HDL and cardiovascular risk in chronic kidney disease

描述（由申请人提供）：美国近七分之一的成年人患有慢性肾脏疾病（CKD），在过去十年中增加了30%。晚期CKD患者肾功能丧失、心血管事件和死亡的风险非常高，心血管疾病是CKD患者死亡的主要原因。虽然对于CKD患者心血管风险如此之高的原因尚不清楚，但我们和其他人已经证明CKD与全身炎症增加、游离脂肪酸升高和氧化应激相关，从而导致内皮功能障碍。我们和其他人已经证明，高密度脂蛋白（HDL）含有降低体外内皮细胞激活和功能障碍水平的因子。此外，有证据表明CKD患者的HDL在组成和功能上发生改变，这可能直接导致内皮功能障碍，导致动脉粥样硬化和肾功能恶化。我们开发了新的质谱方法来评估HDL的组成和基于细胞的分析来评估HDL保护内皮细胞功能的能力。这些试验的结合提供了对HDL抗炎能力的分子的全面研究。我们的总体假设是CKD引起HDL组成的改变，这些改变导致内皮功能障碍增加，肾小球丢失和心血管疾病（CVD）的风险增加。我们还假设饮食和运动，一种改善体内内皮功能的干预，将导致HDL组成的有益变化。因此，我们的目标是更好地了解HDL组成和功能变化与内皮功能障碍和临床结果的关系。我们将利用nih资助的三个具有良好特征的临床研究来阐明HDL保护内皮细胞功能的机制。为了实现这些目标，我们提出以下目标：1)全面表征CKD人群中HDL的组成和功能；2)识别和量化与心脏事件、肾脏疾病进展和死亡相关的HDL组成和功能的变化；3)确定健康生活方式干预是否能改变CKD受试者的HDL组成并恢复其抗炎特性。本研究将确定CKD患者HDL的分子变化及其与体内和体外内皮功能障碍的关系。此外，我们的研究将确定在死亡风险大大增加的人群中与心血管和肾脏结局相关的HDL组成的变化。

DESCRIPTION (provided by applicant): Nearly one in every seven adults in America has chronic kidney disease (CKD), representing a 30% increase in the past decade. Individuals with advanced CKD are at extraordinarily high risk for loss of kidney function, cardiovascular events, and death, and cardiovascular disease is the leading cause of death in people with CKD. While much is unknown about why cardiovascular risk in individuals with CKD is so high, we and others have demonstrated that CKD is associated with increased systemic inflammation, elevated free fatty acids, and oxidative stress that lead to dysfunction of the endothelium. We and others have shown that high density lipoproteins (HDL) contain factors that reduce the level of activation and dysfunction of endothelial cells in vitro. Moreover, there is evidence that HDL from patients with CKD is altered in composition and function, which may directly cause endothelial dysfunction and lead to atherosclerosis and worsening kidney function. We have developed novel mass spectrometric methods to assess HDL composition and cell-based assays to assess the ability of HDL to preserve endothelial cell function. The combination of these assays provides for a comprehensive investigation of the molecules that contribute to HDL's anti-inflammatory capacity. Our overall hypothesis is that CKD causes changes to HDL composition and that these changes lead to increased endothelial dysfunction and greater risk of glomerular loss and cardiovascular disease (CVD). We also hypothesize that diet and exercise, an intervention that improves endothelial function in vivo, will lead to beneficial changes in HDL composition. Our goal is therefore to better understand the association of changes in HDL composition and function with endothelial dysfunction and clinical outcomes. We will take advantage of three well-characterized, NIH-funded clinical studies to elucidate the mechanisms behind HDL's ability to preserve endothelial cell function. To achieve these objectives, we propose the following aims: 1) Comprehensively characterize HDL composition and function in the CKD population; 2) Identify and quantify the changes in HDL composition and function that are associated with cardiac events, progression of kidney disease, and death; and 3) Determine whether healthy lifestyle interventions modify HDL composition and restore its anti-inflammatory properties in CKD subjects. This proposal will identify the molecular changes in HDL in subjects with CKD and how they are associated with endothelial dysfunction in vitro and in vivo. Moreover, our studies will identify the changes in HDL composition that are associated with cardiovascular and renal outcomes in a population at greatly increased risk of death.