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American Journal of Pathology, Vol 127, 569-579, Copyright © 1987 by American Society for Investigative Pathology

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Renal injury induced by long-term administration of cyclosporin A to rats

T Bertani, N Perico, M Abbate, C Battaglia and G Remuzzi

Chronic administration of cyclosporin A (CyA) to animals and humans results in renal damage characterized by tubulointerstitial lesions and renal insufficiency. This nephrotoxicity limits the use of CyA in the management of graft rejection. Despite recent investigations in this area, relatively few studies correlate structural and functional abnormalities in animals undergoing long-term CyA treatment. The authors therefore treated 30 rats with CyA at the dose of 40 mg/kg/48 hr for up to 5 months. An additional group of 30 rats was given the vehicle alone and was considered as a control group. Renal morphology and function were studied. For evaluation of the effect of drug withdrawal, a third group of 25 animals received CyA for 3 months and was followed for another 2 additional months after drug withdrawal. The results show that the chronic administration of CyA to rats induced complex renal morphologic changes, associated with renal insufficiency, polyuria, and enhanced sodium excretion. Withdrawal of the drug resulted in almost complete normalization of morphologic and functional parameters. The early morphologic expression of CyA nephrotoxicity was isometric vacuolization and loss of brush border involving the proximal tubular cells, followed by a peculiar lesion in distal tubular cells due to glycogen accumulation. Glomerular and interstitial damage was mild and appeared only after 3 months of CyA administration. No vascular abnormalities were found in rats treated with CyA for 5 months. A CyA-induced decrease in the glomerular filtration rate (GFR) correlates with brush border loss but not with isometric vacuolization. The distal tubular glycogen accumulation was associated with the development of polyuria and enhanced sodium excretion. Given the high blood sugar level and severe glycosuria in animals treated chronically with CyA, it is also concluded that CyA possesses a diabetogenic effect which is likely to be responsible for glycogen accumulation at the tubular level.