To identify urinary biomarkers that can distinguish active renal involvement in Lupus Nephritis (LN), a severe manifestation of systemic lupus erythematosus (SLE). Urine from 117 subjects, comprised of inactive SLE, active non-renal lupus, active LN, and healthy controls, were subjected to Proximity Extension Assay (PEA) based comprehensive proteomics followed by ELISA validation in an independent, ethnically diverse cohort. Proteomic data is also cross-referenced to renal transcriptomic data to elucidate cellular origins of biomarkers. Systems biology analyses revealed progressive activation of cytokine signaling, chemokine activity and coagulation pathways, with worsening renal disease. In addition to validating 30 previously reported biomarkers, this study uncovers several novel candidates. Following ELISA validation in an independent cohort of different ethnicity, the six most discriminatory biomarkers for active LN were urinary ICAM-2, FABP4, FASLG, IGFBP-2, SELE and TNFSF13B/BAFF, with ROC AUC ≥80%, with most correlating strongly with clinical disease activity. Transcriptomic analyses of LN kidneys mapped the likely origin of these proteins to intra-renal myeloid cells (CXCL16, IL-1RT2, TNFSF13B/BAFF), T/NK cells (FASLG), leukocytes (ICAM2) and endothelial cells (SELE). In addition to confirming the diagnostic potential of urine ALCAM, CD163, MCP1, SELL, ICAM1, VCAM1, NGAL and TWEAK for active LN, this study adds urine ICAM-2, FABP4, FASLG, IGFBP-2, SELE, and TNFSF13B/BAFF as additional markers that warrant systematic validation in larger cross-sectional and longitudinal cohorts.

中文翻译：

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邻近延伸分析蛋白质组学和肾脏单细胞转录组学揭示了活动性狼疮肾炎的新型尿液生物标志物

旨在鉴定可区分狼疮性肾炎 (LN)（系统性红斑狼疮 (SLE) 的严重表现）活动性肾脏受累的尿液生物标志物。来自 117 名受试者（包括非活动性 SLE、活动性非肾性狼疮、活动性 LN 和健康对照）的尿液接受了基于邻近延伸测定 (PEA) 的综合蛋白质组学分析，随后在一个独立的、种族多样化的队列中进行了 ELISA 验证。蛋白质组数据还与肾脏转录组数据交叉引用，以阐明生物标志物的细胞起源。系统生物学分析揭示了细胞因子信号传导、趋化因子活性和凝血途径的逐渐激活，以及肾脏疾病的恶化。除了验证 30 种先前报道的生物标志物之外，这项研究还发现了几种新的候选生物标志物。在不同种族的独立队列中进行 ELISA 验证后，活动性 LN 的六种最具辨别力的生物标志物是尿液 ICAM-2、FABP4、FASLG、IGFBP-2、SELE 和 TNFSF13B/BAFF，ROC AUC ≥80%，其中大多数具有强烈相关性具有临床疾病活动性。 LN 肾脏的转录组分析将这些蛋白质的可能起源映射到肾内骨髓细胞（CXCL16、IL-1RT2、TNFSF13B/BAFF）、T/NK 细胞（FASLG）、白细胞（ICAM2）和内皮细胞（SELE）。除了确认尿液 ALCAM、CD163、MCP1、SELL、ICAM1、VCAM1、NGAL 和 TWEAK 对活动性 LN 的诊断潜力外，本研究还添加了尿液 ICAM-2、FABP4、FASLG、IGFBP-2、SELE 和 TNFSF13B/BAFF作为需要在更大的横截面和纵向队列中进行系统验证的额外标记。