Pathophysiological Basis of Distal Renal Tubular Acidosis: Lessons from Animal Models

A number of potential defects may impair acidification either directly or indirectly in segments of the distal nephron. Papillary micropuncture studies have validated the urine minus blood PCO2 (U-B PCO2) obtained during a bicarbonate diuresis as a reliable qualitative index of distal nephron proton pump integrity. Microelectrode determination of both PCO2 and disequilibrium pH in the papillary collecting duct in a number of experimental models of distal renal tubular acidosis (DRTA) have demonstrated at least four types of defects: 1) The permeability or “gradient” defect is best exemplified by the amphotericin B lesion, where reduction in net acid excretion is the result of backleak of bicarbonate during excretion of an acid urine. During bicarbonate loading, the U-B PCO2 is normal, however, demonstrating that the pump is not defective; 2) Voltage-dependent rate defects are induced by amiloride or lithium. As a result of the decrease in voltage in the cortical collecting tubule (CCT) both H+ and K+ secretion are reduced; 3) Nonvoltage mediated pump defects occur in the postobstructed kidney and, when corrected for voltage, are present in aldosterone deficiency; 4) Impaired buffer delivery or production compromises net acid excretion. Ammonium production is decreased in chronic hyperkalemia and with reduction of GFR. Ammonium excretion is impaired in hyperkalemia because a decrease in ammonium transport by the TALH reduces ammonium accumulation in the inner medulla and, thus, impedes transfer of ammonia into the inner medullary collecting duct. Mixed defects also exist, e.g., in aldosterone deficiency hyperkalemia impairs ammonium excretion while aldosterone deficiency compromises the capacity of the proton pump.