Medical Physiology, 3rd Edition

Generation of a Hyperosmotic Medulla and Urine

Understanding the mechanisms involved in forming a hyperosmotic or hypo-osmotic urine requires knowing (1) the solute and water permeability characteristics of each tubule segment, (2) the osmotic gradient between the tubule lumen and its surrounding interstitium, (3) the active transport mechanisms that generate the hyperosmotic medullary interstitium, and (4) the “exchange” mechanisms that sustain the hyperosmotic medullary compartment.

The renal medulla is hyperosmotic to blood plasma during both antidiuresis (low urine flow) and water diuresis

The loop of Henle plays a key role in both the dilution and the concentration of the urine. The main functions of the loop are to remove NaCl—more so than water—from the lumen and deposit this NaCl in the interstitium of the renal medulla. By separating tubule NaCl from tubule water, the loop of Henle participates directly in forming dilute urine. Conversely, because the TAL deposits this NaCl into the medullary interstitium, thus making it hyperosmotic, the loop of Henle is indirectly responsible for elaborating concentrated urine. As discussed below, urea also contributes to the hyperosmolality of the medulla.

Figure 38-2A shows approximate values of osmolality in the tubule fluid and interstitium during an antidiuresis produced, for example, by water restriction. Figure 38-2B illustrates the comparable information during a water diuresis produced, for example, by high water intake. In both conditions, interstitial osmolality progressively rises from the cortex to the tip of the medulla (corticomedullary osmolality gradient). The difference between the two conditions is that the maximal interstitial osmolality during antidiuresis, ~1200 mOsm (see Fig. 38-2A), is more than twice that achieved during water diuresis, ~500 mOsm (see Fig. 38-2B).

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FIGURE 38-2 Nephron and interstitial osmolalities. A, Water restriction (antidiuresis). B, High water intake (water diuresis). The numbers in the boxes are osmolalities (in mOsm) along the lumen of the nephron and along the corticomedullary axis of the interstitium. In A, the interstitial osmolality values in the green boxes come from Figure 38-7. The outflow of blood from the vasa recta is greater than the inflow, which reflects the uptake of water reabsorbed from the collecting ducts. Blue arrows indicate passive water movements. Green arrows indicate passive solute movements. Red arrows indicate active solute movements. NKCC2, Na/K/Cl cotransporter 2.

Because of the NaCl pumped out of the rather water-impermeable TAL, the tubule fluid at the end of this segment is hypo-osmotic to the cortical interstitium during both antidiuresis and water diuresis. However, beyond the TAL, luminal osmolalities differ considerably between antidiuresis and diuresis. In antidiuresis, the fluid becomes progressively more concentrated from the ICT to the end of the nephron (see Fig. 38-2A). In contrast, during water diuresis, the hypo-osmolality of the tubule fluid is further accentuated as the fluid passes along segments from the DCT to the end of the nephron segments that are relatively water impermeable and continue to pump NaCl out of the lumen (see Fig. 38-2B). During antidiuresis, the tubule fluid in the ICT, CCT, OMCD, and IMCD more or less equilibrates with the interstitium, but it fails to do so during water diuresis. This marked difference in osmotic equilibration reflects the action of AVP, which increases water permeability in each of the previously mentioned four segments.

NaCl transport generates only a ~200-mOsm gradient across any portion of the ascending limb, but countercurrent exchange can multiply this single effect to produce a 900-mOsm gradient between cortex and papilla

Developing and maintaining the hyperosmolality of the medullary interstitium depends on the net transport of NaCl across the rather water-impermeable wall of the ascending limb of the loop of Henle, from lumen to interstitium. This salt reabsorption increases the osmolality of the interstitium and decreases the osmolality of the fluid within the lumen. The limiting NaCl concentration gradient that the tubule can develop at any point along its length is only ~200 mOsm, and this concentration alone could not explain the ability of the kidney to raise the osmolality of the papilla to 1200 mOsm. The kidney can achieve such high solute levels only because the hairpin loops of Henle create a countercurrent flow mechanism that multiplies the “single” transverse gradient of 200 mOsm. The result is an osmotic gradient of 900 mOsm along both the axis of the lumen of the ascending limb and the corticomedullary axis of the interstitium. In addition to the hairpin shape of the loop of Henle, a distinct pattern of salt and water permeabilities along the loop of Henle also contributes to osmotic multiplication.

