1 Department of Pediatrics, University of British Columbia, BC Children's Hospital Vancouver, BC, Canada. 2 Department of Pediatrics and Child Health, University of Manitoba, Children's Hospital at Health Sciences Center, Winnipeg, MB, Canada. 3 Department of Pathology, University of Manitoba, Health Sciences Center, Winnipeg, MB, Canada. 4 The Metabolomics Innovation Center, University of Alberta, Edmonton, AB, Canada. 5 Section of Nephrology, Department of Internal Medicine, University of Manitoba, Health Sciences Center, Winnipeg, MB, Canada. 6 Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada. 7 Manitoba Center for Proteomics and Systems Biology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
Transplantation. 2017 Oct;101(10):2553-2561. doi: 10.1097/TP.0000000000001662.
Biomarkers are needed that identify patients with antibody-mediated rejection (AMR). The goal of this study was to evaluate the utility of urinary metabolomics for early noninvasive detection of AMR in pediatric kidney transplant recipients.
Urine samples (n = 396) from a prospective, observational cohort of 59 renal transplant patients with surveillance or indication biopsies were assayed for 133 unique metabolites by quantitative mass spectrometry. Samples were classified according to Banff criteria for AMR and partial least squares discriminant analysis was used to identify associated changes in metabolite patterns by creating a composite index based on all 133 metabolites.
Urine samples of patients with (n = 40) and without AMR (n = 278) were analyzed and a classifier for AMR was identified (area under receiver operating characteristic curve = 0.84; 95% confidence interval, 0.77-0.91; P = 0.006). Application of the classifier to "indeterminate" samples (samples that partially fulfilled Banff criteria for AMR; n = 65) yielded an AMR score of 0.19 ± 0.15, intermediate between scores for AMR and No AMR (0.28 ± 0.14 and 0.10 ± 0.13 respectively, P ≤ 0.001). The AMR score was associated with the presence of donor-specific antibodies, biopsy indication, Banff ct, t, ah and cg scores, and retained accuracy when applied to subclinical cases (creatinine, <25% increase from baseline) or had minimal or no transplant glomerulopathy (Banff cg0-1). Exploratory classifiers that segregated samples based on concurrent T cell-mediated rejection (TCMR) identified overlapping metabolite signatures between AMR and TCMR, suggesting similar pathophysiology of tissue injury.
These preliminary findings identify a urine metabolic classifier for AMR. Independent validation is needed to verify its utility for accurate, noninvasive AMR detection.
需要生物标志物来识别抗体介导的排斥反应（AMR）患者。本研究的目的是评估尿代谢组学在儿科肾移植受者早期无创检测 AMR 中的应用。
对 59 例接受监测或有指征活检的肾移植患者前瞻性观察队列的 396 例尿样进行了 133 种独特代谢物的定量质谱分析。根据 Banff 标准对样本进行分类，并通过创建基于所有 133 种代谢物的综合指数，利用偏最小二乘判别分析识别代谢物模式相关变化，从而识别与 AMR 相关的变化。
分析了 AMR 患者（n=40）和无 AMR 患者（n=278）的尿液样本，并确定了 AMR 的分类器（受试者工作特征曲线下面积=0.84；95%置信区间，0.77-0.91；P=0.006）。将该分类器应用于“不确定”样本（部分符合 AMR Banff 标准的样本；n=65），得到 AMR 评分 0.19±0.15，介于 AMR 和无 AMR 之间（分别为 0.28±0.14 和 0.10±0.13，P≤0.001）。AMR 评分与供体特异性抗体的存在、活检指征、Banff ct、t、ah 和 cg 评分相关，应用于亚临床病例时仍具有准确性（肌酐，自基线增加<25%）或最小或无移植肾小球病（Banff cg0-1）。基于同时发生的 T 细胞介导排斥反应（TCMR）对样本进行分类的探索性分类器，确定了 AMR 和 TCMR 之间存在重叠的代谢物特征，提示组织损伤的病理生理机制相似。
这些初步发现确定了 AMR 的尿液代谢分类器。需要进行独立验证以验证其用于准确、无创 AMR 检测的实用性。
