Metabolomics and Renal Functional Reserve

最大肾小球滤过率（GFR）和静息GFR之间的差异，或肾功能 肾储备（RFR）已被提议作为肾脏健康和功能的补充措施。正如 临床医生安排其他器官功能的动态测试（例如，心脏负荷试验和肺功能试验） 为了获得静态测量无法获得的信息，肾功能负荷试验，如RFR 可以提供GFR单一估计值中不包含的有价值的信息。在肾脏病学中，RFR尚未被 作为衡量肾脏健康或阿基或CKD进展风险的指标进行充分测试。一个主要的障碍， RFR的广泛测试是测量的复杂性，需要注入外源性 滤过标志物，然后是尿液和/或血浆收集，用于测量GFR，无论是之前还是之后， 生理刺激，如口服蛋白质负荷。该R21应用程序的总体目标是开发新的 通过一项创新性研究（包括经典生理学研究）， 测量和最新代谢组学分析。在目标1中，我们建议研究100名 包括50名健康志愿者和50名慢性肾脏病（CKD）患者。受试者的GFR 通过在生理刺激（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的人内重现性， 研究相关生物变量和饮食作为RFR及其再现性的决定因素。我们还将 检测尿肌酐清除率的变化是否与GFR的变化充分相关， 尿碘酞清除率在目标2中，我们将对血浆样本进行非靶向代谢组学分析 在目标1中收集，以发现与RFR相关的代谢物。代谢组由小分子 分子（通常< 1500道尔顿，包括糖、氨基酸、有机酸、核苷酸、酰基肉毒碱， 和脂质）。代谢组学技术的进步现在允许相对 约1000种已知代谢物的定量。肾脏对血浆代谢组产生重大影响。的 从基线样本中发现可预测RFR的代谢物，可以用一种 时间血液测试，而不需要蛋白质或其他生理刺激。梅托希亚， 刺激前后与RFR的相关性可用于开发类似于口服葡萄糖的测试 糖尿病的耐受性测试这一R21提案的预期结果是一个真正的范式转变， 开发新的肾病诊断测试，以改善诊断、风险预测和临床试验 设计

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.