Figure 38-3 illustrates a simplified, schematized model of a countercurrent-multiplier system. imageN38-2 The kidney in this example establishes a longitudinal osmotic gradient of 300 mOsm from cortex (300 mOsm) to the papilla (600 mOsm) by iterating (i.e., multiplying) a single effect that is capable of generating a transepithelial osmotic gradient of only 200 mOsm. Of course, if we had used more cycles, we could have generated a corticomedullary gradient that was even greater. For example, after 39 cycles in our example, the interstitial osmolality at the tip of the loop of Henle would be ~1200 mOsm. Therefore, the countercurrent arrangement of the loop of Henle magnifies the osmotic work that a single ascending-limb cell can perform. Among mammals, the length of the loop of Henle—compared with the thickness of the renal cortex—determines the maximal osmolality of the medulla. imageN38-3

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FIGURE 38-3 Stepwise generation of a high interstitial osmolality by a countercurrent multiplier. This example illustrates in a stepwise fashion how a countercurrent-multiplier system in the loop of Henle increases the osmolality of the medullary interstitium. Heavy boundaries of ascending limb and early DCT indicate that these nephron segments are rather impermeable to water, even in the presence of AVP. The numbers refer to the osmolality (in mOsm) of tubule fluid and interstitium. The top panel shows the starting condition (step 0) with isosmotic fluid (~300 mOsm) throughout the ascending and descending limbs and in the interstitium. Each cycle comprises two steps. imageN38-2 Step 1 is the “single effect”: NaCl transport from the lumen of the ascending limb to the interstitium, which instantaneously equilibrates with the lumen of the descending limb (steps 1, 3, 5, and 7). Step 2 is an “axial shift” of tubule fluid along the loop of Henle (steps 2, 4, and 6), with an instantaneous equilibration between the lumen of the descending limb and the interstitium. Beginning with the conditions in step 0, the first single effect is NaCl absorption across the rather water-impermeable ascending limb. At each level, we assume that this single effect creates a 200-mOsm difference between the ascending limb (which is water impermeable) and a second compartment: the combination of the interstitium and descending limb (which is water permeable). Thus, the osmolality of the ascending limb falls to 200 mOsm, whereas the osmolality of the interstitium and descending limb rise to 400 mOsm (step 1). The shift of new isosmotic fluid (~300 mOsm) from the proximal tubule in the cortex into the descending limb pushes the column of tubule fluid along the loop of Henle, decreasing osmolality at the top of the descending limb and increasing osmolality at the bottom of the ascending limb. Through instantaneous equilibration, the interstitium—with an assumed negligible volume—acquires the osmolality of the descending limb, thereby diluting the top of the interstitium (step 2). A second cycle starts with net NaCl transport out of the ascending limb (step 3), which again generates an osmotic gradient of 200 mOsm—at each transverse level—between the ascending limb on the one hand and the interstitium and descending limb on the other. After the axial shift of tubule fluid and instantaneous equilibration of the descending limb with the interstitium (step 4), osmolality at the bottom of the ascending limb exceeds that in the preceding cycle. With successive cycles, interstitial osmolality at the tip of the loop of Henle rises progressively from 300 (step 0) to 400 (step 1) to 500 (step 3) to 550 (step 5) and then to 600 mOsm (step 7). Thus, in this example, the kidney establishes a longitudinal osmotic gradient of 300 mOsm from the cortex (300 mOsm) to the papilla (600 mOsm) by iterating (i.e., multiplying) a single effect that is capable of generating a transepithelial osmotic gradient of only 200 mOsm. Step 7A adds the collecting duct and shows the final event of urine concentration: allowing the fluid in the collecting duct to osmotically equilibrate with the hyperosmotic interstitium, which produces a concentrated urine. (Based on a model in Pitts RF: Physiology of the Kidney and Body Fluids. Chicago, Year Book, 1974.)

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Simplifications in the Countercurrent-Multiplier Model in Figure 38-3

Contributed by Emile Boulpaep, Walter Boron

The model shown in Figure 38-3 is simplified in several respects.

• Perhaps the most significant simplification is that we regard the ascending limb as being functionally uniform from bottom to top. In fact, the bottom of the ascending limb is “thin” (tALH), whereas the top is “thick” (TAL). Both the tALH and the TAL separate salt from water, but by very different mechanisms. As discussed in the text, the “single effect” is the result of passive NaCl reabsorption in the thin and active NaCl reabsorption in the thick ascending limb (see p. 811).

• We assume that at every site, the ascending limb establishes a transepithelial gradient of 200 mOsm.

