LOW-DOSE CYCLOSPORINE NEPHROTOXICITY IN THE RAT

The nephrotoxicity of cyclosporin (CsA) continues to be a clinical pro blem that detracts from its obvious benefits as an immunosuppressive a gent. Animal models designed to study the problem have generally relie d either on chronic administration of high doses of the drug or acute administration of single i.v. doses. The present study establishes a m odel of CsA nephrotoxicity using doses of the drug comparable to those used in man administered over a time period sufficient for haemodynam ic and structural changes to become evident. The technique used measur es glomerular filtration rate (GFR) and effective renal plasma flow (E RPF) by the plasma clearance of chromium EDTA and iodohippuran respect ively. This has the advantage of allowing sequential measurements in i ndividual animals. Significant impairment of GFR was seen in animals t reated intraperitoneally with doses of CsA as low as 5 mg/kg/day. CsA 7.5 mg/kg/day caused a significant reduction in ERPF, and at 10 mg/kg/ day and greater filtration fraction also declined significantly. Detai led histological examination of the kidneys from these animals also re vealed significant tubular dilatation at 10 mg/kg/day and above. This model of CsA toxicity circumvents many of the problems associated with other models. The animals can be studied longitudinally and the perio d of administration has relevance to clinic practice. This work provid es the basis for further studies which can closely mimic the clinical situation using doses similar to those used for human maintenance immu nosuppression.