Cardiovascular Disease, Endothelial Dysfunction, Kidney Disease, Muscle Mitochondrial Function, Sarcopenia
Conditions
Keywords
Glutamine, Chronic Kidney Disease
Brief summary
The primary goal of proposed investigation is to study the impact of oral glutamine supplementation on muscle mitochondrial and endothelial cell function measured mitochondrial energetics and vascular function using 31P magnetic resonance spectroscopy and optical spectroscopy (MRS/OS) among persons with moderate-severe CKD. The secondary objective is to describe the impact of oral glutamine supplementation on mitochondrial metabolic profile as well as inflammatory and oxidative stress biomarkers among persons with chronic kidney disease.
Detailed description
Chronic kidney disease is associated with endothelial cell dysfunction and muscle wasting contributing to the heightened risk of cardiovascular morbidity, mortality and functional limitation. Accumulation of toxins in renal disease may adversely impact endothelial cell nitric oxide bioavailability and endothelial Nitric Oxide Synthase (eNOS) function consequently heightening oxidative stress and suppressing mitochondrial biogenesis. To date no studies have investigated potential therapies for endothelial and muscle dysfunction in renal disease target mitochondrial metabolic and energetic processes. Animal studies of uremia underscore mitochondrial dysfunction as a potential precursor for endothelial dysfunction. In particular, uremia has been linked to a proteomic signature indicative of metabolic blockage of TCA cycle activity and fatty acid beta-oxidation. Both of these processes are localized to the mitochondria and may suggest that decreased mitochondrial mass or function may augur endothelial dysfunction in renal disease. Glutamine, an anaplerotic agent and precursor to the antioxidant glutathione, is a potential therapeutic agent bypassing the metabolic block associated with reduced TCA cycle and improving antioxidant reserve. The primary goal of proposed investigation is to study the impact of oral glutamine supplementation on muscle mitochondrial and endothelial cell function measured mitochondrial energetics and vascular function using 31P MRS/OS among persons with moderate-severe CKD. The secondary objective is to describe the impact of oral glutamine supplementation on mitochondrial metabolic profile as well as inflammatory and oxidative stress biomarkers among persons with chronic kidney disease.
Interventions
DIETARY_SUPPLEMENTFirst Intervention (14 days)
Oral Glutamine or Maltodextrin for 2 weeks
OTHERWashout (3 weeks)
No study product is taken prior to beginning crossover
DIETARY_SUPPLEMENTSecond Intervention (14 days)
Oral Glutamine or Maltodextrin for 2 weeks
Sponsors
New York Medical College
Emory University
Vanderbilt University
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of Washington
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to 69 Years
Healthy volunteers
No
Inclusion criteria
* Adults between 20 and 69 years of age * Diagnosis of moderate-severe CKD, defined in this study as an estimated glomerular filtration rate (eGFR) of ≤60ml/min/1.73m2 using the Chronic Kidney Disease Epidemiology Collaboration equation * Ability to understand and provide informed consent to participate in the study
Exclusion criteria
* On chronic dialysis * Expectation to start dialysis within 6 months or dialysis access in place. * Pregnant * Have physical immobility (defined by wheelchair use) * Insulin dependent diabetes * Have implants incompatible with MRI * Exercise limiting cardiopulmonary disease (e.g. angina, severe heart valve disease, severe COPD, coronary ischemia) * Use of anticoagulation (i.e. warfarin) * Baseline systolic blood pressure \>160 or diastolic blood pressure \>100 * Inflammatory conditions (e.g. autoimmune disease, HIV) * Thyroid disease * Dementia or inability to consent * Cirrhosis, active/chronic hepatitis * Use medications interfering with muscle or mitochondrial function, including steroids, anti-psychotic, Coenzyme Q-10, immunosuppresssives, antivirals, and muscle relaxants * Weight \>300 lbs * Personal history or family history of deep vein thrombosis, pulmonary embolism * Active malignancy * Patients hospitalized within the past 60 days for any reason. * Patients with a history of a major atherosclerotic event (defined as combined incidence of myocardial infarction, urgent target-vessel revascularization, coronary bypass surgery, and stroke) within 3 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Muscle Mitochondrial Function | 2 weeks | 31P MRS/OS was used to measure mitochondrial phosphorylation capacity (ATPmax). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Force-time Integral Area Under the Curve in Active Agent vs. Placebo | 2 weeks | To test if glutamine improves objective isometric muscle fatigue by comparing the measurement of FTI from each arm. Muscle fatigability was tested by calculating FTI as the area under the force-time curve during isometric force generated at 70 % of maximal voluntary contraction (MVC), |
