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Exercise Study Testing Enhanced Energetics of Muscle Mitochondria in CKD (ESTEEM-CKD)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02923063
Recruitment Status : Recruiting
First Posted : October 4, 2016
Last Update Posted : February 26, 2020
Information provided by (Responsible Party):
University of California, Davis

Brief Summary:
Skeletal muscle dysfunction (sarcopenia) is an under-recognized target organ complication of CKD with substantial adverse clinical consequences of disability, hospitalization, and death. Sarcopenia in this proposal is defined by impaired metabolism and physical function associated with decreased skeletal muscle mass or function. Skeletal muscle tissue relies on mitochondria to efficiently utilize oxygen to generate ATP. Impaired mitochondrial energetics is a central mechanism of sarcopenia in CKD. The investigators propose a series of studies designed to shed light on the pathophysiology of sarcopenia in persons with CKD not treated with dialysis. Investigators will conduct a randomized-controlled intervention trial of combined resistance training and aerobic exercise vs. health education to assess changes in skeletal muscle mitochondrial function, metabolism and physical function. Investigators hypothesize that exercise improves mitochondrial function and physical function in persons with CKD. If successful, these experiments will identify novel pathophysiologic mechanisms for CKD-associated sarcopenia. The proposed study will provide useful insight into benefits associated with exercise among patients with CKD and investigate mechanisms associated with improved metabolism, muscle function and physical function in population.

Condition or disease Intervention/treatment Phase
Moderate-severe Chronic Kidney Disease Not Treated With Dialysis Non-insulin Dependent Diabetic Kidney Disease Behavioral: Combined Aerobic and Resistance Exercise Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized, Controlled Trial of Combined Aerobic and Resistance Exercise on Muscle Mitochondrial Function and Metabolism
Actual Study Start Date : January 16, 2020
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : April 2022

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Combined Aerobic and Resistance Exercise

Exercise will be supervised by exercise trainers 3 days per week for 12 weeks. Aerobic intervention sessions of 30-minute duration will target 60-80% of the maximal heart rate (or rating of perceived exertion of 13 on a scale of 6-20). We will encourage adherence to 50% ambulatory based and 50% cycling based aerobic exercise each session targeting the same goal heart rate.

Resistance exercises occur 3 times weekly. The load will be adjusted for each exercise as needed on successive sets to ensure that subjects achieved momentary failure in the target repetition range. The load will be increased based on the supervising researcher's assessment of what would be required to reach momentary failure in the desired loading range; if less than 8 repetitions were accomplished, the load was similarly decreased. All routines will be directly supervised by the research team to ensure proper performance of the respective routines.

Behavioral: Combined Aerobic and Resistance Exercise
Combined aerobic and resistance exercise session thrice weekly for 12 weeks

No Intervention: Usual Care
The control group will receive a one-time counseling session on appropriate dietary and physical activity recommendations. They will receive a "Go4Life Workout to go" sample exercise routing created by the national institutes on aging (NIA).

Primary Outcome Measures :
  1. Mitochondrial phosphorylation capacity (ATPmax) by in-vivo 31P MRS [ Time Frame: 12 weeks ]
    leg muscles

  2. Quadriceps muscle work efficiency [ Time Frame: 12 weeks ]
    Work efficiency calculated by cycler ergometry VO2

Secondary Outcome Measures :
  1. Change in physical performance [ Time Frame: 12 weeks ]
    6 minute walking distance (meters)

  2. Change in Systemic oxidative stress (markers of arachidonic acid peroxidation) [ Time Frame: 12 weeks ]
    Plasma isofurans (pg/min)

  3. Change in aerobic capacity (VO2max) (ml/kg/min) [ Time Frame: 12 weeks ]
    mM (millimole)

  4. Monocyte bioenergetics [ Time Frame: 12 weeks ]
    Reserve Capacity (pmo/min/mcg protein)

  5. Change in muscle fatigue [ Time Frame: 12 weeks ]
    Force-time integral using biodex in isometric mode

  6. Muscle mitochondrial reactive oxygen species production from permeabilized muscle fibers. [ Time Frame: 12 weeks ]
    hydrogen peroxide (H2O2) production (pmol/min/mg protein)

