Study of Inflammation and Oxidative Stress in Persons Undergoing Dialysis

Little is known about how some drugs affect inflammation or clotting factors in people receiving hemodialysis. It is not yet known if these drugs help prevent heart damage as they do in people not undergoing hemodialysis or whether they could increase the risk of heart problems. The purpose of the study is to measure certain chemicals in the blood and see how those chemicals may change during hemodialysis when certain drugs are given.

• Cardiovascular disease in the leading cause of death in patients with chronic kidney disease undergoing hemodialysis.
• Traditional risk factors do not adequately predict cardiovascular morbidity and mortality in patients with chronic kidney disease.
• Increased oxidative stress, inflammation and impaired fibrinolysis contribute to cardiovascular risk in chronic kidney disease patients undergoing hemodialysis.
• Activation of the RAAS may contribute to oxidative stress and inflammation in individuals with chronic kidney disease
• Activation of the kallikrein-kinin system during hemodialysis may increase fibrinolysis but may also contribute to inflammation in chronic kidney disease
• Despite data from clinical trials demonstrating that ARBs and ACE inhibitors decrease cardiovascular mortality, delay progression to cardiovascular disease and decrease the incidence of diabetes in the general population little is known about the impact of these agents on cardiovascular morbidity and mortality in patients with end- stage renal disease (ESRD) undergoing hemodialysis
• ACE inhibitors and ARBS differ in their mechanisms of action and their effects on inflammatory biomarkers

• Renal Dialysis
• Hemodialysis

• Drug: ramipril
  After a washout period, subject will undertake 3 study periods with one of the three treatments: Ramipril initiated at 2.5 mg/d for 2 days followed by 5 mg for a total of nine days
  Other Name: Altace
• Drug: valsartan
  After a three week washout period, each subject will undertake 3 study periods with one of three treatment: Valsartan initiated at 80 mg/d for 2 days followed by 160 mg/d for a total of 9 days
  Other Name: Diovan
• Drug: Placebo
  After a three week washout period, subject will undertake 3 study periods with one of three treatments: Placebo (inactive pill) for nine days.
  Other Name: Placebo

• Active Comparator: 1
  After a three week washout period, the subject will be undertake 3 study periods with one of three treatments, placebo, ramipril or valsartan
  Intervention: Drug: ramipril
• Active Comparator: 2
  After a three week washout period, each subject will be randomized to receive one of the three treatments, placebo, ramipril or valsartan
  Intervention: Drug: valsartan
• Placebo Comparator: 3
  After a three week washout period, each subject will undertake 3 study periods with one of the three treatments, placebo, ramipril or valsartan
  Intervention: Drug: Placebo

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/kg
• History of functional transplant less than 6 months prior to study
• Use of anti-inflammatory medications other than aspirin < 325 mg/d
• 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