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

TRANSPORT OF ACIDS AND BASES

Gerhard Giebisch and Erich Windhager

The lungs and the kidneys are largely responsible for regulating the acid-base balance of the blood (see Chapter 28). They do so by independently controlling the two major components of the body’s major buffering system: CO2 and HCO3 (Fig. 39-1). Chapter 31 focuses on how the lungs control plasma [CO2]. In this chapter, we see how the kidneys control plasma [HCO3].

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Figure 39-1 Acid-base balance. All values are for a 70-kg person ingesting a typical “Western” acid-ash diet. The values in the boxes are approximations. ECF, extracellular fluid.

ACID-BASE BALANCE AND THE OVERALL RENAL HANDLING OF ACID

Although the lungs excrete a large amount of CO2, a potential acid formed by metabolism, the kidneys are crucial for excreting nonvolatile acids

The kidneys play a critical role in helping the body rid itself of excess acid that accompanies the intake of food or that forms in certain metabolic reactions. By far, the largest potential source of acid is CO2production (Table 39-1A), which arises during oxidation of carbohydrates, fats, and most amino acids (see Chapter 58). An adult ingesting a typical Western diet produces ~15,000 mmol/day of CO2. This CO2would act as an acid if it went on to form H+ and HCO3 (see Chapter 28). Fortunately, the lungs excrete this prodigious amount of CO2 by diffusion across the alveolar-capillary barrier (see Chapter 30), thus preventing the CO2 from forming H+.

Table 39-1 Metabolic Sources of Nonvolatile Acids and Bases

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However, metabolism also generates nonvolatile acids—such as sulfuric acid, phosphoric acid, and various organic acids—that the lungs cannot handle (Table 39-1B). In addition, metabolism generates nonvolatile bases, which end up as HCO3 (Table 39-1C). Subtracting the metabolically generated base from the metabolically generated acid leaves a net endogenous H+ production of ~40 mmol/day for a person weighing 70 kg. The strong acids contained in a typical Western acid-ash diet (20 mmol/day of H+ gained) and the obligatory loss of bases in stool (10 mmol/day of OH lost) represent an additional acid load to the body of 30 mmol/day. Thus, the body is faced with a total load of nonvolatile acids (i.e., not CO2) of ~70 mmol/day— or ~1 mmol/kg body weight—derived from metabolism, diet, and intestinal losses. The kidneys handle this acid load by “dividing” 70 mmol/day of carbonic acid (H2CO3): excreting ~70 mmol/day of H+ into the urine and simultaneously transporting 70 mmol/day of new HCO3 into the blood. Once in the blood, this new HCO3 neutralizes the daily load of 70 mmol of nonvolatile acid.

Were it not for the tightly controlled excretion of H+ by the kidney, the daily load of ~70 mmol of nonvolatile acids would progressively lower plasma pH and, in the process, exhaust the body’s stores of bases, especially HCO3. The result would be death by relentless acidification. Indeed, one of the characteristic symptoms of renal failure is severe acidosis caused by acid retention. The kidneys continuously monitor the acid-base parameters of the extracellular fluid and adjust their rate of acid secretion to maintain the pH of extracellular fluid within narrow limits. (See Note: Acidoses of Renal Origin)

In summary, although the lungs excrete an extremely large amount of a potential acid in the form of CO2, the kidneys play an equally essential role in the defense of the normal acid-base equilibrium, because they are the sole effective route for neutralizing nonvolatile acids.

To maintain acid-base balance, the kidney must not only reabsorb virtually all filtered HCO3, but must also secrete into the urine the daily production of nonvolatile acids

As discussed, the major functions of the kidney, in terms of acid-base balance, are to secrete acid into the urine and thus to neutralize the nonvolatile acids that metabolism produces. However, before the kidney can begin to accomplish these tasks, it has to deal with a related and even more serious problem: retrieving from the tubule fluid virtually all HCO3 filtered by the glomeruli.

Each day, the glomeruli filter 180 L of blood plasma, each liter containing 24 mmol of HCO3, so that the daily filtered load of HCO3 is 180 L × 24 mM = 4320 mmol. If this filtered HCO3 were all left behind in the urine, the result would be equivalent to an acid load in the blood of 4320 mmol, or catastrophic metabolic acidosis (see Chapter 28). The kidneys handle this problem by reclaiming virtually all the filtered HCO3. As discussed in the next section, the kidney accomplishes this task by secreting H+ into the tubule lumen and titrating the 4320 mmol/day of filtered HCO3 to CO2 and H2O.

After the kidney reclaims virtually all the filtered HCO3 (i.e., 4320 mmol/day), how does it deal with the acid load of 70 mmol/day produced by metabolism, diet, and intestinal losses? If we simply poured 70 mmol of nonvolatile acid into the ~1.5 L of “unbuffered” urine produced each day, urinary [H+] would be 0.070 mol/1.5 L = 0.047 M, which would correspond to a pH of ~1.3. The lowest urine pH that the kidney can achieve is ~4.4, which corresponds to an [H+] that is three orders of magnitude lower than required to excrete the 70 mmol/day of nonvolatile acids. The kidneys solve this problem by binding the H+ to buffers that the kidney can excrete within the physiological range of urinary pH values. Some of these buffers the kidney filters—for example, phosphate, creatinine, and urate. Because of its favorable pK of 6.8 and its relatively high rate of excretion, phosphate is the most important nonvolatile filtered buffer. The other major urinary buffer is NH3/NH+4, which the kidney synthesizes. After diffusing into the tubule lumen, the NH3 reacts with secreted H+ to form NH+4. Through adaptive increases in the synthesis of NH3 and excretion of NH+4, the kidneys can respond to the body’s need to excrete increased loads of H+.

Does the kidney eliminate the 70 mmol/day of nonvolatile acids by simply filtering and then excreting them in the urine? After the 70 mmol/day nonvolatile acid challenge presents itself to the extracellular fluid, the body deals with this challenge in three steps:

Step 1: Extracellular HCO3 neutralizes most of the H+ load:

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Thus, HCO3 decreases by an amount that is equal to the H+ it consumes, thereby producing an equal amount of CO2 in the process. Non-HCO3 buffers (B + H+ ∫ BH+; see Chapter 28) in the blood neutralize most of the remaining H+load:

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Thus, B, too, decreases by an amount that is equal to the H+ it consumes. A very tiny fraction of the H+ load (<0.001%; see Chapter 28) escapes buffering by either HCO3 or B. This remnant H+ is responsible for a small drop in the extracellular pH.

Step 2: The lungs excrete the CO2 formed in Equation 39-1. The body does not excrete the HB generated in Equation 39-2, but rather converts it back into B, as discussed later.

