Non-invasive biomarkers are promising tools for improving kidney allograft rejection monitoring, but their clinical adoption requires more evidence in specifically designed studies. To address this unmet need, we designed the EU-TRAIN study, a large prospective multicentric unselected cohort funded by the European Commission. Here, we included consecutive adult patients who received a kidney allograft in nine European transplant centers between November 2018 and June 2020. We prospectively assessed gene expression levels of 19 blood messenger RNAs, four antibodies targeting non–human leukocyte antigen (HLA) endothelial antigens, together with circulating anti-HLA donor-specific antibodies (DSA). The primary outcome was allograft rejection (antibody-mediated, T cell–mediated, or mixed) in the first year post-transplantation. Overall, 412 patients were included, with 812 biopsies paired with a blood sample. CD4 gene expression was significantly associated with rejection, while circulating anti-HLA DSA had a significant association with allograft rejection and a strong association with antibody-mediated rejection. All other tested biomarkers, including AKR1C3, CD3E, CD40, CD8A, CD9, CTLA4, ENTPD1, FOXP3, GZMB, ID3, IL7R, MS4A1, MZB1, POU2AF1, POU2F1, TCL1A, TLR4, and TRIB1, as well as antibodies against angiotensin II type 1 receptor, endothelin 1 type A receptor, C3a and C5a receptors, did not show significant associations with allograft rejection. The blood messenger RNAs and non-HLA antibodies did not show an additional value beyond standard of care monitoring parameters and circulating anti-HLA DSA to predict allograft rejection in the first year post-transplantation. Thus, our results open avenues for specifically designed studies to demonstrate the clinical relevance and implementation of other candidate non-invasive biomarkers in kidney transplantation practice.

中文翻译：

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在一项前瞻性多中心未选择队列研究中评估肾同种异体移植物排斥反应的无创生物标志物 （EU-TRAIN）


非侵入性生物标志物是改善肾同种异体移植物排斥反应监测的有前途的工具，但其临床采用需要在专门设计的研究中提供更多证据。为了满足这一未满足的需求，我们设计了 EU-TRAIN 研究，这是一个由欧盟委员会资助的大型前瞻性多中心未选择队列。在这里，我们纳入了 2018 年 11 月至 2020 年 6 月期间在 9 个欧洲移植中心接受同种异体肾移植的连续成年患者。我们前瞻性评估了 19 种血液信使 RNA 的基因表达水平，四种靶向非人白细胞抗原 （HLA） 内皮抗原的抗体，以及循环抗 HLA 供体特异性抗体 （DSA）。主要结局是移植后第一年的同种异体移植物排斥反应 （抗体介导、T 细胞介导或混合）。总共纳入 412 例患者，其中 812 例活检与血样配对。CD4 基因表达与排斥反应显著相关，而循环抗 HLA DSA 与同种异体移植物排斥反应显著相关，与抗体介导的排斥反应密切相关。所有其他测试的生物标志物，包括 AKR1C3、CD3E、CD40、CD8A、CD9、CTLA4、ENTPD1、FOXP3、GZMB、ID3、IL7R、MS4A1、MZB1、POU2AF1、POU2F1、TCL1A、TLR4 和 TRIB1，以及针对血管紧张素 II 1 型受体、内皮素 1 A 型受体、C3a 和 C5a 受体的抗体，未显示与同种异体移植物排斥反应的显着相关性。血液信使 RNA 和非 HLA 抗体在预测移植后第一年同种异体移植物排斥反应的标准护理监测参数和循环抗 HLA DSA 之外没有显示出额外的价值。 因此，我们的结果为专门设计的研究开辟了途径，以证明其他候选无创生物标志物在肾移植实践中的临床相关性和实施。