Physiology_Levy

Physiology_Levy. AVP secretion, only occurs 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 the pathways are the same as those involved in the volume and pressure-related regulation of AVP secretion. Angiotensin II acting on cells of the thirst center 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.


Physiology_Levy

Physiology_Levy. 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. It is interesting to note that cold water is more effective in reducing the thirst sensation. 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 only completely satisfied when the plasma osmolality or blood volume or pressure is corrected.


Physiology_Levy

Physiology_Levy. It should be apparent that the AVP and thirst systems work in concert to maintain water balance. An increase in plasma osmolality evokes drinking and, via AVP action on the kidneys, conservation of water. Conversely, when plasma osmolality is decreased, thirst is suppressed and, in the absence of AVP, 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, maintaining 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. Renal Mechanisms for Dilution and Concentration of Urine


Physiology_Levy

Physiology_Levy. As already noted, water excretion is regulated separately from solute excretion. For this to occur the kidneys must be able to excrete urine that is either hypoosmotic or hyper-osmotic 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 , 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 amount 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. Thus excretion


Physiology_Levy

Physiology_Levy. 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. Thus excretion of both dilute and concentrated urine requires normal function of the loop of Henle.


Physiology_Levy

Physiology_Levy. Excretion of hypoosmotic urine is relatively easy to understand. The nephron must simply reabsorb solute from the tubular fluid and not allow water reabsorption 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 AVP) the distal tubule and collecting duct also dilute the tubular fluid by reabsorbing solute but not water. Excretion of hyperosmotic urine is more complex and thus more difficult to understand. This process in essence


Physiology_Levy

Physiology_Levy. Excretion of hyperosmotic urine is more complex and thus more difficult to understand. This process in essence With adequate access to water, the thirst mechanism can prevent development of hyperosmolality. This mechanism is responsible for the polydipsia seen in response to the polyuria of both central and nephrogenic diabetes insipidus. Most individuals ingest water/beverages 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 of time. When this occurs, 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 study of participants in the Boston Marathon found that 13% of the runners developed hyponatremia during the course of the race.


Physiology_Levy

Physiology_Levy. 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 (and 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. The maximum amount of water that can be excreted by the kidneys (e.g., 18 L/day) depends on the amount of solute excreted, which in turn depends on food intake. For example, with maximally dilute urine (Uosm = 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:


Physiology_Levy

Physiology_Levy. If solute excretion 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 Uosm = 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. dAlmond CS et al. Hyponatremia among runners in the Boston Marathon. N Engl J Med 2005;352:1150-1556.


Physiology_Levy

Physiology_Levy. dAlmond CS et al. Hyponatremia among runners in the Boston Marathon. N Engl J Med 2005;352:1150-1556. involves removing water from the tubular fluid without solute. Because water movement is passive, driven by an osmotic gradient, the kidney must generate a hyperosmotic compartment into which water is reabsorbed, without solute, osmotically from the tubular fluid. The hyperosmotic compartment in the kidney that serves this function is the interstitium of the renal medulla. Henle’s loop is critical for generating the hyperosmotic medullary interstitium. Once established, this hyperosmotic compartment drives water reabsorption from the collecting duct and thereby concentrates urine. Fig. 35.6 summarizes tubular fluid osmolality at several points along the nephron, both in the absence and presence


Physiology_Levy

Physiology_Levy. Fig. 35.6 summarizes tubular fluid osmolality at several points along the nephron, both in the absence and presence CHAPTER 35 Control of Body Fluid Osmolality and Volume of AVP. Note that tubular fluid entering the loop of Henle from the proximal tubule is isoosmotic with respect to plasma and is so regardless of the absence or presence of AVP. Also, tubular fluid leaving the thick ascending limb is hypoosmotic with respect to plasma, both in the absence and presence of AVP. The osmolality of tubular fluid along the collecting duct is hypoosmotic with respect to plasma in the absence of AVP and becomes progressively hyperosmotic (i.e., from cortex to inner medulla) in the presence of AVP.


Physiology_Levy

Physiology_Levy. Establishment and maintenance of the hyperosmotic medullary interstitium has been a subject of study for more than 50 years. Despite this intense study, the most accepted model for how the medullary osmotic gradient is established, especially within the inner medulla, is incomplete and not consistent with more recent experimental findings regarding the transport properties of the nephron segments in this region of the kidney. With the caveat that the current model needs refinement, it is presented here because it embodies some fundamental concepts that underlie the process.


Physiology_Levy

Physiology_Levy. In the current model the medullary interstitial osmotic gradient is established by a process termed countercurrent multiplication. By this process, solute (principally NaCl) is reabsorbed without water from the ascending limb of Henle’s loop into the surrounding medullary interstitium. This decreases the osmolality in the tubular fluid and raises the osmolality of the interstitium at this point. The increased osmolality of the interstitium then causes water to be reabsorbed from the descending limb of Henle’s loop, thus increasing the tubular fluid osmolality in this segment. Thus at any point along the loop of Henle the fluid in the ascending limb has an osmolality less than fluid in the adjacent descending limb. This osmotic difference was termed the single effect. Because of the countercurrent flow of tubular fluid in the descending (fluid flowing into the medulla) and ascending (fluid flow out of the medulla) limbs, this single effect could be multiplied, resulting in an osmotic


Physiology_Levy

Physiology_Levy. flow of tubular fluid in the descending (fluid flowing into the medulla) and ascending (fluid flow out of the medulla) limbs, this single effect could be multiplied, resulting in an osmotic gradient within the medullary interstitium, where the tip of the papilla has an osmolality of 1200 mOsm/kg H2O compared to 300 mOsm/kg H2O at the corticomedullary junction.


Physiology_Levy

Physiology_Levy. Fig. 35.7 schematically depicts the processes for excreting a dilute urine (water diuresis) as well as a concentrated urine (antidiuresis). Three key concepts underlie these processes: 1. Urine is concentrated by AVP-dependent reabsorption of water from the collecting duct. 2. Reabsorption of NaCl from the ascending limb of Henle’s loop dilutes the tubular fluid and at the same time generates a high [NaCl] in the medullary interstitium (up to 600 mmol/L at the tip of the papilla), which then drives water reabsorption from the collecting duct. 3. Urea accumulates in the medullary interstitium (up to 600 mmol/L), which allows the kidneys to excrete urine with the same high urea concentration. This allows large amounts of urea to be excreted with relatively little water. First, how the kidneys excrete dilute urine (water diure sis) when AVP levels are low or zero is considered. The following numbers refer to those encircled in


Physiology_Levy

Physiology_Levy. Fig. 35.7A + AVP: 140 − AVP: 140 + AVP: 290 Cortex + AVP: 1200 + AVP: 1200 − AVP: 600 − AVP: 50 • Fig. 35.6 Tubular fluid osmolality along the nephron in the presence (+AVP) and in the absence (−AVP) of arginine vasopressin. See text for details. (Adapted from Sands JM et al. Urine concentration and dilution. In: Brenner and Rector’s The Kidney. 9th ed. Philadelphia: Saunders; 2012.) 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 ). (NOTE: Water is reabsorbed from the segments of the proximal tubule via AQP1.) 2.


Physiology_Levy

Physiology_Levy. Water is reabsorbed from the thin descending limb of Henle’s loop. Most of this water is reabsorbed in the outer medulla, thereby limiting the amount of water added to the deepest part of the inner medullary interstitial space and thus preserving the hyperosmolality of this region of the medulla. (NOTE: Water is reabsorbed via AQP1.) 3. In the inner medulla the terminal portion of the descending thin limb and all of the thin ascending limb is impermeable to water. (NOTE: AQP1 is not expressed.) These same nephron segments express the Cl− channel CLC-K1, which mediates Cl− reabsorption, with Na+ following via the paracellular pathway. This passive reabsorption of NaCl without concomitant water reabsorption begins the process of diluting the tubular fluid. 4.


Physiology_Levy

Physiology_Levy. 4. The thick ascending limb of the loop of Henle is also impermeable to water and actively reabsorbs NaCl from the tubular fluid and thereby dilutes it further (see ). 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 (see Fig. 35.6 5. The distal tubule and cortical portion of the collecting duct actively reabsorb NaCl. In the absence of AVP these segments are not permeable to water (i.e., AQP2 is not present in the apical membrane of the cells). Thus when AVP 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 (see Fig. 35.6 6.


Physiology_Levy

Physiology_Levy. Fig. 35.6 6. The medullary collecting duct actively reabsorbs NaCl. Even in the absence of AVP, this segment is slightly permeable to water and some water is reabsorbed. 7. The urine has an osmolality as low as approximately 50 mOsm/kg H2O and contains low concentrations of NaCl. 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 AVP levels are high is considered. The following numbers refer to those encircled in Fig. 35.7B : 1–4. These steps are similar to those for production of dilute urine. An important point in understanding how a concentrated urine is produced is to recognize that while 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.


Physiology_Levy

Physiology_Levy. • Fig. 35.7 Schematic of nephron segments involved in urine dilution and concentration. Henle’s loops of juxtamedullary nephrons are shown. A, Mechanism for excretion of dilute urine (water diuresis). AVP) is absent and the collecting duct is essentially impermeable to water. Note also that during a 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 excretion of a concentrated urine (antidiuresis). Plasma AVP levels are maximal and the collecting duct is highly permeable to water. Under this condition the medullary interstitial gradient is maximal. See text for details.


Physiology_Levy

Physiology_Levy. Accumulation of NaCl in the medullary interstitium is crucial for production of urine hyperosmotic to plasma, because it provides the osmotic driving force for water reabsorption by the medullary collecting duct. As already noted, AVP stimulates NaCl reabsorption 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. 5.


Physiology_Levy

Physiology_Levy. 5. Because of NaCl reabsorption by the ascending limb of the loop of Henle, the fluid reaching the collecting duct is hypoosmotic with respect to the surrounding interstitial fluid. Thus an osmotic gradient is established across the collecting duct. In the presence of AVP, which increases the water permeability of the latter portion of the distal tubule and the collecting duct by causing insertion of AQP2 into the luminal membrane of the cells, water diffuses out of the tubule lumen and the tubule fluid osmolality increases. This diffusion of water out of the lumen of the collecting duct begins the process of urine concentration. The maximum osmolality the fluid in the distal tubule and cortical portion of the collecting duct can attain is approximately 290 mOsm/kg H2O (i.e., the same as plasma), which is the osmolality of the interstitial fluid and plasma within the cortex of the kidney. 6.


Physiology_Levy

Physiology_Levy. 6. As the tubular fluid descends deeper into the medulla, water continues to be reabsorbed from the collecting duct, increasing the tubular fluid osmolality to 1200 mOsm/ kg H2O at the tip of the papilla. 7. The urine produced when AVP levels are elevated has an osmolality of 1200 mOsm/kg H2O and contains high concentrations of urea and other nonreabsorbed solutes. Urine volume under this condition can be as low as 0.5 L/day.


