Physiology 5th Ed.

WATER BALANCE—CONCENTRATION AND DILUTION OF URINE

Body fluid osmolarity is maintained at a value of about 290 mOsm/L (for simplicity, 300 mOsm/L) by processes called osmoregulation. Even small deviations in body fluid osmolarity produce a set of hormonal responses that alter water reabsorption by the kidneys, attempting to return osmolarity back toward the normal value. These renal mechanisms for water reabsorption are responsible for maintaining constant body fluid osmolarity. As with other renal regulatory mechanisms, control of water balance is exerted at the level of the late distal tubule and collecting duct.

Variations in water reabsorption produce variations in urine osmolarity. Urine osmolarity can vary from as low as 50 mOsm/L to as high as 1200 mOsm/L. The following descriptors are used to describe urine osmolarity: When urine osmolarity is equal to blood osmolarity, it is called isosmotic urine. When urine osmolarity is higher than blood osmolarity, it is called hyperosmotic urine. When urine osmolarity is lower than blood osmolarity, it is called hyposmotic urine.

Regulation of Body Fluid Osmolarity

The regulation of body fluid osmolarity is best illustrated by two commonplace examples. The first example is the body’s response to water deprivation; the second is the body’s response to drinking water.

Response to Water Deprivation

Figure 6-36 shows the events that occur when a person is deprived of drinking water (e.g., person is lost in the desert for 12 hours with no source of drinking water). The circled numbers in the figure correlate with the following steps:

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Figure 6–36 Responses to water deprivation. See the text for an explanation of the circled numbers. ADH, Antidiuretic hormone.

1.          Water is continuously lost from the body in sweat and in water vapor from the mouth and nose (called insensible water loss). If this water is not replaced by drinking water, then plasma osmolarity increases.

2.          The increase in osmolarity stimulates osmoreceptors in the anterior hypothalamus, which are exquisitely sensitive and are stimulated by increases in osmolarity of less than 1 mOsm/L.

3.          Stimulation of the hypothalamic osmoreceptors has two effects. It stimulates thirst, which drives drinking behavior. It also stimulates secretion of ADH from the posterior pituitary gland.

4.          The posterior pituitary gland secretes ADH. ADH circulates in the blood to the kidneys, where it produces an increase in water permeability of the principal cells of the late distal tubule and collecting duct.

5.          The increase in water permeability results in increased water reabsorption (5a) in the late distal tubule and collecting ducts. As more water is reabsorbed by these segments, urine osmolarity increasesand urine volume decreases (5b).

6.          Increased water reabsorption means that more water is returned to the body fluids. Coupled with increased thirst and drinking behavior, plasma osmolarity is decreased, back toward the normal value. This system is an elegant example of negative feedback, in which the original disturbance (increased plasma osmolarity) causes a set of feedback responses (secretion of ADH and increased water reabsorption) that restore plasma osmolarity to its normal value.

Response to Water Drinking

Figure 6-37 shows the series of events that occur when a person drinks water. These responses will be easy to understand because they are the exact opposite of those described for water deprivation. Again, the circled numbers in the figure correspond to the following steps:

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Figure 6–37 Responses to water drinking. See the text for an explanation of the circled numbers. ADH, Antidiuretic hormone.

Video: Countercurrent multiplier

1.          When a person drinks water, the ingested water is distributed throughout the body fluids. Because the amount of solute in the body is unchanged, the added water will dilute the body fluids and cause a decrease in plasma osmolarity.

2.          The decrease in plasma osmolarity inhibits osmoreceptors in the anterior hypothalamus.

3.          Inhibition of the osmoreceptors has two effects. It decreases thirst and suppresses water drinking behavior. It also inhibits secretion of ADH from the posterior pituitary gland.

4.          When ADH secretion is inhibited, circulating levels of ADH are reduced and less ADH is delivered to the kidneys. As a result of the lower ADH levels, there is a decrease in water permeability of the principal cells of the late distal tubule and collecting ducts.

5.          The decrease in water permeability results in decreased water reabsorption by the late distal tubule and collecting ducts (5a). The water that is not reabsorbed by these segments is excreted, decreasing urine osmolarity and increasing urine volume (5b).

6.          Because less water is reabsorbed, less water is returned to the circulation. Coupled with the inhibition of thirst and the suppression of water drinking, plasma osmolarity increases back toward the normal value.

