Bicarbonate reabsorption

Mg < 1 mEq/L) depletion (renal ammoniagenesis, renal H+ losses, and stimulate renal bicarbonate reabsorption)... 

As kidney function declines, bicarbonate reabsorption is maintained, but hydrogen excretion is decreased because the ability of the kidney to generate ammonia is impaired. The positive hydrogen balance leads to metabolic acidosis, which is characterized by a serum bicarbonate level of 15 to 20 mEq/L (15 to 20 mmol/L). This picture is generally seen when the GFR declines below 20 to 30 mL/minute.38... 

The excretion of water soluble waste via the kidneys requires filtration followed by selective reabsorption from and secretion into the renal tubules. Regulation of normal blood pH within very strict limits due to proton secretion and bicarbonate reabsorption is a major role of the kidney. 

Figure 8.4 Rote of carbonic anhydrase in proton secretion and bicarbonate reabsorption...

Inhibition of proximal tubule brush border carbonic anhydrase decreases bicarbonate reabsorption, and this accounts for their diuretic effect. In addition, carbonic anhydrase inhibitors affect both distal tubule and collecting duct H+ secretion by inhibiting intracellular carbonic anhydrase. 

Bicarbonate reabsorption by the proximal tubule is thus dependent on carbonic anhydrase. This enzyme can be inhibited by acetazolamide and other carbonic anhydrase inhibitors. 

Apical membrane Na+/H+ exchange (via NHE3) and bicarbonate reabsorption in the proximal convoluted tubule cell. Na+/K+ ATPase is present in the basolateral membrane to maintain intracellular sodium and potassium levels within the normal range. Because of rapid equilibration, concentrations of the solutes are approximately equal in the interstitial fluid and the blood. Carbonic anhydrase (CA) is found in other locations in addition to the brush border of the luminal membrane. 

Acetazolamide can cause a metabolic acidosis in 50% of elderly patients (SEDA-11,199) occasionally (particularly if salicylates are being given or renal function is poor) the acidosis can be severe. It does this by inhibiting renal bicarbonate reabsorption. This effect is of particular use in treating patients with chronic respiratory acidosis with superimposed metabolic alkalosis. Life-threatening metabolic acidosis is rarely observed in the absence of renal insufficiency and/or diabetes mellitus. In three patients with central nervous system pathology alone conventional doses of acetazolamide resulted in severe metabolic acidosis (34). After withdrawal it took up to 48 hours for the metabolic acidosis and accompanying hyperventilation to resolve. 

Sodium bicarbonate reabsorption by the proximal tubule is initiated by the action of a Na+/H+ exchanger located in the luminal membrane of the proximal tubule epithelial cell (Figure 15-3). This transport system allows sodium to enter the cell from the tubular lumen in exchange for a proton from inside the cell. As in all portions of the nephron, Na+/K+ ATPase in the basolateral... 

Inhibition of carbonic anhydrase activity profoundly depresses bicarbonate reabsorption in the proximal tubule. At its maximal safely administered dosage, 85% of the bicarbonate reabsorptive capacity of the superficial proximal tubule is inhibited. Some bicarbonate can still be absorbed at other nephron sites by carbonic anhydrase-independent mechanisms, and the overall effect of maximal acetazolamide dosage is about 45% inhibition of whole kidney bicarbonate reabsorption. Nevertheless, carbonic anhydrase inhibition causes significant bicarbonate losses and hyperchloremic metabolic acidosis. Because of this and the fact that HCO3" depletion leads to enhanced NaCl reabsorption by the remainder of the nephron, the diuretic efficacy of acetazolamide decreases significantly with use over several days. 

CAIs alter renal function primarily by inhibiting carbonic anhydrase in the proximal tubule, which results in decreased bicarbonate reabsorption. The net effect of the renal actions of acetazolamide therapy is alkaliniza-tion of the urine and metabolic acidosis. Metabolic acidosis results from the initial bicarbonate loss and persists with continued acetazolamide use. Moderate metabolic acidosis develops in most patients. Reabsorption of bicarbonate independent of carbonic anhydrase prevents severe acidosis. Initially, acetazolamide produces diuresis, but urinary output decreases with the development of metabolic acidosis. In addition, decreased urinary citrate excretion follows acetazolamide therapy and has been attributed to the metabolic acidosis it produces. A high urinary pH and low urinary citrate concentration are conducive to precipitation of calcium phosphate in both the renal papillae and the urinary tract. 

Acetazolamide can cause a metabolic acidosis in 50% of elderly patients (SEDA-11,199) occasionally (particularly if salicylates are being given or renal function is poor) the acidosis can be severe. It does this by inhibiting renal bicarbonate reabsorption. This effect is of particular... 

The authors postulated that the mechanism of topiramate-induced acidosis is inhibition of carbonic anhydrase in the proximal renal tubule, resulting in impaired proximal bicarbonate reabsorption. Blood gases should be obtained in patients taking topiramate who develop hyperventilation and changes in mental status. 

Klotman PE and Yarger WE. Reduction of renal blood flow and proximal bicarbonate reabsorption in rats by gentamicin. Kidney Int24 638-643,1983. 

Angiotensin converting enzyme inhibitors and angiotensin receptor blockers are likely to exacerbate the pre-renal state caused by the diarrhea and volume depletion that follow the use of OSPS (Table 3). Of the 21 cases of APhN reported in the largest series to date, 14 were receiving one of these two agents [30]. In addition to their effects on volume status, ACE-I and ARB lead to a decline in angiotensin-II dependent bicarbonate reabsorption in the proximal tubule [58]. 

