Medical Physiology A Cellular and Molecular Approach, Updated 2nd Ed.


Gerhard Giebisch and Erich Windhager


The kidney can generate a urine as dilute as 30 mOsm (1/10 of plasma osmolality) or as concentrated as 1200 mOsm (4× plasma osmolality)

In the steady state, water intake and output must be equal (Table 38-1). The body’s three major sources of water are (1) water ingested, (2) water contained within foods that we eat, and (3) water produced by aerobic metabolism as mitochondria convert foodstuffs and O2 to CO2 and H2O (see Chapter 58).

Table 38-1 Input and Output of Water




Amount (mL)

Ingested fluids


Ingested food









Amount (mL)







Exhaled air




(Data from Valtin H: Renal Dysfunction: Mechanisms Involved in Fluid and Solute Imbalance, p 21. Boston: Little, Brown, 1979.)

The major route of water loss is usually through the kidneys, the organs that play the central role in regulating water balance. The feces are usually a minor route of water output (see Chapter 44). Although the production of sweat can increase markedly during exercise or at high temperatures, sweat production is geared to help regulate body core temperature (see Chapter 59), not body water balance. Water also evaporates from the skin and is lost in the humidified air exhaled from the lungs and air passages. The figures summarized in Table 38-1 obviously vary, depending on diet, physical activity, and the environment (e.g., temperature and humidity).

The kidney adjusts its water output to compensate for either abnormally high or abnormally low water intake or for abnormally high water losses through other routes. The kidney excretes a variable amount of solute, depending especially on salt intake. However, for a normal diet, the excreted solute is ~600 mOsmol/day. For average conditions of water and solute intake and output, this 600 mOsmol is dissolved in a daily urine output of 1500 mL. A key principle is that, regardless of the volume of water they excrete, the kidneys must excrete ~600 mOsmol/day. Stated somewhat differently, the product of urine osmolality and urine output is approximately constant:


Therefore, to excrete a wide range of water volumes, the human kidney must produce urine having a wide range of osmolalities. For example, when the kidney excretes the 600 mOsmol dissolved in 1500 mL of urine each day, urine osmolality must be 400 mOsm:


When the intake of water is especially high, the human kidney can generate urine having an osmolality as low as ~30 mOsm. Because the kidneys may still need to excrete 600 mOsmol of solutes, the urine volume in an extreme water diuresis would be as high as 20 L/day.


However, when it is necessary to conserve water (e.g., with restricted water intake; excessive loss by sweat or stool), the kidney is capable of generating urine with an osmolality as high as ~1200 mOsm. Therefore, with an average solute load, the minimal urine volume can be as low as ~0.5 L/day:


Therefore, the kidney is capable of diluting the urine ~10-fold with respect to blood plasma, but it is capable of concentrating the urine only ~4-fold. Renal failure reduces both the concentrating and diluting ability.

Free water clearance is positive if the kidney produces urine that is less concentrated than plasma and negative if the kidney produces urine that is more concentrated than plasma

A urine sample can be thought of as consisting of two moieties: (1) the volume that would be necessary to dissolve all the excreted solutes at a concentration that is isosmotic with blood plasma; and (2) the volume of pure or solute-free water—or, simply, free water—that one must add (or subtract) to the previous volume to account for the entire urine volume. As discussed later, the kidney generates free water in the tubule lumen by reabsorbing solutes, mainly NaCl, in excess of water along nephron segments with low water permeability. When the kidney generates free water, the urine becomes dilute (hypo-osmotic). Conversely, when the kidney removes water from an isosmotic fluid, the urine becomes concentrated (hyperosmotic). When the kidney neither adds nor subtracts free water from the isosmotic moiety, the urine is isosmotic with blood plasma.

