Dynamic Changes in Erythrocyte 2,3 DPG as a Driver of Cardiac Dysfunction in End Stage Kidney Disease

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ABSTRACT End-stage renal disease (ESRD) and its associated complications are disproportionately higher in veterans compared to the general U. S. population. Approximately 45,500 veterans currently receive hemodialysis. In the U.S., there is an estimated 500,000 ESRD patients receiving maintenance hemodialysis and this number is predicted to rise to over 1 million by 2030. In veterans on dialysis, cardiovascular disease is the leading cause of death and the risk of death is particularly high on the day of dialysis. The long-term goal of the candidate is to conduct research that will lead to improved cardiovascular outcomes in dialysis patients, a highly relevant goal for the health of American veterans. Research: This proposal will evaluate novel mechanisms by which dialysis-driven risk factors contribute to cardiovascular disease. Dialysis-related alterations in RBC phosphate metabolites lead to myocardial tissue hypoxia and intra-dialytic hypotension and understanding the mechanisms of these changes should lead to new therapeutic strategies for ameliorating cardiovascular mortality in this population. Specific Aim 1 will utilize an in vitro model to investigate dialysis specific factors affecting 2,3-DPG concentrations. Specific Aim 2 will examine the relationship between changes in 2,3-DPG and hypotensive episodes during dialysis sessions. Specific Aim 3 will determine whether changes in 2,3-DPG during dialysis are associated with myocardial dysfunction, utilizing a novel quantitative imaging methodology based on real time echocardiography. Candidate: The program is designed to help Dr. Sharma develop into an independent and productive researcher investigating cardiovascular complications of chronic kidney disease, focusing on phosphate metabolism and eventually other aspects of chronic kidney disease-mineral bone disorder (CKD-MBD), both topics highly relevant to the VA patient population. Dr. Sharma's training objectives in this proposal include to: 1) develop expertise in the physiology of dialysis- related alterations in erythrocyte 2,3-DPG associated with myocardial tissue hypoxia/ischemia and intra-dialytic hypotension 2) develop expertise in interpretation, and advanced processing of multi- parametric echocardiographic images 3) gain skills in laboratory techniques supporting translational studies as well as related advanced bio-statistical approaches. Dr. Sharma will accomplish these activities through studies supervised by her mentors, coursework, and participation in workshops. Mentors: Dr. Sharma has assembled a team of accomplished scientists with proven track records in the mentorship of academicians including her primary mentor- Dr. Kim-Lien Nguyen, who serves veterans as a non-invasive cardiologist/cardiac imaging expert at the Greater Los Angeles VA and leads a productive, well-funded cardiovascular imaging research laboratory focused on the development, translation, and application of advanced cardiovascular imaging techniques, including echocardiography (ultrasound) and magnetic resonance. Dr. Sharma's co-mentors are senior investigators and renowned in their respective fields: Dr. Tomas Ganz (RBC biology and iron), Dr. Isidro Salusky (mineral metabolism and CKD), and Dr. Joachim Ix (cardiovascular complications and CKD, Physician Scientist at VA San Diego). They will instruct and assist the applicant during completion of the project, data analysis, manuscript preparation, and formulation of future clinical trials and grant applications. Dr. Sharma will take didactic courses to obtain further training in quantitative biomarker analyses, pertinent aspects of quantitative echocardiography and also obtain hands-on training in image interpretation and relevant laboratory techniques. Dr. Sharma has the full support of her institution, and her career development will benefit from ongoing partnerships with UCLA, a world-renowned research university with a wide range of resources.