PREVENTION OF CYCLOSPORINE NEPHROTOXICITY WITH A PLATELET-ACTIVATING-FACTOR (PAF) ANTAGONIST

Background. Cyclosporin (CsA) is a potent immunosuppressive drug whose main side-effect is nephrotoxicity. In the kidney, CsA induces vasoco nstriction with a decrease in renal blood flow (RBF) and glomerular fi ltration rate (GFR) and a significant increase in renal vascular resis tance (RVR). CsA enhances platelet-activating factor (PAF) synthesis i n mesangial cells in vitro. PAF, a secondary mediator of anaphylaxis a nd inflammation, exhibits vasoactive properties in the kidney similar to those of CsA. Methods. The in situ autoperfused rat kidney model wa s used to investigate whether PAF plays a role in the haemodynamic inj ury induced by CsA. Results. In this model, CsA (40 mg/kg and 20 mg/kg i.v.) induced a significant decrease in RBF and in GFR and an increas e in RVR. BN 52021, a potent and specific PAF antagonist (20 mg/kg i.v . bolus dose) induced a significant increase in GFR (137 +/- 32% of in itial value, P < 0.05). BN 52021 (20 and 10 mg/kg) also significantly prevented the decline in RBF and GFR induced by CsA. Conclusions. We h ave demonstrated that the PAF antagonist BN 52021 can minimize the alt eration of renal function induced by CsA.