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Kidney There are about one million nephrons per kidney, each of which is made up of five main functional segments: The glomeruli, The proximal convoluted tubules, The loops of Henle, The distal convoluted tubules and The collecting ducts Kidneys have multiple physiological functions, which can be b...

Kidney There are about one million nephrons per kidney, each of which is made up of five main functional segments: The glomeruli, The proximal convoluted tubules, The loops of Henle, The distal convoluted tubules and The collecting ducts Kidneys have multiple physiological functions, which can be broadly categorized as the excretion of waste products, the homeostatic regulation of the ECF volume and composition, and endocrine. In order to achieve these functions, they receive a rich blood supply, amounting to about 25% of the cardiac output. The excretory and homeostatic functions are achieved through filtration at the glomerulus and tubular reabsorption. In addition to the excretory function and acid– base control, the kidneys have important endocrine functions, including: production of 1,25-dihydroxyvitamin D, the active metabolite of vitamin D, which is produced following hepatic hydroxylation of 25-hydroxyvitamin by the renal enzyme 1- hydroxylase, production of erythropoietin, which stimulates erythropoiesis. The glomeruli act as filters which are permeable to water and low molecular weight substances, but impermeable to macromolecules.  This impermeability is determined by both size and charge, with proteins smaller than albumin (68 kDa) being filtered, and positively charged molecules being filtered more readily than those with a negative charge. The filtration rate is determined by:  The differences in hydrostatic and oncotic pressures between the glomerular capillaries and the lumen of the nephron  The nature of the glomerular basement membrane  The total glomerular area available for filtration. The total volume of the glomerular filtrate amounts to about 170 L/day, and has a composition similar to plasma except that it is almost free of protein. The proximal convoluted tubule is responsible for the obligatory reabsorption of much of the glomerular filtrate, with further reabsorption in the distal convoluted tubule being subject to homeostatic control mechanisms. In the proximal tubule, energy‐dependent mechanisms reabsorb about 75% of the filtered Na+ and all of the K+, HCO3, amino acids and glucose, with an isoosmotic amount of water. In the ascending limb of the loop of Henle, Cl− is pumped out into the interstitial fluid, generating the medullary hypertonicity on which the ability to excrete concentrated urine depends. This removal of Na+ and Cl− in the ascending limb results in the delivery to the distal convoluted tubule of hypotonic fluid containing only 10% of the filtered Na+ and 20% of the filtered water. The further reabsorption of Na+ in the distal convoluted tubule is under the control of aldosterone, and generates an electrochemical gradient which promotes the secretion of K+ and H+. The collecting ducts receive the fluid from the distal convoluted tubules and pass through the hypertonic renal medulla. In the absence of vasopressin, the cells lining the ducts are impermeable to water,  resulting in the excretion of dilute urine. Vasopressin stimulates the incorporation of aquaporins into the cell membranes. Water can then be passively reabsorbed under the influence of the osmotic gradient between the duct lumen and the interstitial fluid, and concentrated urine is excreted. The composition of urine differs markedly from that of plasma, and therefore of the filtrate. Transport of charged ions tends to produce an electrochemical gradient that inhibits further transport, This is minimized by two processes.  Isosmotic transport This occurs mainly in the proximal tubules and reclaims the bulk of filtered essential constituents. Active transport of one ion leads to passive movement of an ion of the opposite charge in the same direction, along the electrochemical gradient. The movement of sodium (Na+) depends on the availability of diffusible negatively charged ions, such as chloride (Cl–). The process is ‘isosmotic’ because the active transport of solute causes equivalent movement of water reabsorption in the same direction. Isosmotic transport also occurs to a lesser extent in the distal part of the nephron.  