CHAPTER 34 Control of Body Fluid Osmolality and Volume

The kidneys maintain the osmolality and volume of body fluids within a narrow range by regulating the excretion of water and NaCl, respectively. This chapter discusses the regulation of renal water excretion (urine concentration and dilution) and NaCl excretion. The composition and volumes of the various body fluid compartments are reviewed in Chapter 2.

CONTROL OF BODY FLUID OSMOLALITY: URINE CONCENTRATION AND DILUTION

As described in Chapter 2, water constitutes approximately 60% of the healthy adult human body. Body water is divided into two compartments (i.e., intracellular fluid [ICF] and extracellular fluid [ECF]), which are in osmotic equilibrium. Water intake into the body generally occurs orally. However, in clinical situations, intravenous infusion is an important route of water entry.

The kidneys are responsible for regulating water balance and under most conditions are the major route for elimination of water from the body (Table 34-1). Other routes of water loss from the body include evaporation from cells of the skin and respiratory passages. Collectively, water loss by these routes is termed insensible water loss because the individual is unaware of its occurrence. The production of sweat accounts for the loss of additional water. Water loss by this mechanism can increase dramatically in a hot environment, with exercise, or in the presence of fever (Table 34-2). Finally, water can be lost from the gastrointestinal tract. Fecal water loss is normally small (≈100 mL/day) but can increase dramatically with diarrhea (e.g., 20 L/day with cholera). Vomiting can also cause gastrointestinal water loss.

Table 34-1 Normal Routes of Water Gain and Loss in Adults at Room Temperature (23° C)

Route	mL/Day
Water Intake
Fluid^*	1200
In food	1000
Metabolically produced from food	300
TOTAL	2500
Water Output
Insensible	700
Sweat	100
Feces	200
Urine	1500
TOTAL	2500

* Fluid intake varies widely for both social and cultural reasons.

Table 34-2 Effect of Environmental Temperature and Exercise on Water Loss and Intake (mL/day) in Adults

Although water loss from sweating, defecation, and evaporation from the lungs and skin can vary with environmental conditions or during pathological conditions, loss of water by these routes cannot be regulated. In contrast, the renal excretion of water is tightly regulated to maintain whole-body water balance. Maintenance of water balance requires that water intake and loss from the body be precisely matched. If intake exceeds loss, positive water balance exists. Conversely, if intake is less than loss, negative water balance exists.

When water intake is low or water loss increases, the kidneys conserve water by producing a small volume of urine that is hyperosmotic with respect to plasma. When water intake is high, a large volume of hypoosmotic urine is produced. In a normal individual, urine osmolality (U_osm) can vary from approximately 50 to 1200 mOsm/kg H₂O, and the corresponding urine volume can vary from approximately 18 to 0.5 L/day.

It is important to recognize that disorders in water balance are manifested by alterations in body fluid osmolality, which are usually measured by changes in plasma osmolality (P_osm). Because the major determinant of plasma osmolality is Na⁺ (with its anions Cl⁻ and HCO₃⁻), these disorders also result in alterations in plasma [Na⁺]. When an abnormal plasma [Na⁺] is observed in an individual, it is tempting to suspect a problem in Na⁺ balance. However, the problem most often relates to water balance, not Na⁺ balance. As described later, changes in Na⁺ balance result in alterations in the volume of ECF, not its osmolality.

Under steady-state conditions, the kidneys control water excretion independently of their ability to control the excretion of various other physiologically important substances such as Na⁺, K⁺, and urea. Indeed, this ability is necessary for survival because it allows water balance to be achieved without upsetting the other homeostatic functions of the kidneys.

The following sections discuss the mechanisms by which the kidneys excrete either hypoosmotic (dilute) or hyperosmotic (concentrated) urine. The control of vasopressin secretion and its important role in regulating excretion of water by the kidneys are also explained (see also Chapter 40).

Antidiuretic Hormone

Antidiuretic hormone (ADH), or vasopressin, acts on the kidneys to regulate the volume and osmolality of urine. When plasma ADH levels are low, a large volume of urine is excreted (diuresis), and the urine is dilute.^* When plasma levels are high, a small volume of urine is excreted (antidiuresis), and the urine is concentrated.