Physiology_Levy

Physiology_Levy. In comparing the two conditions just described, it should be apparent that a relatively constant volume of dilute tubular fluid is delivered to the AVP-sensitive portions of the nephron (latter portion of the distal tubule and collecting duct). Plasma AVP levels then determine the amount of water reabsorbed by these segments. When AVP levels are low, a relatively small volume of water is reabsorbed by these segments and a large volume of hypoosmotic urine is excreted (up to 10% of the filtered water). When AVP levels are high, a large volume of water is reabsorbed by these same segments and a small volume of hyperosmotic urine is excreted (<1% of filtered water). During antidiuresis, most of the water is reabsorbed in the distal tubule and cortical and outer medullary portions of the collecting duct. Thus a relatively small volume of fluid reaches the inner medullary collecting duct where it is then reabsorbed. This distribution of water reabsorption along the length of the collecting


Physiology_Levy

Physiology_Levy. duct. Thus a relatively small volume of fluid reaches the inner medullary collecting duct where it is then reabsorbed. This distribution of water reabsorption along the length of the collecting duct (i.e., cortex > outer medulla > inner medulla) allows for maintenance of a hyperosmotic interstitial environment in the inner medulla by minimizing the amount of water entering this compartment.


Physiology_Levy

Physiology_Levy. • Fig. 35.8 The medullary interstitial gradient comprises primarily NaCl and urea. The concentrations for NaCl and urea depicted reflect those found in the antidiuretic state (i.e., excretion of hyperosmotic urine). See text for details. (Adapted from Sands JM et al. Urine concentration and dilution. In: Brenner and Rector’s The Kidney. 9th ed. Philadelphia: Elsevier; 2012.) 100200300400500600Concentration(mmol/L)CortexO termed llaInnerMed llaUreaNacl


Physiology_Levy

Physiology_Levy. As noted earlier, the interstitial fluid of the renal medulla is critically important in concentrating urine. The osmotic pressure of the interstitial fluid provides the driving force for reabsorbing water from both the descending thin limb of the loop of Henle and the collecting duct. The principal solutes of the medullary interstitial fluid are NaCl and urea, but the concentration of these solutes is not uniform throughout the medulla (i.e., a gradient exists from cortex to papilla). Other solutes also accumulate in the medullary interstitium (e.g., NH4 + and K+), but the most abundant solutes are NaCl and urea. For simplicity, this discussion assumes that NaCl and urea are the only solutes.


Physiology_Levy

Physiology_Levy. Fig. 35.8 , NaCl and urea accumulate in the renal medulla, and the interstitial fluid at the tip of the papilla of the inner medulla reaches a maximum osmolality of 1200 mOsm/kg H2O, with approximately 600 mOsm/kg H2O attributable to NaCl (300 mmol/L) and 600 mOsm/ kg H2O attributable to urea (600 mmol/L). Establishment of the NaCl gradient is essentially complete at the transition between the outer and inner medulla. The medullary gradient for NaCl results from accumulation of NaCl reabsorbed by the nephron segments in the medulla during countercurrent multiplication. The most important segment in this regard is the ascending limb of the loop of Henle. Urea accumulation within the medullary interstitium is more complex and occurs most effectively when hyperosmotic urine is excreted (i.e., antidiuresis). When dilute urine is produced, especially over extended periods, the osmolality of the medullary interstitium declines (see


Physiology_Levy

Physiology_Levy. Fig. 37.7A ). This reduced osmolality is almost entirely caused by a decrease in the concentration of urea. This decrease reflects washout by the vasa recta (discussed later) and diffusion of urea from the interstitium into the tubular fluid within the medullary portion of the collecting duct, which is permeable to urea even in the absence of AVP. (NOTE: The cortical and outer medullary portions of the collecting duct have a low permeability to urea, whereas the inner medullary portion has a relatively high permeability because of the presence of the urea transporters UT-A1 and UT-A3, the expression of which is increased by AVP.) Some of this reabsorbed urea is secreted into the thin descending limbs of Henle’s loops via the urea transporter UT-A2, and some enters the vasa recta via the UT-B transporter. The urea that is secreted into the descending thin limbs of Henle’s loops is then trapped in the nephron until it again reaches the medullary collecting duct, where it can reenter the


Physiology_Levy

Physiology_Levy. transporter. The urea that is secreted into the descending thin limbs of Henle’s loops is then trapped in the nephron until it again reaches the medullary collecting duct, where it can reenter the medullary interstitium. Thus urea recycles from the interstitium to the nephron and back into the interstitium. This process of urea recycling facilitates accumulation of urea in the medullary interstitium, where it can attain a concentration at the tip of the papilla of 600 mmol/L.


Physiology_Levy

Physiology_Levy. As described, the hyperosmotic medulla is essential for concentrating the tubular fluid within the collecting duct. Because water reabsorption from the collecting duct is driven by the osmotic gradient established in the medullary interstitium, urine can never be more concentrated than that of the interstitial fluid in the papilla. Thus any condition that reduces the medullary interstitial osmolality impairs the ability of the kidneys to maximally concentrate urine. Urea within the medullary interstitium contributes to the total osmolality of the urine. However, because the inner medullary collecting duct is highly permeable to urea, especially in the presence of AVP, urea cannot drive water reabsorption across this nephron segment. Instead, urea in the tubular fluid and medullary interstitium equilibrate, and a small volume of urine with a high concentration of urea is excreted.


Physiology_Levy

Physiology_Levy. It is the medullary interstitial NaCl concentration that is responsible for reabsorbing water from the medullary collecting duct and thereby concentrating the nonurea solutes (e.g., NH4 + salts, K+ salts, creatinine) in the urine.


Physiology_Levy

Physiology_Levy. The vasa recta, the capillary networks that supply blood to the medulla, are highly permeable to solute and water. As with the loop of Henle, the vasa recta form a parallel set of hairpin loops within the medulla (see ). Not only do the vasa recta bring nutrients and oxygen to the medullary nephron segments, but more importantly they also remove the excess water and solute that is continuously added to the medullary interstitium by these nephron seg eOn a typical diet the kidneys must excrete 450 mmol/day of urea. At a maximal urine [urea] of 600 mmol/L this amount of urea can be excreted in less than 1 L of urine. However, if the maximal urine [urea] is reduced because of a decrease in the medullary interstitial fluid [urea], a larger urine volume would be needed to excrete the 450 mmol/day of urea (e.g., 2.25 L of urine would be required if the maximal urine [urea] was only 200 mM).


Physiology_Levy

Physiology_Levy. CHAPTER 35 Control of Body Fluid Osmolality and Volume ments. The ability of the vasa recta to maintain the medullary interstitial gradient is flow dependent. A substantial increase in vasa recta blood flow dissipates the medullary gradient (i.e., washout of osmoles from the medullary interstitium). Alternatively, reduced blood flow reduces oxygen delivery to the nephron segments within the medulla. Because transport of salt and other solutes requires oxygen and ATP, reduced medullary blood flow decreases salt and solute transport by nephron segments in the medulla. As a result the medullary interstitial osmotic gradient cannot be maintained. Assessment of Renal Diluting and Concentrating Ability


Physiology_Levy

Physiology_Levy. Assessment of Renal Diluting and Concentrating Ability Assessment of renal water handling includes measurements of urine osmolality and the volume of urine excreted. The range of urine osmolality is from 50 to 1200 mOsm/kg H2O. The corresponding range in urine volume is 18 L to as little as 0.5 L/day. These ranges are not fixed and vary from individual to individual. They can also be affected by disease processes, and as noted previously they are dependent on the amount of solute the kidneys must also excrete. The ability of the kidneys to dilute or concentrate urine requires the separation of solute and water (i.e., the single effect of the countercurrent multiplication process). This separation of solute and water in essence generates a volume of water that is “free of solute.” When urine is dilute, solute-free water is excreted from the body. When urine is concentrated, solute-free water is returned to the body (i.e., conserved).


Physiology_Levy

Physiology_Levy. For the kidneys to maximally excrete solute-free water (i.e., 18 L/day) the following conditions must be met: 1. AVP must be absent; without it the collecting duct does not reabsorb a significant amount of water. 2. The tubular structures that separate solute from water (i.e., dilute the tubule fluid) must function normally. In the absence of AVP the following nephron segments can dilute the luminal fluid: ascending thin limb of Henle’s loop thick ascending limb of Henle’s loop Because of its high transport rate, the thick ascending limb is quantitatively the most important nephron segment involved in the separation of solute and water.


Physiology_Levy

Physiology_Levy. Because of its high transport rate, the thick ascending limb is quantitatively the most important nephron segment involved in the separation of solute and water. 3. An adequate amount of tubular fluid must be delivered to the aforementioned nephron sites for maximal separation of solute and water. Factors that reduce delivery (e.g., decreased GFR or enhanced proximal tubule reabsorption) impair the kidneys’ ability to maximally excrete solute-free water. Similar requirements also apply to conservation of water by the kidneys. For the kidneys to conserve water maximally (6–8 L/day) the following conditions must be met: 1. An adequate amount of tubular fluid must be delivered to those nephron segments that separate solute from water; the most important segment in this regard is the


Physiology_Levy

Physiology_Levy. In response to elevated AVP levels In response to decreased AVP levelsthe kidneys retain 1 L of water the kidneys excrete 1 L of waterreturning osmolality and [Na˜] returning osmolality and [Na˜]to normal, but increasing ECF volume. to normal, but reducing ECF volume.


Physiology_Levy

Physiology_Levy. • Fig. 35.9 Impact of changes in Na+ balance on ECFV. (1) Addition of NaCl (without water) to the ECF increases the [Na+] and osmolality. (2) The increase in ECF osmolality stimulates secretion of AVP from the posterior pituitary, which than acts on the kidneys to conserve water. (3) Decreased renal excretion of water together with water ingestion restore plasma osmolality and plasma [Na+] to normal. However, the ECFV is now increased by 1 L. (4) Removal of NaCl (without water) from the ECF decreases plasma [Na+] and plasma osmolality. (5) The decrease in ECF osmolality inhibits AVP secretion. In response to the decrease in plasma AVP the kidneys excrete water. (6) Increased renal excretion of water returns the plasma [Na+] and plasma osmolality to normal. However, ECFV is now decreased by 1 L. As illustrated, changes in Na+ balance alter ECFV because of the efficiency of the AVP system to maintain normal body fluid osmolality. (Adapted from Koeppen BM, Stanton BA. Renal Physiology.


Physiology_Levy

Physiology_Levy. by 1 L. As illustrated, changes in Na+ balance alter ECFV because of the efficiency of the AVP system to maintain normal body fluid osmolality. (Adapted from Koeppen BM, Stanton BA. Renal Physiology. 5th ed. Philadelphia: Elsevier; 2013.) thick ascending limb of Henle’s loop. Delivery of tubular fluid to Henle’s loop depends on GFR and proximal tubule reabsorption.


