Genes, Fibrinolysis and Endothelial Dysfunction- Dialysis Aim 3

Phase 3

Terminated

Conditions: Oxidative Stress
Endothelial Dysfunction

Interventions: Drug: valsartan (ARB)
Drug: ramipril (ACE inhibitor)
Drug: Placebo

Registration Number: NCT00878969

Lead Sponsor: Vanderbilt University

Brief Summary: The purpose of the study is to see how two classes of blood pressure medications,angiotensin-converting enzyme inhibitors (Ace inhibitors) and angiotensin receptor blockers (ARBs), differ in their long term effects on certain chemicals in the body and on the carotid arteries.

Detailed Description: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 78

Inclusion Criteria

Age 18 years or older
On thrice weekly chronic hemodialysis for at least 6 months
Clinically stable, adequately dialyzed [single-pool Kt/V > 1.2 or Urea Reduction Ratio (URR) > 65%] thrice weekly, with polysulphone membrane for at least 3 consecutive months prior to study

Exclusion Criteria

History of functional transplant less than 6 months prior to study
Use of immunosuppressive drugs within 1 month prior to study
History of active connective tissue disease
History of acute infectious disease within one month prior to study
AIDS (HIV seropositivity is not an exclusion criteria)
History of myocardial infarction or cerebrovascular event within 3 months
Advanced liver disease
Gastrointestinal dysfunction requiring parental nutrition
Active malignancy excluding basal cell carcinoma of the skin
History of ACE inhibitor-associated cough (intolerable) or angioedema
Ejection fraction less than 30%
Inability to discontinue ACE inhibitor or ARB
Predialysis potassium repeatedly higher than 6.0 mmol/L (confirmed on a repeated blood draw)
Anticipated live donor kidney transplant
Pregnancy or breast-feeding
History of poor adherence to hemodialysis or medical regimen
Inability to provide consent

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Valsartan	valsartan (ARB)	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
Ramipril	ramipril (ACE inhibitor)	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
Placebo	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

Primary Outcome Measures

Name	Time	Method
Interleukin-6 (IL-6)	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.

Secondary Outcome Measures