Hemodialysis-Induced Symptom, Mitochondrial Diseases
Conditions
Brief summary
The overarching goal of this study is to determine the role of chronic kidney disease and the activation of the kallikrein-kinin system during hemodialysis on the development of mitochondrial dysfunction; the investigators will measure mitochondrial function using the gold standard method, 31-phosphorus magnetic resonance spectroscopy. The investigators will test the hypothesis that endogenous bradykinin promotes mitochondrial dysfunction in patients undergoing hemodialysis. The investigators will first perform a randomized, placebo-controlled, double-blind, cross-over study measuring the effect of Icatibant (HOE-140), a bradykinin B2 receptor blocker, on mitochondrial function.
Interventions
DRUGIcatibant
Subjects will receive either Icatibant or placebo in the first study day. After a washout period of 3 weeks, participant will receive the other treatment. Icatibant (50µg/kg/h) or placebo will be infused for 1 hour prior to the initiation of dialysis and continue through hemodialysis. Hemodialysis session will last approximately 4 hours. Two hours after the end of hemodialysis, The investigators will evaluate mitochondrial function by 31 phosphorus magnetic resonance spectroscopy.
DRUGPlacebo
Subjects will receive either Icatibant or placebo in the first study day. After a washout period of 3 weeks, participant will receive the other treatment. Icatibant (50µg/kg/h) or placebo will be infused for 1 hour prior to the initiation of dialysis and continue through hemodialysis. Hemodialysis session will last approximately 4 hours. Two hours after the end of hemodialysis, the investigators will evaluate mitochondrial function by 31 phosphorus magnetic resonance spectroscopy.
Sponsors
Vanderbilt University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 78 Years
Healthy volunteers
No
Inclusion criteria
* Adult patients who have been on maintenance hemodialysis for at least 6 months
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phosphocreatine (PCR) Recovery Time After Knee Extension Assessed by 31 Phosphorus Magnetic Resonance Spectroscopy (31P-MRS) | Up to 2 hours after completion of drug infusion | Mitochondria function will be evaluated using 31P-MRS, which evaluates the concentration of phospho-creatine (PCr) and other phosphate-energy carrier molecules. After basal measurements, subjects will be asked to perform 90 seconds of knee extension followed by 4 minutes of rest. The exercise/rest cycle will be repeated 3 times. Magnetic resonance spectra will be used to calculate concentrations of inorganic phosphate (Pi), PCr, and adenosine triphosphate (ATP). The time constant tau of PCr recovery (time to achieve 66.3% maximal concentration during recovery) will be used to determine mitochondrial function. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Systolic Blood Pressure | 30 minutes before hemodialysis, during dialysis, and up to 1 hour after hemodialysis | Blood pressure will be monitored every 15 minutes, before, during, and after hemodialysis. |
Countries
United States
Participant flow
Recruitment details
Cross-over design, eleven individuals receive both treatments, Icatibant and placbo
Participants by arm
| Arm | Count |
|---|---|
| Icatibant Then Placebo Icatibant will be intravenously infused at a rate of 50 ug/kg/h for 1 hour prior to the initiation of dialysis and continue through hemodialysis (4 hours)
Washout, then
Placebo will be intravenously infused at the same rate of Icatibant (50 ug/kg/h) for 1 hour prior to the initiation of dialysis and continue through hemodialysis (4 hours)
Two hours after the end of hemodialysis, the investigators will evaluate mitochondrial function by 31 phosphorus magnetic resonance spectroscopy. | 5 |
| Placebo Then Icatibant Placebo will be intravenously infused at the same rate of Icatibant (50 ug/kg/h) for 1 hour prior to the initiation of dialysis and continue through hemodialysis (4 hours).
Washout, then
Placebo will be intravenously infused at the same rate of Icatibant (50 ug/kg/h) for 1 hour prior to the initiation of dialysis and continue through hemodialysis (4 hours).
Two hours after the end of hemodialysis, the investigators will evaluate mitochondrial function by 31 phosphorus magnetic resonance spectroscopy. | 6 |
| Total | 11 |
Baseline characteristics
| Characteristic | Icatibant Then Placebo | Total | Placebo Then Icatibant |
|---|---|---|---|
| Age, Continuous | 45.2 years STANDARD_DEVIATION 11.08 | 44.73 years STANDARD_DEVIATION 10.65 | 44.3 years STANDARD_DEVIATION 11.32 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 8 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 2 Participants | 1 Participants |
| Region of Enrollment United States | 5 participants | 11 participants | 6 participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 1 Participants |
| Sex: Female, Male Male | 3 Participants | 8 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 11 |
| other Total, other adverse events | 1 / 11 | 1 / 11 |
| serious Total, serious adverse events | 0 / 11 | 2 / 11 |
Outcome results
Primary
Phosphocreatine (PCR) Recovery Time After Knee Extension Assessed by 31 Phosphorus Magnetic Resonance Spectroscopy (31P-MRS)
Mitochondria function will be evaluated using 31P-MRS, which evaluates the concentration of phospho-creatine (PCr) and other phosphate-energy carrier molecules. After basal measurements, subjects will be asked to perform 90 seconds of knee extension followed by 4 minutes of rest. The exercise/rest cycle will be repeated 3 times. Magnetic resonance spectra will be used to calculate concentrations of inorganic phosphate (Pi), PCr, and adenosine triphosphate (ATP). The time constant tau of PCr recovery (time to achieve 66.3% maximal concentration during recovery) will be used to determine mitochondrial function.
Time frame: Up to 2 hours after completion of drug infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Icatibant | Phosphocreatine (PCR) Recovery Time After Knee Extension Assessed by 31 Phosphorus Magnetic Resonance Spectroscopy (31P-MRS) | 60.59 seconds | Standard Deviation 13.94 |
| Placebo | Phosphocreatine (PCR) Recovery Time After Knee Extension Assessed by 31 Phosphorus Magnetic Resonance Spectroscopy (31P-MRS) | 62.66 seconds | Standard Deviation 29.4 |
Secondary
Systolic Blood Pressure
Blood pressure will be monitored every 15 minutes, before, during, and after hemodialysis.
Time frame: 30 minutes before hemodialysis, during dialysis, and up to 1 hour after hemodialysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Icatibant | Systolic Blood Pressure | 30 minutes before hemodialysis | 123.36 mmHg | Standard Deviation 15.83 |
| Icatibant | Systolic Blood Pressure | during dialysis | 122.5454545 mmHg | Standard Deviation 16.87224725 |
| Icatibant | Systolic Blood Pressure | up to 1 hour after hemodialysis | 119.09 mmHg | Standard Deviation 19.06 |
| Placebo | Systolic Blood Pressure | 30 minutes before hemodialysis | 125.27 mmHg | Standard Deviation 25.04 |
| Placebo | Systolic Blood Pressure | during dialysis | 122.18 mmHg | Standard Deviation 23.23 |
| Placebo | Systolic Blood Pressure | up to 1 hour after hemodialysis | 124.09 mmHg | Standard Deviation 19.9 |