids, derived from the enzymatic metabolism of arachidonic acid, mainly by constitutively expressed cyclo-oxygenase-1 (COX-1) or inducible COX-2 (see Fig. 14.32). COX-1 is highly expressed in the collecting duct, while COX-2 expression is restricted to the macula densa. Both COX isoforms convert arachidonic acid to the same product, the bioactive but unstable prostanoid precursor, prostaglandin H2 (PGH2). PGH2 is converted to:

• PGE₂ (formed by PDE₂ synthase in the collecting duct, responsible for natriuretic and diuretic effects)
• PGD₂ (undetermined significance, produced in proximal tubule)
• prostacyclin (PGI₂) (mainly synthesized in the interstitial and vascular compartment)
• thromboxane A₂ (vasoconstrictor, mainly synthesized in glomerulus).

They all act through G-coupled transmembrane receptors.

Prostaglandins maintain renal blood flow and glomerular filtration rate in the face of reductions induced by vasoconstrictor stimuli such as angiotensin II, catecholamines and α-adrenergic stimulation. In the presence of renal underperfusion, inhibition of prostaglandin synthesis by non-steroidal anti-inflammatory drugs results in a further reduction in GFR, which is sometimes sufficiently severe as to cause acute renal failure. Renal prostaglandins also have a natriuretic renal tubular effect and antagonize the action of antidiuretic hormone. Renal prostaglandins do not regulate salt and water excretion in normal subjects, but in some circumstances, such as chronic renal failure, prostaglandin-induced vasodilatation is involved in maintaining renal blood flow. Patients with chronic renal failure are thus vulnerable to further deterioration in renal function on exposure to non-steroidal anti-inflammatory drugs, as are elderly patients in many of whom renal function is compromised by renal vascular disease and/or the effects of ageing upon the kidney. Moreover, in conditions such as volume depletion, which are associated with high renin release (facilitated by prostaglandins), inhibition of prostaglandin synthesis may lead to hyperkalaemia due to hyporeninaemic hypoaldosteronism (since angiotensin II is the main stimulus for aldosterone).

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