More than 400,000 people with chronic kidney disease undergo hemodialysis each year in the United States. These individuals have a substantially increased risk of death due to cardiovascular disease compared to the general population. Biomarkers of oxidative stress and inflammation correlate with cardiovascular mortality in this population. We and others have shown that hemodialysis stimulates the endogenous kallikrein-kinin system. We have also shown that hemodialysis induces a systemic inflammatory response characterized by a doubling in concentrations of the inflammatory cytokine IL-6. During the last period of this grant we have determined that, in addition to stimulating t-PA release, bradykinin induces oxidative stress and inflammation in the human forearm vasculature and contributes to the fibrinolytic and inflammatory response to cardiopulmonary bypass, a procedure similar to hemodialysis in terms of blood-membrane interactions. In this proposal we build on our prior studies to test the hypothesis that Ang II and bradykinin-stimulated inflammation, in the setting of impaired endothelial responses to bradykinin, contributes to the risk of cardiovascular events in chronic kidney disease patients undergoing maintenance hemodialysis.
In Aim 1, we will use a bradykinin BB2 receptor antagonist, HOE 140, to test the hypothesis that endogenous bradykinin contributes to both the fibrinolytic and inflammatory responses observed during hemodialysis, particularly in individuals treated with an angiotensin-converting enzyme (ACE) inhibitor. We propose that the fibrinolytic response to hemodialysis is impaired in patients with documented coronary artery disease.
In Aim 2, we will test the hypothesis that ACE inhibition and angiotensin AT1 receptor blockade differ in their effects on fibrinolysis, oxidative stress, and inflammation during hemodialysis.
In Aim 3, we will test the hypothesis that these two classes of drugs also differ in their long-term effects on fibrinolysis, oxidative stress, and inflammation, and on carotid intima-media thickness. We will also determine whether B2 receptor gene polymorphisms impact on fibrinolysis, oxidative stress, and inflammation in this aim. With a growing prevalence of obesity and diabetes, the number of people with chronic kidney disease undergoing maintenance hemodialysis is expected to increase. The NIH has prioritized reducing deaths due to cardiovascular disease in patients with chronic kidney disease as a goal of Healthy People 2010. The proposed studies will help us to understand the mechanisms leading to the increased burden of cardiovascular disease in individuals undergoing maintenance hemodialysis and to develop better pharmacologic strategies to reduce cardiovascular mortality in this high risk patient population.

Public Health Relevance

Each year more than 400,000 patients undergo hemodialysis for chronic kidney disease in the United States. These individuals have a markedly increased risk of death due to cardiovascular disease compared to the general population. The proposed studies will help us to understand the mechanisms leading to the increased burden of cardiovascular disease in individuals undergoing maintenance hemodialysis and to develop better pharmacologic strategies to reduce cardiovascular mortality in this high risk patient population.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL065193-12
Application #
8296054
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Sarkar, Rita
Project Start
2000-08-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
12
Fiscal Year
2012
Total Cost
$397,091
Indirect Cost
$106,390
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Siew, Edward D; Himmelfarb, Jonathan (2013) The inexorable rise of AKI: can we bend the growth curve? J Am Soc Nephrol 24:3-5
Balaguer, J M; Yu, C; Byrne, J G et al. (2013) Contribution of endogenous bradykinin to fibrinolysis, inflammation, and blood product transfusion following cardiac surgery: a randomized clinical trial. Clin Pharmacol Ther 93:326-34
Gamboa, Jorge L; Pretorius, Mias; Todd-Tzanetos, Deanna R et al. (2012) Comparative effects of angiotensin-converting enzyme inhibition and angiotensin-receptor blockade on inflammation during hemodialysis. J Am Soc Nephrol 23:334-42
Chan, Kevin E; Ikizler, T Alp; Gamboa, Jorge L et al. (2011) Combined angiotensin-converting enzyme inhibition and receptor blockade associate with increased risk of cardiovascular death in hemodialysis patients. Kidney Int 80:978-85
Lee, Craig R; Pretorius, Mias; Schuck, Robert N et al. (2011) Genetic variation in soluble epoxide hydrolase (EPHX2) is associated with forearm vasodilator responses in humans. Hypertension 57:116-22
Himmelfarb, Jonathan (2011) Optimizing patient safety during hemodialysis. JAMA 306:1707-8
Hung, Adriana M; Crawford, Dana C; Griffin, Marie R et al. (2010) CRP polymorphisms and progression of chronic kidney disease in African Americans. Clin J Am Soc Nephrol 5:24-33
Fong, Pete; Stafforini, Diana M; Brown, Nancy J et al. (2010) Increased blood flow induces oxidative stress through an endothelium- and nitric oxide-independent mechanism. Free Radic Biol Med 49:301-5
Adam, Albert; Montpas, Nicolas; Keire, David et al. (2010) Bradykinin forming capacity of oversulfated chondroitin sulfate contaminated heparin in vitro. Biomaterials 31:5741-8
Pretorius, Mias; Brown, Nancy J (2010) Endogenous nitric oxide contributes to bradykinin-stimulated glucose uptake but attenuates vascular tissue-type plasminogen activator release. J Pharmacol Exp Ther 332:291-7

Showing the most recent 10 out of 52 publications