Deep phenotyping of autonomic dysfunction in chronic kidney disease

New York University School Of Medicine, New York NY

Investigators

Linked publications, trials & patents

Abstract

PROJECT SUMMARY/ABSTRACT The overarching goals of this K23 proposal are to improve understanding of the role played by the autonomic nervous system (ANS) in the cardiovascular (CV) complications of chronic kidney disease (CKD) and to facilitate the career development of the candidate, Qandeel Soomro MD, MS, a Nephrologist in the Division of Nephrology at the NYU Grossman School of Medicine. Through a mentored training and research experience, the candidate will develop the requisite skills and preliminary data needed to become an independent researcher investigating autonomic physiology in the setting of CKD and testing interventions to prevent the CV sequelae of ANS dysfunction in this setting. The five-year plan includes in-depth training and didactics in ANS function testing, causal inference methods, and clinical trial design and operations under the primary mentorship of David Charytan MD, MSc. CV autonomic dysfunction is an important contributor to cardiovascular morbidity and mortality in the general population and has been implicated in the strong association of kidney and heart disease. However, prior studies in the setting of CKD have not investigated the potential causes of ANS dysfunction, have focused solely on evaluating sympathetic hyperactivity, have limited ANS interrogation to testing of heart rate variability data, failed to adequately account for the effects of diabetes, and have had limited sample size and focused solely on dialysis-requiring end stage kidney disease. This incomplete characterization has limited understanding and the development of diagnostic tools or targeted therapies that could improve CV outcomes in this high-risk population. Our overarching hypotheses are that ANS function worsens with decline in kidney function with the phenotype shifting from a predominantly parasympathetic dysfunction in early stages of CKD to a sympathetic one in more advanced CKD, that inflammation is a key mediator of ANS dysfunction, and that non-invasive vagal stimulation will substantially improve ANS dysfunction. Three specific aims are proposed: 1) Deeply phenotype autonomic dysfunction in CKD using a comprehensive battery of tests longitudinally and cross-sectionally; 2) Quantify the association of inflammation and autonomic dysfunction in CKD using causal inference methods; and 3) Perform a pilot trial of trans-auricular vagal nerve stimulation to improve ANS function in CKD. Results from this proposal will improve understanding of ANS function in CKD, provide initial feasibility and safety data on a novel therapeutic option, and inform the design of interventional studies to reduce the burden of CV disease and mortality in a highly vulnerable population. Completion of this K award, will position the candidate for her long- term goals of improving the lives of patients with CKD by conducting independent investigations into the physiology and treatment of CV disease in CKD.