Trial of Oral Glutamine on Mitochondrial Function in CKD

Cardiovascular Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02838979
• Other study ID #: 47861
• Secondary ID: 5K23DK099442
• Status: Completed
• Phase: Phase 2
• Start date: February 25, 2016
• Est. completion date: January 31, 2018

Study information

• Verified date: March 2022
• Source: University of Washington
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 11
• Est. completion date: January 31, 2018
• Est. primary completion date: October 1, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 20 Years to 69 Years

Eligibility

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

Related Conditions & MeSH terms

• Cardiovascular Disease
• Cardiovascular Diseases
• Endothelial Dysfunction
• Kidney Disease
• Kidney Diseases
• Muscle Mitochondrial Function
• Sarcopenia

Intervention

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

Locations

Country	Name	City	State
United States	Kidney Research Institute, University of Washington	Seattle	Washington

Sponsors (5)

Lead Sponsor	Collaborator
University of Washington	Emory University, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), New York Medical College, Vanderbilt University

Country where clinical trial is conducted

United States, 

References & Publications (3)

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Primary	Muscle Mitochondrial Function	31P MRS/OS was used to measure mitochondrial phosphorylation capacity (ATPmax).	2 weeks
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),	2 weeks
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.	2 weeks