Corticopapillary Osmotic Gradient

To understand how the kidneys participate in osmoregulation, it is first necessary to appreciate the creation and role of the corticopapillary osmotic gradient. Descriptively, it is a gradient of osmolarity in the interstitial fluid of the kidney from the cortex to the papilla (see Fig. 6-1 for anatomic divisions of the kidney). The osmolarity of the cortex is approximately 300 mOsm/L, similar to the osmolarity of other body fluids. Moving from the cortex to the outer medulla, inner medulla, and papilla, the interstitial fluid osmolarity progressively increases. At the tip of the papilla, the osmolarity can be as high as 1200 mOsm/L.

The question arises as to the origin of the corticopapillary osmotic gradient. What solutes contribute to the osmotic gradient, and what mechanisms deposit these solutes in the interstitial fluid? The answers can be found in two processes: countercurrent multiplication, a function of the loop of Henle, which deposits NaCl in the deeper regions of the kidney; and urea recycling, a function of the inner medullary collecting ducts, which deposits urea.

Countercurrent Multiplication

Countercurrent multiplication is a function of the loop of Henle. Its role in the formation of the corticopapillary osmotic gradient is to deposit NaCl in the interstitial fluid of the deeper regions of the kidney.Figure 6-38 shows a single loop of Henle and the process of countercurrent multiplication, explained subsequently in a stepwise fashion. For didactic purposes, the loop of Henle is initially shown with no corticopapillary gradient; osmolarity is 300 mOsm/L throughout the loop and in the surrounding interstitial fluid. Countercurrent multiplication will build up a gradient of osmolarity in the interstitial fluid through a repeating two-step process. The first step is called the single effect, and the second step is the flow of tubular fluid.

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Figure 6–38 Mechanism of countercurrent multiplication in a loop of Henle. See the text for an explanation of the circled numbers; numbers are osmolarities of tubular fluid or interstitial fluid; arrows show the direction of fluid flow; heavy outline shows water impermeability of the ascending limb.

SINGLE EFFECT

The single effect refers to the function of the thick ascending limb of the loop of Henle. In the thick ascending limb, NaCl is reabsorbed via the Na+-K+-2Clcotransporter. Because the thick ascending limb is impermeable to water, water is not reabsorbed along with NaCl, thereby diluting the tubular fluid in the ascending limb. The NaCl, which is transported out of the thick ascending limb, enters the interstitial fluid, increasing its osmolarity. Because the descending limb is permeable to water, water flows out of the descending limb until its osmolarity increases to the level of the adjacent interstitial fluid. Thus, as a result of the single effect, the osmolarity of the ascending limb decreases and the osmolarities of the interstitial fluid and the descending limb increase. ADH increases the activity of Na+-K+-2Cl cotransporter and, therefore, enhances the single effect. For example, in conditions where circulating levels of ADH are high (e.g., dehydration), the corticopapillary osmotic gradient is augmented; in conditions where circulating levels of ADH are low (e.g., central diabetes insipidus), the corticopapillary osmotic gradient is diminished.

FLOW OF TUBULAR FLUID

Since glomerular filtration is an ongoing process, fluid flows continuously through the nephron. As new fluid enters the descending limb from the proximal tubule, an equal volume of fluid must leave the ascending limb and enter the distal tubule. The new fluid that enters the descending limb will have an osmolarity of 300 mOsm/L because it has come from the proximal tubule. At the same time, the high osmolarity fluid in the descending limb (created by the single effect) is pushed down toward the bend of the loop of Henle.

The two-step process for establishing the corticopapillary osmotic gradient is illustrated in Figure 6-37. Again, in the initial state, the loop of Henle and the surrounding interstitial fluid have no corticopapillary osmotic gradient. The circled numbers on the figure correlate with the following steps involved in creating the gradient:

1.          Step 1 is the single effect. As NaCl is reabsorbed out of the ascending limb and deposited in the surrounding interstitial fluid, water is left behind in the ascending limb. As a result, interstitial fluid osmolarity increases to 400 mOsm/L and the fluid in the ascending limb is diluted to 200 mOsm/L. Fluid in the descending limb equilibrates with the interstitial fluid, and its osmolarity also becomes 400 mOsm/L.

