Document text
Principal Investigator: Keri Elizabeth Lunsford
Organization: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
Fiscal Year: 2024
Award: $748,049
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
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.
Terms: <7S Gamma Globulin><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antigens><Award><Biological><Biological Markers><Biometrics><Biometry><Biostatistics><Blood Plasma><Blood Serum><Blood leukocyte><Body Composition><CX(3)C protein><Cause of Death><Cell Body><Cells><Cellular Immune Function><Cessation of life><Chemokine (C-X3-C Motif) Ligand 1><Chemotactic Cytokines><Cirrhosis><Clinical><Clinical Assessment Tool><Clinical Data><Clinical Protocols><Clinical assessments><Collection><Complement><Complement Proteins><Data><Death><Development><Dimensions><Early Intervention><Ethics><Evaluation><Evolution><Exhibits><FKN protein><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Fractalkine><Futility><HCV><Hepatic Transplantation><Hepatitis C virus><Homologous Chemotactic Cytokines><IgG><Immune><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune Markers><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune Tolerance><Immune system><Immunes><Immunodeficiency and Immunosuppression Disorders><Immunoglobulin G><Immunologic Diseases><Immunologic Markers><Immunologic Stimulation><Immunologic Tolerance><Immunological Diseases><Immunological Dysfunction><Immunological Stimulation><Immunological System Dysfunction><Immunostimulation><Impairment><Infection><Inflammation><Inflammatory><Inflammatory Response><Intercrines><Laboratories><Leukocytes><Leukocytes Reticuloendothelial System><Link><Liquid substance><Liver><Liver Grafting><Liver Transplant><MMP3><MMP3 gene><Machine Learning><Malnutrition><Marrow leukocyte><Measurement><Measures><Medical><Metabolic stress><Modeling><Muscle Atrophy><Muscular Atrophy><NIDDK><National Institute of Diabetes and Digestive and Kidney Diseases><Nutritional Deficiency><Organ><Outcome><Outcome Study><Oxidative Phosphorylation><Oxidative Phosphorylation Pathway><PBMC><Patients><Performance><Peripheral Blood Mononuclear Cell><Phenotype><Physiologic><Physiological><Plasma><Plasma Serum><Population><Predicting Risk><Prevalence><Process><Protein-Calorie Malnutrition><Protein-Energy Malnutrition><Proteomics><Publishing><Qualifying><RNA Seq><RNA sequencing><RNAseq><Radiography><Reticuloendothelial System, Serum, Plasma><Risk><Risk Assessment><Roentgenography><SIS cytokines><SL-1><STMY><STMY1><STR1><Sampling><Scientist><Sentinel><Serum><Severities><Small Inducible Cytokine D1><Testing><Time><Transplant Recipients><Transplant Surgeon><Transplantation><Undernutrition><Validation><Waiting Lists><White Blood Cells><White Cell><adaptive immunity><bio-markers><biobank><biologic><biologic marker><biomarker><biomarker array><biomarker panel><biorepository><chemoattractant cytokine><chemokine><chronic liver injury><cirrhotic><clinical risk><cohort><complementation><computer based prediction><cytokine><death risk><developmental><dietary deficiency><ethical><exhaustion><flow cytophotometry><fluid><forecasting risk><frailty><hepatic body system><hepatic organ system><high risk><hypoimmunity><immune deficiency><immune function><immune system tolerance><immune unresponsiveness><immune-based biomarkers><immunodeficiency><immunogen><immunological biomarkers><immunological markers><immunological paralysis><improved><improved outcome><indexing><infection recurrence><innovate><innovation><innovative><insight><intrahepatic><liquid><liver transplantation><machine based learning><malnourished><marker panel><metabolism measurement><metabolomics><metabonomics><mortality><mortality risk><multiomics><multiple omics><muscle breakdown><muscle degradation><muscle deterioration><muscle loss><muscle wasting><novel><nutrition deficiency><nutrition deficiency disorder><nutritional deficiency disorder><panomics><patient stratification><post-transplant><post-transplantation><posttransplant><posttransplantation><predict risk><predict risks><predicted risk><predicted risks><predicting risks><predictive modeling><predictive risk><predicts risk><prevent><preventing><radiologic imaging><radiological imaging><recurrent infection><recurring infection><risk prediction><risk predictions><risk stratification><sarcopenia><sarcopenic><senescence><senescent><statistics><stratified patient><stratify risk><therapeutic target><tool><transcriptome sequencing><transcriptomic sequencing><transcriptomics><transplant><transplant patient><validations><waitlist><wasting><white blood cell><white blood corpuscle>