The urine output is the sum of the rate at which kidney excretes the isosmotic moiety of urine (osmolal clearance, COsm) and the rate at which it excretes free water (free water clearance [CH2O]):


Of course, CH2O is negative (i.e., excretion of negative free water) if the kidney removes free water and produces concentrated urine. We compute COsm in the same way we would compute the clearance of any substance from the blood (see Chapter 33):


POsm is the osmolality of blood plasma. The osmolal clearance is the hypothetical volume of blood (in milliliters) that the kidneys fully clear of solutes (or osmoles) per unit time. For example, if the daily solute excretion (UOsm · image) is fixed at 600 mOsmol/day, and POsm is 300 mOsmol/L, then Equation 38-6 tells us that COsm has a fixed value of 2 L/day.

We can obtain CH2O only by subtraction:


Indeed, CH2O does not conform to the usual definition of clearance because CH2O is not (UH2O · image)/PH2O. Nevertheless, this apparent misnomer has been accepted by renal physiologists and nephrologists. (See Note: "Effective Osmolal-less" versus "Osmolal-less" Water Clearance)

The range of CH2O values for the human kidney is related to the extremes in urine osmolality, as shown for the following three examples:

Isosmotic Urine If the osmolalities of the urine and plasma are the same (UOsm = POsm), then osmolal clearance equals urine flow:


Therefore, Equation 38-7 tells us that CH2O must be zero.

Dilute Urine If the urine is more dilute than plasma (image > COsm), then the difference between image and COsm is the positive CH2O. When the kidney maximally dilutes the urine to 30 mOsm, the total urine flow (image) must be 20 L/day (see Equation 38-3):


Concentrated Urine If the urine is more concentrated than plasma (image < COsm), then the difference between image and COsm is a negative number, the negative CH2O. When the kidney maximally concentrates the urine to 1200 mOsm, the total urine flow must be 0.5 L/day (see Equation 38-4):


Thus, the kidneys can generate CH2O of as much as +18 L/day under maximally diluting conditions, or as little as –1.5 L/day under maximally concentrating conditions. This wide range of CH2O represents the kidneys’ attempt to stabilize the osmolality of extracellular fluid in the face of changing loads of solutes or water. From the extreme CH2O that the kidneys can achieve, we can conclude that the organism withstands the challenge of water load better than a water deficit.


The kidney generates concentrated urine by using osmosis to drive water from the tubule lumen, across a water-permeable epithelium, into a hypertonic interstitium

The kidney generates dilute urine by pumping salts out of the lumen of tubule segments that are impermeable to water. What is left behind is tubule fluid that is hypo-osmotic (dilute) with respect to the blood.

How does the kidney generate concentrated urine? One approach could be to pump water actively out of the tubule lumen. However, water pumps do not exist (see Chapter 5). Instead, the kidney uses osmosis as the driving force to concentrate the contents of the tubule lumen. The kidney generates the osmotic gradient by creating a hypertonic interstitial fluid in a confined compartment, the renal medulla. The final step for making a hyperosmotic urine is to thread a water-permeable tube—the medullary collecting duct (MCD)—through this hyperosmolar compartment. The result is that the fluid in the tubule lumen can equilibrate with the hypertonic interstitium, thus generating concentrated urine.

Although net absorption of H2O occurs all along the nephron, not all segments alter the osmolality of the tubule fluid. The proximal tubule, regardless of the final osmolality of the urine, reabsorbs two thirds of the filtered fluid isosmotically (i.e., the fluid reabsorbed has the same osmolality as plasma). The loop of Henle reabsorbs salt in excess of water, so that the fluid entering the distal convoluted tubule (DCT) is hypo-osmotic. Whether the final urine is dilute or concentrated depends on whether water reabsorption occurs in more distal segments: the initial and cortical collecting tubules (ICT and CCT) and the outer and inner MCDs (OMCD and IMCD). Arginine vasopressin(AVP)—also called antidiuretic hormone (ADH)—regulates the variable fraction of water reabsorption in these four nephron segments. Figure 13-9shows the structure of AVP.

