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 非洲裔美国人受到慢性和末期肾脏疾病的影响不成比例：而35％ 透析患者是非裔美国人，只有13.2％的美国人口是非裔美国人。一个因素 导致这种差异的是自身免疫性疾病的高发病率，尤其是全身性狼疮 红斑（SLE），存在于非裔美国人人口中。狼疮肾炎是常见的并发症 5.4％的受影响个体的SLE导致终结阶段肾脏疾病（ESRD）。非裔美国人和 与高加索人相比，已知西班牙裔狼疮肾炎的结果更差。发病率 非裔美国人的GFR或其他肾脏疾病的减少为38％，而SLE的高加索人为19％ [1]。狼疮肾炎的当前分类方案，作为国际之间的共同努力 肾脏病学会与肾脏病理学会（ISN/RPS）完全基于6个子类 形态学标准，从最小（I类）到高级硬化肾脏疾病（VI类）[2]。 但是，这种分类系统明显缺乏，因为它无法预测结果，尤其是在 识别那些患有早期疾病的患者，其发展为ESRD的风险最大。需要的是 改进了基于疾病过程的病理生理学的分类系统。这样的分类是 期望更好地预测结果，因此在指导患者的治疗方面更有用 狼疮肾炎。 与向ESRD进展相关的两种主要类型的狼疮肾炎（LN）是增生的LN（类别 III和IV）和膜LN（V类），所有这些都是由积累在 肾小球和肾小管间质。膜LN患者的管理尤其有问题 可能保持静止或积极发展到ESRD，当前的分类系统不提供指导 患者将进步，也不是如何最好地管理这个具有挑战性的患者人群。阿卡纳计划 根据基于膜LN的改进的分类系统 肾小球中存在的免疫复合物。在第一阶段结束时，我们希望定义一个 自身抗原和驱动膜LN的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肾小球病的驱动因素相关联， 包括PLA2R-和THSD7A相关的膜肾小球病。在第二阶段，我们将开始 确定不同膜LN亚类的患者的结果，我们还将发展 针对这些自身抗原的抗体对血清学，免疫组织化学和免疫荧光测定法 可以将其部署在诊断测定中。在第三阶段，我们将将这些测定法商业化并继续 研究后市场环境中的结果和对治疗的反应。

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