Development and Internal Validation of a Pretransplant Biomarker Panel for Mortality Prediction Following Liver Transplant

Importance: Current pretransplant clinical scoring systems fail to accurately estimate post-liver transplant (LT) survival, making recipient selection challenging. Persistent immune dysfunction contributes to early LT recipient mortality but is not captured by existing models. Objective: To identify plasma biomarkers of pretransplant immune dysfunction and to develop a biomarker-based pre-LT risk stratification tool to predict post-LT mortality. Design, Setting, and Participants: Prospective biomarker analysis of consecutively enrolled adult LT recipients was conducted. Healthy controls were included for baseline comparison. Patients undergoing LT at Houston Methodist Hospital (October 1, 2013, to December 31, 2017) and Rutgers/University Hospital (January 1, 2019, to March 31, 2021) were enrolled under an institutional review board-approved protocol, and data were censored on March 31, 2023, and analyzed. Patients with cirrhosis older than 18 years undergoing deceased donor LT were included. Exclusion criteria were age greater than 70 years, cancer other than hepatocellular carcinoma, retransplant, status 1A, intraoperative mortality, multivisceral transplant (except liver-kidney), and sample availability. Exposures: Plasma cytokine, chemokine, and immune exhaustion biomarkers were quantified using multiplex Luminex assays at the time of transplant. Clinical, demographic, and laboratory data were extracted from institutional databases. Main Outcomes and Measures: The primary outcome was all-cause mortality within 1 year of LT. Secondary outcomes included graft survival, infections, rejection, readmissions, and 24-month survival. Results: A total of 779 adult LTs were performed between 2007 and 2017, with prospective biomarker analysis of 279 consecutively enrolled LT recipients between 2018 and 2022. Median (IQR) participant age was 56.7 (48.2-62.5) years, and 110 of 279 patients (39.4%) were female. Pre-LT plasma levels of B-cell activating factor, C-C motif chemokine ligand 1, eotaxin, fractalkine, interleukin 1β (IL-1β), sIL-6Rβ, metalloproteinase (MMP) 2, and MMP3 were significantly associated with 1-year post-LT mortality. Multivariable Cox proportional hazards modeling identified fractalkine and MMP3 as independent predictors of early post-LT mortality. These were used to develop the Liver Immune Frailty Index (LIFI), stratifying patients into low, moderate, and high risk. One-year mortality was 1.9%, 10.3%, and 63.6% for LIFI-low, -moderate, and -high, respectively. Relative risk of death within 1 year was 5.43 (95% CI, 1.59-18.60; P < .001) for LIFI-moderate and 33.41 (95% CI, 11.48-97.25; P < .001) for LIFI-high compared to LIFI-low. LIFI demonstrated strong discrimination (C statistic, 0.83) and was associated with post-LT infections, longer hospital stays, and reduced patient survival. Conclusions and Relevance: Per the results of this diagnostic/prognostic study, LIFI identifies LT candidates with severe immune dysfunction at high risk for early post-LT mortality, offering a preoperative, objective tool to refine transplant candidacy, guide perioperative management, and improve LT outcomes.