Step 3: The kidneys regenerate the HCO3 and B in the extracellular fluid by creating new HCO3 at a rate that is equal to the rate of H+ production (i.e., ~70 mmol/day). Thus, over the course of a day, 70 mmol more HCO3 exits the kidneys through the renal veins than entered through the renal arteries. Most of this new HCO3 replenishes the HCO3 consumed by the neutralization of nonvolatile acids, thereby maintaining extracellular [HCO3] at ~24 mM. The remainder of this new HCO3 regenerates B:

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Again, the lungs excrete the CO2 formed in Equation 39-3, just as they excrete the CO2 formed in Equation 39-1. Thus, by generating new HCO3, the kidneys maintain constant levels of both HCO3 and the deprotonated forms of non-HCO3 buffers (B) in the extracellular fluid.

Table 39-2 summarizes the three components of net urinary acid excretion. Historically, component 1 is referred to as titratable acid, the amount of base one must add to a sample of urine to bring its pH back up to the pH of blood plasma. The titratable acid does not include the H+ the kidneys excrete as NH+4, which is component 2. Because the pK of the NH3/NH+4 equilibrium is greater than 9, almost all the NH+4buffer in the urine is in the form of NH+4, and titrating urine from an acid pH to a pH of 7.4 will not appreciably convert NH+4 to NH3. If no filtered HCO3 were lost in component 3, the generation of new HCO3 by the kidneys would be the sum of components 1 and 2. To the extent that filtered HCO3 is lost in the urine, the new HCO3 must exceed the sum of components 1 and 2.

Table 39-2 Components of Net Urinary Acid Excretion

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The kidneys also can control HCO3 and B following an alkaline challenge, produced, for example, by ingesting alkali or by vomiting (which leads to a loss of HCl, equivalent to a gain in NaHCO3). The kidney responds by decreasing net acid excretion—that is, by sharply reducing the excretion rates of titratable acid and NH+4. The result is a decrease in the production of new HCO3. With an extreme alkali challenge, the excretion of urinary HCO3 also increases and may exceed the combined rates of titratable acid and NH+4 excretion. In other words, component 3 in Table 39-2 exceeds the sum of components 1 and 2, so that net acid excretion becomes negative, and the kidney becomes a net excretor of alkali. In this case, the kidneys return less HCO3 to the extracellular fluid through the renal veins than entered the kidneys through the renal arteries.

Secreted H+ titrates HCO3 to CO2 (HCO3 reabsorption) and also titrates filtered non-HCO3 buffers and endogenously produced NH3 (nonvolatile acid excretion)

As we have seen, the kidney can reabsorb nearly all of the filtered HCO3 and excrete additional acid into the urine as both titratable acid and NH+4. The common theme of these three processes is H+ secretionfrom the blood into the lumen. Thus, the secreted H+ can have three fates. It can titrate (1) filtered HCO3, (2) filtered phosphate (or other filtered buffers that contribute to the “titratable acid”), and (3) NH3, both secreted and, to a lesser extent, filtered.

Titration of Filtered HCO3 (HCO3 Reabsorption) Extensive reabsorption reclaims almost all the filtered HCO3 (>99.9%). As discussed in the next major section, the kidney reabsorbs HCO3 at specialized sites along the nephron. However, regardless of the site, the basic mechanism of HCO3 reabsorption is the same (Fig. 39-2A): H+ transported into the lumen by the tubule cell titrates filtered HCO3 to CO2plus H2O. One way that this titration can occur is by H+ interacting with HCO3 to form H2CO3, which, in turn, dissociates to yield H2O and CO2. However, the reaction H2CO3 → H2O + CO2 is far too slow to convert the entire filtered load of HCO3 to CO2 plus H2O. The enzyme carbonic anhydrase (CA)—which is present in many tubule segments—bypasses this slow reaction by splitting HCO3 into CO2 and OH (Table 39-1). The secreted H+ neutralizes this OH so that the net effect is to accelerate the production of H2O and CO2.

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Figure 39-2 Titration of luminal buffers by secreted H+A and B, Generic models of H+ secretion at various sites along the nephron. The red arrows represent diverse transport mechanisms. C, Ammonium handling by the proximal tubule.

The apical membranes of these H+-secreting tubules are highly permeable to CO2, so that CO2 produced in the lumen, as well as the H2O, diffuses into the tubule cell. Inside the tubule cell, the CO2 and H2O regenerate intracellular H+ and HCO3 with the aid of CA. Finally, the cell exports these two products, thereby moving the H+ out across the apical membrane into the tubule lumen and the HCO3 out across the basolateral membrane into the blood. Thus, for each H+ secreted into the lumen, one HCO3 disappears from the lumen, and one HCO3 appears in the blood. However, the HCO3 that disappears from the lumen and the HCO3 that appears in the blood are not the same molecule. To secrete H+ and yet keep intracellular pH within narrow physiological limits (see Chapter 28), the cell closely coordinates the apical secretion of H+ and the basolateral exit of HCO3.

Two points are worth re-emphasizing. First, HCO3 reabsorption does not represent net H+ excretion into the urine. It merely prevents the loss of the filtered alkali. Second, even though HCO3 reabsorption is simply a reclamation effort, this process consumes by far the largest fraction of the H+ secreted into the tubule lumen. For example, reclaiming the 4320 mmol of HCO3 filtered each day requires 4320 mmol of H+ secretion, far more than the additional 70 mmol/day of H+ secretion necessary for neutralizing nonvolatile acids.

Titration of Filtered Non-HCO3 Buffers (Titratable Acid Formation) The H+ secreted into the tubules can interact with buffers other than HCO3 and NH3. The titration of the non-NH3, non-HCO3 buffers (B)—mainly HPO2−4, creatinine, and urate—to their conjugate weak acids (BH) constitutes the titratable acid discussed earlier.

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The major proton acceptor in this category of buffers excreted in the urine is HPO2−4, although creatinine also makes an important contribution; urate and other buffers contribute to a lesser extent. Figure 39-2B shows the fate of H+as it protonates phosphate from its divalent form (HPO2−4) to its monovalent form (H2PO4). Because low luminal pH inhibits the apical Na/phosphate cotransporter (NaPi) in the proximal tubule, and NaPi carries H2PO4 less effectively than HPO2−4 (see Chapter 36), the kidneys tend to excrete H+- bound phosphate in the urine. For each H+ it transfers to the lumen to titrate HPO2−4, the tubule cell generates one new HCO3 and transfers it to the blood (Fig. 39-2B).

