Development of biomarkers for improved classification of membranous lupus nephritis

开发生物标志物以改进膜性狼疮性肾炎的分类

• 批准号: 9796488
• 负责人: Christopher P Larsen
• 金额: $ 30.09万
• 依托单位: NEPHROPATHOLOGY ASSOCIATES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-26 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9796488
• 关键词: Affect; African American; Antibodies; Antigen-Antibody Complex; Antigens; Archives; Arteries; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmunity; Basement membrane; Biological Assay; Biological Markers; Caucasians; Chronic; Classification; Classification Scheme; Clinical; Complement; Complication; Deposition; Detection; Development; Diagnosis; Dialysis procedure; Disease; End stage renal failure; Functional disorder; Glomerular capsule structure; Goals; Healthcare; Hispanics; Immune; Immunofluorescence Immunologic; Immunoglobulin G; Incidence; Incubated; Individual; Inflammatory; Injury; International; Joints; Kidney; Kidney Diseases; Lead; Lupus Nephritis; Mass Spectrum Analysis; Membranous Glomerulonephritis; Minority; Morbidity - disease rate; Nephrology; Notification; Outcome; Outcome Study; Pathogenicity; Pathology; Patients; Peptides; Phase; Physical shape; Population; Process; Proteins; Proteome; Proteomics; Reaction; Renal Tissue; Reporting; Residual state; Risk; Serological; Societies; Stains; Subgroup; System; Systemic Lupus Erythematosus; Testing; Therapeutic Intervention; Therapeutic immunosuppression; Time; Tissue Sample; Tissues; Tubular formation; Western Blotting; base; biobank; biomarker development; candidate validation; diagnostic assay; improved; kidney biopsy; laser capture microdissection; mortality; novel; novel marker; outcome prediction; patient population; phase 2 study; post-market; programs; response; success

SUMMARY/ABSTRACT African Americans are disproportionately affected by chronic and end stage kidney disease: while 35% of patients on dialysis are African American, only 13.2% of the U.S. population is African American. One factor contributing to this disparity is the high incidence of autoimmune disease, especially systemic lupus erythematosus (SLE), present in the African American population. Lupus nephritis is a common complication of SLE that leads to end stage renal disease (ESRD) in 5.4% of affected individuals. African Americans and Hispanics are known to have worse outcomes with lupus nephritis compared to Caucasians. The incidence of reduced GFR or other renal disease in African Americans is 38% compared to 19% in Caucasians with SLE [1]. The current classification scheme of lupus nephritis, put forth as a joint effort between the International Society of Nephrology and the Renal Pathology Society (ISN/RPS) recognizes 6 subclasses, based entirely on morphological criteria, ranging from minimal (Class I) to advanced sclerosing kidney disease (Class VI) [2]. However, this classification system is markedly deficient in that it poorly predicts outcomes, especially in identifying those patients with early disease at greatest risk for progressing to ESRD. What is needed is an improved classification system based on the pathophysiology of the disease process. Such a classification is expected to better predict outcomes and would therefore be more useful in guiding therapy of patients with lupus nephritis. The two major types of lupus nephritis (LN) associated with progression to ESRD are proliferative LN (Classes III and IV) and membranous LN (Class V), all of which are driven by immune complexes that accumulate in the glomerulus and tubulointerstitium. Patients with membranous LN are especially problematic to manage, as they may remain quiescent or actively progress to ESRD, and the current classification system offers no guidance into which patients will progress, nor how best to manage this challenging patient population. Arkana plans to develop an improved classification system for membranous LN based on the antigenic composition of the immune complexes present in glomeruli. At the conclusion of Phase I, we expect to have defined a proteomic profile of autoantigens and complement factors that drive membranous LN. In addition, we will correlate these drivers of autoimmunity with those present in other forms of membranous glomerulopathy, including PLA2R- and THSD7A-associated membranous glomerulopathy. In the Phase II, we will begin to determine outcomes in patients with different subclasses of membranous LN, and we will also develop antibodies against these autoantigens into serological, immunohistochemical and immunofluorescence assays that can be deployed in diagnostic assays. In the Phase III, we will commercialize these assays and continue to study outcomes and response to therapy in the post-market setting.