Ion exchange This occurs mainly in the more distal parts of the nephrons and is important for fine adjustment after bulk reabsorption has taken place. Ions of the same charge, usually cations, are exchanged and neither electrochemical nor osmotic gradients are created. Therefore, during cation exchange there is insignificant net movement of anions or water. For example, Na+ may be reabsorbed in exchange for potassium (K+) or hydrogen (H+) ions. Na+ and H+ exchange also occurs proximally, but at that site it is more important for bicarbonate reclamation than for fine adjustment of solute reabsorption. Other substances, such as phosphate and urate, are secreted into, as well as reabsorbed from, the tubular lumen. The tubular cells do not deal actively with waste products such as urea and creatinine to any significant degree. Most filtered urea is passed in urine (which accounts for most of the urine’s osmolality), but some diffuses back passively from the collecting ducts with water; by contrast, some creatinine is secreted into the tubular lumen. BIOCHEMISTRY OF RENAL DISORDERS It is convenient to subdivide the causes of impaired renal function into pre‐renal, renal and post‐renal. Pre‐renal causes may develop whenever there is reduced renal perfusion, and are essentially the result of a physiological response to hypovolaemia or a drop in blood pressure. This causes renal vasoconstriction and a redistribution of blood such that there is a decrease in GFR, but preservation of tubular function. Stimulation of vasopressin secretion and of the renin–angiotensin–aldosterone system causes the excretion of small volumes of concentrated urine with a low Na content. Renal blood flow also falls in congestive cardiac failure, and may be further reduced if such patients are treated with potent diuretics. If pre‐renal causes are not treated adequately and promptly by restoring renal perfusion, there can be a progression to intrinsic renal failure. Renal causes may be due to acute kidney injury or chronic kidney disease, with reduction in glomerular filtration. Post‐renal causes occur due to outflow obstruction, which may occur at different levels (i.e. in the ureter, bladder or urethra), due to various causes (e.g. renal stones, prostatism, genitourinary cancer).  As with pre‐renal causes, this may in turn cause damage to the kidney. Renal dysfunction of any kind affects all parts of the nephrons to some extent, although sometimes either glomerular or tubular dysfunction is predominant. The net effect of renal disease on plasma and urine depends on the proportion of glomeruli to tubules affected and on the number of nephrons involved. To understand the consequences of renal disease it may be useful to consider the hypothetical individual nephrons, first with a low glomerular filtration rate (GFR) and normal tubular function, and then with tubular damage but a normal GFR. It should be emphasized that these are hypothetical examples, as in clinical reality a combination of varying degree may exist.  Estimation of glomerular function the GFR provides a useful index of the numbers of functioning glomeruli. It gives an estimate of the degree of renal impairment by disease. Accurate measurement of the GFR by clearance tests requires determination of the concentrations, in plasma and urine, of a substance that is filtered at the glomerulus, but which is neither reabsorbed nor secreted by the tubules; its concentration in plasma needs to remain constant throughout the period of urine collection. It is convenient if the substance is present endogenously, and important for it to be readily measured. Its clearance is given by Clearance= UV /P, where U is the concentration in urine, V is the volume of urine produced per minute and P is the concentration in plasma. When performing this calculation manually, care should be taken to ensure consistency of units, especially for the plasma and urine concentrations.  To accurately measure glomerular filtration rate, the substance used for clearance test should have the following characters:- (1) Should be completely filtered at the glomerulus. (2) Should not be metabolized in the body. (3) It should be non toxic. (4) Should neither be secreted or reabsorbed at the tubules. (5) easily measured. Inulin (a complex plant carbohydrate) meets these criteria, apart from the fact that it is not an endogenous compound, and needs to be administered by IV infusion. This makes it completely impractical for routine clinical use, but it remains the original standard against which other measures of GFR are assessed. In routine laboratory practice most assessments of GFR are based on measurements of creatinine, measurement of which is simple and cheap, but which has some well‐known limitations. Urea measurements have historically been part of panels of tests of renal function, but suffer from even more limitations. Assessment of GFR using cystatin C may offer a number of advantages, but is not in widespread use since its measurement is considerably more expensive. creatinine