Development of biomarkers for improved classification of membranous lupus nephritis

总结/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%的 透析患者是非洲裔美国人，只有13.2%的美国人口是非洲裔美国人。一个因素 导致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），目前在非洲裔美国人的人口。狼疮性肾炎是一种常见的并发症 SLE导致终末期肾病（ESRD）的5.4%的受影响的个人。非裔美国人和 众所周知，与白人相比，西班牙裔狼疮性肾炎的预后更差。的发生率 非裔美国人GFR或其他肾脏疾病降低的比例为38%，而白人SLE患者为19% [1]的文件。狼疮性肾炎的治疗方法有哪些？ 肾脏病学会和肾脏病理学会（ISN/RPS）承认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，这种分类系统明显存在缺陷，因为它预测结果很差，特别是在 确定那些早期疾病患者进展为ESRD的风险最大。所需要的是一种 基于疾病过程的病理生理学的改进的分类系统。这种分类是 预期能更好地预测结果，因此在指导患者治疗方面更有用。 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 III和IV）和膜LN（V类），所有这些都是由免疫复合物驱动的，这些免疫复合物积累在 肾小球和肾小管。膜性LN患者尤其难以管理，因为他们 可能保持静止或积极进展为ESRD，目前的分类系统没有提供指导 患者将进展到什么阶段，也不知道如何最好地管理这一具有挑战性的患者群体。Arkana计划在 基于以下抗原组成，开发膜性LN的改进分类系统： 肾小球中的免疫复合物。在第一阶段结束时，我们预计已经确定了一个 自身抗原和补体因子驱动膜性LN的蛋白质组学图谱。此外，我们将 将这些自身免疫驱动因素与其他形式的膜性肾小球病中存在的驱动因素相关联， 包括PLA 2 R和THSD 7A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LN患者的结局，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，我们将商业化这些检测，并继续 研究上市后环境中的治疗结局和反应。

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.