Trial of Oral Glutamine on Mitochondrial Function in CKD

NCT ID: NCT02838979

Last Updated: 2022-07-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 11 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-02-25
• Study Completion Date: 2018-01-31

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.

Conditions

Cardiovascular Disease; Sarcopenia; Endothelial Dysfunction; Muscle Mitochondrial Function; Kidney Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

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

Group Type: EXPERIMENTAL

First Intervention (14 days)

Intervention Type: DIETARY_SUPPLEMENT

Oral Glutamine or Maltodextrin for 2 weeks

Washout (3 weeks)

Intervention Type: OTHER

No study product is taken prior to beginning crossover

Second Intervention (14 days)

Intervention Type: DIETARY_SUPPLEMENT

Oral Glutamine or Maltodextrin for 2 weeks

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

Group Type: EXPERIMENTAL

First Intervention (14 days)

Intervention Type: DIETARY_SUPPLEMENT

Oral Glutamine or Maltodextrin for 2 weeks

Washout (3 weeks)

Intervention Type: OTHER

No study product is taken prior to beginning crossover

Second Intervention (14 days)

Intervention Type: DIETARY_SUPPLEMENT

Oral Glutamine or Maltodextrin for 2 weeks

Interventions

First Intervention (14 days)

Oral Glutamine or Maltodextrin for 2 weeks

Intervention Type: DIETARY_SUPPLEMENT

Washout (3 weeks)

No study product is taken prior to beginning crossover

Intervention Type: OTHER

Second Intervention (14 days)

Oral Glutamine or Maltodextrin for 2 weeks

Intervention Type: DIETARY_SUPPLEMENT

Eligibility Criteria

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

• Minimum Eligible Age: 20 Years
• Maximum Eligible Age: 69 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

New York Medical College

OTHER

Sponsor Role: collaborator

Emory University

OTHER

Sponsor Role: collaborator

Vanderbilt University

OTHER

Sponsor Role: collaborator

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: collaborator

University of Washington

OTHER

Sponsor Role: lead

Responsible Party

Jonathan Himmelfarb

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jonathan Himmelfarb, MD

Role: PRINCIPAL_INVESTIGATOR

Kidney Research Insitute

Locations

Kidney Research Institute, University of Washington

Seattle, Washington, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 2119459 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 18930151 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 19715755 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

5K23DK099442

Identifier Type: NIH

Identifier Source: secondary_id

View Link

47861

Identifier Type: -

Identifier Source: org_study_id