患者内他克莫司变异性与慢性活跃抗体介导的排斥反应无关。

Tacrolimus intra-patient variability is not associated with chronic active antibody mediated rejection.

机构信息

Department of Nephrology and Transplantation, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.

Department of Pathology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.

出版信息

PLoS One. 2018 May 10;13(5):e0196552. doi: 10.1371/journal.pone.0196552. eCollection 2018.

BACKGROUND

Chronic active antibody mediated rejection (c-aABMR) is a major cause of long-term kidney allograft loss. It is hypothesized that frequent sub-therapeutic exposure to immunosuppressive drugs, in particular tacrolimus (Tac), is a risk factor for the development of c-aABMR. The intra-patient variability (IPV) in Tac exposure may serve as a substitute biomarker for underexposure and/or non-adherence. In this study, the association between Tac IPV and the development of c-aABMR was investigated.

METHODS

We retrospectively included 59 patients diagnosed with c-aABMR and compared them to 189 control patients matched for age, year of transplantation and type of kidney donor. The Tac IPV was calculated from pre-dose tacrolimus concentrations measured over a 3 year period preceding the diagnosis of c-aABMR. The mean Tac predose concentrations (C0), Tac IPV, renal allograft function and graft survival were compared between the groups.

RESULTS

Tac IPV was 24.4% for the cases versus 23.6% for the controls (p = 0.47). The mean Tac C0 was comparable for the cases (5.8 ng/mL) and control patients (6.1 ng/mL, p = 0.08). Only in the c-aABMR group a significant decline in both mean Tac C0 and allograft function over the timespan of 3 years was observed (p = 0.03 and p<0.001). Additionally, in the group of c-aABMR patients a high IPV was associated with inferior graft survival (p = 0.03).

CONCLUSIONS

A high Tac IPV per se does not predispose to the development of c-aABMR but is associated with inferior graft survival once c-aABMR is diagnosed.

背景

慢性活动性抗体介导的排斥反应（c-aABMR）是导致长期肾移植失败的主要原因。据推测，免疫抑制剂药物（特别是他克莫司（Tac））的频繁亚治疗暴露是导致 c-aABMR 发展的一个危险因素。Tac 暴露的患者内变异（IPV）可能是药物暴露不足和/或不依从的替代生物标志物。本研究旨在探讨 Tac IPV 与 c-aABMR 发展之间的关系。

方法

我们回顾性纳入了 59 例诊断为 c-aABMR 的患者，并与 189 例年龄、移植年份和供肾类型匹配的对照患者进行比较。在诊断 c-aABMR 前 3 年内，通过测量 Tac 谷浓度计算 Tac IPV。比较两组 Tac 预剂量浓度（C0）、Tac IPV、肾移植功能和移植物存活率。

结果

病例组 Tac IPV 为 24.4%，对照组为 23.6%（p=0.47）。病例组的 Tac C0 均值（5.8ng/mL）与对照组（6.1ng/mL，p=0.08）相当。仅在 c-aABMR 组观察到 3 年内 Tac C0 和移植物功能均显著下降（p=0.03 和 p<0.001）。此外，在 c-aABMR 患者组中，高 IPV 与移植物存活率降低相关（p=0.03）。