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Abstract: TH-PO446

Proteomic Identification of Urine Biomarkers of Pediatric Nephrotic Syndrome

Session Information

Category: Glomerular Diseases

  • 1302 Glomerular Diseases: Immunology and Inflammation

Authors

  • Cummins, Timothy, University of Louisville, Louisville, Kentucky, United States
  • Merchant, Michael, University of Louisville, Louisville, Kentucky, United States
  • Wilkey, Daniel Wade, University of Louisville, Louisville, Kentucky, United States
  • Jortani, Saeed A., University of Louisville, Louisville, Kentucky, United States
  • Rane, Madhavi J., University of Louisville, Louisville, Kentucky, United States
  • Mariani, Laura H., University of Michigan, Ann Arbor, Michigan, United States
  • Dougherty, Julie, Nationwide Children's Hospital, Columbus, Ohio, United States
  • Kamigaki, Yu, Nationwide Children's Hospital, Columbus, Ohio, United States
  • Pathmasiri, Wimal, University of North Carolina System, Chapel Hill, North Carolina, United States
  • Mcritchie, Susan, University of North Carolina System, Chapel Hill, North Carolina, United States
  • Sumner, Susan Jenkins, University of North Carolina System, Chapel Hill, North Carolina, United States
  • Smoyer, William E., Nationwide Children's Hospital, Columbus, Ohio, United States
  • Klein, Jon B., University of Louisville, Louisville, Kentucky, United States
Background

The molecular pathophysiology of nephrotic syndrome (NS) remains unclear for the majority of children. While most children with minimal change disease (MCD) have a good response to glucocorticoid (GC) therapy, those with focal segmental glomerulosclerosis (FSGS) often respond poorly, with either no remission or only partial remission of proteinuria. Development of glomerular disease biomarkers that reliably predict response to treatment and/or define molecular pathways regulating treatment responsiveness vs. resistance could greatly improve outcomes in pediatric NS. We hypothesized that comparison of urine proteomes in children with MCD vs. FSGS could identify urinary biomarkers able to distinguish disease activity and molecular pathways regulating these differences.

Methods

We performed quantitative proteomic analyses of sequential urine samples from children with biopsy-proven MCD and FSGS enrolled in the CureGN Consortium to identify and compare putative mechanistic differences between disease activity and remission in FSGS and MCD. We analyzed 216 patient urine specimens by 2D-LC-MS/MS and identified 1,100 unique proteins using MaxQuant and Scaffold-5 Q+, applying strict FDR (1%) with 2-peptide identification required. Proteomics data were analyzed using MetaboAnalyst 5.0 to conduct univariate and multivariate statistical analyses to identify candidate urine biomarkers of disease activity vs. remission in FSGS and MCD.

Results

Urine proteome profiles in children with partial remission (UPCR 0.3-1.5) in both FSGS and MCD were nearly indistinguishable from the active (UPCR 1.5-3.5) or nephrotic (UPCR >3.5) states. Notably, proteomic profiles in complete remission (UPCR<0.3) were clearly distinct from all other levels of disease activity for both FSGS and MCD. Additionally, urinary ORM1 and C3 levels were significantly elevated in the nephrotic state vs. complete remission, with proteomic findings confirmed on subsequent immunoassays.

Conclusion

These findings suggest urinary ORM1 and C3 are candidate biomarkers of disease activity in childhood nephrotic syndrome, which may also have mechanistic implications for disease progression or treatment resistance.

Funding

  • NIDDK Support