Tubule fluid is isosmotic in the proximal tubule, becomes dilute in the loop of Henle, and then either remains dilute or becomes concentrated by the end of the collecting duct

Figure 38-1 shows two examples of how tubule fluid osmolality (expressed as the ratio TFOsm/POsm) changes along the nephron. The first is a case of water restriction, in which the kidneys maximally concentrate the urine and excrete a minimal volume of water (antidiuresis). The second is a case of ingestion of excess water, in which the kidneys produce a large volume of dilute urine (water diuresis). In both cases, the tubule fluid does not change in osmolality along the proximal tubule, and it becomes hypotonic to plasma by the end of the thick ascending limb of the loop of Henle (TAL), also known as the diluting segment (see Chapter 35). Therefore, the fluid entering the DCT is hypo-osmotic with respect to plasma, regardless of the final urine osmolality.


Figure 38-1 Relative osmolality of the tubule fluid along the nephron. Plotted on the y-axis is the ratio of the osmolality of the tubule fluid (TF) to the osmolality of the plasma (P); plotted on the x-axis is a representation of distance along the nephron. The red record is the profile of relative osmolality (i.e., TF/Posmolality) for water restriction, whereas the blue record is the profile for high water intake. (Data from Gottschalk CW: Physiologist 1961; 4:33-55.)

Under conditions of restricted water intake or hydropenia, elevated levels of AVP increase the water permeability of the nephron from the ICT to the end of the IMCD. As a result, the osmolality of the tubule fluid increases along the ICT (Fig. 38-1, red curve), achieving the osmolality of the cortical interstitium—which is the same as the osmolality of plasma (~290 mOsm)—by the end of this nephron segment. No additional increase in osmolality occurs along the CCT, because the tubule fluid is already in osmotic equilibrium with the surrounding cortical interstitium. However, in the MCDs, the luminal osmolality rises sharply as the tubule fluid equilibrates with the surrounding medullary interstitium, which becomes increasingly more hyperosmotic from the corticomedullary junction to the papillary tip. Eventually the tubule fluid reaches osmolalities that are as much as four times higher than the plasma. Thus, the MCDs are responsible for concentrating the final urine.

In summary, the two key elements in producing a concentrated urine are the hyperosmotic medullary interstitium that provides the osmotic gradient and the AVP that raises the water permeability of the distal nephron. How the kidney generates this interstitial hyperosmolality is discussed in the next subchapter, and the role of AVP is discussed in the last subchapter.

Under conditions of water loading, depressed AVP levels cause the water permeability of the distal nephron to remain low. However, the continued reabsorption of NaCl along the distal nephron effectively separates salt from water and leaves a relatively hypotonic fluid behind in the tubule lumen. Thus, the tubule fluid becomes increasingly hypotonic from the DCT throughout the remainder of the nephron (Fig. 38-1, blue curve).


Understanding the mechanisms involved in forming a hypertonic or hypotonic 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 to 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 later, urea also contributes to the hypertonicity 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, however, 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 (Fig. 38-2A), is more than twice that achieved during water diuresis, ~500 mOsm (Fig. 38-2B).


Figure 38-2 Nephron and interstitial osmolalities. A, Water restriction (antidiuresis). B, High water intake (water diuresis). The numbers in boxes are osmolalities (mOsm) along the lumen of the nephron and along the corticomedullary axis of the interstitium. The outflow of blood from the vasa recta is greater than the inflow, a finding reflecting the uptake of water reabsorbed from the collecting ducts.

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 (Fig. 38-2A). In contrast, during water diuresis, the hypotonicity 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 (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.

Although NaCl transport generates a gradient of only ~200 mOsm across any portion of the ascending limb, the countercurrent system can multiply this single effect to produce a 900-mOsm gradient between the cortex and the 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, osmotic multiplication also depends on a distinct pattern of salt and water permeabilities along the loop of Henle.

