Physiology_Levy

Physiology_Levy. Fig. 36.4 CHAPTER 36 Potassium, Calcium, and Phosphate Homeostasis 3% 10% to 50% 9% 5% to 30% • Fig. 36.4 K+ transport along the nephron. Excretion of K+ depends on the rate and direction of K+ transport by the late segment of the distal tubule and collecting duct. Percentages refer to the amount of filtered K+ reabsorbed or secreted by each nephron segment. Arrows indicate direction of transport. Left, Dietary K+ depletion. An amount of K+ equal to 1% of the filtered load of K+ is excreted. Right, Normal and increased dietary K+ intake. An amount of K+ equal to 15% to 80% of the filtered load is excreted. CCD, cortical collecting duct; DT, distal tubule; IMCD, inner medullary collecting duct; PT, proximal tubule; TAL, thick ascending limb.


Physiology_Levy

Physiology_Levy. TAL, thick ascending limb. Exercise-induced changes in plasma [K+] do not usually produce symptoms and are reversed after several minutes of rest. However, vigorous exercise can lead to life-threatening hyperkalemia in individuals (1) who have endocrine disorders that affect release of insulin, epinephrine (a β-adrenergic agonist), or aldosterone; (2) whose ability to excrete K+ is impaired (e.g., renal failure); or (3) who take certain medications, such as β1-adrenergic blockers. For example, during vigorous exercise, plasma [K+] may increase by at least 2 to 4 mEq/L in individuals who take β1-adrenergic receptor antagonists for hypertension. Because acid-base balance, plasma osmolality, cell lysis, and exercise do not maintain plasma [K+] at a normal value, they do not contribute to K+ homeostasis (see


Physiology_Levy

Physiology_Levy. Box 36.1 ). The extent to which these pathophysiological states alter plasma [K+] depends on the integrity of the homeostatic mechanisms that regulate plasma [K+] (e.g., secretion of epinephrine, insulin, and aldosterone). Because K+ is not bound to plasma proteins, it is freely filtered by the glomerulus. When individuals ingest 100 mEq of K+ per day, urinary K+ excretion is about 15% of the amount filtered. Accordingly K+ must be reabsorbed along the nephron. When dietary K+ intake increases, however, K+ excretion can exceed the amount filtered. Thus K+ can also be secreted.


Physiology_Levy

Physiology_Levy. The proximal tubule reabsorbs about 67% of the filtered K+ under most conditions. Approximately 20% of the filtered K+ is reabsorbed by the loop of Henle, and as with the proximal tubule, the amount reabsorbed is a constant fraction of the amount filtered. In contrast to these segments, which can only reabsorb K+ , the distal tubule and collecting duct are able to reabsorb or secrete K+ . The rate of K+ reabsorption or secretion by the distal tubule and collecting duct depends on a variety of hormones and factors. When 100 mEq/day of K+ is ingested, it is secreted by these nephron segments. A rise in dietary K+ intake increases K+ secretion. K+ secretion can increase the amount of K+ that appears in urine so that it approaches 80% of the amount filtered (see Fig. 36.4 , right panel). In contrast, a low-K+ diet activates K+ reabsorption along the distal tubule and collecting duct so that urinary excretion falls to about 1% of the K+ filtered by the glomerulus (see


Physiology_Levy

Physiology_Levy. Fig. 36.4 , left panel). The kidneys cannot reduce K+ excretion to the same low levels as they can for Na+ (i.e., 0.2%). Therefore hypokalemia can develop in individuals placed on a K+-deficient diet. Because the magnitude and direction of K+ transport by the distal tubule and collecting duct are variable, the overall rate of urinary K+ excretion is determined by these tubular segments. Cellular Mechanism of K+ Secretion by Principal Cells and Intercalated Cells Fig. 36.5A illustrates the cellular mechanisms of K+ secretion by principal cells in the late segment of the distal • Fig. 36.5 Cellular mechanism of K+ secretion by principal cells (A) and α-intercalated cells (B) in the late segment of the distal tubule and collecting duct. α-Intercalated cells contain very low levels of Na+,K+-ATPase in the basolateral membrane (not shown). K+ depletion increases K+ reabsorption by α-intercalated cells by stimulating the H+,K+-ATPase (HKA).


Physiology_Levy

Physiology_Levy. In individuals with advanced renal disease, the kidneys are unable to eliminate ingested K+ from the body. Therefore plasma [K+] rises. The resulting hyperkalemia reduces the resting membrane potential (i.e., the voltage becomes less negative), and this reduced potential decreases the excitability of neurons, cardiac cells, and muscle cells by inactivating fast Na+ channels, which are critical for the depolarization phase of the action potential (see


Physiology_Levy

Physiology_Levy. Fig. 36.1 ). Severe rapid increases in plasma [K+] can lead to cardiac arrest and death. In contrast, in patients taking diuretic drugs for hypertension, urinary K+ excretion often exceeds dietary K+ intake. Accordingly K+ balance is negative and hypokalemia develops. This decline in extracellular [K+] hyperpolarizes the resting cell membrane (i.e., the voltage becomes more negative) and reduces the excitability of neurons, cardiac cells, and muscle cells. Severe hypokalemia can lead to paralysis, cardiac arrhythmias, and death. Hypokalemia can also impair the ability of the kidneys to concentrate urine and can stimulate renal production of NH4 + , which affects acid-base balance (see ). Therefore maintenance of high intracellular [K+], low extracellular [K+], and a high [K+] gradient across cell membranes is essential for a number of cellular functions.


Physiology_Levy

Physiology_Levy. CHAPTER 36 Potassium, Calcium, and Phosphate Homeostasis tubule and the collecting duct. Secretion from blood into the tubule lumen is a two-step process: (1) uptake of K+ from blood across the basolateral membrane by Na+,K+-ATPase and (2) diffusion of K+ from the cell into tubular fluid via K+ channels (ROMK and BK). A K+/ Cl− symporter (KCC1) in the apical plasma membrane also secretes K+ . Na+,K+-ATPase creates a high intracellular [K+] that provides the chemical driving force for exit of K+ across the apical membrane through K+ channels. Although K+ channels are also present in the basolateral membrane, K+ preferentially leaves the cell across the apical membrane and enters the tubular fluid. K+ transport follows this route for two reasons. First, the electrochemical gradient of K+ across the apical membrane favors its downhill movement into tubular fluid. Second, the permeability of the apical membrane to K+ is greater than that of the basolateral membrane. Therefore K+


Physiology_Levy

Physiology_Levy. of K+ across the apical membrane favors its downhill movement into tubular fluid. Second, the permeability of the apical membrane to K+ is greater than that of the basolateral membrane. Therefore K+ preferentially diffuses across the apical membrane into tubular fluid. K+ secretion across the apical membrane via the K+/Cl− symporter is driven by the favorable concentration gradient of K+ between the cell and tubular fluid. The three major factors that control the rate of K+ secretion by the late segment of the distal tubule and the collecting duct are: 1.


Physiology_Levy

Physiology_Levy. the activity of Na+,K+-ATPase 2. the driving force (electrochemical gradient for K+ channels and the chemical concentration gradient for the K+/Cl− symporter) for movement of K+ across the apical membrane 3. the permeability of apical membrane K+ channels to K+ Every change in K+ secretion by principal cells results from an alteration in one or more of these factors (Fig. 36.6 α-Intercalated cells reabsorb K+ by a H+ , K+-ATPase transport mechanism (HKA) located in the apical membrane (see Fig. 36.5B ). This transporter mediates K+ uptake across the apical plasma membrane in exchange for H+ . K+ exit from intercalated cells into the blood is mediated by a K+ channel. Reabsorption of K+ is activated by a low-K+ diet. Regulation of K+ Secretion by the Distal Tubule and Collecting Duct


Physiology_Levy

Physiology_Levy. Regulation of K+ Secretion by the Distal Tubule and Collecting Duct Regulation of K+ excretion is achieved mainly by alterations in K+ secretion by principal cells of the late segment of the distal tubule and collecting duct. Plasma [K+] and aldosterone are the major physiological regulators of K+ secretion. Ingestion of a K+-rich meal also stimulates renal K+ excretion by a mechanism involving an unknown gut-dependent mechanism. Arginine vasopressin (AVP), also stimulates K+ secretion; however, it is less important than plasma [K+] and aldosterone. Other factors, including the flow rate of tubular fluid and acid-base balance, influence secretion of K+ by the distal tubule and collecting duct. However, they are not homeostatic mechanisms, because they disturb K+ balance ( Box 36.2 Plasma [K+] is an important determinant of K+ secretion by the distal tubule and collecting duct. Hyperkalemia (e.g., resulting from a high-K+ diet or from rhabdomyolysis)


Physiology_Levy

Physiology_Levy. Box 36.2 Plasma [K+] is an important determinant of K+ secretion by the distal tubule and collecting duct. Hyperkalemia (e.g., resulting from a high-K+ diet or from rhabdomyolysis) Fig. 36.6 Cellular mechanism of K+ secretion by principal cells. The numbers indicate where K+ secretion is regulated. 1, Na+,K+-ATPase; 2, electrochemical gradient of K+ across the apical membrane; 3, permeability of the apical membrane to K+ . Fig. 36.7 Effects of aldosterone on secretion of K+ by principal cells in the late segment of the distal tubule and collecting duct. Numbers refer to the five effects of aldosterone discussed in text. K+ K+ ˜ K+ permeability + ˜ CAP ˜ SGK˜ ENaC ˜Na+,K+-ATPase + + Na+ ATP 2 1 3 4 5 IN THE CLINIC • BOX 36.2 Major Factors and Hormones Influencing K+Excretion Physiological: Keep K+ Balance Constant Pathophysiological: Displace K+ Balance


Physiology_Levy

Physiology_Levy. IN THE CLINIC • BOX 36.2 Major Factors and Hormones Influencing K+Excretion Physiological: Keep K+ Balance Constant Pathophysiological: Displace K+ Balance Flow rate of tubule fluid Acid-base disorders Glucocorticoids stimulates secretion of K+ within minutes. Several mechanisms are involved. First, hyperkalemia stimulates Na+ , K+-ATPase and thereby increases K+ uptake across the basolateral membrane. This uptake raises intracellular [K+] and increases the electrochemical driving force for exit of K+ across the apical membrane. Second, hyperkalemia also increases the permeability of the apical membrane to K+ . Third, hyperkalemia stimulates secretion of aldosterone by the adrenal cortex, which as discussed later, acts synergistically with plasma [K+] to stimulate secretion of K+ . Fourth, hyperkalemia also increases the flow rate of tubular fluid, which as discussed later, stimulates secretion of K+ by the distal tubule and collecting duct.


Physiology_Levy

Physiology_Levy. Hypokalemia (e.g., caused by a low-K+ diet or loss of K+ in diarrhea fluid) decreases K+ secretion via actions opposite those described for hyperkalemia. Hence hypokalemia inhibits Na+,K+-ATPase, decreases the electrochemical driving force for efflux of K+ across the apical membrane, reduces permeability of the apical membrane to K+ , and decreases plasma aldosterone levels. Chronic hypokalemia (plasma [K+] < 3.5 mEq/L) occurs most often in patients who receive diuretics for hypertension. Hypokalemia also occurs in patients who vomit, undergo nasogastric suction, have diarrhea, abuse laxatives, or have hyperaldosteronism. Hypokalemia occurs because excretion of K+ by the kidneys exceeds dietary intake of K+ . Vomiting, nasogastric suction, diuretics, and diarrhea can all decrease ECF volume (ECFV), which in turn stimulates secretion of aldosterone (see ). Because aldosterone stimulates excretion of K+ by the kidneys, its action contributes to development of hypokalemia.


Physiology_Levy

Physiology_Levy. Chronic hyperkalemia (plasma [K+] > 5.0 mEq/L) occurs most frequently in individuals with reduced urine flow, low plasma aldosterone levels, and renal disease in which the glomerular filtration rate (GFR) falls below 20% of normal. In these individuals, hyperkalemia occurs because excretion of K+ by the kidneys is less than dietary intake of K+ . Less common causes of hyperkalemia occur in people with deficiencies in insulin, epinephrine, and aldosterone secretion or in people with metabolic acidosis caused by inorganic acids.


