Abstract:

Objective To investigate the effect of polymorphisms of CYP3A5 gene mutation on the metabolism of tacrolimus in renal transplantation recipients after surgery，and to compare the differences in followup parameters of patients with different metabolic function genotypes after kidney transplantation. Methods The recipients who received allograft kidney transplantation from January 2016 to December 2018 were selectedconsecutively，and the data of each follow-up in the perioperative period of kidney transplantation and the electronicmedical record system after the operation were sorted out，mainly including the general information before the operation，the dose of tacrolimus taken at each follow-up time point（the second week，one month，three months，six months，one year and two years after the operation），the concentration-dose ratio，liver and kidney functionpostoperative complications. CYP3A5 genotype was determined by PCR-SSP method before surgery，and kidney transplant recipients were divided into CYP3A5*1 expression group（AA，AG，28 cases in total）and CYP3A5*1 non-expression group（GG，124 cases in total）according to different genotypes. The differences of clinical indicators between the two groups during the follow-up period were compared and systematically analyzed. Results In this study，a total of 152 recipients of kidney transplantation were included according to the above criteria，including 30 recipients of living donor transplants from relatives and 122 recipients of DCD transplants. There were 52 females（34.21%）with an average age of（43.90±10.81）years and an average weight of（65.51±12.02）kg. Patients were divided into groups according to the difference of CYP3A5 expression，and the preoperative basic data 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 demographic clinical characteristics between the two groups. The C0/D value of tacrolimus in the CYP3A5*1 expression group was significantly lower than that in the CYP3A5*1 non-expression group at week 2，month 1，3，6，year 1 and year 2 after renal transplantation（P ＜ 0.01）. Thedaily tacrolimus dose of the CYP3A5*1 expression group was also significantly lower than that of the CYP3A5*1non-expression group at each of the above follow-up time points（P ＜ 0.01）. At the 1st month and 2nd year of follow-up after kidney transplantation，the serum trough concentration of tacrolimus in CYP3A5*1 expression group was significantly lower than that in CYP3A5*1 non-expression group（P ＜ 0.01）. There was no significant difference in blood tacrolimus concentration between the two groups at the follow-up time points of 2 weeks，3 months，6 months and 1 year（P ＞ 0.05）. There were no significant differences in serum creatinine，transaminase，hemoglobin， blood glucose levels，renal biopsy pathological types and postoperative complications between the two groups at each follow-up time point（P ＞ 0.05）. Conclusion Compared with CYP3A5*1 non-expression group，patients in CYP3A5*1 expression group metabolized tacrolimus faster after taking tacrolimus，and higher tacrolimus dose is usually required to reach the target blood concentration range after transplantation. The differences of CYP3A5 gene polymorphism among different renal transplant recipients have no significant negative effects on postoperative liver and kidney function，blood glucose level，graft rejection，graft survival and adverse events. 

Key words:

CYP3A5, Kidney transplantation, Tacrolimus, Gene polymorphism

摘要：

目的 探讨 CYP3A5 基因突变后产生的多态性对肾移植受者术后他克莫司在体内代谢的影响，同时比较携带不同代谢功能基因型患者在肾移植术后随访指标的差异。方法 连续选取 2016 年1 月至 2018 年 12 月 3 年间接受同种异体肾移植术的受者，分类整理其肾移植的围术期以及术后的电子病历系统中的每次随访数据资料，主要包括术前的一般资料、各个随访时间点（术后第 2 周、1 个月、3 个月、6 个月、1 年和 2 年）服用他克莫司的剂量情况、浓度剂量比值、肝肾功能、术后并发症等资料。术前通过 PCR-SSP 法测定患者 CYP3A5 基因型，根据基因型的不同将受者分为 CYP3A5*1 表达组（即 AA、 AG，共 28 例）与 CYP3A5*1 非表达组（即 GG，共 124 例）。 比较并系统分析两组研究人群在随访期内各项临床指标的区别。结果 在本研究中，根据上述标准，共纳入肾移植受者 152 例，其中亲属捐献来源的活体移植 30 例，DCD 移植 122 例。 女性 52例（34.21%），平均年龄为（43.90±10.81）岁，平均体重为（65.51±12.02）kg。 依照患者的 CYP3A5 表达分型差异进行分组，分析两组研究人群的术前基本资料， 结果显示两组的基本临床特征无统计学差异。 在不同随访时间点，CYP3A5*1 表达组的患者的他克莫司C0/D 值均显著低于 CYP3A5*1 非表达组（P ＜ 0.01）。并且，单日他克莫司剂量亦显著低于 CYP3A5*1 非表达组（P ＜ 0.01）。 在肾移植术后随访的第 1 个月、第 2 年，CYP3A5*1 表达组的他克莫司血药谷浓度的水平显著低于 CYP3A5*1 非表达组（P ＜ 0.01）；而在术后第 2 周、3 个月、6 个月、1 年这 4 个随访时间点，两组他克莫司血药浓度无统计学差异（P ＞ 0.05）。两组受者的肝肾功、血红蛋白、血糖水平及随访期内的并发症无显著统计学差异（P ＞ 0.05）。结论 与CYP3A5*1 非表达组相比，CYP3A5*1 表达组患者对他克莫司的代谢更快，不同肾移植受者 CYP3A5 基因多态性的差异对术后并发症以及不良事件的发生无明显消极作用。 

关键词:

细胞色素 P450 酶系 3A5 , 肾移植 , 他克莫司 , 基因多态性 ,