Tubular Secretion in Chronic Kidney Disease

 描述(由申请人提供)：肾小球滤过率(GFR)是肾功能的既定测量，用于定义慢性肾脏疾病(CKD)的存在和严重程度。肾脏的不同生理功能不太可能仅靠GFR来实现。近端小管分泌是一种基本的、肾脏特有的机制，用于快速清除循环中残留的溶质和给药。我们开发和验证了新的检测方法来测量由近端小管分泌初步清除的内源性标志物。我们使用这些标记物来证明在CKD患者中估计的肾小管分泌功能相对于GFR有相当大的个体水平差异。这项资助提出了两个平行的目标，以促进对近端小管分泌功能的了解。首先，我们将评估前瞻性慢性肾功能不全队列研究中的分泌功能，并确定与CKD并发症和主要临床结果的相关性。其次，我们将在广泛的肾功能范围内招募初级队列患者，并比较估计的肾小管分泌功能与GFR在预测肾脏药物清除方面的作用。拟议研究的潜在应用包括早期发现慢性肾脏病，改善对肾脏疾病患者的监测，以及优化肾脏用药剂量策略。

 DESCRIPTION (provided by applicant): The glomerular filtration rate (GFR) is the established measurement of kidney function that is used to define the presence and severity of chronic kidney disease (CKD). The diverse physiological functions of the kidneys are unlikely to be captured by GFR alone. Proximal tubule secretion is an essential, kidney-specific mechanism for rapidly eliminating retained solutes and administered medications from the circulation. We developed and validated novel assays to measure endogenous markers that are primary cleared by proximal tubule secretion. We used these markers to demonstrate considerable individual-level variability in estimated tubule secretion function relative to GFR among CKD patients. This grant proposes two parallel aims to advance understanding of proximal tubule secretion function. First, we will estimate secretion function in the prospective Chronic Renal Insufficiency Cohort study and determine associations with CKD complications and major clinical outcomes. Second, we will recruit a primary cohort of patients across a broad range of kidney function and compare estimated tubule secretion function versus GFR for predicting renal drug clearances. Potential applications of the proposed studies include earlier detection of CKD, improved monitoring of kidney disease patients, and optimized renal medication dosing strategies.