Exercise & Supplements for Chronic Kidney Disease

(NeurovEx Trial)

Recruiting at 2 trial locations

Overseen By Jeanie Park, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Emory University

Must not be taking: Central alpha agonists, MAO inhibitors

Disqualifiers: Severe CKD, Drug abuse, Heart disease, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 22

Duration: 6-14 weeks

150 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores why individuals with chronic kidney disease (CKD) often struggle with exercise and experience elevated blood pressure during physical activity. Researchers aim to determine if regular cycling and treatments like 6R-BH4 pills (a supplement) or amino acid supplements (histidine and beta-alanine) can enhance exercise capacity and manage blood pressure. Participants will be divided into groups to test various combinations of exercise and supplements. This trial suits those with stage III or IV CKD who do not exercise regularly and are willing to adhere to the study protocol. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are currently taking central alpha agonists (like clonidine) or monoamine oxidase (MAO) inhibitors.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that 6R-BH4 is generally safe for individuals with chronic kidney disease (CKD). It can reduce stress-related nerve activity and improve blood flow. The FDA has already approved it for another condition, indicating its well-established safety. However, its effects on blood pressure and exercise in CKD remain under investigation.

Exercise training is safe and effective for CKD patients, enhancing physical function without major risks. Activities like cycling can improve fitness and quality of life.

Research suggests that histidine and beta-alanine supplements are safe at normal doses. High doses of histidine might lower zinc levels or affect cognition, but these side effects are rare. Beta-alanine is generally safe at the doses studied.

Overall, past studies have demonstrated the safety of these treatments, but ongoing trials will continue to confirm their safety for CKD patients during exercise. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for chronic kidney disease because they explore novel combinations that could enhance patient outcomes. While traditional treatments often focus on medication and dialysis, this trial incorporates exercise and supplements like 6R-BH4, histidine, and beta-alanine. These supplements are thought to improve kidney function by enhancing blood flow and reducing oxidative stress, which is different from conventional approaches. The integration of exercise aims to boost overall health, making these treatments a holistic approach to managing the disease. This fresh angle could offer benefits beyond what existing therapies provide, potentially leading to better quality of life for patients.

What evidence suggests that this trial's treatments could be effective for chronic kidney disease?

Research has shown that regular exercise can improve health for people with chronic kidney disease (CKD). It can increase physical activity levels and may slow disease progression. In this trial, participants in different arms will receive various combinations of exercise and supplements. One arm will study the effects of 6R-BH4, which studies suggest can help lower the high blood pressure CKD patients often experience during exercise, potentially making activity easier. Another arm will focus on histidine and beta-alanine supplementation, which has been examined for its potential to help with anemia in CKD, though results remain unclear. This trial aims to determine if these methods can help CKD patients exercise more effectively and manage blood pressure during physical activity. ^{1 3 6 7 8}

Who Is on the Research Team?

Joe Nocera, PhD

Principal Investigator

Emory University

Are You a Good Fit for This Trial?

This trial is for adults with moderate to severe chronic kidney disease (stages III or IV), which means their kidneys don't filter blood well. They should have stable kidney function without major changes in the last 3 months and not be regular exercisers, working out less than 40 minutes per week.

Inclusion Criteria

My kidney function is moderately to severely reduced.

My kidney function has been stable, with less than a 30% drop in efficiency.

Does not exercise regularly (defined as exercising less than 20 minutes twice per week)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Baseline Assessment

Measurement of vein constriction response to adrenaline, muscle pH, and muscle oxygenation in CKD patients versus controls

1-2 weeks

1-2 visits (in-person)

Treatment

Participants undergo exercise training or stretching, with or without 6R-BH4 or histidine and beta-alanine supplementation, 3 times per week

6-14 weeks

18-42 visits (in-person)

Follow-up

Participants are monitored for changes in muscle oxygenation, vascular responsiveness, and blood pressure response during exercise

4 weeks

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• 6R-BH4
• Exercise training
• Histidine and beta-alanine supplementation

Trial Overview The study looks at why patients with CKD struggle with exercise and high blood pressure during it. It tests if cycling, a drug called Kuvan (6R-BH4), or supplements like histidine and beta-alanine can help improve these issues. Some participants will receive placebos instead of actual drugs.

How Is the Trial Designed?

