- An international study identifies a genetic variant at the SUSD1 locus associated with the risk of renal impairment in people with decompensated cirrhosis.

 
- More than 70 researchers, including scientists from CNAG, analysed genetic and clinical data from over 5,000 people of diverse ancestries to investigate the genetic factors underlying this association.
 
- Published in The Lancet Gastroenterology & Hepatology, the findings shed light on an immune pathway that explain the connection between liver and kidney dysfunction and open new avenues for therapeutic approaches.
 
 
 
October 16, 2026. When the liver fails, the kidneys can be affected too. Cirrhosis, a condition in which the liver becomes progressively damaged and loses its ability to function properly, can lead to serious complications as the disease advances. In its most severe stage, known as decompensated cirrhosis, kidney injury is a frequent and serious complication. While age, sex and the severity of liver disease are known to influence kidney function, the contribution of genetic differences has remained unclear. To address this question, an international group of more than 70 researchers have come together to investigate the biological mechanisms behind kidney dysfunction in advanced cirrhosis. 
 
The study identifies SUSD1 as a genetic risk locus that helps explain why some patients are more susceptible to kidney injury. The research, published in The Lancet Gastroenterology & Hepatology, was led by the Hôpital Universitaire de Bruxelles Université Libre de Bruxelles, and the European Foundation for the Study of Chronic Liver Failure (EF CLIF); with contributions from Centro Nacional de Análisis Genómico (CNAG) and Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)–Hospital Clínic de Barcelona. 
 
The research involved almost 5,000 people with decompensated cirrhosis across nine cohorts. The analysis, which included people from different genetic ancestries, identified a significant genetic region around the SUSD1 gene that was consistently associated with serum creatinine, a blood marker commonly used to assess kidney function. The association was replicated across four independent cohorts, with a similar effect observed in people of European and admixed American genetic ancestries.
 
 
A step further: identifying the cells involved
 
Identifying a genetic association is only the first step. The researchers then used several complementary approaches to investigate how the genetic finding might affect SUSD1 activity and which biological processes could be involved. By combining the genetic results with single-cell and spatial analyses of liver, blood and kidney tissue, they were able to explore which cells show the highest SUSD1 activity and how they may be involved in kidney dysfunction. The analyses, performed at Centro Nacional de Análisis Genómico (CNAG), pointed to plasmacytoid dendritic cells, a type of immune cell, and type-I interferon, a protein involved in the immune response, as possible links between genetic variation and kidney injury.
 
“The single-cell analyses allowed us to move from a genetic association to a plausible cellular mechanism. Across liver, blood and kidney, they consistently pointed to plasmacytoid dendritic cells as a major SUSD1-expressing population, with increased SUSD1 expression and type-I interferon activity in patients with renal impairment. However, these approaches are observational and provide snapshots of complex tissues. They can identify associations and localise biological signals, but they cannot establish whether the SUSD1–pDC–interferon axis directly causes kidney injury. Functional and longitudinal studies will be needed to test this mechanism,” said Juan C. Nieto, Immunologist in the Single Cell Genomics Group at CNAG.
 
“A key lesson from this study is that integrating genetic, single-cell, and spatial transcriptomic data provides a 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 contributes a critical piece of the puzzle, collectively linking genetic susceptibility to specific cellular pathways and tissue-level processes”, said co-first author Joan Clària, Director of the Grifols Chair and Head of Translational Operations at EF CLIF, and Group Leader of the Inflammation and Liver Disease group at IDIBAPS–Hospital Clínic de Barcelona.
 
 
Potential implications and future research
 
The study reveals a genetic link to renal impairment in patients with decompensated cirrhosis and points to a possible role for the immune system. This provides a new piece of the puzzle in understanding why kidney complications develop in some patients but not others. The next step will be to determine how SUSD1 variants affect immune-cell function and whether changes in this pathway contribute directly to kidney injury.
 
“The next steps should address two questions raised by the study. First, how does the progression of cirrhosis affect the association reported here? The fact that the association with kidney failure was not observed among patients with compensated cirrhosis and was even protective among heathy subjects suggest mechanisms reminiscent of antagonistic pleiotropy. The second question is whether the SUSD1–pDC–interferon pathway contributes directly to kidney injury. Elucidating this question should stimulate the discovery of clinically actionable biomarkers for assessing the risk of kidney impairment in patients with decompensated cirrhosis and perhaps result in the identification of novel therapeutic approaches for treating HRS-AKI, which is responsive to terlipressin in only 30%-40% of patients”, said senior author Richard Moreau, Director of EF CLIF.
 
 
The research drew on the CANONIC, PREDICT, ACLARA, ANRS CO12 CirVir and CIRRAL cohorts and publicly available resources including UK Biobank and the Kidney Precision Medicine Project.
 
Other authors in the study are Lukas Otero Sanchez, Clélia Galvanin, Ferran Aguilar, Richard Layese, Matteo Serra, Laura Jiménez-Gracia, Paula Nieto, Darko Castven, Sona Frankova, Milan Jirsa, David Tornai, Anna Curto-Vilalta, Alberto Queiroz Farias, Maria Papp, Patricia Momoyo Zitelli, Paolo Caraceni, Giacomo Zaccherini, Luciana L Goncalves, Carlo Alessandria, Gustavo Pereira, Wim Laleman, Adrian C Gadano, Salvatore Piano, Angelo Z Mattos, Desislava Germanova, Valério Lucidi, Daphnée Soret, Line Carolle Ntandja Wandji, Frank Erhard Uschner, Aldo Torre, Victor Vargas, Liliana S C Mendes, Rajeshwar P Mookerjee, Carlos Benitez, Mario R Alvares-da-Silva, Myriam Remmelink, Paulo L Bittencourt, Agustin Albillos, Claudia Alves Couto, Rafael Bañares, Manuel Mendizabal, Delphine Degré, Claudio L Toledo, Martin Janicko, Daniel F Mazo, Mauricio Castillo Barradas, William Bernal, Adelina Zarela Lozano Miranda, P Martín Padilla-Machaca, Alexander Zipprich, René Malé-Velázquez, Christophe Moreno, André Castro Lyra, Flair Carrilho, Javier Fernandez, Jonel Trebicka, Rajiv Jalan, Paolo Angeli, Horia Stefanescu, Pierre-Emmanuel Rautou, Stephan Buch, Alexandre Louvet, Jens U Marquardt, Thierry Gustot, Holger Heyn, Vicente Arroyo, Nathalie Ganne-Carrié, Jan Sperl, Philippe Mathurin, Pierre Nahon, and Eric Trépo.
 
 
 
 
REFERENCE ARTICLE
 
Otero 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. Lancet Gastroenterol Hepatol 2026. DOI: 10.1016/S2468-1253(26)00217-7