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中华临床实验室管理电子杂志 ›› 2019, Vol. 07 ›› Issue (03) : 156 -161. doi: 10.3877/cma.j.issn.2095-5820.2019.02.006

所属专题: 文献

实验研究

他克莫司个体内高变异度与肾移植受者移植结局的关系探讨
马建军1, 陈瑶1, 李亚梅1, 白杨娟1, 邹远高1, 唐江涛1,()   
  1. 1. 610041 成都,四川大学华西医院实验医学科免疫实验室
  • 收稿日期:2018-08-02 出版日期:2019-08-28
  • 通信作者: 唐江涛

Relationship between high intra-patient variability of tacrolimus and transplant outcome in renal transplant recipients

Jianjun Ma1, Yao Chen1, Yamei Li1, Yangjuan Bai1, Yuangao Zou1, Jiangtao Tang1,()   

  1. 1. Department of Laboratory Medicine, West China Hospital of Sichuan University, Chengdu 610041, China
  • Received:2018-08-02 Published:2019-08-28
  • Corresponding author: Jiangtao Tang
  • About author:
    Corresponding author: Tang Jiangtao, Email:
引用本文:

马建军, 陈瑶, 李亚梅, 白杨娟, 邹远高, 唐江涛. 他克莫司个体内高变异度与肾移植受者移植结局的关系探讨[J]. 中华临床实验室管理电子杂志, 2019, 07(03): 156-161.

Jianjun Ma, Yao Chen, Yamei Li, Yangjuan Bai, Yuangao Zou, Jiangtao Tang. Relationship between high intra-patient variability of tacrolimus and transplant outcome in renal transplant recipients[J]. Chinese Journal of Clinical Laboratory Management(Electronic Edition), 2019, 07(03): 156-161.

目的

探讨他克莫司(tacrolimus,Tac)个体内变异度(intra-patient variability,IPV)是否与肾移植受者慢性移植物失功密切相关。

方法

选取2009年1月至2016年12月在四川大学华西医院肾移植中心进行肾移植且在术后长期随访的肾移植受者共1167人,用移植后7~12月期间的Tac全血浓度计算得到Tac IPV。设定的结局(含终点)包括:(1)移植物衰竭,再移植,(再)开始透析,或肾小球滤过率(glomerular filtration rate,eGFR)≤15 ml/min,活检证实的急性排斥反应(biopsy-proven acute rejection,BPAR);(2)组织学确定的移植肾小球病;(3)移植后12个月到最后一次随访期间,血清肌酐浓度加倍;(4)最后一次随访。分析不同IPV组肾移植受者肾脏功能差异,生存时间差异以及出现慢性移植物失功的情况。

结果

纳入研究的1167位患者中,有79(6.8%)位到达了移植物失功的终点。肾移植受者移植后7~12月Tac IPV平均值为25.7%;高IPV组移植后第15个月血清肌酐显著高于低IPV组(P<0.05),第15、21、24个月eGFR显著低于低IPV组(P<0.05)。多因素Cox回归分析结果显示:Tac IPV对肾移植预后的预测有一定作用,但并不显著(P=0.051,Harzards ratio:1.015,95%CI:1.000-1.031)。而受者的年龄、性别、移植后6 h的移植物功能,是移植物存活的独立预测因子。

结论

高Tac IPV与肾移植受者移植物失功有一定临床相关性,同时高Tac IPV是预测肾移植受者移植后两年内肾脏功能的重要实验室指标。

Objective

To investigate whether intra-patient variability (IPV) of tacrolimus (Tac) is closely related to chronic graft dysfunction in renal transplant recipients.

Methods

A total of 1167 renal transplant recipients were enrolled in this study. Their surgical operations were carried out during January 2009 and December 2016 in West China Hospital of Sichuan University. Tac IPV was obtained from whole blood during 7 and 12 months after transplantation. Set outcomes (including endpoints) include: (1) graft failure, retransplantation, (re) start dialysis, or glomerular filtration rate (eGFR) less than 15 ml/min, biopsy-proven acute rejection (BPAR); (2) histologically confirmed glomerulopathy; (3)12 months after transplantation to during the last follow-up period, serum creatinine concentration was doubled; (4) the last follow-up. The renal function, survival time and chronic graft failure of renal transplant recipients in different IPV groups were analyzed.

Results

Of the 1167 patients in this study, 79 (6.8%) reached the end point of graft failure. The mean value of Tac IPV in 7~12 months after transplantation was 25.7%. Serum creatinine was significantly higher in 15 months after transplantation in the high IPV group than in the low IPV group (P < 0.05), and eGFR was significantly lower in the 15, 21, 24 months after transplantation in the high IPV group than in the low IPV group (P < 0.05). Multivariate Cox regression analysis showed that Tac IPV had some effect on predicting the prognosis of renal transplantation, but it was not significant (P=0.051, Harzards ratio=1.015, 95%CI: 1.000-1.031). The recipients′ age, sex and graft function at 6 months after transplantation were independent predictors of graft survival.