摘要/摘要 非裔美国人不成比例地受到慢性和终末期肾病的影响：而 35% 接受透析的患者是非裔美国人，美国人口中只有 13.2% 是非裔美国人。一个因素 造成这种差异的原因是自身免疫性疾病的高发病率，特别是系统性狼疮 红斑狼疮 (SLE)，存在于非洲裔美国人中。狼疮性肾炎是一种常见的并发症 导致 5.4% 受影响个体罹患终末期肾病 (ESRD) 的 SLE。非裔美国人和 众所周知，与白种人相比，西班牙裔狼疮肾炎的预后更差。发病率 非裔美国人的 GFR 或其他肾脏疾病降低率为 38%，而患有 SLE 的白种人为 19% [1]。目前狼疮性肾炎的分类方案是国际组织共同努力提出的 肾脏病学会和肾脏病理学会 (ISN/RPS) 认可 6 个亚类，完全基于 形态学标准，范围从轻微（I 类）到晚期硬化性肾病（VI 类）[2]。 然而，这种分类系统明显有缺陷，因为它对结果的预测很差，特别是在 识别那些处于进展为 ESRD 风险最高的早期疾病患者。需要的是一个 基于疾病过程的病理生理学改进的分类系统。这样的分类是 预计可以更好地预测结果，因此对于指导患有以下疾病的患者的治疗更有用 狼疮性肾炎。 与进展为 ESRD 相关的两种主要类型的狼疮性肾炎 (LN) 是增殖性 LN（类别 III 和 IV）和膜性 LN（V 类），所有这些都是由积累在 肾小球和肾小管间质。膜性淋巴结患者的治疗尤其困难，因为他们 可能处于静止状态或主动进展为 ESRD，并且当前的分类系统没有提供任何指导 患者将进展到哪些阶段，以及如何最好地管理这一具有挑战性的患者群体。阿卡纳计划 根据抗原组成开发改进的膜性淋巴结分类系统 肾小球中存在的免疫复合物。在第一阶段结束时，我们期望定义一个 驱动膜性 LN 的自身抗原和补体因子的蛋白质组学特征。此外，我们将 将这些自身免疫的驱动因素与其他形式的膜性肾小球病中存在的驱动因素联系起来， 包括 PLA2R 和 THSD7A 相关的膜性肾小球病。在第二阶段，我们将开始 确定不同亚类膜性淋巴结患者的结果，我们还将开发 针对这些自身抗原的抗体进行血清学、免疫组织化学和免疫荧光测定 可以用于诊断分析。在第三阶段，我们将把这些检测方法商业化并继续 研究上市后环境中的结果和治疗反应。

项目成果

NELL1 is a target antigen in malignancy-associated membranous nephropathy.

• DOI: 10.1016/j.kint.2020.07.039
• 发表时间: 2021-04
• 期刊: Kidney international
• 影响因子: 19.6
• 作者: Caza TN;Hassen SI;Dvanajscak Z;Kuperman M;Edmondson R;Herzog C;Storey A;Arthur J;Cossey LN;Sharma SG;Kenan DJ;Larsen CP
• 通讯作者: Larsen CP

Neural cell adhesion molecule 1 is a novel autoantigen in membranous lupus nephritis.

• DOI: 10.1016/j.kint.2020.09.016
• 发表时间: 2021-07
• 期刊: Kidney international
• 影响因子: 19.6
• 作者: Caza TN;Hassen SI;Kuperman M;Sharma SG;Dvanajscak Z;Arthur J;Edmondson R;Storey A;Herzog C;Kenan DJ;Larsen CP
• 通讯作者: Larsen CP