Genes, Fibrinolysis and Endothelial Dysfunction- Dialysis Aim 3
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|ClinicalTrials.gov Identifier: NCT00878969|
Recruitment Status : Terminated (insufficient enrollment and retention)
First Posted : April 9, 2009
Results First Posted : February 15, 2016
Last Update Posted : February 15, 2016
|Condition or disease||Intervention/treatment||Phase|
|Oxidative Stress Endothelial Dysfunction||Drug: valsartan (ARB) Drug: ramipril (ACE inhibitor) Drug: Placebo||Phase 3|
More than 400,000 individuals with chronic kidney disease undergo hemodialysis each year in the United States. Atherosclerotic cardiovascular disease is the leading cause of mortality in these patients. Conventional risk factors for coronary artery disease (CAD) do not adequately explain this increased mortality, whereas biomarker of oxidative stress and inflammation correlate with clinical outcomes. Even with the use of biocompatible membranes, hemodialysis induces a systemic inflammatory reaction characterized by complement activation, leukocyte activation and the generation of reactive oxygen species and cytokines. Oxidative stress and inflammation promote endothelial dysfunction, a predictor of atherosclerotic cardiovascular events.
The purpose of the study is to test the hypothesis that angiotensin-converting enzyme inhibition and angiotensin receptor blockade differ in their long term effects on biomarkers of fibrinolysis, oxidative stress,inflammation and on carotid intima-media thickness (IMT), a predictor of cardiovascular events, in patients with chronic kidney disease undergoing maintenance hemodialysis.
Endogenous Bradykinin (BK) contributes to the hypotensive and pro-fibrinolytic effects of ACE inhibitors. It has been determined that endogenous BK contributes to the vasodilator effects of acute and chronic ACE inhibition. Studies have found that BK stimulates vascular tissue plasminogen activator (t-PA) release through a BK B2 receptor-dependent, nitric oxide (NO) and cyclooxygenase-independent pathway. Hemodialysis patients demonstrates endothelial dysfunction. Data suggests that t-PA release may be attenuated during stimulation of the endogenous kallikrein-kinin system by hemodialysis.
Intra-arterial infusion of BK increases vascular release of F2- isoprostanes, markers of oxidative stress, BK infusions also increase net release of the inflammatory cytokine interleukin-6 (IL-6). Preliminary data raise the possibility that activation of the endogenous kallikrein-kinin system during dialysis could promote inflammation in individuals with chronic kidney disease who are treated with an ACE inhibitor.
Cardiopulmonary bypass activates the endogenous kallikrein-kinin system and causes a systemic inflammatory response. Like hemodialysis, cardiopulmonary bypass activates the endogenous kallikrein-kinin system, increasing BK concentrations. In smokers, who like hemodialysis patients exhibit endothelial dysfunction, the t-PA response to BK was attenuated during cardiopulmonary bypass.
ACE inhibition enhances fibrinolysis and decreases inflammation following cardiopulmonary bypass. The short-term effect of both ACE inhibition and angiotensin II type 1 (AT1) receptors on markers of fibrinolysis and inflammation during dialysis are currently being studied.
Circulating BK concentrations are increased during hemodialysis in individuals treated with an ACE inhibitors compared to those treated with an AT1 receptor blocker.
Bradykinin receptor blockade and the fibrinolytic and inflammatory response to hemodialysis. It is hypothesized that subjects with CAD, the t-PA response to hemodialysis will be blunted compared to that measured in subjects without evidence of CAD, whereas the inflammatory response wil be similar or enhanced.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||78 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Primary Purpose:||Health Services Research|
|Official Title:||Genes, Fibrinolysis and Endothelial Dysfunction- Dialysis Aim 3|
|Study Start Date :||January 2010|
|Actual Primary Completion Date :||June 2015|
|Actual Study Completion Date :||June 2015|
Active Comparator: Valsartan
80 mg of valsartan (ARB) taken orally on a daily basis for 1 week followed by 160 mg of valsartan taken orally on a daily basis for 18 months
Drug: valsartan (ARB)
Other Name: Diovan
Active Comparator: Ramipril
2.5 mg of ramipril (ACE inhibitor) taken orally on a daily basis for 1 week followed by 5 mg of ramipril taken orally on a daily basis for 18 months
Drug: ramipril (ACE inhibitor)
Other Name: Altace
Placebo Comparator: Placebo
matching placebo taken orally on a daily basis for 1 week followed by matching placebo taken orally on a daily basis for 18 months
Other Name: Inactive pill
- Interleukin-6 (IL-6) [ Time Frame: baseline and 18 months ]IL-6 is a sensitive laboratory assay for serum levels of interleukin-6, which is a pro-inflammatory cytokine used to evaluate the inflammatory response.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00878969
|United States, Tennessee|
|Vanderbilt University Medical Center|
|Nashville, Tennessee, United States, 37232|
|Principal Investigator:||Nancy J Brown, MD||Vanderbilt University Medical Center|
|Principal Investigator:||Talat A Ikilzer, MD||Vanderbilt University Medical Center|
|Principal Investigator:||Jonathan Himmelfarb, MD||University of Washington|