Trial of Oral Glutamine on Mitochondrial Function in CKD

Randomized Cross-over Trial of Oral L-Glutamine vs Maltodextrin on Mitochondrial Function in Chronic Kidney Disease

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.

Study Overview

• Status: Completed
• Conditions: Cardiovascular Disease; Sarcopenia; Endothelial Dysfunction; Kidney Disease; Muscle Mitochondrial Function
• Intervention / Treatment: Dietary supplement: First Intervention (14 days); Other: Washout (3 weeks); Dietary supplement: Second Intervention (14 days)

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.

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98104
      • Kidney Research Institute, University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 69 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Oral L-Glutamine first, then Maltodextrin; 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	Dietary supplement: First Intervention (14 days); Oral Glutamine or Maltodextrin for 2 weeks; Other: Washout (3 weeks); No study product is taken prior to beginning crossover; Dietary supplement: Second Intervention (14 days); Oral Glutamine or Maltodextrin for 2 weeks
Experimental: Maltodextrin first, then L-glutamine; 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	Dietary supplement: First Intervention (14 days); Oral Glutamine or Maltodextrin for 2 weeks; Other: Washout (3 weeks); No study product is taken prior to beginning crossover; Dietary supplement: Second Intervention (14 days); Oral Glutamine or Maltodextrin for 2 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Muscle Mitochondrial Function	31P MRS/OS was used to measure mitochondrial phosphorylation capacity (ATPmax).	2 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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),	2 weeks
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.	2 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	2 weeks

Collaborators and Investigators

• Sponsor: University of Washington
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Emory University; Vanderbilt University; New York Medical College
• Investigators: Principal Investigator: Jonathan Himmelfarb, MD, Kidney Research Insitute

Publications and helpful links

General Publications

• Ziegler TR, Benfell K, Smith RJ, Young LS, Brown E, Ferrari-Baliviera E, Lowe DK, Wilmore DW. Safety and metabolic effects of L-glutamine administration in humans. JPEN J Parenter Enteral Nutr. 1990 Jul-Aug;14(4 Suppl):137S-146S. doi: 10.1177/0148607190014004201.
• Amara CE, Marcinek DJ, Shankland EG, Schenkman KA, Arakaki LS, Conley KE. Mitochondrial function in vivo: spectroscopy provides window on cellular energetics. Methods. 2008 Dec;46(4):312-8. doi: 10.1016/j.ymeth.2008.10.001. Epub 2008 Oct 16.
• Jones DP, Liang Y. Measuring the poise of thiol/disulfide couples in vivo. Free Radic Biol Med. 2009 Nov 15;47(10):1329-38. doi: 10.1016/j.freeradbiomed.2009.08.021. Epub 2009 Aug 26.

Study record dates

Study Major Dates

• Study Start (Actual): February 25, 2016
• Primary Completion (Actual): October 1, 2017
• Study Completion (Actual): January 31, 2018

Study Registration Dates

• First Submitted: July 8, 2016
• First Submitted That Met QC Criteria: July 15, 2016
• First Posted (Estimate): July 20, 2016

Study Record Updates

• Last Update Posted (Actual): July 14, 2022
• Last Update Submitted That Met QC Criteria: June 21, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Chronic Kidney Disease; Glutamine
• Additional Relevant MeSH Terms: Nervous System Diseases; Urologic Diseases; Neurologic Manifestations; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Muscular Atrophy; Atrophy; Cardiovascular Diseases; Kidney Diseases; Sarcopenia
• Other Study ID Numbers: 47861; 5K23DK099442 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No