Glomerular transcriptomics predicts long term outcome and identifies therapeutic strategies for patients with assumed benign IgA nephropathy

Mariell Rivedal, Havard Mikkelsen, Hans-Peter Marti, Lili Liu, Krzysztof Kiryluk, Thomas Knoop, Rune Bjoerneklett, Yngvar Lunde Haaskjold, Jessica Furriol, Sabine Leh, Flavia Paunas, Janka Babickova, Andreas Scherer, Camille Serre, Oystein Eikrem, Philipp Strauss

Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

Sammanfattning

Some patients diagnosed with benign IgA nephropathy (IgAN) develop a progressive clinical course, not predictable by known clinical or histopathological parameters. To assess if gene expression can differentiate between progressors and non-progressors with assumed benign IgAN, we tested microdissected glomeruli from archival kidney biopsy sections from adult patients with stable clinical remission (non-progressors, n=21) or undergoing progression (n=15) within a 25-year time. Based on 1 240 differentially expressed genes from patients with suitable sequencing results, we identified IgAN progressors (n=8) and non-progressors (n=9) using a two-component classifier, including APOL5 and ZXDC genes, predicting disease progression with 88% accuracy, 75% sensitivity and 100% specificity (AUC=0.875). Ten genes from our transcriptomics data overlapped with an external genome-wide association study (GWAS) dataset, although the gene set enrichment test was not statistically significant. We also identified 45 drug targets in the DrugBank database, including angiotensinogen, a target of sparsentan, currently investigated for IgAN treatment. Two validation cohorts were used for validation key results by immunohistochemistry and the
nCounter® technology. Thus, glomerular mRNA sequencing from diagnostic kidney biopsies from patients with assumed benign IgAN can differentiate between future progressors and non-progressors at the time of diagnosis, on average 21.6 years before progressive disease is documented.
Originalspråkengelska
TidskriftKidney International
Volym105
Nummer4
Sidor (från-till)717-730
Antal sidor14
ISSN0085-2538
DOI
StatusPublicerad - 2024
MoE-publikationstypA1 Tidskriftsartikel-refererad

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