Physiology_Levy

Physiology_Levy. Chronically elevated (i.e., ≥24 hours) plasma aldosterone levels enhance secretion of K+ across principal cells in the late segment of the distal tubule and collecting duct (i.e., aldosterone-sensitive distal nephron [ASDN]) via five mechanisms (Fig. 36.7 ): (1) by increasing the amount of Na+,K+-ATPase in the basolateral membrane; (2) by increasing expression of the epithelial sodium channel (ENaC) in the apical cell membrane; (3) by elevating SGK1 (serum glucocorticoid-stimulated kinase) levels, which also increases expression of ENaC in the apical membrane and activates K+ channels; (4) by stimulating CAP1 (channelactivating protease, also called prostatin), which directly activates ENaC; and (5) by stimulating the permeability of the apical membrane to K+ . Aldosterone increases the permeability of the apical membrane to K+ by increasing the number of K+ channels in the membrane. However, the cellular mechanisms involved in this response are not completely known. Increased


Physiology_Levy

Physiology_Levy. the permeability of the apical membrane to K+ by increasing the number of K+ channels in the membrane. However, the cellular mechanisms involved in this response are not completely known. Increased expression of Na+,K+-ATPase facilitates uptake of K+ across the basolateral membrane into cells and thereby elevates intracellular [K+]. The increase in the number and activity of Na+ channels enhances entry of Na+ into the cell from tubular fluid, an effect that depolarizes the apical membrane voltage. Depolarization of the apical membrane and increased intracellular [K+] enhance the electrochemical driving force for secretion of K+ from the cell into the tubule fluid. Taken together, these actions increase uptake of K+ into the cell across the basolateral membrane and enhance exit of K+ from the cell across the apical membrane. Secretion of aldosterone is increased by hyperkalemia and by angiotensin II (after activation of the renin-angiotensin system). Secretion of aldosterone is


Physiology_Levy

Physiology_Levy. from the cell across the apical membrane. Secretion of aldosterone is increased by hyperkalemia and by angiotensin II (after activation of the renin-angiotensin system). Secretion of aldosterone is decreased by hypokalemia and natriuretic peptides released from the heart.


Physiology_Levy

Physiology_Levy. CHAPTER 36 Potassium, Calcium, and Phosphate Homeostasis Although an acute (e.g., within hours) increase in aldosterone levels enhances the activity of Na+,K+-ATPase, K+ excretion does not increase immediately. The reason for this relates to the effect of aldosterone on Na+ reabsorption and tubular flow. Aldosterone stimulates reabsorption of Na+ and water and thus decreases tubular flow. Reduction in flow in turn decreases K+ secretion (as discussed in more detail later). However, chronic stimulation of Na+ reabsorption increases the ECFV and thereby returns tubular flow to normal. These actions allow a direct stimulatory effect of aldosterone on the ASDN to enhance K+ excretion. Although AVP does not affect urinary K+ excretion, this hormone does promote secretion of K+ by the ASDN (Fig.


Physiology_Levy

Physiology_Levy. Although AVP does not affect urinary K+ excretion, this hormone does promote secretion of K+ by the ASDN (Fig. 36.8 ). AVP increases the electrochemical driving force for exit of K+ across the apical membrane of principal cells by stimulating uptake of Na+ across the apical membrane of these cells. The increased Na+ uptake reduces the electrical potential difference across the apical membrane (i.e., the interior of the cell becomes less negatively charged). Despite this effect, AVP does not change K+ secretion by these nephron segments. The reason for this relates to the effect of AVP on tubular fluid flow. AVP decreases flow of tubular fluid by stimulating water reabsorption. The decrease in tubular flow in turn reduces secretion of K+ (explained later). The inhibitory effect of decreased flow of tubular fluid offsets the stimulatory effect of AVP on the electrochemical driving force for exit of K+ across the apical membrane (see


Physiology_Levy

Physiology_Levy. Fig. 36.8 ). If AVP did not increase the electrochemical gradient favoring K+ secretion, urinary K+ excretion would fall as AVP levels increased and urinary flow rates decreased. Hence K+ balance would change in • Fig. 36.8 Opposing effects of AVP and urine flow rate on secretion of K+by the ASDN. K+secretion is stimulated by an increase in urinary flow rate and reduced by a fall in AVP levels. In contrast, K+secretion is reduced by a decrease in urinary flow rate and increased by a rise in AVP levels. Because the effects of flow and AVP oppose each other, net K+secretion is not affected by water diuresis or antidiuretics. ˜ Urinary flow rate Water diuresis DT/CCD K+ secretion ˛ AVP levels Constant K+ balance ˛ Urinary flow rate DT/CCD K+ secretion ˜ AVP levels Antidiuresis + _ _ + response to alterations in water balance. Thus the effects of AVP on the electrochemical driving force for exit of K+ across the apical membrane and on tubule flow enable urinary K+ excretion to be


Physiology_Levy

Physiology_Levy. + response to alterations in water balance. Thus the effects of AVP on the electrochemical driving force for exit of K+ across the apical membrane and on tubule flow enable urinary K+ excretion to be maintained constant despite wide fluctuations in water excretion.


Physiology_Levy

Physiology_Levy. Plasma [K+], aldosterone, and AVP play important roles in regulating K+ balance; however, the factors and hormones discussed next perturb K+ balance (see Box 36.2 Flow of Tubular Fluid A rise in the flow of tubular fluid (e.g., with diuretic treatment, ECFV expansion) stimulates secretion of K+ within minutes, whereas a fall (e.g., ECFV contraction caused by hemorrhage, severe vomiting, or diarrhea) reduces secretion of K+ by the late segment of the ASDN. Increments in tubular fluid flow are more effective in stimulating secretion of K+ as dietary K+ intake is increased. Recent studies on the primary cilium in principal cells have elucidated some of the mechanisms whereby increased flow stimulates secretion of K+ (


Physiology_Levy

Physiology_Levy. Fig. 36.9 ). Increased flow bends the primary cilium in principal cells, which activates the PKD1/PKD2 Ca++-conducting channel complex. This allows more Ca++ to enter principal cells and increases intracellular [Ca++]. The increase in [Ca++] activates BK K+ channels in the apical plasma membrane, which enhances K+ secretion from the cell into the tubule fluid. Increased flow may also stimulate secretion of K+ by other mechanisms. As flow increases, such as after administration of diuretics or as the result of an increase in ECFV, so does the [Na+] of tubule fluid. This increase in [Na+] facilitates entry of Na+ across the apical membrane of ASDN cells, thereby decreasing the cells’


Physiology_Levy

Physiology_Levy. K+ K+ ° Flow stimulates Na+ entry, which reduces Vm ° Flow Cilia bend activates PKD1/PKD2 and Ca++ entry ° Flow bends cilia ° Ca++ activates Na+ Ca++ ATP 1 25 4 3 • Fig. 36.9 Cellular mechanism whereby an increased flow rate of tubule fluid stimulates secretion of K+ by principal cells. See text for details. interior negative membrane potential. This depolarization of the cell membrane potential increases the electrochemical driving force that promotes secretion of K+ across the apical cell membrane into tubule fluid. In addition, increased uptake of Na+ into cells activates the Na+,K+-ATPase in the basolateral membrane, thereby increasing uptake of K+ across the basolateral membrane and consequently elevating [K+]. However, it is important to note that an increase in flow rate during a water diuresis does not have a significant effect on excretion of K+ , most likely because during a water diuresis the [Na+] of tubule fluid does not increase as flow rises.


Physiology_Levy

Physiology_Levy. Another factor that modulates secretion of K+ is the [H+] of ECF. Acute alterations (within minutes to hours) in the pH of plasma influences secretion of K+ by the ASDN. Alkalosis (i.e., plasma pH above normal) increases secretion of K+ , whereas acidosis (i.e., plasma pH below normal) decreases it. An acute acidosis reduces K+ secretion via two mechanisms: (1) it inhibits Na+,K+-ATPase and thereby reduces cell [K+] and the electrochemical driving force for exit of K+ across the apical membrane, and (2) it reduces the permeability of the apical membrane to K+ . Alkalosis has the opposite effects. The effect of metabolic acidosis on excretion of K+ is time dependent. As already noted, and illustrated in Fig. 36.10 , acute metabolic acidosis reduces K+ excretion. However, when metabolic acidosis lasts for several days, urinary K+ excretion is stimulated (see


Physiology_Levy

Physiology_Levy. Fig. 36.10 , acute metabolic acidosis reduces K+ excretion. However, when metabolic acidosis lasts for several days, urinary K+ excretion is stimulated (see Fig. 36.10 ). This occurs because chronic metabolic acidosis decreases reabsorption of water and solutes (e.g., NaCl) by the proximal tubule by


Physiology_Levy

Physiology_Levy. Fig. 36.10 ). This occurs because chronic metabolic acidosis decreases reabsorption of water and solutes (e.g., NaCl) by the proximal tubule by ROMK is the primary channel in the apical membrane of principal cells that mediates K+ secretion. Four ROMK subunits make up a single channel. In addition the BK K+ channel, which is activated by elevations in intracellular [Ca++], is also expressed in the apical membrane. The BK channel mediates the flow-dependent increase in K+ secretion discussed earlier. Interestingly, knockout of the KCNJ1 gene (ROMK) causes increased excretion of NaCl and K+ by the kidneys, thereby leading to reduced ECFV and hypokalemia. Although this effect is somewhat perplexing, it should be noted that ROMK is also expressed in the apical membrane of the thick ascending limb (TAL) of Henle’s loop, where it plays a very important role in recycling of K+ across the apical membrane, an effect that is critical for operation of the Na+/ K+/2Cl− symporter (see


Physiology_Levy

Physiology_Levy. Fig. 36.7 ). In the absence of ROMK, reabsorption of NaCl by the TAL is reduced, which leads to loss of NaCl in urine. Reduction of NaCl reabsorption by the TAL also reduces the positive transepithelial luminal voltage, which is the driving force for reabsorption of K+ by this nephron segment. Thus the reduction in paracellular K+ reabsorption by the TAL increases urinary K+ excretion even when the cortical collecting duct is unable to secrete the normal amount of K+ because of a lack of ROMK channels. The cortical collecting duct, however, does secrete K+ even in ROMK knockout mice via the flow and Ca++-dependent BK K+ channel expressed in the apical membrane of principal cells.


Physiology_Levy

Physiology_Levy. inhibiting Na+,K+-ATPase. Hence the flow of tubular fluid is augmented along the ASDN. Inhibition of water and NaCl reabsorption by the proximal tubule also decreases ECFV and thereby stimulates secretion of aldosterone. In addition, chronic acidosis caused by inorganic acids increases plasma [K+], which stimulates secretion of aldosterone. The rise in tubular fluid flow, plasma [K+], and aldosterone levels offsets the effects of acidosis on cell [K+] and apical membrane permeability, and K+ secretion rises. Thus metabolic acidosis may either inhibit or stimulate excretion of K+ , depending on the duration of the disturbance. As noted, acute metabolic alkalosis stimulates excretion of K+ . Chronic metabolic alkalosis, especially in association with ECFV contraction, significantly increases renal K+ excretion because of the associated increased levels of aldosterone.


Physiology_Levy

Physiology_Levy. CHAPTER 36 Potassium, Calcium, and Phosphate Homeostasis • Fig. 36.10 Acute versus chronic effect of metabolic acidosis on excretion of K+. See text for details. ECV, effective circulating volume. ˛ Na+,K+-ATPase activity ˛ K+ permeability of apical membrane ˛ Apical membrane K+ gradient Metabolic acidosis Acute Chronic Distal tubule and collecting duct principal cells ˜ Na+,K+-ATPase activity ˜ K+ permeability of apical membrane ˜ K+ secretion ˜ K+ excretion Skeletal muscle cell Proximal tubule cell ˛ H+/K+ exchange ˜ NaCl and H2O reabsorption ˜ ECV ˛ Plasma [K+] ˛ Tubule fluid flow rate Distal tubule and collecting duct principal cells ˛ Aldosterone ˛ Aldosterone ˛ K+ secretion ˛ K+ excretion Glucocorticoids increase urinary K+ excretion. This effect is mediated in part by an increase in GFR, which enhances the urinary flow rate, a potent stimulus of K+ excretion, and by stimulation of SGK1 activity (see earlier).