  7. Self-reported fatigue (NIH PROMIS Fatigue) [ Time Frame: 12 weeks ]
    self reported fatigue

  8. Self-reported physical function (PROMIS mobility) [ Time Frame: 12 weeks ]
    self reported difficulty with mobility

Other Outcome Measures:
  1. Walking economy during 6 minute walk [ Time Frame: 12 weeks ]
    Assessement of energetic cost of walking during a submaximal 6 minute walk test using COSMED

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Moderate-severe CKD determined by estimated glomerular filtration rate (eGFR) <50ml/min per 1.73m2
  • No history chronic treatment with dialysis.
  • Age 18 years old to 75 years
  • Sedentary defined as self-reporting no more than 1 day per week of regular (structured) endurance exercise (EE) [e.g., brisk walking, jogging/running, cycling, elliptical, or swimming activity that results in feelings of increased heart rate or rapid breathing (EE), and/or sweating] or resistance exercise (RE) (resulting in muscular fatigue) lasting no more than 60 minutes in the past year

Exclusion Criteria:

  • Current or previous transplantation
  • Current pregnancy
  • Wheelchair dependence
  • Oxygen dependent Chronic obstructive pulmonary disease (COPD)
  • Shortness of breath after walking <100 steps on flat surface
  • Weight >300 pounds
  • HIV infection or hepatitis viral infection
  • Liver cirrhosis
  • Active malignant cancer other than non-melanomatous skin cancer
  • Drugs that alter mitochondrial function:

    • muscle relaxants (methocarbamol, baclofen, tizanidine, carisoprodol, cyclobenzaprine)
    • oral steroids (Equivalent of 10mg or more of prednisone daily)
    • anti-viral medications (tenofovir, zalcitabine, didanosine, stavudine, lamivudine, zidovudine, abacavir, adefovir, interferon, ribavirin, efavirenz, dasabuvir, ombitasvir)
    • oral calcineurin inhibitors (Tacrolimus, Cyclosporine)
    • Antiepileptic drugs (Phenytoin, phenobarbital, carbamazepine, valproic acid, oxcarbazepine, ethosuximide, zonisamide, topiramate, and vigabatrin)
    • Antipsychotics (haloperidol, thioridazine, risperidone, quetiapine, clozapine, olanzapine and aripiprazole)
  • Drugs- anticoagulants or antiplatelets

    • Anticoagulants, any 1 (coumadin, rivaroxaban, apixaban, dabigatran, edoxaban)
    • Antiplatelets, any 2 (aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticagrelor, ticlopidine, vorapaxar)
  • Implants that prohibit MRI measurements or trauma involving metal fragments
  • Pacemaker
  • Vascular stent: bare metal or any recently placed (within 6 months)
  • Current substance abuse
  • Institutionalization
  • Current participation in an interventional trial
  • Inability to provide informed consent without a proxy respondent
  • Non-English speaking
  • Any condition which in the judgement of the clinical investigator places the participant at risk from participation in the study.

Additional Criteria:

  • On chronic dialysis
  • Expectation to start dialysis within 6 months.
  • Insulin dependent diabetes
  • Baseline systolic blood pressure >170 or diastolic blood pressure >100

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02923063

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Contact: Baback Roshanravan, MD MS MSPH 5307540893

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United States, California
UC Davis Health Recruiting
Sacramento, California, United States, 98104
Contact: Bob Roshanravan, MD MS MSPH    530-754-0893   
Principal Investigator: Baback Roshanravan, MD MS         
Principal Investigator: Javier Lopez, MD         
Sub-Investigator: Erik Henricson, PhD         
Sponsors and Collaborators
University of California, Davis
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Principal Investigator: Baback Roshanravan, MD MS MSPH UC Davis
Principal Investigator: Javier Lopez, MD UC Davis Department of Medicine/Division of Cardiology
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Responsible Party: University of California, Davis Identifier: NCT02923063    
Other Study ID Numbers: 1343904
First Posted: October 4, 2016    Key Record Dates
Last Update Posted: February 26, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of California, Davis:
Chronic Kidney Disease
Mitochondrial Metabolism
Physical Performance
Exercise Intolerance
Muscle Fatigue
Additional relevant MeSH terms:
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Kidney Diseases
Renal Insufficiency, Chronic
Diabetic Nephropathies
Urologic Diseases
Renal Insufficiency
Diabetes Complications
Diabetes Mellitus
Endocrine System Diseases