Conclusion

High Tac IPV is clinically associated with graft failure in renal transplant recipient and is an important medical indicator for predicting renal function in renal transplant recipients within two years after transplantation.

表1 肾移植受者基本临床资料
图1 Tac IPV分布图
图2 低IPV组和高IPV组的Kaplan-Meier生存曲线分析
表2 单因素Cox比例风险回归分析
表3 多因素Cox回归分析
表4 低IPV组和高IPV组进行独立样本t检验
1
Hart A, Smith JM, Skeans MA, et al. OPTN/SRTR 2016 annual data report: kidney[J]. Am J Transplant, 2018,18(Suppl 1):18-113.
2
Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation[J]. Clin Pharmacokinet, 2004,43(10):623-653.
3
Bekersky I, Dressler D, Mekki Q. Effect of time of meal consumption on bioavailability of a single oral 5 mg tacrolimus dose[J]. J Clin Pharmacol, 2001,41(3):289-297.
4
Bekersky I, Dressler D, Mekki QA. Effect of low- and high-fat meals on tacrolimus absorption following 5 mg single oral doses to healthy human subjects[J]. J Clin Pharmacol, 2001,41(2):176-182.
5
Shuker N, van Gelder T, Hesselink DA. Intra-patient variability in tacrolimus exposure: causes, consequences for clinical management[J]. Transplant Rev (Orlando), 2015,29(2):78-84.
6
Pashaee N, Bouamar R, Hesselink DA, et al. CYP3A5 genotype is not related to the intrapatient variability of tacrolimus clearance[J]. Ther Drug Monit, 2011,33(3):369-371.
7
Spierings N, Holt DW, MacPhee IA. CYP3A5 genotype had no impact on intrapatient variability of tacrolimus clearance in renal transplant recipients[J]. Ther Drug Monit, 2013,35(3):328-331.
8
Yong CJ, Jung LY, Bok JS, et al. CYP3A5*3 genotype associated with intrasubject pharmacokinetic variation toward tacrolimus in bioequivalence study[J]. Ther Drug Monit, 2010,32(1):67-72.
9
Tang JT, Andrews LM, van Gelder T, et al. Pharmacogenetic aspects of the use of tacrolimus in renal transplantation: recent developments and ethnic considerations[J]. Expert Opin Drug Metab Toxicol, 2016,12(5):555-565.
10
Borra LC, Roodnat JI, Kal JA, et al. High within-patient variability in the clearance of tacrolimus is a risk factor for poor long-term outcome after kidney transplantation[J]. Nephrol Dial Transplant, 2010,25(8): 2757-2763.
11
Ro H, Min SI, Yang J, et al. Impact of tacrolimus intraindividual variability and CYP3A5 genetic polymorphism on acute rejection in kidney transplantation[J]. Ther Drug Monit, 2012,34(6):680-685.
12
Sapir-Pichhadze R, Wang Y, Famure O, et al. Time-dependent variability in tacrolimus trough blood levels is a risk factor for late kidney transplant failure[J]. Kidney Int, 2014,85(6):1404-1411.
13
Shuker N, Shuker L, van Rosmalen J, et al. A high intrapatient variability in tacrolimus exposure is associated with poor long-term outcome of kidney transplantation[J]. Transpl Int, 2016,29(11):1158-1167.
14
Tullius SG, Tran H, Guleria I, et al. The combination of donor and recipient age is critical in determining host immunoresponsiveness and renal transplant outcome[J]. Ann Surg, 2010,252(4):662-674.
15
Shi YY, Hesselink DA, van Gelder T. Pharmacokinetics and pharmocodynamics of immunosuppressive drugs in elderly kidney transplant recipients[J]. Transplant Rev, 2015,29(4):224-230.
16
Salvadori M, Rosati A, Bock A, et al. Estimated one-year glomerular filtration rate is the best predictor of long-term graft function following renal transplant[J]. Transplantation, 2006,81(2):202-206.
17
Lieber SR, Helcer J, Shemesh E. Monitoring drug adherence[J]. Transplant Rev(Orlando), 2015,29(2):73-77.
18
Takahashi K, Abe R, Usuki S, et al. Safety and efficacy of once-daily modified-release tacrolimus in kidney transplant recipients: interim analysis of multicenter postmarketing surveillance in Japan[J]. Transplant Proc, 2014,46(2):406-410.
19
Stiff F, Stolk LML, Undre N, et al. Lower variability in 24-hour exposure during once-daily compared to twice-daily tacrolimus formulation in kidney transplantation[J]. Transplantation, 2014,97(7):775-780.
20
Shuker N, Cadogan M, van Gelder T, et al. Conversion from twice-daily to once-daily tacrolimus does not reduce intrapatient variability in tacrolimus exposure[J]. Ther Drug Monit, 2015,37(2):262-269.
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