Physiology_Levy

Physiology_Levy. As discussed, the rate of urinary K+ excretion is frequently determined by simultaneous changes in hormone levels, acid-base balance, or the flow rate of tubule fluid ( 36.1 ). The powerful effect of flow often enhances or opposes the response of the ASDN to hormones and changes in acid-base balance. This interaction can be beneficial in the case of hyperkalemia, in which the increase in flow enhances excretion of K+ and thereby restores K+ homeostasis. However, this interaction can also be detrimental, as in the case of alkalosis, in which changes in flow and acid-base status alter K+ homeostasis.


Physiology_Levy

Physiology_Levy. Overview of Calcium and Inorganic Phosphate Homeostasis are multivalent ions that subserve many complex and vital functions. Ca++ is an important cofactor in many enzymatic reactions; it is a key second messenger in numerous signaling pathways; it plays an important role in neural transduction, blood clotting, and muscle contraction; and it is a critical component of the extracellular matrix, cartilage, teeth, and bone. Pi, like Ca++ , is a key component of bone. Pi is essential for metabolic aAt physiological pH, inorganic phosphate exists as HPO4 − and H2PO4 − (pK = 6.8). For simplicity, we collectively refer to these ion species as Pi. Modified from Field MJ et al. In Narins R (ed). Textbook of Nephrology: Clinical Disorders of Fluid and Electrolyte Metabolism. 5th ed. New York: McGraw-Hill; 1994.


Physiology_Levy

Physiology_Levy. The cellular mechanisms whereby changes in the K+ content of the diet and acid-base balance regulate secretion of K+ by the early segment of the ASDN have recently been elucidated. Elevated K+ intake increases secretion of K+ by several mechanisms, all related to increased serum [K+]. Hyperkalemia increases the activity of the ROMK channel in the apical plasma membrane of principal cells. Moreover, hyperkalemia inhibits reabsorption of NaCl and water by the proximal tubule, thereby increasing the ASDN flow rate, a potent stimulus to secretion of K+ . Hyperkalemia also enhances [aldosterone], which increases K+ secretion by three mechanisms. First, aldosterone increases the number of K+ channels in the apical plasma membrane. Second, aldosterone stimulates uptake of K+ across the basolateral membrane by increasing the number of Na+,K+-ATPase pumps, thereby enhancing the electrochemical gradient driving secretion of K+ across the apical membrane. Third, aldosterone increases movement of


Physiology_Levy

Physiology_Levy. membrane by increasing the number of Na+,K+-ATPase pumps, thereby enhancing the electrochemical gradient driving secretion of K+ across the apical membrane. Third, aldosterone increases movement of Na+ across the apical membrane, which depolarizes the apical plasma membrane voltage and thus increases the electrochemical gradient, promoting secretion of K+ . A low-K+ diet dramatically reduces secretion of K+ by the ASDN by increasing the activity of protein tyrosine kinase, which causes ROMK channels to be endocytosed from the apical plasma membrane, thereby reducing K+ secretion. Acidosis decreases secretion of K+ by inhibiting the activity of ROMK channels, whereas alkalosis stimulates secretion of K+ by enhancing ROMK channel activity.


Physiology_Levy

Physiology_Levy. processes, including formation of adenosine triphosphate (ATP), and it is an important component of nucleotides, nucleosides, and phospholipids. Phosphorylation of proteins is an important mechanism of cellular signaling, and Pi is an important buffer in cells, plasma, and urine.


Physiology_Levy

Physiology_Levy. In adults the kidneys play important roles in regulating total body Ca++ and Pi by excreting the amount of Ca++ and Pi that is absorbed by the intestinal tract (normal bone remodeling results in no net addition of Ca++ and Pi to, or Ca++ and Pi release from, bone). If plasma concentrations of Ca++ and Pi decline substantially, intestinal absorption, bone resorption (i.e., loss of Ca++ and Pi from bone), and renal tubular reabsorption increase and return plasma concentrations of Ca++ and Pi to normal levels. During growth and pregnancy, intestinal absorption exceeds urinary excretion, and these ions accumulate in newly formed fetal tissue and bone. In contrast, bone disease (e.g., osteoporosis) or a decline in lean body mass increases urinary Ca++ and Pi loss without a change in intestinal absorption. These conditions produce a net loss of Ca++ and Pi from the body. Finally, during chronic renal failure, Pi accumulates in the body because absorption by the intestinal tract exceeds


Physiology_Levy

Physiology_Levy. absorption. These conditions produce a net loss of Ca++ and Pi from the body. Finally, during chronic renal failure, Pi accumulates in the body because absorption by the intestinal tract exceeds excretion in the urine. This can lead to accumulation of Pi in the body and changes in bone (see the In The Clinic box discussion of chronic renal failure).


Physiology_Levy

Physiology_Levy. This brief introduction reveals that the kidneys, in conjunction with the GI tract and bone, play a major role in maintaining plasma Ca++ and Pi levels as well as Ca++ and Pi balance (see ). Accordingly this section of the chapter discusses Ca++ and Pi handling by the kidneys, with an emphasis on the hormones and factors that regulate urinary excretion.


Physiology_Levy

Physiology_Levy. Cellular processes in which Ca++ plays an important role include bone formation, cell division and growth, blood coagulation, hormone-response coupling, and electrical stimulus-response coupling (e.g., muscle contraction, neurotransmitter release). Nearly 99% of Ca++ is stored in bone and teeth, approximately 1% is found in ICF, and 0.1% in ECF. The total Ca++ concentration ([Ca++]) in plasma is 10 mg/dL (2.5 mM or 5 mEq/L), and its concentration is normally maintained within very narrow limits. Approximately 50% of the Ca++ in plasma is ionized, 40% is bound to plasma proteins (mainly albumin), and 10% is complexed to several anions, including Pi, HCO3 − , citrate, and SO42− (Fig. 36.11 ). The pH of plasma influences this distribution ( Fig. 36.12). Acidemia increases the


Physiology_Levy

Physiology_Levy. Fig. 36.12). Acidemia increases the CHAPTER 36 Potassium, Calcium, and Phosphate Homeostasis 1.25 mmol/L E A S 0.25 mmol/L R 1.0 mmol/L D • Fig. 36.12 Effect of pH on plasma [Ca++]. (From Koeppen BM, Stanton BA. Renal Physiology. 5th ed. Philadelphia: Elsevier; 2013.) • Fig. 36.11 Distribution of Ca++ in plasma. (From Koeppen BM, Stanton BA. Renal Physiology. 5th ed. Philadelphia: Elsevier; 2013.) • Fig. 36.13 Effect of Ca++ on nerve and muscle excitability. (From Koeppen BM, Stanton BA. Renal


Physiology_Levy

Physiology_Levy. Physiology. 5th ed. Philadelphia: Elsevier; 2013.) percentage of ionized Ca++ at the expense of Ca++ bound to proteins, whereas alkalemia decreases the percentage of ionized Ca++, again by altering the Ca++ bound to proteins. Individuals with alkalemia are susceptible to tetany (tonic muscular spasms), whereas individuals with acidemia are less susceptible to tetany, even when total plasma Ca++ levels are reduced. The increase in [H+] in patients with metabolic acidosis causes more H+ to bind to plasma proteins, Pi, HCO3 − , citrate, and SO42− , thereby displacing Ca++ . This displacement increases the plasma concentration of ionized Ca++ . In alkalemia the [H+] of plasma decreases. Some H+ ions dissociate from plasma proteins, Pi, HCO3 − , citrate, and SO42− in exchange for Ca++ , thereby decreasing the plasma concentration of ionized Ca++ . In addition, the plasma albumin concentration also affects ionized plasma [Ca++].


Physiology_Levy

Physiology_Levy. Hypoalbuminemia increases the ionized [Ca++], whereas hyperalbuminemia decreases ionized plasma [Ca++]. The total measured plasma [Ca++] does not reflect the total ionized [Ca++], which is the physiologically relevant measure of plasma [Ca++]. A low ionized plasma [Ca++] (hypocalcemia) increases the excitability of nerve and muscle cells and can lead to hypocalcemic tetany. Tetany associated with hypocalcemia occurs because hypocalcemia causes the threshold potential to shift to more negative values (i.e., closer to the resting membrane voltage) ( Fig. 36.13). An elevated ionized plasma [Ca • Fig. 36.14 Overview of Ca++ homeostasis. PTH, parathyroid hormone. (From Koeppen BM, Stanton BA. Renal Physiology. 5th ed. Philadelphia: Elsevier; 2013.) arrhythmias, lethargy, disorientation, and even death.


Physiology_Levy

Physiology_Levy. This effect of hypercalcemia occurs because an elevated plasma [Ca++] causes the threshold potential to shift to less negative values (i.e., farther from the resting membrane voltage). Plasma [Ca++] is regulated within a very narrow range, primarily by parathyroid hormone (PTH), calcitriol (1,25-dihydroxyvitamin D), the active metabolite of vitamin D3, and plasma Ca++ , and this regulation will be discussed next. Within cells, Ca++ is sequestered in the endoplasmic reticulum and mitochondria, or it is bound to proteins. Thus the free intracellular [Ca++] is very low (≈100 nM). The large concentration gradient for [Ca++] across cell membranes is maintained by a Ca++-ATPase pump (PMCa1b) in all cells and by a 3Na+/Ca++ exchanger (NCX1) in some cells. Overview of Calcium Homeostasis


Physiology_Levy

Physiology_Levy. Overview of Calcium Homeostasis Ca++ homeostasis depends on two factors: (1) the total amount of Ca++ in the body and (2) the distribution of Ca++ between bone and ECF. The total body Ca++ level is determined by the relative amounts of Ca++ absorbed by the intestinal tract and excreted by the kidneys (Fig.


Physiology_Levy

Physiology_Levy. 36.14 ). The intestinal tract absorbs Ca++ through an active carrier-mediated transport mechanism that is stimulated by calcitriol, the active metabolite of vitamin D3 that is produced in the proximal tubule of the kidneys. Net Ca++ absorption by the intestine is normally 200 mg/day, but it can increase to 600 mg/day when calcitriol levels rise. In adults, Ca++ excretion by the kidneys equals the amount absorbed by the GI tract (200 mg/day), and it changes in bIn clinical practice the terms hypercalcemia and hypocalcemia are often used to describe a high or low total plasma [Ca++], respectively, even though this usage is not the physiologically correct usage of hypercalcemia and hypocalcemia.


Physiology_Levy

Physiology_Levy. parallel with intestinal absorption. Thus in adults, Ca++ balance is maintained because the amount of Ca++ ingested in an average diet (1000 mg/day) equals the amount lost in feces (800 mg/day, the amount that escapes absorption by the intestinal tract) plus the amount excreted in urine (200 mg/day). The second factor that controls Ca++ homeostasis is the distribution of Ca++ between bone and ECF (see


Physiology_Levy

Physiology_Levy. Fig. 36.14 ). Two hormones (PTH and calcitriol ) regulate the distribution of Ca++ between bone and ECF and thereby, in concert with the kidneys, regulate plasma [Ca++]. PTH is secreted by the parathyroid glands, and its secretion is stimulated by a decline in plasma [Ca++] (i.e., hypocalcemia). Plasma Ca++ is an agonist of the calcium sensing receptor (CaSR), which is located in the plasma membrane of chief cells in parathyroid glands (discussed later). Hypercalcemia activates the CaSR, which decreases PTH release, whereas hypocalcemia reduces CaSR activity that in turn increases PTH release. PTH increases plasma [Ca++] by: (1) stimulating bone resorption, (2) increasing Ca++ reabsorption by the distal tubule of the kidney, and (3) stimulating the production of calcitriol, which in turn increases Ca++ absorption by the intestinal tract and facilitates PTH-mediated bone resorption. Production of calcitriol in the kidney is stimulated by hypocalcemia and hypophosphatemia. Calcitriol


Physiology_Levy

Physiology_Levy. increases Ca++ absorption by the intestinal tract and facilitates PTH-mediated bone resorption. Production of calcitriol in the kidney is stimulated by hypocalcemia and hypophosphatemia. Calcitriol increases plasma [Ca++], primarily by stimulating Ca++ absorption from the intestinal tract. It also facilitates the action of PTH on bone and enhances Ca++ reabsorption in the kidneys by increasing expression of key Ca++ transport and binding proteins in the kidneys (details discussed later). In addition, cCalcitonin is secreted by thyroid C cells (parafollicular cells), and its secretion is stimulated by hypercalcemia. Calcitonin decreases plasma [Ca++], mainly by stimulating bone formation (i.e., deposition of Ca++ in bone). Although it plays an important role in Ca++ homeostasis in lower vertebrates, calcitonin plays only a minor role in Ca++ homeostasis in humans, so it will not be discussed further.