Figure 38-3 illustrates a simplified, schematized model of a countercurrent-multiplier system. The kidney in this example establishes a longitudinal osmotic gradient of 300 mOsm from cortex (300 mOsm) to 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. 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. (See Note: Simplifications of the Countercurrent Multiplier Model in Figure 38-3Spectrum of Urinary Concentrating Abilities among Different Mammals)


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 (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. 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, thus decreasing osmolality at the top of the descending limb and increasingosmolality 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), again generating 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 of the preceding cycle. With successive cycles, interstitial osmolality at 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 (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 equilibrate osmotically with the hyperosmotic interstitium, producing a concentrated urine. (Based on a model by Pitts RF: Physiology of the Kidney and Body Fluids. Chicago, Year Book, 1974.) (See Note: Simplifications of the Countercurrent Multiplier Model in Figure 38-3)

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 thick ascending limb

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 using a combination of transcellular and paracellular pathways (Fig. 38-4). For the transcellular pathway, the TAL cell takes up Na+ and Clthrough 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 through the tight junctions. Using these two pathways, the TAL can generate a single effect as large as 200 mOsm.


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: Prog Cardiovasc Dis 1961; 3:395-431.)

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] occurs—owing to the pumping of NaCl out of the TAL (see Chapter 35)—that is largely responsible for producing the hypertonicity. 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 (Fig. 38-4) is the result of the unique water and urea permeabilities of the collecting tubules and ducts (Fig. 38-2A).

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 to levels higher than 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 ClC-K1 channel is selectively localized to the tALH (overt diabetes insipidus [DI] in ClCK1 knockout mice). At the tip of the papilla interstitial [Na+] and [Cl] are each ~300 mM (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 caused by a favorable urea gradient and by 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 inner medullary collecting duct reabsorbs urea and produces 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 protein-rich diets. Indeed, investigators have long known that the higher the dietary protein content, the greater is the concentrating ability.

Urea Handling The renal handling of urea is complex (see Chapter 36). The kidney filters urea in the glomerulus and reabsorbs about half in the proximal tubule. In juxtamedullary nephrons, the tDLH and the tALH secrete urea into the tubule lumen. Finally, the IMCD reabsorbs urea. 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 60% or more (maximal urine flow). Because we are interested in understanding the role of urea in establishing a hypertonic 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.


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 single red box indicates the fraction of the filtered load secreted by the tALH, and the single 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 after these segments. The values in the boxes are approximations. (See Note: Urea Reabsorption in the Distal Nephron)

As the tubule fluid enters the TAL, the [urea] is severalfold 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 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 (through the urea transporter UT-A1; see Chapter 36) and basolateral membrane (through UT-A3) promote the outward facilitated diffusion of urea from the IMCD lumen, through the IMCD cells, and into the medullary interstitium. 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 through a 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 tDHL and tALH of juxtamedullary (i.e., long-loop) nephrons. This concentration gradient drives urea into the tDLH through UTA-2 and into the tALH through an as-yet unidentified transporter. 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 earlier, [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, (2) secretion of urea from interstitium into the thin limbs, and (3) delivery of urea up into the cortex and back down through 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, 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 mechanism and relatively low blood flow minimize the washout of the medullary hypertonicity

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 hypertonicity that is critical for concentrating urine. Figure 38-6A shows a hypothetical, poorly designed 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, thus reflecting a loss of water or a gain of solutes. Because these movements occur at the expense of the medullary interstitium, the interstitium’s hyperosmolality would be washed out into the blood. The greater the blood flow through this straight/unlooped blood vessel, the greater the medullary washout would be.


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), thus 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 hypertonic 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 by 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 to the medulla and the need to avoid washout of medullary hypertonicity.

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, thus creating an efficient countercurrent exchange mechanism (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] (Fig. 38-4A). 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 through facilitated diffusion, mediated by the UT-B1 and UT-B2 urea transporter (see Chapter 36). 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 cause the descending vasa recta to gain solute and lose water, but they cause the ascending vessels to lose solute and gain water. Thus, at any level, the descending and ascending vessels exchange solutes and water through—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. (See Note: Anatomic Arrangements between Vasa Recta and Thin Limbs in the Medulla)

The total mass of solute and water leaving the medulla each minute through the ascending vasa recta must exceed the total inflow of solute and water into the medulla through 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, and in the steady state most of this leaves the interstitium by way of the tALH (Fig. 38-5, red box). The blood of the vasa recta carries away the balance or excess urea (Fig. 38-5, brown box). The blood also carries off the excess NaCl that enters the interstitium from the ascending limb of the loop of Henle and, to some extent, from the MCDs.