• In Figure 38-3, we separate the generation of the single effect (left column) from the axial movement of fluid along the loop (right column). In fact, the two occur simultaneously.

• Figure 38-3 considers only four cycles rather than the essentially limitless number of cycles in the real kidney. Thus, in our example, we reached an osmolality of only 600 mOsm at the tip of the loop, whereas 1200 mOsm would be a more realistic maximal value. More iterations would generate a larger tip osmolality.

• The model does not include any dissipation of the gradient along the corticomedullary axis by either diffusion or by washout via medullary blood flow. In the text, we noted that after 39 cycles of our model, we would eventually achieve an osmolality of 1200 mOsm at the tip of the loop. What we did not say is that if we had continued with even more iterations, we would have achieved even higher, unrealistic osmolalities. In the real kidney, a balance between the single effect and washout would create a stable corticomedullary gradient of osmolality.

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Spectrum of Urinary Concentrating Abilities among Different Mammals

Contributed by Erich Windhager, Gerhard Giebisch

The countercurrent-multiplication theory accounts for the observation that the osmolality of the final urine in different species is roughly proportional to the relative length of the loop of Henle. Comparing the absolute lengths of loops of Henle is a gross simplification because of the large variation in the absolute size of kidneys in different species. A better correlation exists between maximal concentrating ability and the ratio of medullary thickness to cortical thickness. For instance, the beaver, whose kidney has no papilla, maximally concentrates the final urine to ~600 mOsm and has a medullary/cortical ratio of 1.3. Humans, on the other hand, achieve a maximal concentration of ~1200 mOsm and have a medullary/cortical ratio of 3.0. Finally, the desert rodent Psammomys, which can achieve a urine osmolality of almost 6000 mOsm, has a medullary/cortical ratio of 10.7.

Another important factor for explaining interspecies differences in concentrating ability is the fraction of nephrons that have long loops of Henle. This fraction varies from 0% (i.e., long loops are totally absent) in the beaver to ~14% in humans to 100% in the desert rodent Psammomys.

In the last panel of Figure 38-3, we include the collecting duct in the model to show the final event of urine concentration: allowing the fluid in the collecting duct to equilibrate osmotically with the hyperosmotic interstitium produces a concentrated urine.

The single effect is the result of passive NaCl reabsorption in the thin ascending limb and active NaCl reabsorption in the TAL

So far, we have treated the ascending limb as a functionally uniform epithelium that is capable of generating a 200-mOsm gradient between lumen and interstitium across a relatively water-impermeable barrier. However, the bottom of the ascending limb is “thin” (tALH), whereas the top is “thick” (TAL). Both the tALH and the TAL separate salt from water, but they transport the NaCl by very different mechanisms. The TAL moves NaCl from lumen out to interstitium via transcellular and paracellular pathways (see Fig. 35-4B). For the transcellular pathway, the TAL cell takes up Na+ and Cl via an apical Na/K/Cl cotransporter and exports these ions to the blood using basolateral Na-K pumps and Cl channels. For the paracellular pathway, the lumen-positive transepithelial voltage drives Na+ from lumen to blood via the tight junctions. Using these two pathways, the TAL can generate a single effect as large as 200 mOsm.

In contrast, the movement of Na+ and Cl from the lumen to the interstitium of the tALH appears to be an entirely passive process. During the debate on the mechanism of NaCl reabsorption in the tALH, several investigators pointed out that it was difficult to imagine how the extraordinarily thin cells of the tALH, with their paucity of mitochondria, could perform intensive active solute transport. Because the concentration of NaCl in the lumen exceeds that of the interstitium of the inner medulla, NaCl is reabsorbed passively. The key question for this model is: How did the luminal [NaCl] in the tALH become so high?

The work of concentrating the NaCl in the lumen was performed earlier, when the fluid was in the thin descending limb (tDLH) of juxtamedullary nephrons. This tDLH has three features that allow it to concentrate luminal NaCl: (1) the tDLH has a high water permeability owing to a high expression of aquaporin 1 (AQP1), (2) the tDLH has a very low permeability to NaCl and a finite urea permeability resulting from the presence of the UT-A2 urea transporter, and (3) the interstitium of the inner medulla has a very high [NaCl] and [urea]. The high interstitial concentrations of NaCl and urea provide the osmotic energy for passively reabsorbing water, which secondarily concentrates NaCl in the lumen of the tDLH.