2.          Step 2 is the flow of fluid. New fluid with an osmolarity of 300 mOsm/L enters the descending limb from the proximal tubule, and an equal volume of fluid is displaced from the ascending limb. As a result of this fluid shift, the high osmolarity fluid in the descending limb (400 mOsm/L) is “pushed down” toward the bend of the loop of Henle. Even at this early stage, you can see that the corticopapillary osmotic gradient is beginning to develop.

3.          Step 3 is the single effect again. NaCl is reabsorbed out of the ascending limb and deposited in interstitial fluid, and water remains behind in the ascending limb. The osmolarity of the interstitial fluid and descending limb fluid increases, adding to the gradient that was established in the previous steps. The osmolarity of the fluid of the ascending limb decreases further (is diluted).

4.          Step 4 is the flow of fluid again. New fluid with an osmolarity of 300 mOsm/L enters the descending limb from the proximal tubule, which displaces fluid from the ascending limb. As a result of the fluid shift, the high osmolarity fluid in the descending limb is pushed down toward the bend of the loop of Henle. The gradient of osmolarity is now larger than it was in step 2.

These two basic steps are repeated until the full corticopapillary gradient is established. As shown in Figure 6-38, each repeat of the two steps increases, or multiplies, the gradient. The size of the corticopapillary osmotic gradient depends on the length of the loop of Henle. In humans, the osmolarity of interstitial fluid at the bend of the loop of Henle is 1200 mOsm/L, but in species with longer loops of Henle (e.g., desert rodents), the osmolarity at the bend can be as high as 3000 mOsm/L.

Urea Recycling

Urea recycling from the inner medullary collecting ducts is the second process that contributes to the establishment of the corticopapillary osmotic gradient. The mechanism of urea recycling is explained inFigure 6-39. The circled numbers on the figure correlate with the following steps:

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Figure 6–39 Mechanism of urea recycling from inner medullary collecting ducts. See the text for an explanation of the circled numbers. ADH, Antidiuretic hormone; [TF], tubular fluid concentration; UT1, urea transporter 1.

1.          In the cortical and outer medullary collecting ducts, ADH increases water permeability, but it does not increase urea permeability. As a result, water is reabsorbed from the cortical and outer medullary collecting ducts, but urea remains behind in the tubular fluid.

2.          This differential effect of ADH on water and urea permeability in cortical and outer medullary collecting ducts causes the urea concentration of tubular fluid to increase.

3.          In the inner medullary collecting ducts, ADH increases water permeability and it increases the transporter for facilitated diffusion of urea, UT1 (in contrast to its effect on only water permeability in cortical and outer medullary collecting ducts).

4.          Because the urea concentration of tubular fluid has been elevated by reabsorption of water in the cortical and outer medullary collecting ducts, a large concentration gradient has been created for urea. In the presence of ADH, the inner medullary collecting ducts can transport urea, and urea diffuses down its concentration gradient into the interstitial fluid. Urea that would have otherwise been excreted is recycled into the inner medulla, where it is added to the corticopapillary osmotic gradient.

As implied in the mechanism, urea recycling also depends on ADH. When ADH levels are high, as in water deprivation, the differential permeability effects occur and urea is recycled into the inner medulla, adding to the corticopapillary osmotic gradient. When ADH levels are low, as in water drinking or in central diabetes insipidus, the differential permeability effects do not occur and urea is not recycled. The positive effect of ADH on urea recycling is the second mechanism by which ADH augments the corticopapillary osmotic gradient (the first is stimulation of Na+-K+-2Cl cotransport and the single effect of countercurrent multiplication). Thus, the corticopapillary osmotic gradient is larger when ADH levels are high (e.g., water deprivation, SIADH) than when ADH levels are low (e.g., water drinking, central diabetes insipidus).

Vasa Recta

The vasa recta are capillaries that serve the medulla and papilla of the kidney. The vasa recta follow the same course as the loop of Henle and have the same hairpin (U) shape. Only 5% of the renal blood flow serves the medulla, and blood flow through the vasa recta is especially low.

The vasa recta participate in countercurrent exchange, which differs from countercurrent multiplication as follows: Countercurrent multiplication, as described, is an active process that establishes the corticopapillary osmotic gradient. Countercurrent exchange is a purely passive process that helps maintain the gradient. The passive properties of the vasa recta are the same as for other capillaries: They are freely permeable to small solutes and water. Blood flow through the vasa recta is slow, and solutes and water can move in and out, allowing for efficient countercurrent exchange.

