Gutter=17> 17. 1 Introduction
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373   balance is maintained. If GFR increases, the filtered load of sodium increases. For example, suppose the GFR rose to 130т1гшп~', the total filtered load of sodium would increase to 26 200 mmoles day"1. Clearly, unless the filtered load is regulated or the transport capacity adjusted, sodium balance will be greatly disturbed.How is the sodium load matched to the transport capacity of the tubules? One current view is that Starling forces regulate fluid uptake from the proximal tubule. If the filtered fraction rises, the oncotic pressure in the peritubular capillaries will be higher than normal and this will augment movement of fluid from the tubular lumen into the capillaries via the lateral intercellular spaces. Since the net filtration pressure determines the GFR, adjustments to the glomerular capillary pressure provide another means by which GFR could be regulated. A mechanism has been proposed in which the level of sodium reabsorbed from the tubular fluid regulates the tone of the afferent and efferent arteri-oles. The cells of the macula densa, which form part of the juxta-glomerular apparatus, sense the sodium load delivered to the distal tubule. In response to a low concentration of sodium in the distal tubule, these cells stimulate the juxtaglomerular cells of the afferent arteriole to release an enzyme, renin, into the blood, which causes formation of angiotensin II (see Section 17.7) which, in turn, constricts the efferent arterioles and so increases the net filtration pressure (Fig. 17.7 and Box 17.2). (Low levels of angiotensin II circulating in the blood have a greater vasoconstrictor effect on the efferent arterioles than on the afferent arterioles.) Such adjustments to arteriolar tone would provide a negative feedback control of the filtered load. In response to an elevated systemic blood pressure the renal blood flow and GFR remain remarkably stable. A decrease in the diameter of the afferent arterioles in response to stretch (see Section 7.6) would offset the rise in pressure and maintain the net filtration pressure and GFR nearly constant. The auto-regulation of renal blood flow is, therefore, essential to the maintenance of the GFR. There are circumstances, however, in which renal blood flow and GFR are reduced. For example, during exercise increased activity in the sympathetic nerves together with an elevation in the concentration of circulating catecholamines (epinephrine and norepinephrine) leads to vasoconstriction in the afferent arterioles. The net filtration pressure falls and with it the GFR. Hemorrhage also leads to pronounced vasoconstriction in the afferent arterioles and a decreased GFR. In severe hemorrhage the release of antidiuretic hormone (ADH) from the posterior pituitary gland greatly increases and adds to the vasoconstrictor effect of sympathetic activation (ADH is also known as vaso-pressin). The resulting intense vasoconstriction can lead to a complete failure of urine production, called anuria. The actions of ADH during hemorrhage (increased water reabsorption and vasoconstriction) contribute to the maintenance of an adequate circulating plasma volume and so help to offset the fall in blood pressure that would otherwise ensue. The proximal tubule absorbs water and solutes by active transport and by facilitated diffusion The proximal tubule reabsorbs about two-thirds of the filtered water, sodium, potassium, chloride, bicarbonate, and other solutes. Under normal circumstances it removes virtually all the filtered glucose, lactate, and amino acids. The driving force for the reabsorption of all of these substances is the sodium pump (Na+, K+-ATPase) which is present on the basolateral surface of the epithelial cells of the proximal tubule. Glucose and other organic substances are taken up by specific carrier proteins that are located in the brush-border membrane. Some of these carriers have now been cloned and their primary structure determined. They behave in many respects like enzymes: they can be saturated by large amounts of substrate and can be inhibited by appropriate agents. For example, glucose transport can be inhibited by other sugars such as galactose. In addition to the glucose carrier, there are five different carriers for the amino acids, a lactate transporter, and at least one carrier for inorganic anions such as phosphate and sulfate. The existence of these carriers and their similarity to enzymes has provided a simple, logical explanation for the existence of transport maxima for the reabsorption and secretion of many substances. How do these carriers work? To take glucose as an example, it is clear that its uptake is not favored by a transepithelial gradient as the filtrate leaving the glomerulus has the same composition as the plasma. Moreover, as glucose is a neutral molecule it cannot be absorbed along an electrical gradient by itself. Experimental evidence has demonstrated