How much does the titratable acid contribute to net acid excretion? The following three factors determine the rate at which these buffers act as vehicles for excreting acid:

1. The amount of the buffer in the glomerular filtrate and final urine. The filtered load of HPO2−4, for example, is the product of plasma [HPO2−4] and glomerular filtration rate (GFR) (see Chapter 33). Plasma phosphate levels may range from 0.8 to 1.5 mM (see Chapter 52). Therefore, increasing plasma [HPO2−4] allows the kidneys to excrete more H+ in the urine as H2PO4. Conversely, decreasing the GFR (as in chronic renal failure) reduces the amount of HPO2−4 available for buffering, lowers the excretion of titratable acid, and thus contributes to metabolic acidosis. Ultimately, the key parameter is the amount of buffer excreted in the urine. In the case of phosphate, the fraction of the filtered load that the kidney excretes increases markedly as plasma [phosphate] exceeds the maximum saturation (Tm; see Chapter 36). For a plasma [phosphate] of 1.3 mM, the kidneys reabsorb ~90%, and ~30 mmol/day appear in the urine.

2. The pK of the buffer. To be most effective at accepting H+, the buffer (e.g., phosphate, creatinine, urate) should have a pK value that is between the pH of the glomerular filtrate and the pH of the final urine. For example, if blood plasma has a pH of 7.4, then only ~20% of its phosphate (pK = 6.8) will be in the form of H2PO4 (Table 39-3). Even if the final urine were only mildly acidic, with a pH of 6.2, ~80% of the phosphate in the urine would be in the form of H2PO4. In other words, the kidney would have titrated ~60% of the filtered phosphate from HPO2−4 to H2PO4. Because creatinine has a pK of 5.0, lowering the pH of the tubule fluid from 7.4 to 6.2 increases the fractional protonation of creatinine from ~0.4% to only ~6%. However, urate has a pK of 5.8, so lowering pH from 7.4 to 6.2 would increase its fractional protonation from 2.5% to 28.5%

Table 39-3 Titration of Buffers

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3. The pH of the urine. Regardless of the pK of the buffer, the lower the urinary pH, the more protonated is the buffer, and the greater is the amount of acid excreted with this buffer. As discussed, lowering the pH of the tubule fluid from 7.4 to 6.2 increases the protonation of creatinine from 0.4% to only ~6%. However, if the final urine pH is 4.4, the fractional protonation of creatinine increases to ~80% (Table 39-3). Thus, creatinine becomes a much more effective buffer during acidosis, when the kidney maximally acidifies the urine.

Titration of Filtered and Secreted NH3 (Ammonium Excretion) The third class of acceptors of luminal H+ is NH3. However, unlike either HCO3 or the bases that give rise to titratable acid (e.g., HPO2−4), most of the luminal NH3 is not filtered in the glomerulus. Instead, most NH3 diffuses into the lumen from the tubule cell (Fig. 39-2C), and some NH+4 may enter the lumen directly through the apical Na-H exchanger NHE3. In the case of the proximal tubule, the conversion of glutamine to α-ketoglutarate (α-KG) generates two NH+4 ions, which form two NH3 and two H+ ions. In addition, the metabolism of α-KG generates two OH ions, which CA converts to HCO3 ions. This new HCO3then enters the blood.

In summary, when renal tubule cells secrete H+ into the lumen, this H+ simultaneously titrates three kinds of buffers: (1) HCO3, (2) HPO2−4 and other buffers that become the titratable acid, and (3) NH3. Each of these three buffers competes with the other two for available H+. In our example, the kidneys secrete 4390 mmol/day of H+ into the tubule lumen. The kidneys use most of this secreted acid—4320 mmol/day or ~98% of the total—to reclaim filtered HCO3. The balance of the total secreted H+ (70 mmol/day) the kidneys use to generate new HCO3.

ACID-BASE TRANSPORT BY DIFFERENT SEGMENTS OF THE NEPHRON

Most nephron segments secrete H+ to varying degrees.

The nephron reclaims virtually all the filtered HCO3 in the proximal tubule (~80%), thick ascending limb (~10%), and distal nephron (~10%)

The kidney reabsorbs the largest fraction of filtered HCO3 (~80%) along the proximal tubule (Fig. 39-3A). By the end of the proximal tubule, luminal pH falls to ~6.8, which represents only a modest transepithelial H+ gradient, compared with the plasma pH of 7.4. Thus, the proximal tubule is a high-capacity, low-gradient system for H+ secretion. The thick ascending limb of the loop of Henle (TAL) reabsorbs an additional 10% of filtered HCO3, so that by the time the tubule fluid reaches the distal convoluted tubule (DCT), the kidney has reclaimed ~90% of the filtered HCO3. The rest of the distal nephron—from the DCT to the inner medullary collecting duct (IMCD)—reabsorbs almost all the remaining ~10% of the filtered HCO3. Although the latter portion of the nephron reabsorbs only a small fraction of the filtered HCO3, it can lower luminal pH to ~4.4. Thus, the collecting tubules and ducts are a low-capacity, high-gradient system for H+ transport. (See Note: Ammonium Secretion by the Medullary Collecting Duct)

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Figure 39-3 Acid-base handling along the nephron. A, The numbered yellow boxes indicate the fraction of the filtered load absorbed by various nephron segments. The green boxes indicate the fraction of the filtered load that remains in the lumen after these segments. B, The red boxes indicate the moieties of acid secretion associated with either the formation of titratable acid or the secretion of NH+4. The yellow boxes indicate the formation of new HCO3 or NH+4 reabsorption by the thick ascending limb. The values in the boxes are approximations.

The amount of HCO3 lost in the urine depends on urine pH. If the [CO2] in the urine were the same as that in the blood, and if urine pH were 5.4, the [HCO3] in the urine would be 0.24 mM, which is 1% of the 24 mM in blood (see Chapter 28). For a urine production of 1.5 L/day, the kidneys would excrete 0.36 mmol/day of HCO3. For a filtered HCO3 load of 4320 mmol/day, this loss represents a fractional excretion of ~0.01%. In other words, the kidneys reclaim ~99.99% of the filtered HCO3. Similarly, at a nearly maximally acidic urine pH of 4.4, urine [HCO3] would be only 0.024 mM. Therefore, the kidneys would excrete only 36 μmol/day of filtered HCO3 and would reabsorb ~99.999%.

The nephron generates new HCO3, mostly in the proximal tubule

The kidney generates new HCO3 in two ways (Fig. 39-3B). It titrates filtered buffers such as HPO2−4 to produce titratable acid, and it titrates secreted NH3 to NH+4. In healthy people, NH+4 excretion is the more important of the two and contributes ~60% of net acid excretion or new HCO3.

