FUNCTIONAL AND STRUCTURAL CHARACTERISTICS OF EXPERIMENTAL FK 506 NEPHROTOXICITY

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Abstract
SUMMARY: 1. FK 506 (Tacrolimus, Prograf®) is a novel Immunosuppressant which is effective in solid organ transplantation and autoimmune diseases. The lack of a suitable animal model has hindered the study of the nephrotoxicity of the drug which has emerged as a common adverse effect in clinical trials. We report both acute and chronic nephrotoxicity with tacrolimus (FK) in which renal structure and function are worsened by sodium depletion.2. Pair fed male Sprague‐Dawley rats were given FK (3 or 6 mg/kg, p.o.) or vehicle for 7, 21 and 42 days on low salt or normal diet. The FK whole blood trough levels achieved (3–10ng/mL) were similar to those observed in FK treated transplant patients.3. In salt depleted animals treated for 7 days, FK (6 mg/kg) decreased renal blood flow and glomerular filtration rate (1.8 ± 0.1 and 0.2 ± 0.1 mL/min per 100g vs 2.9 ± 0.2 and 1.1 ± 0.1 mL/min per 100 g in the vehicle group, Pvs 30 ± 4 ng AI/mL per h in the vehicle group, P< 0.05). Animals given normal salt diets did not develop significant histological lesions even up to 42 days.6. Sodium depletion is critical for the development of FK induced progressive striped tubulointerstitial fibrosis associated with an increase in PRA. These data suggest a role for the renin‐angiotensin system in the pathogenesis of functional and structural changes of chronic FK nephrotoxicity.