that the uptake of glucose (and amino acids) is sodium dependent. Since the concentration of sodium in the cells of the proximal tubule is about 10—20 mM, the movement of sodium from the tubular lumen (where the sodium concentration is 140 mM) into these cells can occur along a favorable concentration gradient. It is this gradient that is exploited by the tubular cells to permit glucose uptake even though there is no concentration gradient in its favor. Both sodium and glucose bind to the carrier and the movement of the sodium down its concentration gradient entrains the inward movement of glucose and both are transported into the cell. The Na+,K+-ATPase of the basolateral membrane then pumps the sodium into the lateral and basal extracellular spaces and the glucose leaves the cell via another carrier protein that is not sodium dependent. The arrangement of these carriers on the cell therefore permits the secondary active transport of glucose (see also Section 4.3). The reabsorption of amino acids also occurs via sodium-linked carrier molecules, as shown in Fig. 17.11. This active transport is so effective that all of the glucose and amino acids are normally removed from the tubular fluid during its passage along the first half of the proximal tubule. The reabsorption of bicarbonate ions is also linked to that of sodium. An Na+/H+ antiporter which exchanges luminal sodium for intracellular hydrogen ions is active in the brush-border 374 17 The kidney and the regulation of the internal environment     Fig. 17.11 The processes responsible for the reabsorption of amino acids in the proximal tubule. Amino acids and sodium cross the apical membrane via a carrier protein. The sodium gradient provides the energy for the uptake process. The amino acids leave the cell via another carrier protein which is not linked to sodium. The sodium gradient in the cells of the proximal tubule is maintained by the activity of the sodium pump (Na+,K1-ATPase) . Glucose and organic acids such as lactate are reabsorbed by similar processes. membrane. Secretion of hydrogen ions into the lumen favors a shift of the carbonic acid—bicarbonate equilibrium towards carbonic acid which is rapidly converted into carbon dioxide and water by the carbonic anhydrase of the brush border. Carbon dioxide diffuses into the tubular cells down its diffusion gradient and is reformed into carbonic acid by intracellular carbonic anhydrase. The bicarbonate formed by this reaction leaves the cell via the basolateral membrane in exchange for chloride and passes into the circulation. The processes involved in bicarbonate absorption are summarized in Fig. 17.12. The uptake of sodium in the first half of the proximal tubule is coupled chiefly with the uptake of organic solutes and anions other than chloride. In the second half of the proximal tubule, sodium reabsorption is coupled with chloride as the bulk of bicarbonate and organic solute absorption has already occurred. As sodium reabsorption in the first half of the proximal tubule has occurred without absorption of chloride, the concentration of chloride in the second half rises to about 140 mM compared to about 115 mM for the filtrate. Some sodium chloride is therefore able to diffuse through the tight junctions down its concentration gradient into the lateral intercellular spaces. In addition, Fig. 17.12 Schematic representation of bicarbonate reabsorption in the proximal tubule. H+ secreted into the lumen lowers the pH of the tubular fluid and this favors the conversion of HCO3 to carbonic acid which is converted to CO2 and water by the carbonic anhydrase (C.A.) of the brush-border membrane. The CO2 diffuses down its concentration gradient into the tubular cell where some is reconverted to carbonic acid by intracellular carbonic anhydrase and ionizes to form HCO3 which leaves the basolateral surface of the cell in exchange for chloride. The H4 that is generated is secreted into the lumen via Na+—H+ exchange to promote further HCO3" reabsorption. sodium and chloride are transported into the tubular cells via the parallel action of Na+/H+ and Cl~/anion exchangers, as shown in Fig. 17.13. Phosphate absorption The phosphate concentration in the plasma plays an important role in determining the rate of bone formation and reabsorption. In addition, phosphate ions are involved in many aspects of cellular function. A person eating a typical diet absorbs about 800 mg (26 mmoles) of phosphorus from the gut each day, mainly as phosphates, and the kidneys must excrete a similar amount to maintain phosphate balance. For a normal person with a plasma phosphate concentration of 1 mM, some 180 mmoles of phosphate are filtered each day. Of this about 80 per cent is reabsorbed by the proximal tubule via the transcellular route. The uptake of phosphate by the tubular cells is mediated by a carrier protein known as a symporter. Like the uptake of glucose and amino acids, phosphate reabsorption by the tubular cells is linked