Low-dose cyclosporin nephrotoxicity in the rat

The nephrotoxicity of cyclosporin (CsA) continues to be a clinical problem that detracts from its obvious benefits as an immunosuppressive agent. Animal models designed to study the problem have generally relied either on chronic administration of high doses of the drug or acute administration of single i.v. doses. The present study establishes a model of CsA nephrotoxicity using doses of the drug comparable to those used in man administered over a time period sufficient for haemodynamic and structural changes to become evident. The technique used measures glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) by the plasma clearance of chromium EDTA and iodohippuran respectively. This has the advantage of allowing sequential measurements in individual animals. Significant impairment of GFR was seen in animals treated 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. Detailed histological examination of the kidneys from these animals also revealed 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 period of administration has relevance to clinic practice. This work provides the basis for further studies which can closely mimic the clinical situation using doses similar to those used for human maintenance immunosuppression.