Genetics and Immune Predictors for Recurrent Glomerular Diseases in the Kidney Allograft

项目总结/摘要 最近开发的强效免疫抑制方案已导致急性免疫缺陷的发生率降低， 排斥和非排斥并发症的发生率增加，包括复发性免疫介导的 肾小球疾病（GD）已经成为肾移植失败的主要原因。 最常见的是伊加肾病（IgAN）、膜性肾病（MN）和弥漫性足细胞病（DP） 原发性GD的原因在天然肾和这些相同的GD移植后可以复发。以本机 肾脏，很明显，免疫和遗传因素是这些GD中的每一个的重要贡献者。 虽然对移植后复发性GD的发病机制知之甚少，但很少有研究表明， 严格的供受者HLA配型和无类固醇免疫抑制方案是 复发性GD。因此，我们假设，类似于GD在天然肾，复发性GD是介导的， 基因组和免疫因素。明确基因组和免疫因素在复发性IgAN、MN和 DP，我们已经开始收集临床数据，供体-受体对的DNA，受体的血清和肾移植物 来自多个移植中心的活检，以汇集最大的移植患者队列， 非复发性GD（至少n= 1，035）。为了确保足够的功率并消除重复研究的需要， 我们正在使用遗传风险评分（GRS）和血清学研究，这些研究以前在当地人中得到了验证。 肾因此，我们制定了一个研究计划，包括三个目标，遵循平行的方法。 在Specific Aim-1中，我们将（1）使用全基因组SNP阵列对患有以下疾病的患者中的供体-受体对进行基因分型： 复发性和非复发性IgAN，产生个体30-SNP IgAN GRS，并测试这些GRS作为 （2）检测移植前血清半乳糖缺陷型IgA 1、IgG抗聚糖抗体水平 抗体（Ab）和组合IgAN风险评分（其将IgAN GRS与上述移植前评分整合 血清水平）作为复发性疾病的预测因子，和（3）比较不同的后 移植GD以鉴定对复发性IgAN特异的免疫信号。 在特异性目标-2中，我们将检测供体和受体MN GRS、抗磷脂酶A2受体Ab和联合 MN风险评分作为复发性MN的预测因子，并鉴定复发性MN的移植物内免疫信号。 在特定目标-3中，我们将检验供体和受体DP GRS和抗肾配蛋白Ab的值作为 复发性DP，并使用转录组学分析来鉴定复发性疾病特异性的免疫信号。 项目的健康相关性：拟议的项目将整合移植领域与新供体 筛查技术和免疫监测。在短期内，该提案承诺定义 这些相对罕见但具有临床意义的复发性GD。从长远来看，该项目有可能 为肾衰竭患者引入新的基因组供体-受体匹配和免疫监测 继发于GD，以降低复发性GD的发生率，并改善肾移植受者的健康。

PROJECT SUMMARY/ABSTRACT The recent development of potent immunosuppressive regimens has led to decreased incidence of acute rejection and increased incidence of non-rejection complications, including recurrent immune-mediated glomerular diseases (GD) which have emerged as leading causes of kidney allograft failure. IgA nephropathy (IgAN), membranous nephropathy (MN), and diffuse podocytopathy (DP) are the most common causes of primary GD in the native kidney and these same GD can recur after transplantation. In the native kidney, it is apparent that immune and genetic factors are important contributors to each of these GD. Although little is known about the pathogenesis of recurrent GD after transplantation, few studies have shown that rigorous donor-recipient HLA matching and steroid-free immunosuppressive regimens are risk factors for recurrent GD. Therefore, we hypothesized that, similar to GD in the native kidney, recurrent GD are mediated by genomic and immune factors. To define the role of genomic and immune factors in recurrent IgAN, MN, and DP, we have begun collecting clinical data, DNA from donor-recipient pairs, recipients’ sera, and kidney allograft biopsies from multiple transplant centers to assemble the largest cohort of transplant patients with recurrent and non-recurrent GD (n=1,035 at least). To ensure adequate power and eliminate the need for replication studies, we are using genetic risk scores (GRS) and serologic studies that has been previously validated in the native kidney. Hence, we developed a research plan composed of three aims that follow parallel approaches. In Specific Aim-1, we will (1) use genome wide SNP arrays to genotype donor-recipient pairs in patients with recurrent and non-recurrent IgAN, generate individual 30-SNP IgAN GRS, and test these GRS as predictors of recurrent disease, (2) test the values of pre-transplant serum levels of galactose-deficient IgA1, IgG anti-glycan antibodies (Ab), and combined IgAN risk scores (which integrate the IgAN GRS with the above pre-transplant serum levels) as predictors for recurrent disease, and (3) compare transcriptomic profiling of different post- transplantation GD to identify immune signals specific for recurrent IgAN. In Specific Aim-2, we will test donor and recipient MN GRS, anti-phospholipase A2 receptor Ab, and combined MN risk scores as predictors for recurrent MN, and identify intra-graft immune signals specific for recurrent MN. In Specific Aim-3, we will test the values of donor and recipient DP GRS and anti-nephrin Ab as predictors for recurrent DP, and use transcriptomic profiling to identify immune signals specific for recurrent disease. Health relatedness of the project: The proposed project will integrate the field of transplantation with novel donor screening technologies and immune monitoring. In the short-term, this proposal promises to define predictors of these relatively rare but clinically relevant recurrent GD. In the long-term, this project has the potential to introduce novel genomic donor-recipient matching and immune monitoring for patients with kidney failure secondary to GD to decrease incidence of recurrent GD, and improve the health of kidney transplant recipients.