Formation of Titratable Acid The extent to which a particular buffer contributes to titratable acid (Fig. 39-2B) depends on the amount of buffer in the lumen and luminal pH. The titratable acid resulting from phosphate is already substantial at the end of the proximal tubule (Table 39-4), even though the proximal tubule reabsorbs ~80% of the filtered phosphate. The reason is that the luminal pH equals the pK of the buffer at the end of the proximal tubule. The titratable acid resulting from phosphate rises only slightly along the classical distal tubule (i.e., DCT, connecting tubule [CNT], and initial collecting tubule [ICT]), because acid secretion slightly exceeds phosphate reabsorption. The titratable acid resulting from phosphate rises further as luminal pH falls to 4.4 along the collecting ducts in the absence of significant phosphate reabsorption.

Table 39-4 Titratable Acidity of Creatinine and Phosphate Along the Nephron*

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Although the late proximal tubule secretes creatinine, the titratable acid resulting from creatinine (Table 39-4) is minuscule at the end of the proximal tubule, because luminal pH is so much higher than creatinine’s pK. However, the titratable acidity resulting from creatinine increases substantially along the collecting ducts as luminal pH plummets. The urine contains other small organic acids (e.g., uric, lactic, pyruvic, and citric acids) that also contribute to titratable acid.

NH+4 Excretion Of the new HCO3 that the nephron generates, ~60% (~40 mmol/day) is the product of net NH+4 excretion (Fig. 39-3B), which is the result of five processes: (1) the proximal tubule actually secretes slightly more than ~40 mmol/day of NH+4; (2) the TAL reabsorbs some NH+4 and deposits it in the interstitium; (3) some of this interstitial NH+4 recycles back to the proximal tubule and thin descending limb (tDLH); (4) some of the interstitial NH+4 enters the lumen of the collecting duct; and finally, (5) some of the interstitial NH+4 enters the vasa recta and leaves the kidney. As we shall see, the liver may use some of this NH+4 to generate urea. Thus, the net amount of new HCO3 attributable to NH+4 excretion is (1) − (2) + (3) + (4) − (5).

ACID-BASE TRANSPORT AT THE CELLULAR AND MOLECULAR LEVEL

The secretion of acid from the blood to the lumen (whether for reabsorption of filtered HCO3, formation of titratable acid, or NH+4 excretion) requires at least three components: (1) transport of H+ (derived from H2O) from tubule cell to lumen, leaving behind intracellular OH; (2) conversion of intracellular OH to HCO3, catalyzed by CA; and (3) transport of newly formed HCO3 from tubule cell to blood.

In addition, because the buffering power of filtered non-HCO3 buffers is not high enough for these buffers to accept sufficient luminal H+, the formation of new HCO3 requires that the kidney generate buffer de novo. This buffer is NH3.

H+ moves across the apical membrane from tubule cell to lumen by three mechanisms: Na-H exchange, electrogenic H+ pumping, and K-H pumping

Although the kidney could, in principle, acidify the tubule fluid either by secreting H+ or by reabsorbing OH or HCO3, the secretion of H+ appears to be solely responsible for acidifying tubule fluid. At least three mechanisms can extrude H+ across the apical membrane; not all of these are present in any one cell.

Na-H Exchanger NHE (see Chapter 5) is responsible for the largest fraction of net H+ secretion. This exchanger is present not only throughout the proximal tubule (Fig. 39-4A, B) but also in the TAL (Fig. 39-4C) and DCT.

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Figure 39-4 A to D, Cell models of H+ secretion.

Of the known isoforms of NHE, NHE3 is particularly relevant for the kidney because it moves more H+ from tubule cell to lumen than any other transporter. The apical NHE3 secretes H+ in exchange for luminal Na+. Because a steep lumen-to-cell Na+ gradient drives this exchange process (see Chapter 5), apical H+ secretion ultimately depends on the activity of the basolateral Na-K pump. (See Note: Renal Na-H Exchangers)

The carboxy termini of the NHEs have phosphorylation sites for various protein kinases. Protein kinase C (PKC) phosphorylates all isoforms, whereas protein kinase A (PKA) phosphorylates only the apical NHE3. In the proximal tubule, PKC activates the apical NHE, but PKA inhibits it. For example, parathyroid hormone inhibits NHE3 through PKA.

Electrogenic H+ Pump A second mechanism for apical H+ secretion by tubule cells is the electrogenic H+ pump, which appears to be a vacuolar-type ATPase (see Chapter 5). The ATP-driven H+ pump can establish steep transepithelial H+ concentration gradients, thus lowering the urine pH to ~4.0 to 5.0. In contrast, NHE, which depends on the 10-fold Na+ gradient across the apical membrane, cannot generate an H+ gradient in excess of ~1 pH unit.

The apical electrogenic H+ pumps are located mainly in a subpopulation of intercalated cells (α cells) of the cortical collecting tubule (CCT) and in cells of the IMCD and outer medullary collecting duct (OMCD; Fig. 39-4D). However, H+ pumps are also present in the apical membrane of the proximal tubule (Fig. 39-4A, B), the TAL (Fig. 39-4C), and the DCT. In addition, an electrogenic H+ pump is also present in the basolateral membrane of β intercalated cells. Mutations in the gene encoding one of the subunits of this H+ pump cause metabolic acidosis (see Chapter 28) in the blood—distal renal tubule acidosis. (See Note: The β Intercalated Cell)

The regulation of the apical H+ pump probably involves several mechanisms. First, the transepithelial electrical potential appears to modulate the H+ pump rate. For instance, aldosterone induces increased apical Na+ uptake by the principal cells in the CCT (see Chapter 35), thus causing an increase in the lumen-negative potential, which, in turn, stimulates the H+ pump. Second, aldosterone stimulates the H+pump independently of changes in voltage. Third, acidosis increases the recruitment and targeting of pump molecules to the apical membranes of α intercalated cells in the ICT and CCT, whereas alkalosis has the opposite effect.

H-K Exchange Pump A third type of H+-secretory mechanism is present in the ICT, the CCT, and the OMCD (Fig. 39-4D): an electroneutral H-K pump (see Chapter 5) that is related to the Na-K pump. Several isoforms of the H-K pump are present in the kidney, and exhibit differential sensitivities to inhibition by drugs such as omeprazole, SCH-28080, and ouabain. The H-K pump retrieves luminal K+ in animals on a low-K+ diet (see Chapter 37) and, as a side effect, produces enhanced H+ secretion that contributes to the generation of hypokalemic metabolic alkalosis.

Carbonic anhydrases in the lumen and cytosol stimulate H+ secretion by accelerating the interconversion of CO2 and HCO3

The CAs (see Fig. 28-3) play an important role in renal acidification by catalyzing the interconversion of CO2 to HCO3. Inhibition of CA by sulfonamides, such as acetazolamide, profoundly slows acid secretion. CA may act at three distinct sites of acid-secreting tubule cells (Fig. 39-4): the extracellular face of the apical membrane, the cytoplasm, and the extracellular face of the basolateral membrane. Two CA isoforms are especially important for tubule cells. The soluble CA II is present in the cytoplasm, whereas a GPI linkage (see Chapter 2) anchors CA IV to the outside of the apical membrane, predominantly in proximal cells.

