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.
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
Type 1 diabetes
Poorly controlled diabetes (HgbA1c>10%)
History of persistent hyperkalemia (K>5.4)
History of persistent hypokalemia (K<3.3)
Crossover
Sodium bicarbonate
DrugSodium bicarbonate will be dosed at 0.8meq per kilogram of ideal body weight daily (1meq is approximately 84mg). We will use the Devine formula to determine ideal body weight. Investigational Drug Services at both UC Davis and Vanderbilt will compound the sodium bicarbonate. Sodium bicarbonate 650 mg tablets will be over-encapsulated and matching placebo capsules will be prepared. Participants will be limited to a maximum of 9 capsules daily (maximum dose = 5850mg of sodium bicarbonate). Capsules will be dispensed to patients in two separate 8-week allotments. The dose will be rounded to the nearest whole capsule and depending on participant preference may be divided into portions taken twice or thrice daily. Given the high probability of interruption in sodium bicarbonate supply and availability, we may need to change brands of sodium bicarbonate intermittently.
placebo
DrugThe placebo and filler for for sodium bicarbonate capsules will be comprised of microcrystalline cellulose. Capsule appearance for control and sodium bicarbonate will be the same.
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.
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.
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).
muscle work efficiency cycle ergometry
joules/ml Oxygen(VO2 peak)
Intermuscular fat by MRI
Percent intermuscular fat.
30 second sit to stand test
number of times patient can get up from sitting position over 30 seconds
PROMIS Fatigue (PRO)
score on NIH PROMIS Fatigue questionnaire
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.
Inflammatory cytokines. TNF-alpha and IL-6
Inflammatory cytokines. Units pg/ml.
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University of California, Davis
Lead sponsor
Vanderbilt University Medical Center
Collaborator
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Collaborator
