Cyclosporin A-induced nephrotoxicity in the rat: relationship to increased plasma renin activity

Cyclosporin A (CsA; 50, 100 or 150 mg/kg) was administered by gavage, daily for 4 days, to groups of normotensive rats. An additional group of animals received the drug vehicle. CsA-induced nephrotoxicity, characterized by reduced glomerular filtration rate (GFR) and urinary sodium flow, enzymuria and proximal tubular cell damage was accompanied by elevated plasma renin activity (PRA). These changes were dose-related at 50 and 100 mg/kg CsA, but were not increased by administration of 150 mg/kg. Circulating trough drug levels were related to dosage. Four days after CsA withdrawal in animals given 50 mg/kg, there was reduced nephrotoxicity and PRA had returned to normal, even though circulating CsA levels had not diminished. Rats given 100 and 150 mg/kg, however, showed no reduction in nephrotoxicity or in PRA. Hyperglycaemia was evident at 4 days in animals given 100 and 150 mg/kg CsA and persisted 4 days after drug withdrawal. There were no accompanying abnormalities in islet cell structure. Continuous administration of CsA (50 mg/kg) to rats for 14 days caused elevated PRA on day 4 but a return to normal levels by day 7. In contrast, significant GFR impairment was evident by day 7 whilst enzymuria was significantly increased from day 4 onwards. CsA nephrotoxicity in the rat is clearly associated with activation of the renin-angiotensin-aldosterone system. Possible mechanisms leading to increased renin release are discussed.