Renal Regulation Of Plasma Bicarbonate Concentration

Figure 1 illustrates the primary mechanisms of H+ and HCO" transport that were described in detail in Chapters 26 and 27. The basic mechanism of moving acid and base from blood to urine or vice versa is the same throughout the nephron. Under normal acid-base conditions, H+ is secreted into the lumen and HCO" moves from the epithelial cells to the blood in both the proximal and distal nephron segments. These regions of the nephron differ only in the mechanisms used to transport H+ and HCO" and the effects of H+ secretion into the lumen. In the proximal tubule, H+ secretion occurs against a small concentration gradient and serves primarily to drive HCO" reabsorption. H+ secreted into the lumen of the proximal tubule is titrated by HCO" to form CO2, and the HCO" generated in the cell by H+ secretion leaves the cell across the basolateral membrane and enters the plasma. In the distal tubule segments that have intercalated cells, H+ secretion produced by the H+-ATPase (adenosine triphosphatase) drives urine pH lower, resulting in the excretion of titratable acidity and ammonium and the generation of new bicarbonate ions that are returned to the blood (described in more detail later). Intercalated cells are found from the distal convoluted tubule to the medullary collecting duct, especially in the late distal convoluted tubule, the connecting tubule, and the cortical and outer medullary pH [H + ] (nM) [H + ] (nM) approximated as

Tubule Lumen

En 11 he I loi cell

Inter*!lili I Siute

Tubule Lumen

Inter*!lili I Siute

FIGURE 1 General mechanism for H+ secretion and return of bicarbonate to the plasma in renal tubular cells. As H+ is actively secreted into the lumen, the H+ concentration within the cells falls and mass balance favors the increased production of HCO^" in the cells. The rising cell HCO^" concentration produces an electrochemical potential gradient that drives the movement of HCO^" out of the cell, which occurs only across the basolateral membrane. This process is present in proximal tubule cells and in intercalated cells of the distal nephron. Only the details of the luminal and basolateral membrane transporters differ.

FIGURE 1 General mechanism for H+ secretion and return of bicarbonate to the plasma in renal tubular cells. As H+ is actively secreted into the lumen, the H+ concentration within the cells falls and mass balance favors the increased production of HCO^" in the cells. The rising cell HCO^" concentration produces an electrochemical potential gradient that drives the movement of HCO^" out of the cell, which occurs only across the basolateral membrane. This process is present in proximal tubule cells and in intercalated cells of the distal nephron. Only the details of the luminal and basolateral membrane transporters differ.

regions of the collecting duct. For convenience, in the remainder of this chapter, these segments will be referred to collectively as the distal nephron.

sufficiently acid luminal fluid to titrate all the filtered HCO^. The distal tubular mechanism for reabsorbing HCO^ is similar to the proximal mechanism except that it is capable of reclaiming the remaining 5-10% of the filtered HCO^ from the tubular fluid. To accomplish this, however, the distal mechanism must be able to secrete H+ against a steep concentration gradient that in the collecting ducts approaches 1000:1 (blood pH 7.4, or 40 • 10~9 M versus a urine pH 4.5, or 32 • 10-6 M). For example, if the luminal CO2 partial pressure is the same as in the plasma (40 mm Hg), the Henderson-Hasselbalch equation shows that the HCO^ concentration is less than 1.0 mmol/L at a urine pH of 6.0. At a urine pH of 5, the HCO^ concentration is ~0.1 mmol/L. The collecting duct is able to develop the greater H+ gradient because active H+ secretion is coupled to ATP hydrolysis by the H+-ATPase located in the luminal membrane (see Fig. 8 in Chapter 27).