Physiology_Levy

Physiology_Levy. 2. Reabsorption of NaCl by the nephron segments must be normal; again, the most important segment is the thick ascending limb of Henle’s loop. 3. A hyperosmotic medullary interstitium must be present. The interstitial fluid osmolality is maintained by NaCl reabsorption by Henle’s loop (conditions 1 and 2) and by effective accumulation of urea. Urea accumulation in turn depends on adequate dietary protein intake. 4. Maximum levels of AVP must be present and the collecting duct must respond normally to AVP. Control of Extracellular Fluid Volume and Regulation of Renal NaCl Excretion The major solutes of ECF are the salts of Na+ (see also the major determinant of ECF osmolality, alterations in Na+ balance are commonly assumed to disturb ECF osmolality. However, under normal circumstances this is not the case because the AVP and thirst systems maintain body fluid osmolality within a very narrow range (discussed earlier). As illustrated in


Physiology_Levy

Physiology_Levy. Fig. 35.9 , adding or removing NaCl from ECF changes this body fluid compartment’s volume and not the [Na+] (compare initial condition and final conditions). For example, addition of NaCl to the ECF (without water) increases the [Na+] and osmolality of this compartment. (ICF osmolality also increases because of osmotic equilibration with the ECF.) In response, AVP secretion and thirst are stimulated, and as a result water is ingested and renal water loss is reduced. This restores plasma osmolality (and serum [Na+]) to their initial values, but the volume of the ECF is now increased. The opposite occurs when NaCl is lost from the ECF. Changes in ECF volume (ECFV) can be monitored by measuring body weight, because 1 L of ECF equals 1 kg of ). Of these, NaCl is the most abundant. Because NaCl is body weight.


Physiology_Levy

Physiology_Levy. The kidneys are the major route for excretion of NaCl from the body. Only about 10% of the Na+ lost from the body each day does so by nonrenal routes (e.g., in perspiration and feces). As such, the kidneys are critically important in regulating ECFV. Under normal conditions the kidneys keep ECFV constant (a state termed euvolemia) by adjusting the excretion of NaCl to match the amount ingested in the diet. If ingestion exceeds excretion, ECFV increases above normal (volume expansion), whereas the opposite occurs if excretion exceeds ingestion (volume contraction).


Physiology_Levy

Physiology_Levy. The typical diet contains approximately 140 mEq/day of Na+ (8 g of NaCl), and thus daily Na+ excretion in urine is also about 140 mEq/day. However, the kidneys can vary excretion of Na+ over a wide range. Excretion rates as low as 10 mEq/day can be attained when individuals are placed on a low-salt diet. Conversely, the kidneys can increase their excretion rate to more than 1000 mEq/day when challenged by ingestion of a high-salt diet. These changes in Na+ excretion can occur with only modest changes in the ECFV and Na+ content of the body.


Physiology_Levy

Physiology_Levy. The response of the kidneys to abrupt changes in NaCl intake typically takes several hours to several days, depending on the magnitude of the change. During this transition period the intake and excretion of Na+ are not matched as they are in the steady state. Thus the individual experiences either positive Na+ balance (intake > excretion) or negative Na+ balance (intake < excretion). However, by the end of the transition period a new steady state is established and intake once again equals excretion. This section reviews the physiology of the receptors that monitor ECFV and explains the various signals that act on the kidneys to regulate NaCl excretion and thereby ECFV. In addition, responses of the various portions of the nephron to these signals is considered.


Physiology_Levy

Physiology_Levy. Concept of Effective Circulating Volume , the ECF is subdivided into two compartments: blood plasma and interstitial fluid. Plasma volume is a determinant of vascular volume and thus blood pressure and cardiac output. Maintenance of Na+ balance, and thus ECFV, involves a complex system of sensors and effector signals that act primarily on the kidneys to regulate NaCl excretion. As can be appreciated from the dependency of vascular volume, blood pressure, and cardiac output on ECFV, this complex system is designed to ensure adequate tissue perfusion. Because the primary sensors of this system are located in the large vessels of the vascular system, changes in vascular volume, blood pressure, and cardiac output are the principal factors regulating renal NaCl excretion (discussed later). In a healthy individual, changes in ECFV result in parallel changes in vascular volume, blood pressure, and cardiac output. Thus a decrease in ECFV results in reduced vascular volume, blood pressure, and


Physiology_Levy

Physiology_Levy. healthy individual, changes in ECFV result in parallel changes in vascular volume, blood pressure, and cardiac output. Thus a decrease in ECFV results in reduced vascular volume, blood pressure, and cardiac output. Conversely, an increase in ECFV results in increased vascular volume, blood pressure, and cardiac output. The degree to which these cardiovascular parameters


Physiology_Levy

Physiology_Levy. CHAPTER 35 Control of Body Fluid Osmolality and Volume change is dependent upon the degree of ECFV contraction or expansion and the effectiveness of cardiovascular reflex mechanisms (see ). When a person is in negative Na+ balance, ECFV is decreased and renal NaCl excretion is reduced. Conversely, with positive Na+ balance there is an increase in ECFV, which results in enhanced renal NaCl excretion (i.e., natriuresis).


Physiology_Levy

Physiology_Levy. However, in some pathological conditions (e.g., congestive heart failure, hepatic cirrhosis), renal excretion of NaCl does not reflect the ECFV. In both of these situations the volume of the ECF is increased. However, instead of increased renal NaCl excretion, as would be expected, renal excretion of NaCl is reduced. To explain renal Na+ handling in these situations, it is necessary to understand the concept of effective circulating volume (ECV). Unlike ECF, ECV is not a measurable and distinct body fluid compartment. Effective circulating volume refers to that portion of the ECF that is contained within the vascular system and is “effectively” perfusing the tissues (effective blood volume and effective arterial blood volume are other commonly used terms). More specifically the ECV reflects the activity of volume sensors located in the vascular system (discussed later).


Physiology_Levy

Physiology_Levy. Patients with congestive heart failure frequently have an increase in ECFV that manifests as increased plasma volume and accumulation of interstitial fluid in the lungs (pulmonary edema) and peripheral tissues (generalized edema). This excess fluid is the result of NaCl and water retention by the kidneys. The kidneys’ response (i.e., retention of NaCl and water) is paradoxical because the ECFV is increased. However, this fluid is not in the vascular system but rather in the interstitial fluid compartment. In addition, blood pressure and cardiac output may be reduced because of poor cardiac performance. Therefore the sensors located in the vascular system respond as they do in ECFV contraction and cause NaCl and water retention by the kidneys. In this situation the ECV, as monitored by the volume sensors, is decreased.


Physiology_Levy

Physiology_Levy. In healthy individuals, ECV varies directly with ECFV and in particular the volume of the vascular system (arterial and venous), the arterial blood pressure, and cardiac output. However, as noted this is not the case in certain pathological conditions. In the remaining sections of this chapter the relationship between ECFV and renal NaCl excretion in healthy adults—where changes in ECV and ECFV occur in parallel—are examined. ECFV (or ECV) is monitored by multiple sensors. A number of these sensors are located in the vascular system, and they monitor its fullness and pressure. These receptors are typically called vascular volume receptors, or because they respond to pressure-induced stretch of the walls of the structure in which they are located (e.g., blood vessels or the cardiac atria and ventricles), they are also referred to as baroreceptors. Volume Sensors in the Low-Pressure Cardiopulmonary Circuit


Physiology_Levy

Physiology_Levy. Volume Sensors in the Low-Pressure Cardiopulmonary Circuit Volume sensors (i.e., baroreceptors) are located within the walls of the left and right atria, right ventricle, and large pulmonary vessels, and they respond to distention of these structures (see 19). Because the low-pressure side of the circulatory system has a high compliance, these sensors respond mainly to the “fullness” of the vascular system. These baroreceptors send signals to the brainstem via afferent fibers in the glossopharyngeal and vagus nerves (cranial nerves IX and X). The activity of these sensors modulates both sympathetic nerve outflow and AVP secretion. For example, a decrease in filling of the pulmonary vessels and cardiac atria increases sympathetic nerve activity and stimulates AVP secretion. Conversely, distention of these structures decreases sympathetic nerve activity. In general, 5% to 10% changes in blood volume and pressure are necessary to evoke a response.


Physiology_Levy

Physiology_Levy. The cardiac atria possess an additional mechanism related to control of renal NaCl excretion. The myocytes of the atria synthesize and store a peptide hormone, atrial natriuretic peptide (ANP). It is released when the atria are distended and, via mechanisms outlined later in this chapter, reduces blood pressure and increases excretion of NaCl and water by the kidneys. The ventricles of the heart also produce a natriuretic peptide, brain natriuretic peptide (BNP), so named because it was first isolated from the brain. Like ANP, BNP is released from myocytes by distention of the ventricles. Its actions are similar to those of ANP. Volume Sensors in the High-Pressure Arterial Circuit


Physiology_Levy

Physiology_Levy. Volume Sensors in the High-Pressure Arterial Circuit Baroreceptors are also present in the arterial side of the circulatory system, located in the wall of the aortic arch, carotid sinus, and afferent arterioles of the kidneys. The aortic arch and carotid baroreceptors send input to the brainstem via afferent fibers in the glossopharyngeal and vagus nerves (cranial nerves IX and X). The response to this input alters sympathetic outflow and AVP secretion. Thus a decrease in blood pressure increases sympathetic nerve activity and AVP secretion. An increase in pressure tends to reduce sympathetic nerve activity (and activate parasympathetic nerve activity). The sensitivity of the high-pressure baroreceptors is similar to that in the low-pressure side of the vascular system; 5% to 10% changes in pressure are needed to evoke a response.


Physiology_Levy

Physiology_Levy. The juxtaglomerular apparatus (JGA) of the kidneys (see ), particularly the afferent arteriole, responds fThe liver and central nervous system also have sensors that respond to changes in blood pressure and [Na+] and then signal the kidneys to alter NaCl excretion. These systems do not appear to be as important as vascular receptors in monitoring changes in ECFV and effecting changes in renal NaCl excretion and are not considered here. directly to changes in pressure. If perfusion pressure in the afferent arteriole is reduced, renin is released from the granular cells. By contrast, renin secretion is suppressed when perfusion pressure is increased. As described later in this chapter, renin determines blood levels of angiotensin II and aldosterone, both of which reduce renal NaCl excretion.