Apical Action of Carbonic Anhydrase (CA IV) In the absence of apical CA, the H+ secreted accumulates in the lumen, thus inhibiting Na-H exchange and H+ secretion. By promoting the conversion of luminal HCO3 to CO2 plus OH, apical CA prevents the lumen from becoming overly acidic and thus substantially relieves this inhibition. Thus, CA promotes high rates of HCO3 reabsorption along the early proximal tubule (Fig. 39-4A).

In the distal nephron (Fig. 39-4D), H+ secretion is less dependent on luminal CA than it is in the early proximal tubule, for two reasons. First, the H+ secretion rate is lower than that in the proximal tubule. Thus, the uncatalyzed conversion of luminal H+ and HCO3 to CO2 and H2O can more easily keep up with the lower H+ secretion rate. Second, in the collecting tubules and ducts the electrogenic H+ pump can extrude H+ against a very high gradient. Therefore, even in the absence of CA, the collecting ducts can raise luminal [H+] substantially and consequently can accelerate the uncatalyzed reaction by mass action.

Cytoplasmic Action of Carbonic Anhydrase (CA II) Cytoplasmic CA accelerates the conversion of intracellular CO2 and OH to HCO3 (Fig. 39-4). As a result, CA II increases the supply of H+ for apical H+extrusion and the supply of HCO3 for the basolateral HCO3 exit step. In the ICT and CCT, the intercalated cells (which engage in acid-base transport) contain CA II, whereas the principal cells do not.

Basolateral Action of Carbonic Anhydrase The role played by basolateral CA IV and CA XIV (an integral membrane protein with an extracellular catalytic domain) is not yet understood. (See Note: Carbonic Anhydrase at the Basolateral Membrane)

Inhibition of Carbonic Anhydrase The administration of drugs that block CA, such as acetazolamide, strongly inhibits HCO3 reabsorption along the nephron and leads to the excretion of an alkaline urine. Because acetazolamide reduces the reabsorption of Na+, HCO3, and water, this drug is also a diuretic (i.e., it promotes urine output). However, a small amount of H+ secretion and of HCO3 reabsorption remains despite the complete inhibition of CA. This remaining transport is related in part to the slow uncatalyzed hydration-dehydration reactions and in part to a buildup of luminal H2CO3, which may diffuse into the cell across the apical membrane (i.e., mimicking the uptake of CO2and H2O). (See Note: The Diuretic Action of the Carbonic Anhydrase Inhibitor Acetazolamide)

HCO3 efflux across the basolateral membrane takes place by electrogenic Na/HCO3 cotransport and Cl-HCO3 exchange

The regulation of the intracellular pH of acid-secreting tubule cells requires that H+ secretion across the apical membrane be tightly linked to, and matched by, the extrusion of HCO3 across the basolateral membrane. Two mechanisms are responsible for HCO3 transport from the cell into the peritubular fluid: electrogenic Na/HCO3 cotransport and Cl-HCO3 exchange.

Electrogenic Na/HCO3 Cotransport (NBCe1) In proximal tubule cells, the electrogenic Na/HCO3 cotransporter NBCe1 (see Chapter 5) is responsible for much of the HCO3 transport across the basolateral membrane. NBCe1 is expressed at highest levels in the S1 portion of the proximal tubule (Fig. 39-4A) and gradually becomes less abundant in the more distal proximal tubule segments (Fig. 39-4B). NBCe1 (SLC4A4) is a 1035 amino acid protein with a molecular weight of ~130 kDa. 4, 4′-Diisothiocyanostilbene-2, 2′-disulfonate (DIDS), an inhibitor of most HCO3 transporters, also inhibits NBCe1. Because, in proximal tubule cells, this transporter usually transports three HCO3ions for each Na+, the electrochemical driving forces cause it to carry these ions from cell to blood. Renal NBCe1 carries two net negative charges and is thus electrogenic. Human mutations that reduce either NBCe1 activity or NBCe1 targeting to the basolateral membrane cause severe metabolic acidosis—proximal renal tubule acidosis. (See Note: The Electrogenic Na/HCO3 Cotransporter NBCe1)

Chronic metabolic and respiratory acidosis, hypokalemia, and hyperfiltration all increase NBCe1 activity. As would be expected, several factors cause parallel changes in the activities of the apical NHE and basolateral Na/HCO3cotransporter and minimize changes in cell pH and [Na+]. Thus, angiotensin II (ANG II) and PKC stimulate both transporters, whereas parathyroid hormone and PKA markedly inhibit both.

Cl-HCO3 Exchange In the S3 segment of the proximal tubule, as well as in the TAL and collecting tubules and ducts, Cl-HCO3 exchangers participate in transepithelial acid-base transport. The AE1 anion exchanger (see Chapter 5) is found in the basolateral membranes of α intercalated cells of the CNT, the ICT, and the CCT (Fig. 39-4D). Basolateral AE2 is present in the TAL (Fig. 39-4C) and the DCT.

NH+4 is synthesized from glutamine by proximal tubules, partly reabsorbed in the loop of Henle, and secreted passively into papillary collecting ducts

As we saw in our discussion of the segmental handling of NH+4 (Fig. 39-3B), the proximal tubule is the main site of renal NH+4 synthesis, although almost all other tubule segments have the capacity to form NH+4. The proximal tubule forms NH+4 largely from glutamine (Fig. 39-5A), which enters tubule cells both from luminal and peritubular fluid through Na+-coupled cotransporters. Inside the mitochondria, glutaminase splits glutamine into NH+4 and glutamate, and then glutamate dehydrogenase splits the glutamate into α-KG and a second NH+4. Ammonium is a weak acid that can dissociate to form H+ and NH3. Because the pK of the NH3/NH+4 equilibrium is ~9.2, the NH3/NH+4ratio is 1:100 at a pH of 7.2. Whereas the cationic NH+4 is only poorly soluble in lipid membranes and therefore cannot readily diffuse across cell membranes, NH3 readily crosses most, but not all, cell membranes. When NH3diffuses from a relatively alkaline proximal tubule or collecting duct cell into the more acidic lumen, the NH3 becomes trapped in the lumen after buffering the newly secreted H+ to form the relatively impermeant NH+4 (Fig. 39-5A). In addition to the diffusion of NH3 across the apical membrane, the apical NHE may directly secrete some NH+4 into the proximal tubule lumen (with NH+4 taking the place of H+).

