Nitrite-boosting Therapy for Improving Physiological Function in Patients With Chronic Kidney Disease

Nitric oxide (NO) is an essential molecule in the body that is decreased in patients with chronic kidney disease (CKD), leading to reductions in vascular, movement ("motor") and cognitive functions. This study will determine if daily oral supplementation (3 months) with a supplement that increases NO in the body, i.e., nitrate-rich beetroot juice, improves vascular, motor and cognitive function in patients with CKD; this study will also provide insight into the biological reasons (mechanisms) by which supplementation with nitrate-rich beetroot juice improves vascular function in these patients. Overall, this research will provide scientific evidence supporting the use of nitrate-rich beetroot juice for preserving physiological function and preventing co-morbid clinical conditions and disability in CKD.

Study Overview

• Status: Recruiting
• Conditions: Chronic Kidney Disease
• Intervention / Treatment: Dietary supplement: Nitrate-rich beetroot juice; Dietary supplement: Nitrate-depleted beetroot juice

• Study Type: Interventional
• Enrollment (Anticipated): 92
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Hannah Lally; Phone Number: 303-735-6410; Email: beetrootstudy@colorado.edu

Study Locations

• United States
  • Colorado
    • Boulder, Colorado, United States, 80309
      • Recruiting
      • Integrative Physiology of Aging Laboratory
      • Contact: Melanie R Zigler, M.S.; Phone Number: 303-492-2485; Email: melanie.connell@colorado.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 28 years to 78 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• CKD stage II-IV (eGFR using the Modification of Diet in Renal Disease (MDRD) prediction equation 20-90 mL/min/1.73m2; stable renal function in the past 3 months)
• Ability to give informed consent
• Albumin > 3.0 g/dL
• Ability to perform motor and cognitive tests (e.g., can rise from a chair, walk for 6 min, climb 10 stairs)
• Free from alcohol dependence or abuse, as defined by the American Psychiatry Association, Diagnostic and Statistical Manual of Mental Disorders (DSM-V)
• Mini-mental state examination score >21 (rationale: to screen for subjects with major cognitive impairment)
• Blood pressure (BP) >100/60 mmHg for past 3 months (rationale: blood pressure below 100/60 mmHg may elevate the normally small risk of hypotension with nitrate supplementation)
• Not taking medications that will interfere with administered medications (e.g., sildenafil interacts with nitroglycerin)
• Body mass index (BMI) <40 kg/m2 (vascular function measurements can be inaccurate in severely obese patients)

Exclusion Criteria:

• Life expectancy <1 year
• Uncontrolled hypertension, defined as blood pressure > 160/100 mmHg in the past 3 months
• History of severe liver disease
• History of severe congestive heart failure (i.e., ejection fraction < 35%)
• History of hospitalizations within the last 3 months
• Active infection or antibiotic therapy
• Warfarin use
• Vasculitis requiring immunosuppressive therapy within the last year
• High dietary nitrate intake or current nitrate/nitrite supplementation; hypersensitivity to nitrates or nitrites
• Glucose-6-phosphate dehydrogenase deficiency or blood methemoglobin >2%
• Unwilling to abstain from use of mouthwash or other oral hygiene practices (e.g., tongue scraping) outside of teeth brushing that disrupt the oral microbiome and would interfere with nitrate conversion to nitrite
• Blood donation within 8 weeks prior to enrolling in the study; unwilling to abstain from donating blood for 8 weeks after completing the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Nitrate-rich beetroot juice; Daily dose of nitrate-rich beetroot juice (70 mL) for 3 months.	Dietary supplement: Nitrate-rich beetroot juice; Daily supplementation with ~100 kcal of nitrate-rich beetroot juice containing 400 mg of dietary nitrate (James White Drinks, UK).
Placebo Comparator: Nitrate-depleted beetroot juice; Daily dose of nitrate-depleted beetroot juice (70 mL) for 3 months. The nitrate-depleted beetroot juice is identical in appearance, taste and caloric content to nitrate-rich beetroot juice, but with nitrate removed.	Dietary supplement: Nitrate-depleted beetroot juice; Daily supplementation with ~100 kcal of nitrate-depleted beetroot juice (James White Drinks, UK).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in vascular endothelial function	as measured by brachial artery flow-mediated dilation	Baseline, 3 months
Change in aortic stiffness	as measured by carotid-femoral pulse wave velocity	Baseline, 3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in oxidative stress-associated suppression of endothelial function assessed as the increase in brachial artery flow-mediated dilation following an ascorbic acid infusion	The influence of oxidative stress on brachial artery flow-mediated dilation will be determined by infusing a supraphysiological dose of ascorbic acid known to scavenge superoxide or isovolumic saline	Baseline, 3 months
Change in endothelial cell markers of oxidative stress	Endothelial cell nitrotyrosine levels will be determined	Baseline, 3 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Motor function composite score	Multiple domains of motor function (including endurance, strength, dexterity) assessed using the NIH Toolbox Motor Battery (aggregated into one reported value)	Baseline, 3 months
Fluid cognition composite score	Multiple domains of cognitive function (including executive function, memory, processing speed) assessed using the NIH Toolbox Cognitive Battery (aggregated into one reported value)	Baseline, 3 months

Collaborators and Investigators

• Sponsor: University of Colorado, Boulder
• Investigators: Principal Investigator: Matthew J Rossman, PhD, University of Colorado, Boulder

Publications and helpful links

General Publications

• Jones AM, Vanhatalo A, Seals DR, Rossman MJ, Piknova B, Jonvik KL. Dietary Nitrate and Nitric Oxide Metabolism: Mouth, Circulation, Skeletal Muscle, and Exercise Performance. Med Sci Sports Exerc. 2021 Feb 1;53(2):280-294. doi: 10.1249/MSS.0000000000002470.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2019
• Primary Completion (Anticipated): July 1, 2023
• Study Completion (Anticipated): July 1, 2024

Study Registration Dates

• First Submitted: January 28, 2019
• First Submitted That Met QC Criteria: January 29, 2019
• First Posted (Actual): February 1, 2019

Study Record Updates

• Last Update Posted (Actual): May 17, 2023
• Last Update Submitted That Met QC Criteria: May 15, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urologic Diseases; Renal Insufficiency; Kidney Diseases; Renal Insufficiency, Chronic
• Other Study ID Numbers: 18-0364

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No