[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.


CONCLUSIONS
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.
Chen
Ye-Hui
YH
Department of Urology, First Municipal People's Hospital of Guangzhou, Guangzhou 510180, China. cyhly@163.com
Liang
Yan-Xiao
YX
Chen
Lin-Qiang
LQ
Lu
Yan-Meng
YM
Liang
Jian-Jian
JJ
Zhang
Jing
J
Qiu
Jiang
J
Xie
Ke-Ji
KJ
Hu
Jian-Bo
JB
Zhong
Wei-de
WD
Wang
Bin
B
Chen
Li-Zhong
LZ
Zheng
Ke-Li
KL
D000818:Animals; D004110:Diltiazem / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology* / Q000648:ultrastructure; D016030:Kidney Transplantation; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D016559:Tacrolimus / Q000633:toxicity*
D004110:Diltiazem; D016559:Tacrolimus