Long-term Cyclosporin Nephrotoxicity in the Rat: Effects on Renal Function and Morphology

Abstract

This long-term study elucidates the development and reversibility of functional and morphological cyclosporin (CsA) nephropathy. Sprague-Dawley rats were given CsA (12.5 or 25 mg/kg per day) for 4, 8 or 16 weeks, or CsA during the first half of the 8- or 16-week period, and vehicle during the second half. Controls were given CsA vehicle throughout the study. Renal function was investigated with clearance methods (inulin, lithium, sodium and potassium). CsA-treated rats developed a focal renal interstitial fibrosis, the severity of which correlated to the accumulated CsA dose given (Kendall's tau = 0.56, P less than 0.0001). This renal lesion was not reversible. CsA reduced GFR and lithium clearance, and increased proximal fractional reabsorption. There was significant correlation (P less than 0.0001) between accumulated CsA dose and severity of functional impairment. Renal function improved following drug withdrawal, but in the compiled material, low-grade nephrotoxicity was evident 4 to 8 weeks after CsA withdrawal: GFR was decreased to 84% (P less than 0.02) of control levels. This indicates that CsA-induced renal focal interstitial fibrosis is progressive during treatment, and is not reversible, while functional CsA nephropathy is progressive but partly reversible if CsA is withdrawn.