Vascular effects of mineralocorticoid receptor antagonism in kidney disease.

 描述（由申请人提供）：这是一个申请K23奖的博士埃里克贾德，在亚拉巴马大学伯明翰肾病学家。Judd博士提出了一种新的慢性肾脏病（CKD）治疗途径，他的长期职业目标是成为一名独立的临床研究者，致力于识别和/或开发CKD特异性疗法。该奖项将使Judd博士有足够的资源和时间来实现以下职业发展目标：（1）成为CKD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方法;（3）成为血管和CKD领域的独立翻译临床研究者。为了实现这些目标，贾德博士组建了一个由主要导师大卫卡尔霍恩博士组成的指导小组（血管功能测试专家，包括血流介导的扩张（FMD）和醛固酮生理学的超声评估），共同导师Michael Allon博士（一名CKD晚期临床试验和血管通路专家），以及3名内容专家：Anupam Agarwal博士，我们机构NIDDK资助的奥布莱恩中心的PI; Rakesh Patel博士，测量氧化应激作为内皮功能标志物的权威;加里卡特博士，临床试验统计方法专家。 血管内皮功能障碍会增加心血管（CV）风险，并促进CKD的进展。盐皮质激素受体（MR）拮抗剂已被证明可改善内皮功能，以及降低CV死亡率和蛋白尿。然而，对MR拮抗剂产生这些药理学作用的特定生化途径知之甚少。Judd博士将通过进行一项随机对照试验，研究MR拮抗作用对中度（III期）CKD患者内皮功能的影响。提出了三个具体目标：目标1：确定螺内酯与阿米洛利相比是否改善III期CKD患者的内皮功能;目标2：确定螺内酯与阿米洛利相比是否与III期CKD患者的内皮功能变化相关;目标3：确定内皮功能障碍是否有助于III期CKD患者的蛋白尿。相关性：更好地了解慢性肾病肾功能下降的机制可能会带来重要的干预措施和预防策略，从而减轻患者的痛苦、护理人员的负担和医疗保健成本。

 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.