Physiology_Levy

Physiology_Levy. hypercalcemia activates the CaSR in the TAL of Henle’s loop, inhibiting Ca++ reabsorption in this segment, resulting in an increase in urinary Ca++ excretion and thereby a reduction in plasma [Ca++]. Hypocalcemia has the opposite effect. Importantly, regulation of Ca++ excretion by the kidneys is one of the major ways the body regulates plasma [Ca++].


Physiology_Levy

Physiology_Levy. Conditions that lower PTH levels (i.e., hypoparathyroidism after parathyroidectomy for an adenoma) reduce plasma [Ca++], which can cause hypocalcemic tetany (intermittent muscular contractions). In severe cases, hypocalcemic tetany can cause death by asphyxiation. Hypercalcemia can also cause lethal cardiac arrhythmias and decreased neuromuscular excitability. Clinically the most common causes of hypercalcemia are primary hyperparathyroidism and malignancy-associated hypercalcemia. Primary hyperparathyroidism results most often from overproduction of PTH caused by a benign tumor of the parathyroid glands. In contrast, malignancy-associated hypercalcemia, which occurs in 10% to 20% of all patients with cancer, is caused by secretion of parathyroid hormone–related peptide (PTHrP), a PTH-like hormone secreted by carcinomas in various organs. Increased levels of PTH and PTHrP cause hypercalcemia and hypercalciuria. Calcium Transport Along the Nephron


Physiology_Levy

Physiology_Levy. Calcium Transport Along the Nephron The Ca++ available for glomerular filtration consists of the ionized fraction and the amount complexed with anions. Thus about 60% of the Ca++ in plasma is available for glomerular filtration. Normally 99% of filtered Ca++ is reabsorbed by the nephron (Fig. 36.15 ). The proximal tubule reabsorbs about 50% to 60% of the filtered Ca++ . Another 15% is reabsorbed in the loop of Henle (mainly the cortical • Fig. 36.15 Overview of Ca++ transport along the nephron. Percentages refer to amount of filtered Ca++ reabsorbed by each segment. CCD, cortical collecting duct; DT, distal tubule; IMCD, inner medullary collecting duct; PT, proximal tubule; TAL, thick ascending limb.


Physiology_Levy

Physiology_Levy. CHAPTER 36 Potassium, Calcium, and Phosphate Homeostasis portion of the TAL), about 10% to 15% is reabsorbed by the distal tubule, and less than 1% is reabsorbed by the collecting duct. About 1% (200 mg/day) is excreted in urine. This fraction is equal to the net amount absorbed daily by the intestinal tract. Ca++ reabsorption by the proximal tubule occurs primarily via the paracellular pathway. This passive paracellular reabsorption of Ca++ is driven by the lumen-positive trans-epithelial voltage (Vte) across the second half of the proximal tubule and by a favorable concentration gradient of Ca++ , both of which are established by transcellular sodium and water reabsorption in the first half of the proximal tubule (see


Physiology_Levy

Physiology_Levy. Ca++ reabsorption by the loop of Henle also occurs primarily via the paracellular pathway. Like the proximal tubule, Ca++ and Na+ reabsorption in the TAL parallel each other. These processes are parallel because of the significant component of Ca++ reabsorption that occurs via passive paracellular reabsorption secondary to Na+ reabsorption that generates a lumen-positive Vte. Loop diuretics inhibit Na+ reabsorption by the TAL of the loop of Henle, and in so doing reduce the magnitude of the lumen-positive Vte (see ). This action in turn inhibits reabsorption of Ca++ via the paracellular pathway. Thus loop diuretics are used to increase renal Ca++ excretion in patients with hypercalcemia.


Physiology_Levy

Physiology_Levy. Mutations in the tight junction protein claudin-16 (CLDN16) reduce the permeability of the paracellular pathway to Ca++ and Mg++ and thereby reduce the diffusive reabsorptive movement of Ca++ and Mg++ across tight junctions in the TAL of Henle’s loop. Familial hypomagnesemic hypercalciuria is caused by mutations in claudin-16, which is a component of the tight junctions in TAL cells. This disorder is characterized by enhanced excretion of Ca++ and Mg++ due to a fall in passive reabsorption of these ions across the paracellular pathway in the TAL. Affected individuals have high levels of Ca++ in their urine, which leads to stone formation (nephrolithiasis).


Physiology_Levy

Physiology_Levy. In the distal tubule where the voltage in the tubule lumen is electrically negative with respect to blood, reabsorption of Ca++ is entirely active because Ca++ is reabsorbed against its electrochemical gradient (Fig. 36.16 ). Thus Ca++ reabsorption by the distal tubule is exclusively transcellular. Calcium enters the cell across the apical membrane through Ca++-permeable epithelial ion channels (TRPV5). Inside the cell, Ca++ binds to calbindin-D28K. The calbindin-Ca++ complex carries Ca++ across the cell and delivers Ca++ to the basolateral membrane, where it is extruded from the cell primarily by the 3Na+/1Ca++ antiporter (NCX1); however, plasma membrane Ca++-ATPase isoform 1b (PMCA1b) may also contribute. Urinary Na+ and Ca++ excretion usually change in parallel. However, excretion of these ions does not always change in parallel, because reabsorption of Ca++ and Na+ by the distal tubule is independent and differentially • Fig. 36.16 Cellular mechanism of Ca++ reabsorption by the


Physiology_Levy

Physiology_Levy. these ions does not always change in parallel, because reabsorption of Ca++ and Na+ by the distal tubule is independent and differentially • Fig. 36.16 Cellular mechanism of Ca++ reabsorption by the distal tubule. Ca++ is reabsorbed exclusively by a cellular pathway. Ca++ enters the cell across the apical membrane via a Ca++-permeable ion channel (TRPV5). Inside cells, Ca++ binds to calbindin (calbindin-D28K), and the Ca++-calbindin complex diffuses across the cell to deliver Ca++ to the basolateral membrane. Ca++ is transported across the basolateral membrane primarily by a 3 (or 4) Na+/Ca++ antiporter (NCX1) and also by a Ca++-H+-ATPase (PMCa1b). Claudin 8 (CLDN8) is a tight junction protein that is impermeable to Ca++ and thereby prevents the back diffusion of Ca++ across the tight junction into the tubule lumen, which is electrically negative compared to the blood side of the cell.


Physiology_Levy

Physiology_Levy. regulated. For example, thiazide diuretics inhibit Na+ reabsorption by the distal tubule and stimulate Ca++ reabsorption by this segment. Accordingly the net effects of thiazide diuretics are to increase urinary Na+ excretion and reduce urinary Ca++ excretion. Because thiazide diuretics reduce urinary Ca++ excretion, they are often given to reduce urinary [Ca++] in individuals who produce Ca++-containing kidney stones. Regulation of Urinary Calcium Excretion


Physiology_Levy

Physiology_Levy. Table 36.2 ). Of these, PTH exerts the most powerful control on renal Ca++ excretion; it is the primary hormone/ factor responsible for maintaining Ca++ homeostasis. Overall this hormone stimulates Ca++ reabsorption by the kidneys (i.e., reduces Ca++ excretion). Although PTH inhibits reabsorption of NaCl and fluid, and therefore Ca++ reabsorption by the proximal tubule, PTH stimulates Ca++ reabsorption by the TAL of the loop of Henle and the distal tubule. Thus the net effect of PTH is to enhance renal Ca++ reabsorption. Changes in plasma [Ca++] also regulate urinary Ca++ excretion, with hypercalcemia increasing excretion and hypocalcemia decreasing excretion. Hypercalcemia increases urinary Ca++ excretion by: (1) reducing proximal tubule Ca++ reabsorption (reduced paracellular reabsorption due to increased interstitial fluid [Ca++]); (2) inhibiting Ca++ reabsorption by the TAL of the loop of Henle via activation of the CaSR located in the basolateral membrane of these cells (NaCl


Physiology_Levy

Physiology_Levy. due to increased interstitial fluid [Ca++]); (2) inhibiting Ca++ reabsorption by the TAL of the loop of Henle via activation of the CaSR located in the basolateral membrane of these cells (NaCl reabsorption is decreased, thereby reducing the magnitude of the lumen-positive Vte); and (3) suppressing Ca++ reabsorption by the distal tubule by reducing PTH levels. As a result, urinary Ca++ excretion increases. Hypocalcemia has the opposite effect on urinary Ca++ excretion, primarily by increasing Ca++ reabsorption by the proximal tubule and TAL. Calcitriol enhances Ca++ reabsorption by the distal tubule, but it is less effective than PTH.


Physiology_Levy

Physiology_Levy. Several factors disturb Ca++ excretion. An increase in plasma [Pi] concentration (e.g., caused by a dramatic increase in dietary intake of Pi or by reduced kidney function) elevates PTH levels both directly and by decreasing the ionized plasma [Ca++] and thereby decreases Ca++ excretion. A decline in plasma [Pi] (e.g., caused by dietary Pi depletion) has the opposite effect (NOTE: with normal kidney function, changes in dietary Pi intake over a sevenfold range has no effect on plasma [Pi]). Changes in ECFV alter Ca++ excretion mainly by affecting NaCl and fluid reabsorption in the proximal tubule. Volume contraction increases NaCl and water reabsorption by the proximal tubule and thereby enhances Ca++ reabsorption. Accordingly, urinary Ca++ excretion declines. Volume expansion has the opposite effect. Acidemia increases Ca++ excretion, whereas alkalemia decreases excretion. Regulation of Ca++ reabsorption by pH


Physiology_Levy

Physiology_Levy. CHAPTER 36 Potassium, Calcium, and Phosphate Homeostasis aPTH inhibits Ca++ reabsorption by the proximal tubule but stimulates reabsorption by the TAL and distal tubule. Overall the net effect is to increase Ca++ reabsorption and thereby reduce urinary Ca++ excretion. CaSR, calcium-sensing receptor. Modified from Mount DB, Yu A. Transport of inorganic solutes: sodium, chloride, potassium, magnesium, calcium and phosphate. In: Brenner BM (ed). Brenner and Rector’s The Kidney. 8th ed. Philadelphia: Saunders; 2008. occurs primarily in the distal tubule. Alkalosis stimulates the apical membrane Ca++ channel (TRPV5), thereby increasing Ca++ reabsorption. By contrast, acidosis inhibits the same channel, thereby reducing Ca++ reabsorption. Finally, as noted earlier, loop diuretics inhibit Ca++ reabsorption by the TAL, and thiazide diuretics stimulate Ca++ reabsorption by the distal tubule.


Physiology_Levy

Physiology_Levy. The calcium-sensing receptor (CaSR) is a receptor expressed in the plasma membrane of cells involved in regulating Ca++ homeostasis; it senses small changes in extracellular [Ca++]. Ca++ binds to CaSR receptors in PTH-secreting cells of the parathyroid gland and calcitriol-producing cells of the proximal tubule. Activation of the receptor by an increase in plasma [Ca++] results in inhibition of PTH secretion and production of calcitriol by the proximal tubule. Moreover, reduction in PTH secretion also contributes to decreased production of calcitriol because PTH is a potent stimulus of calcitriol synthesis. By contrast, a fall in plasma [Ca++] has the opposite effect on PTH and calcitriol secretion.


Physiology_Levy

Physiology_Levy. The CaSR also maintains Ca++ homeostasis by directly regulating Ca++ excretion by the kidneys. CaSRs in the TAL respond directly to changes in plasma [Ca++] and regulate Ca++ absorption. An increase in plasma [Ca++] activates CaSR in the TAL and inhibits Ca++ absorption, thereby stimulating urinary Ca++ excretion. By contrast, a fall in plasma [Ca++] leads to an increase in Ca++ absorption by the TAL and a corresponding decrease in urinary Ca++ excretion. Thus the direct effect of plasma [Ca++] on CaSRs in the TAL acts in concert with changes in PTH, which regulates Ca++ reabsorption by the distal tubule to regulate urinary Ca++ excretion and thereby maintain Ca++ homeostasis.