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 gives up water to the medullary interstitium as the tubule fluid becomes more concentrated. Therefore, in the steady state, the ascending vasa recta must also remove 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. Although no precise measurements have been made, it is likely that the 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 medullary collecting duct produces concentrated urine by osmosis, driven by the osmotic gradient between the medullary interstitium and the lumen

In contrast to the loop of Henle, which acts as a countercurrent multiplier, and the loop-shaped vasa recta, which act as a countercurrent exchanger, the MCD is 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.


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.

Thus, the presence of urea per se in the lumen of the collecting tubules and ducts is actually a handicap for the osmotic concentration of the urine, because the luminal urea tends to pull water back into the tubule lumen. Fortunately, the IMCD partially compensates for this problem by having a relatively low reflection coefficient for urea (Σurea), thus converting any transepithelial difference in urea concentration into a smaller difference in effective osmotic pressure (see Chapter 20). The Σ for urea is 0.74, whereas that for NaCl is 1.0. Thus, water reabsorption continues in the IMCD even though [urea] in tubule fluid exceeds that in the interstitium. The combination of a high interstitial [NaCl] and high ΣNaCl promotes NaCl-driven water absorption. A low Σurea minimizes urea-driven water secretion.

The kidney also compensates for having a high [urea] in the lumen of the MCDs by having a high interstitial [urea], which—to some extent—osmotically balances the urea in the lumen of the papillary collecting ducts. Were it not for urea accumulation in the medullary interstitium, interstitial [NaCl] would have to be much higher, and this, in turn, would require increased NaCl transport in the TAL.

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 known. 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 for excreting nitrogenous waste. Second, as we have already seen, the kidney actually takes advantage of urea to generate maximally concentrated urine. Thus, 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, 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 hypotonic, so that a larger osmotic gradient exists 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 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.

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

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

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

5. 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.

6. Pathophysiology: Central DI reduces plasma AVP levels, whereas nephrogenic DI reduces renal responsiveness to AVP (see the box titled Diabetes Insipidus).


Large-bodied neurons in the paraventricular and supraoptic nuclei of the hypothalamus synthesize AVP, a nonapeptide also known as ADH. These neurons package the AVP and transport it along their axons to the posterior pituitary, where they release AVP through a breech in the blood-brain barrier into the systemic circulation (see p. 875). In Chapter 40, we discuss how increased plasma osmolality and decreased effective circulating volume increase AVP release. AVP has synergistic effects on two target organs. First, at rather high circulating levels, such as those seen in hypovolemic shock, AVP acts on vascular smooth muscle to cause vasoconstriction (see Chapter 23) and thus to increase blood pressure. Second, and more importantly, AVP acts on the kidney, where it is the major regulator of water excretion. AVP increases water reabsorption by enhancing the water permeabilities of the collecting tubules and ducts and also by stimulating urea transport across the cells of the IMCD.

AVP increases water permeability in all nephron segments beyond the distal convoluted tubule

Of the water remaining in the DCT, the kidney reabsorbs a variable fraction in the segments from the ICT to the end of the nephron. Absorption of this final fraction of water is under the control of circulating AVP. In the kidney, AVP (1) increases water permeability in all the segments beyond the DCT, (2) increases urea permeability in the IMCD, and (3) increases active NaCl reabsorption in the TAL.

Figure 38-8 summarizes the water permeability of various nephron segments. The water permeability is highest in the proximal tubule and tDHL. The high water permeability in these segments reflects the abundant presence of AQP1 water channels (see Chapter 3) in the apical and basolateral cell membranes.


