Liver transplantation is the only known cure for end-stage liver disease, but it remains elusive to the 1 in 5 patients who dies on the U.S. waitlist before reaching transplant. Prioritization of patients with cirrhosis for liver transplantation is based on their risk of mortality, determined entirely by their laboratory-based Model for End- Stage Liver Disease (MELDNa) score. While MELDNa accurately predicts 90-day mortality in most cirrhotic patients, it underestimates it in up to 20% whose extrahepatic manifestations of chronic liver failure, such as muscle wasting and under-nutrition (which we have termed frailty), are not captured by their MELDNa score. We have demonstrated that instruments that measure physical frailty predict waitlist mortality in cirrhotic patients independent of MELDNa. Furthermore, we have developed a novel clinical liver frailty index, from grip strength, chair stands, and balance, that reclassifies 1 in 5 patients to their accurate survival status, compared to MELDNa alone. This serves as proof-of-concept that the construct of physical frailty can signify- cantly improve mortality risk prediction in cirrhotic patients; but it must be administered in person. For this reason, it cannot be incorporated into a national liver allocation system because candidates must update their MELDNa score frequently but are often located hundreds of miles away from their transplant center. What is needed to more effectively prioritize patients with cirrhosis for liver offers is a blood biomarker - drawn with the MELDNa score - that can distinguish the frail from the non-frail. Using mass spectrometry- based proteomics on biospecimens from patients enrolled in our FrAILT Study, we identified 10 candidate serum protein biomarkers that are differentially expressed in frail compared to non-frail patients with cirrhosis. Here, we propose to leverage 300 additional patient-identified biospecimens from our existing biorepository to quantify these 10 candidate serum protein biomarkers of physical frailty using ELISAs, derive a composite laboratory frailty index associated with the clinical phenotype of frailty, and develop a composite index from both laboratory frailty biomarkers and MELDNa components that predicts mortality. Focusing on predictors through the phenotype of frailty - which we have already demonstrated to be strongly predictive of mortality - is a biologically rational method of reducing dimensionality to more efficiently enhance mortality prediction. This R21 will provide the data necessary for a subsequent R01 application to externally validate this composite laboratory frailty index in a larger, multi-center cohort of patients with cirrhosis for the outcome of mortality. A laboratory-based frailty index fills a pragmatic clinical need for a metric of frailty that does not require in-person testing, and a composite index that improves mortality risk prediction in this population has the potential to more accurately prioritize liver transplant candidates by medical urgency within the national liver allocation system. Ultimately, by more effectively allocating scarce donor livers to those in greatest need, we can reduce mortality on the liver transplant waitlist and help more patients achieve a cure for their end-stage liver disease.
The current metric to prioritize patients on the liver transplant waitlist underestimates mortality risk in up to 20% of patients with cirrhosis whose severity of extrahepatic manifestations of chronic liver failure, such as muscle wasting and under-nutrition, is not captured by this laboratory-based Model for End-Stage Liver Disease (MELDNa) metric. We have demonstrated that performance-based instruments of ?frailty? can improve mortality risk prediction in patients with cirrhosis, but these instruments must be administered in person. In this project, we will develop both a laboratory liver frailty index for clinical care and a composite index to improve mortality prediction that can ultimately be incorporated into a national liver allocation scheme to reduce mortality on the liver transplant waitlist.
