Relevant research between high intrapatient variability in tacrolimus and immune-mediated graft injury after liver transplantation

doi:10.3877/cma.j.issn.1674-3903.2022.02.001

Abstract

Abstract:

Objective

To investigate whether intrapatient variability (IPV) of tacrolimus was closely related to immune-mediated graft injury in liver transplant recipients.

Methods

A retrospective cohort study was conducted in 288 patients who underwent classical orthotopic liver transplantation in the Liver Transplantation Center of the First Affiliated Hospital of Xi'an Jiaotong University from January 2015 to December 2019. Tacrolimus IPV was calculated from at least 5 tacrolimus trough samples obtained between months 2 and 6 after liver transplantation and expressed as the coefficient of variation (CV). The composite endpoints included: ①Immune-mediated graft injury 6 months after liver transplantation, including chronic rejection and late acute rejection proven by biopsy; ②Liver function injury caused by the toxic effects of immunosuppressants 6 months after liver transplantation; ③Cytomegalovirus (CMV) viremia 6 months after liver transplantation. The recipients were divided into the low CV group and the high CV group with the mean value of CV as the critical value. The proportion of recipients reaching the composite endpoints were compared between the two groups, and the influencing factors of immune-mediated graft injury after liver transplantation were analyzed. Normal distribution measurement data shown in the form of (±s) were compared by independent sample t test. Nonnormally distributed measurement data shown in the form of median (full distance) were compared by Mann-Whitney U test. Count data shown in the form of percentage were compared with Chi-square test. The Kaplan-Meier method was used to plot the survival curve, and the log-rank test was used for comparison. Cox proportional hazard model was used to analyze the risk factors of immune-mediated graft injury after liver transplantation, and variables with P≤0.20 in univariate analysis were analyzed by step-back method for multivariate analysis. P<0.05 for difference was considered statistically significant.

Results

As of June 30, 2021, the 288 liver transplant recipients were included in the study, the follow-up ranged from 6 to 76 months, with an average of (37±16) months. And 37/288 (12.85%) patients reached the composite endpoint. The CV from 2 to 6 months after liver transplantation was normally distributed, and the average value of CV was (28.11±10.72)%. The average value of CV was used as the critical value to construct the low CV group (CV<28.11%) and high CV group (CV≥28.11%). No statistically significant differences in age and sex of donors, and age, sex, body mass index, primary disease, preoperative model score of end-stage liver disease, preoperative Child-Pugh score, postoperative immunosuppressive treatment protocol, incidence rate of chronic rejection of recipients, and tacrolimus C0, total bilirubin and ALT within 2 to 6 months after liver transplantation between the two groups (all P>0.05). However, the incidence rates of late acute rejection (3.13% vs. 0, P<0.05) and CMV viremia (5.47% vs. 1.25%, P<0.05) were higher in the high CV group than that in the low CV group; the proportion of liver transplant recipients reaching the composite endpoints was higher in the high CV group than that in the low CV group [18.0% (23/128) vs. 8.8% (14/160), χ²=5.397, P<0.05]. It showed that the time of liver transplant recipients reaching the composite endpoint in high CV group was less than that in low CV group [(1764±72) d vs. (1909±51) d, χ²=6.367, P<0.05)]. Cox proportional hazard model analysis showed that donor age, pre-transplant Child-Pugh score of recipients, total bilirubin and tacrolimus CV within 2 to 6 months after liver transplantation were independent risk factors for immune-mediated graft injury (HR=1.034, 2.353, 1.011 and 0.450, all P<0.05).

Conclusions

The high tacrolimus IPV (CV≥28.11%) within 2 to 6 months after liver transplantation was significantly associated with immune-mediated graft injury after liver transplantation. And, the high tacrolimus IPV exposure may lead to the increased incidence of late acute rejection and CMV viremia.

Key words: Tacrolimus, Intrapatient variability, Coefficient of variation, Liver transplant, Acute rejection, Cytomegalovirus viremia, Graft injury

Min Tian, Bo Wang, Xuemin Liu, Xiaogang Zhang, Kun Guo, Yu Li, Liangshuo Hu, Jinxia Huo, Yi Lyu. Relevant research between high intrapatient variability in tacrolimus and immune-mediated graft injury after liver transplantation[J]. Chinese Journal of Transplantation(Electronic Edition), 2022, 16(02): 65-71.

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URL: https://zhyzzz.cma-cmc.com.cn/EN/10.3877/cma.j.issn.1674-3903.2022.02.001