Physiology_Levy

Physiology_Levy. Constriction of a renal artery (e.g., by an atherosclerotic plaque) reduces perfusion pressure to that kidney. This reduced perfusion pressure is sensed by the afferent arteriole of the JGA and results in renin secretion. The elevated renin levels increase the production of angiotensin II, which in turn increases systemic blood pressure via its vasoconstrictor affect on arterioles throughout the vascular system. The increased systemic blood pressure is sensed by the JGA of the contralateral kidney (i.e., the kidney without stenosis of its renal artery), and renin secretion from that kidney is suppressed. In addition the high levels of angiotensin II also inhibit renin secretion by the contralateral kidney (negative feedback). Treatment of patients with constricted renal arteries includes surgical repair of the stenotic artery, administration of angiotensin II receptor blockers, or administration of an inhibitor of angiotensin-converting enzyme (ACE). The ACE inhibitor blocks


Physiology_Levy

Physiology_Levy. includes surgical repair of the stenotic artery, administration of angiotensin II receptor blockers, or administration of an inhibitor of angiotensin-converting enzyme (ACE). The ACE inhibitor blocks conversion of angiotensin I to angiotensin II.


Physiology_Levy

Physiology_Levy. When the vascular volume sensors have detected a change in ECFV, they send signals to the kidneys, which results in an appropriate adjustment in NaCl and water excretion. Accordingly, when the ECFV is expanded, renal NaCl and water excretion are increased. Conversely, when the ECFV is contracted, renal NaCl and water excretion are reduced. The signals involved in coupling the volume sensors to the kidneys are both neural and hormonal. These are summarized in Box 35.1 , as are their effects on renal NaCl and water excretion. , sympathetic nerve fibers innervate the afferent and efferent arterioles of the glomerulus as well as the cells of the nephron. With ECFV contraction, activation of the lowand high-pressure vascular baroreceptors results in stimulation of sympathetic nerve activity, including those fibers innervating the kidneys. This stimulation has the following effects: 1.


Physiology_Levy

Physiology_Levy. The afferent and efferent arterioles are constricted (mediated by α-adrenergic receptors). This vasoconstriction (the effect is greater on the afferent arteriole) decreases the hydrostatic pressure within the glomerular capillary lumen, which results in a decrease in GFR. With this decrease in GFR, the filtered amount of Na+ is reduced. 2. Renin secretion is stimulated by the cells of the afferent arterioles (mediated by β-adrenergic receptors). As • BOX 35.1 Signals Involved in Control of Renal NaCl and Water Excretion Renal Sympathetic Nerves (↑Activity: reabsorption along the nephron Renin-Angiotensin-Aldosterone (↑Secretion: II stimulates Na+ reabsorption along the nephron stimulates Na+ reabsorption in the distal tubule and collecting duct and to a lesser degree in the thick ascending limb of Henle’s loop


Physiology_Levy

Physiology_Levy. II stimulates Na+ reabsorption along the nephron stimulates Na+ reabsorption in the distal tubule and collecting duct and to a lesser degree in the thick ascending limb of Henle’s loop Natriuretic Peptides: ANP, BNP & Urodilatin (↑Secretion: ↑NaCl Excretion) and water reabsorption by the collecting duct secretion and inhibition of AVP action on the distal tubule and collecting duct AVP (↑Secretion: ↓H2O Excretion) ↑H2O reabsorption by the distal tubule and collecting duct described later, renin ultimately increases the circulating levels of angiotensin II and aldosterone, both of which stimulate Na+ reabsorption by the nephron.


Physiology_Levy

Physiology_Levy. 3. NaCl reabsorption along the nephron is directly stimulated (mediated by α-adrenergic receptors on the cells of the nephron). Because of the large amount of Na+ reabsorbed by the proximal tubule, the effect of increased sympathetic nerve activity is quantitatively most important for this segment. As a result of these actions, increased renal sympathetic nerve activity decreases NaCl excretion, an adaptive response that works to restore ECFV to normal. With ECFV expansion, renal sympathetic nerve activity is reduced. This generally reverses the effects just described. Cells in the afferent arterioles (juxtaglomerular cells, also known as granular cells) are the site of synthesis, storage, and release of the proteolytic enzyme renin. Three factors are important in stimulating renin secretion: 1.


Physiology_Levy

Physiology_Levy. Perfusion pressure. The afferent arteriole behaves as a high-pressure baroreceptor. When perfusion pressure to the kidneys is reduced, renin secretion is stimulated. Conversely, an increase in perfusion pressure inhibits renin release. 2. Sympathetic nerve activity. Activation of the sympathetic nerve fibers that innervate the afferent arterioles increases renin secretion (mediated by β-adrenergic receptors). CHAPTER 35 Control of Body Fluid Osmolality and Volume Renin secretion is decreased as renal sympathetic nerve activity is decreased.


Physiology_Levy

Physiology_Levy. Renin secretion is decreased as renal sympathetic nerve activity is decreased. 3. Delivery of NaCl to the macula densa. Delivery of NaCl to the macula densa regulates GFR by a process termed tubuloglomerular feedback (see ). In addition the macula densa plays a role in renin secretion. When NaCl delivery to the macula densa is decreased, renin secretion is enhanced. Conversely, an increase in NaCl delivery inhibits renin secretion. It is likely that macula densa–mediated renin secretion helps maintain systemic arterial pressure under conditions of a reduced vascular volume. For example, when vascular volume is reduced, perfusion of body tissues (including the kidneys) decreases. This in turn decreases GFR and the filtered amount of NaCl. The reduced delivery of NaCl to the macula densa stimulates renin secretion, which acts through angiotensin II (a potent vasoconstrictor) to increase blood pressure and thereby maintain tissue perfusion.


Physiology_Levy

Physiology_Levy. Although many tissues express renin (e.g., brain, heart, adrenal gland), juxtaglomerular (JG) cells are the primary source of circulating renin; they are located in the afferent arterioles of the kidneys. Renin secretion is stimulated by a decrease in intracellular [Ca++], a response opposite that of most secretory cells, where secretion is stimulated by an increase in intracellular [Ca++]. Renin secretion is also stimulated by an increase in intracellular cAMP levels. Conversely, anything that increases intracellular [Ca++] will inhibit renin secretion. Renin secretion is also inhibited by increases in intracellular cyclic guanosine monophosphate (cGMP).


Physiology_Levy

Physiology_Levy. Stretch of the afferent arteriole, angiotensin-II, and endothelin increase intracellular [Ca++] and thus inhibit renin secretion by JG cells. The stimulatory effect of sympathetic nerve activity on renin secretion is mediated by norepinephrine, which increases intracellular cAMP (via β-adrenergic receptors). Prostaglandin E2 also increases JG cell cAMP levels and therefore stimulates renin secretion. Natriuretic peptides and nitric oxide (NO) inhibit renin secretion by increasing intracellular cGMP. Control of renin secretion by the macula densa is complex and appears to involve several paracrine factors, including ATP, adenosine, and prostaglandin E2 (see


Physiology_Levy

Physiology_Levy. Fig. 35.10 summarizes the essential components of the renin-angiotensin-aldosterone system (RAAS). Renin alone does not have a physiological function; it functions solely as a proteolytic enzyme. Its substrate is a circulating protein, angiotensinogen, which is produced by the liver. Angiotensinogen is cleaved by renin to yield a 10–amino acid peptide, angiotensin I. Angiotensin I also has no known physiological function, and it is cleaved to an 8–amino acid peptide, angiotensin II, by angiotensin-converting enzyme (ACE) found on the surface of vascular endothelial cells. Lung and renal endothelial cells are important sites for the conversion of angiotensin I to angiotensin II. ACE also • Fig. 35.10 Schematic representation of the essential components of the renin-angiotensin-aldosterone system (RAAS). Activation of this system results in a decrease in excretion of Na+ and water by the kidneys. NOTE: Angiotensin I is converted to angiotensin II by an angiotensin-converting enzyme that


Physiology_Levy

Physiology_Levy. (RAAS). Activation of this system results in a decrease in excretion of Na+ and water by the kidneys. NOTE: Angiotensin I is converted to angiotensin II by an angiotensin-converting enzyme that is present on all vascular endothelial cells. As shown, the endothelial cells within the lungs play a significant role in this conversion process. See text for details.


Physiology_Levy

Physiology_Levy. degrades bradykinin, a potent vasodilator. Angiotensin II has several important physiological functions: 1. stimulation of aldosterone secretion by the adrenal cortex 2. arteriolar vasoconstriction, which increases blood pressure 3. stimulation of AVP secretion and thirst 4. enhancement of NaCl reabsorption by the proximal tubule, thick ascending limb of Henle’s loop, the distal tubule, and the collecting duct (Of these segments the effect on the proximal tubule is quantitatively the largest.) Angiotensin II is an important secretagogue for aldoste rone. An increase in plasma K+ concentration is the other important stimulus for aldosterone secretion (see ). Aldosterone is a steroid hormone produced by the glomerulosa cells of the adrenal cortex and acts in a number of ways on the kidneys (see also


Physiology_Levy

Physiology_Levy. Chapters 34, 36, and ). With regard to regulation of the ECFV, aldosterone reduces NaCl excretion by stimulating its reabsorption by several nephron segments. Most importantly it stimulates NaCl reabsorption in the aldosterone-sensitive distal nephron (ASDN), which consists of the latter portion of the distal tubule and the collecting duct. To a lesser extent it also stimulates NaCl reabsorption by the thick ascending limb of Henle’s loop and the early portion of the distal tubule. Aldosterone sensitivity is conferred by the presence of mineralocorticoid receptors as well as the enzyme 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2). Because the mineralocorticoid receptor also binds glucocorticoids, 11β-HSD2 is required for aldosterone specificity because it metabolizes glucocorticoids and thus prevents them from binding to the mineralocorticoid receptor. The aldosterone-sensitive distal nephron expresses both the mineralocorticoid receptor and 11β-HSD2.


Physiology_Levy

Physiology_Levy. ). In the ASDN it increases the abundance and activity of ENaC in the apical membrane of principal cells. This increases Na+ entry into cells across the apical membrane. Extrusion of Na+ from cells across the basolateral membrane occurs by Na+,K+-ATPase, the abundance of which is also increased by aldosterone. Thus aldosterone increases reabsorption of NaCl from the tubular fluid by distal nephron segments, whereas reduced levels of aldosterone decreases the amount of NaCl reabsorbed by these segments. Although the principal site of action of aldosterone is the ASDN, aldosterone also increases the abundance of the Na+/Cl− symporter in the distal tubule and the Na+/K+/2Cl− symporter in the thick ascending limb of Henle’s loop. Box 35.1 , activation of the RAAS, as occurs with ECFV depletion, decreases excretion of NaCl


Physiology_Levy

Physiology_Levy. Diseases of the adrenal cortex can alter aldosterone levels and thereby impair the ability of the kidneys to maintain Na+ balance and euvolemia. With decreased secretion of aldosterone (hypoaldosteronism), the reabsorption of NaCl, mainly by the aldosterone-sensitive distal nephron, is reduced and NaCl is lost in the urine. Because urinary NaCl loss can exceed the amount of NaCl ingested in the diet, negative Na+ balance ensues and ECFV decreases. In response to ECFV contraction, sympathetic tone is increased and levels of renin, angiotensin II, and AVP are elevated. With increased aldosterone secretion (hyperaldosteronism) the effects are the opposite; NaCl reabsorption by the aldosterone-sensitive distal nephron is enhanced and excretion of NaCl is reduced. Consequently, ECFV is increased, sympathetic tone is decreased, and levels of renin, angiotensin II, and AVP are decreased. As described later, ANP and BNP levels are also elevated in this setting.