IN THE CLINIC

In the clinical setting, hypoosmolality (a reduction in plasma osmolality) shifts water into cells, and this process results in cell swelling. Symptoms associated with hypoosmolality are related primarily to swelling of brain cells. For example, a rapid fall in P_osm can alter neurological function and thereby cause nausea, malaise, headache, confusion, lethargy, seizures, and coma. When P_osm is increased (i.e., hyperosmolality), water is lost from cells. The symptoms of an increase in P_osm are also primarily neurological and include lethargy, weakness, seizures, coma, and even death.

Symptoms associated with changes in body fluid osmolality vary depending on how quickly the osmolality is changed. Rapid changes in osmolality (i.e., over a period of hours) are less well tolerated than changes that occur more gradually (i.e., over a period of days to weeks). Indeed, individuals in whom alterations in body fluid osmolality have developed over an extended period may be entirely asymptomatic. This reflects the ability of cells over time to either eliminate intracellular osmoles, as occurs with hypoosmolality, or generate new intracellular osmoles in response to hyperosmolality and thus minimize changes in cell volume of the neurons. This has important clinical implications when treating a patient with abnormal plasma osmolality. For example, rapid correction of osmolality of an individual who has had long-standing hypoosmolality of body fluids can lead to demyelination, especially of the pons, the results of which are irreversible. Depending on the extent of pontine demyelination, this condition can be fatal.

ADH is a small peptide that is nine amino acids in length. It is synthesized in neuroendocrine cells located within the supraoptic and paraventricular nuclei of the hypothalamus.^* The synthesized hormone is packaged in granules that are transported down the axon of the cell and stored in nerve terminals located in the neurohypophysis (posterior pituitary). The anatomy of the hypothalamus and pituitary gland is shown in Figure 34-1.

Figure 34-1 Anatomy of the hypothalamus and pituitary gland (midsagittal section). Also shown are pathways involved in regulating secretion of ADH. Afferent fibers from the baroreceptors are carried in the vagus and glossopharyngeal nerves. The closed box is an expanded view of the hypothalamus and pituitary gland.

AT THE CELLULAR LEVEL

The gene for ADH is found on chromosome 20. It contains approximately 2000 base pairs with three exons and two introns. The gene codes for a preprohormone that consists of a signal peptide, the ADH molecule, neurophysin, and a glycopeptide (copeptin). As the cell processes the preprohormone, the signal peptide is cleaved off in the rough endoplasmic reticulum. Once packaged in neurosecretory granules, the preprohormone is further cleaved into ADH, neurophysin, and copeptin molecules. The neurosecretory granules are then transported down the axon to the posterior pituitary and stored in the nerve endings until released. When the neurons are stimulated to secrete ADH, the action potential opens Ca⁺⁺ channels in the nerve terminal, which raises intracellular [Ca⁺⁺] and causes exocytosis of the neurosecretory granules. All three peptides are secreted in this process. Neurophysin and copeptin do not have an identified physiological function.

Secretion of ADH by the posterior pituitary can be influenced by several factors. The two primary physiological regulators of ADH secretion are the osmolality of the body fluids (osmotic) and the volume and pressure of the vascular system (hemodynamic). Other factors that can alter ADH secretion include nausea (stimulates), atrial natriuretic peptide (inhibits), and angiotensin II (stimulates). A number of drugs, prescription and nonprescription, also affect secretion of ADH. For example, nicotine stimulates secretion, whereas ethanol inhibits secretion.

Osmotic Control of ADH Secretion

Changes in the osmolality of body fluids play the most important role in regulating secretion of ADH; changes as minor as 1% are sufficient to alter it significantly. Although neurons in the supraoptic and paraventricular nuclei respond to changes in body fluid osmolality by altering their secretion of ADH, it is clear that there are separate cells in the anterior hypothalamus that are exquisitely sensitive to changes in body fluid osmolality and therefore play an important role in regulating the secretion of ADH.^* These cells, termed osmoreceptors, appear to behave as osmometers and sense changes in body fluid osmolality by either shrinking or swelling. The osmoreceptors respond only to solutes in plasma that are effective osmoles (see Chapter 1). For example, urea is an ineffective osmole when the function of osmoreceptors is considered. Thus, elevation of the plasma urea concentration alone has little effect on ADH secretion.

