Improving Kidney Function Assessment in Health and Disease

改善健康和疾病中的肾功能评估

• 批准号: 10527334
• 负责人: Lesley Ann Inker
• 金额: $ 73.77万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10527334
• 关键词: Adverse event; Benchmarking; Biological; Biological Assay; Black race; Blood; Blood specimen; Caring; Characteristics; Chronic Disease; Chronic Kidney Failure; Clinical; Clinical Practice Guideline; Collaborations; Creatinine; Cystatins; Data; Development; Diet; Disease; Dose; Epidemiology; Equation; Ethnic Origin; Evaluation; Filtration; Foundations; Geography; Glomerular Filtration Rate; Goals; Health; Health Services Accessibility; Heart failure; Hospitalization; Individual; Inflammation; Investigation; Joints; Kidney Diseases; Knowledge; Laboratories; Liquid Chromatography; Liver Failure; Mass Spectrum Analysis; Measures; Methods; Modeling; Muscular Atrophy; Obesity; Outcome; Participant; Patients; Persons; Pharmaceutical Preparations; Physiological; Population; Population Heterogeneity; Prognosis; Property; Public Health; Race; Renal function; Research; Research Design; Science; Serum; Statistical Methods; Techniques; Testing; United States; Validation; Weight; Work; access restrictions; analytical method; biomarker evaluation; biomarker panel; candidate selection; clinical decision-making; clinical practice; cohort; cost efficient; demographics; design; experience; improved; innovation; marginalization; mass spectrometer; metabolomics; multiplex assay; novel; novel strategies; outcome prediction; patient population; post gamma-globulins; predictive modeling; racial diversity; reduced muscle mass

Accurate assessment of kidney function is fundamental to the care of all patients, but current methods to estimate GFR have error rates of 35-60% in important populations as well as variable accuracy across race, ethnicity and geography, leading to errors in critical decisions, drug dosing, and determination of prognosis. Current GFR estimates include a coefficient for Black vs non-Black which may restrict access to care. As a result, there are critical knowledge gaps in evaluation and management of GFR in health and disease. Our goal is to develop a valid and robust GFR estimate optimized for an individual person that meets the critical unmet need for a confirmatory test. The confirmatory test will use a panel of endogenous filtration markers to estimate GFR (peGFR) from a single blood sample using an equation that does not require serum creatinine or demographic characteristics. Our research team has extensive experience in biomarker evaluation, GFR estimation, epidemiology, laboratory science and metabolomics. Our preliminary data provide proof of concept that a panel of novel metabolites that does not include serum creatinine or demographics can eliminate bias and greatly improve precision of GFR estimates in patients with heart failure and reduced muscle mass; and that novel techniques can be used to produce a high-accuracy and parsimonious prediction model. Aim 1 Using global metabolomic discovery (~1000+ metabolites) on five cohorts (N=2583), we will select candidate metabolites based on maximal joint association with mGFR as well as biological and physiological assessment of their properties as filtration markers. Markers that show acceptable analytical properties in initial testing will be incorporated into a liquid chromatography tandem mass spectrometer (LC-MS/MS) multiplex assay. Aim 2: We propose to use a spectrum of novel approaches, such as marginalizing predictions to down- weight outlier metabolites and kernel nearest neighbor weighted average predictions, to maximize precision as well as robustness across multiple diverse populations and to compare these approaches to a benchmark model developed using superlearner ensemble modeling techniques. Development and external validation in ~3036 and ~3465 participants across 8 and 12 studies, respectively. Aim 3: We propose to evaluate the impact of panel eGFR in patients with heart and liver failure (N=1796) on clinical decisions and outcomes. The expected outcome is development of panel eGFR that can be used as a confirmatory test and ultimately incorporated into clinical practice guidelines. The proposal is highly innovative as it is comprehensive spanning discovery, validation, assessment of clinical utility in populations not previously been studied and use of novel statistical methods to compute individualized GFR estimates. The proposal is significant because it will enable generalizable and accurate individualized GFR estimates in health and disease, particularly diseases with unacceptably GFR estimation high error rates and diverse racial, ethnic and geographic groups.

准确评估肾功能是所有患者护理的基础，但目前的方法 估计 GFR 在重要人群中的错误率为 35-60%，并且不同种族的准确度存在差异， 种族和地理位置，导致关键决策、药物剂量和预后确定的错误。 目前的 GFR 估计包括黑人与非黑人的系数，这可能会限制获得护理的机会。作为一个 因此，在健康和疾病方面的 GFR 评估和管理方面存在严重的知识差距。 我们的目标是开发一个有效且稳健的 GFR 估计值，并针对个人进行优化，以满足以下要求： 验证性测试的关键未满足需求。验证性测试将使用一组内源性过滤 使用不需要血清的方程从单个血液样本中估计 GFR (peGFR) 的标记物 肌酐或人口特征。我们的研究团队在生物标志物方面拥有丰富的经验 评估、GFR 估计、流行病学、实验室科学和代谢组学。我们的初步数据 提供概念证明，一组不包括血清肌酐或的新型代谢物 人口统计学可以消除偏差并大大提高心力衰竭患者 GFR 估计的准确性 肌肉质量减少；并且可以使用新颖的技术来产生高精度和 简约的预测模型。 目标 1 利用五个队列 (N=2583) 的全球代谢组学发现（约 1000 多种代谢物），我们将选择 基于与 mGFR 的最大关节关联以及生物和生理学的候选代谢物 评估它们作为过滤标记的特性。初始时显示出可接受的分析特性的标记物 测试将纳入液相色谱串联质谱仪 (LC-MS/MS) 多重检测 化验。目标 2：我们建议使用一系列新颖的方法，例如边缘化预测以降低 权重异常代谢物和内核最近邻加权平均预测，以最大限度地提高精度 以及跨多个不同人群的稳健性，并将这些方法与基准进行比较 使用超级学习者集成建模技术开发的模型。开发和外部验证 8 项和 12 项研究分别有约 3036 名和约 3465 名参与者。目标 3：我们建议评估 心力衰竭和肝衰竭患者 (N=1796) 的面板 eGFR 对临床决策和结果的影响。 预期结果是开发 eGFR 面板，可用作验证性测试，并最终 纳入临床实践指南。该提案内容全面，极具创新性 涵盖先前未研究和使用的人群中的临床效用的发现、验证和评估 计算个性化 GFR 估计值的新统计方法。该提案意义重大，因为它 将能够对健康和疾病进行普遍且准确的个性化 GFR 估计，特别是 GFR 估计错误率高且种族、民族和地理群体多样化的疾病令人难以接受。