非侵入性生物标志物是改善肾移植排斥反应监测的有希望的工具,但他们的临床采用需要更多的证据在专门设计的研究。为了解决这个未满足的需求,我们设计了欧盟火车研究,由欧盟委员会资助的大型前瞻性多中心未选择队列。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.我们前瞻性地评估了19种血液信使RNA的基因表达水平,针对非人白细胞抗原(HLA)内皮抗原的四种抗体,与循环抗HLA供体特异性抗体(DSA)。主要结果是同种异体移植排斥(抗体介导的,T细胞介导的,或混合)在移植后的第一年。总的来说,包括412例患者,与血液样本配对的812个活检。CD4基因表达与排斥反应显著相关,而循环抗HLADSA与同种异体移植排斥反应显著相关,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,以及抗血管紧张素II1型受体的抗体,内皮素1A型受体,C3a和C5a受体,没有显示与同种异体移植排斥的显著关联。血液信使RNA和非HLA抗体没有显示超出护理监测参数和循环抗HLADSA标准的额外价值来预测移植后第一年的同种异体移植物排斥。因此,我们的结果为专门设计的研究开辟了道路,以证明其他候选非侵入性生物标志物在肾移植实践中的临床意义和实施.
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.