In the interstitium, [Na+], [Cl], and [urea] all rise along the axis from the cortex to the papillary tip of the renal medulla (Fig. 38-4). In the outer medulla, a steep rise in interstitial [Na+] and [Cl]—owing to the pumping of NaCl out of the TAL (see p. 731)—is largely responsible for producing the hyperosmolality. Although urea makes only a minor contribution in the outermost portion of the outer medulla, [urea] rises steeply from the middle of the outer medulla to the papilla. At the tip of the papilla, urea and NaCl each contribute half of the interstitial osmolality. As discussed in the next section, this steep interstitial [urea] profile in the inner medulla (see Fig. 38-4) is the result of the unique water and urea permeabilities of the collecting tubules and ducts (see Fig. 38-2A).

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FIGURE 38-4 Concentration profiles of Na+, Cl, and urea along the corticomedullary axis. The data are from hydropenic dogs. (Data from Ullrich KJ, Kramer K, Boylan JW: Present knowledge of the counter-current system in the mammalian kidney. Progr Cardiovasc Dis 3:395–431, 1961.)

Knowing that NaCl and urea contribute to the high osmolality of the inner medullary interstitium, we can understand how the tDLH passively elevates [NaCl] in the lumen above that in the interstitium. NaCl is the main solute in the lumen at the tip of the papilla but urea contributes to the luminal osmolality. As the luminal fluid turns the corner and moves up the tALH, it encounters a very different epithelium, one that is now impermeable to water but permeable to NaCl. The Cl channel ClC-K1, selectively localized to the tALH, likely plays a pivotal role in this passive NaCl reabsorption. Indeed, mice lacking this channel have a urinary concentration defect. At the tip of the papilla interstitial [Na+] and [Cl] are each ~300 mM (see Fig. 38-4). Luminal [Na+] and [Cl], each in excess of 300 mM, provide a substantial gradient for passive transcellular reabsorption of Na+ and Cl. As we see in the next section, urea enters the tALH passively due to a favorable urea gradient and a urea permeability of the tALH larger than that of the tDLH. The entry of urea opposes the osmotic work achieved by the passive reabsorption of NaCl. Even though the mechanism and magnitude of the single effect is different in the tALH and the TAL, the result is the same. At any level, osmolality in the lumen of the ascending limb is lower than it is in the interstitium.

The IMCD reabsorbs urea, producing high levels of urea in the interstitium of the inner medulla

Because urea comes from protein breakdown, urea delivery to the kidney—and, therefore, the contribution of urea to the medullary hyperosmolality—is larger with consumption of protein-rich diets. Indeed, investigators have long known that the higher the dietary protein content, the greater the concentrating ability.

Urea Handling

The renal handling of urea is complex (see pp. 770–772). The kidney filters urea in the glomerulus and reabsorbs about half in the proximal tubule (Fig. 38-5, step 1). In juxtamedullary nephrons, the tDLH and the tALH secrete urea into the tubule lumen (see Fig. 38-5, step 2). Some urea reabsorption occurs along the TAL up through the CCT (see Fig. 38-5, step 3). Finally, the IMCD reabsorbs urea (see Fig. 38-5, step 4). The net effect is that the kidney excretes less urea into the urine than it filters. Depending on urine flow (see Fig. 36-2), the fractional excretion may be as low as ~15% (minimal urine flow) or as high as ~65% or more (maximal urine flow). Because we are interested in understanding the role of urea in establishing a hyperosmotic medullary interstitium, in Figure 38-5 we consider an example in which maximal AVP produces minimal urine flow (i.e., antidiuresis), a condition already illustrated in Figure 38-2A.

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FIGURE 38-5 Urea recycling. Under conditions of water restriction (antidiuresis), the kidneys excrete ~15% of the filtered urea. The numbered yellow boxes indicate the fraction of the filtered load that various nephron segments reabsorb. The red box indicates the fraction of the filtered load secreted by the tALH and the brown box indicates the fraction of the filtered load carried away by the vasa recta. The green boxes indicate the fraction of the filtered load that remains in the lumen at various sites. The values in the boxes are approximations. imageN38-8

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Urea Reabsorption in the Distal Nephron

