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Abstract: TH-PO1042

Functional Subclasses of Nephrotic Syndrome Identified Using Consensus Non-Negative Matrix Factorization Clustering of Kidney Tubulointerstitial Tissue Transcriptome

Session Information

Category: Glomerular Diseases

  • 1203 Glomerular Diseases: Clinical, Outcomes, and Trials

Authors

  • Hamidi, Habib, University of Michigan, Ann Arbor, Michigan, United States
  • Eddy, Sean, University of Michigan, Ann Arbor, Michigan, United States
  • Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States
  • Sedor, John R., Cleveland Clinic, Cleveland, Ohio, United States
  • O'Toole, John F., Cleveland Clinic, Cleveland, Ohio, United States
  • Holzman, Lawrence B., University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Mariani, Laura H., University of Michigan, Ann Arbor, Michigan, United States
Background

Interstitial fibrosis and tubular atrophy are common patterns of injury in glomerular diseases, but it is unknown whether multiple mechanisms can result in this pattern of injury and if mechanisms change as disease progresses. Consensus non-negative matrix factorization (NMF) is a clustering approach used with tumor specimen transcriptomics to identify functionally relevant subtypes.

Methods

NMF clustering was applied to tubular mRNA expression from kidney biopsies from the NEPTUNE cohort, a prospective cohort of children and adults with nephrotic syndrome enrolled at the time of clinically indicated kidney biopsy. Individual gene expression levels from the tubular compartment were normalized to mean expression to maximize individual patient differences. Cox proportional hazards models were fit for complete proteinuria remission (CR, UPCR <0.3 mg/mg) and ESRD/40% eGFR decline. Significance analysis of microarray identified cluster specific differentially expressed genes that were used in pathway enrichment analysis to determine functional relevance.

Results

NMF separated 188 patients into 4 clusters which did not differ age (p 0.46), sex (p 0.77) or UPCR (p 0.46). The clusters did not segregate by disease etiology (Fig). Cluster 2 had lower mean eGFR (56 mL/min vs 83, 66 and 66; p <0.01) and greater UPCR (5.1 vs 2.8, 2.1,4.0; p <0.01), black race (39.5% vs 25%, 12%, 6%, p <0.01). In unadjusted models, cluster 2 had less CR (HR 0.65, p-value 0.14) and greatest loss of eGFR (HR 2.8, p-value <0.01). Pathway enrichment of cluster-specific genes demonstrated unique processes (Fig).

Conclusion

NMF identified functional subclasses in the tubular kidney tissue mRNA of patients with nephrotic syndrome which crossed traditional diagnostic classifications of FSGS, MCD and MN. Functional analysis revealed both shared and specific pathways associated with the clusters which could help to identify therapeutic targets.

Funding

  • NIDDK Support