End Stage Renal Disease
Conditions
Keywords
Randomized, Cross-Over, Conventional, Daily, Hemodialysis
Brief summary
More than 80% of patients with end stage renal disease have hypertension; 70% of whom are poorly controlled using conventional Hemodialysis therapy. An expanded extracellular fluid volume and an increase in peripheral vascular resistance as a result of hemodynamic/trophic effects of an increased sympathetic nerve activity, angiotensin II, asymmetrical dimethyl arginine, and decreased nitric oxide are the most frequently quoted mechanisms contributing to hypertension in this population. The intermittent nature of conventional hemodialysis treatments (4 hours, 3 days/week) results in the majority of patients having a sustained expansion of the extracellular fluid volume that likely contributes to the activation of neurohormonal pathways. However, daily therapy including short daily hemodialysis (2 hours, 6 days/week) and nocturnal hemodialysis (6-8 hours, 5-6 days/week) improve or even normalize blood pressure. Short daily hemodialysis appears to improve blood pressure secondary to a reduction in extracellular fluid volume (7,8) whereas the improvement in blood pressure with nocturnal hemodialysis occurs by a reduction in peripheral vascular resistance (8,9,10). This is consistent with the Katzarski et al experience (7-8 hours, 3 days/week) and one randomized controlled trial in which blood pressure control was due to normalization of extracellular fluid volume in some patients and a reduction in peripheral vascular resistance in others. The majority of the studies in daily dialysis are observational, do not include a run-in period to optimize blood pressure management and have not explored the mechanisms of improvement in blood pressure in detail. We have designed a 9 month study to determine if the mechanism by which short daily hemodialysis is associated with an improvement in blood pressure control is secondary to changes in sympathetic nervous system activity and/ or extracellular fluid volume. Additionally we would like to explore the potential impact of short daily dialysis, compared to conventional dialysis, on markers of inflammation and oxidative stress in detail.
Detailed description
Patients with end stage renal disease have an adjusted risk of cardiovascular mortality that is 10-20 times greater than the general population. Of the modifiable risk factors, hypertension occurs in 80% of patients with end stage renal disease and is poorly controlled in 70% of patients. In several observational studies of daily hemodialysis, blood pressure has improved despite a reduction in the number of antihypertensive medications. A randomized crossover study in short daily hemodialysis also showed an improvement in systolic blood pressure and a reduction in left ventricular mass index. In limited investigation, the mechanism(s) responsible for the improvement in blood pressure have been attributed to a reduction in extracellular fluid volume (short daily) and a reduction in peripheral vascular resistance (nocturnal hemodialysis). The studies to date have been limited by failing to include a run in phase to optimize extracellular fluid volume prior to the initiation of daily dialysis. Additionally, only one study used a standardized algorithm for the management of blood pressure which is vital as the treatments are not blinded. We have designed a randomized, unblinded, 9 month cross-over study to determine the mechanism of blood pressure control on patients receiving conventional (3 times /week) HD to short daily HD (6 times /week 2 hrs/tx). After completing a 3 month run-in phase on conventional HD in which patient's dry weight and antihypertensive medications will be adjusted using a standardized algorithm, patients are to be randomized to a 3 month cross-over of daily HD versus conventional HD. The mechanism of improved blood pressure control will be explored using bioelectrical impedance to measure extracellular fluid volume (ECFV) and muscle sympathetic nerve activity (MSNA) as well as plasma catecholamines to measure the activity of the sympathetic nervous system. Additionally the effect of short daily HD, compared to conventional HD, on reactive oxygen species and markers of inflammation will be examined in Dr. Rhian Touyz lab. Lastly we will determine the patient's treatment preference.
Interventions
PROCEDUREMicroneurography
Muscle sympathetic nerve activity measurement will be obtained using microneurography. Approximately 10-20% of microneurography recordings are not interpretable due to technical problems. For this reason, blood samples will be collected at the same time that the microneurography is to be done. These test will be done at 3 time points throughout the study.
PROCEDUREBioimpedance testing
bioimpedance measurement of extracellular fluid volume will be measured at the end of each 3 month period. This test will be done at 3 time points throughout the study.
Sponsors
Heart and Stroke Foundation of Ontario
University of Ottawa
Ottawa Hospital Research Institute
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Systolic Hypertension * They are able to make the time commitment for daily therapy * They are capable of giving informed consent.
