Multi-Center Validation and Biologic Assessment of a Novel Pre-Transplant Biomarker Panel to Predict Liver Transplant Recipient Mortality

PROJECT SUMMARY Due to organ shortage, livers are transplanted in order of recipient medical urgency; however, ethical principles dictate avoidance of futile transplantation. The most common cause of death early after liver transplant (i.e. futility) relates to consequences of an immune system which is frail or dysfunctional prior to transplant. We

have previously identified the Liver Immune Frailty Index (LIFI), a pre-transplant biomarker panel that predicts risk of early post-transplant death. In our discovery cohort of 279 liver transplant recipients, pre- transplant measurement of LIFI, based on HCV IgG, and plasma Fractalkine, and MMP3, can discriminate risk

of death within one-year following liver transplant with a c-statistic of 0.84 and a false-positive rate of 4%. LIFI- low corresponds to 1.4% one-year mortality compared with 58.3% for LIFI-high. Multicenter validation is necessary to advance the LIFI as an objective clinical index to predict the risk of liver transplant futility.

Mechanistically, our data suggest that immune frailty may relate to skewed intracellular energetics and immune cell exhaustion. These alterations likely result from severe cirrhosis-associated immune dysfunction. In preliminary studies, LIFI was determined at the time of transplant. Pre-transplant immune dysfunction is likely a

fluid process and may also be responsible for decompensation and death on the waitlist. Based on this, we hypothesize that patients listed for LT exhibit both progressive pre-LT immune dysfunction (immune frailty) and cirrhosis-related physical frailty, which predisposes patients to wait-list and early post-LT mortality. The

cumulative effect is detectable with serum biomarkers of immune dysfunction. To evaluate this, we have established the Liver Immune Frailty Evaluation (LIFE) Consortium, comprised of six centers whose volume encompasses almost 10% of annual US liver transplants. Plasma, PBMCs, radiographic, and clinical

data will be collected from waitlisted patients at LIFE centers. In Aim 1, we will perform multicenter validation and refinement of the LIFI. In Aim 2, we will longitudinally assess biomarkers of immune dysfunction and AI- driven body composition analysis (physical frailty) among waitlisted patients who either receive liver transplant

or who expire due to severe decompensation prior to or early post-liver transplant. We will also expand our understanding of the development of immune frailty through targeted multiomic assessment. This study serves as a direct extension and complement to our ongoing evaluation of severe pre-transplant immune dysfunction,

currently supported by a NIDDK K08 Award. Outcomes from this study will advance LIFI as a novel objective index for pre-transplant patient assessment, and will expand understanding of immune frailty development. IMPACT: LIFI is an innovative index that provides crucial insight into liver transplant candidate immune

function and risk of post-transplant mortality, and no alternative pre-transplant clinical indices provide this key data. Validation and pre-transplant correlation of LIFI is critical to improve transplant timing, prevent wasting of livers in high-risk patients, and identify therapeutic targets to reverse immune frailty and improve outcomes.