Medical Physiology, 3rd Edition

Acid-Base Balance and the Overall Renal Handling of Acid

Whereas the lungs excrete the large amount of CO2 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 39-1, section A), which occurs during oxidation of carbohydrates, fats, and most amino acids (see pp. 1185–1187). An adult ingesting a typical Western diet produces ~15,000 mmol/day of CO2. This CO2 would act as an acid if it went on to form H+ and image (see p. 630). Fortunately, the lungs excrete this prodigious amount of CO2 by diffusion across the alveolar-capillary barrier (see p. 673), preventing the CO2 from forming H+.

TABLE 39-1

Metabolic Sources of Nonvolatile Acids and Bases

A. Reactions Producing CO2 (merely a potential acid)

1. Complete oxidation of neutral carbohydrate and fat → CO2 + H2O

2. Oxidation of most neutral amino acids → Urea + CO2 + H2O

B. Reactions Producing Nonvolatile Acids

1. Oxidation of sulfur-containing amino acids → Urea + CO2 + H2O + H2SO4 → 2 H+ + image (Examples: methionine, cysteine)

2. Metabolism of phosphorus-containing compounds → H3PO4 → H+ + image

3. Oxidation of cationic amino acids → Urea + CO2 + H2O + H+ (e.g., lysine+, arginine+)

4. Production of nonmetabolizable organic acids → HA → H+ + A (e.g., uric acid, oxalic acid)

5. Incomplete oxidation of carbohydrate and fat → HA → H+ + A (e.g., lactic acid, keto acids)

C. Reactions Producing Nonvolatile Bases

1. Oxidation of anionic amino acids → Urea + CO2 + H2O + image (e.g., glutamate, aspartate)

2. Oxidation of organic anions → CO2 + H2O + image (e.g., lactate, acetate)

However, metabolism also generates nonvolatile acids—such as sulfuric acid, phosphoric acid, and various organic acids—that the lungs cannot handle (see Table 39-1, section B). In addition, metabolism generates nonvolatile bases, which end up as image (see Table 39-1, section C). 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 image into the blood. Once in the blood, this new image 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 image. The result would be death by relentless acidification. Indeed, one of the characteristic symptoms of renal failure is severe acidosis caused by acid retention. imageN39-1 The kidneys continuously monitor the acid-base parameters of the extracellular fluid (ECF) and adjust their rate of acid secretion to maintain the pH of ECF within narrow limits.

N39-1

Acidoses of Renal Origin

Contributed by Erich Windhager, Gerhard Giebisch

Any overall decrease in the ability of the kidneys to excrete the daily load of ~70 mmol of nonvolatile acids will lead to metabolic acidosis. In the strict sense of the term, renal tubular acidosis (RTA) is an acidosis that develops secondary to the dysfunction of renal tubules. In addition, an overall decrease in useful renal mass and GFR—as occurs in end-stage renal disease—also leads to an acidosis of renal origin. One system of organizing these maladies recognizes five types of RTAs:

• Uremic acidosis or RTA of glomerular insufficiency. The fundamental problem is a decrease in the total amount of NH3 that the proximal tubule can synthesize from glutamine (see pp. 829–831).

• Proximal (type 2) RTA. A specific dysfunction of the proximal tubule reduces the total amount of image that these nephron segments reabsorb.

• Classical distal (type 1) RTA. A specific dysfunction of the distal tubule reduces the total amount of image that these nephron segments reabsorb. The mechanisms can include mutations of key proteins involved in distal H+ secretion, such as H pumps and Cl-HCO3 exchangers.

• Generalized (type 4) RTA. A global dysfunction of the distal tubule—secondary to aldosterone deficiency or aldosterone resistance (see p. 835)—leads to a reduced net excretion of acid.

• Type 3 RTA. Rare defects in CAII lead to defects in both proximal and distal H+ secretion.

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 image but also secrete generated nonvolatile acids

In terms of acid-base balance, the major task of the kidney is to secrete acid into the urine and thus to neutralize the nonvolatile acids that metabolism produces. However, before the kidney can begin to achieve this goal, it must deal with a related and even more serious problem: retrieving from the tubule fluid virtually all image filtered by the glomeruli.

Each day, the glomeruli filter 180 L of blood plasma, each liter containing 24 mmol of image, so that the daily filtered load of image is 180 L × 24 mM = 4320 mmol. If this filtered image were all left behind in the urine, the result would be equivalent to an acid load in the blood of 4320 mmol, or a catastrophic metabolic acidosis (see p. 635). The kidneys avoid this problem by reclaiming virtually all the filtered image through secretion of H+ into the tubule lumen and titration of the 4320 mmol/day of filtered image to CO2 and H2O.