clearance Creatine is synthesised in the liver, kidneys and pan- creas, and is transported to its sites of usage, principally muscle and brain. About 1–2% of the total muscle creatine pool is converted daily to creatinine through the spontaneous, nonenzymatic loss of water. Creatinine is an end‐product of nitrogen metabolism, and as such undergoes no further metabolism, but is excreted in the urine. Creatinine production reflects the body’s total muscle mass. Creatinine meets some of the criteria for use as a measure of glomerular filtration mentioned above. Plasma creatinine concentration may not remain constant over the period of urine collection but it is filtered freely at the glomerulus. A larger amount, up to 10% of urinary creatinine, is actively secreted into the urine by the tubules. Its measurement in plasma is subject to analytical over- estimation. In practice, the effects of tubular secretion and analytical overestimation tend to cancel each other and creatinine clearance is a reasonable approximation to the GFR. As the GFR falls, however, creatinine clearance progressively overestimates the true GFR. Plasma creatinine If endogenous production of creatinine remains constant, the amount of it excreted in the urine each day becomes constant and the plasma creatinine concentration will then be inversely proportional to creatinine clearance. The reference range for serum creatinine in adults is 64–111 μmol/L in males and 50–98 μmol/L in females. The form of the relationship between creatinine concentration and creatinine clearance is that a raised plasma creatinine is a good indicator of impaired renal function, but a normal creatinine does not necessarily indicate normal renal function.creatinine may not be elevated until the GFR has fallen by as much as 50%. However, a progressive rise in serial creatinine measurements, even within the reference range, indicates declining renal function, and is part of the definition of acute kidney injury. Creatinine clearance or plasma creatinine? Measurement of plasma creatinine is more precise than measurement of creatinine clearance, as there are two extra sources of imprecision in clearance measurements – timed measurement of urine volume and urine creatinine. Accuracy of urine collections is very dependent on the care with which the procedure has been explained or supervised and patients’ cooperation. The combination of these errors causes an imprecision (1 SD) in the creatinine clearance of about 10% , They have been superseded by calculation of the eGFR (Estimation of glomerular filtration rate). Low plasma creatinine concentration A low creatinine is found in subjects with a small total muscle mass. Plasma creatinine is therefore lower in children than in adults, and values are, on aver- age, normally lower in women than in men. Abnormally low values may be found in wasting diseases and starvation, and in patients treated with corticosteroids, due to their protein catabolic effect. Creatinine synthesis is increased in pregnancy, but this is more than offset by the combined effects of the retention of fluid and the physiological rise in GFR that occurs in pregnancy, so plasma creatinine is usually low. High plasma creatinine concentration Plasma creatinine concentration tends to be higher in subjects with a large muscle mass. Other nonrenal causes of increased plasma creatinine include: Transient, small increases may occur after vigorous exercise Some analytical methods are not specific for creatinine. For example, plasma creatinine will be overestimated by some methods in the presence of high concentrations of acetoacetate or cephalosporin antibiotics. Some drugs (e.g. salicylates, cimetidine) compete with creatinine for its tubular transport mechanism, thereby reducing tubular secretion of creatinine and elevating plasma creatinine. If nonrenal causes can be excluded, an increased plasma creatinine indicates a fall in GFR, which can be due to pre‐renal, renal or post‐ renal causes Plasma urea Urea is formed in the liver from ammonia released by deamination of amino acids. Over 75% of nonprotein nitrogen is excreted as urea, mainly by the kidneys; small amounts are lost through the skin and the GI tract. Urea measurements are widely available, and have come to be accepted as offering a measure of renal function. However, as a test of renal function, plasma urea is inferior to plasma creatinine, since 50% or more of urea filtered at the glomerulus is passively reabsorbed through the tubules, and this fraction increases if urine flow rate decreases, such as in dehydration. It is also more affected by diet than creatinine. Low plasma urea concentration Less urea is synthesised in the liver if there is reduced availability