When the effective osmolality of plasma increases, the osmoreceptors send signals to ADH-synthesizing/secreting cells located in the supraoptic and paraventricular nuclei of the hypothalamus, and synthesis and secretion of ADH are stimulated. Conversely, when the effective osmolality of plasma is reduced, secretion is inhibited. Because ADH is rapidly degraded in plasma, circulating levels can be reduced to zero within minutes after secretion is inhibited. As a result, the ADH system can respond rapidly to fluctuations in body fluid osmolality.

Figure 34-2, A, illustrates the effect of changes in plasma osmolality on circulating ADH levels. The slope of the relationship is quite steep and accounts for the sensitivity of this system. The set point of the system is the plasma osmolality value at which ADH secretion begins to increase. Below this set point, virtually no ADH is released. The set point varies among individuals and is genetically determined. In healthy adults, it varies from 275 to 290 mOsm/kg H₂O (average, ≈280 to 285 mOsm/kg H₂O). Several physiological factors can also change the set point in a given individual. As discussed later, alterations in blood volume and pressure can shift it. In addition, pregnancy is associated with a decrease in the set point.

Figure 34-2 Osmotic and hemodynamic control of secretion of ADH. A, Effect of changes in plasma osmolality (constant blood volume and pressure) on plasma ADH levels. B, Effect of changes in blood volume or pressure (constant plasma osmolality) on plasma ADH levels. C, Interactions between osmolality and blood volume and pressure stimuli on plasma ADH levels.

Hemodynamic Control of ADH Secretion

A decrease in blood volume or pressure also stimulates secretion of ADH. The receptors responsible for this response are located in both the low-pressure (left atrium and large pulmonary vessels) and the high-pressure (aortic arch and carotid sinus) sides of the circulatory system. Because the low-pressure receptors are located in the high-compliance side of the circulatory system (i.e., venous) and because the majority of blood is in the venous side of the circulatory system, these low-pressure receptors can be viewed as responding to overall vascular volume. The high-pressure receptors respond to arterial pressure. Both groups of receptors are sensitive to stretch of the wall of the structure in which they are located (e.g., cardiac atrial wall, wall of the aortic arch) and are termed baroreceptors. Signals from these receptors are carried in afferent fibers of the vagus and glossopharyngeal nerves to the brainstem (solitary tract nucleus of the medulla oblongata), which is part of the center that regulates heart rate and blood pressure (see also Chapter 18). Signals are then relayed from the brainstem to the ADH-secreting cells of the supraoptic and paraventricular hypothalamic nuclei. The sensitivity of the baroreceptor system is less than that of the osmoreceptors, and a 5% to 10% decrease in blood volume or pressure is required before ADH secretion is stimulated. This is illustrated in Figure 34-2, B. A number of substances have been shown to alter the secretion of ADH through their effects on blood pressure, including bradykinin and histamine, which lower pressure and thus stimulate ADH secretion, and norepinephrine, which increases blood pressure and inhibits ADH secretion.

Alterations in blood volume and pressure also affect the response to changes in body fluid osmolality (see Fig. 34-2, C). With a decrease in blood volume or pressure, the set point is shifted to lower osmolality values and the slope of the relationship is steeper. In terms of survival of the individual, this means that when faced with circulatory collapse, the kidneys will continue to conserve water, even though by doing so they reduce the osmolality of body fluids. With an increase in blood volume or pressure, the opposite occurs. The set point is shifted to higher osmolality values, and the slope is decreased.

Actions of ADH on the Kidneys

The primary action of ADH on the kidneys is to increase the permeability of the collecting duct to water. In addition and importantly, ADH increases the permeability of the medullary portion of the collecting duct to urea. Finally, ADH stimulates reabsorption of NaCl by the thick ascending limb of Henle’s loop, the distal tubule, and the collecting duct.

The actions of ADH on permeability of the collecting duct to water have been studied extensively. ADH binds to a receptor on the basolateral membrane of the cell. This receptor is termed the V₂ receptor (i.e., vasopressin 2 receptor).^* Binding to this receptor, which is coupled to adenylyl cyclase via a stimulatory G protein (G_s), increases intracellular levels of cAMP. The rise in intracellular cAMP activates protein kinase A (PKA), which ultimately results in the insertion of vesicles containing aquaporin-2 (AQP2) water channels into the apical membrane of the cell, as well as the synthesis of more AQP2 (Fig. 34-3). With the removal of ADH, these water channels are reinternalized into the cell, and the apical membrane is once again impermeable to water. This shuttling of water channels into and out of the apical membrane provides a rapid mechanism for controlling permeability of the membrane to water. Because the basolateral membrane is freely permeable to water as a result of the presence of AQP3 and AQP4 water channels, any water that enters the cell through apical membrane water channels exits across the basolateral membrane, thereby resulting in net absorption of water from the tubule lumen.

