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Abstract: SA-PO715

Glomerular Transcriptomics Predicts Outcome and Identifies Therapeutic Strategies for Assumed Benign IgA Nephropathy

Session Information

Category: Pathology and Lab Medicine

  • 1700 Pathology and Lab Medicine

Authors

  • Rivedal, Mariell, Universitetet i Bergen, Bergen, Hordaland, Norway
  • Mikkelsen, Håvard, Universitetet i Bergen, Bergen, Hordaland, Norway
  • Marti, Hans-Peter, Universitetet i Bergen, Bergen, Norway
  • Knoop, Thomas, Universitetet i Bergen, Bergen, Norway
  • Bjoerneklett, Rune, Universitetet i Bergen, Bergen, Norway
  • Haaskjold, Yngvar Lunde, Universitetet i Bergen, Bergen, Norway
  • Furriol, Jessica, Universitetet i Bergen, Bergen, Norway
  • Leh, Sabine, Helse Bergen HF, Bergen, Norway
  • Apeland, Terje, Helse Stavanger HF, Stavanger, Norway
  • Paunas, Flavia Teodora ioana, Helse Fonna HF, Haugesund, Norway
  • Babickova, Janka, Universitetet i Bergen, Bergen, Hordaland, Norway
  • Scherer, Andreas, Helsingin yliopisto, Helsinki, Finland
  • Eikrem, Oystein, Universitetet i Bergen, Bergen, Norway
  • Strauss, Philipp, Universitetet i Bergen, Bergen, Hordaland, Norway
Background

In a previous study of patients with IgA nephropathy (IgAN) with assumed benign disease, we have shown that 18.6% of patients develop a progressive clinical course, which was not predicted by any known clinical nor histopathological parameters (Knoop 2017, Nephrol Dial Transplant). We aim to differentiate between future progressors and non-progressors with assumed benign IgAN by using glomerular transcriptomics from diagnostic kidney biopsies and to investigate whether this can identify drugs to be used in those patients.

Methods

We included adult progressive patients (n=15) and patients with remitting disease (non-progressors, n=21) from our previously reported IgAN cohort, with a mean follow-up time of 21.6 years, and assembled an internal validation cohort. Glomerular laser-capture microdissection was performed from 10µm archival kidney biopsy sections, RNA extracted and sequenced with the SMARTer Stranded Total RNA-Seq kit – Pico Input Mammalian (Clontech Laboratories, California, USA). Expression key results were validated in publicly available cohorts and on the protein level with immunohistochemistry in our internal cohorts.

Results

Based on the 1,240 differentially expressed glomerular genes from the initial kidney biopsies, we were able to identify which patients will be IgAN progressors and non-progressors using a two-component classifier. The classifier predicted disease progression with 88% accuracy, 75% sensitivity and 100% specificity (AUC=0.875), more accurate than the recommended International IgAN Prediction Tool. We identified 45 possible drug targets, including angiotensinogen, a target of sparsentan, currently investigated as therapy in IgAN (NCT03762850 and NCT04663204). The findings on upregulation of angiotensinogen, which was independent of blood pressure, were validated in an internal IgAN validation cohort. Interestingly, complement activation did not play a major role in our data.

Conclusion

Glomerular mRNA sequencing from diagnostic kidney biopsies from assumed benign IgAN can differentiate between future progressors and non-progressors at the time of biopsy, on average 21.6 years before progressive disease is documented.

Funding

  • Commercial Support