Exclusion criteria
* They are expected to receive a transplant within the next 12 months * If they are considering a switch to peritoneal dialysis * They are not expected to survive 12 months * They have infections that require isolation (Vancomycin Resistant Enterococcus, Methicillin Resistant Staphylococcus Aureus, Hepatitis B) * They have known symptomatic dilated cardiomyopathy (New York Association Class II or III with left ventricle ejection fraction of <0.35
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Systolic Blood Pressure Over the Third Month of Each Treatment Arm | Average of the last month of the 3 month intervention | The average of 2 measurements taken pre each dialysis session in the third month of treatment were compared when the patients were on conventional hemodialysis compared to short daily hemodialysis. SBP was taken in accordance with guidelines from the Canadian Hypertension Society |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To Determine Patient Modality Preference. | at study completion | each participant will complete a questionaire regarding modality preference |
| To Determine if the Mechanism by Which Short Daily Hemodialysis is Associated With Changes in Extracellular Fluid Volume | once the final participant has completed all intervention procedures, approx. 3 months | The extracellular fluid volume will be measured using bioelectrical impedance to determine if the mechanism by which short daily hemodialysis is associated with an improvement in blood pressure control is secondary to changes in extracellular fluid volume. |
| To Determine if Short Daily Hemodialysis, Compared to Conventional Hemodialysis Maintains Metabolic Homeostasis | once the last participant has completed run in phase and after randomization, approx. 3 months | Serum phosphate values from the end of the three month run in phase and after randomization used to measure metabolic homeostasis |
| To Determine if the Enhance Control of Blood Pressure With Daily Hemodialysis Compare to Conventional Hemodialysis is Associated With a Reduction in Oxidative Stress. | once the final participant has completed all intervention procedures, approx. 3 months | — |
| To Determine if the Enhance Control of Blood Pressure With Daily Hemodialysis Compare to Conventional Hemodialysis is Associated With a Reduction in Markers of Inflammation | once the final participant has completed all intervention procedures, approx. 3 months | — |
Countries
Canada
Participant flow
Recruitment details
22 patients were recruited from the hemodialysis (HD) units of the Ottawa Hospital. 3 patients withdrew prior to randomization. 19 patients complete the conventional arm of the study, 2 patients withdrew during the short daily HD arm - they are included in the intention to treat analysis
Pre-assignment details
There was a 3 month run in phase in which blood pressure was optimized prior to randomization. The 3 patients who were not randomized - 1) withdrew consent, he did not want his blood pressure taken routinely in dialysis, 2) one patient had concerns about medications being removed during daily dialysis that could not be reconciled, 3) screen failure
Participants by arm
| Arm | Count |
|---|---|
| All Participants All patients in the study were randomized after the 3 month run in phase to either Conventional HD or Short Daily HD for 3 months and then crossed over to the other treatment arm for 3 months | 19 |
| Total | 19 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants |
| Age, Continuous | 53 years STANDARD_DEVIATION 13 |
| Region of Enrollment Canada | 19 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 19 | 0 / 19 |
| serious Total, serious adverse events | 1 / 19 | 0 / 19 |
Outcome results
Primary
Mean Systolic Blood Pressure Over the Third Month of Each Treatment Arm
The average of 2 measurements taken pre each dialysis session in the third month of treatment were compared when the patients were on conventional hemodialysis compared to short daily hemodialysis. SBP was taken in accordance with guidelines from the Canadian Hypertension Society
Time frame: Average of the last month of the 3 month intervention
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Short Daily Hemodialysis | Mean Systolic Blood Pressure Over the Third Month of Each Treatment Arm | 139 mm Hg | Standard Deviation 14 |
| Conventional Hemodialysis | Mean Systolic Blood Pressure Over the Third Month of Each Treatment Arm | 142 mm Hg | Standard Deviation 17 |
Secondary
To Determine if Short Daily Hemodialysis, Compared to Conventional Hemodialysis Maintains Metabolic Homeostasis
Serum phosphate values from the end of the three month run in phase and after randomization used to measure metabolic homeostasis
