CRIC Ancillary Study: Carbamylated low-density lipoprotein and cardiovascular eve

描述（由申请人提供）： 本提案利用来自CRIC研究的丰富信息，调查非传统风险因素血清cLDL作为CKD患者心脏事件和动脉硬化相关风险因素的效用。这项建议已得到审评委辅助指导委员会的批准，将包括约3，600名患有轻度至中度肾病的审评委参与者，他们已接受长达五年或直至死亡的随访。血尿素分解形成氰酸盐，氰酸盐可能通过称为氨甲酰化的过程改变蛋白质，包括低密度脂蛋白（LDL）。我们最近的研究表明，cLDL具有与动脉粥样硬化相关的所有生物学效应。此外，我们已经证明了由于慢性肾衰竭或慢性尿素消耗而导致血浆cLDL升高的小鼠中主动脉粥样硬化的发展。最后，在人体研究中，终末期肾病（ESKD）患者的血浆cLDL浓度显著升高。我们的假设是，cLDL与CKD患者的流行、复发和偶发心血管疾病以及动脉硬化（颈动脉内膜中层厚度[IMT]和冠状动脉钙化[CAC]）相关。次要目的是确定血清cLDL与血清尿素和/或肾功能水平（估计的肾小球滤过率[eGFR]）之间的关系。我们制备了cLDL抗体，并建立了一种灵敏、特异的cLDL夹心ELISA检测方法。这项辅助研究不会对参与患者造成负担，并将检查CKD患者中潜在的重要非传统动脉粥样硬化风险因素。该提案是及时的，因为2003-2007年期间入组的患者的心血管事件目前正在评估中，数据将在2010年之前提供。 公共卫生相关性： 肾病患者患心脏病的风险很高。传统的心脏病风险因素如高胆固醇并不能解释这种风险。肾脏疾病患者的血尿素氮水平较高，可以通过称为氨甲酰化的过程转化为修饰蛋白质的产物。本提案的总体目标是利用作为NIH资助的慢性肾功能不全队列（CRIC）研究的一部分收集的大量信息，评价氨甲酰化LDL（cLDL）（一种非传统CV风险因素）与慢性肾脏疾病患者心血管疾病的相关性。

DESCRIPTION (provided by applicant): The present proposal investigates the utility of a nontraditional risk factor, serum cLDL, as a risk factor associated with cardiac events and arteriosclerosis in patients with CKD utilizing the wealth of information from the CRIC Study. This proposal has been approved by the CRIC Ancillary Steering Committee and will include approximately 3,600 CRIC participants with mild to moderate renal disease who have been followed for up to five years or until death. Blood urea dissociates to form cyanate that may alter proteins including low-density lipoprotein (LDL) by a process known as carbamylation. Our recent studies demonstrate that cLDL has all of the biological effects relevant to atherosclerosis. In addition, we have demonstrated the development of aortic atherosclerosis in mice that have elevated plasma cLDL due either to chronic kidney failure or chronic urea consumption. Finally, in human studies, end-stage kidney disease (ESKD) patients have significantly elevated plasma cLDL concentration. Our hypothesis is that cLDL is associated with prevalent, recurrent, and incident cardiovascular disease and with measures of arteriosclerosis (carotid intima-media thickness [IMT] and coronary artery calcification [CAC]) in patients with CKD. A secondary objective is to determine the relationship between serum cLDL and serum urea and/or level of renal function (estimated glomerular filtration rate [eGFR]). We have raised the antibody to measure cLDL and have developed a sensitive and specific cLDL sandwich ELISA assay. This ancillary study will cause no burden on participating patients and will examine a potentially important non-traditional atherosclerotic risk factor in patients with CKD. This proposal is timely because the cardiovascular events in patients who have been enrolled during 2003-2007 are currently being evaluated and the data will be available by 2010. PUBLIC HEALTH RELEVANCE: Patients with kidney disease have a high risk of developing heart disease. Traditional risk factors for heart disease like high cholesterol do not explain this risk. Patients with kidney disease have higher levels of blood urea nitrogen, which can be transformed into products that modify proteins by a process known as carbamylation. The overall goal of this proposal is to utilize the wealth of information that has been gathered as part of the NIH-funded Chronic Renal Insufficiency Cohort (CRIC) Study to evaluate the relevance of carbamylated LDL (cLDL), a nontraditional CV risk factor, to cardiovascular disease in patients with chronic kidney disease.