JHEP reports : innovation in hepatology · 2026
Serum receptor-interacting protein kinase 3 (RIPK3) is associated with transplant-free survival in acute liver failure.
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Mehta Gautam, Ding Chengyi, Soffientini Ugo, Speiser Jaime L, Bahnassi Sarah, Dara Lily, Durkalski Valerie, Lee William M, Karvellas Constantine J, US Acute Liver Failure Study Group
Аннотация
BACKGROUND & AIMS: Prognostication in acute liver failure (ALF) due to acetaminophen or drug-induced liver injury remains challenging. Biologically informed prognostic biomarkers may complement existing tools and improve early risk stratification. We aimed at investigating the associations between circulating mediators of inflammatory cell death and 21-day transplant-free survival (TFS) in ALF.
METHODS: We conducted a nested case-control study of 176 adults with ALF due to acetaminophen or drug-induced liver injury; they were selected from the Acute Liver Failure Study Group registry. Serum levels of receptor-interacting protein kinase 3 (RIPK3), mixed lineage kinase domain-like protein (MLKL), gasdermin D (GSDMD), and gasdermin E (GSDME) were measured at admission (Day 1) and Day 4. Associations with 21-day TFS were evaluated using multivariable logistic regression and receiver operating characteristic analyses. Machine learning methods were used to characterize patient heterogeneity and assess the robustness of biomarker-outcome associations.
RESULTS: At Day 21, 86 patients with ALF were alive without a liver transplant, whereas 90 died or received a liver transplant. Lower admission RIPK3 levels were independently associated with 21-day TFS after adjustment for clinically relevant covariates, including etiology, MELD score, and organ support requirements (adjusted odds ratio 1.10 per 1 ng/ml decrease; 95% CI 1.03-1.17). Incorporation of RIPK3 into clinical models at admission improved discrimination compared with established prognostic tools (AUROC 0.87; 95% CI, 0.81-0.92). The prognostic association of RIPK3 was most evident in patients with greater physiological severity at presentation.
CONCLUSIONS: Serum RIPK3 is independently associated with TFS in ALF and improves the discriminative performance of clinical prognostic models. These findings support RIPK3 as a candidate prognostic biomarker in ALF.
IMPACT AND IMPLICATIONS: In this study of 176 patients with ALF, lower serum receptor-interacting protein kinase 3 (RIPK3) levels were independently associated with 21-day transplant-free survival. The incorporation of RIPK3 into established prognostic tools improved discrimination between survivors and non-survivors. This study has particular clinical relevance to patients with ALF who had a higher burden of multiorgan failure, in whom the prognostic association of RIPK3 was more evident. Incorporating RIPK3 in current prognostic models may assist clinical decisions regarding which patients with ALF require transplantation vs. those who may recover with medical therapy; however, future prospective studies are needed to validate these findings.
METHODS: We conducted a nested case-control study of 176 adults with ALF due to acetaminophen or drug-induced liver injury; they were selected from the Acute Liver Failure Study Group registry. Serum levels of receptor-interacting protein kinase 3 (RIPK3), mixed lineage kinase domain-like protein (MLKL), gasdermin D (GSDMD), and gasdermin E (GSDME) were measured at admission (Day 1) and Day 4. Associations with 21-day TFS were evaluated using multivariable logistic regression and receiver operating characteristic analyses. Machine learning methods were used to characterize patient heterogeneity and assess the robustness of biomarker-outcome associations.
RESULTS: At Day 21, 86 patients with ALF were alive without a liver transplant, whereas 90 died or received a liver transplant. Lower admission RIPK3 levels were independently associated with 21-day TFS after adjustment for clinically relevant covariates, including etiology, MELD score, and organ support requirements (adjusted odds ratio 1.10 per 1 ng/ml decrease; 95% CI 1.03-1.17). Incorporation of RIPK3 into clinical models at admission improved discrimination compared with established prognostic tools (AUROC 0.87; 95% CI, 0.81-0.92). The prognostic association of RIPK3 was most evident in patients with greater physiological severity at presentation.
CONCLUSIONS: Serum RIPK3 is independently associated with TFS in ALF and improves the discriminative performance of clinical prognostic models. These findings support RIPK3 as a candidate prognostic biomarker in ALF.
IMPACT AND IMPLICATIONS: In this study of 176 patients with ALF, lower serum receptor-interacting protein kinase 3 (RIPK3) levels were independently associated with 21-day transplant-free survival. The incorporation of RIPK3 into established prognostic tools improved discrimination between survivors and non-survivors. This study has particular clinical relevance to patients with ALF who had a higher burden of multiorgan failure, in whom the prognostic association of RIPK3 was more evident. Incorporating RIPK3 in current prognostic models may assist clinical decisions regarding which patients with ALF require transplantation vs. those who may recover with medical therapy; however, future prospective studies are needed to validate these findings.