Effects of Sodium Bicarbonate in CKD Stages 3 and 4: A Randomized, Placebo-Controlled, Multicenter Clinical Trial

Abstract

Rationale & objective: Metabolic acidosis associated with chronic kidney disease (CKD) may contribute to muscle dysfunction and bone disease. We aimed to test whether treatment with sodium bicarbonate improves muscle and bone outcomes.

Study design: Multicenter, randomized, placebo-controlled, clinical trial.

Setting & participants: 149 patients with CKD stages 3 and 4 between July 2011 and April 2016 at 3 centers in Cleveland, OH, and the Bronx, NY.

Intervention: Sodium bicarbonate (0.4 mEq per kg of ideal body weight per day) (n=74) or identical-appearing placebo (n=75).

Outcomes: Dual primary outcomes were muscle function assessed using sit-to-stand test and bone mineral density. Muscle biopsies were performed at baseline and 2 months. Participants were seen at baseline and 2, 6, 12, and 24 months.

Results: Mean baseline serum bicarbonate level was 24.0±2.2 (SD) mEq/L and mean baseline estimated glomerular filtration rate was 36.3±11.2mL/min/1.73m2. Baseline characteristics did not differ between groups. Mean serum bicarbonate levels in the intervention arm during follow-up were 26.4±2.2, 25.5±2.3, 25.6±2.6, and 24.4±2.8 mEq/L (at 2, 6, 12, and 24 months). These were significantly higher than in the placebo group (P<0.001). Compared to the placebo group, participants randomly assigned to sodium bicarbonate treatment had no significant differences in sit-to-stand time (5 repetitions: P=0.1; and 10 repetitions P=0.07) or bone mineral density (P=0.3). Sodium bicarbonate treatment caused a decrease in serum potassium levels that was of borderline statistical significance (P=0.05). There were no significant differences in estimated glomerular filtration rates, blood pressure, weight, serious adverse events, or levels of muscle gene expression between the randomly assigned groups.

Limitations: Initial mean serum bicarbonate level was in the normal range.

Conclusions: Sodium bicarbonate therapy in patients with CKD stages 3 and 4 significantly increases serum bicarbonate and decreases potassium levels. No differences were found in muscle function or bone mineral density between the randomly assigned groups. Larger trials are required to evaluate effects on kidney function.

Funding: National Institutes of Health grant.

Trial registration: Registered at ClinicalTrials.gov with study number NCT01452412.

Keywords: Chronic kidney disease (CKD); alkali therapy; bone mineral density; metabolic acidosis; metabolic bone disease; muscle function; randomized controlled trial (RCT); sit-to-stand; sodium bicarbonate.

Conflict of interest statement

Financial Disclosure: The authors declare that they have no relevant financial interests.

Copyright © 2019 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1.

Participant flow diagram.

Figure 2.. Effects of sodium bicarbonate versus placebo administration on bicarbonate, potassium and blood pressure.

Changes in serum bicarbonate (A), serum potassium (B) and blood pressure (C) over 2 years of treatment with either sodium bicarbonate or placebo.

Figure 2.. Effects of sodium bicarbonate versus placebo administration on bicarbonate, potassium and blood pressure.

Changes in serum bicarbonate (A), serum potassium (B) and blood pressure (C) over 2 years of treatment with either sodium bicarbonate or placebo.

Figure 2.. Effects of sodium bicarbonate versus placebo administration on bicarbonate, potassium and blood pressure.

Changes in serum bicarbonate (A), serum potassium (B) and blood pressure (C) over 2 years of treatment with either sodium bicarbonate or placebo.

Figure 3.. Protein and gene expression within the m. vastus lateralis muscle of CKD patients with sodium bicarbonate versus placebo administration.

Western blotting of muscle lysates (Visit 1 and 2 correspond to Baseline and 2 months, respectively) (A), expression of phosphorylated Akt (normalized to total Akt) (B), 14-kDa actin fragment density (C), and messenger RNA for the E3 ubiquitin ligases MuRF1 (muscle RING-finger protein 1) (D), and atrogin 1 (E), IL-6 (F), TNF-α (G), and CD68 (H), before and after 2 months of sodium bicarbonate (n=5) or placebo (n=7). For IL-6 and CD68, one outlier in the placebo group was excluded due to values >3 standard deviations above the mean at both baseline and 2 month visits. P>0.05 for all comparisons.