of amino acids for deamination, as in the case of starvation or malabsorption,However, in extreme starvation, plasma urea may rise, as increased muscle protein breakdown then provides the major source of fuel. In patients with severe liver disease (usually chronic), urea synthesis may be impaired leading to a fall in plasma urea. Plasma urea may fall as a result of water retention associated with inappropriate vasopressin secretion or dilution of plasma with IV fluids. High plasma urea concentration Causes of high urea largely overlap with causes of impaired renal function and can likewise be considered under the headings of pre‐ renal, renal and post‐ renal causes: Increased production of urea in the liver occurs on high protein diets, or as a result of increased protein catabolism (e.g. due to trauma, major surgery, extreme starvation). It may also occur after haemorrhage into the upper GI tract, which gives rise to a ‘protein meal’ of blood. Plasma urea increases relatively more than plasma creatinine in pre‐ renal impairment of renal function. This is because the reduced urine flow in turn causes increased passive tubular reabsorption of urea. Thus shock, due to burns, haemorrhage or loss of water and electrolytes (e.g. severe diarrhoea), may lead to a disproportionately increased plasma urea in comparison with creatinine. Back‐pressure on the renal tubules enhances back‐diffusion of urea, so that plasma urea rises disproportionately more than plasma creatinine. Cystatin C Cystatin C is a small protein produced at a constant rate by all nucleated cells. It is relatively freely filtered at the glomerulus and reabsorbed and broken down in the proximal tubule. It has no other route of elimination. It fulfills many of the requirements of a marker of the GFR. Studies have shown that it accurately reflects GFR throughout life, including in children and the elderly. It is not affected by dietary meat intake, but may be influenced by thyroid status and obesity. It is stable in blood samples and readily measured by immunoassay. Cystatin C has been repeatedly confirmed as being superior to creatinine as a marker of GFR. The widespread adoption of cystatin C as a measure of GFR in routine clinical practice has been hampered by its measurement being much more expensive than that of creatinine. Estimation of glomerular filtration rate A number of large studies of renal function have allowed the derivation of equations for calculating an estimate of the GFR from more readily measured parameters. One such formula for eGFR was  developed from a large study of patients with renal impairment (the Modification of Diet in Renal Disease (MDRD). It uses creatinine, age, sex and ethnic origin Estimated GFR (eGFR) is now widely reported on laboratory report forms. The eGFR is the basis for detecting and staging chronic kidney disease. Other equations, including versions incorporating cystatin C, are available. The cystatin C equations offer at best a modest improvement in accuracy over creatinine based equations.  Estimation of tubular function Specific disorders affecting the renal tubules may affect the ability to concentrate urine or to excrete an appropriately acidic urine, or may cause impaired reabsorption of amino acids, glucose, phosphate, etc. In some conditions, these defects occur singly; in others, multiple defects are present. Renal tubular disorders may be congenital or acquired, the congenital disorders all being very rare. The functions tested most often are renal concentrating power and the ability to produce an acid urine. The healthy kidney has a considerable reserve capacity for reabsorbing water, and for excreting H+ and other ions, only exceeded under exceptional physiological loads. Moderate impairment of renal function may reduce this reserve, and this is revealed when loading tests are used to stress the kidney. Tubular function tests are only used when there is reason to suspect that a specific abnormality is present. Urine osmolality and renal concentration tests Urine osmolality varies widely in health, between 50 and 1250 mmol/kg, depending upon the body’s requirement to produce a maximally dilute or a maximally concentrated urine. The failing kidney loses its capacity to concentrate urine at a relatively late stage. Renal concentration tests are not normally required in patients with established chronic kidney disease, and indeed may be dangerous. However, the tests may be indicated in patients with polyuria in whom common causes (e.g. diabetes mellitus) have first been excluded. Formal tests of renal concentrating power measure the concentration of urine produced in response either to fluid deprivation or to intramuscular (IM) injection of 1‐deamino, 8‐D‐ arginine