After the kidney reclaims virtually all the filtered image (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 image, which the kidney synthesizes. After diffusing into the tubule lumen, the NH3 reacts with secreted H+ to form image. Through adaptive increases in the synthesis of NH3 and excretion of image, the kidneys can respond to the body's need to excrete increased loads of H+.

The kidney does not simply eliminate the 70 mmol/day of nonvolatile acids by filtering and then excreting them in the urine. Rather, the body deals with the 70-mmol/day acid challenge in three steps:

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

image

(39-1)

Thus, image decreases by an amount that is equal to the H+ it consumes, and an equal amount of CO2 is produced in the process. image buffers (see p. 635) in the blood neutralize most of the remaining H+load:

image

(39-2)

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 Fig. 28-7, panel 2A) escapes buffering by either image or B. This remnant H+ is responsible for a small drop in the extracellular pH.

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

Step 3: The kidneys regenerate the image and B in the ECF by creating new image 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 image exits the kidneys via the renal veins than entered via the renal arteries. Most of this new image replenishes the image consumed by the neutralization of nonvolatile acids, so that extracellular [image] is maintained at ~24 mM. The remainder of this new image regenerates B:

image

(39-3)

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

Table 39-2 lists 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 image, which is component 2. Because the pK of the image equilibrium exceeds 9, almost all of the total ammonium buffer in the urine is in the form of image, and titrating urine from an acid pH to a pH of 7.4 will not appreciably convert image to NH3. If no filtered image were lost in component 3, the generation of new image by the kidneys would be the sum of components 1 and 2. To the extent that filtered image is lost in the urine, the new image must exceed the sum of components 1 and 2. imageN39-2

TABLE 39-2

Components of Net Urinary Acid Excretion

   

1

 

2

 

3

Net urinary acid excretion

=

Excreted H+ bound to phosphate (as image), creatinine, and uric acid

+

Excreted H+ bound to NH3 (as image)

Excretion of filtered image

N39-2

Urinary Excretion of Carboxylates

Contributed by Peter Aronson, Gerhard Giebisch

In addition to the loss of filtered image in the urine, the excretion of organic anions that can undergo conversion to image (e.g., lactate, citrate) would represent a loss of alkali into the urine, which in principle would need to be taken into account in computing net renal acid excretion. Because the proximal tubule normally reabsorbs nearly all of these carboxylates (see p. 779), this component of alkali loss is minor under most circumstances.

The kidneys also can control image 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 image. The result is a decrease in the production of new image. With an extreme alkali challenge, the excretion of urinary image also increases and may exceed the combined rates of titratable acid and image 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 image to the ECF via the renal veins than entered the kidneys via the renal arteries.

Secreted H+ titrates image to CO2 (image reabsorption) and also titrates filtered image buffers and endogenously produced NH3

As we have seen, the kidney can reabsorb nearly all of the filtered image and excrete additional acid into the urine as both titratable acid and image. The common theme of these three processes is H+ secretion from the blood into the lumen. Thus, the secreted H+ can have three fates. It can titrate (1) filtered image, (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 image (“image Reabsorption”)

Extensive reabsorption reclaims almost all of the filtered image (>99.9%). As discussed beginning on page 825, the kidney reabsorbs image at specialized sites along the nephron. However, regardless of the site, the basic mechanism of image reabsorption is the same (Fig. 39-2A): H+ transported into the lumen by the tubule cell titrates filtered image to CO2 plus H2O. One way that this titration can occur is by H+interacting with image 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 image to CO2 plus H2O. The enzyme carbonic anhydrase (CA) imageN18-3—which is present in many tubule segments—bypasses this slow reaction by splitting image into CO2 and OH (see Table 39-1). The secreted H+ neutralizes this OH so that the net effect is to accelerate the production of H2O and CO2.

image

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 the 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 image 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 image out across the basolateral membrane into the blood. Thus, for each H+ secreted into the lumen, one image disappears from the lumen, and one image appears in the blood. However, the image that disappears from the lumen and the image that appears in the blood are not the same molecule! To secrete H+ and yet keep intracellular pH within narrow physiological limits (see pp. 644–645), the cell closely coordinates the apical secretion of H+ and the basolateral exit of image.

Two points are worth re-emphasizing. First, image reabsorption does not represent net H+ excretion into the urine. It merely prevents the loss of the filtered alkali. Second, even though image 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 image 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 image Buffers (Titratable-Acid Formation)

The H+ secreted into the tubules can interact with buffers other than image and NH3. The titration of the non-NH3image buffers (B)—mainly image, creatinine, and urate—to their conjugate weak acids (HB) constitutes the titratable acid discussed on page 823.

image

(39-4)

