Diabetes Clinical Trial
— Senergy-CKDOfficial title:
Randomized Cross-over Trial of Sodium Bicarbonate on Muscle Mitochondrial Energetics and Physical Endurance in Chronic Kidney Disease and Metabolic Acidosis
Skeletal muscle metabolic health is critical for mobility and an underrecognized target of metabolic acidosis in chronic kidney disease. Impaired muscle mitochondrial metabolism underlies poor physical endurance increasing the risk of mobility disability. The proposed project will use precise in vivo tools to study the pathophysiology of poor physical endurance in a clinical trial treating metabolic acidosis among persons living with chronic kidney disease.
Status | Recruiting |
Enrollment | 80 |
Est. completion date | July 30, 2026 |
Est. primary completion date | December 31, 2025 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 21 Years to 85 Years |
Eligibility | Inclusion Criteria: - Moderate-severe CKD determined by eGFR <50ml/min per 1.73m2 by CKD EPI equation on at least 2 consecutive occasions. - Metabolic acidosis defined as bicarbonate level<24 on two consecutive occasions. Bicarbonate level of 24 or less allowed if eGFR<=45ml/min per 1.73m2 - Age 21 to 85 years old Exclusion Criteria: - Type 2 diabetes managed with insulin treatment - Poorly controlled diabetes (HgbA1c>10%) - History of persistent hyperkalemia (K>5.4) - Chronic treatment with renal replacement therapy - History of aortic dissection or severe valvular heart disease - Exercise induced angina - Uncontrolled cardiac dysrhythmia - Oxygen dependent COPD - Symptomatic claudication - End stage liver disease - Mobility disability defined as inability to walk without human assistance - Dementia or psychosis - Patients who cannot consent - Active use of IV drugs - Non-english speaking - History of transplant - Implants that prohibit MRI measurements or trauma involving metal fragments - Pacemaker - Expectation to start dialysis during the course of study. - Any condition which in the judgement of the clinical investigator places the participant at risk from participation in the study. |
Country | Name | City | State |
---|---|---|---|
United States | Vanderbilt University Medical Center | Nashville | Tennessee |
United States | University of California Davis Health | Sacramento | California |
Lead Sponsor | Collaborator |
---|---|
University of California, Davis | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Vanderbilt University Medical Center |
United States,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | Muscle mitochondrial respiration from in situ high resolution respirometry of muscle biopsy tissue | We will determine mitochondrial respiration and oxidative stress under different respiratory states including subsaturating and saturating ADP (state 3), using a combination of complex I (glutamate + malate) and complex II (succinate) substrates, state 4 respiration (proton leak in the absence of ADP and the presence of oligomycin), and fully uncoupled respiration using FCCP. The assay for mtH2O2 production is based on the rate of production of the fluorescent molecule, resorufin, when Amplex Red reacts with H2O2 as described. We a priori select mtH2O2 of reverse electron transport (succinate as substrate in the absence of ADP) as our primary endpoint given the evidence that complex I is the predominant source of mtROS during aerobic exercise. Units are pmol/sec. | 16 weeks | |
Other | Inflammatory cytokines. TNF-alpha and IL-6 | Inflammatory cytokines. Units pg/ml. | 16 weeks | |
Primary | muscle mitochondrial oxidative capacity by 31P MRS | We will use 31P MRS to evaluate the concentration of phospho-creatine (PCr) and other phosphate-energy carrier molecules in limb muscles. After one minute of basal resting measurements, patients will be asked to perform two knee extensions every second against ankle weights 5-10% of the maximal voluntary contraction. The exercise protocol will last 60-90 seconds (a total of 60 knee extensions) followed by 6 minutes of rest. The intensity of the exercise decreases phosphocreatine (PCr) levels with minimal change in muscle pH. Spectra analysis was performed with AMARES from the jMRUI software package. Spectra are used to calculate the relative concentrations of inorganic phosphate (Pi), PCr, and ATP. PCr recovery will be measured through 6min of rest and fit with a monoexponential equation. | 16 weeks | |
Primary | Insulin sensitivity (SI) by insulin clamp | Primary endpoint for the hyperinsulinemic euglycemic clamp testing will be insulin sensitivity defined as (glucose disposal rate - concentration of infused glucose)/(insulin concentration at steady state - fasting insulin concentration). Units are mg/min per microunit per milliliter. | 16 weeks | |
Primary | total work performed on cycle ergometry VO2 | Total work will be obtained by cycle ergometry using standard protocol measuring oxygen uptake starting at 0 watts (W) at 60 rotations per minute (rpm) increasing by 25W every 2 minutes until volitional exhaustion adapting a prior protocol used in CKD patients. The primary measure will be total work completed (Joules). | 16 weeks | |
Primary | muscle work efficiency cycle ergometry | joules/ml Oxygen(VO2 peak) | 16 weeks | |
Primary | Walking endurance by 6-minute walk | Meters | 16 weeks | |
Primary | FACIT-F Fatigue (PRO) | score on FACIT-F questionnaire | 16 weeks | |
Secondary | Intermuscular fat by MRI | Percent intermuscular fat. | 16 weeks | |
Secondary | 30 second sit to stand test | number of times patient can get up from sitting position over 30 seconds | 16 weeks | |
Secondary | PROMIS Fatigue (PRO) | score on NIH PROMIS Fatigue questionnaire | 16 weeks |
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