| Muscle Fatigue | 2 weeks | To test the effect of glutamine supplementation on muscle endurance, sum of the muscle force (force-time integral, FTI, N\*s) normalized to maximum voluntary contraction (MVC, N) generated during voluntary contraction. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Plasma NAD+ Levels | 2 weeks | To test if glutamine improves plasma NAD+ compared to placebo. Plasma NAD+ concentrations were quantified in mM using 31p MRS based in vivo assay. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| L-Glutamine First, Then Maltodextrin Subjects will first receive 0.4 g/kg/day of L-glutamine (Nutrestore, EMMAUS Life Sciences, Inc Torrance, CA) first, then crossover taking Maltodextrin. | 6 |
| Maltodextrin First, Then L-glutamine Subjects will first receive Identical appearing maltodextrin powder first, then crossover to taking L-glutamine. | 5 |
| Total | 11 |
Baseline characteristics
| Characteristic | L-Glutamine First, Then Maltodextrin | Total | Maltodextrin First, Then L-glutamine |
|---|---|---|---|
| Age, Continuous | 57 years STANDARD_DEVIATION 16.6 | 58 years STANDARD_DEVIATION 13.3 | 58 years STANDARD_DEVIATION 9.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 11 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 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 | 5 Participants | 8 Participants | 3 Participants |
| Region of Enrollment United States | 6 participants | 11 participants | 5 participants |
| Sex: Female, Male Female | 4 Participants | 5 Participants | 1 Participants |
| Sex: Female, Male Male | 2 Participants | 6 Participants | 4 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 | 0 / 11 | 0 / 11 |
| serious Total, serious adverse events | 0 / 11 | 0 / 11 |
Outcome results
Primary
Muscle Mitochondrial Function
31P MRS/OS was used to measure mitochondrial phosphorylation capacity (ATPmax).
Time frame: 2 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-Glutamine | Muscle Mitochondrial Function | 0.88 mM ATP/s | Standard Deviation 0.3 |
| Maltodextrin | Muscle Mitochondrial Function | 0.90 mM ATP/s | Standard Deviation 0.34 |
p-value: 0.15ANOVA
Secondary
Change in Force-time Integral Area Under the Curve in Active Agent vs. Placebo
To test if glutamine improves objective isometric muscle fatigue by comparing the measurement of FTI from each arm. Muscle fatigability was tested by calculating FTI as the area under the force-time curve during isometric force generated at 70 % of maximal voluntary contraction (MVC),
Time frame: 2 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-Glutamine | Change in Force-time Integral Area Under the Curve in Active Agent vs. Placebo | 58.87 N*s | Standard Deviation 24.07 |
| Maltodextrin | Change in Force-time Integral Area Under the Curve in Active Agent vs. Placebo | 52.36 N*s | Standard Deviation 21.22 |
p-value: 0.86ANOVA
Secondary
Muscle Fatigue
To test the effect of glutamine supplementation on muscle endurance, sum of the muscle force (force-time integral, FTI, N\*s) normalized to maximum voluntary contraction (MVC, N) generated during voluntary contraction.
Time frame: 2 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-Glutamine | Muscle Fatigue | 2.52 s-1 | Standard Deviation 1.09 |
| Maltodextrin | Muscle Fatigue | 2.41 s-1 | Standard Deviation 1.03 |
p-value: 0.44ANOVA
Post Hoc
Maximal Voluntary Contraction
To test if glutamine improves maximal voluntary contraction compared to placebo. Maximum voluntary contraction (MVC) was determined by the isometric force generated using first dorsal interosseous (FDI) muscle against a force transducer.
Time frame: 2 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-Glutamine | Maximal Voluntary Contraction | 23.6 N/m | Standard Deviation 6.834 |
| Maltodextrin | Maximal Voluntary Contraction | 23.22 N/m | Standard Deviation 8.967 |
p-value: 0.6ANOVA
Other Pre-specified
Plasma NAD+ Levels
To test if glutamine improves plasma NAD+ compared to placebo. Plasma NAD+ concentrations were quantified in mM using 31p MRS based in vivo assay.
Time frame: 2 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-Glutamine | Plasma NAD+ Levels | 0.95 mM | Standard Deviation 0.25 |
| Maltodextrin | Plasma NAD+ Levels | 0.98 mM | Standard Deviation 0.19 |
p-value: 0.36ANOVA