The major proton acceptor in this category of buffers excreted in the urine is image, 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 (image) to its monovalent form (image). Because low luminal pH inhibits the apical Na/phosphate cotransporter (NaPi) in the proximal tubule, and NaPi carries image less effectively than image (see pp. 785–786), the kidneys tend to excrete H+-bound phosphate in the urine. For each H+ it transfers to the lumen to titrate image, the tubule cell generates one new image and transfers it to the blood (see 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 (see p. 732) of image, for example, is the product of plasma [image] and glomerular filtration rate (GFR). Plasma phosphate levels may range from 0.8 to 1.5 mM (see p. 1054). Therefore, increasing plasma [image] allows the kidneys to excrete more H+ in the urine as image. Conversely, decreasing the GFR (as in chronic renal failure) reduces the amount of image 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 p. 786). 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 image (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 image. In other words, the kidney would have titrated ~60% of the filtered phosphate from image to image. 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

 

% PROTONATED BUFFER

pH

PHOSPHATE (pK = 6.8)

URATE (pK = 5.8)

CREATININE (pK = 5.0)

7.4

20.1

2.5

0.4

6.2

79.9

28.5

5.9

4.4

99.6

96.2

79.9

3. The pH of the urine. Regardless of the pK of the buffer, the lower is 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 pH of the final urine is 4.4, the fractional protonation of creatinine increases to ~80% (see 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 image or the bases that give rise to “titratable acid” (e.g., image), glomerular filtration contributes only a negligible quantity of NH3because plasma [NH3] concentration is exceedingly low. Instead, urinary NH3 derives mainly from diffusion into the lumen from the proximal-tubule cell (see Fig. 39-2C), with some image entering the lumen directly via the apical Na-H exchanger NHE3. In the case of the proximal tubule, the conversion of glutamine to α-ketoglutarate (α-KG) generates two image ions, which form two NH3 and two H+ ions. In addition, the metabolism of α-KG generates two OH ions, which CA converts to image ions. This new image then enters the blood. imageN39-3

N39-3

Ammonium Secretion by the Medullary Collecting Duct

Contributed by Erich Windhager, Gerhard Giebisch, Emile Boulpaep, Walter Boron

Ammonium secretion by the medullary collecting duct is critical for renal image excretion. As described in Figure 39-5C, the TAL of juxtamedullary nephrons reabsorbs some image and deposits this image in the medullary interstitium, where it is partitioned between ammonium and ammonia according to the equilibrium image ⇌ NH3 + H+. As pointed out in Figure 39-5D, this interstitial image (and NH3) can have three fates: (1) some recycles back to the late proximal tubule and descending thin limb of Henle, (2) some bypasses the cortex by being secreted into the medullary collecting duct, and (3) some is washed out by the blood for export to the liver.

The mechanism of pathway (2) is depicted in Figure 39-5E. NH3 diffuses from the medullary interstitium, through the tubule cell and into the lumen. The NH3 moves via members of the Rh family at both the basolateral and apical membranes. The parallel extrusion of H+ across the apical membrane of the collecting-duct cell provides the luminal H+ that then titrates the luminal NH3 to image, which is excreted. This luminal H pumping also generates OH inside the cells. Although not shown in Figure 39-5E, intracellular CA converts this newly created OH (along with H2O) to image, and basolateral Cl-HCO3exchangers then export this newly created image to the interstitium. The image, of course, ultimately is washed out by the blood. Thus, for each image formed in the lumen of the collecting duct by this route, the tubule cell transfers one “new” image to the blood.

Figure 39-5E also shows that the Na-K pump can also transport image directly into the collecting-duct cell. This intracellular image can then dissociate into NH3 (which can diffuse into the lumen) and H+(which moves into the lumen via the apical H pump), with the ultimate formation of image in the lumen. The image that enters the collecting-duct lumen by this route does not generate a new image ion.

eFigure 39-1 shows the most recent model for how the TAL handles NH3 and CO2.

image

EFIGURE 39-1 Proposed model for CO2 and NH3 transport across the apical and basolateral membranes of TAL and α-intercalated cells in the collecting duct. Dashed arrows represent the possible diffusion of CO2 or NH3 across plasma membranes. NKCC2, Na/K/Cl cotransporter 2. (Republished with permission from Geyer RR, Parker MD, Toye AM, et al: Relative CO2/NH3 permeabilities of human RhAG, RhBG and RhCG. J Membrane Biology 246(12):915-926, F8, 2013.)

References

Geyer RR, Musa-Aziz R, Qin X, Boron WF. Relative CO2/NH3 selectivities of mammalian aquaporins 0-9. Am J Physiol Cell Physiol. 2013;304:C985–C994.

Weiner ID, Verlander JW. Ammonia transport in the kidney by Rhesus glycoproteins. Am J Physiol Renal Physiol. 2014;306(10):F1107–F1120.

In summary, when renal-tubule cells secrete H+ into the lumen, this H+ simultaneously titrates three kinds of buffers: (1) image, (2) image 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 image. The balance of the total secreted H+, 70 mmol/day, the kidneys use to generate new image.