The effect of chronic renal insufficiency on cyclosporine nephrotoxicity

Despite cyclosporine's efficacy in preventing rejection, its use has been hampered by nephrotoxicity. Questions remain concerning its application in patients with decreased renal function. The purpose of this study was to 1) establish a reliable animal model with chronic renal insufficiency (CRI) to study cyclosporine (CyA) nephrotoxicity, and 2) compare the long-term (50 day) severity of CyA nephrotoxicity in CRI versus normal animals. Fischer 344 rats were divided into six groups (15 to 22 each). In three groups, CRI was induced by a 5/6th nephrectomy (three groups were sham operated). After three wks., daily i.p. injections of olive oil, CyA at five mg./kg., or CyA at 30 mg./kg. daily were administered. Serum and urine were collected at 10 day intervals for the determination of biochemical indices of renal function. Animals were sacrificed after 50 days of treatment and renal histology was evaluated by light and electron microscopy. Chronic CyA treatment was well tolerated by both intact and CRI rats, suggesting that this is a reliable model for long-term CyA toxicity studies. CyA decreased renal function at day 50 in both CRI and intact animals. CRI of mild to moderate degree had little effect on the biochemical and histological indices of CyA induced nephrotoxicity. CRI does appear to potentiate the metabolic toxicity that occurs after chronic treatment with high dose CyA.