Figure 34-3 Action of ADH via the V₂ receptor on the principal cell of the late distal tubule and collecting duct. See text for details. A.C., adenylyl cyclase; AP2, aquaporin-2 gene; AQP2, aquaporin-2; CRE, cAMP response element; CREB-P, phosphorylated cAMP response element–binding protein; -P, phosphorylated proteins.

(Adapted and modified from Brown D, Nielsen S. In Brenner BM [ed]: The Kidney, 7th ed. Philadelphia, Saunders, 2004.)

In addition to the acute effects of ADH just described, ADH regulates the expression of AQP2 (and AQP3). When large volumes of water are ingested over an extended period (e.g., psychogenic polydipsia), expression of AQP2 and AQP3 in the collecting duct is reduced. As a consequence, when water ingestion is restricted, these individuals cannot maximally concentrate their urine. Conversely, in states of restricted water ingestion, expression of AQP2 and AQP3 in the collecting duct increases and thus facilitates the excretion of maximally concentrated urine.

IN THE CLINIC

Inadequate release of ADH from the posterior pituitary results in the excretion of large volumes of dilute urine (polyuria). To compensate for this loss of water, the individual must ingest large volumes of water (polydipsia) to maintain constant body fluid osmolality. If the individual is deprived of water, the body fluids will become hyperosmotic. This condition is called central diabetes insipidus or pituitary diabetes insipidus. Central diabetes insipidus can be inherited, although this is rare. It occurs more commonly after head trauma and with brain neoplasms or infections. Individuals with central diabetes insipidus have a urine-concentrating defect that can be corrected by the administration of exogenous ADH.

The inherited (autosomal dominant) form of central diabetes insipidus has been shown to represent multiple mutations in the ADH gene. In patients with this form of central diabetes insipidus, mutations have been identified in all regions of the ADH gene (i.e., ADH, copeptin, and neurophysin). The most common mutation is found in the neurophysin portion of the gene. In each of these situations there is defective trafficking of the peptide, with abnormal accumulation in the endoplasmic reticulum. It is believed that this abnormal accumulation in the endoplasmic reticulum results in death of the ADH secretory cells of the supraoptic and paraventricular nuclei.

The syndrome of inappropriate ADH secretion (SIADH) is a common clinical problem characterized by plasma ADH levels that are elevated above what would be expected on the basis of body fluid osmolality and blood volume and pressure—hence the term inappropriate ADH secretion. Individuals with SIADH retain water, and their body fluids become progressively hypoosmotic. In addition, their urine is more hyperosmotic than expected based on the low body fluid osmolality. SIADH can be caused by infections and neoplasms of the brain, drugs (e.g., antitumor drugs), pulmonary diseases, and carcinoma of the lung. Many of these conditions stimulate secretion of ADH by altering neural input to the ADH secretory cells. However, small cell carcinoma of the lung produces and secretes a number of peptides, including ADH.

It is also clear that expression of AQP2 (and in some instances also AQP3) varies in pathological conditions associated with disturbances in urine concentration and dilution. As discussed elsewhere, AQP2 expression is reduced in a number of conditions associated with impaired urine-concentrating ability. By contrast, in conditions associated with water retention, such as congestive heart failure, hepatic cirrhosis, and pregnancy, AQP2 expression is increased.

AT THE CELLULAR LEVEL

The gene for the V₂ receptor is located on the X chromosome. It codes for a 371–amino acid protein that is in the family of receptors that have seven membrane-spanning domains and are coupled to heterotrimeric G proteins. As shown in Figure 34-3, binding of ADH to its receptor on the basolateral membrane activates adenylyl cyclase. The increase in intracellular cAMP then activates protein kinase A (PKA), which results in phosphorylation of AQP2 water channels, as well as increased transcription of the AQP2 gene via activation of a cAMP-response element (CRE). Vesicles containing phosphorylated AQP2 move toward the apical membrane along microtubules driven by the molecular motor dynein. Once near the apical membrane, proteins called SNAREs interact with vesicles containing AQP2 and facilitate fusion of these vesicles with the membrane. The addition of AQP2 to the membrane allows water to enter the cell driven by the osmotic gradient (lumen osmolality < cell osmolality). The water then exits the cell across the basolateral membrane through AQP3 and AQP4 water channels, which are constitutively present in the basolateral membrane. When the V₂ receptor is not occupied by ADH, the AQP2 water channels are removed from the apical membrane by clathrin-mediated endocytosis, thus rendering the apical membrane once again impermeable to water. The endocytosed AQP2 molecules may be either stored in cytoplasmic vesicles, ready for reinsertion into the apical membrane when ADH levels in plasma increase, or degraded.

