Functional and histopathologic effects of rapamycin on mouse kidney.

The effect of rapamycin (RAPA) on kidney function and histopathology was assessed in two strains of mice. Male C3H/HeJ mice were treated with RAPA for 4 days at doses of 25, 50, 75, and 100 mg/kg, ip and male C3H/HeJ or female Balb/cJ mice were both treated for 7 days at doses of 75, 150 and 200 mg/kg. Cyclosporine (CsA) was also administered to female Balb/cJ mice at doses of 50, 100, 150 and 200 mg/kg, ip. RAPA-treated mice had elevated BUN levels but the effect was not dose-dependent and was not present in the high dose, 7-day study conducted in the C3H/HeJ mice. Body weights were significantly depressed in both of the 7 day studies but not in the 4 day study. Histopathologic examination of the kidneys revealed the presence of intracytoplasmic vacuolization in the proximal tubules in both of the 7 day studies at the higher dose only. There were no drug-related deaths. In the CsA-treated mice, multiple deaths were recorded in both the 150 mg/kg and 200 mg/kg dose groups, probably related to neurotoxicity, and BUN levels were elevated in the 100 mg/kg dose group. In conclusion, RAPA's effects on kidney function were minimal at doses 50 times higher than its therapeutic dose established in the mouse. RAPA exhibited a better therapeutic index than CsA in the mouse.