Physiology_Levy

Physiology_Levy. Mutations in the gene coding for CaSR cause disorders in Ca++ homeostasis. Familial hypocalciuric hypercalcemia (FHH) is a haploinsufficient state caused by an inactivating mutation of CaSR. The hypercalcemia is caused by deranged Ca++-regulated PTH secretion (i.e., the set point for Ca++-regulated PTH secretion is shifted such that PTH levels are elevated at any level of plasma [Ca++], and are not suppressed in the setting of hypercalcemia). The hypocalciuria is caused by enhanced Ca++ reabsorption in the TAL and distal tubule owing to elevated PTH levels and defective CaSR regulation of Ca++ transport in the kidneys. Autosomal-dominant hypoparathyroidism is caused by an activating mutation in CaSR. Activation of CaSRs causes deranged Ca++-regulated PTH secretion (i.e., the set point for Ca++-regulated PTH secretion is shifted such that PTH levels are decreased at any level of plasma [Ca++]). Hypercalciuria results and is caused by decreased PTH levels and defective CaSR-regulated


Physiology_Levy

Physiology_Levy. Ca++-regulated PTH secretion is shifted such that PTH levels are decreased at any level of plasma [Ca++]). Hypercalciuria results and is caused by decreased PTH levels and defective CaSR-regulated Ca++ transport in the kidneys.


Physiology_Levy

Physiology_Levy. Pi is an important component of many organic molecules, including DNA, RNA, ATP, nucleotides, nucleosides, and phospholipids and intermediates of metabolic pathways. Like Ca++ it is a major constituent of bone. Its concentration in plasma is an important determinant of bone formation and resorption. In addition, urinary Pi is an important buffer (i.e., it is one of many titratable acids) involved in the maintenance of acid-base balance (see ). Some 85% of Pi is located in bone and teeth, 14% is located in the ICF, and 1% is located in the ECF. Normal plasma • Fig. 36.17 Overview of Pi homeostasis. (From Koeppen BM, Stanton BA. Renal Physiology. 5th ed. Philadelphia: Elsevier; 2013.) [Pi] is 3 to 4 mg/dL (1–1.5 mM). Pi in plasma is ionized (45%), complexed (30%), and bound to protein (25%). Phosphate deficiency causes muscle weakness, rhabdomyolysis, and reduced bone mineralization resulting in rickets (in children) and osteomalacia (in adults). Overview of Phosphate Homeostasis


Physiology_Levy

Physiology_Levy. Overview of Phosphate Homeostasis A general scheme of Pi homeostasis is shown in


Physiology_Levy

Physiology_Levy. Fig. 36.17 . Maintenance of Pi homeostasis depends on two factors: (1) the amount of Pi in the body and (2) the distribution of Pi between the ICF and ECF compartments. Total body Pi levels are determined by the relative amount of Pi absorbed by the intestinal tract versus the amount excreted by the kidneys. Pi absorption by the intestinal tract occurs via active and passive mechanisms; Pi absorption increases as dietary Pi rises, and it is stimulated by calcitriol. Despite variations in Pi intake between 800 and 1500 mg/day, in adults (i.e., the steady state) the kidneys maintain total body Pi balance constant by excreting an amount of Pi in the urine equal to the amount absorbed by the intestinal tract (normal bone remodeling results in no net addition of Pi to, or Pi release from, bone). By contrast, during growth, Pi is accumulated in the body. Renal Pi excretion is the primary mechanism by which the body regulates Pi balance and thereby Pi homeostasis.


Physiology_Levy

Physiology_Levy. The second factor that maintains Pi homeostasis is distribution of Pi among bone and the ICF and ECF compartments. Regulation of plasma [Pi] is controlled by two hormones, PTH and calcitriol, in concert with the kidneys (see Fig. 36.17 ). Release of Pi from bone is stimulated by the same hormones (i.e., PTH and calcitriol) that release Ca++ from this pool. Thus release of Pi from bone is always accompanied by release of Ca++ . The kidneys also make an important contribution to maintaining plasma [Pi] within a narrow range (1–1.5 mM). Pi excretion by the kidneys is regulated by PTH and calcitriol (see Fig. 36.17 ). PTH increases Pi excretion, whereas calcitriol inhibits Pi excretion. Plasma [Pi] is determined by: (1) intestinal absorption, (2) storage in bone, and (3) Pi excretion by the kidneys. Maintenance of plasma [Pi] is essential for optimal Ca++-Pi complex formation required for bone mineralization without deposition of Ca++-Pi in vascular and other soft tissues.


Physiology_Levy

Physiology_Levy. A rise in plasma [Pi] directly stimulates PTH synthesis and release and also decreases the ionized [Ca++], which stimulates PTH release by its interaction with the CaSR. PTH enhances urinary Pi excretion by inhibiting proximal tubule Pi reabsorption. Hyperphosphatemia also decreases calcitriol production by the proximal tubule, which leads to a reduction in Pi absorption by the intestine. Both the increase in PTH and the decrease in calcitriol reduce plasma [Pi]. Phosphate Transport Along the Nephron Fig. 36.18 summarizes Pi transport by the various portions of the nephron. The proximal tubule reabsorbs 80% of the Pi filtered by the glomerulus; the loop of Henle, distal tubule, and collecting duct reabsorb negligible amounts of Pi. Therefore approximately 20% of the Pi filtered across the glomerular capillaries is excreted in urine. Pi reabsorption by the proximal tubule occurs by a transcellular route (


Physiology_Levy

Physiology_Levy. Pi reabsorption by the proximal tubule occurs by a transcellular route ( Fig. 36.19 ). Pi uptake across the apical membrane of the proximal tubule occurs via two Na+/Pi symporters (IIa and IIc). Type IIa transports 3Na+ with one divalent Pi (HPO42−), and carries positive charge into the cell. Type IIc transports 2Na+ with one monovalent Pi (H2PO4 −) and is electrically neutral. Pi exits across the basolateral membrane by a Pi-inorganic anion antiporter that has not been characterized. CHAPTER 36 Potassium, Calcium, and Phosphate Homeostasis • Fig. 36.18 Pi transport along the nephron. Pi is reabsorbed primarily by the proximal tubule. Percentages refer to the amount of the filtered Pi reabsorbed by each nephron segment. Approximately 20% of the filtered Pi is excreted. CCD, cortical collecting duct; DT, distal tubule; IMCD, inner medullary collecting duct; PT, proximal tubule; TAL, thick ascending limb.


Physiology_Levy

Physiology_Levy. In patients with chronic renal failure, the kidneys cannot excrete Pi. Because of continued Pi absorption by the intestinal tract, Pi accumulates in the body and plasma [Pi] rises. The excess Pi complexes with Ca++ and reduces the ionized plasma [Ca++]. Pi accumulation also decreases production of calcitriol. This response reduces Ca++ absorption by the intestine, an effect that further reduces plasma [Ca++]. This reduction in plasma [Ca++] increases PTH secretion and Ca++ release from bone. These actions result in renal osteodystrophy (i.e., increased bone resorption with replacement by fibrous tissue, which renders bone more susceptible to fracture). Chronic hyperparathyroidism (i.e., elevated PTH levels due the fall in plasma [Ca++]) during chronic renal failure can lead to metastatic calcifications in which Ca++ and Pi precipitate in arteries, soft tissues, and viscera. Deposition of Ca++ and Pi in the heart may cause myocardial failure. Prevention and treatment of


Physiology_Levy

Physiology_Levy. to metastatic calcifications in which Ca++ and Pi precipitate in arteries, soft tissues, and viscera. Deposition of Ca++ and Pi in the heart may cause myocardial failure. Prevention and treatment of hyperparathyroidism and Pi retention include a low-Pi diet or administration of a “phosphate binder” (i.e., an agent that forms insoluble Pi salts and thereby renders Pi unavailable for absorption by the intestinal tract) in the diet. Supplemental Ca++ and calcitriol are also prescribed to increase plasma [Ca++].


Physiology_Levy

Physiology_Levy. • Fig. 36.19 Cellular mechanisms of Pi reabsorption by the proximal tubule. The apical transport pathway contains two Na+/Pi symporters, one that transports three Na+for each Pi (IIa) and one that transports two Na+for each Pi (IIc). Pi leaves the cell across the basolateral membrane by an unknown mechanism. ATP, adenosine triphosphate. TubularfluidBloodPiPiK˜Na˜2Na˜Pi3Na˜ATPIIaIIc? Fibroblast growth factor 23 (FGF-23) increases renal Pi excretion and thereby contributes to regulation of plasma [Pi] (see Fig. 36.17 ). FGF-23 is secreted by osteocytes and osteoblasts and inhibits Pi reabsorption and calcitriol production by the proximal tubule. Secretion of FGF-23 is stimulated by sustained hyperphosphatemia, PTH, and calcitriol. Activating mutations in the FGF23 gene cause hypophosphatemia, low plasma calcitriol, and rickets/osteomalacia, whereas inactivating mutations cause hyperphosphatemia, high serum calcitriol, and calcification of soft tissue.


Physiology_Levy

Physiology_Levy. Regulation of Urinary Phosphate Excretion Table 36.3 Fig. 36.20 ). Increased plasma Pi reduces TABLE Summary of Hormones and Factors 36.3 Affecting Pi Reabsorption by Proximal Tubule


Physiology_Levy

Physiology_Levy. PTH Decrease FGF-23 Decrease Phosphate loading Decrease Phosphate depletion Increase Metabolic acidosis: chronic Decrease Metabolic alkalosis: chronic Increase ECFV expansion Decrease Growth hormone Increase Glucocorticoids Decrease • Fig. 36.20 Overview of the major hormones regulating plasma [Pi]. FGF-23, fibroblast growth factor 23; PTH, parathyroid hormone. Dashed lines indicate negative feedback. (From Koeppen BM, Stanton BA. Renal Physiology. 5th ed. Philadelphia: Elsevier; 2013.) plasma [Ca++] and therefore increases plasma PTH, which increases Pi excretion by the kidneys. PTH, the most important hormone that controls Pi excretion, inhibits Pi reabsorption by the proximal tubule and thereby increases Pi excretion. PTH reduces Pi reabsorption by stimulating endocytic removal of Na+/Pi transporters from the brush border membrane of the proximal tubule. Increased plasma Pi also increases FGF-23, which inhibits Pi reabsorption and calcitriol production by the proximal tubule.


Physiology_Levy

Physiology_Levy. Na+/Pi transporters from the brush border membrane of the proximal tubule. Increased plasma Pi also increases FGF-23, which inhibits Pi reabsorption and calcitriol production by the proximal tubule. Elevated plasma Pi also suppresses calcitriol production, which results in a decrease in intestinal Pi reabsorption. Dietary Pi intake also regulates Pi excretion by mechanisms unrelated to changes in PTH levels. Pi loading increases excretion, whereas Pi depletion decreases it. Changes in dietary Pi intake modulate Pi transport by altering the transport rate of each Na+/Pi symporter and the number of symporters in the apical membrane of the proximal tubule.


Physiology_Levy

Physiology_Levy. ECFV also affects Pi excretion. Expansion of the ECF enhances Pi excretion by: (1) increasing GFR and thus the filtered load of Pi; (2) decreasing Na/Pi coupled reabsorption, which reduces ECFV, and (3) reducing plasma [Ca++], thereby increasing PTH, which inhibits Pi reabsorption in the proximal tubule. Acid-base balance also influences Pi excretion; chronic acidosis increases Pi excretion, and chronic alkalosis decreases it. These effects of acid-base balance, like the effect of PTH, are mediated by changes of expression of the Na /Pi symporters in the apical membrane. Systemic acidosis increases glucocorticoid secretion, and glucocorticoids increase excretion of Pi by inhibiting Pi reabsorption by the proximal tubule. This inhibition, together with the direct effect of acidosis on Pi reabsorption by the proximal tubule, enables the distal tubule and collecting duct to secrete more H+ as titratable acid and to generate more HCO3 − because Pi is an important urinary buffer. Growth


Physiology_Levy

Physiology_Levy. reabsorption by the proximal tubule, enables the distal tubule and collecting duct to secrete more H+ as titratable acid and to generate more HCO3 − because Pi is an important urinary buffer. Growth hormone decreases Pi excretion.


