Obesity, renin-angiotensin-aldosterone blockade, and chronic kidney disease

描述（由申请人提供）：肥胖是一个普遍存在的公共卫生问题，是导致各种并发症日益普遍的原因，这些并发症增加了死亡率，降低了生活质量。肥胖是慢性糖尿病发生发展的重要危险因素

DESCRIPTION (provided by applicant): Obesity is a pervasive public health issue, and is responsible for a growing prevalence of diverse comorbidites that increase mortality and reduce quality of life. Obesity is an important risk factor for the development and progression of chronic kidney disease (CKD), independent of other associated illnesses such as type 2 diabetes. Increased activation of the renin-angiotensin-aldosterone system (RAAS) is a principal mechanism of obesity-associated renal disease. RAAS blockers, specifically angiotensin converting enzyme inhibitors (ACE- Is) and angiotensin receptor blockers (ARBs), attenuate adverse renal outcomes in patients with both diabetic and non-diabetic nephropathies, with increased effect in patients with a higher degree of baseline proteinuria. RAAS blockers also delay the onset of microalbuminuria in diabetic patients without any baseline renal disease. Obese patients seem to be more sensitive to the hemodynamic effects of RAAS blockade than normal-weight individuals. However, little is known about the long-term renoprotective effects of RAAS blockade in obesity-associated, non-diabetic kidney disease. The objective of the proposed study is to perform a retrospective, population-based cohort study using The Health Improvement Network (THIN) to evaluate the effect of RAAS blockade on the development and progression of CKD in obese patients. We will employ marginal structural modeling for time-updated exposure to ACE-Is and ARBs, and will adjust for various key confounders, including number of antihypertensive medications and degree of blood pressure control. This study of obese, non-diabetic, hypertensive patients will determine 1) if RAAS blockade is protective against adverse renal outcomes compared to other antihypertensive therapies, and 2) if the presence of baseline renal dysfunction or 3) baseline proteinuria modifies the association between RAAS blockade and development of adverse renal outcomes. The proposed study will provide critical insights into the potential role of RAAS blockade in mitigating renal complication in the obese population. This work, together with the formal masters degree program described in the application, will provide the applicant, Dr. Jordana Cohen, with intensive training in biostatistics, clinical epidemiology, database management, and analytic methods that will allow her to establish a clinical research focus in obesity, hypertension, and CKD. The program will also involve multifaceted career development with complementary mentors with expertise in epidemiology, hypertension, obesity, and CKD-based research. The long-term objectives of Dr. Cohen for this grant are to analyze and interpret the data for this project, prepare manuscripts for publication, apply the results to the design of future studies in this area, and use the result as a foundation of a K award application.