NEPHROTOXICITY OF FK-506 IN THE RAT - STUDIES ON GLOMERULAR AND TUBULAR FUNCTION, AND ON THE RELATIONSHIP BETWEEN EFFICACY AND TOXICITY

Recent studies in liver and kidney transplant recipients revealed a ne phrotoxic adverse effect of the new macrolide immunosuppressant FK-506 . Therefore the effect of FK-506 0.1 to 0.8 mg per kg per day was inve stigated in rats using clearance methods including lithium clearance. In rats given FK-506 or placebo during 1 week the nephrotoxicity of FK -506 was characterized by a slight reduction of inulin clearance. The end proximal delivery as measured by the lithium clearance was decreas ed by FK-506. In rats treated for 4 weeks with FK-506 0.8 mg/kg/day th e glomerular filtration rate (GFR) had decreased to 23% of the GFR fou nd in controls (P < 0.001), while end proximal delivery was only 8% of normal. Renal histopathological investigation showed a slight but sta tistically significant increase of tubular basophilia and atrophy in F K-506-treated rats. Skin transplantation studies in the same rat strai n showed a dose-dependent immunosuppressive effect of FK-506. FK-506 0 .8 mg/kg was significantly more immunosuppressive than 0.2 or 0.4 mg/k g, so it was concluded that the lower doses of FK-506 did not fully ex ploit the drug's immunosuppressive potential. Thus in a dosage inside the therapeutic range defined from skin transplantations, FK-506 gener ated a number of toxic effects including a considerable nephrotoxic ef fect. The FK-506 induced changes in glomerular and tubular function wa s a close match to the changes found in cyclosporin A nephrotoxicity. The present study suggests that FK-506 nephrotoxicity is caused by con striction of preglomerular vessels.