RENAL SYSTEM DISEASE

any of the diseases or disorders that affect the human excretory system. They include benign and malignant tumours, infections and inflammations, and obstruction by calculi. Diseases can have an impact on the elimination of wastes and on the conservation of an appropriate amount and quality of body fluid. Many of the manifestations of renal disease can be accounted for in terms of disturbance of these two functions, and the alleviation of symptoms in those renal diseases that cannot be cured depends on knowledge of how these two functions are affected. The eliminatory process does not, of course, end with the formation of urine; the urine has to pass down the ureters to the bladder, be stored there, and voided, usually under voluntary control. The whole mechanism can be deranged by structural changes in the lower urinary tract, by infection, or by neurological disorders that lead to abnormal emptying of the bladder. Disturbance of the lower urinary tract is an important cause of pain and distress, notably during pregnancy and in the elderly; and it can lead to serious and progressive damage to the kidneys, either by interfering with the drainage of urine or by allowing bacterial infection to have access to the kidney. Additional reading For information on renal system disease, the following may be consulted: H.E. de Wardener, The Kidney: An Outline of Normal and Abnormal Function, 5th ed. (1985), a clearly written textbook; Sir D.A.K. Black and N.F. Jones (eds.), Renal Disease, 4th ed. (1979), a multiple-author book that concentrates on selected areas of current development; Barry M. Brenner and J. Michael Lazarus (eds.), Acute Renal Failure (1983); Barry M. Brenner and Floyd C. Rector, Jr. (eds.), The Kidney, 3rd ed., 2 vol. (1986); Robert W. Schrier (ed.), Renal and Electrolyte Disorders, 3rd ed. (1986); Stuart L. Stanton (ed.), Clinical Gynecologic Urology (1984); Donald W. Seldin and Gerhard Giebisch (eds.), The Kidney: Physiology and Pathophysiology (1985); Norman M. Kaplan, Barry M. Brenner, and John H. Laragh (eds.), The Kidney in Hypertension (1987). Human excretion Formation and composition of urine The urine leaving the kidney differs considerably in composition from the plasma entering it (Table 1). The study of renal function must account for these differences; e.g., the absence of protein and glucose from the urine, a change in the pH of urine as compared with that of plasma, and the high levels of ammonia and creatinine in the urine, while sodium and calcium remain at similar low levels in both urine and plasma. A large volume of ultrafiltrate (i.e., a liquid from which the blood cells and the blood proteins have been filtered out) is produced by the glomerulus into the capsule. As this liquid traverses the proximal convoluted tubule, most of its water and salts are reabsorbed, some of the solutes completely and others partially; i.e., there is a separation of substances that must be retained from those due for rejection. Subsequently the loop of Henle, distal convoluted tubule, and collecting ducts are mainly concerned with the fine control of water and electrolyte balance. Glomerular filtration Urine formation begins as a process of ultrafiltration of a large volume of blood plasma from the glomerular capillaries into the capsular space, colloids such as proteins being held back while crystalloids (substances in true solution) pass through. In humans, the average capillary diameter is five to 10 micrometres (a micrometre is 0.001 millimetre). The wall of each loop of capillaries has three layers. The inner layer consists of flat nucleated endothelial cells arranged to form numerous pores, or fenestrae, 50100 nanometres in diameter (a nanometre is 0.000001 millimetre), which allow the blood to make direct contact with the second layer, a basement membrane. The basement membrane of the capillaries, similar to that which occurs in the lining of many other structures and organs, is a continuous layer of hydrated collagen and glycopeptides. Although once thought to be homogeneous, it appears to consist of three layers that differ in the content of polyanionic glycopeptides. The membrane is negatively charged (anionic), owing to its relatively high content of sialic and aspartic acids. Also present are glycosaminoglycans, such as heparin sulfate. The third, external layer consists of large epithelial cells called podocytes. These cells make contact with the outer surface of the basement membrane by slender cytoplasmic extensions called pedicels (foot processes). These processes are slightly expanded at their point of contact with the basement membrane and are separated from each other by slitlike spaces about 20 to 30 nanometres across. A fine membrane (slit diaphragm) closes the slitlike spaces near the basement membrane. There are two physical processes by which glomerular filtrate may pass the barrier of the glomerular wallsimple diffusion and bulk flow. In bulk flow, the solute in the glomerular filtrate with water passes through pores in the basement membrane. In either case the ultimate restriction