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Figure 39-5 A to E, Ammonium handling. B, In juxtamedullary nephrons, the secretion of NH+4 into the tubule lumen of the tDLH occurs mainly in the outer portion of the medulla. In D, the numbered boxes indicate the three fates of the NH+4 reabsorbed by TAL. PEP, phosphoenolpyruvate.

A second consequence of NH+4 synthesis is that the byproduct α-KG participates in gluconeogenesis, which indirectly generates HCO3 ions. As shown in Figure 39-5A, the metabolism of two glutamines generates four NH3 and two α-KG. Gluconeogenesis of these two α-KG, along with four H+, forms one glucose and four HCO3 ions. Accordingly, for each NH+4 secreted into the tubule lumen, the cell secretes one new HCO3 into the peritubular fluid.

In juxtamedullary nephrons, which have long loops of Henle, the tDLH may both secrete and reabsorb NH3. Tubule fluid may become alkaline along the tDLH, titrating NH+4 to NH3 and promoting NH3 efflux from the tubule lumen (i.e., reabsorption). Conversely, reabsorption of NH+4 by the TAL (see following paragraph) creates a gradient favoring NH3 diffusion into the lumen of the tDLH. Modeling of these processes predicts net secretion of NH3 into the tDLH in the outer medulla (Fig. 39-5D) and net absorption in the inner medulla (not shown). In the thin ascending limb, NH+4 reabsorption may occur by diffusion of NH+4 into the interstitium.

In contrast to the earlier segments, the TAL reabsorbs NH+4 (Fig. 39-5C). Thus, much of the NH+4 secreted by the proximal tubule and tDLH does not reach the DCT. Because the apical membrane of the TAL is unusual in having very low NH3 permeability, the TAL takes up NH+4 across the apical membrane by using two transport mechanisms, the Na/K/Cl cotransporter and the K+ channels. Indeed, inhibiting the Na/K/Cl cotransporter blocks a significant fraction of NH+4 reabsorption, a finding suggesting that NH+4 can replace K+ on the cotransporter. Ammonium leaves the cell across the basolateral membrane as NH3, thus leading to accumulation of NH+4 in the renal medulla.

The NH+4 that has accumulated in the interstitium of the medulla has three possible fates (Fig. 39-5D). First, some dissociates into H+ and NH3. The late proximal tubule and the early tDLH take up this NH3 by nonionic diffusion and trap it as NH+4 (Fig. 39-5B). Thus, NH+4 recycles between the proximal tubule/tDLH and the TAL.

Second, some of the interstitial NH+4 dissociates into H+ and NH3, which enters the lumen of the cortical and medullary collecting ducts by nonionic diffusion. There, H+ actively secreted into the lumen titrates the NH3 to NH+4(Fig. 39-5E). In addition, the Na-K pump may carry NH+4 into cells of the medullary collecting ducts, and NH+4 may be substituted for K+. To the extent that NH+4 moves directly from the TAL to the medullary collecting duct, it represents a bypass of the cortical portions of the distal nephron. This bypass prevents cortical portions of the distal nephron from losing NH3 by diffusion from the lumen into the cortical interstitium and thus keeps the toxic NH3from entering the circulation.

The third fate of medullary NH+4 is washout, the return of a small fraction of the NH+4 to the systemic circulation for eventual detoxification by the liver. In the steady state, the buildup of NH+4 in the medulla leads to a sharp increase of [NH+4] along the corticomedullary axis.

Because the liver synthesizes glutamine (see Chapter 46), the main starting material for NH+4 production in the kidney, hepatorenal interactions are important in the overall process of NH+4 excretion (Fig. 39-6). The liver disposes of ~1000 mmol/day of amino groups during the catabolism of amino acids. Some of these amino groups become NH+4 through deamination reactions, and some end up as amino groups on either glutamate or aspartate through transamination reactions.

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Figure 39-6 Cooperation between the liver and kidney in excreting nitrogen derived from amino acid breakdown. In this example, we assume a release of 940 mmol/day of amino groups, resulting in the urinary excretion of 450 mmol/day of urea (900 mmol/day of amino nitrogen) and 40 mmol/day of NH+4. The values in the boxes are approximations.

Of the ~1000 mmol/day of catabolized amino groups, the liver detoxifies ~95% by producing urea (see Chapter 46), which the kidneys excrete (see Chapter 36). One −NH2 in urea comes from an NH+4 that had dissociated to form NH3 and H+, the other −NH2 comes from aspartate, and the C=O comes from HCO3. The net result is the generation of urea and two acid equivalents.

The liver detoxifies the remaining ~5% of catabolized amino groups by converting NH+4 and glutamate to glutamine. This reaction does not generate acid-base equivalents. The proximal tubule cells take up this hepatic glutamine and use it as the source of the NH+4 that they secrete into the tubule lumen as they generate one new HCO3 (Fig. 39-5A).

Thus, the two hepatorenal mechanisms for disposing of catabolized amino groups have opposite effects on HCO3. For each catabolized amino group excreted as urea, the liver consumes the equivalent of one HCO3. For each catabolized amino group excreted as NH+4 by the glutamine pathway, the proximal tubule produces one new HCO3 (Fig. 39-6). To the extent that the kidney excretes NH+4, the liver consumes less HCO3 as it synthesizes urea.

REGULATION OF RENAL ACID SECRETION

A variety of physiological and pathophysiological stimuli can modulate renal H+ secretion as well as NH3 synthesis. Most of these factors produce coordinated changes in apical and basolateral acid-base transport, as well as in NH3production.

Respiratory acidosis stimulates renal H+ secretion

The four fundamental pH disturbances are respiratory acidosis and alkalosis and metabolic acidosis and alkalosis (see Fig. 28-11). In each case, the initial and almost instantaneous line of defense is the action of buffers—both in the extracellular and intracellular compartments—to minimize the magnitude of the pH changes (see Chapter 28). However, restoring the pH to a value as close to normal as possible requires slower, compensatory responses from the lungs or kidneys.

In respiratory acidosis, in which the primary disturbance is an increase in arterial PCO2, the compensatory response is an increase in renal H+ secretion, which translates to increased production of new HCO3through NH+4 excretion. The opposite occurs in respiratory alkalosis. These changes in H+ secretion tend to correct the distorted [HCO3]/[CO2] ratios that occur in primary respiratory acid-base derangements.