Figure 38-8 Water permeability in different nephron segments. Note that the x-axis scale is logarithmic. (From Knepper MA, Rector FC: In Brenner BM [ed]: The Kidney, pp 532-570. Philadelphia: WB Saunders, 1996.)

In marked contrast to the proximal tubule and tDLH, the following few segments—from the tALH to the connecting tubule—have very low water permeabilities. In the absence of AVP, the next tubule segments, the ICT and CCT, have rather low water permeabilities, whereas the MCDs are virtually impermeable to water. However, AVP dramatically increases the water permeabilities of the collecting tubules (ICT and CCT) and ducts (OMCD and IMCD) by causing AQP2 water channels to insert into the apical membrane (see later). A third type of water channel, AQP3, is present in the basolateral cell membranes of MCDs. Like AQP1, AQP3 is insensitive to AVP.

Given the favorable osmotic gradients discussed in the preceding subchapter, high levels of AVP cause substantial water reabsorption to occur in AVP-sensitive nephron segments. In contrast, when circulating levels of AVP are low, for instance after ingestion of large amounts of water, the water permeability of these nephron segments remains low. Therefore, the fluid leaving the DCT remains hypotonic as it flows down more distal nephron segments. In fact, in the absence of AVP, continued NaCl absorption makes the tubule fluid even more hypotonic, resulting in a large volume of dilute urine (Fig. 38-1).

AVP, acting through cAMP, causes vesicles containing aquaporin 2 water channels to fuse with the apical membrane of principal cells of the collecting tubules and ducts

AVP binds to V2 receptors in the basolateral membrane of the principal cells from the ICT to the end of the nephron (Fig. 38-9). Receptor binding activates the Gs heterotrimeric G protein, thus stimulating adenylyl cyclase to generate cAMP (see Chapter 3). The latter activates protein kinase A, which phosphorylates unknown proteins that play a role in the trafficking of intracellular vesicles containing AQP2 and the fusion of these vesicles with the apical membrane. These water channels are AVP sensitive, not in the sense that AVP modulates their single-channel water conductance, but rather in the context of their density in the apical membrane. In conditions of low AVP, AQP2 water channels are mainly in the membrane of intracellular vesicles just beneath the apical membrane. In the membrane of these vesicles, the AQP2 water channels are present as aggregophores—aggregates of AQP2 proteins. Under the influence of AVP, the vesicles containing AQP2 move to the apical membrane of principal cells of the collecting tubules and ducts. By exocytosis (see Chapter 2), these vesicles fuse with the apical membrane, thus increasing the density of AQP2. When AVP levels in the blood decline, endocytosis retrieves the water channel–containing aggregates from the apical membrane and shuttles them back to the cytoplasmic vesicle pool. (See Note: Multiple Effects of AVP on AQP2 Activity)


Figure 38-9 Cellular mechanism of AVP action in the collecting tubules and ducts.

The apical water permeability of principal cells depends not only on AVP levels, but also on certain other factors. For example, high [Ca2+]i and high [Li+] both inhibit adenylyl cyclase, thus decreasing [cAMP]i, reducing water permeability, and producing a diuresis. A similar inhibition of AQP2 insertion, and hence a decrease in water permeability, occurs when agents such as colchicine disrupt the integrity of the cytoskeleton. Conversely, inhibitors of phosphodiesterase (e.g., theophylline), which increase [cAMP]i, tend to increase the osmotic water permeability.

AVP enhances the urinary-concentrating mechanism by stimulating the urea transporter UT-A1 in the inner medullary collecting ducts, thus increasing urea reabsorption

AVP promotes water reabsorption not only by increasing the water permeability of the collecting tubules and ducts, but also by enhancing the osmotic gradients across the walls of the inner and perhaps the OMCD. In the outermedulla, AVP acts through the cAMP pathway to increase NaCl reabsorption by the TAL. AVP acts by stimulating apical Na/K/Cl cotransport and K+ recycling across the apical membrane (see Chapter 35). The net effect is to increase the osmolality of the outer medullary interstitium and thus enhance the osmotic gradient favoring water reabsorption by the OMCD. In addition, AVP stimulates the growth of TAL cells in animals that are genetically devoid of AVP. This hormone also stimulates Na+ reabsorption in the CCT, largely by activating apical Na+ channels (ENaC). These observations on the TAL and CCT were all made on rodents. In humans, these TAL and CCT mechanisms may have only minor significance.