Time frame: once the last participant has completed run in phase and after randomization, approx. 3 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Short Daily Hemodialysis | To Determine if Short Daily Hemodialysis, Compared to Conventional Hemodialysis Maintains Metabolic Homeostasis | Serum Phosphate at end of 3 month run-in phase | 1.61 mmol/Litre | Standard Deviation 0.53 |
| Short Daily Hemodialysis | To Determine if Short Daily Hemodialysis, Compared to Conventional Hemodialysis Maintains Metabolic Homeostasis | Serum phosphate after randomization | 1.58 mmol/Litre | Standard Deviation 0.41 |
| Conventional Hemodialysis | To Determine if Short Daily Hemodialysis, Compared to Conventional Hemodialysis Maintains Metabolic Homeostasis | Serum Phosphate at end of 3 month run-in phase | 1.61 mmol/Litre | Standard Deviation 0.53 |
| Conventional Hemodialysis | To Determine if Short Daily Hemodialysis, Compared to Conventional Hemodialysis Maintains Metabolic Homeostasis | Serum phosphate after randomization | 1.82 mmol/Litre | Standard Deviation 0.65 |
Secondary
To Determine if the Enhance Control of Blood Pressure With Daily Hemodialysis Compare to Conventional Hemodialysis is Associated With a Reduction in Markers of Inflammation
Time frame: once the final participant has completed all intervention procedures, approx. 3 months
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Short Daily Hemodialysis | To Determine if the Enhance Control of Blood Pressure With Daily Hemodialysis Compare to Conventional Hemodialysis is Associated With a Reduction in Markers of Inflammation | IL-6 Baseline | 1.55 pg/mL |
| Short Daily Hemodialysis | To Determine if the Enhance Control of Blood Pressure With Daily Hemodialysis Compare to Conventional Hemodialysis is Associated With a Reduction in Markers of Inflammation | IL-6 After Randomization | 1.52 pg/mL |
| Conventional Hemodialysis | To Determine if the Enhance Control of Blood Pressure With Daily Hemodialysis Compare to Conventional Hemodialysis is Associated With a Reduction in Markers of Inflammation | IL-6 After Randomization | 1.45 pg/mL |
| Conventional Hemodialysis | To Determine if the Enhance Control of Blood Pressure With Daily Hemodialysis Compare to Conventional Hemodialysis is Associated With a Reduction in Markers of Inflammation | IL-6 Baseline | 1.55 pg/mL |
Secondary
To Determine if the Enhance Control of Blood Pressure With Daily Hemodialysis Compare to Conventional Hemodialysis is Associated With a Reduction in Oxidative Stress.
Time frame: once the final participant has completed all intervention procedures, approx. 3 months
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Short Daily Hemodialysis | To Determine if the Enhance Control of Blood Pressure With Daily Hemodialysis Compare to Conventional Hemodialysis is Associated With a Reduction in Oxidative Stress. | TBARS Baseline | 2.3 mmol/ml MDA equivalent |
| Short Daily Hemodialysis | To Determine if the Enhance Control of Blood Pressure With Daily Hemodialysis Compare to Conventional Hemodialysis is Associated With a Reduction in Oxidative Stress. | TBARS After Randomization | 2.0 mmol/ml MDA equivalent |
| Conventional Hemodialysis | To Determine if the Enhance Control of Blood Pressure With Daily Hemodialysis Compare to Conventional Hemodialysis is Associated With a Reduction in Oxidative Stress. | TBARS Baseline | 2.3 mmol/ml MDA equivalent |
| Conventional Hemodialysis | To Determine if the Enhance Control of Blood Pressure With Daily Hemodialysis Compare to Conventional Hemodialysis is Associated With a Reduction in Oxidative Stress. | TBARS After Randomization | 2.4 mmol/ml MDA equivalent |
Secondary
To Determine if the Mechanism by Which Short Daily Hemodialysis is Associated With Changes in Extracellular Fluid Volume
The extracellular fluid volume will be measured using bioelectrical impedance to determine if the mechanism by which short daily hemodialysis is associated with an improvement in blood pressure control is secondary to changes in extracellular fluid volume.
Time frame: once the final participant has completed all intervention procedures, approx. 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Short Daily Hemodialysis | To Determine if the Mechanism by Which Short Daily Hemodialysis is Associated With Changes in Extracellular Fluid Volume | 15.4 Litres | Standard Deviation 2.8 |
| Conventional Hemodialysis | To Determine if the Mechanism by Which Short Daily Hemodialysis is Associated With Changes in Extracellular Fluid Volume | 15.2 Litres | Standard Deviation 3.2 |
Secondary
To Determine Patient Modality Preference.
each participant will complete a questionaire regarding modality preference
Time frame: at study completion
Population: The trial did not include a questionnaire regarding modality preference as originally planned