Contributed by Erich Windhager, Gerhard Giebisch

Of the urea filtered in the glomerulus, the proximal tubule reabsorbs ~50% by solvent drag (see p. 770), leaving ~50% remaining in the nephron lumen as the fluid enters the tDLH. As the thin limbs of juxtamedullary nephrons (which make up ~10% of all nephrons) dip into the inner medulla (remember, these are the only nephrons whose loops of Henle dip into the inner medulla—see Figure 33-2), they secrete—under maximal antidiuretic conditions—an amount of urea equivalent to ~50% of the total filtered load of urea summed over all of the nephrons. In other words, by the time the luminal fluid of juxtamedullary nephrons reaches the beginning of the TAL, the luminal urea content must be an extremely high fraction of the filtered load of these nephrons. The superficial nephrons, on the other hand, have ~50% of their filtered load of urea remaining (the fraction not reabsorbed by their proximal tubules) by the time their fluid reaches the beginning of their TAL. Averaging over all nephrons—the juxtamedullary nephrons with high urea levels and superficial nephrons with low urea levels—the fluid entering the “average” TAL has an amount of urea that corresponds to 100% of the total filtered load of urea for the entire kidney. This is the 100% in the green box that points to the TAL in Figure 38-5.

Figure 38-5 indicates that, by time the tubule fluid reaches the junction of the outer and inner medulla, only 70% of the total filtered load of urea remains. Because the TAL, DCT, CNT, and CCT all have low urea permeabilities, it is perhaps somewhat surprising that 30% should have disappeared. Box 3 in the figure shows 30% of the total filtered load of urea being reabsorbed. Two events contribute to this 30%: (1) In the relatively few nephrons that are juxtamedullary, the [urea] in the TAL and CCT is very high, providing a gradient for passive urea loss in the cortex, where the interstitial [urea] is little more than that in plasma (i.e., ~5 mM). (2) In the collecting-duct system, fluid from the many superficial nephrons (each of which has a relatively low amount of its filtered load of urea remaining) admixes with that from the few juxtamedullary nephrons (each of which has far more than its filtered load of urea remaining), producing a blend with an intermediate level of urea remaining. Thus, the admixture of a few hundred percent remaining (from the juxtamedullary nephrons) with 50% remaining (from the superficial nephrons) contributes to the overall decrease in the percent of urea remaining to 70%.

As the tubule fluid enters the TAL, the [urea] is several-fold higher than it is in the plasma because ~100% of the filtered load of urea remains, even though earlier nephron segments have reabsorbed water. All nephron segments from the TAL to the OMCD, inclusive, have low permeabilities to urea. In the presence of AVP, however, all segments from the ICT to the end of the nephron have high water permeabilities and continuously reabsorb fluid. As a result, luminal [urea] gradually rises, beginning at the ICT and reaching a concentration as much as 8-fold to 10-fold higher than that in blood plasma by the time the tubule fluid reaches the end of the OMCD.

The IMCD differs in an important way from the three upstream segments: Although AVP increases only water permeability in the ICT, CCT, and OMCD, AVP increases water and urea permeability in the IMCD. In the IMCD, the high luminal [urea] and the high urea permeabilities of the apical membrane (via the urea transporter UT-A1; see p. 770) and basolateral membrane (via UT-A3) promote the outward facilitated diffusion of urea from the IMCD lumen, through the IMCD cells, and into the medullary interstitium (see Fig. 38-5, step 4). As a result, urea accumulates in the interstitium and contributes about half of the total osmolality in the deepest portion of the inner medulla. In addition, in the outer portion of the inner medulla, active urea reabsorption occurs via an Na/urea cotransporter in the apical membrane of the early IMCD.

Because of the accumulation of urea in the inner medullary interstitium, [urea] is higher in the interstitium than it is in the lumen of the tDLH and tALH of juxtamedullary (i.e., long-loop) nephrons. This concentration gradient drives urea into the tDLH via UT-A2 and into the tALH via an unidentified transporter (see Fig. 38-5, step 2). The secretion of urea into the tDLH and tALH accounts for two important observations: First, more urea (i.e., a greater fraction of the filtered load) emerges from the tALH than entered the tDLH. Second, as noted above, [urea] in the TAL is considerably higher than that in blood plasma.

Urea Recycling

The processes that we have just described—(1) absorption of urea from IMCD into the interstitium (see Fig. 38-5, step 4), (2) secretion of urea from the interstitium into the thin limbs (see Fig. 38-5, step 2), and (3) delivery of urea up into the cortex and back down via nephron segments from the TAL to the IMCD—are the three elements of a loop. This urea recycling is responsible for the buildup of a high [urea] in the inner medulla. A small fraction of the urea that the IMCD deposits in the interstitium moves into the vasa recta (see Fig. 38-5, step 5), which removes it from the medulla and returns it either to superficial nephrons or to the general circulation.