Recently, individuals have been found who have activating (gain-of-function) mutations in the V₂ receptor gene. Thus, the receptor is constitutively activated, even in the absence of ADH. These individuals have laboratory findings similar to those seen in SIADH, including reduced plasma osmolality, hyponatremia (reduced plasma [Na⁺]), and urine more concentrated than would be expected from the reduced body fluid osmolality. However, unlike SIADH, where circulating levels of ADH are elevated and thus responsible for water retention by the kidneys, these individuals have undetectable levels of ADH in their plasma. This new clinical entity has been termed “nephrogenic syndrome of inappropriate antidiuresis.”

ADH also increases the permeability of the terminal portion of the inner medullary collecting duct to urea. This results in an increase in reabsorption of urea and an increase in the osmolality of the medullary interstitial fluid. The apical membrane of medullary collecting duct cells contains two different urea transporters (UT-A1 and UT-A3).^* ADH, acting through the cAMP/PKA cascade, increases permeability of the apical membrane to urea. This increase in permeability is associated with phosphorylation of UT-A1 and perhaps also UT-A3. Increasing the osmolality of the interstitial fluid of the renal medulla also increases the permeability of the collecting duct to urea. This effect is mediated by the phospholipase C pathway and involves phosphorylation by protein kinase C. Thus, this effect is separate and additive to that of ADH.

In addition to its acute effect on permeability of the collecting duct to urea, ADH also increases the abundance of UT-A1 in states of chronic water restriction. In contrast, with water loading (i.e., suppressed ADH levels), UT-A1 abundance in the collecting duct is reduced.

ADH also stimulates reabsorption of NaCl by the thick ascending limb of Henle’s loop and by the distal tubule and cortical segment of the collecting duct. This increase in Na⁺ reabsorption is associated with increased abundance of key Na⁺ transporters: 1Na⁺-1K⁺-2Cl⁻ symporter (thick ascending limb of Henle’s loop), Na⁺-Cl⁻ symporter (distal tubule), and the epithelial Na⁺ channel (ENaC, in the distal tubule and collecting duct). It is thought that stimulation of NaCl transport by the thick ascending limb may help maintain the hyperosmotic medullary interstitium that is necessary for the absorption of water from the medullary portion of the collecting duct (see later).

Thirst

In addition to affecting the secretion of ADH, changes in plasma osmolality and blood volume or pressure lead to alterations in the perception of thirst. When body fluid osmolality is increased or blood volume or pressure is reduced, the individual perceives thirst. Of these stimuli, hypertonicity is the more potent. An increase in plasma osmolality of only 2% to 3% produces a strong desire to drink, whereas decreases in blood volume and pressure in the range of 10% to 15% are required to produce the same response.

As already discussed, there is a genetically determined threshold for ADH secretion (i.e., a body fluid osmolality above which ADH secretion increases). Similarly, there is a genetically determined threshold for triggering the sensation of thirst. However, the thirst threshold is higher than the threshold for ADH secretion. On average, the threshold for ADH secretion is approximately 285 mOsm/kg H₂O, whereas the thirst threshold is approximately 295 mOsm/kg H₂O. Because of this difference, thirst is stimulated at a body fluid osmolality at which secretion of ADH is already maximal.

The neural centers involved in regulating water intake (the thirst center) are located in the same region of the hypothalamus involved in regulating ADH secretion. However, it is not certain whether the same cells serve both functions. Indeed, the thirst response, like the regulation of ADH secretion, occurs only in response to effective osmoles (e.g., NaCl). Even less is known about the pathways involved in the thirst response to decreased blood volume or pressure, but it is believed that they are the same as those involved in the volume- and pressure-related regulation of ADH secretion. Angiotensin II, acting on cells of the thirst center (subfornical organ), also evokes the sensation of thirst. Because angiotensin II levels are increased when blood volume and pressure are reduced, this effect of angiotensin II contributes to the homeostatic response that restores and maintains body fluids at their normal volume.