Physiology_Levy

Physiology_Levy. Klotho, which was identified in 1997, is highly expressed in the early distal tubule of the kidney. Klotho knockout mice have a phenotype that resembles chronic kidney disease (CKD), including soft tissue calcification, hyperphosphatemia, and elevated plasma FGF-32. Klotho exists as both a membrane-bound and a soluble protein. The membrane-bound form is a coreceptor for FGF-23, thus Klotho promotes Pi excretion by the kidneys and reduces serum levels of 1,25-dihydroxyvitamin D3. Soluble circulating Klotho has a number of additional functions, including modulating ion transport and Wnt signal transduction, inhibiting reninangiotensin signaling, and modulating FGF-23 regulation of PTH production. A considerable body of experimental data suggests that Klotho may be a biomarker for CKD, and that Klotho deficiency may contribute to development of CKD. Moreover, experimental data also suggest that Klotho therapy may slow the progression of CKD.


Physiology_Levy

Physiology_Levy. CHAPTER 36 Potassium, Calcium, and Phosphate Homeostasis 667 • Fig. 36.21 Overview of the major hormones regulating plasma [Ca++]. Dashed lines indicate negative feedback. FGF-23, fibroblast growth factor 23; PTH, parathyroid hormone. (From Koeppen BM, Stanton BA. Renal Physiology. 5th ed. Philadelphia: Elsevier; 2013.) Integrative Review of Parathyroid Hormone and Calcitriol on Ca++ and Pi Homeostasis


Physiology_Levy

Physiology_Levy. Integrative Review of Parathyroid Hormone and Calcitriol on Ca++ and Pi Homeostasis Fig. 36.21 , PTH has numerous effects on Ca++ and Pi homeostasis. Hypocalcemia is the major stimulus of PTH secretion. PTH stimulates bone resorption, increases urinary Pi excretion, decreases urinary Ca++ excretion, and stimulates production of calcitriol, which stimulates Ca++ and Pi absorption by the intestine. Because changes in Pi handling in bone, intestines, and kidneys tend to balance out, PTH increases plasma [Ca++] while having little effect on plasma [Pi]. Overall a rise in plasma PTH levels in response to hypocalcemia returns plasma [Ca++] to the normal range. A decline in plasma [Ca++] has the opposite effect. Calcitriol (the active form of vitamin D) also plays an important role in Ca++ and Pi homeostasis ( Fig. 36.22


Physiology_Levy

Physiology_Levy. Calcitriol (the active form of vitamin D) also plays an important role in Ca++ and Pi homeostasis ( Fig. 36.22 The primary action of calcitriol is to stimulate Ca++ and Pi absorption by the intestine. To a lesser degree it acts with PTH to release Ca++ and Pi from bone and to decrease Ca++ excretion by the kidneys. The net effect of calcitriol is to increase plasma [Ca++] and [Pi]. Thus the major stimuli of calcitriol production are hypocalcemia via PTH and hypophosphatemia (i.e., a low plasma [Pi]). In the absence of glucocorticoids (e.g., in Addison’s disease), excretion of Pi is depressed, as is the ability of the kidneys to excrete titratable acid and to generate new HCO3 − . Growth hormone increases reabsorption of Pi by the proximal tubule. As a result, growing children are in positive Pi balance and have a higher plasma [Pi] than adults, and this elevated [Pi] is important for bone formation.


Physiology_Levy

Physiology_Levy. • Fig. 36.22 Activation of calcitriol (vitamin D3) and its effect on Ca++ and Pi homeostasis. Hypocalcemia (via PTH) and hypophosphatemia are the major stimuli of the metabolism of calcifediol to calcitriol in the kidneys. The net effect of calcitriol is to increase plasma [Ca++] and [Pi]. (From Koeppen BM, Stanton BA. Renal Physiology. 5th ed. Philadelphia: Elsevier; 2013.) 1. K+ homeostasis is maintained by the kidneys, which adjust K+ excretion to match dietary K+ intake, and by the hormones insulin, epinephrine, and aldosterone, which regulate the distribution of K+ between the ICF and ECF compartments. Other events, such as cell lysis, exercise, and changes in acid-base balance and plasma osmolality, disturb K+ homeostasis and plasma [K+]. 2.


Physiology_Levy

Physiology_Levy. 2. Excretion of K+ by the kidneys is determined by the rate and direction of K+ transport by the distal tubule and collecting duct. Secretion of K+ by these tubular segments is regulated by plasma [K+], aldosterone, and AVP. In contrast, changes in tubular fluid flow and acid-base disturbances perturb K+ excretion by the kidneys. In K+-depleted states, K+ secretion is inhibited and the distal tubule and collecting duct reabsorb K+ . 3. The kidneys, in conjunction with the intestinal tract and bone, play a vital role in regulating plasma [Ca++] and [Pi]. 4. Plasma [Ca++] is regulated by PTH and calcitriol. Calcitonin is not a major regulatory hormone in humans. Ca++ excretion by the kidneys is regulated by PTH, plasma [Ca++], and calcitriol and is altered by changes in acid-base status, ECFV, and plasma Pi. 5. Ca++ reabsorption by the TAL and distal tubule are regulated by PTH and calcitriol, both of which stimulate Ca++ reabsorption, and by plasma [Ca++]. 6.


Physiology_Levy

Physiology_Levy. 5. Ca++ reabsorption by the TAL and distal tubule are regulated by PTH and calcitriol, both of which stimulate Ca++ reabsorption, and by plasma [Ca++]. 6. Plasma [Pi] is regulated by PTH, FGF-23, and calcitriol. Pi excretion is regulated by PTH, FGF-23, dietary phosphate, and growth hormone and is altered by acid base balance, ECFV expansion, and glucocorticoids. Bone tumors secrete FGF-23, which enhances renal Pi excretion and thereby causes hypophosphatemia, hyperphosphatemia, and a defect in bone mineralization (i.e., osteomalacia). Biber J, et al. Phosphate transporters and their function. Annu Rev Physiol. 2013;75:535-550. Christov M, Juppner H. Insights from genetic disorders of phosphate homeostasis. Semin Nephrol. 2013;33:143-157. Miller T. Control of renal calcium, phosphate, electrolyte, and water excretion by the calcium-sensing receptor. Best Pract Res Clin Endocrinol Metab. 2013;27:345-358.


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Physiology_Levy. Miller T. Control of renal calcium, phosphate, electrolyte, and water excretion by the calcium-sensing receptor. Best Pract Res Clin Endocrinol Metab. 2013;27:345-358. Palmer BF. Regulation of potassium homeostasis. Clin J Am Soc Nephrol. 2015;10:1050-1060. Patel A. The primary cilium calcium channels and their role in flow sensing. Pflugers Arch. 2015;467:157-165. Pearce D, et al. Collecting duct principal cell transport processes and their regulation. Clin J Am Soc Nephrol. 2015;10:135-146. Bernardo JF, Friedman PA. Renal calcium metabolism. In. In: Alpern RJ, et al., eds. Seldin and Giebisch’s The Kidney: CHAPTER 36 Potassium, Calcium, and Phosphate Homeostasis Physiology and Pathophysiology. 5th ed. Waltham, MA: Elsevier; 2013:2225. Berndt TJ, Kumar R. Clinical disturbances of phosphate homeostasis. In: Alpern RJ, et al., eds. Seldin and Giebisch’s The Kidney: Physiology and Pathophysiology. 5th ed. Waltham, MA: Elsevier; 2013:2369.


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Physiology_Levy. Malnic G, et al. Regulation of K+ excretion. In: Alpern RJ, et al., eds. Seldin and Giebisch’s The Kidney: Physiology and Pathophysiology. 5th ed. Waltham, MA: Elsevier; 2013:1659. Murer H, et al. Proximal tubular handling of phosphate. In: Alpern RJ, et al., eds. Seldin and Giebisch’s The Kidney: Physiology and Pathophysiology. 5th ed. Waltham, MA: Elsevier; 2013:2351. Smogorzewski MJ, et al. Disorders of calcium, magnesium, and phosphate balance. In: Taal MW, et al., eds. Brenner and Rector’s The Kidney. 9th ed. Philadelphia: Saunders; 2012:689. Wang W, Huang CL. The molecular biology of renal K+ channels. In: Alpern RJ, et al., eds. Seldin and Giebisch’s The Kidney: Physiology and Pathophysiology. 5th ed. Waltham, MA: Elsevier; 2013: 1601. Upon completion of this chapter the student should be able to answer the following questions: 1. How does HCO3 − operate as a buffer, and why is it an important buffer of the extracellular fluid? 2.


Physiology_Levy

Physiology_Levy. How does HCO3 − operate as a buffer, and why is it an important buffer of the extracellular fluid? 2. How does metabolism of food produce acid and alkali, and what effect does the composition of the diet have on systemic acid-base balance? 3. What is the difference between volatile and nonvolatile acids, and what is net endogenous acid production (NEAP)? 4. How do the kidneys and lungs contribute to systemic acid-base balance, and what is renal net acid excretion (RNAE)? 5. Why are urinary buffers necessary for excretion of acid by the kidneys? 6. What are the mechanisms for H+ transport in the various segments of the nephron, and how are these mechanisms regulated? 7. How do the various segments of the nephron contribute to the process of reabsorbing the filtered HCO3 −? 8. How do the kidneys produce new HCO3 −? 9. How is ammonium produced by the kidneys, and how does its excretion contribute to renal acid excretion? 10.


Physiology_Levy

Physiology_Levy. 8. How do the kidneys produce new HCO3 −? 9. How is ammonium produced by the kidneys, and how does its excretion contribute to renal acid excretion? 10. What are the major mechanisms by which the body defends itself against changes in acid-base balance? 11. What are the differences between simple metabolic and respiratory acid-base disorders, and how are they differentiated by arterial blood gas measurements? he concentration of H+ in body fluids is low compared with that of other ions. For example, Na+ is present at a concentration some three million times greater than that of H+ ([Na+] = 140 mEq/L; [H+] = 40 nEq/L). Because of the low [H+] of the body fluids, it is commonly expressed as the negative logarithm, or pH.


Physiology_Levy

Physiology_Levy. Virtually all cellular, tissue, and organ processes are sensitive to pH. Indeed, life cannot exist outside of a range of extracellular fluid (ECF) pH from 6.8 to 7.8 (160–16 nEq/L of H+). Normally the pH of ECF is maintained between 7.35 and 7.45. As described in the pH of intracellular fluid (ICF) is slightly lower (7.1–7.2) but also tightly regulated.


Physiology_Levy

Physiology_Levy. Each day, acid and alkali are ingested in the diet. Also, cellular metabolism produces a number of substances that have an impact on the pH of body fluids. Without appropriate mechanisms to deal with this daily acid and alkali load and thereby maintain acid-base balance, many processes necessary for life could not occur. This chapter reviews the maintenance of whole-body acid-base balance. Although the emphasis is on the role of the kidneys in this process, the roles of the lungs and liver are also considered. In addition the impact of diet and cellular metabolism on acid-base balance is presented. Finally, disorders of acid-base balance are considered, primarily to illustrate the physiological processes involved. Throughout this chapter, acid is defined as any substance that adds H+ to body fluids, whereas alkali is defined as a substance that removes H+ from body fluids. The HCO3 − Buffer System


Physiology_Levy

Physiology_Levy. The HCO3 − Buffer System Bicarbonate (HCO3 −) is an important buffer of the ECF. With a normal plasma [HCO3 −] of 23 to 25 mEq/L and a volume of 14 L (for a 70-kg individual) the ECF can potentially buffer 350 mEq of H+ . The HCO3 − buffer system differs from the other buffer systems of the body (e.g., phosphate) because it is regulated by both the lungs and kidneys. This is best appreciated by considering the following reaction: Equation 37.1 As indicated the first reaction (hydration/dehydration of CO2) is the rate-limiting step. This normally slow reaction is greatly accelerated in the presence of carbonic anhydrase. The second reaction, ionization of H2CO3 to H+ and HCO3 − , is virtually instantaneous.


