THE EFFECT OF CYCLOSPORINE-A ON CATIONIZED BOVINE SERUM ALBUMIN-INDUCED NEPHROPATHY IN NZW RABBITS

The effect of cyclosporin A (CyA) was studied on the morphology and protein excretion of a rabbit chronic serum sickness nephritis using cationized bovine serum albumin (cBSA). One group of rabbits was given intravenous (i.v.) immunizing doses of cBSA and Escherichia coli endotoxin. One week later, these animals began a 6-week i.v. injection schedule of cBSA only. A second group followed the same injection protocol, but was given intramuscular (i.m.) CyA for 3 days prior to the immunizing dose of cBSA/endotoxin and throughout the subsequent cBSA schedule. A third group was given i.m. CyA only. Regular blood samples for CyA levels were taken from animals given the drug. Two 24-h urine samples were obtained from all animals in the study. Analysis of the blood samples showed that immunosuppressive levels of CyA were achieved after two i.m. doses of CyA. These levels were maintained during the course of the schedule. Morphologically, all rabbits completing the cBSA only injection schedule showed evidence of an immune-mediated glomerulopathy with variably severe membranous and endocapillary proliferative change. Less than half the rabbits in the cBSA/CyA group showed any evidence of membranous change. The glomeruli of animals given CyA only were normal. No morphological evidence of CyA toxicity was seen in any animal given the drug. The proteinuria profiles, however, suggested that as well as reducing protein excretion in rabbits given cBSA, CyA may interact with the immunizing dose of cBSA to produce an early, reversible, nephrotoxic effect. These results show that (a) immunosuppressive levels of CyA can be efficiently obtained and maintained by the i.m. route, (b) commencing CyA treatment before initiating cBSA injections ameliorates cBSA glomerulopathy in the majority of rabbits tested, and (c) using this protocol, no significant CyA-induced morphological effects are seen.