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References 30

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组别	例数	年龄(岁，±s)	男性[例(%)]	体质指数(kg/m²，±s)	恶性原发病[例(%)]	术前MELD评分(分，±s)	术前Child-Pugh评分(分，±s)
低CV组	160	46±10	121(75.6)	23±4	45(28.1)	19±9	10.0±2.0
高CV组	128	48± 9	97(75.8)	22±4	47(36.7)	18±9	10.1±1.9
t/χ²值	-	1.410	0.001	0.909	2.416	0.158	0.440
P值	-	>0.05	>0.05	>0.05	>0.05	>0.05	>0.05
组别	例数	术后2~6个月			免疫抑制维持方案为他克莫司+MMF[例(%)]	急性排斥反应[例(%)]	慢性排斥反应[例(%)]	CMV血症[例(%)]
组别	例数	他克莫司C0(ng/mL，±s)	总胆红素[μmol/L，M(min，max)]	ALT(U/L，±s)	免疫抑制维持方案为他克莫司+MMF[例(%)]	急性排斥反应[例(%)]	慢性排斥反应[例(%)]	CMV血症[例(%)]
低CV组	160	6.8±1.0	16.7(1.8, 212.6)	42.5±31.2	147(91.9)	0	1(0.6)	2(1.2)
高CV组	128	6.9±1.2	18.3(4.2，311.0)	47.0±42.7	119(93.0)	4(3.1)	1(0.8)	7(5.5)
t/U/χ²值	-	-1.027	9618	-0.992	0.120	5.070	0.025	4.181
P值	-	>0.05	>0.05	>0.05	>0.05	<0.05	>0.05	<0.05

组别	例数	年龄(岁，±s)	男性[例(%)]	体质指数(kg/m²，±s)	恶性原发病[例(%)]	术前MELD评分(分，±s)	术前Child-Pugh评分(分，±s)
低CV组	160	46±10	121(75.6)	23±4	45(28.1)	19±9	10.0±2.0
高CV组	128	48± 9	97(75.8)	22±4	47(36.7)	18±9	10.1±1.9
t/χ²值	-	1.410	0.001	0.909	2.416	0.158	0.440
P值	-	>0.05	>0.05	>0.05	>0.05	>0.05	>0.05
组别	例数	术后2~6个月			免疫抑制维持方案为他克莫司+MMF[例(%)]	急性排斥反应[例(%)]	慢性排斥反应[例(%)]	CMV血症[例(%)]
组别	例数	他克莫司C0(ng/mL，±s)	总胆红素[μmol/L，M(min，max)]	ALT(U/L，±s)	免疫抑制维持方案为他克莫司+MMF[例(%)]	急性排斥反应[例(%)]	慢性排斥反应[例(%)]	CMV血症[例(%)]
低CV组	160	6.8±1.0	16.7(1.8, 212.6)	42.5±31.2	147(91.9)	0	1(0.6)	2(1.2)
高CV组	128	6.9±1.2	18.3(4.2，311.0)	47.0±42.7	119(93.0)	4(3.1)	1(0.8)	7(5.5)
t/U/χ²值	-	-1.027	9618	-0.992	0.120	5.070	0.025	4.181
P值	-	>0.05	>0.05	>0.05	>0.05	<0.05	>0.05	<0.05

变量		单因素分析			多因素分析
变量		HR值	95%可信区间	P值	HR值	95%可信区间	P值
供者年龄(岁)		1.034	1.004~1.064	<0.05	1.033	1.004~1.063	<0.05
受者年龄(岁)		1.000	0.962~1.039	>0.05	-	-	-
受者体质指数(kg/m²)		1.074	0.980~1.176	>0.05	1.072	0.980~1.171	>0.05
受者肝移植前MELD评分		1.014	0.962~1.068	>0.05	-	-	-
受者肝移植前Child-Pugh评分(分)
	<10	1.000			1.000
	≥10	3.092	1.164~8.212	<0.05	2.353	1.169~4.739	<0.05
受者原发病性质
	良性	1.000			1.000
	恶性	2.127	0.933~4.848	>0.05	1.918	0.863~4.266	>0.05
肝移植术后2~6个月他克莫司血药浓度CV
	≥28.11%	1.000			1.000
	<28.11%	0.422	0.210~0.845	<0.05	0.450	0.225~0.900	<0.05
肝移植术后2~6个月TBiL(μmol/L)		1.012	1.007~1.017	<0.05	1.011	1.007~1.016	<0.05
肝移植术后2~6个月ALT(U/L)		1.000	0.992~1.008	>0.05	-	-	-

变量		单因素分析			多因素分析
变量		HR值	95%可信区间	P值	HR值	95%可信区间	P值
供者年龄(岁)		1.034	1.004~1.064	<0.05	1.033	1.004~1.063	<0.05
受者年龄(岁)		1.000	0.962~1.039	>0.05	-	-	-
受者体质指数(kg/m²)		1.074	0.980~1.176	>0.05	1.072	0.980~1.171	>0.05
受者肝移植前MELD评分		1.014	0.962~1.068	>0.05	-	-	-
受者肝移植前Child-Pugh评分(分)
	<10	1.000			1.000
	≥10	3.092	1.164~8.212	<0.05	2.353	1.169~4.739	<0.05
受者原发病性质
	良性	1.000			1.000
	恶性	2.127	0.933~4.848	>0.05	1.918	0.863~4.266	>0.05
肝移植术后2~6个月他克莫司血药浓度CV
	≥28.11%	1.000			1.000
	<28.11%	0.422	0.210~0.845	<0.05	0.450	0.225~0.900	<0.05
肝移植术后2~6个月TBiL(μmol/L)		1.012	1.007~1.017	<0.05	1.011	1.007~1.016	<0.05
肝移植术后2~6个月ALT(U/L)		1.000	0.992~1.008	>0.05	-	-	-

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