Novel Cardiac Risk Factors & Endothelial Function in CKD

描述(由申请人提供)： 心血管疾病是慢性肾脏疾病患者发病率和死亡率的主要原因。这种额外的风险只是部分归因于传统心血管危险因素的高度流行。主要研究人员的目标是建立作为一名独立研究人员的职业生涯，其广泛目标是了解导致心血管疾病的病理生理机制，并制定有效的预防策略，以减轻肾脏疾病中心血管疾病的负担。这项拟议的研究将利用两个国家糖尿病、消化和肾脏疾病研究所(NIDDK)赞助的试验数据，调查非糖尿病慢性肾脏疾病早期心血管疾病发展的潜在机制。总体假设是：非糖尿病慢性肾脏疾病的特征是炎症、氧化应激和胰岛素抵抗的标记物早期升高，这些危险因素与该患者群体中的心血管疾病有关。 肾脏疾病饮食调整(MDRD)研究是一项针对慢性肾脏疾病早期患者的大型随机对照试验。MDRD研究的参与者主要有不同病因的非糖尿病肾脏疾病。多囊肾病停止进展试验是一项旨在减缓常染色体显性遗传性多囊肾病(ADPKD)患者肾脏疾病进展的随机试验。这两个患者群体提供了一个独特的机会来研究肾脏疾病和新的心脏危险因素之间的关系，并在没有糖尿病、透析和营养不良等重要混杂因素的情况下，研究这些新的危险因素在心血管疾病病理生理中的作用。 这项研究假设将通过三个具体目标进行检验：1.确定慢性肾脏疾病早期的炎症、氧化应激、胰岛素抵抗和内皮功能障碍是否与心血管疾病有关。2.确定ADPKD是否与炎症、胰岛素抵抗和氧化应激有关；3.确定炎症、胰岛素抵抗和氧化应激是否与ADPKD患者的内皮功能障碍相关，以测量肱动脉反应性和外周动脉血压。 该提案中正在调查的新风险因素可用于识别高危患者，以进行有针对性的干预，以预防或推迟与心血管疾病相关的不良后果。申请者选择了一群杰出的导师和合作者来支持这个项目。这一奖项将为梅农博士提供从受训人员过渡到首席研究员所需的最后培训。

DESCRIPTION (provided by applicant): Cardiovascular disease is the leading cause of morbidity and mortality among patients with chronic kidney disease. This excess risk is only partly attributable to a high prevalence of traditional cardiovascular risk factors. The principal investigator's goal is to establish a career as an independent investigator with the broad objectives of understanding of the pathophysiologic mechanisms leading to cardiovascular disease and developing effective preventive strategies to reduce the burden of cardiovascular disease in kidney disease. The proposed study will investigate the mechanisms underlying development of cardiovascular disease in the earlier stages of non-diabetic chronic kidney disease utilizing data from two National Institutes of Diabetes & Digestive & Kidney Diseases (NIDDK) sponsored trials. The overall hypothesis is that: Non-diabetic chronic kidney disease is characterized by early elevation of markers of inflammation, oxidative stress and insulin resistance, and that these risk factors are associated with cardiovascular disease in this patient population. The Modification of Diet in Renal Disease (MDRD) Study was a large randomized controlled trial of patients in the earlier stages of chronic kidney disease. Participants in the MDRD Study had predominantly non-diabetic kidney disease of varying etiologies. The Halt Progression of Polycystic Kidney Disease trial is a randomized trial to slow the progression of kidney disease in patients with autosomal dominant polycystic kidney disease (ADPKD). These two patient populations provide a unique opportunity to examine the relationship between kidney disease and novel cardiac risk factors, and to study the role of these novel risk factors in the pathophysiology of cardiovascular disease, in the absence of important confounders such as diabetes, dialysis and malnutrition. The study hypothesis will be tested using three specific aims: 1. To determine whether inflammation, oxidative stress, insulin resistance, and endothelial dysfunction in the earlier stages of chronic kidney disease are associated with cardiovascular disease. 2. To determine whether ADPKD is associated with inflammation, insulin resistance, and oxidative stress 3. To determine whether inflammation, insulin resistance, and oxidative stress are associated with endothelial dysfunction, measured as brachial artery reactivity and peripheral artery tonometry, in ADPKD. The novel risk factors under investigation in this proposal could serve to identify high-risk patients for targeted interventions to prevent or delay the adverse outcomes associated with cardiovascular disease. The applicant has chosen a group of distinguished mentors and collaborators to support this project. This award will provide Dr. Menon with the final training necessary for her to make the transition from trainee to principal investigator.