Physiology_Levy

Physiology_Levy. by the kidneys. The RAAS is suppressed with ECFV expansion, and renal NaCl excretion is therefore enhanced. The body produces a number of substances that act on the kidneys to increase NaCl excretion (see ). Of these, natriuretic peptides produced by the heart and kidneys are best understood and will be the focus of the following discussion. The heart produces two natriuretic peptides. Atrial myocytes produce and store the peptide hormone ANP, and ventricular myocytes produce and store BNP. Both peptides are secreted when the heart dilates (i.e., during volume expansion, with heart failure), and they relax vascular smooth muscle and promote NaCl and water excretion by the kidneys. The kidneys also produce a related natriuretic peptide termed urodilatin. Its actions are limited to promoting NaCl excretion by the kidneys. In general the actions of these natriuretic peptides as they relate to renal NaCl and water excretion antagonize those of the RAAS. These actions include: 1.


Physiology_Levy

Physiology_Levy. Vasodilation of the afferent and vasoconstriction of the efferent arterioles of the glomerulus. This increases the GFR and the filtered amount of NaCl. 2. Inhibition of renin secretion by the afferent arterioles. 3. Inhibition of aldosterone secretion by the glomerulosa cells of the adrenal cortex. This occurs via two mechanisms: (a) inhibition of renin secretion by the juxtaglomerular cells, thereby reducing angiotensin II– induced aldosterone secretion, and (b) direct inhibition of aldosterone secretion by the glomerulosa cells of the adrenal cortex. 4. Inhibition of NaCl reabsorption by the collecting duct, which is also caused in part by reduced levels of aldosterone. However, natriuretic peptides increase cGMP, which inhibits cation channels in the apical membrane of medullary collecting duct cells and thereby decreases NaCl reabsorption.


Physiology_Levy

Physiology_Levy. CHAPTER 35 Control of Body Fluid Osmolality and Volume 5. Inhibition of AVP secretion by the posterior pituitary and AVP action on the collecting duct. These effects decrease water reabsorption by the collecting duct and thus increase excretion of water in the urine. The net effect of natriuretic peptides is to increase excre tion of NaCl and water by the kidneys. Hypothetically a reduction in circulating levels of these peptides would be expected to decrease NaCl and water excretion, but convincing evidence for this has not been reported. As discussed previously, a decreased ECFV stimulates AVP secretion by the posterior pituitary. Elevated levels of AVP decrease water excretion by the kidneys, which serves to reestablish euvolemia. Control of NaCl Excretion During Euvolemia


Physiology_Levy

Physiology_Levy. Control of NaCl Excretion During Euvolemia Maintenance of Na+ balance and therefore euvolemia requires precise matching of the amount of NaCl ingested with the amount excreted from the body. As already noted the kidneys are the major route for NaCl excretion. Accordingly, in a euvolemic individual we can equate daily urine NaCl excretion with daily NaCl intake. As noted, the amount of NaCl excreted by the kidneys can vary widely. Under conditions of salt restriction (i.e., low-NaCl diet), virtually no NaCl appears in the urine. Conversely, in individuals who ingest large quantities of NaCl, renal NaCl excretion can exceed 1000 mEq/day. The time course for adjustment of renal NaCl excretion varies (hours to days) and depends on the magnitude of the change in NaCl intake. Acclimation to large changes in NaCl intake requires a longer time than acclimation to small changes in intake. The general features of NaCl transport along the nephron are illustrated in


Physiology_Levy

Physiology_Levy. The general features of NaCl transport along the nephron are illustrated in Fig. 35.11 . Most (67%) of the Na+ filtered by the glomerulus is reabsorbed by the proximal tubule. An additional 25% is reabsorbed by the thick ascending limb of the loop of Henle, and the remainder by the distal tubule and collecting duct. In a normal adult the filtered amount (load) of Na+ is approximately 25,000 mEq/day: Equation 35.1 Filtered load of Na+= (GFR) × (Plasma [Na+ ]) = (180 L/day) × (140 mEq/L) , mEq/day With a typical diet, less than 1% of this filtered load is excreted in urine (≈140 mEq/day). Because of the large filtered load of Na+ , small changes in its reabsorption by the nephron can profoundly affect Na+ balance and thus ECFV. For example, an increase in Na+ excretion from 1% gThe percentage of the filtered load excreted in urine is termed fractional excretion. In this example the fractional excretion of Na+ is 140 mEq/day ÷ 25,200 mEq/day = 0.005, or 0.5%.


Physiology_Levy

Physiology_Levy. • Fig. 35.11 Segmental Na+ reabsorption. The percentage of the filtered load of Na+ reabsorbed by each nephron segment is indicated. PT, proximal tubule; TAL, thick ascending limb; DT, distal tubule; CD, cortical collecting duct. to 3% of the filtered load represents an additional loss of approximately 500 mEq/day of Na+ . Because the ECF Na+ concentration is 140 mEq/L, such a Na+ loss would decrease the ECFV by more than 3 L (i.e., water excretion would parallel the loss of Na+ to maintain body fluid osmolality constant: 500 mEq/day ÷ 140 mEq/L = 3.6 L/day of fluid loss). Such fluid loss in a 70-kg individual would represent a 26% decrease in ECFV.


Physiology_Levy

Physiology_Levy. In euvolemic individuals the nephron segments distal to the loop of Henle (distal tubule and collecting duct) are the main nephron segments where Na+ reabsorption is adjusted to maintain excretion at a level appropriate for dietary intake. However, this does not mean the other portions of the nephron are not involved in this process. Because the reabsorptive capacity of the distal tubule and collecting duct is limited, these other portions of the nephron (i.e., proximal tubule and loop of Henle) must reabsorb the bulk of the filtered load of Na+ . Thus during euvolemia, Na+ handling by the nephron can be explained by two general processes: 1.


Physiology_Levy

Physiology_Levy. Na+ reabsorption by the proximal tubule and loop of Henle is regulated so that a relatively constant portion of the filtered load of Na+ is delivered to the distal tubule. The combined action of the proximal tubule and loop of Henle reabsorbs approximately 92% of the filtered load of Na+ , and thus 8% of the filtered load is delivered to the distal tubule. 2. Reabsorption of this remaining portion of the filtered load of Na+ by the distal tubule and collecting duct is regulated so that the amount of Na+ excreted in the urine matches the amount ingested in the diet. Thus these later nephron segments make final adjustments in Na+ excretion to maintain the euvolemic state. Mechanisms for Maintaining Constant Delivery of NaCl to the Distal Tubule


Physiology_Levy

Physiology_Levy. Mechanisms for Maintaining Constant Delivery of NaCl to the Distal Tubule A number of mechanisms maintain a constant delivery of Na+ to the beginning of the distal tubule. These processes are autoregulation of the GFR (and thus the filtered load of Na+), glomerulotubular balance, and load dependency of Na+ reabsorption by the loop of Henle. Autoregulation of the GFR (see ) allows maintenance of a relatively constant filtration rate over a wide range of perfusion pressures. Because the filtration rate is constant, the filtered load of Na+ is also constant.


Physiology_Levy

Physiology_Levy. Despite the autoregulatory control of GFR, small variations occur. If these changes are not compensated for by an appropriate adjustment in Na+ reabsorption by the nephron, Na+ excretion would change markedly. Fortunately, Na+ reabsorption in the euvolemic state, especially by the proximal tubule, changes in parallel with changes in GFR. This phenomenon is termed glomerulotubular balance. Thus if GFR increases, the amount of Na+ reabsorbed by the proximal tubule also increases. The opposite occurs if GFR decreases (see for a more detailed description of glomerulotubular balance). The final mechanism that helps maintain constant delivery of Na+ to the distal tubule and collecting duct involves the ability of the loop of Henle to increase its reabsorptive rate in response to increased delivery of Na+ . Regulation of Distal Tubule and Collecting Duct NaCl Reabsorption


Physiology_Levy

Physiology_Levy. Regulation of Distal Tubule and Collecting Duct NaCl Reabsorption When delivery of Na+ is constant, small adjustments in Na+ reabsorption, primarily by the ASDN, are sufficient to balance excretion with intake. Aldosterone is the primary regulator of Na+ reabsorption by the ASDN and thus of NaCl excretion. When aldosterone levels are elevated, Na+ reabsorption by these segments is increased (Na+ excretion is decreased). When aldosterone levels are decreased, Na+ reabsorption is decreased (NaCl excretion is increased). Other factors have been shown to alter Na+ reabsorption by the ASDN (e.g., angiotensin II and natriuretic peptides), but their role during euvolemia is unclear.


Physiology_Levy

Physiology_Levy. As long as variations in dietary intake of NaCl are minor, the mechanisms previously described can regulate renal Na+ excretion appropriately and thereby maintain euvolemia. However, these mechanisms cannot effectively handle significant changes in NaCl intake. When NaCl intake changes significantly, ECFV expansion or contraction occurs. In such cases, additional factors act on the kidneys to adjust Na+ excretion and thereby reestablish the euvolemic state. Control of NaCl Excretion With Volume Expansion


Physiology_Levy

Physiology_Levy. Control of NaCl Excretion With Volume Expansion During ECFV expansion, the high-pressure and low-pressure vascular volume sensors send signals to the kidneys that result in increased excretion of NaCl and water. The signals acting on the kidneys include: ˜ AVP ° ANP and BNP Heart Brain ˜ Aldosterone Lung Adrenal gland ° Na+, H2O excretion ˜ Renin ° Urodilatin ˜ Sympathetic activity 2 1 3 ˜ Angiotensin I ˜ Angiotensin II Volume expansion UNa+V = °GFR ˜PNa+ – ˜R • Fig. 35.12 Integrated response to ECFV expansion. Numbers refer to the description of the response in the text. ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; GFR, glomerular filtration rate; PNa+, plasma [Na+]; R, tubular reabsorption of Na+; UNa+V, Na+ excretion rate. 1. decreased activity of renal sympathetic nerves 2. release of ANP and BNP from the heart and urodilatin in the kidneys 3. inhibition of AVP secretion from the posterior pituitary and decreased AVP action on the collecting duct 4.