to sodium. The phosphate leaves 17.5 Tubular absorption and secretion 375   Fig. 17.13 A diagrammatic representation of the processes involved in chloride reabsorption in the proximal tubule. Sodium and chloride enter the cell across the apical membrane via the parallel activity of Na'—H+ and an exchanger that couples chloride movement to the efflux of an organic anion (here represented as В ) which is recycled. Chloride leaves the cell via chloride channels in the basolateral surface. Some sodium and chloride is reabsorbed via the paracellular pathway as a consequence of water movement (solvent drag). the cells via the basolateral membrane by an anion exchange process. The level of phosphate excretion is governed by the availability of transporters in the proximal tubule. The renal threshold for phosphate is just below the normal plasma levels and the carriers are fully saturated when plasma phosphate is about 2.5 mM. Thus phosphate excretion occurs because the transport capacity of the tubules is close to the filtered load. Changes in the activity of the carriers in response to changes in the circulating level of parathyroid hormone regulate the amount of phosphate excreted (see Chapter 12). (No phosphate is absorbed by the loop of Henle or collecting ducts and only half of the remaining phosphate is reabsorbed by the distal tubule so that about 10—15 per cent of the filtered load is excreted under normal circumstances.) Water absorption in the proximal tubule is directly linked to solute uptake The uptake of sodium, chloride, glucose, and other solutes by the tubular cells results in a transfer of osmotically active particles from the tubular lumen to the extracellular space. To maintain osmotic equilibrium, water moves from the tubular lumen to the extracellular space. While some of this water moves via the cells to maintain osmolality (the transcellular pathway) some water apparently passes to the lateral extracellular space via the tight junctions (the paracellular pathway). The water absorbed in the proximal tubule is not regulated independently of the reabsorption of solutes (unlike water reabsorption in the distal nephron—see Section 17.8), consequently this is sometimes known as the obligatory phase of water reabsorption. The osmotically driven water uptake entrains other solutes, and some, such as potassium, magnesium, and calcium are believed to be partially reabsorbed in this way. Protein lost in the glomerular filtrate is reabsorbed by pinocytosis The glomerular filtrate contains a small amount of protein (about 40 mg I"1 compared to 65—80 g l~x in plasma) but as the kidneys form about 180 liters of filtrate a day, about 7 g of protein are filtered. Such a loss would significantly alter the body's nitrogen balance. To avoid this, the cells of the proximal tubule engulf the proteins in the filtrate by pinching off a small volume of filtrate containing protein and absorbing it into the cell by endocytosis. This process is also called pinocytosis. The vesicles formed within the cells (the endocytotic vesicles) fuse with the lysosomes of the cell and the proteins they contain are degraded by the proteolytic enzymes of the lysosomes. The ami no acids released by this process are then transported across the basolateral membrane and absorbed back into the bloodstream (Fig. 17.14). Under normal circumstances virtually no protein is found in the urine. If, however, the glomerulus becomes diseased significant amounts of protein may pass into the filtrate. Since the proximal tubule has a very limited capacity for reabsorbing protein, some will be lost to the urine which will have a frothy appearance as the protein lowers the surface tension. This is known as proteinuria and is always a sign of some abnormality of kidney function. Proteinuria also occurs following hemolysis as hemoglobin is small enough to be filtered by the glomerulus (see Section 17.4). Furthermore, the hemoglobin will give the urine a reddish appearance. Secretion by the cells of the proximal tubule In addition to their reabsorptive activities, the cells of the proximal tubule actively secrete a variety of substances into the tubule lumen. Many metabolites are eliminated from the blood in this way, including bile salts, creatinine, hippurates, prostaglandins, and urate. In addition, the kidney also eliminates many foreign substances by secretion, including drugs such as penicillin, quinine, and salicylates (aspirin). These substances are ionized at physiological pH and two low-specificity transport systems are involved, one for anions such as PAH and one for cations such as 376 17 The kidney and the regulation of the internal environment   Fig. 17.14 A schematic representation of endocytosis and protein breakdown in a proximal tubule cell. Plasma proteins escaping into the filtrate become bound to the surface membrane of the brush border. The membrane-bound proteins are absorbed into coated pits from where they become absorbed into endosomes