Physiology_Levy

Physiology_Levy. The second reaction, ionization of H2CO3 to H+ and HCO3 − , is virtually instantaneous. aCarbonic anhydrase (CA) actually catalyzes the following reaction: (e.g., citrate) •Fig. 37.1 Overviewofacid-basebalance.Thelungsandkidneysworktogethertomaintainacid-basebalance.ThelungsexcreteCO2(volatileacid),andthekidneysexcreteacid(renalnetacidexcretion[RNAE])equaltonetendogenousacidproduction(NEAP),whichreflectsdietaryintake,cellularmetabolism,andlossofacidandalkali(e.g.,HCO3− lossinfeces)fromthebody.Seetextfordetails.(FromKoeppenBM,StantonBA.Renal Physiology. 5thed.Philadelphia:Elsevier;2013.) The Henderson-Hasselbalch equation is used to quantitate how changes in CO2 and HCO3 − effect pH: Equation 37.2 Equation 37.3 [HCO3 − ]pH = 6 1. + log 0 03. PCO2


Physiology_Levy

Physiology_Levy. The Henderson-Hasselbalch equation is used to quantitate how changes in CO2 and HCO3 − effect pH: Equation 37.2 Equation 37.3 [HCO3 − ]pH = 6 1. + log 0 03. PCO2 In these equations the amount of CO2 is determined from the partial pressure of CO2 (PCO2) and its solubility (α) in solution. For plasma at 37°C, α has a value of 0.03. Also, pK′ is the negative logarithm of the overall dissociation constant for the reaction in Eq. 37.1 and has a value for plasma at 37°C of 6.1. Alternatively the relationship between HCO3 − and CO2 on the [H+] can be determined as follows: Equation 37.4


Physiology_Levy

Physiology_Levy. Eq. 37.1 and has a value for plasma at 37°C of 6.1. Alternatively the relationship between HCO3 − and CO2 on the [H+] can be determined as follows: Equation 37.4 Inspection of Eqs. 36.3 and 36.4 show that pH and [H+] vary when either [HCO3 −] or PCO2 are altered. Disturbances of acid-base balance that result from a change in [HCO3 −] are termed metabolic acid-base disorders, whereas those resulting from a change in PCO2 are termed respiratory acid-base disorders. These disorders are considered in more detail in a subsequent section. The kidneys are primarily responsible for regulating the [HCO3 −] of ECF, whereas the lungs control the PCO2. Overview of Acid-Base Balance


Physiology_Levy

Physiology_Levy. Overview of Acid-Base Balance The diet of humans contains many constituents that are either acid or alkali. In addition, cellular metabolism produces acid and alkali. Finally, alkali is normally lost each day in feces. As described later, although diet dependent, the net effect of these processes is the addition of acid to body fluids. For acid-base balance to be maintained, acid must be excreted from the body at a rate equivalent to its addition. If acid addition exceeds excretion, acidosis results. Conversely, if acid excretion exceeds addition, alkalosis results.


Physiology_Levy

Physiology_Levy. Fig. 37.1 , the major constituents of the diet are carbohydrates and fats. When tissue perfusion is adequate, O2 is available to tissues, and insulin is present at normal levels, carbohydrates and fats are metabolized to CO2 and H2O. On a daily basis, 15 to 20 moles of CO2 are generated through this process. Normally this large quantity of CO2 is effectively eliminated from the body by the lungs. Therefore this metabolically derived CO2 has no impact on acid-base balance. CO2 is usually termed volatile acid because it has the potential to generate H+ after hydration with H2O (see Eq. 36.1 ). Acid not derived directly from hydration of CO2 is termed nonvolatile acid (e.g., lactic acid).


Physiology_Levy

Physiology_Levy. The cellular metabolism of other dietary constituents also has an impact on acid-base balance. For example, cysteine and methionine, sulfur-containing amino acids, yield sulfuric acid when metabolized, whereas hydrochloric acid results from metabolism of lysine, arginine, and histidine. A portion of this nonvolatile acid load is offset by production of HCO3 − through metabolism of the amino acids aspartate and glutamate. On average the metabolism of dietary amino acids yields net nonvolatile acid production. Metabolism of certain organic anions (e.g., citrate) results in production of HCO3 − , which offsets nonvolatile acid production to some degree. Overall in individuals ingesting a meat-containing diet, acid production exceeds HCO3 − production. In contrast, a vegetarian diet produces less nonvolatile acid. In addition to the metabolically derived acids and alkalis, the foods ingested contain acid and alkali. For example, the presence of phosphate (H2PO4 −) in ingested food


Physiology_Levy

Physiology_Levy. less nonvolatile acid. In addition to the metabolically derived acids and alkalis, the foods ingested contain acid and alkali. For example, the presence of phosphate (H2PO4 −) in ingested food increases the dietary acid load. Finally, during digestion, some HCO3 − is normally lost in feces. This loss is equivalent to the addition of nonvolatile acid to the body. In an individual ingesting a meat-containing diet, dietary intake, cellular metabolism, and fecal HCO3 − loss result in addition of approximately 0.7 to 1.0 mEq/kg body weight of nonvolatile acid to the body each day (50–100 mEq/day for most adults). This acid, referred to as net endogenous acid production (NEAP), results in an equivalent loss of HCO3 − from the body that must be replaced.


Physiology_Levy


Physiology_Levy

Physiology_Levy. Nonvolatile acids do not circulate throughout the body but are immediately neutralized by the HCO3 − in ECF. Equation 37.5 Equation 37.6 This neutralization process yields the Na+ salts of the strong acids and removes HCO3 − from the ECF. Thus HCO3 − minimizes the effect of these strong acids on the pH of ECF. As noted previously, ECF contains approximately 350 mEq of HCO3 − . If this HCO3 − were not replenished, the daily production of nonvolatile acids (≈70 mEq/day) would deplete the ECF of HCO3 − within 5 days. To maintain acid-base balance the kidneys must replenish the HCO3 − lost by neutralization of the nonvolatile acids, a process termed renal net acid excretion (RNAE). Net Acid Excretion by the Kidneys


Physiology_Levy

Physiology_Levy. Net Acid Excretion by the Kidneys Under steady-state conditions, NEAP must equal RNAE to maintain acid-base balance. Although NEAP varies from individual to individual and from day to day in anyone individual, it is not regulated. Instead the kidneys regulate RNAE to match NEAP and in so doing replenish the HCO3 − (new HCO3 −) lost by neutralization of nonvolatile acids. In addition the kidneys must prevent the loss of HCO3 − in urine. This latter task is quantitatively more important because the filtered load of HCO3 − is approximately 4320 mEq/day (24 mEq/L × 180 L/day = 4320 mEq/day), compared with only 50 to 100 mEq/day needed to balance NEAP.


Physiology_Levy

Physiology_Levy. Both reabsorption of filtered HCO3 − and excretion of acid are accomplished via H+ secretion by the nephrons. Thus in a single day the nephrons must secrete approximately 4390 mEq of H+ into the tubular fluid. Most of the secreted serves to reabsorb the filtered load of HCO3 . Only 50 to 100mEq of H+ , an amount equivalent to NEAP, is excreted in urine. As a result of this acid excretion, urine is normally acidic. The kidneys cannot excrete urine more acidic than pH 4.0 to 4.5. Even at a pH of 4.0, only 0.1 mEq/L of H+ can be excreted. Therefore to excrete sufficient acid, the kidneys excrete H+ with urinary buffers such as phosphate (Pi).


Physiology_Levy

Physiology_Levy. Other constituents of urine can also serve as buffers (e.g., creatinine), although their role is less important than Pi. Collectively the various urinary buffers are termed titratable acid. This term is derived from the method by which these buffers are quantitated in the laboratory. Typically, alkali (OH−) is added to a urine sample to titrate its pH to that of plasma (i.e., 7.4). The amount of alkali added is equal to the H+ titrated by these urine buffers and is termed titratable acid.


Physiology_Levy

Physiology_Levy. Excretion of H+ as a titratable acid is insufficient to balance NEAP. An additional and important mechanism by which the kidneys contribute to maintenance of acid-base balance is through synthesis and excretion of ammonium (NH4 +). The mechanisms involved in this process are discussed in more detail later in this chapter. With regard to renal regulation of acid-base balance, each NH4 + excreted in urine results in the return of one HCO3 − to the systemic circulation, which replenishes the HCO3 − lost during neutralization of the nonvolatile acids. Thus production and excretion of NH4 + , like excretion of titratable acid, is equivalent to excretion of acid by the kidneys. In brief the kidneys contribute to acid-base homeostasis by reabsorbing the filtered load of HCO3 − and excreting an bThe titration reaction is: HPO42−+ H+↔ H2PO4 − . This reaction has a pK of approximately 6.8. amount of acid equivalent to NEAP. This process can be quantitated as follows:


Physiology_Levy

Physiology_Levy. amount of acid equivalent to NEAP. This process can be quantitated as follows: Equation 37.7 where (UNH4+× V˜ ) and (UTA × V˜ ) are the rates of excretion (mEq/day) of NH4 + and titratable acid (TA), and (UHCO3−× V˜ ) is the amount of HCO3 − lost in urine (equivalent to adding H+ to the body). Again, maintenance of acid-base balance means that net acid excretion must equal nonvolatile acid production. Under most conditions, very little HCO3 − is excreted in urine. Thus net acid excretion essentially reflects titratable acid and NH4 + excretion. Quantitatively, titratable acid accounts for approximately one-third and NH4 + for two-thirds of RNAE. HCO3 − Reabsorption Along the Nephron Eq. 37.7 , net acid excretion is maximized when little or no HCO3 − is excreted in urine. Indeed, under most circumstances, very little HCO3 − appears in urine. Because HCO3 − is freely filtered at the glomerulus, approximately 4320 mEq/day is delivered to the nephrons and is then reabsorbed.


Physiology_Levy

Physiology_Levy. Fig. 37.2 summarizes the contribution of each nephron segment to reabsorption of filtered HCO3 − . The proximal tubule reabsorbs the largest portion of the filtered load of HCO3 − . Fig. 37.3 summarizes the primary cThis equation ignores the small amount of free H+ excreted in urine. As already noted, urine with a pH = 4.0 contains only 0.1 mEq/L of H+ .


Physiology_Levy

Physiology_Levy. Fig. 37.3 summarizes the primary cThis equation ignores the small amount of free H+ excreted in urine. As already noted, urine with a pH = 4.0 contains only 0.1 mEq/L of H+ . transport processes involved. H+ secretion across the apical membrane of the cell occurs by both a Na+/H+ antiporter and H+-ATPase (V-type). The Na+/H+ antiporter (NHE3) is the predominant pathway for H+ secretion (accounts for ≈ two-thirds of HCO3 − reabsorption) and uses the lumen-to-cell [Na+] gradient to drive this process (i.e., •Fig. 37.2 SegmentalreabsorptionofHCO3− .ThefractionofthefilteredloadofHCO3− reabsorbedbythevarioussegmentsofthenephronisshown.NormallytheentirefilteredloadofHCO3− isreabsorbedandlittleornoHCO3− appearsintheurine.CCD,corticalcollectingduct;DT,distaltubule;IMCD,innermedullarycollectingduct;PT,proximaltubule;TAL,thickascendinglimb.