Physiology_Levy

Physiology_Levy. release of ANP and BNP from the heart and urodilatin in the kidneys 3. inhibition of AVP secretion from the posterior pituitary and decreased AVP action on the collecting duct 4. decreased renin secretion and thus decreased production of angiotensin II 5. decreased aldosterone secretion, which is caused by reduced angiotensin II levels, and elevated natriuretic peptide levels The integrated response of the nephron to these signals is Fig. 35.12 . Three general responses to ECFV expansion occur (the numbers match those encircled in


Physiology_Levy

Physiology_Levy. Fig. 35.12 . Three general responses to ECFV expansion occur (the numbers match those encircled in Fig. 35.12 1. GFR increases. GFR increases mainly as a result of the decrease in sympathetic nerve activity. Sympathetic fibers innervate the afferent and efferent arterioles of the glomerulus and control their diameter. Decreased sympathetic nerve activity leads to arteriolar dilation and an increase in renal plasma flow (RPF). Because the effect appears to be greater on the afferent arterioles, the hydrostatic pressure within the glomerular capillary is increased, thereby increasing the GFR. Because RPF increases to a greater degree than GFR, the filtration fraction (GFR/RPF) decreases. Natriuretic peptides also increase GFR by dilating the afferent arterioles and constricting the efferent arterioles. Thus the increased natriuretic peptide levels that occur during ECFV expansion contribute to this response. With the increase in GFR, the filtered load of Na+ increases.


Physiology_Levy

Physiology_Levy. 2. The reabsorption of Na+ decreases in the proximal tubule and loop of Henle. Several mechanisms reduce Na+ reabsorption by the proximal tubule. Because activation of the sympathetic nerve fibers that innervate this nephron segment stimulates proximal tubule Na+ reabsorption, the decreased sympathetic nerve activity that results from ECFV expansion decreases Na+ reabsorption. In addition, angiotensin II directly stimulates Na+ reabsorption by the proximal tubule. Because angiotensin II levels are also reduced under this condition, proximal tubule Na+ reabsorption decreases as a result. Starling forces across the proximal tubule also change. The elevated hydrostatic pressure within the glomerular capillaries in ECFV expansion also tends to increase the hydrostatic pressure within the peritubular capillaries. In addition the decrease in filtration fraction reduces the peritubular oncotic pressure. These alterations in the capillary Starling forces (i.e., hydrostatic and oncotic) reduce


Physiology_Levy

Physiology_Levy. capillaries. In addition the decrease in filtration fraction reduces the peritubular oncotic pressure. These alterations in the capillary Starling forces (i.e., hydrostatic and oncotic) reduce the absorption of solute (e.g., NaCl) and water from the lateral intercellular space and thus reduce tubular reabsorption of NaCl (see for a complete description of this mechanism). Both the increase in the filtered load and the decrease in NaCl reabsorption by the proximal tubule result in delivery of more NaCl to the loop of Henle. Because activation of sympathetic nerves and angiotensin II and aldosterone stimulate NaCl reabsorption by the thick ascending limb of the loop of Henle, the reduced nerve activity and low angiotensin II and aldosterone levels that occur with ECFV expansion reduce NaCl reabsorption by the thick ascending limb. Thus the fraction of the filtered load delivered to the distal tubule is increased.


Physiology_Levy

Physiology_Levy. 3. Na+ reabsorption decreases in the distal tubule and collecting duct. As noted, the amount of Na+ delivered to the distal tubule exceeds that observed in the euvolemic state (i.e., the amount of Na+ delivered to the distal tubule varies in proportion to the degree of ECFV expansion). This increased load of Na+ overwhelms the reabsorptive capacity of the distal tubule and the collecting duct, and this capacity is also impaired by reduced levels of angiotensin II and aldosterone, as well as increased levels of natriuretic peptides. The final component in the response to ECFV expansion is increased excretion of water. As Na+ excretion increases, plasma osmolality begins to fall. This decreases secretion of AVP. AVP secretion is also decreased in response to the elevated levels of natriuretic peptides. In addition, natriuretic peptides inhibit the action of AVP on the collecting duct. Together, these effects decrease water reabsorption by the collecting duct and thereby increase water


Physiology_Levy

Physiology_Levy. peptides. In addition, natriuretic peptides inhibit the action of AVP on the collecting duct. Together, these effects decrease water reabsorption by the collecting duct and thereby increase water excretion by the kidneys. Thus excretion of NaCl and water occurs in concert; euvolemia is restored and body fluid osmolality remains constant. The time course of this response (hours to days) depends on the magnitude of the ECFV expansion. Thus if the degree of ECFV expansion is small, the mechanisms just described generally restore euvolemia within 24 hours. However, with large degrees of ECFV expansion, the response can take several days.


Physiology_Levy

Physiology_Levy. In brief, the renal response to ECFV expansion involves the integrated action of all parts of the nephron; (1) the amount of Na+ filtered is increased, (2) Na+ reabsorption by the proximal tubule and loop of Henle is reduced (glomerulotubular balance does not occur under this condition), and (3) reabsorption of Na+ by the distal tubule and collecting duct is decreased (while the delivery of Na+ is increased), primarily secondary to a reduction in aldosterone. In summary, ECFV expansion leads to a reduction in Na+ reabsorption by both the proximal tubule and the ASDN, which results in excretion of a larger fraction of the filtered Na+ , thereby restoring euvolemia. Control of NaCl Excretion With Volume Contraction During ECFV contraction, the high-pressure and low-pressure vascular volume sensors send signals to the kidneys to reduce NaCl and water excretion and thereby restore ECFV. The signals that act on the kidneys include: 1. 2.


Physiology_Levy

Physiology_Levy. 2. increased secretion of renin, which results in elevated angiotensin II levels and thus increased secretion of aldosterone by the adrenal cortex 3. inhibition of ANP and BNP secretion by the heart and urodilatin production by the kidneys 4. stimulation of AVP secretion by the posterior pituitary The integrated response of the nephron to these signals is illustrated in Fig. 35.13 . The general response is as follows (the numbers correlate with those encircled in Fig. 35.13): 1. GFR decreases. Afferent and efferent arteriolar constriction occurs as a result of increased renal sympathetic nerve activity. The effect appears to be greater on the afferent than on the efferent arteriole, because the hydrostatic pressure in the glomerular capillaries fall, which thereby decreases GFR. Because RPF decreases more than GFR, filtration fraction increases. The decrease in GFR reduces the filtered amount of Na+ . 2.


Physiology_Levy

Physiology_Levy. 2. Na+ reabsorption by the proximal tubule and loop of Henle is increased. Several mechanisms augment Na+ reabsorption in the proximal tubule. For example, increased sympathetic nerve activity and angiotensin II levels directly stimulate Na+ reabsorption. The decreased hydrostatic pressure within the glomerular capillaries also leads to a decrease in the hydrostatic pressure within the peritubular capillaries. In addition, as just noted, the increased filtration fraction results in an increase in the peritubular oncotic pressure. These alterations in the capillary Starling forces facilitate movement of fluid from the lateral intercellular space into the capillary and thereby stimulate reabsorption of NaCl and water by the proximal tubule (see for a complete description of this mechanism). Increased sympathetic nerve activity as well as elevated levels of angiotensin II and aldosterone stimulate Na+ reabsorption by the thick ascending limb. 3.


Physiology_Levy

Physiology_Levy. Na+ reabsorption by the distal tubule and collecting duct is enhanced. The small amount of Na+ that is delivered to the ASDN, owing to decreased filtration and increased reabsorption by the proximal tubule and loop of Henle, is almost completely reabsorbed because transport in the segments of the ASDN is enhanced. Stimulation of Na+ reabsorption by the ASDN is primarily the result of increased aldosterone levels, although increased sympathetic nerve activity and increased angiotensin II levels may also contribute to this response. Lastly, levels of natriuretic peptides, which inhibit collecting duct reabsorption, are reduced. Finally, water reabsorption by the latter portion of the distal tubule and the collecting duct is enhanced by AVP, the levels of which are elevated through activation of the lowand high-pressure vascular volume sensors as well as by the elevated levels of angiotensin II. As a result, water excretion is reduced. Because both water and Na+ are retained by the


Physiology_Levy

Physiology_Levy. of the lowand high-pressure vascular volume sensors as well as by the elevated levels of angiotensin II. As a result, water excretion is reduced. Because both water and Na+ are retained by the kidneys in equal proportions, euvolemia is reestablished and ˜ AVP ° ANP and BNP Heart Brain ˜ Aldosterone Lung Adrenal gland ° Na+, H2O excretion ˜ Renin ˜ Sympathetic activity 2 1 3 ˜ Angiotensin I ˜ Angiotensin II Volume contraction • Fig. 35.13 Integrated response to ECFV contraction. Numbers refer to the description of the response in the text. ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; GFR, glomerular filtration rate; PNa+, plasma [Na+]; R, tubular reabsorption of Na+; UNa+V, Na+ excretion rate.


Physiology_Levy

Physiology_Levy. body fluid osmolality remains constant. The time course of this restoration of ECFV (hours to days) and the degree to which euvolemia is attained depend on the magnitude of ECFV contraction as well as the dietary intake of Na+ . Euvolemia can be restored more rapidly if additional NaCl is ingested in the diet. In brief, the nephron’s response to ECFV contraction involves the integrated action of all its segments: (1) the 1.


Physiology_Levy

Physiology_Levy. In brief, the nephron’s response to ECFV contraction involves the integrated action of all its segments: (1) the 1. Regulation of body fluid osmolality (i.e., steady-state balance) requires that the amount of water added to the body exactly matches the amount lost from the body. Water is lost from the body by several routes (e.g., during respiration, with sweating, and in feces). The kidneys are the only regulated route of water excretion. Excretion of water by the kidneys is regulated by AVP secreted from the posterior pituitary. When AVP levels are high, the kidneys excrete a small volume of hyperosmotic urine. When AVP levels are low, a large volume of hypoosmotic urine is excreted. 2.


Physiology_Levy

Physiology_Levy. 2. Disorders of water balance alter body fluid osmolality. Because Na+ with its anions are the major determinant filtered amount of Na+ is decreased, (2) reabsorption in the proximal tubule and loop of Henle is enhanced (GFR is decreased, whereas proximal reabsorption is increased, and thus glomerulotubular balance does not occur under this condition), and (3) delivery of Na+ to the ASDN is reduced. This decreased delivery, together with enhanced Na+ and water reabsorption by the ASDN, virtually eliminates Na+ from the urine and reduces urine volume. of ECF osmolality, disorders of water balance manifest as changes in ECF [Na+]. Positive water balance (intake > excretion) results in a decrease in body fluid osmolality and hyponatremia. Negative water balance (intake < excretion) results in an increase in body fluid osmolality and hypernatremia.


Physiology_Levy

Physiology_Levy. 3. The volume of the ECF is determined by the amount of Na+ in this compartment. To maintain a constant ECFV (i.e., euvolemia) NaCl excretion must match NaCl intake. The kidneys are the major route for regulating excretion of NaCl from the body. Volume sensors located primarily in the vascular system monitor volume and pressure. When ECFV expansion occurs, neural and hormonal signals are sent to the kidneys to increase excretion of NaCl and water and thereby restore euvolemia. When ECFV contraction occurs, neural and hormonal signals are sent to the kidneys to decrease NaCl and water excretion and Berl T. Vasopressin antagonists. N Engl J Med. 2015;372:2207-2216. Bichet DG. Polyuria and diabetes insipidus. In: Alpern RJ, et al., eds. Seldin and Giebisch’s The Kidney: Physiology and Pathophysiology. 5th ed. Philadelphia: Academic Press; 2013.


