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Nephrotoxicity of FK-506 in the rat. Studies on glomerular and tubular function, and on the relationship between
F T Nielsen1, P P Leyssac, E Kemp
1Laboratory of Nephropathology, Odense University Hospital, Denmark.
Abstract:
Recent studies in liver and kidney transplant recipients revealed a nephrotoxic 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 investigated 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 decreased by FK-506. In rats treated for 4 weeks with FK-506 0.8 mg/kg/day the glomerular filtration rate (GFR) had decreased to 23% of the GFR found in controls (P < 0.001), while end proximal delivery was only 8% of normal. Renal histopathological investigation showed a slight but statistically significant increase of tubular basophilia and atrophy in FK-506-treated rats. Skin transplantation studies in the same rat strain 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/kg, so it was concluded that the lower doses of FK-506 did not fully exploit the drug's immunosuppressive potential. Thus in a dosage inside the therapeutic range defined from skin transplantations, FK-506 generated a number of toxic effects including a considerable nephrotoxic effect. The FK-506 induced changes in glomerular and tubular function was a close match to the changes found in cyclosporin A nephrotoxicity. The present study suggests that FK-506 nephrotoxicity is caused by constriction of preglomerular vessels.
Insights
The immunosuppressant FK-506 (tacrolimus) causes kidney damage in rats, similar to cyclosporine A. Lower doses showed less immunosuppression but still induced nephrotoxicity, suggesting preglomerular vessel constriction.
Area of Science:
- Nephrology
- Pharmacology
- Transplantation Immunology
Background:
- Macrolide immunosuppressant FK-506 (tacrolimus) has shown nephrotoxic effects in transplant recipients.
- Understanding FK-506's renal impact is crucial for optimizing immunosuppressive therapy.
Purpose of the Study:
- To investigate the dose-dependent nephrotoxic and immunosuppressive effects of FK-506 in a rat model.
- To compare FK-506's nephrotoxicity with that of cyclosporine A.
Main Methods:
- Rats were administered FK-506 (0.1-0.8 mg/kg/day) or placebo for 1 or 4 weeks.
- Renal function was assessed using clearance methods, including inulin and lithium clearance.
- Glomerular filtration rate (GFR) and end proximal delivery were measured.
- Renal histopathology and skin transplantation assays were performed.
Main Results:
- FK-506 administration led to reduced inulin clearance and end proximal delivery.
- A 4-week treatment with FK-506 (0.8 mg/kg) significantly decreased GFR to 23% of control levels.
- Histopathology revealed tubular basophilia and atrophy in FK-506-treated rats.
- FK-506 demonstrated dose-dependent immunosuppression, with higher doses being more effective.
Conclusions:
- FK-506 exhibits significant nephrotoxicity within its therapeutic immunosuppressive range.
- The observed renal functional and histological changes closely resemble cyclosporine A nephrotoxicity.
- The study suggests FK-506-induced nephrotoxicity may result from preglomerular vascular constriction.