Group I: Exercise training + 6R-BH4 Experimental Treatment 3 Interventions

Participants randomized to this arm will exercise on a stationary bicycle for 20-45 minutes, 3 times per week, for 6-12 weeks. This arm will also take the study drug 6R-BH4.

Group II: Exercise training + histidine and beta-alanine Active Control 2 Interventions

Participants randomized to this arm will exercise on a stationary bicycle for 20-45 minutes, 3 times per week, for 6-12 weeks. This arm will also take histidine and beta-alanine supplementation.

Group III: Exercise training + histidine and beta-alanine placebo Active Control 2 Interventions

Participants randomized to this arm will exercise on a stationary bicycle for 20-45 minutes, 3 times per week, for 6-12 weeks. This arm will also take a placebo to match the histidine and beta-alanine supplementation.

Group IV: Exercise training + 6R-BH4 placebo Active Control 3 Interventions

Participants randomized to this arm will exercise on a stationary bicycle for 20-45 minutes, 3 times per week, for 6-12 weeks. This arm will also take a placebo to match the study drug 6R-BH4.

Group V: Stretching + 6R-BH4 Active Control 3 Interventions

Participants randomized to this arm will do muscle stretching and toning for 20-45 minutes, 3 times per week, for 6-12 weeks. This arm will also take the study drug 6R-BH4.

Group VI: Stretching + placebo Placebo Group 3 Interventions

Participants randomized to this arm will do muscle stretching and toning for 20-45 minutes, 3 times per week, for 6-12 weeks. This arm will also take a placebo instead of the active study drug.

Who Is Running the Clinical Trial?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Published Research Related to This Trial

In a study of 26 chronic kidney disease patients, blood flow restriction training led to significant increases in the diameter of the radial artery, indicating potential benefits for vascular health, but did not outperform conventional exercise without blood flow restriction.

Both blood flow restriction and control groups showed increases in cephalic vein diameter, suggesting that physical training is beneficial for vascular adaptations in patients with arteriovenous fistulas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does blood flow restriction training increase the diameter of forearm vessels in chronic kidney disease patients? A randomized clinical trial. Barbosa, JB., Maia, TO., Alves, PS., et al.[2019]

Aerobic exercise and resistance training can significantly improve health outcomes in chronic kidney disease (CKD) patients by reducing inflammation, increasing insulin sensitivity, and potentially enhancing kidney function, as evidenced by improvements in glomerular filtration rate (GFR) and reductions in microalbuminuria.

Combining both aerobic and resistance training during dialysis has been shown to enhance muscle strength, physical functionality, and overall quality of life, suggesting that exercise could be a vital component in the management and prevention of CKD progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of aerobic exercise and resistance training in patients with and without chronic kidney disease. Moinuddin, I., Leehey, DJ.[2022]

Patients with chronic kidney disease (CKD) who are on dialysis typically have low exercise capacity and physical functioning, but regular exercise training can significantly improve these aspects.

Despite the clear benefits of exercise for CKD patients, the nephrology community has not yet integrated exercise recommendations into standard care practices, highlighting a need for better implementation of exercise counseling in treatment plans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Implementing exercise: what do we know? Where do we go? Painter, P.[2022]

An exercise program combining supervised training and home-based training significantly improved physical fitness in patients with chronic kidney disease (CKD), as shown by increased metabolic equivalent tasks (METs) and 6-minute walk distance after 10 months.

The study found no serious adverse events related to the exercise training, indicating that this intervention is safe for patients with CKD, although the study was not specifically designed to assess safety outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exercise training in CKD: efficacy, adherence, and safety. Howden, EJ., Coombes, JS., Strand, H., et al.[2022]

Resistance training (RT) significantly improved muscle strength, renal function, and reduced renal fibrosis in a rat model of chronic kidney disease (CKD) over a 10-week period.

However, when combined with oral L-arginine (L-arg) supplementation, the benefits of RT were negated, indicating that L-arg may interfere with the positive effects of exercise on CKD outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

l-Arginine supplementation blunts resistance exercise improvement in rats with chronic kidney disease. Souza, MK., Moraes, MR., Rosa, TS., et al.[2019]

A 1-year cardiac rehabilitation program showed no overall significant changes in renal function markers for patients with cardiovascular disease, but those with mild-to-moderate chronic kidney disease (CKD) experienced a notable improvement in their estimated glomerular filtration rate (eGFR).