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Physiology_Levy. Bichet DG. Polyuria and diabetes insipidus. In: Alpern RJ, et al., eds. Seldin and Giebisch’s The Kidney: Physiology and Pathophysiology. 5th ed. Philadelphia: Academic Press; 2013. Brown D, Fenton RA. The cell biology of vasopressin action. In: Taal MW, et al., eds. Brenner and Rector’s The Kidney. 9th ed. Philadelphia: Saunders; 2012. Dantzler WH, et al. Urine-concentrating mechanism in the inner medulla: function of the thin limbs of the loops of Henle. Clin J Am Soc Nephrol. 2014;9:1781-1789. Danziger J, Zeidel M. Osmotic homeostasis. J Am Soc Nephrol. 2015;10:852-862. Knepper MA, et al. Molecular physiology of water balance. N Engl J Med. 2015;372:1349-1358. Nielsen S, et al. Aquaporin water channels in mammalian kidney. In: Alpern RJ, et al., eds. Seldin and Giebisch’s The Kidney: Physiology and Pathophysiology. 5th ed. Philadelphia: Academic Press; 2013.


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Physiology_Levy. Robertson GL. Thirst and vasopressin. In: Alpern RJ, et al., eds. Seldin and Giebisch’s The Kidney: Physiology and Pathophysiology. 5th ed. Philadelphia: Academic Press; 2013. Sands JM, et al. Urine concentration and dilution. In: Taal MW, et al., eds. Brenner and Rector’s The Kidney. 9th ed. Philadelphia: Saunders; 2012. Sands JM, Layton HE. The urine concentrating mechanism and urea transporters. In: Alpern RJ, et al., eds. Seldin and Giebisch’s The Kidney: Physiology and Pathophysiology. 5th ed. Philadelphia: Academic Press; 2013. Sands JM, Layton HE. Advances in understanding the urine-concentrating mechanism. Annu Rev Physiol. 2014;76:387-409. Schrier RW. Systemic arterial vasodilation, vasopressin, and vasopres sinase in pregnancy. J Am Soc Nephrol. 2010;21:570-572. Sterns RH. Disorders of plasma sodium–causes, consequences, and correction. N Engl J Med. 2015;372:55-65.


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Physiology_Levy. thereby restore euvolemia. The sympathetic nervous system, the RAAS, and natriuretic peptides are important components of the system that maintain steady-state Na+ balance. Verbalis JG. Disorders of water balance. In: Taal MW, et al., eds. Brenner and Rector’s The Kidney. 9th ed. Philadelphia: Saunders; 2012. Eladari D, et al. A new look at electrolyte transport in the distal tubule. Annu Rev Physiol. 2012;74:325-349. Gamba G, et al. Sodium chloride transport in the loop of Henle, distal convoluted tubule, and collecting duct. In: Alpern RJ, et al., eds. Seldin and Giebisch’s The Kidney: Physiology and Pathophysiology. 5th ed. Philadelphia: Academic Press; 2013. Mount DB. Transport of sodium, chloride, and potassium. In: Taal MW, et al., eds. Brenner and Rector’s The Kidney. 9th ed. Philadelphia: Saunders; 2012. Mount DB. Thick ascending limb of the loop of Henle. Clin J Am Soc Nephrol. 2014;9:1974-1986.


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Physiology_Levy. Mount DB. Thick ascending limb of the loop of Henle. Clin J Am Soc Nephrol. 2014;9:1974-1986. Palmer LG, Schnermann J. Integrated control of Na transport along the nephron. Clin J Am Soc Nephrol. 2015;10:676-687. Pearce D, et al. Aldosterone regulation of transport. In: Taal MW, et al., eds. Brenner and Rector’s The Kidney. 9th ed. Philadelphia: Saunders; 2012. Pearce D, et al. Collecting duct principal cell transport processes and their regulation. Clin J Am Soc Nephrol. 2015;10:135-146. Slotki IN, Skorecki KL. Disorders of sodium balance. In: Taal MW, et al., eds. Brenner and Rector’s The Kidney. 9th ed. Philadelphia: Saunders; 2012. Staub O, Loffing J. Mineralocorticoid action in aldosterone sensitive distal nephron. In: Alpern RJ, et al., eds. Seldin and Giebisch’s The Kidney: Physiology and Pathophysiology. 5th ed. Philadelphia: Academic Press; 2013. Subramanya AR, Ellison DH. Distal convoluted tubule. Clin J Am Soc Nephrol. 2014;9:2147-2163.


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Physiology_Levy. Subramanya AR, Ellison DH. Distal convoluted tubule. Clin J Am Soc Nephrol. 2014;9:2147-2163. Vesley DL. Natriuretic hormones. In: Alpern RJ, et al., eds. Seldin and Giebisch’s The Kidney: Physiology and Pathophysiology. 5th ed. Philadelphia: Academic Press; 2013. Weinstein AM. Sodium and chloride transport: proximal nephron. In: Alpern RJ, et al., eds. Seldin and Giebisch’s The Kidney: Physiology and Pathophysiology. 5th ed. Philadelphia: Academic Press; 2013. Potassium, Calcium, and Phosphate Homeostasis Upon completion of this chapter the student should be able to answer the following questions: 1. How does the body maintain K+ homeostasis? 2. What is the distribution of K+ within the body compartments? Why is this distribution important? 3. What are the hormones and factors that regulate plasma K+ levels? Why is this regulation important? 4.


Physiology_Levy

Physiology_Levy. 3. What are the hormones and factors that regulate plasma K+ levels? Why is this regulation important? 4. How do the various segments of the nephron transport K+ , and how does the mechanism of K+ transport by these segments determine how much K+ is excreted in the urine? 5. Why are the distal tubule and collecting duct so important in regulating K+ excretion? 6. How do plasma K+ levels, aldosterone, vasopressin, tubular fluid flow rate, and acid-base balance influence K+ excretion? 7. What is the physiological importance of calcium (Ca++) and inorganic phosphate (Pi)? 8. How does the body maintain Ca++ and Pi homeostasis? 9. What roles do the kidneys, intestinal tract, and bone play in maintaining plasma Ca++ and Pi levels? 10. What hormones and factors regulate plasma Ca++ and Pi levels? 11. What are the cellular mechanisms responsible for Ca++ and Pi reabsorption along the nephron? 12. What hormones regulate renal Ca++ and Pi excretion by the kidneys? 13.


Physiology_Levy

Physiology_Levy. 11. What are the cellular mechanisms responsible for Ca++ and Pi reabsorption along the nephron? 12. What hormones regulate renal Ca++ and Pi excretion by the kidneys? 13. What is the role of the calcium-sensing receptor (CaSR)? 14. What are some of the more common clinical disorders of Ca++ and Pi homeostasis? 15. What is the role of the kidneys in the production of calcitriol (active form of vitamin D)? 16. What effects do loop and thiazide diuretics have on Ca++ excretion?


Physiology_Levy

Physiology_Levy. 15. What is the role of the kidneys in the production of calcitriol (active form of vitamin D)? 16. What effects do loop and thiazide diuretics have on Ca++ excretion? Potassium (K+) is one of the most abundant cations in the body, and it is critical for many cell functions, including regulation of cell volume, regulation of intracellular pH, synthesis of DNA and protein, growth, enzyme function, resting membrane potential, and cardiac and neuromuscular activity. Despite wide fluctuations in dietary K+ intake, [K+] in cells and extracellular fluid (ECF) remains remarkably constant. Two sets of regulatory mechanisms safeguard K+ homeostasis. First, several mechanisms regulate [K+] in the ECF. Second, other mechanisms maintain the amount of K+ in the body constant by adjusting renal K+ excretion to match dietary K+ intake. It is the kidneys that regulate excretion of K+ .


Physiology_Levy

Physiology_Levy. Total body [K+] is 50 mEq/kg of body weight, or 3600 mEq for a 70-kg individual. Ninety-eight percent of the K+ in the body is located within cells, where the average [K+] is 150 mEq/L. High intracellular [K+] is required for many cell functions, including cell growth and division and volume regulation. Only 2% of total body [K+] is located in the ECF, where its normal concentration is approximately 4 mEq/L. A [K+] in ECF that exceeds 5.0 mEq/L constitutes hyperkalemia. Conversely, a [K+] in ECF of less than 3.5 mEq/L constitutes hypokalemia.


Physiology_Levy

Physiology_Levy. Hypokalemia is one of the most common electrolyte disorders in clinical practice and can be observed in as many as 20% of hospitalized patients. The most frequent causes of hypokalemia include administration of diuretic drugs, surreptitious vomiting (e.g., bulimia), and severe diarrhea. Gitelman syndrome (a genetic defect in the Na+/ Cl− symporter in the apical membrane of distal tubule cells) also causes hypokalemia (see Chapter 36). Hyperkalemia is also a common electrolyte disorder and is seen in 1% to 10% of hospitalized patients. Hyperkalemia often occurs in patients with renal failure, in patients taking drugs such as angiotensin-converting enzyme (ACE) inhibitors and K+-sparing diuretics, in patients with hyperglycemia (i.e., high blood sugar), and in the elderly. Pseudohyperkalemia, a falsely high plasma [K+], is caused by traumatic lysis of red blood cells during blood drawing. Red blood cells, like all cells, contain K+ , and lysis of red blood cells releases K+ into plasma,


Physiology_Levy

Physiology_Levy. a falsely high plasma [K+], is caused by traumatic lysis of red blood cells during blood drawing. Red blood cells, like all cells, contain K+ , and lysis of red blood cells releases K+ into plasma, thereby artificially elevating plasma [K+].


Physiology_Levy

Physiology_Levy. The large concentration difference of K+ across cell membranes (≈146 mEq/L) is maintained by the operation of Na+,K+-ATPase. This [K+] gradient is important in • Fig. 36.2 Electrocardiographs from individuals with varying plasma • Fig. 36.1 Effects of variations in plasma [K+] on resting membrane potential of skeletal muscle. Hyperkalemia causes membrane potential to become less negative, which decreases excitability by inactivating the fast Na+ channels responsible for the depolarizing phase of the action potential. Hypokalemia hyperpolarizes the membrane potential and thereby reduces excitability because a larger stimulus is required to depolarize the membrane potential to the threshold potential. Resting indicates “normal” resting membrane potential. Normal threshold indicates the membrane threshold potential.