Under normal conditions, with a plasma HCO^ concentration of 24 mmol/L and a glomerular filtration rate (GFR) of 130 mL/min, 3.1 mmol of HCO^ are filtered and 3.1 mmol are reabsorbed every minute, which is equivalent to about 4.5 mol of HCO^ filtered and returned to the plasma by reabsorption every day. Normally, the urine contains virtually no HCO^, however, as shown in Fig. 2, when the plasma HCO^ concentration increases above 25 mmol/L, the excess filtered HCO^ appears in the urine. Increases in the plasma HCO^ may occur as a consequence of the ingestion of HCO^ or other bases, the metabolism of salts of organic acids, or the loss of acid as occurs with vomiting. The plasma level at which HCO^ appears in the urine is referred to as the plasma threshold for

Bicarbonate Reabsorption

Bicarbonate reabsorption occurs in the proximal tubule, and to a more limited extent in the distal nephron segments, because of the active secretion of H+, which titrates luminal HCO^ to CO2 and water. The proximal tubular mechanism is a high-capacity system that accounts for the absorption of 90-95% of the filtered load of HCO^ so normally little HCO^ flows on to the distal nephron segments. In the proximal tubule, this process is catalyzed by luminal carbonic anhydrase, so the introduction of an inhibitor of carbonic anhy-drase depresses the reabsorption of HCO^ by the proximal tubule and results in the excretion of HCO^ together with Na+. This is the basis of the mild diuretic and natriuretic action of carbonic anhydrase inhibitors such as acetazolamide (Diamox).

Despite its high HCO^ reabsorptive capacity, the proximal tubule is limited by its ability to generate a

FIGURE 2 Effect of plasma bicarbonate concentration on bicarbonate excretion rate. Virtually no bicarbonate is excreted at plasma bicarbonate concentrations below 25 mmol/L, which is often referred to as the plasma threshold for bicarbonate. Above this plasma concentration, bicarbonate excretion increases with increasing plasma bicarbonate concentration.

Plasma Bicarbonate Concentration (mmol/L)

FIGURE 2 Effect of plasma bicarbonate concentration on bicarbonate excretion rate. Virtually no bicarbonate is excreted at plasma bicarbonate concentrations below 25 mmol/L, which is often referred to as the plasma threshold for bicarbonate. Above this plasma concentration, bicarbonate excretion increases with increasing plasma bicarbonate concentration.

HCO-. Thus, the basic mechanism for excreting excess HCO- is by an "overflow" of filtered HCO- into the urine whenever the plasma concentration rises above normal levels, unless there is another signal that alters HCO- reabsorption.

Regulation of HCO- Reabsorption

Table 2 lists the factors that alter H+ secretion and, thus, HCO- reabsorption by the proximal tubule. First, as would be expected, one of the most important factors is the systemic acid-base status, as reflected by the plasma pH. Acidemia (plasma pH <7.4) is a direct stimulus to H+ secretion, whereas alkalemia (plasma pH > 7.4) is an inhibitor. It is found that chronic acidosis causes an increase in the activity of the Na+-H+ exchanger in the proximal tubule and the H+-ATPase in the intercalated cells, whereas alkalosis produces the opposite effect. Second, increases in plasma Pco2 stimulate HCO- reabsorption, whereas a fall in Pco2 depresses it. This effect of Pco2 on HCO- reabsorption is evidenced as a shift in the curve relating HCO- excretion to the plasma HCO-concentration, as shown in Fig. 3. With an elevation in Pco2, the threshold for HCO- excretion is shifted to higher plasma HCO- concentrations, and the opposite is observed with a fall in Pco2. This mechanism is part of the renal adaptation to respiratory acidosis and alkalosis. For example, as described later, when hyperventilation decreases the plasma PCO2 and, thus, produces alkalosis, HCO- reabsorption is decreased in response to the fall in Pco2 and the resulting urinary loss of HCO- counteracts the alkalosis.

The third factor in Table 2 is the plasma K+ concentration. HCO- reabsorption is increased in hypokalemia and decreased in hyperkalemia. It is likely that the intracellular K+ concentration rather than the plasma K+ concentration is the important variable, but the intracellular concentration tends to rise or fall in proportion to the extracellular or plasma concentration. Depletion of intracellular K+ augments the renal tubular capacity for reabsorbing HCO- and results in an increase in the plasma HCO- concentration above normal levels with no urinary loss.

TABLE 2 Factors That Alter H+ Secretion and HCO Reabsorption by the Proximal Tubule

Increase

Decrease

Acidosis

" Pco2 (as in respiratory acidosis) Hypokalemia

# ECF volume with Cl- depletion

Alkalosis

# PCO2 (as in respiratory alkalosis) Hyperkalemia t ECF volume

Plasma Bicarbonate Concentration (mmol/L)

FIGURE 3 Effect of respiratory alkalosis and acidosis on the plasma bicarbonate threshold.

