Genes, Fibrinolysis and Endothelial Dysfunction- Dialysis Aim 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.

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