Biomarkers for Early and Late Stage Chronic Allograft Nephropathy by Genomic Profiling of Peripheral Blood

Despite significant improvements in life expectancy of kidney transplant patients due to advances in surgery and immunosuppression, Chronic Allograft Nephropathy (CAN) remains a daunting problem. A complex network of cellular mechanisms in both graft and peripheral immune compartments complicates the non-invasive diagnosis of CAN, which still requires biopsy histology. This is compounded by non-immunological factors contributing to graft injury. There is a pressing need to identify and validate minimally invasive biomarkers for CAN to serve as early predictors of graft loss and as metrics for managing long-term immunosuppression. This study attempts to identify sets of unique transcript biomarkers with high predictive accuracy for both mild and moderate/severe CAN. These biomarkers are the necessary first step to a genomic classification of CAN based on peripheral blood and the targets for a prospective, serial-monitoring clinical study. We used DNA microarrays and bioinformatics to identify candidate genomic markers of mild and moderate/severe CAN in peripheral blood of two distinct cohorts (n=42 and n=35, respectively) of kidney transplant patients with biopsy-documented histology.

尽管外科手术与免疫抑制治疗技术的进步已显著提升肾移植患者的预期寿命，但慢性移植物肾病（Chronic Allograft Nephropathy，CAN）仍是一项棘手的临床难题。移植物与外周免疫微环境中存在复杂的细胞调控网络，使得CAN的无创诊断难度陡增，目前仍需依赖活检组织学检查进行确诊。而导致移植物损伤的非免疫性因素进一步加重了这一困境。因此，临床亟需识别并验证适用于CAN的微创生物标志物，以此作为移植物功能丧失的早期预警指标，同时用于长期免疫抑制治疗的管理与疗效评估。本研究旨在筛选出对轻度、中度/重度CAN均具备高预测准确性的独特转录本生物标志物集。此类生物标志物是基于外周血实现CAN基因组分型的必要前置步骤，同时可作为前瞻性连续监测临床研究的核心靶点。本研究借助DNA微阵列技术与生物信息学方法，在两个独立队列（分别纳入n=42与n=35名经活检组织学确诊的肾移植患者）的外周血中，筛选出轻度、中度/重度CAN的候选基因组标志物。