Respiratory acidosis stimulates H+ secretion in at least two ways. First, an acute elevated PCO2 directly stimulates proximal tubule cells to secrete H+, as shown by applying solutions in which it is possible to change PCO2 without altering basolateral pH or [HCO3]. However, isolated changes in basolateral pH (i.e., without an accompanying change in [HCO3] or PCO2)—which also produce large changes in pHi—have a negligible effect in the short term. Thus, proximal tubule cells directly sense basolateral CO2. Second, chronic respiratory acidosis leads to adaptive responses that upregulate acid-base transporters. For example, activities of the apical NHE and the basolateral Na/HCO3cotransporter are elevated in membrane vesicles that have been isolated from animals that were previously exposed to high PCO2 levels. These adaptive changes persist for some time, even after PCO2 levels have returned to normal. Such a sustained increase in transporter activity may help to explain why, once H+ secretion has adapted, reversing the original respiratory acidosis may produce rebound metabolic alkalosis.

Metabolic acidosis stimulates both proximal H+ secretion and NH3 production

The first compensatory response to metabolic acidosis is increased alveolar ventilation, which blows off CO2 (see Chapter 32) and thus corrects the distorted [HCO3]/[CO2] ratio in primary metabolic acidosis. The kidneys can also participate in the compensatory response, assuming, of course, that the acidosis is not the consequence of renal disease. An acute fall in basolateral [HCO3] stimulates proximal H+secretion, probably by enhancing HCO3 efflux from the proximal tubule cell through the Na/HCO3 cotransporter and also by reducing HCO3 backleak through tight junctions from interstitial fluid to tubule lumen. Proximal tubule cells also directly sense basolateral HCO3 and respond to decreases in [HCO3] by increasing H+-secretory rates. (See Note: Use of Out-of-Equilibrium Solutions to Probe the Chemosensitivity of the Proximal Tubule)

In chronic metabolic acidosis, the adaptive responses of the proximal tubule are probably similar to those outlined earlier for chronic respiratory acidosis. These include upregulation of apical Na-H exchange and electrogenic H+pumping, as well as basolateral Na/HCO3 cotransport (Fig. 39-7). For example, when one isolates brush border membranes from the renal cortex of animals made chronically acidotic, NHE3 activity is significantly increased. Therefore, the proximal tubule cell adapts to chronic acidosis, possibly by increasing the number of transporters. The upregulation appears to involve activation of PKC, a serine/threonine kinase (see Chapter 3). In proximal tubule cells, chronic intracellular acidosis also stimulates a member of the Src family of receptor-associated tyrosine kinases (see Chapter 3). Indeed, herbimycin, a tyrosine-kinase inhibitor, blocks upregulation of NHE3 in chronic acidosis. Endothelin appears to be essential for the upregulation of NHE3 in chronic metabolic acidosis.

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Figure 39-7 The effects of chronic acidosis on proximal tubule function. *Enhanced Na citrate reabsorption is a defense against acidosis by conversion of citrate to HCO3. The price paid is enhanced stone formation because luminal citrate reduces stone formation by complexing with Ca2+. Indeed, acidotic patients tend to develop Ca2+-containing kidney stones. NBC, electrogenic Na/HCO3 contransporter; NHE3, Na-H exchanger 3.

The parallel activation of apical and basolateral transporters minimizes changes in pHi, whereas it increases transepithelial HCO3 reabsorption. An important and still unresolved question concerns the continued response of tubule cells to chronic acidosis even after the coordinated stimulation of apical and basolateral acid-base transporters has returned pHi to normal.

In addition to the increased H+ secretion, the other ingredient needed to produce new HCO3 is enhanced NH3 production. Together, the two increase NH+4 excretion. Indeed, the excretion of NH+4 into the urine increases markedly as a result of the adaptive response to chronic metabolic acidosis (Fig. 39-8A). Thus, the ability to increase NH3 synthesis is an important element in the kidney’s defense against acidotic challenges. Indeed, as chronic metabolic acidosis develops, the kidneys progressively excrete a larger fraction of urinary H+ as NH+4. As a consequence, the excretion of titratable acid becomes a progressively smaller fraction of total acid excretion.

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Figure 39-8 Effect of acid-base disturbances on renal acid-base transport. (A, Data from Pitts RF: Fed Proc 1948; 7:418-426; B, data from Alpern RJ, Cogan MG, Rector FC: J Clin Invest 1983; 71:736-746.)

The adaptive stimulation of NH3 synthesis, which occurs in response to a fall in pHi, involves stimulation of both glutaminase and phosphoenolpyruvate carboxykinase (PEPCK). The stimulation of mitochondrial glutaminase increases the conversion of glutamine to NH+4 and glutamate (Fig. 39-5A). The stimulation of PEPCK enhances gluconeogenesis and thus the conversion of α-KG (the product of glutamate deamination) to glucose.

Metabolic alkalosis reduces proximal H+ secretion and, in the cortical collecting tubule, may even provoke HCO3 secretion

Figure 39-8B illustrates the response of the proximal tubule to metabolic alkalosis. As shown in the upper curve, when the peritubular capillaries have a physiological [HCO3], increasing the luminal [HCO3] causes H+ secretion to increase steeply up to a luminal [HCO3] of ~45 mM. The reason is that the incremental luminal HCO3 is an additional buffer that minimizes the luminal acidification in the vicinity of the apical H+ transporters.

As shown in the lower curve in Figure 39-8B, when the peritubular blood has a higher than physiological [HCO3]—that is, metabolic alkalosis—H+ secretion is lower for any luminal [HCO3]. The likely explanation is that the increase in blood [HCO3] (1) depresses the rate at which the Na/HCO3 cotransporter moves HCO3 from cell to blood and (2) increases paracellular HCO3 backleak from interstitium to lumen.

So far, we have discussed the effect of metabolic alkalosis on H+ secretion by the proximal tubule. In the ICT and CCT, metabolic alkalosis can cause the tubule to switch from secreting H+ to secreting HCO3into the lumen. The α intercalated cells in the ICT and CCT secrete H+, by using an apical H+ pump and a basolateral Cl-HCO3 exchanger, which is AE1 (SLC4A1; Fig. 39-4D). Metabolic alkalosis, over a period of days, shifts the intercalated cell population, thus increasing the proportion of β intercalated cells at the expense of α cells. Because β cells have the opposite apical versus basolateral distribution of H+pumps and Cl-HCO3 exchangers, they secrete HCO3 into the lumen and tend to correct the metabolic alkalosis. The apical Cl-HCO3 exchanger in β cells is pendrin (SLC26A4; see Fig. 35-5F). (See Note: The β Intercalated Cell)

By increasing HCO3 delivery to the tubules, an increased glomerular filtration rate enhances HCO3 reabsorption (glomerulotubular balance for HCO3)

