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

同种异体移植肾中复发性肾小球疾病的遗传学和免疫预测因子

基本信息

批准号：
10637158
负责人：
Ibrahim Batal
金额：
$ 37.99万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10637158
关键词：
Acute Address Allografting Antibodies Biopsy Clinical Data DNA Data Development Diffuse Disease Donor Selection Ensure Failure Fc Receptor Focal and Segmental Glomerulosclerosis Future Galactose Gene Expression Profiling Genetic Genetic Models Genetic Predisposition to Disease Genetic Risk Genomics Genotype Goals Health IGA Glomerulonephritis IgA1 Immune Immune Targeting Immune signaling Immunoglobulin G Immunologic Factors Immunologic Monitoring Immunotherapy Incidence Individual Inherited Kidney Kidney Diseases Kidney Failure Kidney Transplantation Mediating Membranous Glomerulonephritis Microanatomy Pathogenesis Patient Monitoring Patients Phospholipase A2 Polysaccharides Prognosis Recurrence Recurrent disease Regimen Renal glomerular disease Request for Applications Research Research Personnel Risk Risk Factors Role SNP array Secondary to Serology Serum Signal Transduction Steroid-resistant idiopathic nephrotic syndrome Steroids Technology Testing Transplant Recipients Transplantation Tumor Necrosis Factor Superfamily Ligands Up-Regulation clinically relevant cohort design disorder control effective therapy follow-up genome wide association study genome-wide improved kidney allograft member nano-string nephrin novel post-transplant precision medicine risk variant transcriptomic profiling transplant centers

项目摘要

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.

项目概要/摘要最近有效的免疫抑制疗法的发展导致急性感染的发生率下降排斥反应和非排斥并发症发生率增加，包括复发性免疫介导的并发症肾小球疾病（GD）已成为肾同种异体移植失败的主要原因。 IgA 肾病 (IgAN)、膜性肾病 (MN) 和弥漫性足细胞病 (DP) 是最常见的原发性 GD 的原因发生在自体肾脏，并且这些 GD 可能在移植后复发。肾，很明显免疫和遗传因素是这些 GD 的重要贡献者。尽管对移植后复发性 GD 的发病机制知之甚少，但很少有研究表明严格的供体-受体 HLA 匹配和无类固醇免疫抑制方案是导致因此，我们发现，与天然肾脏中的 GD 类似，复发性 GD 是介导的。通过基因组和免疫因素来确定基因组和免疫因素在复发性 IgAN、MN 和 IgAN 中的作用。 DP，我们已经开始收集临床数据、供体-受体对的 DNA、受体血清和同种异体肾移植物来自多个移植中心的活组织检查，以汇集最大的复发性和慢性移植患者群体非复发性 GD（至少 n=1,035）为了确保足够的功效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，这些研究先前已在本地进行了验证因此，我们制定了一项由三个目标组成的研究计划，这些目标遵循并行的方法。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的供体-受体对进行基因分型：复发性和非复发性 IgAN，生成单独的 30-SNP IgAN GRS，并测试这些 GRS 作为预测因子疾病复发，（2）检测移植前血清中半乳糖缺乏型IgA1、IgG抗聚糖水平值抗体 (Ab) 和组合 IgAN 风险评分（将 IgAN GRS 与上述移植前评分相结合）血清水平）作为复发性疾病的预测因子，并且（3）比较不同治疗后的转录组学分析移植 GD 来识别针对复发性 IgAN 的特异性免疫信号。在 Specific Aim-2 中，我们将测试供体和受体 MN GRS、抗磷脂酶 A2 受体抗体以及组合 MN 风险评分作为复发性 MN 的预测因子，并识别针对复发性 MN 的移植物内免疫信号。在 Specific Aim-3 中，我们将测试供体和受体 DP GRS 和抗去氧肾上腺素抗体的值作为预测因子复发性 DP，并使用转录组分析来识别针对复发性疾病的特异性免疫信号。项目的健康相关性：拟议项目将移植领域与新的供体相结合在短期内，该提案有望定义预测因素。这些相对罕见但临床相关的复发性 GD 从长远来看，该项目有潜力。为肾衰竭患者引入新型基因组供体-受体匹配和免疫监测继发于 GD，以减少 GD 复发的发生率，并改善肾移植受者的健康。