prior to their breakdown by lysosomes. Fig. 17.15 A schematic represenration of the secretion of organic anions (e.g. PAH) into the lumen of the proximal tubule. PAH crosses the basolateral membrane in exchange for di- and tricarboxylate anions (here represented as (ХСОО^)5) and is secreted into the lumen down its chemical gradient in exchange for another organic anion such as urate. The di- and tricarboxylates are reabsorbed into the cell via a sodium-dependent transporter. creatinine. As with the transport of amino acids and glucose from the lumen into the tubular cells, these carriers are proteins and their transport capacity can be saturated. Since infusion of penicillin can depress the secretion of PAH and other organic anions (and vice versa) these molecules appear to be secreted by the same transport system. As there is little structural similarity between the various organic anions, the transport is said to be of low specificity. Organic cations are secreted by a low-specificity carrier system that is specific for cations. Active secretion provides the kidney with a very efficient means of elimination of protein-bound substances which could otherwise only be eliminated very slowly by filtration.The secretion of organic anions such as PAH occurs by a two-stage process. The anion is taken up into the tubular cell across the basolateral membrane in exchange for a-ketoglutarate and other di- or tricarboxylate anions which diffuse down their concentration gradients. As the concentration of PAH (or other organic anion) in the cell rises, it passes into the tubule lumen via an anion-exchange protein located in the apical membrane. The di- and tricarboxylates re-enter the cells of the proximal tubule via a sodium-dependent symporter that is located in the basolateral membrane (Fig. 17.15). тагу
17.7 The distal tubules regulate the ionic balance of the body 377   17.6 Tubular transport in the loop of Henle On entering the descending thin limb of the loop of Henle, the tubular fluid is still isotonic with the plasma. As it passes down the descending limb, the tubular fluid becomes more hypertonic. The cells of the descending limb are thin and flattened and do not actively transport significant amounts of salts so that this change in osmolality is the result of passive movement of water into the medullary interstitium and of sodium chloride and urea into the tubule. The movement of solute and water occurs through the tight junctions of the epithelium. The osmolality of the tubular fluid reaches its peak at the hairpin bend. For the longest loops, which reach the tips of the renal papillae, the osmolality may reach 1200 mosmoles kg"1. For loops that do not penetrate so deeply into the medulla the peak osmolality will be less. In contrast to the cells of the thin descending limb, the epithelial cells of the ascending limb possess a sodium and chloride sym-porter which transports sodium, potassium, and chloride into the cell across the apical membrane. Significantly, the wall of the ascending limb is impermeable to water so that the osmolality of the tubular fluid falls as the cells of the ascending limb transport sodium chloride into the interstitium. By the time the tubular fluid has reached the beginning of the distal tubule it has an osmolality of about 150 mosmoles kg"1. The detailed mechanisms responsible for generating the osmotic gradient along the length of the loop of Henle will be discussed later (Section 17.8). Only the details of the transport mechanisms will be discussed here. Nevertheless, the changes in the osmolality of the tubular fluid as it passes along the loop of Henle are fundamental to the process of osmoregulation. The thick ascending limb of the loop of Henle transports sodium, potassium, and chloride from the lumen via an electroneutral symporter (Fig. 17.16). As with the other epithelial cells of the kidney, the driving force is provided by the sodium pump of the basolateral membrane. Some potassium ions leak back into the tubular fluid through potassium channels, causing the tubular lumen to be positively charged with respect to the interstitial space. This positive electrical gradient provides the driving force for the reabsorption of sodium, potassium, calcium, and magnesium via the paracellular pathway. Although significant amounts of ions can be absorbed in this way, water does not follow. The properties of the tight junctions of the ascending loop of Henle differ from those of the proximal tubule in this important respect. Summary