Countercurrent exchange is illustrated schematically in Figure 6-40. The figure shows a single vasa recta, with its descending limb and ascending limb. Blood entering the descending limb has an osmolarity of 300 mOsm/L. As this blood flows down the descending limb, it is exposed to interstitial fluid with increasingly higher osmolarity (the corticopapillary osmotic gradient). Because the vasa recta are capillaries, small solutes such as NaCl and urea diffuse into the descending limb and water diffuses out, allowing blood in the descending limb of the vasa recta to equilibrate osmotically with the surrounding interstitial fluid. At the bend of the vasa recta, the blood has an osmolarity equal to that of interstitial fluid at the tip of the papilla, 1200 mOsm/L. In the ascending limb, the opposite events occur. As blood flows up the ascending limb, it is exposed to interstitial fluid with decreasing osmolarity. Small solutes diffuse out of the ascending limb and water diffuses in, and the blood in the ascending limb of the vasa recta equilibrates with the surrounding interstitial fluid.

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Figure 6–40 Countercurrent exchange in the vasa recta. Solid dark blue arrows show the direction of solute movement; dashed green arrows show the direction of water movement; thick light blue arrows show blood flow through the vasa recta; numbers are osmolarity in mOsm/L.

In Figure 6-40, notice that the blood leaving the vasa recta has an osmolarity of 325 mOsm/L, which is slightly higher than the osmolarity of the original blood that entered it. Some of the solute from the corticopapillary osmotic gradient was picked up and will be carried back to the systemic circulation. With time, this process could dissipate the corticopapillary osmotic gradient. The gradient normally does not dissipate, however, because the mechanisms of countercurrent multiplication and urea recycling continuously replace any solute that is carried away by blood flow.

Antidiuretic Hormone

As described in the preceding section, ADH has three actions on the renal tubule. (1) It increases the water permeability of the principal cells of the late distal tubule and collecting ducts. (2) It increases the activity of the Na+-K+-2Cl cotransporter of the thick ascending limb, thereby enhancing countercurrent multiplication and the size of the corticopapillary osmotic gradient. (3) It increases urea permeability in the inner medullary collecting ducts (but not in the cortical or outer medullary collecting ducts), enhancing urea recycling and the size of the corticopapillary osmotic gradient.

Of these actions, the effect on water permeability of the principal cells is the best known and physiologically is the most important. In the absence of ADH, the principal cells are impermeable to water. In the presence of ADH, water channels, or aquaporins, are inserted in the luminal membrane of the principal cells, making them permeable to water. The following steps are involved in the action of ADH on the principal cells (Fig. 6-41). These steps correspond to the circled numbers in the figure:

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Figure 6–41 Cellular mechanism of action of antidiuretic hormone in the principal cell of the late distal tubule and collecting duct. See the text for an explanation of the circled numbers. AC, Adenylyl cyclase; ADH, antidiuretic hormone; AQP2, aquaporin 2; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate, or cyclic AMP; Gs, stimulatory G protein; R, V2 receptor.

1. When circulating levels of ADH are high, ADH is delivered to the principal cells via the peritubular capillary blood. V2 receptors for ADH, present in the basolateral membrane, are coupled to adenylyl cyclase via a stimulatory G protein (Gs).

2. When ADH binds to the receptors, adenylyl cyclase is activated and catalyzes the conversion of ATP to cAMP.

3. and 4. cAMP activates protein kinase A. Activated protein kinase A then causes phosphorylation of intracellular structures. The identity of these structures is uncertain, although possibilities include microtubules and microfilaments, which are involved in intracellular shuttling mechanisms.

5. and 6. After the phosphorylation step, vesicles containing water channels are shuttled to and inserted into the luminal membrane of the principal cell, thus increasing its water permeability. The specific water channel that is controlled by ADH is aquaporin 2 (AQP2). Using freeze-fracture electron microscopy, the water channels in the luminal membrane can be visualized in clusters calledintramembranous particles. The presence and number of intramembranous particle clusters correlate with the presence and magnitude of water permeability of principal cells, suggesting that the particle clusters are an anatomic representation of the water channels.

Production of Hyperosmotic Urine

By definition, hyperosmotic, or concentrated, urine has an osmolarity that is higher than blood osmolarity. Hyperosmotic urine is produced when the circulating levels of ADH are high, as occurs in water deprivation or in SIADH. The mechanisms are shown in Figure 6-42.