The sensation of thirst is satisfied by the act of drinking even before sufficient water is absorbed from the gastrointestinal tract to correct the plasma osmolality. Oropharyngeal and upper gastrointestinal receptors appear to be involved in this response. However, relief of the thirst sensation via these receptors is short-lived, and thirst is completely satisfied only when plasma osmolality or blood volume or pressure is corrected.

IN THE CLINIC

The collecting ducts of some individuals do not respond normally to ADH. These individuals cannot maximally concentrate their urine and consequently have polyuria and polydipsia. This clinical entity is termed nephrogenic diabetes insipidus to distinguish it from central diabetes insipidus. Nephrogenic diabetes insipidus can result from a number of systemic disorders and, more rarely, occurs as a result of inherited disorders. Many of the acquired forms of nephrogenic diabetes insipidus are the result of decreased expression of AQP2 in the collecting duct. Decreased expression of AQP2 has been documented in the urine-concentrating defects associated with hypokalemia, lithium ingestion (some degree of nephrogenic diabetes insipidus develops in 35% of individuals who take lithium for bipolar disorder), ureteral obstruction, a low-protein diet, and hypercalcemia. The inherited forms of nephrogenic diabetes insipidus reflect mutations in the ADH receptor (V₂ receptor) or the AQP2 molecule. Of these, approximately 90% of hereditary forms of nephrogenic diabetes insipidus are the result of mutations in the V₂ receptor gene, with the other 10% being the result of mutations in the AQP2 gene. Because the gene for the V₂ receptor is located on the X chromosome, these inherited forms are X-linked. To date, more than 150 different mutations in the V₂ receptor gene have been described. Most of the mutations result in trapping of the receptor in the endoplasmic reticulum of the cell; only a few cases result in the surface expression of a V₂ receptor that will not bind ADH. The gene coding for AQP2 is located on chromosome 12 and is inherited as both an autosomal recessive and an autosomal dominant defect. As noted in Chapter 1, aquaporins exist as homotetramers. This homotetramer formation explains the difference between the two forms of nephrogenic diabetes insipidus. In the recessive form, heterozygotes produce both normal AQP2 and defective AQP2 molecules. The defective AQP2 monomer is retained in the endoplasmic reticulum of the cell, and thus the homotetramers that do form contain only normal molecules. Accordingly, mutations in both alleles are required to produce nephrogenic diabetes insipidus. In the autosomal dominant form, the defective monomers can form tetramers with normal monomers, as well as with defective monomers. However, these tetramers are unable to traffic to the apical membrane.

It should be apparent that the ADH and thirst systems work in concert to maintain water balance. An increase in plasma osmolality evokes drinking and, via ADH action on the kidneys, the conservation of water. Conversely, when plasma osmolality is decreased, thirst is suppressed, and in the absence of ADH, renal water excretion is enhanced. However, most of the time fluid intake is dictated by cultural factors and social situations. This is especially the case when thirst is not stimulated. In this situation, maintenance of normal body fluid osmolality relies solely on the ability of the kidneys to excrete water. How the kidney accomplishes this is discussed in detail in the following sections of this chapter.

IN THE CLINIC

With adequate access to water, the thirst mechanism can prevent the development of hyperosmolality. Indeed, it is this mechanism that is responsible for the polydipsia seen in response to the polyuria of both central and nephrogenic diabetes insipidus.

Water intake is also influenced by social and cultural factors. Thus, individuals will ingest water even in the absence of the thirst sensation. Normally, the kidneys are able to excrete this excess water because they can excrete up to 18 L/day of urine. However, in some instances, the volume of water ingested exceeds the kidneys’ capacity to excrete water, especially over short periods. When this occurs, the body fluids become hypoosmotic. An example of how water intake can exceed the capacity of the kidneys to excrete water is long-distance running. A recent study of participants in the Boston Marathon found that hyponatremia developed in 13% of the runners during the course of the race.^* This reflected the practice of some runners of ingesting water, or other hypotonic drinks, during the race to remain “well hydrated.” In addition, water is produced from the metabolism of glycogen and triglycerides used as fuels by the exercising muscle. Because over the course of the race they ingested, as well as generated through metabolism, more water than their kidneys were able to excrete or was lost by sweating, hyponatremia developed. In some racers the hyponatremia was severe enough to elicit the neurological symptoms described previously.