The preceding discussion focused on the situation in antidiuresis, in which AVP levels are high and the kidney concentrates urea in the inner medulla. The converse situation pertains in water diuresis, when circulating levels of AVP are low. The kidney reabsorbs less water along the ICT, CCT, OMCD, and IMCD. Furthermore, with low AVP levels, the IMCD has lower permeability to both urea and water. In addition, urea may be actively secreted by an apical Na-urea exchanger located in the apical membrane of the most distal portions of the IMCD. Therefore, during water diuresis, the interstitial [urea] is lower, and more urea appears in the urine.

The vasa recta's countercurrent exchange and relatively low blood flow minimize washout of medullary hyperosmolality

The simplified scheme for the countercurrent multiplier presented in Figure 38-3 did not include blood vessels. If we were simply to introduce a straight, permeable blood vessel running from papilla to cortex, or vice versa, the blood flow would soon wash away the papillary hyperosmolality that is critical for concentrating urine. Figure 38-6A shows a hypothetical kidney with only descending vasa recta. Here, blood would flow from cortex to papilla and then exit the kidney. Because the blood vessel wall is permeable to small solutes and water, the osmolality of the blood would gradually increase from 300 to 1200 mOsm during transit from cortex to papilla, reflecting a loss of water or a gain of solutes. Because these movements occur at the expense of the medullary interstitium, the blood would wash out the interstitium's hyperosmolality. The greater the blood flow through this straight/unlooped blood vessel, the greater would be the medullary washout.

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FIGURE 38-6 Model of countercurrent exchange. A, If blood simply flows from the cortex to the medulla through a straight tube, then the blood exiting the medulla will have a high osmolality (750 mOsm), washing out the osmolality gradient of the medullary interstitium. The numbers in the yellow boxes indicate the osmolality (in mOsm) inside the vasa recta, and the numbers in the green boxes indicate the osmolality of the interstitial fluid. B, If blood flows into and out of the medulla through a hairpin loop, then the water will leave the vessel and solute will enter along the entire descending vessel and part of the ascending vessel. Along the rest of the ascending vessel, the fluxes of water and solute are reversed. The net effect is that the blood exiting the medulla is less hyperosmotic than that in A (450 versus 750 mOsm), so that the kidney better preserves the osmotic gradient in the medulla. The values in the boxes are approximations. (Data from a model in Pitts RF: Physiology of the Kidney and Body Fluids. Chicago, Year Book, 1974.)

The kidney solves the medullary-washout problem in two ways. First, compared with the blood flow in the renal cortex, which is one of the highest (per gram of tissue) of any tissue in the body, the blood flow through the medulla is relatively low, corresponding to no more than 5% to 10% of total renal plasma flow. This low flow represents a compromise between the need to deliver nutrients and oxygen to the medulla and the need to avoid washout of medullary hyperosmolality.

Second, and far more significant, the kidney uses a hairpin configuration, with the descending and ascending vasa recta both entering and leaving through the same region, which creates an efficient countercurrent exchange mechanism (see Fig. 38-6B) in the blood vessels. The vasa recta have a hairpin configuration, but no capacity for active transport. We start with the osmotic stratification in the medullary interstitium that the countercurrent multiplier generated in the presence of high AVP levels. This osmotic stratification results in part from a gradient of [Na+] + [Cl], but also from a similarly directed cortex-to-papilla gradient of [urea] (see Fig. 38-4). As isosmotic blood enters the hyperosmotic milieu of the medulla, which has high concentrations of NaCl and urea, NaCl and urea diffuse into the lumen of the descending vasa recta, whereas water moves in the opposite direction. This entry of urea into the descending vasa recta occurs via facilitated diffusion, mediated by the UT-B1 and UT-B2 urea transporters (see p. 770). The result is that the osmolality of the blood increases as the blood approaches the tip of the hairpin loop. As the blood rounds the curve and heads up toward the cortex inside the ascending vasa recta, that blood eventually develops a higher solute concentration than the surrounding interstitium. As a consequence, NaCl and urea now diffuse from the lumen of the vasa recta into the interstitium, whereas water moves into the ascending vasa recta.