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Figure 6–42 Mechanisms for production of hyperosmotic (concentrated) urine in the presence of antidiuretic hormone (ADH). Arrows show location of water reabsorption; heavy outline shows water-impermeable portions of the nephron; numbers are osmolarity of tubular fluid or interstitial fluid.

Steps in Production of Hyperosmotic Urine

Before the mechanism is described in detail, a few general comments should be made about the format of Figure 6-42. The numbers on the figure give the osmolarity at various points along the nephron and in the interstitial fluid. The heavily outlined portion of the thick ascending limb and early distal tubule indicates that these segments are impermeable to water. The arrows represent water reabsorption in different segments of the nephron.

Note that the initial glomerular filtrate has the same osmolarity as the blood, 300 mOsm/L, but the urine osmolarity is much higher (1200 mOsm/L) than blood osmolarity. Notice also that the corticopapillary osmotic gradient is in place, having been established by the ongoing processes of countercurrent multiplication and urea recycling. The two basic questions concerning formation of hyperosmotic urine are,How does the kidney produce urine that is more concentrated than blood, and what determines how high the urine osmolarity will be? The following steps are involved in producing hyperosmotic urine:

1.          The osmolarity of glomerular filtrate is identical to that of blood, 300 mOsm/L, because water and small solutes are freely filtered. The osmolarity remains at 300 mOsm/L along the entire proximal convoluted tubule, even though a significant volume of water is reabsorbed. This occurs because water is always reabsorbed in exact proportion to solute; that is, the process is isosmotic. The isosmotic process also can be expressed in terms of [TF/P]osm: In glomerular filtrate, [TF/P]osm = 1.0 and remains constant along the proximal tubule.

2.          In the thick ascending limb of the loop of Henle, NaCl is reabsorbed via the Na+-K+-2Cl cotransporter. However, because the cells of the thick ascending limb are impermeable to water, water reabsorption cannot accompany solute reabsorption. As solute is reabsorbed, water is left behind and the tubular fluid is diluted. The osmolarity of tubular fluid leaving this segment is 100 mOsm/L. Thus, the thick ascending limb also is called the diluting segment.

3.          In the early distal tubule, NaCl is reabsorbed by an Na+-Cl cotransporter. Like the thick ascending limb, cells of the early distal tubule are impermeable to water and water reabsorption cannot follow solute reabsorption. Here, the osmolarity of tubular fluid becomes even more dilute, as low as 80 mOsm/L. Thus, the early distal tubule also is called the cortical diluting segment (cortical because the distal tubule is located in the cortex, rather than in the medulla where the thick ascending limb is found).

4.          In the late distal tubule, the principal cells are permeable to water in the presence of ADH. Recall that the fluid entering the late distal tubule is quite dilute, 80 mOsm/L. Because the cells are now permeable to water, water flows out of the tubular fluid by osmosis, driven by the osmotic gradient across the cells (i.e., is reabsorbed). Water reabsorption will continue until the tubular fluid equilibrates osmotically with the surrounding interstitial fluid. The tubular fluid leaving the distal tubule is equilibrated with the interstitial fluid of the cortex, and it has an osmolarity of 300 mOsm/L.

5.          In the collecting ducts, the mechanism is the same as that described for the late distal tubule. The principal cells of the collecting ducts are permeable to water in the presence of ADH. As tubular fluid flows down the collecting ducts, it is exposed to interstitial fluid with increasingly higher osmolarity (i.e., the corticopapillary osmotic gradient). Water will be reabsorbed until the tubular fluid equilibrates osmotically with surrounding interstitial fluid. The final urine will reach the osmolarity present at the tip of the papilla, which, in this example, is 1200 mOsm/L.

The two questions about production of hyperosmotic urine have been answered. How is urine rendered hyperosmotic? Urine becomes hyperosmotic, in the presence of ADH, by equilibration of tubular fluid in the collecting ducts with the high osmolarity of the corticopapillary gradient. The corticopapillary osmotic gradient is established by countercurrent multiplication, a function of the loop of Henle, and by urea recycling, a function of the inner medullary collecting ducts. How high will the urine osmolarity be? Final urine osmolarity, in the presence of ADH, will be equal to the osmolarity at the bend of the loop of Henle (the tip of the papilla).

