Serum Receptor-Interacting Protein Kinase 3 (RIPK3) Is Associated with Transplant-Free Survival in Acute Liver Failure.

BACKGROUND AND AIMS: Prognostication in acute liver failure (ALF) due to acetaminophen (APAP) and other causes of drug-induced liver injury (DILI) remains challenging. Biologically informed prognostic biomarkers may complement existing tools and improve early risk stratification. The aim of this study was to investigate 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 selected from the Acute Liver Failure Study Group registry due to APAP and DILI. 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 (ROC) analyses. Machine learning methods were used to characterise patient heterogeneity and assess robustness of biomarker-outcome associations. RESULTS: 86 ALF patients were alive at day 21 without a liver transplant (LT), while 90 died or received LT. Lower admission RIPK3 levels were independently associated with 21-day TFS after adjustment for clinically relevant covariates, including aetiology, 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 transplant-free survival in ALF and improves the discriminative performance of clinical prognostic models. These findings support RIPK3 as a candidate prognostic biomarker in ALF.