One can find throughout the popular press the admonition to drink eight 8-oz glasses of water a day (the 8 × 8 recommendation). Drinking this volume of water is said to provide innumerable health benefits. As a result, it seems that everyone now has a water bottle as a constant companion. Although ingesting this volume of water over the course of a day (approximately 2 L) will not harm most individuals, there is no scientific evidence to support the beneficial health claims ascribed to the 8 × 8 recommendation.^† Indeed most individuals get adequate amounts of water through the food that they ingest and the fluids taken with those meals.

The maximum amount of water that can be excreted by the kidneys depends on the amount of solute excreted, which in turn depends on food intake. For example, with maximally dilute urine (U_osm = 50 mOsm/kg H₂O), the maximum urine output of 18 L/day will be achieved only if the solute excretion rate is 900 mmol/day.

Equation 34-1

If excretion of solute is reduced, as commonly occurs in the elderly with reduced food intake, the maximum urine output will decrease. For example, if solute excretion is only 400 mmol/day, a maximum urine output (at U_osm = 50 mOsm/kg H₂O) of only 8 L/day can be achieved. Thus, individuals with reduced food intake have a reduced capacity to excrete water.

^* See Almond CS et al: Hyponatremia among runners in the Boston Marathon. N Engl J Med 2005; 352:1150, 2005.)

^† See Valtin H: “Drink at least eight glasses of water a day.” Really? Is there scientific evidence for “8×8”? Am J Physiol Reg Integr Comp Physiol 283:R993, 2002.)

Renal Mechanisms for Dilution and Concentration of Urine

Under normal circumstances, excretion of water is regulated separately from excretion of solutes. For this to occur, the kidneys must be able to excrete urine that is either hypoosmotic or hyperosmotic with respect to body fluids. This ability to excrete urine of varying osmolality in turn requires that solute be separated from water at some point along the nephron. As discussed in Chapter 33, reabsorption of solute in the proximal tubule results in reabsorption of a proportional amount of water. Hence, solute and water are not separated in this portion of the nephron. Moreover, this proportionality between proximal tubule water and solute reabsorption occurs regardless of whether the kidneys excrete dilute or concentrated urine. Thus, the proximal tubule reabsorbs a large portion of the filtered load of solute and water, but it does not produce dilute or concentrated tubular fluid. The loop of Henle, in particular, the thick ascending limb, is the major site where solute and water are separated. Consequently, excretion of both dilute and concentrated urine requires normal function of the loop of Henle.

Excretion of hypoosmotic urine is relatively easy to understand. The nephron must simply reabsorb solute from the tubular fluid and not allow reabsorption of water to also occur. As just noted and as described in greater detail later, reabsorption of solute without concomitant water reabsorption occurs in the ascending limb of Henle’s loop. Under appropriate conditions (i.e., in the absence of ADH), the distal tubule and collecting duct also dilute the tubular fluid.

Excretion of hyperosmotic urine is more complex and thus more difficult to understand. This process in essence involves removing water from the tubular fluid without solute. Because water movement is passive and driven by an osmotic gradient, the kidney must generate a hyperosmotic compartment that then reabsorbs water osmotically from the tubular fluid. The compartment in the kidney that serves this function is the interstitium of the renal medulla. Henle’s loop, in particular, the thick ascending limb, is critical for generating the hyperosmotic medullary interstitium. Once established, this hyperosmotic compartment drives reabsorption of water from the collecting duct and thereby concentrates the urine.

Figure 34-4 summarizes the essential features of the mechanisms whereby the kidneys excrete either dilute or concentrated urine. Table 34-3 summarizes the transport and passive permeability properties of the nephron segments involved in these processes.

Figure 34-4 Schematic of the nephron segments involved in dilution and concentration of urine. Henle’s loops of juxtamedullary nephrons are shown. A, Mechanism for the excretion of dilute urine (water diuresis). ADH is absent, and the collecting duct is essentially impermeable to water. Note also that during water diuresis the osmolality of the medullary interstitium is reduced as a result of increased vasa recta blood flow and entry of some urea into the medullary collecting duct. B, Mechanism for the excretion of concentrated urine (antidiuresis). Plasma ADH levels are maximal, and the collecting duct is highly permeable to water. Under this condition, the medullary interstitial gradient is maximal.

