Kidney injury is a frequent, serious complication of decompensated cirrhosis, but individual susceptibility remains poorly understood. While age, sex and liver disease severity influence kidney function, the role of host genetics has been unclear.

To address this, researchers analyzed genetic data from 3220 patients with decompensated cirrhosis across five cohorts, including the CANONIC, PREDICT and ACLARA studies. The findings were then validated in a further 1728 patients with decompensated cirrhosis from four independent cohorts.

The multi-ancestry analysis identified a genome-wide significant risk locus at the SUSD1 gene region that was consistently associated with serum creatinine, a blood marker commonly used to assess kidney function. The findings were replicated across all independent cohorts, with a similar effect observed in patients with European and admixed American genetic ancestries.

The association between SUSD1 and higher creatinine was observed in people with decompensated cirrhosis, but not in those with compensated cirrhosis. In people without cirrhosis, SUSD1 was instead associated with a very small decrease in creatinine. Together, these findings suggest that the effect of the genetic variant depends on the disease context and that its association with renal impairment may be clinically relevant specifically in decompensated cirrhosis.

“What is particularly interesting about this finding is the context specificity of the association. We observed no meaningful association between SUSD1 and renal impairment in the general population or in patients with compensated cirrhosis, while the association was observed in patients with decompensated cirrhosis. This suggests that the effect of this genetic variant may become relevant in the specific context of decompensated cirrhosis, potentially providing new insights into the biological mechanisms underlying renal impairment in this population”, said first author Lukas Otero Sanchez, Postdoctoral Researcher and Resident in Hepatology and Digestive Oncology at Hôpital Universitaire de Bruxelles and Université Libre de Bruxelles, Brussels, Belgium. “The link we observed between SUSD1 expression, plasmacytoid dendritic cells and interferon responses also provides a potential biological pathway that warrants further investigation”, he added.

Patients carrying the risk allele rs2099161[C] presented with higher levels of serum creatinine and were more likely to have kidney failure when they entered the study. The association was strongest among patients carrying two copies of the risk allele: compared with people carrying two copies of the alternative allele, their odds of kidney failure were 60% higher.

The same pattern was observed for kidney failure developing during the first week in the CANONIC cohort. This allele was also associated with a higher likelihood of receiving terlipressin, a treatment used in patients with cirrhosis and kidney failure.

These associations were specific to kidney-related outcomes, with no comparable association with other organ failures, blood pressure, systemic inflammatory markers, mortality or the development of acute-on-chronic liver failure (ACLF).

These findings connect the SUSD1 rs2099161[C] allele not only with a laboratory measure of kidney function, but also with clinically relevant kidney complications.

“The associations with kidney failure and terlipressin use strengthen the link between this genetic finding and clinically important kidney complications. The main value at this stage is the insight it offers into the biology of kidney dysfunction in decompensated cirrhosis. Our results point to an immune pathway that warrants further investigation, but they do not establish that this variant can predict an individual patient’s outcome or determine which treatment they should receive”, said senior author Eric Trépo, Hepatologist and Senior Research Associate at Hôpital Universitaire de Bruxelles and Université Libre de Bruxelles, Brussels, Belgium.