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.

肝移植是唯一已知终末期肝病的治疗方法，但它仍然难以捉摸 在接受移植之前在美国等待名单上死亡列表的五分之一的患者中有1名患者。优先级 肝硬化进行肝移植的患者是基于死亡率的风险，确定 完全通过其基于实验室的末期肝病（MELDNA）评分的模型。而Meldna 准确地预测大多数肝硬化患者的90天死亡率，它低估了多达20％ 慢性肝衰竭的肝外表现，例如肌肉浪费和 不足（我们称为“脆弱”）的不足，并未被其MELDNA得分所捕获。 我们已经证明了衡量物理脆弱的工具预测候补名单死亡率 肝硬化患者独立于MeldNA。此外，我们已经开发了一种新型的临床肝 从握力强度，椅子支架和平衡中，脆弱的指数将5个患者重新分类为 与单独使用Meldna相比，它们的准确生存状态。这是概念证明 身体脆弱的构造可以指示cirrhotic的死亡率风险预测 患者;但必须亲自管理。因此，它不能纳入 国家肝分配系统，因为候选人必须经常更新其MELDNA评分，但是 通常位于距其移植中心数百英里的地方。 更有效地将肝硬化患者优先排序的是血液 生物标志物（以MELDNA得分绘制）可以将脆弱与非怪胎区分开。使用 质谱蛋白质组学对我们脆弱研究的患者的生物测量蛋白质组学，我们 确定了10种候选血清蛋白生物标志物，它们在脆弱中差异表达 与肝硬化的非网络患者相比。在这里，我们建议利用300个额外 我们现有的生物库中的患者鉴定的生物测量来量化这10个候选者 使用ELISA的身体虚弱的血清蛋白质生物标志物，得出复合实验室脆弱 与脆弱的临床表型相关的指数，并从两者中发展出复合指数 预测死亡率的实验室脆弱生物标志物和MELDNA成分。专注于预测因子 通过脆弱的表型 - 我们已经证明是有力预测的 死亡率 - 是一种将维度降低至更有效的生物学合理方法 提高死亡率预测。 该R21将提供随后的R01应用所需的数据以进行外部验证 该复合实验室脆弱指数在较大的多中心肝硬化患者中 为了死亡的结果。一个基于实验室的脆弱指数满足了对务实的临床需求 不需要面对面测试的脆弱度量，以及改进的综合指数 该人群中的死亡率风险预测有可能更准确地优先考虑肝脏 国家肝脏分配系统内的医疗急需移植候选者。 最终， 通过更有效地将稀缺的供体肝脏分配给最需要的肝脏，我们可以减少 肝移植候补名单上的死亡率，并帮助更多的患者治愈他们的治疗方法 末期肝病。