Children with methylmalonic acidemia frequently develop chronic renal insufficiency, for reasons unknown. We administered MMA chronicaally to rats to test the hypothesis that MMA is nephrotoxic. Methods: 3-wk-old Sprague-Dawley rats received MMA (pH 7.2-7.4), 20mg/100g BW daily by SQ injection X 6 wks (N=6), then in drinking water (40mg/100g BW/day) for 6 more wks. Two rats received MMA in drinking water from the outset (20mg/100g BW/day X 4 wks, 40mg/100g BW/day X 8 wks). Five rats received saline injections twice daily X 6 wks. Urine and blood were collected every 2 wks. Renal biopsy was performed at 6 wks and necropsy at 12 wks. Urinary MMA was measured by stable isotope dilution gas chromatography- mass spectometry. Results: MMA-treated rats and controls were similar in food and water intake, weight gain, serum creatinine and BUN. SQ or oral MMA produced high urinary MMA levels (e.g., 1646 μM/mM creatinine at 6 wks (mean), vs. 8.26 in controls). Six of 8 MMA-treated rats had proteinuria, that was first detected at 2 wks and thereafter increased (Table). After 12 wks of MMA, glomeruli appeared normal but tubules of proteinuric rats were variably dilated (especially in the renal medulla) with proteinaceous casts and flattened epithelium. By EM, tubular epithelium showed variable mitochondrial swelling and disorganization of cristae, dilated smooth endoplasmic reticulum, dilatation of basolateral intercellular spaces, and more secondary lysosomes than controls. Conclusions: Chronic administration of MMA rats causes renal injury, which histologically appears to predominantly affect tubular epithelial cells. These findings suggest that chronic renal insufficiency associated with methylmalonic acidemia results from nephrotoxicity of MMA.

Table 1 Table: Urinary protein excretion in MMA-treated and control rats (mg/24 hrs)