The Relationship Between FK506 Metabolic Rate And Early BK Virus Infection After Kidney Transplantation

Objective:To evaluate the correlation between the FK506 metabolic rate and BK virus infection early after kidney transplantation.In order to guide the prevention of BK virus infection after kidney transplantation one step further.Methods:From March 2017 to August 2017,patients undergoing allograft kidney transplantation in ward Ⅱ of department of urology of 309th hospital of PLA were selected as the subjects.According to inclusion and exclusion criteria,appropriate cases were selected,in whom the CYP3A5 gene polymorphisms were detected.Then the included cases were divided into"fast metabolism group"(genotype CYP3A5*1/*3,CYP3A5*1/*1)and "slow metabolism group"(genotype CYP3A5*3/*3)according to the results of gene detection.The clinical data of patients were collected including preoperative record of demographic data,perioperative period clinical data,follow-up monitoring indicators,BK virus infection(BK viruria,BK viremia,BKVN),FK506 drug concentration and the oral dose of tacrolimus,and then the metabolic rate of FK506(concentration/dose ratio,C/D value)was calculated according to the formula.Follow-up was carried out monthly in a total of 6 months period.Results:A total of 80 patients were enrolled in this study.The mutation rate of CYP3A5*3 allelic gene is 73.1%."Fast metabolism group"(CYP3A5*1/*1,CYP3A5*1/*3)had 38 cases and"Slow metabolism group"(CYP3A5*3/*3)had 42 cases.There was no statistical significance between the two groups on age,gender,height,weight,BMI,donor type and immune induction regime.FK506 blood trough concentration between "Fast metabolism group" and "slow metabolism group" has no statistical difference within 6 months after transplantation.But monthly tacrolimus daily dose and C/D value have significant difference between both groups(P<0.01).The average C/D value of the fast metabolism group is 1.26(0.73-2.21),which of the slow metabolism group is 2.24(1.18-4.37).In addition,two group of average C/D value shows normal distribution by Kolmogorov-Smirnov test(fast metabolism of group P=0.15,slow metabolism group P=0.12).Thus,"fast metabolism group" C/D value = 1.31 + 0.36,and "slow metabolism group" C/D value = 2.18 + 0.71.Try to use the midpoint of two sets of data as the demarcation of the metabolic rate of FK506(C/D value =1.745).Compare this new method with CYP3A5 genotype on the efficacy in distinguishing population on FK506 metabolism rate.McNemar test shows that there is no significant difference between the two methods(P=0.17),and Kappa=0.528(P<0.001)suggests a moderate consistency of the two methods.The incidence of BK virus related events are as follows:BK viruria 26 cases(32.5%),BK viremia 8 cases(10%),BKVN 1 case(1.3%).In "fast metabolism group",BK viruria 14 cases(36.8%),BK viremia 7 cases(18.4%),BKVN 1 case(2.6%);in "slow metabolism group",BK viruria 12 cases(28.6%),BK viremia 1 case(2.4%),no BKVN.The incidence of BK viremia of "fast metabolic group" was significantly higher than that of the "slow metabolic group"(P=0.02).The incidence of BK viruria and BKVN of two groups has no significant difference in statistics.The incidence of complications within 6 months after transplantation are as follows:DGF 17 cases(21.3%),AR 17 cases(21.3%),FK506 renal toxicity 12 cases(15%),FK506 neurotoxicity 18 cases(22.5%),NOD AT 18 cases(22.5%),pulmonary infection 18 cases(22.5%),urinary tract infection 22 cases(27.5%).The incidence of FK506 nephrotoxicity between tow groups has significant difference by Chi square test(P=0.02).If all subjects enrolled are divided into FK506 fast and slow metabolic by C/D values(C/D value =1.745),there is no significant difference on the incidence of all complications after renal transplantation(P>0.05).Univariate and multiple Logistic regression analysis reveal two factors on BK viruria incidence which have statistical significance:ATG(OR=4.84,95%CI induced by 1.12-20.82,P=0.03)and the urinary tract infection(OR= 0.28,95%CI 0.08-0.95,P=0.04).CONCLUSIONS:1.With similar FK506 concentration,the dosage of tacrolimus in genotype CYP3A5*1/*1 and CYP3A5*1/*3 group was significantly higher than that in CYP3A5*3/*3 group at 1-6 months after renal transplantation,and C/D value of genotype CYP3A5*1/*1 and CYP3A5*1/*3 group was significantly lower than that of CYP3A5*3/*3 group.2.C/D value can be used as a simple and practical tool to distinguish the population of different FK506 metabolism rate(C/D<1.745 as fast metabolism,C/D>1.745as slow metabolism).However,its clinical value remains to be verified.3.Detection of CYP3A5 genotype before operation or calculation of "C/D value" early after operation can help doctors identify high-risk patients,and take corresponding intervention to prevent BKV infection and improve the survival rate of renal allograft.4.The incidence of FK506 nephrotoxicity in FK506 slow metabolism group(genotype CYP3A5*3/*3)was significantly higher than that in fast metabolism group(genotype CYP3A5*1/*3,CYP3A5*1/*1)within 6 months after renal transplantation.5.ATG regimen is an independent risk factor for BK virus infection after renal transplantation.Urinary tract infection within 6 months after renal transplantation is an independent protective factor for BK viruria after renal transplantation.