to the passage of filtrate appears to lie in the hydrated gel structure of the basement membrane. The negative electrostatic charge in the membrane is an additional restrictive force for negatively charged anionic macromolecules, such as albumin (molecular weight 69,000), while larger protein molecules are restricted by size alone. On the other hand, proteins of smaller molecular sizee.g., neutral gelatin (35,000)pass through freely. It is possible that the endothelial cell layer may also help to exclude very large molecules and blood cells and that a similar effect is exerted by the slit pores and diaphragm. The normal process of glomerular filtration depends upon the integrity of the glomerulus, which in turn depends upon its proper nutrition and oxygenation. If glomeruli are damaged through disease or lack of oxygen they become more permeable, allowing plasma proteins to enter the urine. Special cells that may be concerned with the formation and maintenance of the basement membrane of the glomerular walls are called mesangial cells. These lie between loops of the glomerular capillaries and form a stalk or scaffolding for the capillary network. They are themselves embedded in a matrix of glycosaminoglycan similar to that of the glomerular capillary basement membrane and may be responsible for its formation. The mesangial cells are also responsible for ridding the basement membrane of large foreign molecules that may be held there in the course of certain diseases. These cells proliferate and the mesangial matrix enlarges in the course of immunologically induced diseases affecting the glomerulus. Human excretion General function of the kidney The kidney has evolved so as to enable humans to exist on land where water and salts must be conserved, wastes excreted in concentrated form, and the blood and the tissue fluids strictly regulated as to volume, chemical composition, and osmotic pressure. Under the drive of arterial pressure, water and salts are filtered from the blood through the capillaries of the glomerulus into the lumen, or passageway, of the nephron, and then most of the water and the substances that are essential to the body are reabsorbed into the blood. The remaining filtrate is drained off as urine. The kidneys, thus, help maintain a constant internal environment despite a wide range of changes in the external environment. Regulatory functions The kidneys regulate three essential and interrelated properties of the tissueswater content, acid-base balance, and osmotic pressurein such a way as to maintain electrolyte and water equilibrium; in other words, the kidneys are able to maintain a balance between quantities of water and the quantities of such chemicals as calcium, potassium, sodium, phosphorus, and sulfate in solution. Unless the concentrations of mineral ions such as sodium, crystalloids such as glucose, and wastes such as urea are maintained within narrow normal limits, bodily malfunction rapidly develops leading to sickness or death. The removal of both kidneys causes urinary constituents to accumulate in the blood (uremia), resulting in death in 1421 days if untreated. (The term uremia does not mean that urea is itself a toxic compound responsible for illness and death.) Whenever the blood contains an abnormal constituent in solution or an excess of normal constituents including water and salts, the kidneys excrete these until normal composition is restored. The kidneys are the only means for eliminating the wastes that are the end products of protein metabolism. They do not themselves modify the waste products that they excrete, but transfer them to the urine in the form in which they are produced in other parts of the body. The only exception to this is their ability to manufacture ammonia. The kidneys also eliminate drugs and toxic agents. Thus, the kidneys eliminate the unwanted end products of metabolism, such as urea, while limiting the loss of valuable substances, such as glucose. In maintaining the acid-base equilibrium, the kidneys remove the excess of hydrogen ions produced from the normally acid-forming diet and manufacture ammonia to remove these ions in the urine as ammonium salts. To carry on its functions the kidney is endowed with a relatively huge blood supply. The blood processed in the kidneys amounts to some 1,200 millilitres a minute, or 1,800 litres (about 475 gallons) a day, which is 400 times the total blood volume and roughly one-fourth the volume pumped each day by the heart. Every 24 hours 170 litres (45 gallons) of water are filtered from the bloodstream into the renal tubules; and by far the greater part of thissome 168.5 litres of water together with salts dissolved in itis reabsorbed by the cells lining the tubules and returned to the blood. The total glomerular filtrate in 24 hours is no less than 5060 times the volume of blood plasma (the blood minus its cells) in the entire body. In a 24-hour period, an average man eliminates only 1.5 litres of water, containing the waste products of metabolism, but the actual volume varies with fluid intake and occupational and environmental