Development of a laboratory frailty index to improve prediction of mortality in patients with cirrhosis awaiting liver transplantation

肝移植是唯一已知的治疗终末期肝病的方法，但它仍然难以达到 在美国等待移植之前死亡的患者中，每5人中就有1人。确定优先顺序 肝硬变患者接受肝移植是基于他们的死亡风险，确定 完全由他们基于实验室的终末期肝病模型(MELDNa)评分。而MELDNa 它准确地预测了大多数肝硬变患者的90天死亡率，低估了高达20% 慢性肝功能衰竭的肝外表现，如肌肉萎缩和 营养不良(我们称之为“脆弱”)，并不反映在他们的MELDNa评分中。 我们已经证明，测量身体虚弱的仪器可以预测等待死亡人数 不依赖MELDNa的肝硬变患者。此外，我们还开发了一种新的临床肝脏 脆弱指数，从握力、椅子站立和平衡，将1/5的患者重新分类为 与单独的MELDNa相比，他们准确的生存状态。这是一个概念证明， 体能脆弱的构建可以显著提高对肝硬变死亡风险的预测 患者；但必须亲自给药。因此，它不能合并到 国家肝脏分配系统，因为考生必须经常更新他们的MELDNa分数，但 通常位于离移植中心数百英里的地方。 为了更有效地优先考虑肝硬变患者，需要的是血液。 生物标记物-用MELDNa评分绘制-可以区分虚弱和非虚弱。vbl.使用 来自我们FrAILT研究的患者的基于质谱仪的蛋白质组学，我们 确定10个在脆弱人群中差异表达的候选血清蛋白生物标志物 与非虚弱的肝硬变患者相比。在这里，我们建议利用额外的300 从我们现有的生物储存库中提取患者识别的生物样本来量化这10个候选 用ELISA检测身体虚弱的血清蛋白生物标记物，得出综合实验室虚弱 与虚弱的临床表型相关的指数，并从两者发展出一个综合指数 实验室脆弱的生物标志物和预测死亡率的MELDNa成分。关注预测因素 通过脆弱的表型--我们已经证明了它可以很好地预测 死亡率-是一种生物上合理的降维方法，可以更有效地 加强死亡率预测。 此R21将提供后续R01应用程序外部验证所需的数据 这一综合实验室脆弱指数在较大的多中心肝硬变患者队列中的应用 死亡的后果。基于实验室的脆弱指数满足了临床上对 不需要亲自测试的脆弱性度量，以及改进的综合指数 这一人群的死亡风险预测有可能更准确地确定肝脏的优先顺序 在国家肝脏分配系统内按医疗紧急情况确定的移植候选者。最终， 通过更有效地将稀缺的捐献肝脏分配给最需要的人，我们可以减少 肝移植等待名单上的死亡率并帮助更多的患者治愈他们的 终末期肝病。

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.