Fig. 17.16 The transport processes responsible for the uptake of sodium and chloride in the thick ascending limb of the loop of Henle. Sodium, potassium, and chloride are transporred into the tubular cells by an electroneutral cotransporter. The diffusion of potassium from the tubular cells into the lumen via potassium channels leads to the development of a lumen positive potential which provides the driving force for the paracellular absorption of cations. Note: in this section of the nephron the ion movements occur without the osmotically driven uprake of water. ^ The reabsorption of sodium, porassium, and water by the proximal tubule and ascending loop of Henle largely takes place regardless of the ionic balance of the body. In the distal tubule and collecting ducts, however, the uptake and secrerion of these ions is closely regulated according to the needs of the body. In addition, the distal tubule plays an important role in both acid—base balance and water balance. Sodium ion uptake by the distal tubule is regulated by the renin—angiotensin system The early part of the distal tubule reabsorbs sodium and chloride ions via a symporter similar to that described for the ascending limb of the loop of Henle. The apical membrane is impermeable to water so rhat the tubular fluid becomes progressively more dilute. In the later part of the distal tubule and in the collecting ducts, sodium reabsorption is linked to potassium secretion by 378 17 The kidney and the regulation of the internal environment  principal cells (P-cells). Sodium enters the P-cells across the apical membrane via channels and is pumped out into the lateral intercellular space by the Na+,K+-ATPase of the basolateral membrane. The potassium that is taken up by the activity of the sodium pump leaves the cell via potassium channels in the apical and basolateral membranes. About 12 per cent of the filtered load of sodium is reabsorbed in the distal tubule and collecting ducts and their capacity to reabsorb sodium is regulated by the activity of the juxtaglomeru-lar apparatus. When the sodium of the fluid in the distal tubule is low the cells of the macula densa cause the juxtaglomerular cells of the arteriole to secrete a proteolytic enzyme called renin into the blood. The exact process by which the macula densa cells stimulate the juxtaglomerular cells is not yet known. Renin converts a plasma peptide called angiotensinogen into angiotensin I. This, in turn, is converted to angiotensin II by converting enzyme which is found on the capillary endothelium of the lungs and some other vascular beds. Angiotensin II acts on the zona glomerulosa cells of the adrenal cortex to stimulate the release of the hormone aldosterone (Fig. 17.17). Aldosterone stimulates the production of sodium channels which become inserted in the apical membranes of the P-cells and the epithelial cells of the thick limb of the ascending loop of Henle. It also stimulates the synthesis of Na+,K+-ATPase molecules which are inserted in the basolateral membrane. By increasing the number of available channels for sodium uptake, aldosterone promotes sodium reabsorption (Fig. 17.18). Sodium moves into the cells down its concentration gradient and is transported to the interstitial fluid by the sodium pump of the basolateral membrane. Increasing the activity of the sodium pump also raises intra-cellular potassium and this can pass into the tubular fluid down its concentration gradient (Fig. 17.19). These adjustments act to increase the ability of the nephron to reabsorb sodium and to Fig. 17.17 The regulation of aldosterone secretion by the sodium load in the distal tubule. The level of circulating renin is regulated by the cells of the macula densa that sense the sodium load delivered to the distal tubule. Low sodium leads to increased renin secretion by the juxtaglomerular cells and ultimately increased sodium reabsorption. secrete potassium. As the action of aldosterone requires the synthesis of new proteins, its effect is not immediate but is delayed by an hour or so and reaches a maximum after about a day (see Fig. 17.18). When the plasma volume is expanded due to an increase in total body sodium, the action of renin is inhibited by atrial  Fig. 17.18 The effect of infusing 10 /xg aldosterone on sodium and potassium excretion in the adrenalectomized dog. Note the time delay before significant changes in sodium and potassium excretion are seen and that the effect of aldosterone considerably outlasts the period of infusion. ^  Fig. 17.19 The tubular secretion of potassium ions in the distal tubule and collecting duct. natriuretic peptide (ANP). The interplay between the renin-angiotensin system and ANP closely regulates renal sodium loss (see Chapter 28). Body potassium balance is maintained by the distal tubules and collecting ducts The diet is rich in potassium, about 4g (lOOmmoles) being ingested each day with a normal diet. As the distribution of potassium ions across the plasma membrane of cells is the principal determinant of their membrane potential there is a need for extracellular potassium to be regulated closely. This is achieved by the activity of the distal tubule and collecting duct. These parts of the nephron actively regulate potassium excretion, increasing potassium uptake in deficiency and secreting it in normal and hyperkalemic (high plasma potassium) states. By the time the filtrate reaches the distal tubule nearly 90 