Effect Of CYP3A5 Gene Polymorphism On Tacrolimus Metabolism And Prognosis In Renal Transplant Recipients

Objective:Objective to explore the effect of CYP3A5 gene polymorphism on tacrolimus metabolism in renal transplant recipients,and analyze the differences of liver and kidney function,renal biopsy,blood glucose level,hemoglobin and adverse events in patients with different CYP3A5 genotypes after renal transplantation.Methods:According to the inclusion and exclusion criteria,152 renal transplant recipients who underwent renal allografts in the second Department of Urology,the first hospital of Jilin University from January 1,2016 to December 31,2018 were selected and divided into CYP3A5*1 expression group（CYP3A5*1/*1,CYP3A5*1/*3,28 cases in total）and CYP3A5*1 non expression group（CYP3A5*3/*3,124 cases in total）.The general clinical data,follow-up period（2 weeks,1 month,3 months,6 months,1 year and 2 years）of tacrolimus,concentration dose ratio（C₀/D value）,liver and kidney function,pathological type of renal biopsy,postoperative urinary tract infection and pulmonary infection were compared and analyzed.Results:Among the 152 kidney transplant recipients included,30 were living donor transplants from relatives and 122 were DCD transplants.There were 52 females（34.21%）.The average age is 43.90±10.81 years old,and the average weight is 65.51±12.02kg.Recipients were grouped according to the expression of CYP3A5,and the basic preoperative data of the two groups of CYP3A5*1 expression group（AA,AG）and non-expression group（GG）were analyzed.The results showed that there was no statistical difference in the basic characteristics between the two groups.The genotypes of the recipients were in accordance with Hardy Weinberg test（P=0.719）.The C₀/D value of tacrolimus(unit:ng·ml^-1mg^-1·kg·d)in CYP3A5*1 expressers at each follow-up time point were 80.21（56.78,112.05）,78.95（71.61,125.91）,109.73（83.36,159.70）,115.70（86.70,141.19）,105.54（84.56,158.12）,102.50（80.23,122.40）respectively,which were significantly lower than those in CYP3A5*1 non-expressers of 115.80（83.49,157.99）,130.61（100.65,164.71）,163.65（122.84,219.45）,155.91（124.50,214.43）,169.96（123.60,242.55）,176.86（128.29,243.98）（P<0.01）.The daily dose of tacrolimus(unit:mg^-1·kg·d)in the CYP3A5*1 expressers was 0.111（0.090,0.138）,0.104（0.078,0.136）,0.077（0.059,0.098）,0.064（0.043,0.077）,0.060（0.041,0.075）,0.053（0.040,0.063）respectively,which were significantly lower than 0.093（0.071,0.111）,0.082（0.065,0.101）,0.055（0.044,0.069）,0.045（0.036,0.057）,0.037（0.029,0.051）,0.034（0.026,0.045）in CYP3A5*1 non-expressers（P<0.01）.At the first month and the second year after operation,the trough concentration of tacrolimus in CYP3A5*1 expressers（unit:ng/ml）was 9.35±1.78 and 5.17±0.92,which was significantly lower than that in CYP3A5*1 non-expressers（10.90±3.06 and 6.20±1.72,P<0.01）.At other follow-up time points,there was no significant difference between the two groups（P>0.05）.There was no significant difference between the two groups in preoperative general information,serum creatinine,ALT,AST,hemoglobin,blood glucose level,pathological type of renal biopsy and postoperative complications（P>0.05）.Conclusions:（1）CYP3A5 gene polymorphism has a significant effect on tacrolimus metabolism in renal transplant recipients.（2）Compared with those without CYP3A5*1 expression,those with CYP3A5*1expression need higher dosage of tacrolimus to reach the target concentration.（3）CYP3A5 gene polymorphism had no significant effect on liver and kidney function,blood glucose level,graft rejection,graft survival and adverse events.