Viewed as a whole, these passive exchange processes not only cause the descending vasa recta to gain solute and lose water, but also cause the ascending vessels to lose solute and gain water. Thus, at any level, the descending and ascending vessels exchange solutes and water via—and at the expense of—the medullary interstitium. Solute recirculates from the ascending vessel, through the interstitium, to the descending vessel. Conversely, the countercurrent exchange mechanism also “short-circuits” the water but in the opposite direction, from the descending vessel, through the interstitium, to the ascending vessel. The net effect is that the countercurrent exchanger tends to trap solutes in and exclude water from the medulla, thereby minimizing dissipation of the corticomedullary osmolality gradient. imageN38-4

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Anatomical Arrangements between the Vasa Recta and Thin Limbs in the Medulla

Contributed by Erich Windhager, Gerhard Giebisch

Although in some species, the ascending and descending vasa recta are closely intermingled in vascular bundles within the medulla, such close contact between the ascending and descending vessels is not necessary to create an effective countercurrent exchanger. It is only necessary that vessels at the same level equilibrate with the same interstitial fluid.

The total mass of solute and water leaving the medulla each minute via the ascending vasa recta must exceed the total inflow of solute and water into the medulla via the descending vasa recta. With regard to solute balance, the renal tubules continuously deposit NaCl and urea in the medullary interstitium. Thus, in the steady state, the vasa recta must remove these solutes lest they form crystals of NaCl and urea in the medullary interstitium. Almost all the urea in the interstitium of the inner medulla comes from the IMCD (see Fig. 38-5, step 4), and in the steady state most of this leaves the interstitium by way of the tALH (see Fig. 38-5, step 2). The blood of the vasa recta carries away the balance or excess urea (see Fig. 38-5, step 5). The vasa recta also carry off the excess NaCl that enters the interstitium from the ascending limb of the loop of Henle and, to some extent, from the MCDs (see Fig. 38-2).

With regard to water balance within the medulla, the descending limb of the loop of Henle and—in the presence of AVP—the MCD continuously give up water to the medullary interstitium (see Fig. 38-2). The ascending vasa recta carry off this excess water from the medulla.

The net effect of managing both solute and water balance in the medulla is that the ascending vasa recta carry out more salt and more water than the descending vasa recta carry in. imageN38-5

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Osmolality of the Ascending versus Descending Vasa Recta

Contributed by Gerhard Giebisch, Eric Windhager

As shown in Figure 38-2A, the net effect of managing both solute and water balance in the medulla is that the ascending vasa recta carry out greater amounts of salt and water than the descending vasa recta carry in. Although no precise measurements have been made, it is likely that the salt concentration—and therefore osmolality—of blood leaving the ascending vasa recta exceeds that of the blood entering the descending vessels by a fairly small amount, perhaps 10 to 30 mOsm.

The MCD produces a concentrated urine by osmosis, driven by the osmotic gradient between the medullary interstitium and the lumen

Whereas the loop of Henle acts as a countercurrent multiplier and the loop-shaped vasa recta act as a countercurrent exchanger, the MCD acts as an unlooped or straight-tube exchanger. The wall of the MCD has three important permeability properties: (1) in the absence of AVP, it is relatively impermeable to water, urea, and NaCl along its entire length; (2) AVP increases its water permeability along its entire length; and (3) AVP increases its urea permeability along just the terminal portion of the tube (IMCD). The collecting duct traverses a medullary interstitium that has a stratified, ever-increasing osmolality from the cortex to the tip of the papilla. Thus, along the entire length of the tubule, the osmotic gradient across the collecting-duct epithelium favors the reabsorption of water from lumen to interstitium.

A complicating factor is that two solutes—NaCl and urea—contribute to the osmotic gradient across the tubule wall. As fluid in the collecting-duct lumen moves from the corticomedullary junction to the papillary tip, the [NaCl] gradient across the tubule wall always favors the osmotic reabsorption of water (Fig. 38-7). For urea, the situation is just the opposite. However, because the ICT, CCT, and OMCD are all relatively impermeable to urea, water reabsorption predominates in the presence of AVP and gradually causes luminal [urea] to increase in these segments. Because the interstitial [urea] is low in the cortex, a rising luminal [urea] in the ICT and CCT opposes water reabsorption in these segments. Even when the tubule crosses the corticomedullary junction, courses toward the papilla, and is surrounded by interstitial fluid with an ever-increasing [urea], the transepithelial urea gradient still favors water movement into the lumen, which is a handicap for the osmotic concentration of the tubule fluid.

image

FIGURE 38-7 Opposing effects of NaCl and urea gradients on urine concentrating ability during antidiuresis. The numbers in the green boxes indicate the osmolalities (in mOsm) of the interstitial fluid.