SIADH

As previously described, the appropriate response to water deprivation is production of hyperosmotic urine. However, in the syndrome of inappropriate ADH (SIADH), hyperosmotic urine is producedinappropriately (Table 6-10). In SIADH, circulating levels of the hormone ADH are abnormally high owing to either excessive secretion from the posterior pituitary following head injury or secretion of ADH from abnormal sites such as lung tumors. In these conditions, ADH is secreted autonomously, without an osmotic stimulus; in other words, ADH is secreted when it is not needed. In SIADH, the high levels of ADH increase water reabsorption by the late distal tubule and collecting ducts, making the urine hyperosmotic and diluting the plasma osmolarity. (Normally, a low plasma osmolarity would inhibit secretion of ADH; however, in SIADH, this feedback inhibition does not occur because ADH is secreted autonomously.) Treatment of SIADH consists of administration of a drug such as demeclocycline,which inhibits the ADH action on the renal principal cells.

Table 6–10 Antidiuretic Hormone Examples of Physiology and Pathophysiology

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ADH, Antidiuretic hormone; SIADH, syndrome of inappropriate antidiuretic hormone.

Production of Hyposmotic Urine

By definition, hyposmotic (dilute) urine has an osmolarity lower than blood osmolarity. Hyposmotic urine is produced when there are low circulating levels of ADH (e.g., water drinking, central diabetes insipidus) or when ADH is ineffective (e.g., nephrogenic diabetes insipidus). The mechanisms for the production of hyposmotic urine are shown in Figure 6-42.

Steps in Production of Hyposmotic Urine

The format of Figure 6-43 is similar to that of Figure 6-42. The numbers give the osmolarity, and the arrow shows water reabsorption. The heavily outlined portion indicates the nephron segments that are impermeable to water, which now include the thick ascending limb and the entire distal tubule and collecting duct. Notice that there is still a corticopapillary osmotic gradient, but it is smaller than in the presence of ADH (see Fig. 6-42). The smaller gradient can be understood from the positive effects that ADH has on countercurrent multiplication and on urea recycling. In the absence of ADH, these processes are diminished and the size of the corticopapillary osmotic gradient also is diminished. The basic questions about formation of hyposmotic urine are, How does the kidney produce urine that is less concentrated than blood, and what determines how low the urine osmolarity will be? The following steps are involved in producing hyposmotic urine:

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Figure 6–43 Mechanisms for production of hyposmotic (dilute) urine in the absence of antidiuretic hormone (ADH). Arrow shows location of water reabsorption; heavy outline shows water-impermeable portions of the nephron; numbers are osmolarity of tubular fluid or interstitial fluid.

1.          Reabsorption in the proximal tubule is not affected by ADH. Thus, in the absence of ADH, fluid is again reabsorbed isosmotically, tubular fluid osmolarity is 300 mOsm/L, and [TF/P]osm = 1.0.

2.          In the thick ascending limb of the loop of Henle, NaCl is reabsorbed via the Na+-K+-2Cl cotransporter. Water is not reabsorbed, however, because of the impermeability of this segment. Thus, the tubular fluid is diluted, and the fluid leaving the thick ascending limb has an osmolarity of 120 mOsm/L. Notice that this osmolarity is not quite as low as in the presence of ADH (see Fig. 6-41) because the dilution step is diminished in the absence of ADH (Na+-K+-2Cl cotransport is inhibited).

3.          In the early distal tubule, dilution continues. NaCl is reabsorbed by the Na+-Cl cotransporter, but the cells are impermeable to water. Thus, tubular fluid that leaves the early distal tubule has an osmolarity of 110 mOsm/L.

4.          The late distal tubule and collecting ducts exhibit the most dramatic and important differences when ADH is low or absent. These segments are now impermeable to water: As tubular fluid flows through them, no osmotic equilibration is possible. Although tubular fluid is exposed to the increasingly higher osmolarity of the corticopapillary osmotic gradient, water is not reabsorbed in response to the osmotic driving force. The final urine, which is not equilibrated with the osmolarity at the tip of the papilla, has an osmolarity of 75 mOsm/L. (Final urine osmolarity is even less than the tubular fluid osmolarity in the early distal tubule because the late distal tubule and collecting duct reabsorb some NaCl. In effect, the late distal tubule and collecting duct also become diluting segments.)

