HDL and cardiovascular risk in chronic kidney disease

高密度脂蛋白和慢性肾脏病的心血管风险

• 批准号: 8370031
• 负责人: ANDREW N HOOFNAGLE
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8370031
• 关键词: Activities of Daily Living; Adult; Aerobic Exercise; Affect; American; Americas; Anti-Inflammatory Agents; Anti-inflammatory; Antiatherogenic; Applications Grants; Atherosclerosis; Attenuated; Biological Assay; Biological Preservation; Blood Vessels; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell physiology; Cells; Cessation of life; Cholesterol; Chronic Kidney Failure; Clinical; Clinical Data; Clinical Research; Cohort Studies; Data; Development; Diet; Disease Pathway; Disease Progression; End stage renal failure; Endothelial Cells; Endothelium; Event; Freedom; Functional disorder; Funding; Future; General Population; Glomerular Filtration Rate; Goals; Health; High Density Lipoproteins; High Prevalence; In Vitro; Individual; Inflammation; Intervention; Investigation; Kidney; Kidney Diseases; Kidney Failure; Laboratories; Lead; Low-Density Lipoproteins; Measures; Methods; Molecular; Myocardial Infarction; National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases; Nonesterified Fatty Acids; Outcome; Oxidative Stress; Pathway interactions; Patients; Persons; Phenotype; Population; Property; Proteins; Public Health; Randomized Controlled Trials; Renal function; Research Institute; Risk; Risk Factors; Staging; Stroke; United States; United States National Institutes of Health; Vasodilation; base; cardiovascular disorder risk; cardiovascular risk factor; design; diet and exercise; high risk; improved; in vivo; inorganic phosphate; lifestyle intervention; macrophage; new therapeutic target; novel; particle; treatment strategy

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. PUBLIC HEALTH RELEVANCE: Individuals with chronic kidney disease (CKD) are much more likely to die of cardiovascular disease and kidney failure than people in the general population. We will measure the composition and function of high density lipoprotein (HDL) particles, and investigate how these changes in HDL cause inflammation in the lining of blood vessels, and increase the risk of poor outcomes in individuals with CKD.

描述（由申请人提供）：美国近七分之一的成年人患有慢性肾病 (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极高，而心血管疾病是 CKD 患者死亡的主要原因。虽然对于 CKD 患者的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有关，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）含有在体外降低内皮细胞活化和功能障碍水平的因子。此外，有证据表明CKD患者的HDL成分和功能发生改变，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 组成，并开发了基于细胞的测定法来评估 HDL 保护内皮细胞功能的能力。这些测定的结合可以对有助于 HDL 抗炎能力的分子进行全面的研究。我们的总体假设是，CKD 会导致 HDL 组成发生变化，这些变化会导致内皮功能障碍增加，并增加肾小球丢失和心血管疾病 (CVD) 的风险。我们还假设饮食和运动（一种改善体内内皮功能的干预措施）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 组成和功能的变化与内皮功能障碍和临床结果的关联。我们将利用 NIH 资助的三项特征明确的临床研究来阐明 HDL 保持内皮细胞功能的能力背后的机制。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) 识别并量化与心脏事件、肾脏疾病进展和死亡相关的 HDL 组成和功能的变化； 3) 确定健康的生活方式干预是否可以改变 CKD 受试者的 HDL 组成并恢复其抗炎特性。该提案将确定 CKD 受试者中 HDL 的分子变化，以及它们与体外和体内内皮功能障碍的关系。此外，我们的研究将确定高密度脂蛋白成分的变化，这些变化与死亡风险大大增加的人群中的心血管和肾脏结果相关。 公共卫生相关性：慢性肾病 (CKD) 患者比普通人群更有可能死于心血管疾病和肾衰竭。我们将测量高密度脂蛋白 (HDL) 颗粒的组成和功能，并研究 HDL 的这些变化如何导致血管内壁炎症，并增加 CKD 患者不良预后的风险。