Metabolomics and Renal Functional Reserve

代谢组学和肾功能储备

• 批准号: 10017198
• 负责人: Sushrut S. Waikar
• 金额: $ 22.91万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017198
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Address; Age; Amino Acids; Anabolism; Animals; Biological; Blood; Blood Tests; Cells; Chronic Kidney Failure; Clinic; Clinical Trials Design; Collection; Consumption; Creatinine; Creatinine clearance measurement; Data; Development; Diabetes Mellitus; Diagnosis; Diagnostic tests; Diet; Disease Progression; Dopamine; Dose; Drug usage; Enrollment; Filtration; Future; Glomerular Filtration Rate; Goals; Health; Hour; Individual; Injections; Intravenous; Iothalamate; Kidney; Kidney Diseases; Lipids; Measurement; Measures; Nephrology; Nucleotides; OGTT; Oral; Organ; Participant; Persons; Physiological; Plasma; Proteins; Pulmonary function tests; Race; Renal function; Reproducibility; Research; Rest; Risk; Risk Assessment; Sampling; Serum; Specimen; Staging; Stimulus; Stress Tests; Subcutaneous Injections; Techniques; Technology; Testing; Thallium Myocardial Perfusion Imaging Stress Test; Time; Urine; acylcarnitine; dalton; healthy volunteer; improved; innovation; interest; metabolome; metabolomics; novel; novel diagnostics; organic acid; response; sample collection; sex; small molecule; sugar; tool; urinary; volunteer

The difference between maximal glomerular filtration rate (GFR) and resting GFR, or renal functional reserve (RFR), has been proposed as a complementary measure of kidney health and function. Just as clinicians order dynamic tests of other organ function (e.g., cardiac stress tests and pulmonary function tests) to obtain information not available through static measurements, a kidney function stress test such as RFR could provide valuable information not contained in a single estimate of GFR. In nephrology, RFR has not been tested adequately as a measure of kidney health or risk of AKI or CKD progression. A major barrier to more widespread testing of RFR is the complexity of the measurement, which requires injection of an exogenous filtration marker followed by urinary and/or plasma collections for measurement of GFR, both before and after a physiological stimulus such as an oral protein load. The overall goal of this R21 application is to develop novel and simpler tools for RFR estimation through an innovative study that includes classical physiological measurements and state of the art metabolomic profiling. In Aim 1, we propose to study RFR in 100 individuals, including 50 healthy volunteers and 50 with chronic kidney disease (CKD). Subjects will have GFR measured through urinary clearance of cold iothalamate before and after a physiological stimulus (oral protein, 1g/kg; or intravenous dopamine, 1.5-2.0 µg/kg/min). We will test the within-person reproducibility of RFR and investigate relevant biological variables and diet as determinants of RFR and its reproducibility. We will also test whether changes in urinary creatinine clearance correlate sufficiently with change in GFR as measured by urinary iothalamate clearance. In Aim 2, we will perform untargeted metabolomic profiling of plasma samples collected in Aim 1 to discover metabolites that correlate with RFR. The metabolome consists of small molecules (typically < 1500 daltons, including sugars, amino acids, organic acids, nucleotides, acylcarnitines, and lipids) in a cell or biological specimen. Advances in metabolomics technologies now permit the relative quantification of ~1000 known metabolites. The kidneys exert a major impact on the plasma metabolome. The discovery of metabolites from baseline samples that predict RFR could allow RFR to be estimated with a one- time blood test, without the need for a protein or other physiological stimulus. Metabolites whose changes from pre- to post-stimulus correlate with RFR could be used for the development of a test analogous to oral glucose tolerance testing for diabetes. The expected result from this R21 proposal is a true paradigm shift through the development of new diagnostic tests in nephrology to improve diagnosis, risk prediction, and clinical trial design.

最大肾小球滤过率（GFR）和静止GFR或肾功能之间的差异 储备（RFR）已被提议作为肾脏健康和功能的完整度量。就像 临床医生订购其他器官功能的动态测试（例如心脏应力测试和肺功能测试） 为了通过静态测量获得无法获得的信息，肾脏功能应力测试（例如RFR） 可以提供GFR单个估计中未包含的有价值的信息。在肾脏科中，RFR还没有 适当地测试作为肾脏健康或AKI或CKD进展风险的度量。更多的障碍 RFR的宽度测试是测量的复杂性，需要注入外源性 过滤标记，然后是用于测量GFR的尿和/或等离子体收集，无论是在A之前还是之后 生理刺激，例如口服蛋白质负荷。该R21应用程序的总体目标是开发新颖 通过包括经典生理学的创新研究，以及更简单的RFR估算工具 测量和最新代谢组分析的状态。在AIM 1中，我们建议在100中研究RFR 个人，包括50名健康志愿者和50名患有慢性肾脏疾病（CKD）的人。受试者将有GFR 通过在物理刺激之前和之后的冷硫氨酰胺的尿中测量（口服蛋白质， 1G/kg;或静脉注射多巴胺，1.5-2.0 µg/kg/min）。我们将测试RFR和RFR的个人可重复性 研究相关的生物学变量和饮食作为RFR的决定剂及其可重复性。我们也会 测试泌尿肌酐清除率的变化是否与GFR的变化正确相关 尿硫氨酰胺清除。在AIM 2中，我们将执行血浆样品的不靶向代谢组分析 收集在AIM 1中以发现与RFR相关的代谢产物。代谢组由小 分子（通常<1500个达尔顿人，包括糖，氨基酸，有机酸，核苷酸，酰基肉碱， 和脂质）在细胞或生物标本中。代谢组学技术的进步现在允许亲戚 量化约1000个已知代谢产物。孩子们对血浆代谢组产生了重大影响。这 从基线样品中发现代谢物可以预测RFR，可以估计RFR 时间血液测试，无需蛋白质或其他物理刺激。代谢物的变化 刺后与RFR相关的刺激后可以用于开发类似于口服葡萄糖的测试 糖尿病的耐受性测试。 R21提案的预期结果是通过 开发肾脏科的新诊断测试，以改善诊断，风险预测和临床试验 设计。