Cummins Timothy D, Mariani Laura H, Wilkey Daniel W, Jortani Saeed A, Helmuth Margaret, Rane Madhavi J, Merchant Michael L, Kamigaki Yu, Theesfeld Chandra, McCown Phillip J, Ju Wenjun, Dougherty Julie A, McRitchie Susan, Pathmasiri Wimal, Kretzler Matthias, Sumner Susan J, Smoyer William E, Klein Jon B
Department of Medicine, Kidney Disease Program, University of Louisville Health Sciences Center, Room 102S Donald Baxter Research Building, Louisville, KY, 40202, USA.
Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, MI, USA.
Sci Rep. 2025 Jul 11;15(1):25064. doi: 10.1038/s41598-025-05150-6.
The molecular pathophysiology of nephrotic syndrome remains largely elusive in pediatric patients. While most children with minimal change disease (MCD) show favorable responses to immunosuppressive therapy, those with focal segmental glomerulosclerosis (FSGS) often exhibit poorer treatment responses, with many experiencing either partial remission or no remission of proteinuria. The need for reliable glomerular disease biomarkers to predict treatment response and understand molecular pathways governing responsiveness and resistance is a critical unmet need in pediatric nephrology. In this study, we sought to characterize urine proteomes in children with MCD and FSGS to identify biomarkers distinguishing disease activity and associated molecular pathways. Using quantitative proteomics, urine proteins from children with MCD and FSGS in the CureGN Study were identified and correlated with disease onset and activity. Unbiased cluster analyses of nephrotic urine proteomes demonstrated a cluster with relatively increased immune response and complement proteins, suggesting important distinctions in disease characteristics within the nephrotic subgroups. These analyses yielded patient subpopulations with proteinuria and distinct urine proteome differences associated with 116 proteins exerting cluster separation in the multivariate analyses. These findings highlight the potential of unsupervised clustering to identify disease subgroups and provide insights into the underlying molecular heterogeneity within nephrotic syndrome, paving the way for more tailored therapeutic strategies and improved patient management.
在儿科患者中，肾病综合征的分子病理生理学在很大程度上仍不清楚。虽然大多数微小病变病（MCD）患儿对免疫抑制治疗反应良好，但局灶节段性肾小球硬化症（FSGS）患儿的治疗反应往往较差，许多患儿蛋白尿部分缓解或未缓解。在儿科肾脏病领域，迫切需要可靠的肾小球疾病生物标志物来预测治疗反应，并了解决定反应性和耐药性的分子途径，这一需求尚未得到满足。在本研究中，我们试图对MCD和FSGS患儿的尿液蛋白质组进行表征，以识别区分疾病活动和相关分子途径的生物标志物。利用定量蛋白质组学，在CureGN研究中鉴定了MCD和FSGS患儿的尿液蛋白质，并将其与疾病发作和活动相关联。对肾病尿液蛋白质组进行无偏聚类分析，发现一个免疫反应和补体蛋白相对增加的聚类，表明肾病亚组内疾病特征存在重要差异。这些分析产生了蛋白尿患者亚群，以及与116种蛋白质相关的明显尿液蛋白质组差异，这些蛋白质在多变量分析中导致聚类分离。这些发现突出了无监督聚类在识别疾病亚组方面的潜力，并为深入了解肾病综合征潜在的分子异质性提供了见解，为更具针对性的治疗策略和改善患者管理铺平了道路。