The two questions about production of hyposmotic urine have been answered. How is urine rendered hyposmotic? Tubular fluid is diluted in the “diluting segments,” which reabsorb NaCl without water. Osmotic equilibration does not occur in the collecting ducts in the absence of ADH, and the dilute urine is excreted. How low will urine osmolarity be? Final urine osmolarity will reflect the combined functions of all the diluting segments including the thick ascending limb and the early distal tubule, as well as the remainder of the distal tubule and collecting ducts.

Hyposmotic urine is produced as the normal response to water drinking. There are, however, two abnormal conditions in which dilute urine is produced inappropriately: central diabetes insipidus andnephrogenic diabetes insipidus. Features of these conditions are summarized in Table 6-10.

Central Diabetes Insipidus

Central diabetes insipidus can follow head injury, in which trauma depletes the posterior pituitary gland of ADH stores. The posterior pituitary is, therefore, unable to secrete ADH in response to an osmotic stimulus. Because circulating levels of ADH are low or zero, the entire distal tubule and collecting ducts are impermeable to water. Hence, large volumes (up to 15 L/day) of dilute urine are excreted. Plasma osmolarity increases to abnormally high values as excessive amounts of water are excreted in the urine (water that would have been reabsorbed if ADH were present). The high plasma osmolarity would normally stimulate ADH secretion, but in central diabetes insipidus, there is no ADH to be secreted from the posterior pituitary gland. Treatment of central diabetes insipidus consists of administration of an ADH analogue, such as 1-deamino-8-D-arginine vasopressin (dDAVP).

Nephrogenic Diabetes Insipidus

Nephrogenic diabetes insipidus involves a defect in the response of the kidneys to ADH. Although ADH secretion from the posterior pituitary gland is normal, a defect in the receptor, the Gs protein, or adenylyl cyclase makes the principal cells unresponsive to ADH.

As a result, ADH fails to increase water permeability in the late distal tubule and collecting ducts. As in central diabetes insipidus, water cannot be reabsorbed by these segments and large volumes of dilute urine are excreted. The plasma osmolarity increases, which stimulates the posterior pituitary to secrete even more ADH. Circulating ADH levels are higher than normal in nephrogenic diabetes insipidus, but these high levels of ADH still are ineffective on principal cells.

Nephrogenic diabetes insipidus is treated with thiazide diuretics. (Administration of an ADH analogue such as dDAVP would be futile because the defect lies in the response to ADH.) To understand the rationale for using thiazide diuretics, first consider the fundamental problem in nephrogenic diabetes insipidus: Because the principal cells are unresponsive to ADH, there is excretion of large volumes of dilute urine. Thiazide diuretics are helpful as follows: (1) They inhibit Na+-Cl cotransport in the early distal tubule, thereby preventing dilution of the urine in this segment. As more NaCl is excreted, the urine is less dilute than it would be without treatment. (2) Thiazide diuretics produce a decrease in GFR and, secondary to decreased Na+ reabsorption, a decrease in ECF volume. The decrease in ECF volume causes an increase in proximal tubule reabsorption via effects on Starling forces. The combination of less water filtered and more water reabsorbed in the proximal tubule means that the total volume of water excreted is decreased.

Free-Water Clearance

Free water is defined as distilled water that is free of solutes (or solute-free water). In the nephron, free water is generated in the diluting segments, where solute is reabsorbed without water. The diluting segments of the nephron are the water-impermeable segments: the thick ascending limb and the early distal tubule.

Measurement of free-water clearance (CH2O) provides a method for assessing the ability of the kidneys to dilute or concentrate the urine. The principles underlying this measurement are as follows: WhenADH levels are low, all of the free water generated in the thick ascending limb and early distal tubule is excreted (because it cannot be reabsorbed by the collecting ducts). The urine is hyposmotic, and free-water clearance is positive. When ADH levels are high, all of the free water generated in the thick ascending limb and the early distal tubule is reabsorbed by the late distal tubule and collecting duct. The urine is hyperosmotic, and free-water clearance is negative.

