Effect Of CYP3A5 And MDR1 Gene Polymorphisms On The Dose And Efficacy Of Tacrolimus In Patients With Membranous Nephropathy

Objective:This study was to investigate the effect of CYP3A5 and MDR1 gene polymorphisms on the dose and efficacy of tacrolimus in patients with primary membranous nephropathy.Research objects and methods:Adopt the method of retrospective analysis,this study included 53 patients with nephrotic syndrome from the Department of Nephrology,Shandong Provincial Hospital from February to December 2016.All of them have been confirmed by renal biopsy,the pathological type is Primary membranous nephropathy.After diagnosis,patients were treated with tacrolimus and glucocorticoid.The clinical efficacy of tacrolimus for more than 6 months was evaluated based on clinical parameters such as renal function,serum albumin,and 24-hour urine protein quantitation.Tacrolimus needs to be taken for more than 6 months,and the use of tacrolimus will be terminated in patients who have not achieved complete or partial remission or have serious adverse reactions after 6 months.During the treatment,the whole blood trough concentration of tacrolimus was maintained at 5～10ng/ml.The CYP3A5 and MDR1 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism(PCR-RELP).The counting data were tested by kruskal-wallis test.One-way analysis of variance was used to analyze the effect of CYP3A5 and MDR1C1236T gene polymorphism on tacrolimus whole blood trough concentration/dose ratio(C0/D).Logistic regression analysis was used to analyze the effect of CYP3A5 and MDR1C1236T gene polymorphisms on the clinical efficacy of tacrolimus in patients with primary membranous nephropathy.Results:Of the 53 patients with primary nephrotic syndrome,for CYP3A5,there were 2,22 and 29 cases with*1/*1,*11/*3 and*3/*3 genotype,respectively,the CYP3A5*3 allele frequency was 75.47%.For MDR C1236T,there were 13,30,and 10 cases with CC,CT and TT genotype,respectively,the frequency of T allele was 47.17%.There was no statistically significant difference in total response rate and complete response rate between CYP3A5*1/*1 and*1/*3 genotypes compared with CYP3A5*3/*3 genotype[(50%,77.27%,79.31%),(50%,50%,48.3%),P>0.05].The CYP3A5*1/*1 and*1/*3 genotypes of C0/D ratio were significantly lower than the CYP3A5*3/*3 genotype(21.47±8.63,24.88±7.98,44.38±10.23 ng/L/mg/(kg d),P<0.01),however,the daily dose of tacrolimus was higher than the CYP3A5*3/*3 genotype(4.88±0.63,4.17±1.02,2.15±1.19 mg/d).There was no significant difference in the total remission rate and complete remission rate between the MDR1C1236T CC,CT and TT genotypes[(69.2%,76.7%,90%),(38.5%,50.0%,60.0%),P>0.05].There was no significant difference in C0/D ratio between CC,CT and TT genotypes(25.69±9.04,22.91±10.42,28.82±11.17ng/L/mg/(kg·d),P>0.05).Logistic regression analysis showed that MDR1C1236T,TT genotype could improve clinical outcome(P=0.021,OR=7.14,95%CI 1.435-89.683),whereas CC and CT genotypes did not.As for CYP3A5genotypes,it did not directly affect the clinical efficacy of tacrolimus(P= 0.377,OR=2.584,95%CI 0.234-31.87).Conclusion and significance:The CYP3A5*1/*1 and*1/*3 genotypes C0/D were significantly lower than the CYP3A5*3/*3 genotype,requiring a higher daily dose of tacrolimus to maintain the whole blood trough concentration.The MDR1C1236T gene polymorphism had no statistically significant effect on the blood concentration of tacrolimus,but the TT genotype could improve the clinical therapeutic effect.The MDR1C1236T genotype may be the clinical effect of tacrolimus in patients with primary membranous nephropathy.Defining CYP3A5 and MDR1 genotypes before treatment with tacrolimus in patients with primary membranous nephropathy can more accurately guide clinical individualized treatment,thus minimizing the risk of insufficient or excessive inhibition of immunosuppression.