More than 500,000 people in United States have end stage renal disease (ESRD), and these individuals suffer from an extremely high incidence of cardiovascular (CV) death. Treatments that are effective in reducing CV mortality in the general population have been less successful in dialysis-dependent ESRD, and new therapies are sorely needed. Traditional CV risk factors are less important in the setting of advanced kidney failure, and the disappointing results with standard therapies appear to be attributable to important differences in the mechanisms underlying CV disease in individuals with ESRD. Sudden death accounts for the vast majority of CV deaths in individuals with ESRD, with a 5-folder higher frequency than atherosclerotic death or myocardial infarction which more commonly account for CV mortality in other settings. These considerations suggest that targeting ESRD-specific mechanisms for sudden CV death rather than mechanisms underlying atherosclerosis and myocardial infarction may be a particularly potent way to improve outcomes in ESRD. However, there are currently no well-established targets or therapies for this purpose. A wealth of data including studies by the applicants demonstrate that myocardial fibrosis and microvascular dropout are dramatically increased in the hearts of individuals with ESRD, and that non-invasive measures of myocardial fibrosis and microvascular disease are highly predictive of CV death, suggesting that fibrosis and microvascular disease are important determinants of sudden CV death. Additional studies show that abnormalities in the bioavailability of nitric oxide and aldosterone are critical and synergistic contributors to the progression of myocardial fibrosis and microvascular disease and that administration of spironolactone or L-arginine improve NO bioavailability, inhibit the effects of aldosterone, and are safe in ESRD. We therefore hypothesize that administration of L-arginine or the aldosterone antagonist spironolactone to patients with dialysis-dependent ESRD will inhibit myocardial fibrosis and microvascular dropout. We will test our 2 specific aims using a 9-month, randomized, placebo- controlled, 2x2 factorial clinical trial conducted at Partners Health Care and Beth Israel Deaconess Medical Center:
Aim 1) To test the hypothesis that blockade of aldosterone using spironolactone improves myocardial fibrosis and microvascular supply in individuals with ESRD as measured using tissue Doppler Echocardiography (TDI) and myocardial perfusion imaging (PET) scans, respectively;
Aim 2) To test the hypothesis that L-arginine, an agent which improves NO bioavailability, improves myocardial fibrosis and microvascular supply as measured by TDI and PET.

Public Health Relevance

Dialysis-dependent End Stage Renal Disease (ESRD) is a common condition accounting for approximately 10% of Medicare expenditures that is associated with extremely high risks of cardiovascular death. The physiology of cardiovascular disease is different in ESRD and in individuals with normal kidney function, and standard therapies appear to be less effective in patients on chronic dialysis. By treating patients with ESRD with spironolactone and L-arginine and analyzing the effects on heart function, this research will lead to novel insights into the biology of heart disease in ESRD that will lead to new, targeted treatment options capable of reducing cardiovascular mortality in this high-risk population.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZRG1-DKUS-L (81))
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Kimmel, Paul
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Brigham and Women's Hospital
United States
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