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

开发实验室衰弱指数以改善等待肝移植的肝硬化患者的死亡率预测

• 批准号: 9979215
• 负责人: Jennifer C. Lai
• 金额: $ 24.2万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979215
• 关键词: Aging; Bilirubin; Biological; Biological Assay; Biological Markers; Blood; Cessation of life; Chronic; Chronology; Cirrhosis; Clinical; Creatinine; Data; Data Collection; Derivation procedure; Development; Dimensions; Elderly; Enrollment; Enzyme-Linked Immunosorbent Assay; Equilibrium; Extrahepatic; Geriatrics; Hand; Hand Strength; Health; Individual; Laboratories; Liver; Liver Cirrhosis; Liver Failure; Liver diseases; Malnutrition; Mass Spectrum Analysis; Measures; Medical; Methods; Modeling; Muscular Atrophy; Organ; Outcome; Patients; Performance; Persons; Phenotype; Physiological; Population; Process; Proteomics; Risk; Scheme; Serum; Serum Proteins; Severities; Sodium; System; Testing; Time; Transplantation; Update; Waiting Lists; balance testing; base; biobank; clinical care; clinical phenotype; cohort; differential expression; experimental study; frailty; functional decline; improved; indexing; instrument; liver transplantation; mortality; mortality risk; novel; performance based measurement; prognostic value; protein biomarkers; sarcopenia; stressor; tool; transplant centers

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.

肝移植是唯一已知的治疗终末期肝病的方法，但它仍然难以捉摸， 五分之一的病人在等待移植前死亡。的优先次序 肝硬化患者进行肝移植是基于他们的死亡风险， 完全由他们基于实验室的终末期肝病模型（MELDNa）评分决定。虽然MELDNa 准确预测大多数糖尿病患者的90天死亡率，低估率高达20% 慢性肝功能衰竭的肝外表现，如肌肉萎缩， 营养不良（我们称之为“虚弱”），没有被他们的MELDNa评分所捕获。 我们已经证明，测量身体虚弱程度的工具可以预测等待名单中的死亡率， 不依赖MELDNa的患者。此外，我们还开发了一种新的临床肝脏， 虚弱指数，包括握力、椅子站立和平衡，将1/5的患者重新分类为 与MELDNa单药相比，其准确的生存状态。这可以作为概念验证， 身体虚弱结构可显著提高死亡风险预测 病人，但必须亲自管理。因此，不能将其并入 国家肝脏分配系统，因为候选人必须经常更新他们的MELDNa评分， 通常位于离移植中心数百英里的地方。 什么是需要更有效地优先考虑肝硬化患者的肝脏提供是血液 生物标志物-用MELDNa评分绘制-可以区分虚弱和非虚弱。使用 基于质谱的蛋白质组学从我们的FrAILT研究中招募的患者的生物标本，我们 鉴定了10种候选血清蛋白生物标志物， 与非虚弱的肝硬化患者相比。在这里，我们建议利用300个额外的 从我们现有的生物储存库中提取患者识别的生物标本，以量化这10种候选物 使用ELISA检测身体虚弱的血清蛋白质生物标志物，得出复合实验室虚弱 与虚弱的临床表型相关的指数，并从两者中开发复合指数。 实验室脆弱生物标志物和MELDNa成分，预测死亡率。关注预测因素 通过脆弱的表型-我们已经证明了这是强烈的预测， 死亡率-是一种生物理性的方法，减少维数，以更有效地 提高死亡率预测。 此R21将为后续R 01应用程序提供必要的数据，以进行外部验证 在一个更大的多中心肝硬化患者队列中， 死亡率的结果。基于实验室的虚弱指数满足了以下实用的临床需求： 一个不需要亲自测试的脆弱指标，以及一个改善 该人群的死亡风险预测有可能更准确地优先考虑肝脏 在国家肝脏分配系统内，根据医疗紧急情况确定移植候选人。 最后， 通过更有效地将稀缺的捐赠肝脏分配给最需要的人， 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疾病。 终末期肝病