[Nephrotoxicity of tacrolimus and preventive effect of diltiazem: experiment with rats].

OBJECTIVE: To study the nephrotoxicity tacrolimus (FK506) at the therapeutic dose the preventive effect of diltiazem (Dil), a calcium antagonist against the FK506-induced pathological changes. METHODS: 24 Sprague-Dawley male rats were randomly divided into 4 equal groups: cyclosporine A (CsA) group, undergoing treatment of CsA at the therapeutic dose after kidney transplantation (25 mg x kg(-1) x d(-1)) for 4 weeks, FK506 group treated with FK506 (0.8 mg x kg(-1) x d(-1)), FK506 + Dil group treated with FK506 (0.8 mg x kg(-1) x d(-1)) and Dil at the dose of 8 mg x kg(-1) x d(-1), and control group. Four weeks later body weight was measured and 24 h urine sample was collected. Then the rats were killed. Their kidneys underwent light and transmission electron microscopy. RESULTS: The body weight ad weight gain, and the weights of both kidney of the CsA group were all significantly lower than those of the other 3 groups (all P < 0.05), and there were not significant differences in there parameters among the other 3 groups. The serum creatinine levels of the FK506 and CsA groups were (36.0 +/- 2.6) and (34.2 +/- 4.5) micromol/L respectively, both significantly higher than those of the FK506 + Dil and control groups [(28.5 +/- 2.1) and (29.2 +/- 3.428) micromol/L respectively, all P < 0.05], however, there was no significant difference between the FK506 + Dil and control groups. The creatinine clearance rate of the FK506 and CsA groups were (0.63 +/- 0.45) and (0.58 +/- 0.39) ml x min(-1) x 100 g(-1) respectively, significantly lower than those of the FK506 + Dil and control groups [(1.55 +/- 0.91) and (1.02 +/- 0.62) mlxmin(-1) x 100 g(-1) respectively, all P < 0.05]. Pathological examination showed epithelial cell cloudy swelling and vacuolization and interstitial fibrosis in the renal tubules, mitochondria swelling and vacuolization in renal tubular epithelial cells, renal arteriole hyalinization, and foot cell conjugation glomerulus, mitochondria swelling and vacuolization in the FK506 and CsA groups, and such changes were relatively mild in the FK506 + Dil group. CONCLUSION: FK506 at renal transplantation therapeutic dose, as well as CsA, induces pathological changes in renal tissues and ultrastructural organization. Dil is able to prevent FK506-induced these pathological changes.

[Prevention of diltiazem in tacrolimus-induced nephrotoxicity: experiment with rats].

OBJECTIVE: To study the nephrotoxicity induced by first oral administration of tacrolimus (FK506) and the prevention of diltiazem (Dil). METHODS: 24 Sprague-Dawley male rats were randomly divided into 4 equal groups: control (n = 6), cyclosporine A (CsA) group (receiving CsA 25 mg.kg(-1).d(-1) so as to develop CsA-induced nephropathy model), FK506 group (receiving FK506 0.8 mg.kg(-1).d(-1), the common renal transplantation therapeutic dose, so as to develop FK506-induced nephropathy model), FK506 + Dil group (receiving CsA 0.8 mg.kg(-1).d(-1) and Dil 8 mg.kg(-1).d(-1)), and control group. Four weeks later body weight was measured, blood samples were collected to examine the creatinine, urea nitrogen, and uric acid, and urine samples were collected to examine the 24 h urine protein, uric acid, and creatinine. Then the rats were killed with their kidneys taken out to undergo histopathological examination. RESULTS: The urine creatinine levels of the CsA and FK506 groups were significantly lower than that of the control group (both P < 0.05), however, there was no significant difference in urine creatinine between the FK506 + Dil group and control group. The blood creatinine levels of both CsA and FK506 groups were significantly higher than those of the FK506 + Dil group and control group (all P < 0.05), however, there was no significant difference in blood creatinine between the FK506 + Dil group and control group. The urea nitrogen level of the CsA group was significantly higher than those of the other 3 groups (all P < 0.05). The creatinine clearance rates of the CsA and FK506 groups were both significantly lower than that of the control group (both P < 0.05), and the creatinine clearance rate of the FK506 + Dil group was between those of the FK506 group and control group, however, with significant differences with both of them. Histopathology examination showed cloudy swelling and vacuolization of the renal tubular epithelial cells in the CsA and FK506 groups. However, the pathological changes of the FK506 + Dil group were remarkably milder in comparison with these 2 groups. CONCLUSION: FK506 and CsA at the renal transplantation therapeutic dose induce nephrotoxicity. Diltiazem prevents FK506-induced nephrotoxicity.