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Phosphate loading attenuates renal tubular dysfunction induced by maleic acid in the dog
Abstract:
The metabolic pathogenesis of the complex renal tubular dysfunction of type II renal tubular acidosis and Fanconi's syndrome (RTA II/FS) acutely induced by maleic acid could depend on the occurrence of a positive feedback loop in cells of the proximal renal tubule: impaired mitochondrial oxidation----increased glucose uptake----increased formation and concentration of phosphorylated glycolytic intermediates----limitation on availability of cellular inorganic phosphate----more severely impaired mitochondrial oxidative metabolism. To test this hypothesis we intravenously administered maleic acid both alone and after initiating intravenously administered neutral sodium phosphate, sodium sulfate, or sodium chloride to 10 unanesthetized trained female dogs undergoing water diuresis. We made the following observations: 1) Administration of maleic acid alone predictably induced dose-dependent increments in urine flow (V) and in renal clearance of HCO3-, Na+, K+, and alpha-aminonitrogen and a pronounced increase in the renal clearance and excretion of citrate. 2) Prior phosphate loading, which increased the plasma concentration of phosphate from 2.5 +/- 0.20 to 11.3 +/- 2 mg/dl: a) attenuated the increment in renal clearance of HCO3- by one-half even though the filtered load of bicarbonate was higher by 37%, owing to the higher values of both GFR and plasma bicarbonate concentration that obtained with phosphate loading; b) prevented the increment in renal clearance and excretion of alpha-aminonitrogen; c) significantly attenuated the increments in V and renal clearance of K+; but d) did not affect the increment in renal clearance and excretion of citrate.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Maleic acid causes renal tubular dysfunction by creating a positive feedback loop involving impaired mitochondrial oxidation and phosphate limitation. Phosphate loading partially prevents this dysfunction, suggesting a key role for phosphate in the pathogenesis of type II renal tubular acidosis and Fanconi's syndrome.
Area of Science:
- Nephrology
- Cellular Metabolism
- Toxicology
Background:
- Type II renal tubular acidosis and Fanconi's syndrome (RTA II/FS) are complex renal tubular dysfunctions.
- Maleic acid is known to acutely induce RTA II/FS.
- The underlying metabolic pathogenesis is hypothesized to involve a positive feedback loop in proximal renal tubule cells.
Purpose of the Study:
- To investigate the metabolic pathogenesis of maleic acid-induced RTA II/FS.
- To test the hypothesis of a positive feedback loop involving impaired mitochondrial oxidation and phosphate limitation.
- To evaluate the effect of phosphate loading on maleic acid-induced renal dysfunction.
Main Methods:
- Intravenous administration of maleic acid to unanesthetized female dogs undergoing water diuresis.
- Comparison of maleic acid administration alone versus prior intravenous neutral sodium phosphate, sodium sulfate, or sodium chloride loading.
- Measurement of urine flow, renal clearance of bicarbonate, sodium, potassium, alpha-aminonitrogen, and citrate.
Main Results:
- Maleic acid alone induced dose-dependent increases in urine flow and clearance of bicarbonate, sodium, potassium, alpha-aminonitrogen, and citrate.
- Phosphate loading attenuated the increase in bicarbonate clearance despite higher filtered loads.
- Phosphate loading prevented the increase in alpha-aminonitrogen clearance and significantly attenuated increases in urine flow and potassium clearance.
Conclusions:
- Phosphate loading partially mitigates maleic acid-induced renal tubular dysfunction.
- The findings support the hypothesis of a positive feedback loop involving phosphate limitation in the pathogenesis of RTA II/FS.
- Phosphate plays a critical role in protecting against maleic acid-induced proximal tubule damage.