The IMCD partially compensates for this problem by acquiring, in response to AVP, a high permeability to urea. The result is a relatively low reflection coefficient for urea (σurea; see p. 468), which converts any transepithelial difference in [urea] into a smaller difference in effective osmotic pressure (see pp. 132–133). Thus, water reabsorption continues from the IMCD even though [urea] in tubule fluid exceeds that in the interstitium. The combination of a high interstitial [NaCl] and high σNaCl (σNaCl = 1.0), along with a low σurea (σurea = 0.74), promotes NaCl-driven water reabsorption. The high AVP-induced urea permeability has the additional effect of raising interstitial [urea], which further reduces the adverse effect of the high luminal [urea] on water reabsorption.

If luminal urea opposes the formation of a concentrated urine, why did the mammalian kidney evolve to have high levels of urea in the lumen of the collecting tubules and ducts? At least two reasons are apparent. First, because urea is the body's major excretable nitrogenous waste, the kidney's ability to achieve high urinary [urea] reduces the necessity to excrete large volumes of water to excrete nitrogenous waste. Second, as we have already seen, the kidney actually takes advantage of urea—indirectly—to generate maximally concentrated urine. In the presence of AVP, the permeability of the IMCD to urea is high, so that large amounts of urea can enter the medullary interstitium. The high interstitial [urea] energizes the increase in luminal [NaCl] in the tDLH, which, in turn, fuels the single effect in the tALH, thus creating the high inner-medullary [NaCl] that is directly responsible for concentrating the urine.

As discussed above in this section, the composition of the inner medullary interstitium determines the composition of the final urine. However, to some extent, the composition of the final urine, as well as the rate of urine flow, also influences the composition of the interstitium. Figure 38-2 shows that the medullary interstitial osmolality is much lower, and the stratification of osmolality from cortex to papillary tip is much less, during water diuresis than during antidiuresis. Two factors contribute to the lesser degree of osmotic stratification under conditions of water diuresis, when levels of AVP are low. First, less urea moves from the IMCD lumen to the interstitium, both because of the low urea permeability of the IMCD and because of the low water permeability of the upstream segments that would otherwise concentrate urea. Second, the MCDs reabsorb some water despite the low AVP levels, and this water dilutes the medullary interstitium. The reasons for this apparent paradox are as follows: (1) even when AVP is low, the water permeability is not zero; (2) the ICT and CCT present a much larger fluid volume to the MCD, because they reabsorb less water when AVP levels are low; and (3) the tubule fluid is more hypo-osmotic, which results in a larger osmotic gradient for transepithelial water movement. With low AVP levels, this larger osmotic gradient overrides the effect of the lower water permeability.

Table 38-2 summarizes factors that modulate urinary concentration ability.

TABLE 38-2

Factors that Modulate Urinary Concentration and Dilution

1. Osmotic gradient of medullary interstitium from corticomedullary junction to papilla:

a. Length of loops of Henle: Species with long loops (e.g., desert rodents) concentrate more than those with short loops (e.g., beaver).

b. Rate of active NaCl reabsorption in the TAL: Increased luminal Na+ delivery to the TAL (high GFR or filtration fraction, and low proximal-tubule Na+ reabsorption) enhances NaCl reabsorption, whereas low Na+ delivery (low GFR, increased proximal Na+ and fluid reabsorption) reduces concentrating ability. High Na-K pump turnover enhances NaCl reabsorption, whereas inhibiting transport (e.g., loop diuretics) reduces concentrating ability.

c. Protein content of diet: High-protein diet, up to a point, promotes urea production and thus accumulation in the inner medullary interstitium, and increased concentrating ability.

2. Medullary blood flow: Low blood flow promotes high interstitial osmolality. High blood flow washes out medullary solutes.

3. Osmotic permeability of the collecting tubules and ducts to water: AVP enhances water permeability and thus water reabsorption.

4. Luminal flow in the loop of Henle and the collecting duct: High flow (osmotic diuresis) diminishes the efficiency of the countercurrent multiplier, and thus reduces the osmolality of the medullary interstitium. In the MCD, high flow reduces the time available for equilibration of water and urea.

5. Pathophysiology: Central diabetes insipidus (DI) reduces plasma AVP levels, whereas nephrogenic DI reduces renal responsiveness to AVP (see Box 38-1).

GFR, glomerular filtration rate.