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.
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