Plasma Bicarbonate Concentration (mmol/L)

FIGURE 3 Effect of respiratory alkalosis and acidosis on the plasma bicarbonate threshold.

Finally, HCO- reabsorption is augmented by decreases in the plasma Cl- concentration and extracellular fluid (ECF) volume. When the body is depleted of Cl- and a hypovolemic status develops, the plasma HCO- concentration increases and the tubular reab-sorptive capacity for HCO- increases, which shifts the HCO- excretion curve (see Fig. 2) toward the right. Conversely, expansion of the body ECF depresses HCO- reabsorption. The reason for this reciprocal relationship is not entirely clear, but relates in part to the need to conserve Na+ after volume depletion. In the presence of ECF volume depletion, Na+ is avidly conserved by the proximal tubule, as discussed in Chapter 29. If Cl- is not available for reabsorption with Na+, protons are secreted in exchange for reabsorbed Na+, resulting in the reabsorption of HCO-. However, the loss of Cl- appears to be an important factor because merely restoring the extracellular fluid volume without replacing Cl- does not correct the alkalosis resulting from HCO- retention.

Bicarbonate Generation by the Distal Nephron

In addition to reabsorbing filtered HCO- in the proximal tubule, the kidney must also regenerate HCO-to replenish the HCO- stores depleted during the buffering of strong acids produced by metabolism. The renal excretion of H+ allows new HCO- generation, as shown in Fig. 1. However, merely excreting acid urine does not account for the necessary daily excretion of H+. Even at the minimum urine pH of 4.5, the excretion of 1-2 L of unbuffered urine would eliminate less than 1 mmol of acid per day, compared with the daily intake and production of about 100 mmol. Thus, the H+ must be excreted in a form other than as a dissociated acid, and this is accomplished by the formation of titratable acidity, i.e., H+ combined with urine buffers such as HPO42— and SO42—.

All buffer anions that are filtered at the glomerulus can augment the excreted titratable acidity, and these anions buffer secreted H+ ions even in the lumen of the proximal tubule. However, the formation of titratable acidity in the proximal tubule is limited by the luminal pH that can be achieved. Maximal titration of urine buffers to their associated acid forms requires the production of more acid urine, which is accomplished primarily by those regions of the nephron that have interacted cells. These regions include the late distal convoluted tubule, the connecting tubule, and the cortical and outer medullary collecting duct that are referred to here collectively as the distal nephron. The effect of urine pH on the rate of excretion of titratable acidity can be best illustrated by phosphate, which is the primary urinary buffer. The pKa of the phosphate buffer system is 6.8, so from the Henderson-Hasselbalch equation, one can compute that at a normal plasma pH of 7.4 the ratio of HPO42— to H2PO4— is 4:1. When the pH falls, as it does in the urine, HPO42— is titrated to H2PO4— and the ratio falls. At the lowest urinary pH of 4.5, virtually all the HPO42— has been converted to H2PO4—:

Other weak acids present in the urine are also titrated to their undissociated acid form by urinary acidification in the distal nephron segments. Although phosphate is usually the major urinary buffer, other weak acids such as creatinine become increasingly important as the urinary pH falls. In diabetic ketoacidosis, ^-hydroxy-butyrate and acetoacetate can be important urinary buffers at low urine pH.

TABLE 3 Factors That Alter H+ Secretion and Formation of Titratable Acidity by the Distal Tubule and Collecting Duct

Increase

Decrease

Acidosis

" Pco2 (as in respiratory acidosis)

Hypokalemia Mineralocorticoid excess (e.g., Cushing's syndrome)

Alkalosis

# Pco2 (as in respiratory alkalosis) Hyperkalemia Mineralocorticoid deficit (e.g., Addison's disease)

Table 3 presents the factors that alter H+ secretion in the distal tubule and collecting duct and, thus, alter the rate of excretion of titratable acidity by changing the urine pH. As in the proximal tubule, H+ secretion by intercalated cells in the distal portions of the nephron is stimulated by (1) acidosis, (2) elevation of plasma PCO2, and (3) hypokalemia, whereas the opposite changes decrease H+ secretion. In contrast to the proximal tubule, ECF volume does not affect distal H+ secretion; however, another factor, variation in plasma mineralocorticoid hormones, operates exclusively in the aldosterone-responsive distal nephron (ARDN) and, thus, has a greater effect on the formation of a maximally acid urine than on HCO— reabsorption. Increased endogenous or exogenous levels of mineralocorticoids and/or the 17-OH glucocorticoids will increase the renal tubular capacity for H+ secretion. Thus, alkalosis is a common accompaniment of Cush-ing's syndrome (excess production of adrenal cortico-steroids; see Chapter 40).

