ELECTRON MICROSCOPIC OBSERVATION OF THE NEPHROTOXICITY IN RATS RECEIVING CYCLOSPORINE

Abstract

The objective of this study is to elucidate the mechanism of cyclosporine (CsA) nephrotoxicity based on patho-morphological observations. Six weeks old male Sprague-Dawley rats were used. The animals were divided into 4 groups according to the dose of CsA administered. Group A or B: 100mg or 300mg/kg/day of CsA was given orally for consecutive 3 weeks. group C: 500mg/kg/day was given for consecutive 2 weeks. Group D: no treatment. The animals in group A and B were sacrificed 1, 2 and 3 weeks after the initial administration. To evaluate the recovery process, they were sacrificed 1 and 2 weeks after cessation of the administration. In group D animals were sacrificed 1 and 2 weeks after the initiation. Renal function was evaluated by biochemical parameters, namely, BUN and creatinine. Pathomorphological observations were performed by microscopy, electron microscopy, and electron microscopic histochemistry (ALPase, ATPase). The microscopic observation disclosed focal vacuolation of the epithelium confined to the proximal tubuli but it was rather mild in its severity and the renal function was not impaired significantly. Electron microscopic study showed a possibility that administered CsA was transfered to epithelial cells of the proximal tubuli through two different pathways in the kidney: one was direct absorption from the tubular lumen and the other was transfer from the circulating blood in the interstitial vessels via the basement membrane. As for the organella, vacuolar changes in the intracellular membrane system, mainly endoplasmic reticulum and increased lysosome were considered to have some relationships to the renal dysfunction induced by the agent.