Study of Inflammation and Oxidative Stress in Persons Undergoing Dialysis

Study Overview
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Brief Summary
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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.

Detailed Description
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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 renin-angiotensin-aldosterone system(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 Angiotensin-converting enzyme(ACE) inhibitors and angiotensin receptor blockers (ARB)S differ in their mechanisms of action and their effects on inflammatory biomarkers

Official Title
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Genes, Fibrinolysis and Endothelial Dysfunction- Dialysis Aim 2

Conditions
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End Stage Renal Failure on Dialysis, Complication of Hemodialysis

Intervention / Treatment
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* Drug: Placebo
* Drug: Ramipril
* Drug: Valsartan


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Placebo, then ramipril, then valsartan<br>placebo, ramipril, valsartan: Subjects were treated sequentially with placebo, ramipril (5mg/day by mouth), then valsartan (160mg/day by mouth). Each drug was given for 7 days after a 3-week washout. | Drug: Placebo<br>* Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis<br>* Other names: matching placebo;Drug: Ramipril<br>* Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis<br>* Other names: Ramipril 2.5mg/d for two days, then 5mg/d for 5 days.;Drug: Valsartan<br>* Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis<br>* Other names: Valsartan 80mg/d for 2 days followed by 160mg/d for 5 days.;|
| Active Comparator: Placebo, then valsartan, then ramipril<br>placebo, ramipril, valsartan: Subjects were treated sequentially with placebo, valsartan (160mg/day by mouth), then ramipril (5mg/day by mouth). Each drug was given for 7 days after a 3-week washout. | Drug: Placebo<br>* Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis<br>* Other names: matching placebo;Drug: Ramipril<br>* Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis<br>* Other names: Ramipril 2.5mg/d for two days, then 5mg/d for 5 days.;Drug: Valsartan<br>* Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis<br>* Other names: Valsartan 80mg/d for 2 days followed by 160mg/d for 5 days.;|
| Active Comparator: Ramipril, then placebo, then valsartan<br>placebo, ramipril, valsartan: Subjects were treated sequentially with ramipril (5mg/day by mouth), then placebo (once a day by mouth), then valsartan (160mg/day by mouth). Each drug was given for 7 days after a 3-week washout. | Drug: Placebo<br>* Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis<br>* Other names: matching placebo;Drug: Ramipril<br>* Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis<br>* Other names: Ramipril 2.5mg/d for two days, then 5mg/d for 5 days.;Drug: Valsartan<br>* Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis<br>* Other names: Valsartan 80mg/d for 2 days followed by 160mg/d for 5 days.;|
| Active Comparator: Valsartan, then placebo, then ramipril<br>placebo, ramipril, valsartan: Subjects were treated sequentially with valsartan (160mg/day by mouth), then placebo (once a day by mouth), then ramipril (5mg/day by mouth). Each drug was given for 7 days after a 3-week washout. | Drug: Placebo<br>* Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis<br>* Other names: matching placebo;Drug: Ramipril<br>* Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis<br>* Other names: Ramipril 2.5mg/d for two days, then 5mg/d for 5 days.;Drug: Valsartan<br>* Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis<br>* Other names: Valsartan 80mg/d for 2 days followed by 160mg/d for 5 days.;|
| Active Comparator: Ramipril, then valsartan, then placebo<br>placebo, ramipril, valsartan: Subjects were treated sequentially with ramipril (5mg/day by mouth), then valsartan (160mg/day by mouth), then placebo (once a day by mouth). Each drug was given for 7 days after a 3-week washout. | Drug: Placebo<br>* Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis<br>* Other names: matching placebo;Drug: Ramipril<br>* Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis<br>* Other names: Ramipril 2.5mg/d for two days, then 5mg/d for 5 days.;Drug: Valsartan<br>* Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis<br>* Other names: Valsartan 80mg/d for 2 days followed by 160mg/d for 5 days.;|
| Active Comparator: Valsartan, then ramipril, then placebo<br>placebo, ramipril, valsartan: Subjects were treated sequentially with then valsartan (160mg/day by mouth), then ramipril (5mg/day by mouth), then placebo (once a day by mouth). Each drug was given for 7 days after a 3-week washout. | Drug: Placebo<br>* Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis<br>* Other names: matching placebo;Drug: Ramipril<br>* Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis<br>* Other names: Ramipril 2.5mg/d for two days, then 5mg/d for 5 days.;Drug: Valsartan<br>* Patients receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker before the study underwent washout for 3 weeks. Subjects were treated with study drug for 7 days and each treatment period was separated by a 3-week washout period. Ramipril was given at dose of 2.5mg/d for two days, then 5mg/d for 5 days. Valsartan was given at 80mg/d for 2 days followed by 160mg/d for 5 days. On the seventh day of each treatment blood samples were collected prior two, during and two hours after dialysis<br>* Other names: Valsartan 80mg/d for 2 days followed by 160mg/d for 5 days.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Interleukin 1 Beta | Mean difference in interleukin 1 beta concentration during treatment with ramipril versus treatment with placebo | During dialysis after one week of study drug | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| F2-Isoprostanes | Mean difference in F2-isoprostanes during dialysis between treatment with ramipril or valsartan and placebo | During dialysis after one week of study drug | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hemodialysis, oxidative stress, inflammation, kallikrein-kinin, angiotensin receptor blockade, angiotensin converting enzyme inhibition, RAAS, fibrinolysis, endothelial dysfunction