In the inner medulla, AVP enhances the urea permeability of the terminal two thirds of the IMCD. The AVP-dependent increase in [cAMP]i that triggers the apical insertion of AQP2-containing vesicles also leads to a phosphorylation of apical UT-A1 urea transporters (see Chapter 36), increasing their activity. The results are a substantial increase in urea reabsorption and thus the high interstitial [urea] that is indirectly responsible for generating the osmotic gradient that drives water reabsorption in the inner medulla.

Segments of the nephron other than the IMCD have varying degrees of urea permeability. However, AVP increases urea permeability only in the apical membrane of the IMCD. In particular, AVP has no effect on other urea transporters: UT-A2 (in tDLH), UT-B1/B2 (in vasa recta), or UT-A3 (basolateral membrane of the IMCD).

Diabetes Insipidus

DI is a fairly rare disorder that occurs in two varieties. The first, neurogenic or central DI, is caused by failure of AVP secretion. The lesion can be either at the level of the hypothalamus (where neurons synthesize AVP) or in the pituitary gland (where neurons release AVP). Central DI can be idiopathic, familial, or caused by any disorder of the hypothalamus or pituitary, such as injury, a tumor, infection, or autoimmune processes. In the second variety, nephrogenic DI, the kidneys respond inadequately to normal or even elevated levels of circulating AVP. Nephrogenic DI can also be idiopathic or familial and may be associated with electrolyte abnormalities (e.g., states of K+ depletion or high plasma [Ca2+]), the renal disease associated with sickle cell anemia, and various drugs (notably Li+ and colchicine).

In both central and nephrogenic DI, patients present with polyuria and polydipsia. If allowed to progress unchecked, the disorder can result in marked hypernatremia, hypotension, and shock. Often the physician first suspects the diagnosis when the patient is deprived of access to water or other fluids. The patient may then quickly become dehydrated, and a random determination of plasma [Na+] may yield a very high value.

The physician can confirm the diagnosis of DI most easily by a fluid deprivation test. The patient will continue to produce a large output of dilute urine, despite the need to conserve fluids. If the patient has central DI, administering a subcutaneous dose of AVP will rapidly increase urine osmolality by more than 50%. In patients with nephrogenic DI, conversely, the increase in urine osmolality will be less. Simultaneous measurements of plasma AVP levels may confirm the diagnosis.

The treatment for central DI is desmopressin acetate (DDAVP) (see Fig. 56-10), a synthetic AVP analogue that patients can take intranasally. Nephrogenic DI, in which the kidneys are resistant to the effects of the hormone, does not respond to DDAVP. In these patients, it is best to treat the underlying disease and also to reduce the elevated plasma [Na+] by administering a diuretic (to produce natriuresis) and by restricting dietary Na+.

The high urine flow in DI is associated with low rates of solute excretion. Therefore, the physician must distinguish DI from states of polyuria accompanied by high rates of solute excretion in the urine (osmotic diuresis). The most frequent cause is chronic renal failure, when a decreasing population of nephrons is charged with excreting the daily load of solutes or other renal diseases associated with compromised proximal fluid and solute transport. Polyuria with excretion of solute-rich urine also occurs in untreated diabetes mellitus. In that case, the polyuria occurs because the high plasma [glucose] leads to the filtration of an amount of glucose that exceeds the capacity of the proximal tubule to retrieve it from the lumen (see Chapter 36). A third cause of osmotic diuresis is the administration of poorly reabsorbable solutes, such as mannitol or HCO3.