The intercalated cells in the distal nephron can respond to alkalosis not only by increasing the urine pH and, thus, preventing the titration of urinary buffers (i.e., reducing or eliminating titratable acidity), but also by actually secreting HCO3— and thus increasing the excretion of this buffer base. As discussed in Chapter 27 and illustrated in Fig. 4, the normal orientation of the H+-ATPase in the luminal membrane and the HCO3—/ Cl— exchange mechanism in the basolateral membrane can be reversed so that protons move toward the plasma and HCO3— is secreted into the lumen. However, the proximal tubule, merely by failing to reabsorb all of the filtered HCO—, is a much more important contributor to HCO3— excretion in alkalosis.

In response to acidosis, the amounts of buffer anions in the urine and the minimum urinary pH set a limit on the quantity of H+ that can be excreted as titratable acidity and, thus, on the ability to restore plasma HCO—. But the kidney has a highly efficient means of overcoming this limitation. It does so by generating increasing amounts of ammonium ion (NH4+) that are excreted in the urine. NH4+ excretion by the kidney helps to raise body HCO3— stores by decreasing the consumption of HCO3— by hepatic ureagenesis.

As illustrated schematically in Fig. 5, the metabolism of amino acids in the liver produces NH4+ and HCO— plus small quantities of SO42— from the sulfur-containing amino acids. The NH4+ and HCO— are converted primarily into urea, which is effectively excreted by the kidney, and glutamine. Glutamine in the circulation can be metabolized in the kidney to NH4+ and a-ketoglutarate. Further metabolism of the a-ketoglutarate results in the production of HCO—,

FIGURE 4 H+ and HCO^ transport in the collecting duct. (A) Normally, the collecting duct actively secretes H+ and returns HCO^ to the plasma. (B) In alkalosis, the orientation of the transporters can be reversed so that HCO7 is secreted into the lumen.

ammonium excretion can increase by 10-fold in diabetic ketoacidosis. Under normal acid-base conditions, the kidney excretes roughly equal amounts of titratable In chronic acidosis, although acidity and NH4+.

FIGURE 4 H+ and HCO^ transport in the collecting duct. (A) Normally, the collecting duct actively secretes H+ and returns HCO^ to the plasma. (B) In alkalosis, the orientation of the transporters can be reversed so that HCO7 is secreted into the lumen.

which leaves renal cells only across their basolateral membranes. Therefore, the excretion of urea by the kidney causes the loss of both NH4+ and HCO—, whereas the metabolism of glutamine results in the excretion of NH4+ and the return of HCO— to the plasma. In other words, when the kidney metabolizes glutamine it essentially restores body HCO— that would otherwise have been lost by the excretion of urea. The effect is to generate additional HCO— that can compensate for the HCO— consumed in the titration of phosphoric and sulfuric acids produced by metabolism, as shown on the right-hand side of Fig. 5.

The kidney is one of the few organs capable of gluconeogenesis, which involves the deamination and deamidation of amino acids and the production of NH4+ especially in proximal tubule cells. In chronic acidosis, the kidney increases the synthesis of the enzymes for gluconeogenesis, particularly glutaminase, and thus increases its capability for ammoniagenesis, that is, the production of NH4+. As shown in Table 4, the rate of both increase, NH4+ becomes the dominant contributor to H+ excretion and, thus, it is the primary contributor to the generation of new HCO— or what might be regarded as sparing HCO— from consumption by urea-genesis. In alkalosis, the excretion of titratable acidity diminishes primarily because H+ secretion is decreased and, thus, the urine pH rises. Glutamine metabolism also decreases, causing less NH4 to be excreted, and thus, less HCO— to be spared from consumption in ureagenesis.

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