Subjects with end stage renal disease (ESRD) suffer a very high rate of cardiovascular mortality. There are more than 500,000 patients with end stage renal disease (ESRD) in the United States, and each has a 25% chance of dying of cerebrovascular or cardiovascular disease within 5 years. Treatments such as statins have proven ineffective in this population. It is likely that biological mechanisms leading to cardiovascular disease in these patients are different from those in subjects without ESRD, yet these mechanisms are poorly understood. It is known that vascular dysfunction (endothelial dysfunction and arterial stiffness) is an independent predictor for mortality in this population. High-sensitivity Troponin T, an extremely sensitive measure of chronic myocardial injury, is a strong, dose-dependent predictor for mortality in this population. The extent to which vascular dysfunction contributes to chronic myocardial injury is unknown. Our overall objectives are 1) to identify potentially modifiable pathways that lead to vascular dysfunction in ESRD and 2) to determine whether endothelial dysfunction and arterial stiffness are independently associated with myocardial injury in ESRD. We will use standardized, non-invasive measures for macrovascular endothelial function (brachial artery flow mediated dilation (FMD%)), microvascular endothelial function (area under the curve (AUC) of the brachial artery velocity-time relationship during reactive hyperemia), and arterial stiffness (assessed as pulse wave velocity (PWV)). First, in a cohort of 120 ESRD study participants, we will evaluate the associations of serological markers of bone metabolism, inflammation, malnutrition, and nitric oxide production with these parameters of vascular dysfunction. We will test whether these vascular parameters are associated with myocardial injury, as measured by high-sensitivity troponin T. Second, in a cohort of 60 kidney transplant recipients, we will compare pre- and post-transplant measures of endothelial function, arterial stiffness and high sensitivity troponin T. These investigations will elucidate which mechanisms of cardiovascular disease are unique to ESRD, and which of these have the most potential for reversibility. Ultimately, such information will facilitate the development of more effective therapeutic strategies for the overwhelming burden of cardiovascular disease in the ESRD population.

Public Health Relevance

In 2007 there were over 500,000 patients with end stage renal disease (ESRD) in the United States, each with a 25% chance of dying of cerebrovascular or cardiovascular disease within 5 years. We currently lack effective therapies for the overwhelming burden of cardiovascular disease in this population. By investigating the mechanisms underlying cardiovascular disease in subjects with ESRD, I hope to design effective therapies to ameliorate their high rate of hospitalizations and death due to cardiovascular 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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Special Emphasis Panel (ZDK1-GRB-G (J2))
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Rankin, Tracy L
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
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Guajardo, Isabella; Ayer, Amrita; Johnson, Alexander D et al. (2018) Sex differences in vascular dysfunction and cardiovascular outcomes: The cardiac, endothelial function, and arterial stiffness in ESRD (CERES) study. Hemodial Int 22:93-102
Dubin, Ruth F; Deo, Rajat; Bansal, Nisha et al. (2017) Associations of Conventional Echocardiographic Measures with Incident Heart Failure and Mortality: The Chronic Renal Insufficiency Cohort. Clin J Am Soc Nephrol 12:60-68
Dubin, Ruth F; Guajardo, Isabella; Ayer, Amrita et al. (2016) Associations of Macro- and Microvascular Endothelial Dysfunction With Subclinical Ventricular Dysfunction in End-Stage Renal Disease. Hypertension 68:913-20
Dubin, Ruth F; Beatty, Alexis L; Teerlink, John R et al. (2014) Associations of tissue Doppler imaging with NT-proBNP and hs-TnT: a pilot study in end-stage renal disease. Echocardiography 31:1205-12
Dubin, Ruth F; Teerlink, John R; Schiller, Nelson B et al. (2013) Association of segmental wall motion abnormalities occurring during hemodialysis with post-dialysis fatigue. Nephrol Dial Transplant 28:2580-5
Mishra, Rakesh K; Dubin, Ruth F (2013) The effects of frequent hemodialysis on left ventricular mass, volumes, and geometry. Clin J Am Soc Nephrol 8:2025-7
Dubin, Ruth F; Li, Yongmei; He, Jiang et al. (2013) Predictors of high sensitivity cardiac troponin T in chronic kidney disease patients: a cross-sectional study in the chronic renal insufficiency cohort (CRIC). BMC Nephrol 14:229