Genes, Fibrinolysis and Endothelial Dysfunction- Dialysis Aim 3

Condition(s) targeted: Oxidative Stress; Endothelial Dysfunction

Intervention: ramipril (ACE inhibitor) (Drug); valsartan (ARB) (Drug); Placebo (Drug)

Phase: Phase 3

Status: Not yet recruiting

Sponsored by: Vanderbilt University

Official(s) and/or principal investigator(s):
Nancy J Brown, MD, Principal Investigator, Affiliation: Vanderbilt University
Talat A Ikilzer, MD, Principal Investigator, Affiliation: Vanderbilt University
Jonathan Himmelfarb, MD, Principal Investigator, Affiliation: University of Washington

Overall contact:
Delia M Woods, BSN, Phone: 615-322-3371, Email: delia.woods@vanderbilt.edu

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.

Official title: Genes, Fibrinolysis and Endothelial Dysfunction- Dialysis Aim 3

Study design: Health Services Research, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Pharmacokinetics Study

Primary outcome: To compare the long term effects of ACE inhibition or angiotensin receptor blockade versus placebo on biomarkers of fibrinolysis, oxidative stress and inflammation in patients with chronic kidney disease undergoing maintenance hemodialysis

Secondary outcome:

To compare the long term effects of ACE inhibition or AT1 receptor blockade versus placebo on carotid intima-media thickness (IMT) in patients with chronic kidney disease undergoing maintenance hemodialysis

Track safety endpoints- hyperkalemia, hypotension, nonfatal myocardial infarction, nonfatal stroke, death from cardiac causes, fatal stroke, death due to any cause.

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 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 t-PA release through a BK B2 receptor-dependent, 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 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 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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

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) thrice weekly, with

polysulphone membrane for at least 3 consecutive months prior to study

Exclusion Criteria:

- Body mass index > 35 mg/kg2

- History of functional transplant less than 6 months prior to study

- Use of anti-inflammatory medications other than aspirin < 325 mg/d

- 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 or angioedema

- Ejection fraction less than 40%

- Inability to discontinue ACE inhibitor or ARB

- Predialysis potassium repeatedly higher than 5. 5 mmol/L (confirmed on a repeated

blood draw)

- Anticipated live donor kidney transplant

- Use of vitamin E > 60 IU/d or vitamin C > 500 mg/d

- Pregnancy, breast-feeding or child-bearing potential

- History of poor adherence to hemodialysis or medical regimen

- Inability to provide consent

Delia M Woods, BSN, Phone: 615-322-3371, Email: delia.woods@vanderbilt.edu

Starting date: July 2009
Ending date: February 2011
Last updated: June 5, 2009