Increasing either luminal flow or luminal [HCO3] significantly enhances HCO3 reabsorption, probably by raising effective [HCO3] (and thus pH) in the microenvironment of H+ transporters in the brush border microvilli. Because a high luminal pH stimulates the NHEs and H+ pumps located in the microvilli of the proximal tubule, increased flow translates to enhanced H+ secretion. This flow dependence, an example of glomerulotubular (GT) balance (see Chapter 35), is important because it minimizes HCO3 loss, and thus the development of a metabolic acidosis, when GFR increases. Conversely, this GT balance of HCO3 reabsorption also prevents metabolic alkalosis when GFR decreases. The flow dependence of HCO3 reabsorption also accounts for the stimulation of H+ transport that occurs after uninephrectomy (i.e., surgical removal of one kidney), when GFR in the remnant kidney rises in response to the loss of renal tissue. (See Note: Flow Dependence of HCO3 Reabsorption)

Extracellular volume contraction stimulates renal H+ secretion by increasing levels of angiotensin II, aldosterone, and sympathetic activity

As discussed in Chapter 40, a decrease in effective circulating volume stimulates Na+ reabsorption by four parallel pathways (see Chapter 40), including activation of the renin-angiotensin-aldosterone axis (and thus an increase in ANG II levels) and stimulation of renal sympathetic nerves (and thus the release of norepinephrine). Both ANG II and norepinephrine stimulate Na-H exchange in the proximal tubule. Because the proximal tubule couples Na+ and H+ transport, volume contraction increases not only Na+ reabsorption but also H+ secretion. Volume expansion has the opposite effect. On a longer time scale, volume depletion also increases aldosterone levels, thereby enhancing H+secretion in cortical and medullary collecting ducts (see later). Thus, the regulation of effective circulating volume takes precedence over the regulation of plasma pH.

Decreased dietary Na+ intake increases apical Na-H exchange activity, even if one assesses the activity in brush border membrane vesicles removed from the animal. A high-Na+ diet has the opposite effect.

Hypokalemia increases renal H+ secretion

As discussed in Chapter 36, acid-base disturbances can cause changes in K+ homeostasis. The opposite is also true. Because a side effect of K+ depletion is increased renal H+ secretion, K+ depletion is frequently associated with metabolic alkalosis. Several lines of evidence indicate that, in the proximal tubule, hypokalemia leads to a marked increase in apical Na-H exchange and basolateral Na/HCO3cotransport. As in other cells, the pH of tubule cells falls during K+ depletion (see Chapter 28). The resulting chronic cell acidification may lead to adaptive responses that activate Na-H exchange and electrogenic Na/HCO3 cotransport, presumably by the same mechanisms that stimulate H+secretion in chronic acidosis (Fig. 39-7). In the proximal tubule, K+ depletion also markedly increases NH3 synthesis and NH+4 excretion, thus increasing urinary H+ excretion as NH+4. Finally, K+ depletion stimulates apical K-H exchange in α intercalated cells of the ICT and CCT (see Chapter 37) and enhances H+ secretion as a side effect of K+ retention.

Just as hypokalemia can cause metabolic alkalosis, hyperkalemia is often associated with metabolic acidosis. A contributory factor may be reduced NH+4 excretion, perhaps because of lower synthesis in proximal tubule cells. In addition, with high luminal [K+] in the TAL, K+ competes with NH+4 for uptake by apical Na/K/Cl cotransporters and K+ channels, thereby reducing NH+4 reabsorption. As a result, the reduced NH+4 levels in the medullary interstitium provide less NH3 for diffusion into the medullary collecting duct. Finally, with high [K+] in the medullary interstitium, K+ competes with NH+4 for uptake by basolateral Na-K pumps in the medullary collecting duct. The net effects are reduced NH+4 excretion and acidosis.

Both glucocorticoids and mineralocorticoids stimulate acid secretion

Chronic adrenal insufficiency (see Chapter 35) leads to acid retention and, potentially, to life-threatening metabolic acidosis. Both glucocorticoids and mineralocorticoids stimulate H+ secretion, but at different sites along the nephron.

Glucocorticoids (e.g., cortisol) enhance the activity of Na-H exchange in the proximal tubule and thus stimulate H+ secretion. In addition, they inhibit phosphate reabsorption and raise the luminal availability of buffer anions for titration by secreted H+.

Mineralocorticoids (e.g., aldosterone) stimulate H+ secretion by three coordinated mechanisms, one direct and two indirect. First, mineralocorticoids directly stimulate H+ secretion in the collecting tubules and ducts by increasing the activity of the apical electrogenic H+ pump and basolateral Cl-HCO3 exchanger (Fig. 39-4D). Second, mineralocorticoids indirectly stimulate H+ secretion by enhancing Na+reabsorption in the collecting ducts (see Chapter 35), thus increasing the lumen-negative voltage. This increased negativity may stimulate the apical electrogenic H+ pump in α intercalated cells to secrete acid. Third, mineralocorticoids—particularly when administered for longer periods of time and accompanied by high Na+ intake—cause K+ depletion and indirectly increase H+ secretion (see previous section).

Diuretics can increase or decrease H+ secretion, depending on how they affect transepithelial voltage, extracellular fluid volume, and plasma [K+]

The effects of diuretics on renal H+ secretion vary substantially from one diuretic to another, depending both on the site and the mechanism of action. From the point of view of acid-base balance, diuretics fall broadly into two groups: those that promote the excretion of a relatively alkaline urine and those that have the opposite effect. (See Note: The Effect of Diuretics on Renal H+ Excretion)

To the first group belong CA inhibitors and K+-sparing diuretics. The CA inhibitors lead to excretion of an alkaline urine by inhibiting H+ secretion. Their greatest effect is in the proximal tubule, but they also inhibit H+ secretion by the TAL and DCT. K+-sparing diuretics—including amiloride, triamterene, and the spironolactones—also alkalinize the urine. Both amiloride and triamterene inhibit the apical epithelial Na+ channels (ENaCs) (see Chapter 35) in the collecting tubules and ducts and render the lumen more positive so that it is more difficult for the electrogenic H+ pump to secrete H+ ions into the lumen. Spironolactones decrease H+ secretion by interfering with the action of aldosterone.

The second group of diuretics—which tend to increase urinary acid excretion and often induce alkalosis—includes loop diuretics such as furosemide (which inhibits the apical Na/K/Cl cotransporter in the TAL) and thiazide diuretics such as chlorothiazide (which inhibits the apical Na/Cl cotransporter in the DCT). These diuretics act by three mechanisms. First, all cause some degree of volume contraction and thus lead to increased levels of ANG II and aldosterone (see Chapter 40), both of which enhance H+ secretion. Second, these diuretics enhance Na+ delivery to the collecting tubules and ducts and consequently increase the electrogenic uptake of Na+, thus raising the lumen-negative voltage and enhancing H+ secretion. Third, this group of diuretics causes K+ wasting; as discussed earlier, K+ depletion enhances H+secretion.

REFERENCES

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Rose BD, Post TW: Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th ed. New York: McGraw-Hill, 2001.

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