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.

Chronic kidney disease (CKD) is highly prevalent affecting 14% of the U.S. population leading to substantial morbidity and reduced quality of life. Older adults with CKD identify maintenance of functional independence as their top priority. Skeletal muscle health is critical for mobility and an underrecognized target of metabolic acidosis (MA) and protein energy wasting in CKD. Skeletal muscle endurance provides a window into muscle metabolic health and muscle quality. Muscle mitochondrial metabolism is central to muscle and walking endurance providing energy from carbohydrates and fats to power repeated muscle contraction. Investigators showed metabolic acidosis and muscle adiposity as the major determinants of muscle mitochondrial function.

Metabolic acidosis (MA) is long believed to be the main mechanism leading to skeletal muscle wasting and peripheral insulin resistance in CKD. Skeletal muscle mitochondrial metabolism is considered a principal determinant of peripheral insulin sensitivity and muscle quality, but little is known of the impact of MA on muscle mitochondrial function. Muscle mitochondrial dysfunction leads to defective lipid metabolism augmenting adiposity and lipotoxic intermediates resulting in insulin resistance, low endurance, and muscle atrophy. Using in vivo 31Phosphorus Magnetic Resonance Spectroscopy (31P MRS) investigators showed that the presence and severity of CKD is strongly associated with impaired muscle mitochondrial capacity to generate ATP translating into poor walking endurance. Investigators also showed MA and muscle adiposity are the major determinants of muscle mitochondrial function. Despite the importance of mitochondrial function to muscle health, it is unknown if treatment of MA benefits muscle mitochondrial function, adiposity or endurance in CKD.

The proposed project will use precise, in vivo 31P MRS and gold-standard testing of peripheral insulin sensitivity by hyperinsulinemic euglycemic clamp to probe the pathophysiology of MA and low endurance in a clinical trial of alkali therapy in CKD and MA. We will compare sodium bicarbonate to placebo in a multicenter randomized, cross-over trial design in 80 persons with moderate-severe CKD and MA. First, the efficacy of 4-months of alkali therapy will be tested comparing sodium bicarbonate versus placebo on muscle metabolic health in a randomized crossover trial in MA. Second, we will test the efficacy of 4-months of alkali therapy comparing sodium bicarbonate versus placebo on improving physical endurance in MA. The rationale is that identification of therapeutic targets for low physical endurance will inform the development of pharmacologic interventions. Long term, it is expected that strategies treating MA will improve exercise tolerance enabling effective engagement in lifestyle interventions improving quality of life in CKD.

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 1 diabetes
• Poorly controlled diabetes (HgbA1c>10%)
• History of persistent hyperkalemia (K>5.4)
• History of persistent hypokalemia (K<3.3)
• Uncontrolled blood pressure (>170/100)
• Chronic treatment with renal replacement therapy
• History of aortic dissection or severe valvular heart disease
• Exercise induced angina
• Uncontrolled cardiac dysrhythmia
• Oxygen dependent chronic obstructive pulmonary disease (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 intraveneous 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.
• Women who are breastfeeding, pregnant, or are wanting to become pregnant
• Any condition which in the judgement of the clinical investigator places the participant at risk from participation in the study.

Exclusion criteria for optional muscle biopsy

• Drugs- anticoagulants or antiplatelets:

  • Anticoagulants, any 1 (coumadin, rivaroxaban, apixaban, dabigatran, edoxaban)
  • Antiplatelets, any 2 (aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticragrelor, ticlopidine, vorapaxar)

• Platelet count <100,000

• International normalized ratio (INR)>1.4

Individual participant data will be available to other investigators on request. The requests will include a proposal outlining the research question, specific exposures, outcomes of interest and analytic plan. All requests will be reviewed by the study principal investigators and coinvestigators prior to release of data. All data will be de-identified.

within 18 months after the conclusion of the study. This data will be available indefinitely