Physiology_Levy

Physiology_Levy. •Fig. 37.3 CellularmechanismforreabsorptionoffilteredHCO3− bycellsoftheproximaltubule.OnlytheprimaryH+ andHCO3− transportersareshown.ATP,adenosinetriphosphate;CA,carbonicanhydrase. secondary active secretion of H+). Within the cell, H+ and HCO3 − are produced in a reaction catalyzed by carbonic anhydrase (CA-II). The H+ is secreted into the tubular fluid, whereas the HCO3 − exits the cell across the basolateral membrane and returns to the peritubular blood. HCO3 − movement out of the cell across the basolateral membrane is coupled to other ions. The majority of HCO3 − exits via a symporter that couples the efflux of Na+ with HCO3 − (sodium bicarbonate symporter, NBC1). Some HCO3 − exits the cell by other transporters, but they are not as important as the Na+/HCO3 − symporter. As noted in


Physiology_Levy

Physiology_Levy. Fig. 37.3 , carbonic anhydrase (CA-IV) is also present in the brush border and basolateral membrane of the cell. The brush border enzyme catalyzes dehydration of H2CO3 in the luminal fluid, whereas the enzyme localized to basolateral membrane facilitates HCO3 − exit from the cell. The movement of CO2 into and out of the cell occurs via AQP1, which is localized to both the luminal and basolateral membranes. The cellular mechanism for HCO3 − reabsorption by the thick ascending limb (TAL) of the loop of Henle is very similar to that in the proximal tubule. H+ is secreted by a Na+/H+ antiporter and H+-ATPase. Like in the proximal tubule, the Na+/H+ antiporter (NHE3) is the predominant pathway for H+ secretion. HCO3 − exit from the cell involves both a Na+/HCO3 − symporter (NBC1) and a Cl−/HCO3 − antiporter (anion exchanger, AE-2). Some HCO3 − may also exit the cell through Cl− channels present in the basolateral membrane.


Physiology_Levy

Physiology_Levy. The distal tubule and collecting duct reabsorb the small amount of HCO3 − that escapes reabsorption by the proximal tubule and loop of Henle. Fig. 37.4 shows the cellular mechanism of H+/HCO3 − transport by the intercalated cells located within these segments (see also One type of intercalated cell secretes H+ (reabsorbs HCO3 −) and is called the A-or α-intercalated cell. Within this cell, H+ and HCO3 − are produced by hydration of CO2; this reaction is catalyzed by carbonic anhydrase (CA-II). H+ is secreted into the tubular fluid via two mechanisms. The first involves an apical membrane H+-ATPase (V-type). The second couples secretion of H+ with reabsorption of via an H+-K+-ATPase similar to those found in the stomach and colon (HKα1 and HKα2). HCO3 − exits the cell across the basolateral membrane in exchange for Cl− (via a Cl−/HCO3 − antiporter, AE-1) and enters the peritubular capillary blood.


Physiology_Levy

Physiology_Levy. A second population of intercalated cells secretes HCO3 − rather than H+ into the tubular fluid (also called B-or dHere and in the remainder of the chapter we focus on the function of intercalated cells. The early portion of the distal tubule, which does not contain intercalated cells, also reabsorbs HCO3 − . The cellular mechanism appears to involve an apical membrane Na+/H+ antiporter (NHE2) and a basolateral Cl−/HCO3 − antiporter (AE2). β-intercalated cells). In these cells the H+-ATPase (V-type) is located in the basolateral membrane and the Cl−/HCO3 − antiporter is located in the apical membrane (see Fig. 37.4).


Physiology_Levy

Physiology_Levy. β-intercalated cells). In these cells the H+-ATPase (V-type) is located in the basolateral membrane and the Cl−/HCO3 − antiporter is located in the apical membrane (see Fig. 37.4). However, the apical membrane Cl−/HCO3 − antiporter is different from the one found in the basolateral membrane of the H+-secreting intercalated cells and has been identified as pendrin. The activity of the HCO3 −-secreting intercalated cell is increased during metabolic alkalosis, when the kidneys must excrete excess HCO3 − . However, under most conditions (e.g., ingestion of a meat-containing diet) H+ secretion predominates in these segments.


Physiology_Levy

Physiology_Levy. The apical membrane of collecting duct cells is not very permeable to H+ , and thus the pH of tubular fluid can become quite acidic. Indeed, the most acidic tubular fluid along the nephron (pH = 4.0–4.5) is produced there. In comparison the permeability of the proximal tubule to H+ and HCO3 − is much higher, and the tubular fluid pH falls to only 6.5 in this segment. As explained later the ability of the collecting duct to lower the pH of the tubular fluid is critically important for excretion of urinary titratable acids and NH4 + . Regulation of H+ Secretion A number of factors influence secretion of H+ and thus reabsorption of filtered HCO3 − by the cells of the nephron. From a physiological perspective the primary factor that regulates H+ secretion by the nephron is a change in systemic acid-base balance. Thus acidosis stimulates RNAE, whereas RNAE is reduced during alkalosis.


Physiology_Levy

Physiology_Levy. The response of the kidneys to changes in acid-base balance includes both immediate changes in the activity and/or number of transporters in the membrane and longer-term changes in the synthesis of transporters. For example, with metabolic acidosis, H+ secretion is stimulated by multiple mechanisms, depending on the particular nephron segment. First, the decrease in intracellular pH that occurs with acidosis will create a more favorable cell-to–tubular fluid H+ gradient and thereby make secretion of H+ across the apical membrane more energetically favorable. Second, the decrease in pH may lead to allosteric changes in transport proteins, thereby altering their kinetics. Lastly, transporters may be shuttled to the membrane from intracellular vesicles. With long-term acidosis the abundance of transporters increases, either by increased transcription of appropriate transporter genes or by increased translation of transporter mRNA.


Physiology_Levy

Physiology_Levy. eA third group of intercalated cells shares features of both H+-secreting and HCO3 −-secreting intercalated cells. The precise function of this cell type in acid-base transport is not fully understood. fTraditionally it was believed that intercalated cells were only involved in acid-base transport. There is now good evidence that NaCl reabsorption is also carried out by intercalated cells (B type). Reabsorption of NaCl occurs by the tandem operation of an apical membrane Cl−/HCO3 − anti-porter (pendrin) and an apical membrane Na+/HCO3 −/2Cl− antiporter (NDCBE). This mechanism of NaCl reabsorption is inhibited by thiazide diuretics. •Fig. 37.4 CellularmechanismsforreabsorptionandsecretionofHCO3− byintercalatedcellsofthedistaltubuleandcollectingduct.OnlytheprimaryH+ andHCO3− transportersareshown.ATP,adenosinetriphosphate;CA,carbonicanhydrase.


Physiology_Levy

Physiology_Levy. •Fig. 37.5 ExamplesofcellularH+ andHCO3− sensors.ATP,adenosinetriphosphate;cAMP,cyclicadenosinemonophosphate;GPCR,Gprotein–coupledreceptor;IRR,insulinreceptor–relatedreceptor;Pyk2,nonreceptortyrosinekinase;sAC,solubleadenylylcyclase.(Adaptedfrom:LevinLR,BuckJ.Annu Rev Physiol 2015;77:347.)


Physiology_Levy


Physiology_Levy

Physiology_Levy. Although some of the effects just described may be attributable directly to acidosis, many of these changes in cellular H+ transport are mediated by hormones or other factors. Three known mediators of the renal response to acidosis are endothelin, cortisol, and angiotensin II. Endothelin (ET-1) Intheproximaltubule,metabolicacidosisincreasesthetransportkineticsoftheNa+/H+ antiporter(NHE3)andincreasesapicalmembraneexpressionoftheNa+/H+ antiporter,H+-ATPase,andthebasolateralNa+/3HCO3− symporter(NBCe1).Inthecollectingduct,acidosisleadstoexocyticinsertionofH+-ATPaseintotheapicalmembraneofintercalatedcells.Withlong-termacidosistheabundanceofkeyacid-basetransportersisincreasedintheproximaltubule(NHE3andNBCe1)andincollectingductintercalatedcells(H+-ATPaseandAE1).Lastly,acidosisdecreasesexpressionoftheCl−/HCO3− antiporterpendrininHCO3−-secretingintercalatedcells.


Physiology_Levy

Physiology_Levy. is produced by endothelial and proximal tubule cells. With acidosis, ET-1 secretion is enhanced. In the proximal tubule, ET-1 stimulates phosphorylation and subsequent insertion of the Na+/H+ antiporter into the apical membrane, and insertion of the Na+/3HCO3 − symporter into the basolateral membrane. ET-1 may mediate the response to acidosis in other nephron segments as well. Acidosis also stimulates secretion of the glucocorticoid hormone cortisol by the adrenal cortex. Cortisol increases the abundance of the Na+/ H+ antiporter and Na+/3HCO3 − symporter in the proximal tubule. Angiotensin II is produced in proximal tubule cells in response to acidosis. It is secreted into the tubular fluid, where it binds to the angiotensin I receptor and thereby stimulates H+ secretion/HCO3 − reabsorption by the proximal tubule. Both cortisol and angiotensin II also stimulate production and secretion of NH4 + by the proximal tubule, which as described later is an important component of the kidney’s


Physiology_Levy

Physiology_Levy. by the proximal tubule. Both cortisol and angiotensin II also stimulate production and secretion of NH4 + by the proximal tubule, which as described later is an important component of the kidney’s response to acidosis.


Physiology_Levy

Physiology_Levy. Acidosis also stimulates secretion of parathyroid hormone (PTH). PTH inhibits phosphate (Pi) reabsorption by the proximal tubule (see ). In so doing, more Pi is delivered to the distal nephron, where it serves as a urinary buffer and thus increases the capacity of the kidneys to excrete titratable acid. The response of the kidneys to alkalosis is less well characterized. RNAE is decreased because of increased urinary HCO3 − excretion and because excretion of titratable acid and NH4 + are reduced. The factors that regulate this response are not well characterized.


Physiology_Levy

Physiology_Levy. Other factors not necessarily related to maintaining acid-base balance can influence secretion of H+ by the cells of the nephron. Because a significant H+ transporter in the nephron is the Na+/H+ antiporter, factors that alter Na+ reabsorption can secondarily affect H+ secretion. For example, with volume contraction (negative Na+ balance), Na+ reabsorption by the nephron is increased (see ), including reabsorption of Na+ via the Na+/H+ antiporter. As a result, H+ secretion is enhanced. This occurs by several mechanisms. One mechanism involves the renin-angiotensinaldosterone system, which is activated by volume contraction. As noted earlier, angiotensin II acts on the proximal tubule to stimulate the apical membrane Na+/H+ antiporter as well as the basolateral Na+/3HCO3 − symporter. To a lesser degree, angiotensin II stimulates H+ secretion in the TAL of Henle’s loop and the early portion of the distal tubule, a process also mediated by the Na+/H+ antiporter. Aldosterone’s primary


Physiology_Levy

Physiology_Levy. a lesser degree, angiotensin II stimulates H+ secretion in the TAL of Henle’s loop and the early portion of the distal tubule, a process also mediated by the Na+/H+ antiporter. Aldosterone’s primary action on the distal tubule and collecting duct is to stimulate Na+ reabsorption by principal cells (see ). However, it also stimulates intercalated cells in these segments to secrete H+ . This effect is both indirect and direct. By stimulating Na+ reabsorption by principal cells, aldosterone hyperpolarizes the transepithelial voltage (i.e., the lumen becomes more electrically negative). This change in transepithelial voltage then facilitates secretion of H+ by intercalated cells. In addition to this indirect effect, aldosterone (and angiotensin II) act directly on intercalated cells to stimulate H+ secretion via H+-ATPase and H+,K+-ATPase.


Physiology_Levy

Physiology_Levy. Another mechanism by which ECF volume (ECFV) contraction enhances H+ secretion (HCO3 − reabsorption) is through changes in peritubular capillary Starling forces. As described in , ECFV contraction alters the peritubular capillary Starling forces such that overall proximal tubule reabsorption is enhanced. With this enhanced reabsorption, more of the filtered load of HCO3 − is reabsorbed. Potassium balance influences secretion of H+ by the proximal tubule. Hypokalemia stimulates and hyperkalemia inhibits H+ secretion. It is thought that K+-induced changes in intracellular pH are responsible at least in part for this effect, with hypokalemia acidifying and hyperkalemia alkalinizing the cells. Hypokalemia also stimulates H+ secretion by the collecting duct. This occurs as a result of increased expression of the H+,K+-ATPase in intercalated cells. Formation of New HCO3 −


Physiology_Levy

Physiology_Levy. Formation of New HCO3 − As discussed previously, reabsorption of the filtered load of HCO3 − is important for maximizing RNAE. However, HCO3 − reabsorption alone does not replenish the HCO3 − lost during neutralization of the nonvolatile acids produced during metabolism. To maintain acid-base balance, the kidneys must replace this lost HCO3 − with new HCO3 − . Generation of new HCO3 − occurs by excretion of titratable acid and by synthesis and excretion of NH4 + . Production of new HCO3 − as a result of titratable acid excretion is depicted in