The bicarbonate/carbonic acid buffer system is an open system; that is, the quantity of buffer present in the system is not fixed but varies according to physiologic need. This flexibility is largely provided by pulmonary excretion of P co2 which can vary significantly and rapidly according to the exigencies of the acid-base milieu. The kidney regulates both bicarbonate excretion and the formation of new bicarbonate and is able to change the rate of these processes when demanded by the acid-base milieu, while pulmonary response to immediate renal compensation requires hours to days to complete.
Although the lungs and kidney are traditionally considered the cornerstone organs of acid-base balance, increasing attention is being given to the role of the liver in acid-base homeostasis. Approximately 1 mol each of bicarbonate and ammonium is generated every day by protein catabolism. The irreversible synthesis of urea by the liver results in consumption of virtually all of this bicarbonate. The rate of this reaction is closely tied to both extracellular pH and bicarbonate concentration. This control, mediated by glutaminase and carbonic anhydrase, can result in significant retention and neutralization of bicarbonate during acidosis. The fixation of ammonium ions into urea slows, but the kidney increases ammonia synthesis and excretion. This process not only prevents ammonia accumulation but also allows hydrogen ion trapping in the distal tubule. Furthermore, hepatic cells without the cellular machinery to fix ammonia into urea avidly use excess ammonia to synthesize glutamine.3 Thus, the liver is the "third organ" of acid-base balance.
The maintenance of bicarbonate homeostasis by the kidney requires reclamation of the daily filtered load of bicarbonate, 85 percent of which occurs in the proximal convoluted tubule. The Na+,K+-ATPase system extrudes sodium into plasma and draws potassium into the tubule cell. The filtrate in the tubule lumen, however, has a sodium concentration equal to that of plasma. An antiporter of sodium and hydrogen ion is driven by this gradient, transporting sodium from the tubule lumen into the tubule cell in exchange for hydrogen ion. The hydrogen ion combines with filtered bicarbonate in the tubule lumen, producing carbonic acid. Carbonic anhydrase, resident in the luminal cell membrane, catalyzes the conversion of carbonic acid to water and CO 2. CO2, which is soluble, diffuses down a concentration gradient into the tubule cell, where cytoplasmic carbonic anhydrase regenerates carbonic acid (and thereby creates the CO 2 concentration gradient). The carbonic acid dissociates, providing hydrogen ion for extrusion and bicarbonate, which enters the plasma. If the rate of proton extrusion is reduced by tubular disease, bicarbonate will be lost until the serum concentration has fallen to a level that can be reclaimed by the limited hydrogen ion extrusion available. This is the pathophysiology underlying proximal renal tubular acidosis (RTA).
The kidney reclaims the balance (approximately 15 percent) of filtered bicarbonate in the distal tubule. Carbonic anhydrase in the cytoplasm of distal tubule cells generates carbonic acid, which dissociates. An electrogenic H +-ATPase on the luminal cell membrane secretes the resulting hydrogen ion into the tubule lumen, where it is titrated by inorganic phosphate or binds to ammonia and is "trapped" in the tubule lumen. The bicarbonate resulting from dissociation of intracellular carbonic acid diffuses into plasma. The loss of H + and HCO3- from the cell maintains electroneutrality, so the process of bicarbonate reclamation in the distal tubule is sodium-independent. Thus, the process of proton secretion in the distal tubule functions not only to reclaim filtered bicarbonate but also to excrete protons generated by metabolism. The failure of proton secretion is the mechanism underlying distal renal tubular acidosis.
The kidney also generates new bicarbonate in the distal tubule in a sodium-dependent process. A Na+,K+-ATPase on the antiluminal cell membrane creates a low intracellular sodium concentration. At the same time, intracellular glutamine is metabolized to bicarbonate and ammonium. Sodium then moves from the tubule lumen into the tubule cell down its concentration gradient, and ammonium moves from the tubule cell into the tubule lumen. (Impairment of ammonium excretion results in its incorporation into urea in the liver, a process that consumes bicarbonate.) Bicarbonate formation by this process may increase 6 to 10 times over 4 to 5 days when acidosis so demands. However, drugs that alter uptake or delivery of sodium to the distal tubule significantly affect this process.
The effect of the kidney on acid-base balance is to prevent bicarbonaturia and to excrete the daily metabolic load of acid. The process of acid excretion allows the kidney to regenerate bicarbonate in proportion to the quantity consumed by buffering of the daily acid load. The result is that urine, especially under conditions of acidosis, can be made almost entirely free of bicarbonate.
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