Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among patients with end-stage renal disease (ESRD). Recent studies have demonstrated the critical role of inflammation, endothelial cell dysfunction, and oxidative injury in the development of cardiovascular disease. These factors appear to be of particular importance in the ESRD population, in whom several of these pathways are altered secondary to the metabolic consequences of renal dysfunction. These metabolic pathways include the L-arginine-nitric oxide (NO) pathway, the formation of methylated arginines via the protein arginine methyltransferase pathway and the methionine-homocysteine cycle. The overall aim of this study is to conduct a randomized, controlled, mechanistic study on the in vivo regulatory mechanisms of these metabolic pathways, and their influence on endothelial dysfunction in patients with CKD and ESRD assess the effects of these pathways on endothelial dysfunction in patients with ESRD and in healthy controls. We will, in addition, explore the nutritional-metabolic interactions of two nutrients found to exert significant influence on these pathways 1) supplementation with arginine and 2) supplementation with folic acid. We will also begin to explore the effect of two important functional genetic factors affecting these pathways: methylentetrahydrofolate reductase (MTHFR) and dimethylarginine dimethyl aminohydrolase (DDAH). Hence, the overall, long term objective is to obtain an integrated understanding of the metabolic, physiologic and genetic mechanisms that contribute to endothelial dysfunction of renal disease, with the ultimate goal of improvement in clinical outcomes of cardiovascular disease in these patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
1K23DK071700-01
Application #
6958383
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2005-09-01
Project End
2010-06-30
Budget Start
2005-09-01
Budget End
2006-06-30
Support Year
1
Fiscal Year
2005
Total Cost
$144,720
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115