per cent of the filtered potassium has been reabsorbed. About two-thirds is normally absorbed by the proximal tubule via the paracel-lular route and some 20 per cent is absorbed by the ascending thick limb of the loop of Henle by cotransport with sodium and chloride ions. In the remainder of the nephron both potassium absorption and potassium secretion can occur and the balance between them determines how much potassium is lost in the urine. Potassium secretion into the tubular fluid occurs via a trans-cellular pathway (Fig. 17.19). It is taken up into the P-cells by the activity of the Na+,K+-ATPase located in the basolateral membrane and it leaves the cell down its electrochemical gradient via potassium channels located in the apical membrane. Under normal circumstances the amount of potassium secreted is determined by its concentration in the plasma. If plasma potassium is elevated, this will directly increase potassium uptake into the cells via the Na+,K+-ATPase. Additionally, if plasma potassium is elevated by as little as 2 mmoles I"1, aldosterone secretion is increased. This in turn stimulates the production of more Na+,K+-ATPase molecules by the P-cells, so augmenting the total transport capacity. In addition to stimulating the production of more Na+,K+-ATPase molecules, aldosterone also stimulates the production of sodium channels in the apical membranes (see above). The resulting increase in sodium uptake further stimulates the activity of the Na+,K+-ATPase of the basolateral membrane. The intercalated cells regulate acid—base balance by secreting hydrogen ions Although most of the filtered bicarbonate is reabsorbed in the proximal tubule and the loop of Henle, there is 1—2 mmoles I"1 in the fluid entering the distal tubule. Under normal circumstances all of this bicarbonate is reabsorbed. The mechanism employed by the intercalated cells differs from that of the proximal tubule. The intercalated cells actively secrete hydrogen ions into the lumen via an ATP-dependent pump. As in the proximal tubule, the decrease in the pH of the tubular fluid favors the conversion of bicarbonate ions to carbon dioxide and water and the liberated carbon dioxide diffuses down its concentration gradient into the tubular cells where carbonic anhydrase catalyses the formation of carbonic acid. Bicarbonate ions then leave the tubular cells via a bicarbonate—chloride exchanger. Active secretion of hydrogen ions into the lumen of the distal tubule and collecting ducts results in a fall in the pH of the tubular fluid that can reach values as low as 4—4.5, much lower than elsewhere in the nephron. As the apical membranes of the cells of the distal tubule and collecting ducts have a very low passive permeability to protons, they cannot diffuse back into the tubular cells. Since a pH of 4 corresponds to a free hydrogen ion concentration of only 0.1 mmoles per liter, only 0.15 mmoles of free hydrogen ion can be excreted each day for a normal daily urine output of 1.5 liters. Nevertheless, the body needs to excrete about 50 mmoles of nonvolatile acid a day, which is chiefly derived from the catabolism of the sulfur-containing amino acids cysteine and methionine. To permit the excretion of this quantity of nonvolatile acid the kidney buffers hydrogen ions with phosphate and generates base by the secretion of ammonium ions (see Section 29.4 for further details). Calcium ions are absorbed from the distal tubule by an active process that can be stimulated by parathyroid hormone About 70 per cent of the filtered load of calcium is reabsorbed in the proximal tubule, 20 per cent is absorbed by the ascending 380 17 The kidney and the regulation of the internal environment  loop of Henle and most of the remainder is absorbed by the distal tubule and cortical collecting duct. Only some 1 per cent is normally excreted.Calcium reabsorption occurs by both transcellular and para-cellular routes in the proximal tubule and the ascending loop of Henle. In the proximal tubule calcium transport occurs mainly via the paracellular pathway as a result of solvent drag. The trans-cellular movement of calcium accounts for only about a third of its uptake. In contrast, in the distal tubule all of the calcium uptake is via the transcellular route. This uptake is driven by passive influx of calcium down its steep electrochemical gradient into the tubular cells coupled to active extrusion of calcium across the basolateral membrane. Calcium uptake by the distal tubule and cortical collecting ducts is stimulated by parathyroid hormone (PTH) which plays a major role in calcium homeostasis. Conversely, an increase in PTH secrerion decreases the reabsorption of phosphate by the proximal tubule. (The regulation of calcium and phosphate balance by PTH and other hormones is considered in greater detail in Chapter 12). Summary l  .The first part of the distal tubule continues the dilution of the tubular fluid that began in the ascending thick limb of the loop of Henle.
