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Abstract: PO1593

Precision Medicine Approach Identifies Patients with IgA Nephropathy at Risk for Progression Using Endothelin Activation Signatures

Session Information

Category: Glomerular Diseases

  • 1203 Glomerular Diseases: Clinical, Outcomes, and Trials

Authors

  • Nair, Viji, University of Michigan, Ann Arbor, Michigan, United States
  • Ju, Wenjun, University of Michigan, Ann Arbor, Michigan, United States
  • Eddy, Sean, University of Michigan, Ann Arbor, Michigan, United States
  • Gunawan, Marvin, Chinook Therapeutics Inc, Vancouver, British Columbia, Canada
  • Olson, N. Eric, Chinook Therapeutics Inc, Vancouver, British Columbia, Canada
  • Wu, Joyce, Chinook Therapeutics Inc, Vancouver, British Columbia, Canada
  • Cox, Jennifer H., Chinook Therapeutics Inc, Vancouver, British Columbia, Canada
  • King, Andrew J., Chinook Therapeutics Inc, Vancouver, British Columbia, Canada
  • Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States
Background

IgA nephropathy (IgAN) is the most common glomerulonephritis globally, with up to 40% of patients at risk of progressing to ESKD. Endothelin (ET) A receptor activation results in mesangial cell (MC) activation, proteinuria, inflammation, and fibrosis, all considered hallmarks of IgAN progression, suggesting the potential for therapeutic benefit of ETA antagonists. The aim of our study was to identify intra-renal transcriptional signatures of ET-activation to stratify patients at high risk of IgAN progression

Methods

We used two approaches to establish a transcriptional signature of ET-activation. First, using a targeted approach, an ET-activation network was generated using three publicly available datasets, produced a geneset of 60 transcripts to create an activity score which was assessed in kidney biopsy profiles in patients with IgAN (n= 25) from the European Renal cDNA Bank (ERCB). In addition, an ET-activation signature was also generated experimentally via RNAseq profiling of primary human MCs simulated with ET1 (4nM) +/- the selective ETA antagonist atrasentan (1nM, 25nM, n=3/group). Pairwise differential gene expression and gene set enrichment analysis (GSEA) was performed.

Results

The targeted analysis showed that the ET-activity score correlated with increased proteinuria (r=0.42, p=0.05) and decreased eGFR (r=-0.47, p=0.02) in patients with IgAN. The transcript network showed enrichment in endothelial and mesangial cell clusters in renal single cell RNASeq profiles. Differential expression analysis identified the ET gene network was reversed by atrasentan in MCs (25nM, n=780 genes, q£0.05). GSEA in MCs revealed up-regulation of cell proliferation, inflammatory and fibrotic networks, with ET1 treatment, which were blocked by atrasentan.

Conclusion

We generated an ET-activation score using a systems biology approach to stratify patients with IgAN. Intra-renal ET-activation signatures were associated with progression, providing additional support for the therapeutic potential of ETA receptor blockade in IgAN patients at high risk of progression. Ongoing work is focused on optimizing the signature, extending findings to additional cohorts and identifying mechanistic biomarkers

Funding

  • Other NIH Support