[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.


CONCLUSIONS
FK506 and CsA at the renal transplantation therapeutic dose induce nephrotoxicity. Diltiazem prevents FK506-induced nephrotoxicity.
Chen
Ye-Hui
YH
Department of Urology, First Municipal People's Hospital of Guangzhou, Guangzhou 510180, China.
Liang
Yan-Xiao
YX
Chen
Lin-Qiang
LQ
Liang
Jian-Jian
JJ
Zhang
Jing
J
Qiu
Jiang
J
Li
Wei-Long
WL
Hu
Jian-Bo
JB
Xie
Ke-Ji
KJ
Zhong
Wei-de
WD
Chen
Li-Zhong
LZ
Zheng
Ke-Li
KL
D000818:Animals; D003401:Creatine / Q000097:blood / Q000652:urine; D016572:Cyclosporine / Q000633:toxicity; D004110:Diltiazem / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000517:prevention & control*; D016030:Kidney Transplantation; D008297:Male; D011184:Postoperative Period; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D016559:Tacrolimus / Q000633:toxicity*
D016572:Cyclosporine; D004110:Diltiazem; D003401:Creatine; D016559:Tacrolimus