Trial of Oral Glutamine on Mitochondrial Function in CKD

Phase 2

Completed

Conditions: Muscle Mitochondrial Function
Sarcopenia
Cardiovascular Disease
Endothelial Dysfunction
Kidney Disease

Interventions: Dietary Supplement: First Intervention (14 days)
Other: Washout (3 weeks)
Dietary Supplement: Second Intervention (14 days)

Registration Number: NCT02838979

Lead Sponsor: University of Washington

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 11

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Oral L-Glutamine first, then Maltodextrin	Washout (3 weeks)	Subjects will receive 0.4 g/kg/day of L-glutamine (Nutrestore, EMMAUS Life Sciences, Inc Torrance, CA) in three divided daily doses OR identical appearing maltodextrin powder. Duration 2 weeks
Oral L-Glutamine first, then Maltodextrin	Second Intervention (14 days)	Subjects will receive 0.4 g/kg/day of L-glutamine (Nutrestore, EMMAUS Life Sciences, Inc Torrance, CA) in three divided daily doses OR identical appearing maltodextrin powder. Duration 2 weeks
Maltodextrin first, then L-glutamine	Washout (3 weeks)	Subjects will crossover to receiving the study product which they did not receive in the first period. Either 0.4 g/kg/day of L-glutamine in three divided daily doses OR identical appearing maltodextrin powder. Duration 2 weeks
Maltodextrin first, then L-glutamine	Second Intervention (14 days)	Subjects will crossover to receiving the study product which they did not receive in the first period. Either 0.4 g/kg/day of L-glutamine in three divided daily doses OR identical appearing maltodextrin powder. Duration 2 weeks
Oral L-Glutamine first, then Maltodextrin	First Intervention (14 days)	Subjects will receive 0.4 g/kg/day of L-glutamine (Nutrestore, EMMAUS Life Sciences, Inc Torrance, CA) in three divided daily doses OR identical appearing maltodextrin powder. Duration 2 weeks
Maltodextrin first, then L-glutamine	First Intervention (14 days)	Subjects will crossover to receiving the study product which they did not receive in the first period. Either 0.4 g/kg/day of L-glutamine in three divided daily doses OR identical appearing maltodextrin powder. Duration 2 weeks

Primary Outcome Measures

Name	Time	Method
Muscle Mitochondrial Function	2 weeks	31P MRS/OS was used to measure mitochondrial phosphorylation capacity (ATPmax).

Secondary Outcome Measures

Name	Time	Method
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.