Because bicarbonate is a small ion, it is freely filtered at the glomerulus. The bicarbonate load delivered to the nephron is approximately 4,500 mEq/day. To maintain acid-base balance, this entire filtered load must be reabsorbed. Bicarbonate reabsorption occurs primarily in the proximal tubule (Fig. 51-1). In the mbular lumen, filtered bicarbonate combines with hydrogen ion secreted by the apical Na+-H+-exchanger to form carbonic acid. The carbonic acid is rapidly broken down to CO2 and water by carbonic anhydrase located on the luminal surface of the brush border membrane. The CO2 then diffuses into the proximal tubular cell, where it reforms carbonic acid in the presence of intracellular carbonic anhydrase. The carbonic acid dissociates to form hydrogen ion, that can again be secreted into the tubular lumen, and bicarbonate that exits the cell across the basolateral membrane and enters the peritubular capillary. 

Proximal (type II) RTA is characterized by defects in proximal tubular reabsorption of bicarbonate. Normally, more than 85% of filtered bicarbonate is reabsorbed in the proximal tubule. Defects in proximal tubular bicarbonate reabsorption result in increased delivery of bicarbonate to the distal nephron, which has a limited capacity for bicarbonate reabsorption. As a result, at a normal serum bicarbonate concentration, the filtered bicarbonate load is incompletely reabsorbed, and is lost in the urine. As the serum bicarbonate concentration falls, the filtered load of bicarbonate is proportionately decreased. A new equilibrium is established in which the kidney is... 

No matter which condition initiated the metabolic alkalosis, abnormalities in renal function underlie its maintenance. Normally, the kidneys are capable of excreting all of the excess bicarbonate presented to them, even during periods of increased bicarbonate loads. As the serum bicarbonate concentration increases, the filtered bicarbonate load exceeds the maximal rate for bicarbonate reabsorption, and the excess bicarbonate is excreted in the urine. Under normal circumstances, the excess bicarbonate is rapidly excreted and metabolic alkalosis does not occur, or is corrected in a matter of hours... 

Mineralocorticoid excess also plays a significant role in the maintenance of metabolic alkalosis. In patients with volume-responsive metabolic alkalosis, intravascular volume depletion stimulates aldosterone secretion. As discussed earlier, excess mineralocorticoid activity may also underlie the generation of metabolic alkalosis. In either situation, the increased mineralocorticoid effect stimulates collecting duct H+ secretion. Metabolic alkalosis may also be maintained by persistent hypokalemia. Hypokalemia has a multitude of effects on renal acid-base homeostasis, enhancing proximal tubular bicarbonate reabsorption, stimulating ammoniagenesis and increasing distal tubular H secretion. ... 

Metabolic compensation occurs when respiratory alkalosis persists for more than 6 to 12 hours. In response to the alkalemia, proximal tubular bicarbonate reabsorption is inhibited and the serum bicarbonate concentration falls. Renal compensation is usually complete within 1 to 2 days. The renal bicarbonaturia, as well as decreased NH4+ and titratable acid excretion, are direct effects of the reduced PaC02 and pH on renal reabsorption of chloride and bicarbonate. The... 

In type II renal tubular acidosis there is a defect in the secretion of hydrogen ions by the proximal tubule. Because the proximal tubule is the major site of bicarbonate reabsorption (4000 mEq of bicarbonate per day as compared to 70 mEq in the distal tubule), the defect in secretion of hydrogen ions in this condition leads to the flooding of the distal tubule with bicarbonate. The capacity of hydrogen ions secreted by the distal tubule to buffer this massive efflux of bicarbonate is soon overwhelmed and, as a result, large quantities of bicarbonate are excreted in the urine. Much more bicarbonate needs to be administered in this condition to correct the acidosis than is necessary in type I renal tubular acidosis. In general, in renal tubular acidosis the impairment in hydrogen ion secretion leads to excretion of potassium ions in urine. 

Respiratory acidosis may be acute or chronic. Acute conditions occur within minutes or htnirs. They are uncompensated. Renal compensation has no time to develop as the mechanisms which adjust bicarbonate reabsorption take 48-72 h to become fully effective. The primary problem in acute respiratory acidosis is alveohir hypoventilation. If airflow is completely or partially reduced, the PCO, in the bltHtd will rise immediately and the H ) will rise quickly (Fig. 2). A resulting low PO, and high PCO. causes coma. If this is not reliev ed rapidly, death results. 

Proximal convoluted tubule (PCT) This segment carries out isosmotic reabsorption of amino acids, glucose, and numerous cations. This is also the major site for sodium chloride and sodium bicarbonate reabsorption. The mechanism for bicarbonate reabsorption is shown in Figure 15-3. Bicarbonate itself is poorly reabsorbed through the luminal mem-... 

Figure 15-3. Mechanisms of sodium bicarbonate reabsorption in the proximal tubule cell. CA, carbonic anhydrase. (Reproduced, with permission, from Katzung BG [editor] Basic Clinical Pharmacology, 8th ed. McGraw-Hill, 2001.)...

The exact tubular site of bicarbonate reabsorption is not known, but stop-flow and micropuncture experiments suggest that it coincides with the site of sodium absorption. Although the mechanism of bicarbonate reabsorption is unknown, no extrarenal hormone appears to control it. 

We have seen that bicarbonate is reabsorbed primarily in the proximal tubule and that the urine is acidified and ammonia excreted in the distal tubule. Any inherited or acquired injury that interferes with bicarbonate reabsorption or urine acidification will lead to acidosis. (Although interference with ammonia excretion could, in theory, also lead to acidosis, it seldom does.)... 

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