^ 1  7.8 The kidneys regulate the osmolality of theplasma by adjusting the amount of water reabsorbed by the collecting ducts In a normal individual, water intake varies widely according to circumstances. As a result the osmolality of urine can range from as little as 50 mosmoles kg"1 following a large water load to around 1200 mosmoles kg"1 in severe dehydration. How do the kidneys produce urine with such a wide range of osmolality? Two key facts are fundamental to understanding how the kidney regulates water balance:
In essence, the kidney generates an osmotic gradient within the medulla by active transport of sodium chloride from the lumen of the ascending loop of Henle into the interstitial space. This gradient is then used to reabsorb water in the more distal regions of the nephron. The amount of water reabsorbed is regulated by the level of ADH circulating in the blood. When the plasma osmolality is low, little ADH is produced and copious dilute urine is produced. Conversely, when plasma osmolality is high ADH secretion is increased. Water reabsorption in the distal nephron is increased with the result that a small volume of concentrated urine is produced. In what follows the mechanisms responsible for establishing the medullary osmotic gradient will first be discussed and this will be followed by a simple account of the way ADH regulates water reabsorption in the distal nephron. Salt transport by the ascending limb of the loop of Henle leads to the generation of a large osmotic gradient in the renal medulla The outer medulla is iso-osmotic with the plasma but the osmolality of the medullary interstitium increases progressively from the cortex to the renal papilla. In the outer medulla the osmolality is about 290 mosmoles kg"1, chiefly attributable to sodium and chloride ions, but in the inner medulla the osmolality reaches 1200 mosmoles kg"1, about half of which is attributable to these ions and half to urea. This remarkable osmotic gradient is formed primarily as a result of active sodium and chloride transport by the thick ascending limb of the loop of Henle without the reabsorption of an osmotic equivalent of water. The crucial factors for the generation of the osmotic gradient are listed below:
17.8 The kidney regulates the osmolality of the plasma 381 collecting duct, and the outer medullary collecting ducts have little passive permeability to ions or to urea.
The active transport of sodium and chloride across the tubular epithelium of the ascending thin and thick limbs of the loop of Henle and distal tubule occurs without concomitant movement of water. The result of this transport is a decrease in the osmolality of the tubular fluid in the thick ascending limb of the loop of Henle and an increase in the osmolality of the fluid surrounding the tubule (i.e. the fluid of the medullary inter-stitium). Thus, as the tubular fluid passes down the descending limb of the loop of Henle it loses water to the medullary inter-stitium and gains sodium and chloride ions, so that its osmolality progressively rises as it flows towards the hairpin bend. In the inner medulla, the fluid in the descending limb becomes further concentrated by the loss of water to the interstitium. At the hairpin bend the osmolality of the tubular fluid is chiefly attributable to sodium and chloride ions (1000 mosmoles kg"1), urea contributing about 200 mosmoles kg"1. As the fluid passes through the ascending thin limb of the loop its osmolality will be greater than that of the interstitium and some sodium, chloride, and urea will diffuse down their concentration gradients into the interstitium. This passive movement of solutes helps to maintain the high osmolality of the interstitium. As mentioned above, sodium and chloride ions are actively transported by the epithelium of the thick ascending limb and the first third of the distal tubule without concomitant movement of water, so that by the time the tubular fluid has reached the middle of the distal tubule its osmolality is less than 100 mosmoles kg"1 (i.e. less than a third of that of plasma). The countercurrent arrangement of the loop of Henle thus multiplies a relatively small transepithelial osmotic gradient into a large longitudinal gradient. The transport processes of the loop of Henle and the resulting changes in osmolality are summarized in Fig. 17.20. Urea is concentrated in the medullary interstitium by a passive process Chemical analysis shows that the osmotic pressure of the interstitial fluid of the inner medulla (which may be 1200— 1400 mosmoles kg"1) is almost equally attributable to sodium chloride and to urea. Like other small solutes, urea is freely filtered at the glomerulus and a significant fraction of the filtered load is reabsorbed passively together with its osmotic equivalent of water in the proximal tubule. As the tubular fluid reaches the loop of Henle the urea concentration is still essentially the same as that of plasma but, by the time the fluid reaches the hairpin bend, urea contributes about 200 mosmoles kg"1. This increase in urea concentration is due to passive secretion of urea from the medullary interstitium. In the thick ascending limb sodium and chloride transport occurs without the movement of water so that the fluid in the distal tubule is hypotonic with respect to plasma. When the urine is concentrated as a result of the action of ADH on the cortical collecting ducts, the osmolality in this part of the nephron can reach that of the plasma (290 mosmoles kg"1) but, unlike the fluid entering the nephron, sodium and chloride ions   Fig. 17.20 A schematic representation of the countercurrent multiplier of the renal medulla. 