This is an application for a K23 for Dr. Patrick Pun, who is a nephrologist and Assistant Professor at Duke University Medical Center. Dr. Pun is establishing himself as a young investigator in patient- oriented clinical research on sudden cardiac death (SCD) in chronic kidney disease (CKD) patients. Through a structured career development plan including formal didactic training in genetic epidemiology and quantitative genetics, mentoring by a dedicated group of accomplished senior investigators and collaborators, and the conduct original research examining unique risk factors for SCD among a large population of patients with moderate CKD, this award will provide Dr. Pun the resources, training and protected time to become a an independent clinical researcher in the field of cardiorenal disease. Dr. Pun's mentoring team includes his primary mentor, Dr. Laura Svetkey (Director of the Duke Hypertension Center and the Vice Chair for Faculty development in the Duke Department of Medicine), and two co-mentors, Dr. John Middleton (Director of Clinical Research in the Duke Division of Nephrology) and Dr. Svati Shah (Associate Professor of Medicine, Center for Human Genetics). CKD affects more than 29 million Americans;compared the general population, these patients have a markedly increased risk of SCD. The precise nature of how CKD promotes SCD risk is not well understood, and traditional cardiovascular risk factors do not adequately explain SCD risk. The overall objective of this application is to identify CKD patients at high risk of malignant arrhythmias and SCD, so that these patients might be targeted for intervention. The central hypothesis of this proposal is that cardiac conduction problems related to serum electrolyte disturbances, genetic influences and resting ECG abnormalities play an important role in determining SCD risk in patients with moderate CKD (CKD stage 3-4). Combining and linking a large prospective longitudinal research database containing clinical data and outcomes from more than 35,000 patients with cardiovascular disease, a genetic biorepository, and extensive medical records, the application contains the following specific aims: (1) To evaluate associations between serum electrolyte levels (potassium, calcium and magnesium) and SCD risk in moderate CKD patients;(2) To evaluate associations between common variants in pro-arrhythmic genes and risk of significant ventricular arrhythmias and SCD in moderate CKD patients;and (3) To evaluate associations between resting ECG measurements of ventricular conduction (QRS duration, QTc interval) and SCD risk in the setting of CKD. Since SCD mechanisms in high-risk CKD patients are poorly understood, this contribution will be significant because it may elucidate mechanisms of disease, provide novel tools for risk stratification and monitoring, and identify specific potential targets for SCD prevention.

Public Health Relevance

More than 29 million Americans have chronic kidney disease, and these individuals are among the highest risk group for sudden cardiac death. An improved understanding of the mechanisms and risk factors implicated in these conditions could lead to important interventions and therapies to prevent the catastrophic outcomes from this disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Mentored Patient-Oriented Research Career Development Award (K23)
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Digestive Diseases and Nutrition C Subcommittee (DDK)
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Rankin, Tracy L
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Duke University
Internal Medicine/Medicine
Schools of Medicine
United States
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Pun, Patrick H (2018) Dialysate potassium concentration: Should mass balance trump electrophysiology? Semin Dial 31:569-575
Makar, Melissa S; Pun, Patrick H (2017) Sudden Cardiac Death Among Hemodialysis Patients. Am J Kidney Dis 69:684-695
Pun, Patrick H; Sheng, Shubin; Sanders, Gillian et al. (2017) Prescription of Guideline-Recommended Implantable Cardioverter Defibrillator and Cardiac Resynchronization Therapy Among Patients Hospitalized With Heart Failure and Varying Degrees of Renal Function. Am J Cardiol 119:886-892
Pun, Patrick H; Goldstein, Benjamin A; Gallis, John A et al. (2017) Serum Potassium Levels and Risk of Sudden Cardiac Death Among Patients With Chronic Kidney Disease and Significant Coronary Artery Disease. Kidney Int Rep 2:1122-1131
Pun, Patrick H; Abdalla, Safa; Block, Geoffrey A et al. (2016) Cinacalcet, dialysate calcium concentration, and cardiovascular events in the EVOLVE trial. Hemodial Int 20:421-31
Pun, Patrick H; Hellkamp, Anne S; Sanders, Gillian D et al. (2015) Primary prevention implantable cardioverter defibrillators in end-stage kidney disease patients on dialysis: a matched cohort study. Nephrol Dial Transplant 30:829-35
Hess, Paul L; Hellkamp, Anne S; Peterson, Eric D et al. (2014) Survival after primary prevention implantable cardioverter-defibrillator placement among patients with chronic kidney disease. Circ Arrhythm Electrophysiol 7:793-9
Pun, Patrick H (2014) The interplay between CKD, sudden cardiac death, and ventricular arrhythmias. Adv Chronic Kidney Dis 21:480-8