INSIGHTS INTO THE BIOCHEMICAL-MECHANISM OF MALEIC ACID-INDUCED FANCONI SYNDROME

Maleic acid administration is known to produce the Fanconi syndrome, a lthough the biochemical mechanism is incompletely understood. In this study the effect of a single injection of maleic acid (50 mg/kg body w t, i.v.) on the rat renal ATPases was examined. Maleic acid rapidly ca used bicarbonaturia, natriuresis, and kaliuresis. When nephron segment s were microdissected, there was an 81 +/- 2% reduction in proximal co nvoluted tubule (PCT) Na-K-ATPase activity (P < 0.005) and a 48 +/- 4% reduction in PCT H-ATPase activity (P < 0.01). Enzyme activity (Na-K- ATPase, H-ATPase, H-K-ATPase) in the medullary thick ascending limb of Henle's loop and distal nephron segments was normal. In vitro, maleic acid (1 and 10 mM) inhibited Na-K-ATPase in PCT, but it had no effect on H-ATPase in PCT. Prior phosphate infusion to maleic acid-treated r ats attenuated urinary bicarbonate wastage by 50% (P < 0.05); activity of proximal tubule Na-K-ATPase and H-ATPase activities were partially protected as compared to the animals given maleic acid alone (P < 0.0 5). Renal cortical ATP levels were not altered al the concentration of maleic acid used in this study (that is, 50 mg/kg body wt), but highe r doses of maleic acid (that is, 500 and 1000 mg/kg body wt) caused AT P levels to fail. Maleic acid did not affect cortical medullary total phosphate concentration, however, P-32 turnover (1 and 24 hr) was alte red by prior phosphate infusion. A protective effect of prior phosphat e loading on the membrane bound Pi pool (insoluble) was seen while the cytosolic Pi pool (soluble) was not different from control. Thus, mal eic acid-induced ''Fanconi'' syndrome Likely results from both direct inhibition of proximal tubule Na-K-ATPase activity and membrane-bound phosphorus depletion. The former mechanism would reduce activity of th e sodium-dependent transporters (that is, Na/H antiporter), while the latter would inhibit the electrogenic proton pump (H-ATPase). The comb ination of reduced proximal tubule Na-H exchange and H-ATPase activiti es would markedly inhibit bicarbonate reabsorption and result in the m etabolic acidosis universally seen in the Fanconi syndrome.