Measurement of CH2O

Free-water clearance (CH2O) is calculated by the following equation:

image

where

CH2O

= Free-water clearance (mL/min)

image

= Urine flow rate (mL/min)

Cosm

= Clearance of osmoles (mL/min)

[U]osm

= Urine osmolarity (mOsm/L)

[P]osm

= Plasma osmolarity (mOsm/L)

SAMPLE PROBLEM. A man has a urine flow rate of 10 mL/min, a urine osmolarity of 100 mOsm/L, and a plasma osmolarity of 290 mOsm/L. What is his free-water clearance, and what is its significance?

SOLUTION. The man’s free-water clearance is calculated as follows:

image

CH2O is a positive value, which means that free water is being excreted. The solute-free water generated in the thick ascending limb and early distal tubule is not reabsorbed by the collecting ducts, but it is excreted. This situation occurs when circulating ADH levels are low, as in water drinking or central diabetes insipidus (or if ADH is ineffective, as in nephrogenic diabetes insipidus).

Significance of CH2O

CH2O can be zero, positive, or negative. The explanations for these values are as follows:

image CH2O is zero. CH2O is zero when no solute-free water is excreted. Under these conditions, urine is isosmotic with plasma (called isosthenuric). It is unusual for CH2O to be zero, but it can occur during treatment with a loop diuretic, where NaCl reabsorption is inhibited in the thick ascending limb. When solute reabsorption is inhibited in the thick ascending limb, no free water is generated at this site: If free water is not generated, it cannot be excreted. Therefore, the ability to dilute the urine during water drinking is impaired in a person who is treated with a loop diuretic. Likewise, the ability to concentrate the urine during water deprivation is impaired because loop diuretics also interfere with generation of the corticopapillary osmotic gradient (by inhibiting Na+-K+-2Cl cotransport and countercurrent multiplication).

image CH2O is positive. CH2O is positive when ADH levels are low or when ADH is ineffective and the urine is hyposmotic. The solute-free water, which is generated in the thick ascending limb and early distal tubule, is excreted in the urine because the late distal tubules and collecting ducts are impermeable to water under these conditions (Box 6-3).

BOX 6–3 Clinical Physiology: Central Diabetes Insipidus

DESCRIPTION OF CASE. A 45-year-old woman is admitted to the hospital following a head injury. She has severe polyuria (producing 1 L of urine every 2 hours) and polydipsia (drinking 3 to 4 glasses of water every hour). During a 24-hour period in the hospital, the woman produces 10 L of urine, containing no glucose. She is placed on overnight water restriction for further evaluation. The following morning, she is weak and confused. Her serum osmolarity is 330 mOsm/L, her serum [Na+] is 164 mEq/L, and her urine osmolarity is 70 mOsm/L. She is treated with dDAVP by nasal spray. Within 24 hours of initiating the treatment, her serum osmolarity is 295 mOsm/L and her urine osmolarity is 620 mOsm/L.

EXPLANATION OF CASE. Following overnight water restriction, the striking observation is that the woman is still producing dilute (hyposmotic) urine despite a severely elevated serum osmolarity. Diabetes mellitus is ruled out as a cause of her polyuria because no glucose is found in her urine. The diagnosis is that the woman has central diabetes insipidus secondary to a head injury.

The woman’s posterior pituitary gland does not secrete ADH, even with a strong osmotic stimulus such as a serum osmolarity of 330 mOsm/L. This absence of ADH results in a profound disturbance of water reabsorption, and she is unable to produce concentrated urine. Her distal tubule and collecting ducts are impermeable to water in the absence of ADH, no water can be reabsorbed by these segments, and her urine is hyposmotic (70 mOsm/L). Because she is excreting excessive amounts of free water, serum osmolarity and serum [Na+] increase. The high serum osmolarity is an intense stimulus for thirst, causing the woman to drink water almost continuously.

TREATMENT. The woman is treated with dDAVP, an ADH analogue that activates V2 receptors on the principal cells. When ADH binds to the V2 receptors, adenylyl cyclase is activated, cAMP is generated, and water channels are inserted in the luminal membrane, which restores water permeability of the principal cells. After initiating dDAVP therapy, the woman produces hyperosmotic urine, restoring her serum osmolarity to normal.

image CH2O is negative. CH2O is negative when ADH levels are high and the urine is hyperosmotic. All of the solute-free water generated in the thick ascending limb and early distal tubule (and more) is reabsorbed by the late distal tubules and collecting ducts. Because negative CH2O is a cumbersome term, the sign is reversed, and it is called free-water reabsorption, or TcH2O (c stands for collecting ducts).