vasopressin (DDAVP), a synthetic analogue of vasopressin.A fluid deprivation test is performed first. If the patient is unable to concentrate the urine adequately following fluid deprivation, then a DDAVP test follows immediately Acute kidney injury The concept of acute kidney disorders is relatively new.The diagnosis of acute kidney injury, and staging of its severity, are based on changes in serum creatinine and urine output. Acute kidney injury is defined by any of the following. increase in serum creatinine by 26.5 μmol/L or more within 48 hours; increase in serum creatinine to 1.5 or more times baseline, which is known or presumed to have occurred within the previous 7 days; urine output of less than 0.5 mL/kg/h for 6 hours. Investigation of acute kidney injury A careful clinical history, especially of taking nephrotoxic drugs, and examination may give clues to the cause of acute kidney injury (AKI). It is essential to exclude reversible causes of pre-renal failure, including hypovolaemia or hypotension, and also post-renal urinary tract obstruction (renal tract imaging may be useful, such as abdominal radiograph if calculi are suspected, and renal tract ultrasound Monitor urine output, plasma urea and creatinine and electrolytes, as well as acid–base status, Hyperkalaemia, hypermagnesaemia, hyperphos- phataemia, hyperuricaemia and metabolic acidosis may occur Recently, urine neutrophil gelatinase-associated lipocalin (NGAL) has been suggested as a marker of renal injury. Chronic kidney disease (CKD) Chronic renal dysfunction [defined as being reduced eGFR, proteinuria, haematuria and/or renal structural abnormalities of more than 90 days’ duration] is usually the end result of conditions such as diabetes mellitus, hypertension, primary glomerulonephritis, autoimmune disease, obstructive uropathy, polycystic disease, renal artery stenosis, infections and tubular dysfunction and the use of nephrotoxic drug abnormal findings in chronic kidney disease Apart from uraemia, hyperkalaemia and metabolic acidosis, other abnormalities that may occur in CKD include the following: Plasma phosphate concentrations rise and plasma total calcium concentrations fall. The increased hydrogen ion concentration increases the proportion of free ionized calcium, the plasma concentration of which does not fall in parallel with the fall in total calcium concentration. Impaired renal tubular function and the raised phosphate concentration inhibit the conversion of vitamin D to the active metabolite and this contributes to the fall in plasma calcium concentration. Usually, hypocalcaemia should be treated only after correction of hyperphosphataemia. After several years of CKD, secondary hyperparathyroidism may cause decalcification of bone, with a rise in the plasma alkaline phosphatase activity. Plasma urate concentrations rise in parallel with plasma urea. Hypermagnesaemia Normochromic, normocytic anaemia due to erythropoietin deficiency is common and, because haemopoiesis is impaired, does not respond to iron therapy; this can be treated with recombinant erythropoietin. One of the commonest causes of death in patients with CKD is cardiovascular disease, in part explained by hypertension and a dyslipidaemia of hypertriglyceridaemia and low high-density lipoprotein cholesterol. Some of these effects may be due to reduced lipoprotein lipase activity. Renal tubular acidosis There are various forms of renal tubular acidosis, which can present as a hyperchloraemic metabolic acidosis. The more common, sometimes called classic, renal tubular acidosis (type I) is due to a distal tubular defect causing a failure of acid secretion by the cortical collecting duct. The urinary pH cannot fall much below that of plasma, even in severe acidosis. The distal luminal cells are abnormally permeable to H+, and this impairs the ability of distal tubules to build up a [H+] gradient between the tubular lumina and cells. The re-entry of H+ into distal tubular cells inhibits CD activity at that site; proximal HCO3– reabsorption is normal. The inability to acidify the urine normally can be demonstrated by using the furosemide test or an NH4Cl load. In renal tubular acidosis type II there is impairment of HCO3– reabsorption in the proximal tubule. Loss of HCO3– may cause systemic acidosis, but the ability to form acid urine when acidosis becomes severe is retained; the response to NH4Cl loading may therefore be normal. Type II renal tubular acidosis is also associated with amino aciduria, phosphaturia and glycosuria. Renal tubular acidosis type IV is associated with hyporeninism hypoaldosteronism and with a hyperkalaemic hyperchloraemic acidosis. Sometimes plasma renin and aldosterone measurement may be useful to confirm this.