factors. With vigorous sweating it may fall to 500 millilitres (about a pint) a day; with a large water intake it may rise to three litres, or six times as much. The kidney can vary its reabsorption of water to compensate for changes in plasma volume resulting from dehydration or overhydration. Human excretion Tests of renal function Quantitative tests Important quantitative tests of renal function include those of glomerular filtration rate, renal clearance, and renal blood flow. Tests are also made to estimate maximal tubular activity, tubular mass, and tubular function. Radiological and other imaging methods are useful noninvasive diagnostic techniques, and renal biopsy is valuable in detecting pathological changes that affect the kidneys. In both clinical and experimental studies one of the most fundamental measures of renal function is that of the glomerular filtration rate (GFR). The GFR is calculated by measuring the specific clearance from the body of a substance believed to be excreted solely by glomerular filtration. The renal clearance of any substance is the volume of plasma containing that amount of the substance that is removed by the kidney in unit time (e.g., in one minute). Clearance, or the volume of plasma cleared, is an artificial concept since no portion of the plasma is ever really cleared in this fashion. It was soon realized, however, that if a substance could be found that was freely filtered by the glomeruli and was neither reabsorbed, metabolized, nor secreted by the renal tubules, its clearance would equal the GFR. This is so in these circumstances because the amount of such a substance excreted in the urine in one minute would equal the amount that has been filtered at the glomeruli in the same time. If the concentration of the substance in the plasma (which is the same as that in the glomerular filtrate) is known, the clearance volume must represent the volume of glomerular filtrate. The first substance identified to be excreted in this way was the polysaccharide inulin (molecular weight about 5,000), which is extracted from the roots of dahlias. Although inulin is not naturally found in human plasma it is nontoxic and can be injected or infused into the bloodstream. Its concentration also can be measured readily and accurately. In the adult male the GFR is 125 millilitres per minute per 1.73 square metres of body surface. In the adult female, the values are about 85 percent of those for the same standard area of body surface. Inulin clearance is now accepted as the standard for estimation of the GFR. Clearance value is not the same as excretion rate. The clearance of inulin and some other compounds is not altered by raising its plasma concentration, because the amount of urine completely cleared of the agent remains the same. But the excretion rate equals total quantity excreted per millilitre of filtrate per minute, and this value is directly proportional to its plasma concentration. Substances, such as urea, whose clearance is less than the GFR must be reabsorbed by the renal tubules, while substances whose clearance is greater than the GFR must be secreted by the renal tubules. Since the discovery of inulin, researchers have identified a small number of other substances that are excreted by the kidney in a similar fashion and that have similar clearance values. These include vitamin B12, circulating free in plasma and unbound to protein, and sodium ferrocyanide. The clearance of creatinine was used as a measure of renal function before inulin was discovered; because this substance is found naturally in plasma, creatinine clearance is still widely used as an approximate measure of the GFR. Creatinine is produced in the body at virtually a constant rate, and its concentration in the blood changes little; accordingly, creatinine clearance is usually measured over a period of 24 hours. There is evidence that in humans creatinine is secreted into the urine by renal tubules as well; however, the amount is small and constant and has little effect on the measure of the GFR. The concept of clearance is also useful in the measurement of renal blood flow. Para-aminohippuric acid (PAH), when introduced into the bloodstream and kept at relatively low plasma concentrations, is rapidly excreted into the urine by both glomerular filtration and tubular secretion. Sampling of blood from the renal vein reveals that 90 percent of PAH is removed by a single circulation of blood through the kidneys. This high degree of PAH extraction by the kidney at a single circulation implies that the clearance of PAH is approximately the same as renal plasma flow (RPF). The 10 percent of PAH that remains in renal venous blood is conveyed in blood that perfuses either nonsecretory tissue, such as fibrous tissue or fat, or parts of the tubule that do not themselves secrete PAH. In practice this small remaining percentage is usually ignored, and the clearance of PAH is referred to as the effective renal plasma flow. In humans PAH clearance is about 600 millilitres per minute, and thus true renal plasma flow is about 700 millilitres per