Physiology_Levy

Physiology_Levy. maintaining the potential difference across cell membranes. Thus K+ is critical for the excitability of nerve and muscle cells, as well as for the contractility of cardiac, skeletal, and smooth muscle cells ( Fig. 36.1 [K+]. See text for details. (Modified from Barker L et al. Principles of Ambulatory Medicine. 5th ed. Baltimore: Williams & Wilkins; 1999.) This rise in plasma [K+], which could have deleterious effects on the electrical activity of the heart and other excitable tissues, is prevented by the rapid (minutes) uptake of K+ into cells. Because excretion of K+ by the kidneys Cardiac arrhythmias are produced by both hypokalemia and hyperkalemia. The electrocardiogram (ECG;


Physiology_Levy

Physiology_Levy. Cardiac arrhythmias are produced by both hypokalemia and hyperkalemia. The electrocardiogram (ECG; Fig. 36.2 ) monitors the electrical activity of the heart and is a fast and easy way to determine whether changes in plasma [K+] influence the heart and other excitable cells. In contrast, measurement of plasma [K+] by the clinical laboratory requires a blood sample, and values are often not immediately available. The first sign of hyperkalemia is the appearance of tall, thin T waves on the ECG. Further increases in plasma [K+] prolong the PR interval, depress the ST segment, and lengthen the QRS interval of the ECG. Finally, as plasma [K+] approaches 10 mEq/L, the P wave disappears, the QRS interval broadens, the ECG appears as a sine wave, and the ventricles fibrillate (i.e., manifest rapid, uncoordinated contractions of muscle fibers). Hypokalemia prolongs the QT interval, inverts the T wave, and lowers the ST segment of the ECG.


Physiology_Levy

Physiology_Levy. After a meal the K+ absorbed by the gastrointestinal (GI) tract enters the ECF within minutes (Fig. 36.3 ). If the K+ ingested during a normal meal (≈33 mEq) were to remain in the ECF compartment (14 L), plasma [K+] would increase by 2.4 mEq/L (33 mEq added to 14 L of ECF): Equation 36.1 14L = 2 4. mEq after a meal is relatively slow (hours), uptake of K+ by cells is essential to prevent life-threatening hyperkalemia. Maintaining total body [K+] constant requires that all the K+ absorbed by the GI tract eventually be excreted by the kidneys. This process requires about 6 hours. Regulation of Plasma [K+] Several hormones, including epinephrine, insulin, and aldosterone, increase uptake of K+ into skeletal muscle, liver, bone, and red blood cells (Box 36.1


Physiology_Levy

Physiology_Levy. Regulation of Plasma [K+] Several hormones, including epinephrine, insulin, and aldosterone, increase uptake of K+ into skeletal muscle, liver, bone, and red blood cells (Box 36.1 Fig. 36.3 ) by stimulating Na+,K+-ATPase, the 1Na+/1K+/2Cl− symporter, and the Na+/Cl− symporter in these cells. Acute stimulation of K+ uptake (i.e., within minutes) is mediated by increased activity of existing Na+,K+-ATPase, 1Na+/1K+/2Cl− , and Na+/Cl− transporters, whereas a chronic increase in K+ uptake (i.e., within hours to days) is mediated by an increase in the quantity of Na+,K+-ATPase. The rise in plasma [K+] that follows K+ absorption by the GI tract stimulates secretion of insulin from the pancreas, release of aldosterone from the adrenal cortex, and secretion of epinephrine from the adrenal medulla (see


Physiology_Levy

Physiology_Levy. Fig. 36.3 ). In contrast, a decrease in plasma [K+] inhibits release of these hormones. Whereas insulin and epinephrine act within a few minutes, aldosterone requires about an hour to stimulate uptake of K+ into cells. • BOX 36.1 Major Factors, Hormones, and Drugs Influencing Distribution of K+Between Intracellular and Extracellular Fluid Compartments Physiological: Keep Plasma [K+] Constant Pathophysiological: Displace Plasma [K+] From Normal CHAPTER 36 Potassium, Calcium, and Phosphate Homeostasis Catecholamines affect the distribution of K+ across cell membranes by activating α-and β2-adrenergic receptors. Stimulation of α-adrenoceptors releases K+ from cells, especially in the liver, whereas stimulation of β2-adrenoceptors promotes K+ uptake by cells.


Physiology_Levy

Physiology_Levy. For example, activation of β2-adrenoceptors after exercise is important in preventing hyperkalemia. The rise in plasma [K+] after a K+-rich meal is greater if the patient has been pretreated with propranolol, a β-adrenoceptor antagonist. Furthermore, release of epinephrine during stress (e.g., myocardial ischemia) can rapidly lower plasma [K+]. Insulin also stimulates uptake of K+ into cells. The importance of insulin is illustrated by two observations. First, the rise in plasma [K+] after a K+-rich meal is greater in patients with diabetes mellitus (i.e., insulin deficiency) than in healthy people. Second, insulin (and glucose to prevent insulin-induced hypoglycemia) can be infused to correct hyperkalemia. Insulin is the most important hormone that shifts K+ into cells after ingestion of K+ in a meal. In patients with chronic kidney disease, although insulin-stimulated glucose uptake into cells is impaired, insulin stimulation of K+ uptake into cells is normal.


Physiology_Levy

Physiology_Levy. • Fig. 36.3 Overview of K+homeostasis. An increase in plasma insulin, epinephrine, or aldosterone stimulates movement of K+into cells and decreases plasma [K+], whereas a fall in plasma concentration of these hormones has the opposite effect and increases plasma [K+]. The amount of K+in the body is determined by the kidneys. An individual is in K+balance when dietary intake and urinary output (plus output by the GI tract) are equal. Excretion of K+by the kidneys is regulated by plasma [K+], aldosterone, and AVP. Diet 100 mEq of K+/day Feces 5–10 mEq of K+/day Urine 90–95 mEq of K+/day Intestinal absorption 90 mEq of K+/day Extracellular fluid 65 mEq of K+ Tissue stores 3435 mEq of K+ Insulin Epinephrine Aldosterone Plasma [K+] AVP Aldosterone


Physiology_Levy

Physiology_Levy. Aldosterone, like catecholamines and insulin, also promotes uptake of K+ into cells. A rise in aldosterone levels (e.g., primary aldosteronism) causes hypokalemia, whereas a fall in aldosterone levels (e.g., Addison’s disease) causes hyperkalemia. As discussed later and as illustrated in Fig. 36.3 , aldosterone also stimulates urinary K+ excretion. Thus aldosterone alters plasma [K+] by acting on uptake of K+ into cells and altering urinary K+ excretion. Box 36.1 ). These factors are not involved in regulation of plasma [K+] but rather alter the movement of K+ between the intracellular fluid (ICF) and ECF and thus cause development of hypokalemia or hyperkalemia.


Physiology_Levy

Physiology_Levy. Metabolic acidosis increases plasma [K+], whereas metabolic alkalosis decreases it. Respiratory alkalosis causes hypokalemia. In contrast, respiratory acidosis has little or no effect on plasma [K+]. Metabolic acidosis produced by addition of inorganic acids (e.g., HCl, H2SO4) increases plasma [K+] much more than an equivalent acidosis produced by accumulation of organic acids (e.g., lactic acid, acetic acid, ketoacids). The reduced pH (i.e., increased [H+]) promotes movement of H+ into cells and the reciprocal movement of K+ out of cells to maintain electroneutrality. This effect of acidosis occurs in part because acidosis inhibits the transporters that accumulate K+ inside cells, including Na+,K+-ATPase and the 1Na+/1K+/2Cl− symporter. In addition, movement of H+ into cells occurs as the cells buffer changes in [H+] of the ECF (see Chapter 37).


Physiology_Levy

Physiology_Levy. Chapter 37). As H+ moves across cell membranes, K+ moves in the opposite direction, and thus cations are neither gained nor lost across cell membranes. Metabolic alkalosis has the opposite effect; plasma [K+] decreases as K+ moves into cells and H+ exits. Although organic acids produce a metabolic acidosis, they do not cause significant hyperkalemia. Two explanations have been suggested for the reduced ability of organic acids to cause hyperkalemia. First, the organic anion may enter the cell with H+ and thereby eliminate the need for K+-H+ exchange across the membrane. Second, organic anions may stimulate insulin secretion, which moves K+ into cells. This movement may counteract the direct effect of the acidosis, which moves K+ out of cells.


Physiology_Levy

Physiology_Levy. The osmolality of plasma also influences the distribution of K+ across cell membranes. An increase in the osmolality of ECF enhances the release of K+ by cells and thus increases extracellular [K+]. Plasma [K+] may increase by 0.4 to 0.8 mEq/L with a 10 mOsm/kg H2O elevation in plasma osmolality. In patients with diabetes mellitus who do not take insulin, plasma [K+] is often elevated, in part because of the lack of insulin and in part because of the increase in plasma [glucose] (i.e., from a normal value of ≈ 100 mg/ dL to as high as ≈ 1200 mg/dL in some cases), which increases plasma osmolality. Hypoosmolality has the opposite action. The alterations in plasma [K+] associated with changes in osmolality are related to changes in cell volume. For example, as plasma osmolality increases, water leaves cells because of the osmotic gradient across the plasma membrane (see Chapter 1).


Physiology_Levy

Physiology_Levy. Chapter 1). Water leaves cells until the intracellular osmolality equals that of ECF. This loss of water shrinks cells and causes [K+] in cells to rise. The rise in intracellular [K+] provides a driving force for the exit of K+ from cells. This sequence increases plasma [K+]. A fall in plasma osmolality has the opposite effect. Cell lysis causes hyperkalemia as a result of addition of intracellular K+ to ECF. Severe trauma (e.g., burns) and some conditions such as tumor lysis syndrome (i.e., chemotherapy-induced destruction of tumor cells) and rhabdomyolysis (i.e., destruction of skeletal muscle) destroy cells and release K+ and other cell solutes into ECF. In addition, gastric ulcers may cause seepage of red blood cells into the GI tract. The blood cells are digested, and the K+ released from the cells is absorbed and can cause hyperkalemia.


Physiology_Levy

Physiology_Levy. More K+ is released from skeletal muscle cells during exercise than during rest. The ensuing hyperkalemia depends on the degree of exercise. In people walking slowly, plasma [K+] increases by 0.3 mEq/L. With vigorous exercise, plasma [K+] may increase by 2.0 or more mEq/L. K+ Excretion by the Kidneys The kidneys play a major role in maintaining K+ balance. As illustrated in


Physiology_Levy

Physiology_Levy. K+ Excretion by the Kidneys The kidneys play a major role in maintaining K+ balance. As illustrated in Fig. 36.3 the kidneys excrete 90% to 95% of the K+ ingested in the diet. Excretion equals intake even when intake increases by as much as 10-fold. This balance in urinary excretion and dietary intake underscores the importance of the kidneys in maintaining K+ homeostasis. Although small amounts of K+ are lost each day in feces and sweat (≈5%–10% of the K+ ingested in the diet), except during severe diarrhea this amount is essentially constant, is not regulated, and therefore is relatively less important than the K+ excreted by the kidneys. K+ secretion from blood into tubular fluid by cells of the distal tubule and collecting duct system is the key factor in determining urinary K+ excretion ( Fig. 36.4