The genetic locus associated with renal impairment
Renal impairment is a common and serious complication of decompensated cirrhosis, but individual susceptibility remains poorly understood. Whilst age, sex and the severity of the kidney disease influence kidney function, the role of host genetics has remained unclear.
To address this question, the research team analysed genetic data from 5,000 patients with decompensated cirrhosis across nine cohorts. The study identified a risk region in the SUSD1 gene, which was consistently associated with renal impairment.
The association with kidney injury and the use of terlipressin reinforces the link between this genetic finding and clinically relevant renal complications. The main value of this discovery at this stage is the insight it provides into the biology of kidney dysfunction in decompensated cirrhosis. “Our results point towards an immune pathway that merits further investigation, but do not prove that this variant can predict the course of a specific patient or determine which treatment they should receive,” said Eric Trépo, senior author and corresponding co-author of the study, hepatologist and senior researcher at the Hôpital Universitaire de Bruxelles and the Université Libre de Bruxelles, in Brussels, Belgium.
The biological pathway linking liver dysfunction to kidney injury
Identifying a genetic association is only the first step. The researchers used several additional approaches to investigate how the genetic finding might affect SUSD1 activity, and what biological processes might be involved.
Precise mapping of the associated region identified a genetic variant that is associated with higher SUSD1 expression in the blood. The team then combined the genetic findings with single-cell and tissue analyses of the liver, blood and kidney to identify the cells in which SUSD1 is most active and to explore the biological processes associated with kidney dysfunction.
In this set of experiments, plasmacytoid dendritic cells, a specialized type of immune cell involved in the production of type I interferon, emerged repeatedly as a key cell type. All studies consistently showed that plasmacytoid dendritic cells had increased SUSD1 expression and type-I-interferon activity in patients with kidney failure.
“A key lesson from this study is that the integration of genetic signalling, single-cell assays, and transcriptomic data provide a very powerful framework for translating statistical associations into plausible biological mechanisms. In the case of SUSD1 and kidney dysfunction in decompensated cirrhosis, each layer of evidence provides a critical piece of the puzzle, collectively linking genetic susceptibility to specific cellular pathways and tissue-level processes,” explains Joan Clària, the study’s corresponding co-author, head of the Inflammation and Liver Disease group at IDIBAPS, a senior consultant in the Biochemistry and Molecular Genetics Department at the Hospital Clinic de Barcelona and director of the Grifols Chair, and head of translational operations at EF CLIF.
Study of reference
Sanchez L, Clària J, Galvanin C et al.
Genetic variants and the risk of renal impairment in decompensated cirrhosis: a multi-ancestry genome-wide association study
The Lancet Gastroenterology & Hepatology, 2026; 0
