Complication of Hemodialysis, End Stage Renal Failure on Dialysis
Conditions
Keywords
hemodialysis, oxidative stress, inflammation, kallikrein-kinin, angiotensin receptor blockade, angiotensin converting enzyme inhibition, RAAS, fibrinolysis, endothelial dysfunction
Brief summary
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
* 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
Interventions
DRUGPlacebo
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
DRUGRamipril
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
DRUGValsartan
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
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Vanderbilt University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Interleukin 1 Beta | During dialysis after one week of study drug | Mean difference in interleukin 1 beta concentration during treatment with ramipril versus treatment with placebo |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| F2-Isoprostanes | During dialysis after one week of study drug | Mean difference in F2-isoprostanes during dialysis between treatment with ramipril or valsartan and placebo |
Countries
United States
Participant flow
Recruitment details
Recruitment started in September 2008 and ended in January 2010 in Vanderbilt outpatients Dialysis Center.
Pre-assignment details
Three consented participants were excluded because of hyperkalemia, hypotension and uncontrollable hypertension.They were enrolled but did not start medication and were considered screen failures. The participants required a washout period from either an agiotensin receptor blocker or an angiotensin converting enzyme inhibitor.
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants After a three week washout period, the subject will be undertake 3 study periods with one of three treatments, placebo, ramipril or valsartan | 16 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Washout After First Study Drug | Adverse Event | 1 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 3 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants |
| Age Continuous | 50.5 years STANDARD_DEVIATION 3.1 |
| Region of Enrollment United States | 16 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 15 | 4 / 15 | 7 / 15 |
| serious Total, serious adverse events | 0 / 15 | 0 / 15 | 1 / 16 |
Outcome results
Primary
Interleukin 1 Beta
Mean difference in interleukin 1 beta concentration during treatment with ramipril versus treatment with placebo
Time frame: During dialysis after one week of study drug
Population: All participants who completed the three arm treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ramipril | Interleukin 1 Beta | 6.18 pg/mL | Standard Error 3.56 |
| Valsartan | Interleukin 1 Beta | 2.16 pg/mL | Standard Error 2.16 |
| Placebo | Interleukin 1 Beta | 1.44 pg/mL | Standard Error 1.49 |
Secondary
F2-Isoprostanes
Mean difference in F2-isoprostanes during dialysis between treatment with ramipril or valsartan and placebo
Time frame: During dialysis after one week of study drug
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ramipril | F2-Isoprostanes | 59.55 pg/mL | Standard Error 27.53 |
| Valsartan | F2-Isoprostanes | 59.03 pg/mL | Standard Error 29.39 |
| Placebo | F2-Isoprostanes | 50.23 pg/mL | Standard Error 22.59 |