minute. Estimation of the GFR and RPF allows the proportion of available plasma perfusing the kidney that is filtered by the glomerulus to be calculated. This is called the filtration fraction and on average in healthy individuals is 125/600, or about 20 percent. Thus about one-fifth of plasma entering the glomeruli leaves as filtrate, the remaining four-fifths continuing into the efferent glomerular arterioles. This fraction changes in a number of clinical disorders, notably hypertension. Reference has already been made to the fact that the renal tubules possess a limited capacity to perform certain of their functions. This is the case, for example, in their ability to concentrate and dilute urine and to achieve a gradient of hydrogen ions between urine and blood. Concentrating power can be tested by depriving the individual of water for up to 24 hours, or, more simply, by introducing a synthetic analogue of ADH into each nostril. The water deprivation test assesses the individual's capacity to produce ADH and the sensitivity of the renal concentrating mechanism to circulating ADH. The use of an analogue of ADH assesses only the sensitivity of the renal tubules to the hormone. The limits of renal ability to excrete acid and establish a gradient of the concentration of hydrogen ions between plasma and urine has been mentioned above. The power of acidification of urine is best estimated by measuring the pH of urine after the administration of ammonium chloride in divided doses over two or three days. Other specific functions that are tested include the individual's ability to conserve sodium, potassium, and magnesium. In general, these tests are carried out by administering diets that are deficient in these electrolytes and then estimating the minimum rate of excretion after several days. Radiological and other imaging investigations Imaging techniques are used to determine the anatomical site, configuration, and level of functioning of the kidneys, pelvis, and ureters. A plain X ray nearly always precedes any other more elaborate investigation, so that the size, outline, and position of the two kidneys, as well as information about the presence or absence of calcium-containing renal stones or zones of calcification can be ascertained. Excretion urography is one of the simplest methods of defining these aspects more precisely, though this radiological method is giving way to noninvasive imaging methods such as ultrasonography and nuclear magnetic resonance (NMR). In excretion urography, the kidneys are observed in X rays after intravenous injection of a radiopaque iodine-containing compound that is excreted largely by glomerular filtration within one hour of the injection. A series of X-ray images (nephrograms) then indicates when the contrast substance first appears and reveals the increasing radiographic density of the renal tissue. The X rays also indicate the position, size, and presence of scarring or tumours in the organs and provide an approximate comparison of function in the two kidneys. Finally the dye collects in the bladder, revealing any rupture or tumour in this organ. Obstruction to the flow of urine also may be revealed by distension of the calyceal system above the site of obstruction. This is more clearly detected by urography, in which contrast medium is injected through a fine catheter introduced either directly into the pelvis of the kidney or into the ureteral orifice visualized during cystoscopy. A micturating cystogram involves the injection of contrast substance into the bladder and is of importance in the investigation of urinary tract infection in childhood. It may show the reflux of urine from the bladder upward into the ureters or kidneys on micturition. Because of the risk of radiation to the gonads this test should be conducted only on certain patients. A radioactive renogram involves the injection of radioactive compounds that are concentrated and excreted by the kidney. The radiation can be detected by placing gamma scintillation counters externally over the kidneys at the back; the counts, transcribed on moving graph paper, yield characteristic time curves for normal and disordered function. A picture of renal circulation can be obtained by introducing a radiopaque substance directly into the abdominal aorta just above the origin of the renal arteries, or directly into the renal arteries themselves. The contrast material yields a renal angiogram, showing the renal vascular tree. The technique is especially valuable in demonstrating the presence of localized narrowing or obstructions in the circulation or of localized dilatations (aneurysms). Tumours, which tend to be well vascularized, are also distinguishable from cysts, which are not well supplied with blood. Ultrasound and NMR have the advantage of being noninvasive and apparently free from risk to the patient. They are useful in detecting tumours of the kidney or adjacent structures and in distinguishing tumours from cysts. Ultrasound techniques are comparatively simple and have replaced other methods in detecting the presence of polycystic kidneys.