Defining subgroups of pediatric nephrotic patients with urine proteomics.
Sci Rep 2025 Jul 11; 15(1):25064.

Abstract

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.

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Cummins TDDepartment of Medicine, Kidney Disease Program, University of Louisville Health Sciences Center, Room 102S Donald Baxter Research Building, Louisville, KY, 40202, USA.
Mariani LHDepartment of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, MI, USA.
Wilkey DWDepartment of Medicine, Kidney Disease Program, University of Louisville Health Sciences Center, Room 102S Donald Baxter Research Building, Louisville, KY, 40202, USA.
Jortani SADepartment of Pathology and Lab Medicine, University of Louisville, Louisville, KY, USA.
Helmuth MDepartment of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, MI, USA.
Rane MJDepartment of Medicine, Kidney Disease Program, University of Louisville Health Sciences Center, Room 102S Donald Baxter Research Building, Louisville, KY, 40202, USA.
Merchant MLDepartment of Medicine, Kidney Disease Program, University of Louisville Health Sciences Center, Room 102S Donald Baxter Research Building, Louisville, KY, 40202, USA.
Kamigaki YCenter for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA. Department of Pediatrics, The Ohio State University, Columbus, OH, USA.
Theesfeld CGenomics and Princeton Precision Health, Princeton University, Princeton, NJ, USA.
McCown PJDepartment of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, MI, USA.
Ju WDepartment of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, MI, USA.
Dougherty JACenter for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA. Department of Pediatrics, The Ohio State University, Columbus, OH, USA.
McRitchie SMetabolomics and Exposome Laboratory, Nutrition Research Institute, University of North Carolina, Chapel Hill, NC, USA. Nutrition Research Institute, University of North Carolina, Chapel Hill, NC, USA.
Pathmasiri WMetabolomics and Exposome Laboratory, Nutrition Research Institute, University of North Carolina, Chapel Hill, NC, USA. Nutrition Research Institute, University of North Carolina, Chapel Hill, NC, USA.
Kretzler MDepartment of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, MI, USA.
Sumner SJMetabolomics and Exposome Laboratory, Nutrition Research Institute, University of North Carolina, Chapel Hill, NC, USA. Nutrition Research Institute, University of North Carolina, Chapel Hill, NC, USA.
Smoyer WECenter for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA. William.smoyer@nationwidechildrens.org. Department of Pediatrics, The Ohio State University, Columbus, OH, USA. William.smoyer@nationwidechildrens.org.
Klein JBDepartment of Medicine, Kidney Disease Program, University of Louisville Health Sciences Center, Room 102S Donald Baxter Research Building, Louisville, KY, 40202, USA. Jon.klein@louisville.edu. Robley Rex VA Medical Center, Louisville, KY, USA. Jon.klein@louisville.edu.
Cure Glomerulonephropathy (CureGN) ConsortiumNo affiliation info available

MeSH

HumansChildProteomicsMaleFemaleBiomarkersProteomeProteinuriaAdolescentNephrotic SyndromeGlomerulosclerosis, Focal SegmentalNephrosis, LipoidChild, PreschoolCluster Analysis

Pub Type(s)

Journal Article

Language

eng

PubMed ID

40646010