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

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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.