In an entirely distinct class of polyurias is primary polydipsia, a psychoneurotic disorder in which patients drink large amounts of fluid. Whereas simple water deprivation benefits a patient with primary polydipsia, it aggravates the condition of a patient with DI.

Role of Aquaporins in Renal Water Transport

Whereas AQP1 is the water channel responsible for a large amount of transcellular fluid movement in the proximal tubule and the tDLH, three related isoforms of the water channel protein—AQP2, AQP3, and AQP4—are present in the principal cells of the collecting ducts. These channels regulate water transport in collecting tubules and ducts. Apical AQP2 is the basis for AVP-regulated water permeability. AQP3 and AQP4 are present in the basolateral membrane of principal cells, where they provide an exit pathway for water movement into the peritubular fluid.

Short-term and long-term regulation of water permeability depends on an intact AQP2 system. In short-term regulation, AVP—through cAMP—causes water channel–containing vesicles from a subapical pool to fuse with the apical membrane (Fig. 38-9). As a result, the number of channels and the water permeability sharply increase. In long-term regulation, AVP—by enhancing transcription of the AQP2 gene—increases the abundance of AQP2 protein in principal cells.

Mutations of several AQP genes lead to loss of function and marked abnormalities of water balance. Examples include sharply decreased fluid absorption along the proximal tubule in AQP1 knockout animals and nephrogenic DI (see the box on this topic) in patients with mutations of the gene for AQP2. An interesting situation may develop during the third trimester of pregnancy, when elevated plasma levels of vasopressinase—a placental aminopeptidase that degrades AVP—may lead to a clinical picture of central DI.

An acquired increase of AQP2 expression often accompanies states of abnormal fluid retention, such as congestive heart failure, hepatic cirrhosis, the nephrotic syndrome, and pregnancy. Some conditions—including acute and chronic renal failure, primary polydipsia, a low-protein diet, and SIADH (see the box titled Syndrome of Inappropriate Antidiuretic Hormone Secretion)—are associated with increased AQP2 levels in the apical membrane.

Syndrome of Inappropriate Antidiuretic Hormone Secretion

The syndrome of inappropriate ADH secretion (SIADH) is the opposite of DI. Patients with SIADH secrete levels of ADH (i.e., AVP) or AVP-like substances that are inappropriately high, given the plasma osmolality. Thus, the urine osmolality is inappropriately high as the kidneys salvage inappropriately large volumes of water from the urine. As a result, total body water increases, the blood becomes hypo-osmolar, plasma [Na+] drops (hyponatremia), and cells swell. If plasma [Na+] falls substantially, cell swelling can cause headaches, nausea, vomiting, and behavioral changes. Eventually, stupor, coma, and seizures may ensue.

Before making the diagnosis of SIADH, the physician must rule out other causes of hyponatremia in which AVP levels may be appropriate. In Chapter 40, we discuss how plasma osmolality and effective circulating volume appropriately regulate AVP secretion. SIADH has four major causes:

1. Certain malignant tumors (e.g., bronchogenic carcinoma, sarcomas, lymphomas, and leukemias) release AVP or AVP-like substances.

2. Cranial disorders (e.g., head trauma, meningitis, and brain abscesses) can increase AVP release.

3. Nonmalignant pulmonary disorders (e.g., tuberculosis, pneumonia, and abscesses) and positive-pressure ventilation also can cause SIADH. (See Note: Pulmonary Disorders Causing SIADH)

4. Several drugs can either stimulate AVP release (e.g., clofibrate, phenothiazines), increase the sensitivity of renal tubules to AVP (e.g., chlorpropamide), or both (e.g., carbamazepine).

Treatment is best directed at the underlying disorder, combined, if necessary and clinically appropriate, with fluid restriction. Patients with a plasma [Na+] <110 mM must receive urgent attention. Infusing hypertonic Na+ is usually effective, but the correction must be gradual or severe neurologic damage can result owing to rapid changes in the volume of neurons, especially in the pontine area of the brainstem.


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