| PurposeThe reaction of renal transplant recipients to Calcineurin Inhibitor is different personaly, CYP3A4(Cytochrome P4503A4)、CYP3A5、ABCB1(ATP binding cassette B1) genetic polymorphisms influence CNI pharmacokinetics. In clinical practice, the blood tacrolimus (Tac) concentration of different individuals is very different. Several studies have reported that the donor and recipient gene polymorphisms play a combined influence on the Pharmacoknetics、kidney graft rejection、 CNI-related Nephrotoxicity. This study Investigated the effects of ABCB1, CYP3A4*1G and CYP3A5*3genetic polymorphisms on FK506trough concentrations in one month after kidney transplantation; investigated the effects of ABCB1, CYP3A4*1G and CYP3A5*3genetic polymorphisms of the recipients on a kidney graft rejection FK506-related Nephrotoxicity. Investigated the association between CYP3A4、CYP3A5、ABCB1genetic polymorphisms of the donors and kidney graft rejection CNI-related Nephrotoxicity. In order to guide treatment individually. MethodsWe Selected62patients who had done kidney transplant operation and use of FK506as a basis for immunotherapy from2003to2011, ABCB1C1236T, G2677T/A, C3435T, CYP3A4*1G, and CYP3A5*3genotypes of the renal recipients were determined by direct sequencing method, and determined the FK506trough concentrations on the3th day、7th day、10th day、14th day、20th day、30th day after transplantation. Retrospective case control study was utilized to identify the association between CYP3A4*1G、 CYP3A5*3、ABCB1genetic polymorphisms of the recipients and FK506trough concentrations early after transplantation; Selected41patients who had done kidney transplant operation and use of FK506as a basis for immunotherapy from2003to2011, ABCB1C1236T, G2677T/A, C3435T, CYP3A4*1G, and CYP3A5*3genotypes of the renal recipients were determined by direct sequencing method, Retrospective case control study was utilized to identify the association between CYP3A5*3、CYP3A4*1G and ABCB1genetic polymorphisms of the renal recipients and kidney graft rejection FK506-related Nephrotoxicity. selected24patients who had done kidney transplant operation and availability of donor whole blood samples from2005to2011, ABCB1C1236T, G2677T/A, C3435T, and CYP3A5*3genotypes of the donor and ABCB1C1236T, G2677T/A, C3435T, and CYP3A5*3genotypes of the renal recipients were determined by direct sequencing method. Retrospective case control study was utilized to identify the association between CYP3A5*3、ABCB1genetic polymorphisms of the donors and kidney graft rejection、CNI-related Nephrotoxicity;Result1、The recipients who received FK506treatment, on the3th day, compared with wild-type homozygote CYP3A5*1*1, the FK506trough concentration (CO) in patients who were CYP3A5*3*3was higher, p=0.000; And CO was higher in CYP3A5*3allele carriers than in CYP3A5*1homozygote, P=0.000. on the7th day, CO in patients who were wild-type homozygote ABCBA11236CC was higher than Heterozygous1236CT, P=0.020; CO in patients who were ABCB12677AT+TT+AA was higher than2677GG and2677AG+TG, P=0.009and0.011; on the10th day, CO and Dose adjusted CO(CO/D) in patients who were ABCB12677AT+TT+AA was higher than2677AG+TG, P=0.004and0.035. CO in patients who were ABCB12677GG was higher than2677AG+TG, P=0.001. on the14th day, CO in patients who were ABCB1G2677T/A GG was higher than2677AG+TG, P=0.048. on the20th day, the CO/D in patients who were CYP3A4*1G HeterozygousAG was higher than wild-type homozygote AA, P=0.017;2、the FK506trough concentration (CO) in patients who carry the linked gene of CYP3A5*3and CYP3A4*1G-GGAG was higher than AAAA on the3th day, P=0.011;The Dose in patients who were GGAG was lower than AAAA on the7th day and the20th day, P=0.040and P=0.020. The Dose in patients who were GGAG was lower than AGAA on the10th day and the14th day, P=0.049and P=0.0153、In the linked genes of CYP3A5*3and CYP3A4*1G, the FK506trough concentration (CO) in patients who carry the GG but without AA was higher than the patients who do not carry the GG on the3th day, P=0.023;4, CYP3A4*1G、CYP3A5*3and ABCB1exon12、21、26genetic polymorphisms of the recipients were not associated with kidney graft rejection、 FK506-related Nephrotoxicity;5、CYP3A5*3and ABCB1exonl2、21、26genetic polymorphisms of the donors were not associated with kidney graft rejection、CNI-related NephrotoxicityConclusionsWe found that when Tacrolimus dosage was no significant difference, CO was higher in CYP3A5*3allele carriers than in CYP3A5*1homozygote. The CO/D in patients who were CYP3A4*1G Heterozygous AG was higher than wild-type homozygote AA. In the linked genes of CYP3A5*3and CYP3A4*1G, CO in patients who carry the GGAG was higher than AAAA; The Dose in patients who were GGAG was lower than AAAA and AGAA. CO in patients who carry the GG but without AA was higher than the patients who do not carry the GG on the3th day. ABCB1C3435T was not associated with the FK506trough concentration. CO and Dose adjusted CO (CO/D) in patients who were ABCB12677AT+TT+AA was higher than2677AG+TG. CO in patients who were ABCB12677AT+TT+AA was higher than2677GG. CO in patients who were ABCB12677GG was higher than2677AG+TG. CO in patients who were wild-type homozygote ABCBA11236CC was higher than Heterozygous1236CT. These results show that CYP3A4、CYP3A5、ABCB1genetic polymorphisms affect the FK506trough concentration (CO), the dose required (D) and Dose adjusted CO (CO/D) in the1month after renal transplantation. So CYP3A4、CYP3A5and ABCBl genetic polymorphisms were helpful to clinic treatment individually. This study demonstrated that CYP3A4*1G、CYP3A5*3and ABCB1C1236T、ABCB1G2677T/A、ABCB1C3435T genetic polymorphisms of donors and recipients were not associated with kidney graft rejection、CNI-related Nephrotoxicity. |
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