Table 34-3 Transport and Permeability Properties of Nephron Segments Involved in Urine Concentration and Dilution

First, how the kidneys excrete dilute urine (water diuresis) when ADH levels are low or zero is considered. The following numbers refer to those encircled in Figure 34-4, A:

1. Fluid entering the descending thin limb of the loop of Henle from the proximal tubule is isosmotic with respect to plasma. This reflects the essentially isosmotic nature of solute and water reabsorption in the proximal tubule (see Chapter 33).

2. The descending thin limb is highly permeable to water and much less so to solutes such as NaCl and urea. (Note: Urea is an ineffective osmole in many tissues, but it is an effective osmole in many portions of the nephron [Table 34-3]). Consequently, as the fluid in the descending thin limb descends deeper into the hyperosmotic medulla, water is reabsorbed (via AQP1) as a result of the osmotic gradient set up across the descending thin limb by both NaCl and urea, which are present at high concentrations in the medullary interstitium (see later). By this process, tubular fluid at the bend of the loop has an osmolality equal to that of the surrounding interstitial fluid. Although the osmolality of tubular and interstitial fluid is similar at the bend of the loop, their compositions differ. The concentration of NaCl in tubular fluid is greater than that in the surrounding interstitial fluid. However, the concentration of urea in tubular fluid is less than that of interstitial fluid (see later).

3. The ascending thin limb is impermeable to water but permeable to NaCl. Consequently, as tubular fluid moves up the ascending limb, NaCl is passively reabsorbed because the concentration of NaCl in tubular fluid is higher than that in interstitial fluid. As a result, the volume of tubular fluid remains unchanged along the length of the thin ascending limb, but the concentration of NaCl decreases. Thus, as fluid ascends through the thin ascending limb, it becomes less concentrated than the surrounding interstitial fluid (i.e., tubular fluid dilution begins).

4. The thick ascending limb of the loop of Henle is impermeable to water and urea. This portion of the nephron actively reabsorbs NaCl from tubular fluid and thereby dilutes it. Dilution occurs to such a degree that this segment is often referred to as the diluting segment of the kidney. Fluid leaving the thick ascending limb is hypoosmotic with respect to plasma (approximately 150 mOsm/kg H₂O).

5. The distal tubule and the cortical portion of the collecting duct actively reabsorb NaCl and are impermeable to urea. In the absence of ADH, these segments are not permeable to water. Thus, when ADH is absent or present at low levels (i.e., decreased plasma osmolality), the osmolality of tubule fluid in these segments is reduced further because NaCl is reabsorbed without water. Under this condition, fluid leaving the cortical portion of the collecting duct is hypoosmotic with respect to plasma (approximately 50 to 100 mOsm/kg H₂O).

6. The medullary collecting duct actively reabsorbs NaCl. Even in the absence of ADH, this segment is slightly permeable to water and urea. Consequently, some urea enters the collecting duct from the medullary interstitium, and a small volume of water is reabsorbed.

7. Urine has an osmolality as low as approximately 50 mOsm/kg H₂O and contains low concentrations of NaCl and urea. The volume of urine excreted can be as much as 18 L/day, or approximately 10% of the glomerular filtration rate (GFR).

Next, how the kidneys excrete concentrated urine (antidiuresis) when plasma osmolality and plasma ADH levels are high is considered. The following numbers refer to those encircled in Figure 34-4, B:

1-4. These steps are similar to those for the production of dilute urine. An important point in understanding how concentrated urine is produced is to recognize that although reabsorption of NaCl by the ascending thin and thick limbs of the loop of Henle dilutes the tubular fluid, the reabsorbed NaCl accumulates in the medullary interstitium and raises the osmolality of this compartment. Accumulation of NaCl in the medullary interstitium is crucial for the production of urine hyperosmotic to plasma because it provides the osmotic driving force for reabsorption of water by the medullary collecting duct. The overall process by which the loop of Henle, in particular, the thick ascending limb, generates the hyperosmotic medullary interstitial gradient is termed countercurrent multiplication^* (Fig. 34-5). As already noted, ADH stimulates reabsorption of NaCl by the thick ascending limb of Henle’s loop. This is thought to maintain the medullary interstitial gradient at a time when water is being added to this compartment from the medullary collecting duct, which would tend to dissipate the gradient.

< div class='tao-gold-member'>

Only gold members can continue reading. Log In or Register to continue