Association of diuretics with change in extracellular volume, natriuretic peptides, symptoms, and cardiovascular outcomes in CKD

我是弗吉尼亚州北德克萨斯州卫生保健系统的肾病学家和初级临床研究员， 学术VA医学中心拥有90多名主要研究人员和320多个研究项目。我的长- 长期职业目标是成为一名独立的VA临床研究人员，专注于改善心血管（CV） 慢性肾脏病（CKD）退伍军人的肾脏预后。我的短期目标是 确定利尿剂对细胞外容积（ECV）超负荷， 脑利钠肽（BNP）和N-末端-pro-BNP（NT-pro-BNP），症状，CV血流动力学 参数和结果，并完成进行临床试验的培训，CV和 心肾研究设计，使用ECV的生物阻抗谱（BIS）测量，以及先进的科学 评估。完成建议的项目，并确保我有适当的培训，以竞争VA 优点审查，我已经设计了一个全面的计划，包括动手指导，课程，会议 出席率和体验式学习，以解决这些具体的内容领域。我组建了一个多元化的团队 致力于我的职业发展的导师，以监督本提案的科学和培训目标。 我们将使用转化科学模型来解决我们的中心假设，即开始或增加 慢性肾脏病退伍军人中的利尿剂与患者水平因素、CV生理学和 人口层面的成果。在第一项研究中，我们将确定是否开始利尿治疗或增加 剂量与BNP和NT-pro-BNP的变化、患者报告的症状负担、住院治疗 CKD 1-3期和血压升高患者的短期血流动力学参数，以及 这些变化是否与ECV的变化相关。本临床试验将纳入46例CKD门诊患者 1-3期，血压>140/90 mmHg。将通过BIS测量ECV，BIS是一种经过验证的非侵入性， 无痛测量ECV。将测量血浆BNP和NT-pro-BNP，以及患者报告的疲乏， 抑郁症和生活质量将使用经验证的问卷进行量化。血流动力学参数 包括血压、脉压、总外周阻力指数和心脏指数 有创心输出量监测。经胸超声心动图将测量左心室质量指数， 瓣膜病和舒张功能障碍。在首次访视时，我将开始或增加噻嗪类药物的剂量， 髓袢利尿剂在干预后4周重复进行超声心动图以外的研究测量， 确定这些参数的变化。我们将比较利钠肽、症状和CV的变化 参数随ECV的变化。其次，我们将确定是否开始利尿剂与非利尿剂 在CKD 1-3期和4-5期患者中与CV和肾脏结局相关， CKD退伍军人数据库。认为CKD患者应接受标准治疗， 血管紧张素转换酶抑制剂（ACEi）或血管紧张素受体阻滞剂（ARB）作为一线治疗 高血压然而，许多CKD患者最终需要额外的抗高血压药物 药物治疗，二线药物的最佳选择仍不清楚。我们将在一个 使用退伍军人事务信息学和计算基础设施（芬奇）的回顾性队列研究 数据库我们将识别CKD患者，他们的首次血压为ACEi或ARB 药物，然后比较第二种药物是利尿剂或非利尿剂的患者的CV结局。 这些项目将建立在CKD的动物和人类研究的基础上， CKD患者的ECV、利钠肽、症状负荷和CV疾病之间的关系，特别是在 1-3，预防性干预措施可能产生最大的影响。拟议的培训计划将确保 成功完成这些项目。最终，从这些研究中获得的知识将支持VA Merit应用于确定利钠肽是否可以指导CKD患者的利尿治疗。

I am a Nephrologist and junior clinical researcher at the VA North Texas Health Care System, an academic VA medical center with over 90 principal investigators and more than 320 research projects. My long- term career goal is to become an independent VA clinical researcher focused on improving cardiovascular (CV) and kidney outcomes in Veterans with chronic kidney disease (CKD). My short-term goals are to conduct crucial initial studies to determine the effects of diuretics on relationships between extracellular volume (ECV) overload, brain natriuretic peptide (BNP) and N-terminal-pro-BNP (NT-pro-BNP), symptoms, CV hemodynamic parameters, and outcomes in Veterans with CKD, and to complete training in conducting a clinical trial, CV and cardiorenal study design, use of bioimpedance spectroscopy (BIS) measurements of ECV, and advanced scientific appraisal. To complete the proposed projects and to ensure that I have the proper training to compete for VA Merit Review, I have designed a comprehensive plan including hands-on mentorship, coursework, conference attendance, and experiential learning to address these specific content areas. I have assembled a diverse team of mentors dedicated to my career development to oversee the scientific and training aims of this proposal. We will use a translational science model to address our central hypothesis, that starting or increasing diuretics in Veterans with CKD is associated with changes in patient-level factors, CV physiology, and population-level outcomes. In the first study, we will determine if initiation of diuretic treatment or increase in dose is associated with changes in BNP and NT-pro-BNP, patient-reported symptom burden, hospitalizations, and short-term hemodynamic parameters in patients with CKD stages 1-3 and elevated blood pressure, and whether these changes correlate with changes in ECV. This clinical trial will include 46 outpatients with CKD stages 1-3 and blood pressure >140/90 mmHg. ECV will be measured by BIS, which is a validated, non-invasive, painless measure of ECV. Plasma BNP and NT-pro-BNP will be measured, and patient-reported fatigue, depression, and quality of life will be quantified using validated questionnaires. Hemodynamic parameters include blood pressure, pulse pressure, total peripheral resistance index, and cardiac index measured by Non- Invasive Cardiac Output Monitoring. A transthoracic echocardiogram will measure left ventricular mass index, valvular disease, and diastolic dysfunction. At the first visit, I will initiate or increase the dose of a thiazide or loop diuretic. Study measures other than echocardiogram will be repeated 4 weeks after the intervention to determine changes in these parameters. We will compare the changes in natriuretic peptides, symptoms, and CV parameters with the change in ECV. Second, we will determine whether initiation of a diuretic vs. non-diuretic is associated with CV and kidney outcomes in patients with CKD stages 1-3 and 4-5 using a large, real-world database of Veterans with CKD. It is considered standard of care that people with CKD should be prescribed an angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) as first-line treatment for high blood pressure. However, many individuals with CKD wind up needing additional anti-hypertensive medications, and the best choice of a second-line agent remains unclear. We will address this question in a retrospective cohort study using the Veterans Affairs Informatics and Computing Infrastructure (VINCI) database. We will identify individuals with CKD who were prescribed an ACEi or ARB as their first blood pressure agent, and then compare CV outcomes between those whose second agent was a diuretic or a non-diuretic. These projects will build on knowledge from animal and human studies of CKD and identify relationships between ECV, natriuretic peptides, symptom burden, and CV disease in patients with CKD, particularly in stages 1-3, in whom preventive interventions may have the greatest impact. The proposed training plan will ensure successful completion of these projects. Ultimately the knowledge gained from these studies will support VA Merit applications to determine whether natriuretic peptides can guide diuretic therapy in patients with CKD.