This suggests that cardiac rehabilitation may be beneficial for enhancing renal function specifically in patients with mild-to-moderate CKD, highlighting the potential for exercise training as a supportive therapy in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of a Cardiac Rehabilitation Program on Renal Function in Patients With Cardiovascular Disease in a One-Year Follow-Up. Fujimi, K., Miura, SI., Matsuda, T., et al.[2020]

Aerobic exercise training can enhance exercise capacity in patients with chronic kidney disease (CKD), while resistance training may improve muscle function, based on a review of 6 trials involving 131 participants.

The review found no reported cardiac events during exercise training, indicating that exercise is a safe intervention for individuals with CKD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Exercise Training on Delaying Disease Progression in Patients with Chronic Kidney Disease: a Review of the Literature. Izumi, A., Kitamura, M., Izawa, KP.[2019]

Exercise training significantly improves maximal exercise capacity, muscle strength, and endurance in patients with chronic kidney disease (CKD) across all stages, including those on dialysis and post-transplant.

Starting exercise training during the predialysis stage is ideal, as it helps combat muscle catabolism, weight loss, and enhances overall quality of life, making it a crucial part of CKD patient care prescribed by nephrologists.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Physical working capacity and muscle strength in chronic renal failure are improved by exercise]. Clyne, N.[2006]

Nutritional interventions are well-supported in managing chronic kidney disease (CKD) and are included in many clinical practice guidelines, highlighting their importance in treatment.

Progressive resistance training (PRT) has been shown to be safe and effective in improving clinical and functional outcomes for patients with CKD, despite having a more limited evidence base compared to aerobic exercise.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progressive resistance training and nutrition in renal failure. Chan, M., Cheema, BS., Fiatarone Singh, MA.[2010]

Aerobic exercise interventions have been shown to improve physical functioning and performance in patients with chronic kidney disease (CKD), with evidence suggesting benefits for blood pressure control, lipid profiles, and mental health.

Despite the known safety and benefits of exercise for CKD patients, many remain inactive, highlighting the need for better assessment and encouragement of physical activity, particularly through low-intensity resistance and aerobic training programs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exercise and chronic kidney disease: current recommendations. Johansen, KL.[2022]

Citations

1. clinicaltrials.biomarin.com clinicaltrials.biomarin.com/clinical-trial/tetrahydrobiopterin-in-patients-with-chronic-kidney-disease-ckd-and-albuminuria/

Tetrahydrobiopterin in Patients With Chronic Kidney ... If 6R-BH4 reduces albuminuria in patients with kidney disease, it may have implications to slow the disease progression as well as decreased ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5002055/

Tetrahydrobiopterin ameliorates the exaggerated exercise ... These findings suggest that 6R-BH 4 ameliorates the augmented BP response during RHG 20% and SHG 30% in CKD patients.

3. cdek.pharmacy.purdue.edu cdek.pharmacy.purdue.edu/trial/NCT00625820/

Trial | NCT00625820 If 6R-BH4 reduces albuminuria in patients with kidney disease, it may have implications to slow the disease progression as well as decreased risk of CVD.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8573752/

Tetrahydrobioterin (BH4) Pathway: From Metabolism to ... These results are in agreement with clinical data reporting significant reductions in both pain and inflammation in rheumatoid arthritis and inflammatory bowel ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S0891584921008182

Newly established LC-MS/MS method for measurement of ... BH4 can be protective for early renal function decline suggesting its deficiency may induce damage on renal function other than ACR progression. Abstract ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4313073/

Tetrahydrobiopterin lowers muscle sympathetic nerve activity ... In conclusion, this study demonstrates that 6R-BH4 significantly lowers sympathetic activity and improves AIx and EID in patients with CKD Stage II and III. We ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10056709/

Associations of Biopterins and ADMA with Vascular ... Patients with CKD stages 3 and 5 and non-CKD controls are included in this study. We report that there was a significant reduction of the biopterin (BH4/BH2) ...

8. sciencedirect.com sciencedirect.com/science/article/pii/S0085253815543512

Tetrahydrobiopterin protects the kidney from ischemia– ... Supplemental BH4 treatment before ischemia significantly reduced ischemia-induced renal dysfunction, and decreased tubular histologic injury ...