Vascular effects of mineralocorticoid receptor antagonism in kidney disease.

盐皮质激素受体拮抗剂在肾脏疾病中的血管作用。

• 批准号: 9267156
• 负责人: Eric K Judd
• 金额: $ 19.45万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9267156
• 关键词: Affect; Alabama; Albuminuria; Aldosterone; American; Amiloride; Award; Biochemical Pathway; Biological Markers; Biostatistical Methods; Blood Pressure; Blood Vessels; Cardiovascular system; Caregiver Burden; Cell surface; Chronic Kidney Failure; Clinical; Clinical Investigator; Clinical Trials; Consumption; Enrollment; F2-Isoprostanes; Funding; Future; Goals; Health Care Costs; Healthcare; Institution; Intervention; Kidney Diseases; Lead; Life Expectancy; Link; Measures; Mediating; Mentored Patient-Oriented Research Career Development Award; Mentors; Mineralocorticoid Receptor; Mineralocorticoids; National Institute of Diabetes and Digestive and Kidney Diseases; Nitric Oxide; Outcome; Oxidative Stress; Participant; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Physiological; Physiology; Plasma; Population; Prevention strategy; Proteinuria; Randomized Controlled Trials; Renal function; Research; Resources; Role; Sodium; Spironolactone; Statistical Methods; Supporting Cell; Testing; Time; Translating; Translations; Ultrasonography; Universities; Urine; Vascular Endothelium; Vascular Smooth Muscle; Vasodilation; Work; authority; blood pressure reduction; brachial artery; cardiovascular risk factor; career; career development; channel blockers; endothelial dysfunction; epithelial Na+ channel; functional decline; improved; innovation; insight; mortality; novel; novel therapeutics; public health relevance; saluretic; treatment group; vascular endothelial dysfunction

 DESCRIPTION (provided by applicant): This is an application for a K23 award for Dr. Eric Judd, a nephrologist at the University of Alabama at Birmingham. Dr. Judd proposes a novel treatment pathway for chronic kidney disease (CKD), and his long-term career goal is to become an independent clinical investigator devoted to identifying and/or developing CKD-specific therapies. This award will allow Dr. Judd the resources and protected time to achieve the following career development goals: (1) to become an expert in endothelial and vascular function in CKD; (2) to implement advanced biostatistical methods in clinical trials (3) to become an independent, translational clinical investigator in the fields of vasculature and CKD. To achieve these goals, Dr. Judd has assembled a mentoring team comprised of a primary mentor, Dr. David Calhoun (an expert in vascular function testing including ultrasound assessment of flow-mediated dilation (FMD) and aldosterone physiology), a co-mentor, Dr. Michael Allon (an expert in clinical trials and vascular access in the late stages of CKD), and 3 content experts: Dr. Anupam Agarwal, PI for the NIDDK funded O'Brien Center at our institution; Dr. Rakesh Patel, an authority in measuring oxidative stress as a marker of endothelial function; and Dr. Gary Cutter, an expert in the statistical methods in clinical trials. Vascular endothelial dysfunction increases cardiovascular (CV) risk and contributes to the progression of CKD. Mineralocorticoid receptor (MR) antagonists have been shown to improve endothelial function, as well as decrease CV mortality and proteinuria. The specific biochemical pathways that produce these pharmacological effects for MR antagonists, however, are poorly understood. Dr. Judd will investigate the effect of MR antagonism on endothelial function in patients with moderate (stage III) CKD by performing a randomized, controlled trial. Three specific aims are proposed: Aim 1: To determine if spironolactone improves endothelial function as compared to amiloride in patients with stage III CKD; Aim 2: To determine if oxidative stress is associated with changes in endothelial function by spironolactone compared to amiloride in patients with stage III CKD; and Aim 3: To determine if endothelial dysfunction contributes to albuminuria in patients with stage III CKD. Relevance: A better understanding of the mechanisms of kidney function decline in CKD could lead to important interventions and prevention strategies, translating into alleviating patient suffering, caregiver burden, and health care costs.

 描述(由申请人提供)：这是阿拉巴马大学伯明翰分校的肾病学家埃里克·贾德博士的K23奖项申请书。贾德博士提出了一种治疗慢性肾脏疾病(CKD)的新途径，他的长期职业目标是成为一名独立的临床研究员，致力于识别和/或开发针对CKD的特定疗法。这一奖项将使贾德博士拥有资源和受保护的时间，以实现以下职业发展目标：(1)成为慢性肾脏病血管内皮和血管功能方面的专家；(2)在临床试验中实施先进的生物统计学方法；(3)成为血管和慢性肾脏病领域的独立、翻译临床研究员。为了实现这些目标，Judd博士组建了一个指导团队，成员包括主要导师David Calhoun博士(血管功能测试方面的专家，包括血流介导扩张(FMD)和醛固酮生理学的超声评估)、共同导师Michael Allon博士(CKD晚期临床试验和血管通道获取方面的专家)以及3名内容专家：NIDDK资助的我们机构O‘Brien中心的PI Anupam Agarwal博士；测量氧化应激作为内皮功能标志的权威Rakesh Patel博士；以及临床试验统计方法专家Gary Cutter博士。血管内皮功能障碍增加心血管(CV)风险，并促进CKD的进展。盐皮质激素受体(MR)拮抗剂已被证明可以改善内皮功能，降低心血管死亡率和蛋白尿。然而，对MR拮抗剂产生这些药理作用的特定生化途径却知之甚少。贾德博士将通过一项随机对照试验，研究MR拮抗剂对中度(III期)CKD患者内皮功能的影响。提出了三个具体目标：目标1：确定与阿米洛利相比，螺内酯是否能改善III期CKD患者的内皮功能；目标2：确定与阿米洛利相比，服用螺内酯的III期CKD患者的内皮功能改变是否与氧化应激有关；以及目标3：确定内皮功能障碍是否导致III期CKD患者的蛋白尿。相关性：更好地了解慢性肾脏病肾功能下降的机制可能导致重要的干预和预防策略，转化为减轻患者痛苦、照顾者负担和医疗成本。