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

描述（由申请人提供）： 本提案利用 CRIC 研究的丰富信息，研究非传统危险因素血清 cLDL 作为与 CKD 患者心脏事件和动脉硬化相关的危险因素的效用。该提案已获得 CRIC 辅助指导委员会的批准，将包括大约 3,600 名患有轻度至中度肾脏疾病的 CRIC 参与者，他们将被跟踪长达五年或直至死亡。血液尿素解离形成氰酸盐，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，我们还证明了由于慢性肾功能衰竭或慢性尿素消耗而血浆 cLDL 升高的小鼠会发生主动脉粥样硬化。最后，在人体研究中，终末期肾病 (ESKD) 患者的血浆 cLDL 浓度显着升高。我们的假设是，cLDL 与 CKD 患者的流行、复发和突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]）指标相关。次要目标是确定血清 cLDL 与血清尿素和/或肾功能水平（估计肾小球滤过率 [eGFR]）之间的关系。我们已经生产出用于测量 cLDL 的抗体，并开发了一种灵敏且特异的 cLDL 夹心 ELISA 检测方法。这项辅助研究不会给参与的患者造成任何负担，并将检查 CKD 患者潜在的重要非传统动脉粥样硬化危险因素。这项建议是及时的，因为目前正在评估 2003-2007 年期间入组的患者的心血管事件，数据将于 2010 年提供。 公共卫生相关性： 患有肾脏疾病的患者患心脏病的风险很高。高胆固醇等心脏病的传统危险因素并不能解释这种风险。肾病患者的血液尿素氮水平较高，可以通过氨甲酰化过程转化为修饰蛋白质的产品。该提案的总体目标是利用 NIH 资助的慢性肾功能不全队列 (CRIC) 研究中收集的大量信息来评估氨甲酰化 LDL (cLDL)（一种非传统心血管危险因素）与慢性肾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.