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

描述(申请人提供)：肥胖是一个普遍存在的公共卫生问题，也是导致多种合并症日益流行的原因，这些合并症增加了死亡率，降低了生活质量。肥胖是慢性阻塞性肺疾病发生和发展的重要危险因素 肾脏疾病(CKD)，独立于其他相关疾病，如2型糖尿病。肾素-血管紧张素-醛固酮系统(RAAS)的激活增加是肥胖相关肾脏疾病的主要机制。RAAS阻滞剂，特别是血管紧张素转换酶抑制剂(ACE-IS)和血管紧张素受体阻滞剂(ARB)，可以减轻糖尿病和非糖尿病肾病患者的不良肾脏结果，对基线蛋白尿程度较高的患者效果更好。RAAS阻滞剂还可以延缓无任何基线肾脏疾病的糖尿病患者的微量白蛋白尿的发生。肥胖患者似乎比正常体重的人对RAAS阻滞剂的血流动力学影响更敏感。然而，RAAS受体阻滞剂在肥胖相关的非糖尿病肾病中的长期肾脏保护作用知之甚少。这项拟议研究的目的是利用健康改善网络(Thin)进行一项基于人群的回顾性队列研究，以评估RAAS阻滞剂对肥胖患者慢性肾脏病的发展和进展的影响。我们将对ACE-IS和ARB的时间更新暴露采用边际结构建模，并将针对各种关键混杂因素进行调整，包括降压药物的数量和血压控制程度。这项针对肥胖、非糖尿病和高血压患者的研究将确定：1)与其他抗高血压治疗相比，RAAS阻断是否对不良肾脏结果具有保护作用；2)基线肾功能障碍的存在或3)基线蛋白尿是否改变了RAAS阻断与不良肾脏结局的发展之间的联系。这项拟议的研究将为RAAS阻滞剂在减轻肥胖人群肾脏并发症方面的潜在作用提供重要的见解。这项工作与申请书中描述的正式硕士学位课程一起，将为申请者乔丹娜·科恩博士提供生物统计学、临床流行病学、数据库管理和分析方法方面的强化培训，使她能够建立肥胖、高血压和慢性肾脏病的临床研究重点。该计划还将涉及多方面的职业发展，并由具有流行病学、高血压、肥胖症和CKD研究专业知识的互补导师进行指导。科恩博士对这笔赠款的长期目标是分析和解释这一项目的数据，准备出版手稿，将结果应用于该领域未来研究的设计，并将结果用作K奖申请的基础。

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.