382 17 The kidney and the regulation of the internal environment  account for much less of the osmolality and urea contributes much more. This situation arises because the powerful transport mechanisms of the thick ascending limb and distal tubule have removed most of the sodium and chloride ions. As the fluid flows into the inner medulla, water is reabsorbed under the influence of ADH and the urea concentration in the urine rises until, in the inner medullary collecting ducts, it exceeds that of the interstitium. Thus urea is concentrated by the abstraction of water. When the urea concentration in the urine is high, its movement from the urine into the medullary interstitium is favored. In the inner medulla, ADH not only increases the permeability of the collecting ducts to water, it also increases their permeability to urea. This adaptation optimizes the conservation of osmotically active urea during dehydration and minimizes its loss from the interstitium during diuresis. The vasa recta provide blood flow to the medulla without depleting the osmotic gradient As described above, the renal medulla receives its blood supply by way of the vasa recta. The blood flow is much less than that of the renal cortex but is sufficient to provide the medullary tissue with nutrients and oxygen. The vasa recta play a further important role: they act to maintain the osmotic gradient of the medulla while removing the sodium and chloride ions that have been reabsorbed. As the vasa recta are derived from the efferent arterioles of the juxtamedullary glomeruli, the blood entering them is isotonic with normal plasma (280—290 mosmoles kg1). The walls of the vasa recta are permeable to salts and water so that the blood they contain progressively increases in osmolality as it passes into the inner medulla by gaining salt and by losing water. By the time it reaches the deepest parts of the medulla, the blood has an osmolality equal to that of the surrounding interstitium. As the blood returns towards the cortex, the reverse sequence occurs and the blood leaving the vasa recta is only slightly hyperosmotic to normal plasma. The countercurrent arrangement of the vasa recta together with their relatively low blood flow helps to maintain the osmolality of the renal medulla while removing the excess salt and water that have been added by the transport processes occurring in the deeper regions of the medulla. Antidiuretic hormone (ADH) regulates the absorption of water from the collecting ducts The absorption of ions by the ascending limb of the loop of Henle results in the tubular fluid becoming hypo-osmotic as it approaches the distal tubule. At this point the tubular epithelium is still relatively impermeable to water. In the last third of the distal tubule and in the collecting ducts water permeability is regulated by the posterior pituitary hormone antidiuretic hormone (ADH or vasopressin). This hormone is secreted in response to increased plasma osmolality or to a reduction in blood pressure. Its secretion is regulated by sensors known as osmoreceptors which are located in the hypothalamus, close to the supra-optic and paraventricular nuclei which produce the hormone and transport it to the posterior pituitary (see Section 12.2). When plasma osmolality is below 285 mosmoles kg"1 ADH secretion by the posterior pituitary is very low and plasma levels are about 1—2 pg ml"1. An increase in plasma osmolality of as little as 3 mosmoles kg"1 is sufficient to stimulate ADH secretion and the degree of stimulation depends on the increase in osmolality above the threshold of 285 mosmoles kg"1 (Fig. 17.21). This osmotic regulation of ADH secretion is central to the control of plasma osmolality. The secretion of ADH is inhibited by atrial natriuretic peptide and some drugs such as ethanol. Fig. 17.21 The effect of changes in plasma osmolality on circulating levels of ADH. ADH increases the permeability of the last third of the distal tubule and that of the whole of the collecting duct to water. The result is a movement of water down its osmotic gradient into the tubular cells and thence into the interstitial fluid and the plasma. This water movement is independent of solute uptake and therefore results in an increase in urine osmolality and a fall in plasma osmolality that is directly related to the amount of water reabsorbed. Consequently, when the body has excess water and the plasma osmolality is less than 285 mosmoles kg"1 ADH secretion will be suppressed. Under these circumstances, water will not be reabsorbed during its passage through the collecting ducts and a large volume of dilute urine will be produced (giving rise to a diuresis). In contrast, ADH secretion is stimu- ^ |
s the filtrate passes along the proximal tubule all the protein, amino
bout 20 per cent of the filtered sodium chloride and water are