Nephrotic Syndrome Rare Disease Clinical Research Network

描述(申请人提供)：由局灶性和节段性肾小球硬化(FSGS)、微小病变病(MCD)和膜性肾病(MN)引起的肾病综合征(NS)是一组罕见的疾病，可导致灾难性的并发症和终末期肾脏疾病。尽管这种疾病很罕见，但它会给个人和社会带来巨大的经济负担。目前使用的以组织病理学为基础的NS分类法是不充分的，未能捕捉到这些疾病的分子基础。最近的发现已经确定了家族性[孟德尔式]FSGS的致病基因，MN的靶向足细胞抗原，以及APOL1变异与非裔美国人NS患者FSGS组织学的关联，提供了无可争辩的证据，表明多种独特的疾病机制可能存在难以区分的组织病理学。对于导致NS的许多独特的肾小球疾病中的每一种，精确医学方法对于识别和执行特定的治疗是必要的。这需要了解肾小球疾病的分子基础。在过去的4年里，海王星通过建立一个包括21个地点的强大的调查基础设施，促进了对NS患者的护理，该机构已经招募了500多名具有严格表型的NS患者，并提供了生物材料和相关的详细临床数据。此外，海王星还建立了强大的培训和辅助研究计划，对所有感兴趣的调查人员开放。在这项更新建议中，我们建议利用这些资源进一步将具有临床意义的终点与肾小球疾病的共同和特定的遗传、分子和结构特征联系起来，以生成新的分子NS分类法，该分类法将允许发现新的治疗靶点和试验设计。两项队列研究将纳入患有(1)非裔美国人的严重NS患者和(2)在活检前首次出现NS的儿科队列患者。这些队列将增加NS疾病表型的关键片段，以反映海王星的完整NS疾病谱。培训和试点计划将继续利用海王星和外展的独特资源，与患者兴趣组织NephCure合作，吸引非专业社区、临床医生和科学家来推动NS研究

DESCRIPTION (provided by applicant): Nephrotic Syndrome (NS) from Focal and Segmental Glomerulosclerosis (FSGS), Minimal Change Disease (MCD) and Membranous Nephropathy (MN) is a group of rare diseases that can cause catastrophic complications and end stage kidney disease. Despite their rarity, this disease group generates an enormous individual and societal economic burden. The currently employed, histopathology-based taxonomy of NS is inadequate and fails to capture the molecular bases of these diseases. Recent discoveries, which have identified causal genes in familial [mendelian] FSGS, the target podocyte antigen characterizing MN, and the association of APOL1 variants with FSGS histology in African American NS patients, provides indisputable evidence that multiple, unique disease mechanisms can present with indistinguishable histopathology. A Precision Medicine approach is necessary to identify and to execute specific therapies for each of the many unique glomerular diseases that result in NS. This requires understanding of the molecular bases of glomerular disease. Over the past 4 years NEPTUNE has advanced the care of NS patients by establishing a robust investigative infrastructure encompassing 21 sites, which has recruited more than 500 rigorously phenotyped NS patients, with biological materials and associated detailed clinical data. In addition, NEPTUNE has established robust training and ancillary study programs open to all interested investigators. In this renewal proposal, we propose to leverage these resources to further associate clinically meaningful endpoints with shared and specific genetic, molecular and structural features of glomerular diseases to generate a new, molecular NS taxonomy that will permit discovery of novel therapeutic targets and trial design. Two cohort studies will enroll NS individuals with (1) severe NS enriched for African Americans and (2) pediatric cohort with NS at time of first presentation prior to biopsy. These cohorts will add critical segments of NS disease phenotypes to reflect the full NS disease spectrum in NEPTUNE. Training and pilot programs will continue to leverage the unique resources in NEPTUNE and outreach in conjunction with patient interest group NephCure engaging lay communities, clinicians and scientists to advance NS research