Sodium Bicarbonate Therapy in Patients with CKD Stages 3 and 4

More than 16 million individuals in the United States are affected by chronic kidney disease (CKD). CKD is associated with numerous comorbidities as well as an increased risk for mortality. There are limited treatments known to slow or stop progression of CKD.

Metabolic acidosis is a known complication of kidney disease; it is unclear whether metabolic acidosis causes further kidney damage.  Results of previous observational studies have suggested an association between lower levels of bicarbonate  and faster progression of kidney disease. Further, poor outcomes have been seen in patients with acid retention, even in the absence of overt metabolic acidosis. Results of several small randomized studies cited benefits of alkali therapy in progression of CKD.

Bone and muscles may also be affected in patients with CKD and chronic metabolic acidosis; muscle dysfunction and bone disease may be associated with metabolic acidosis in patients with CKD. Michal L. Melamed, MD, MHS, and colleagues recently conducted a multicenter, randomized, placebo-controlled clinical trial designed to examine whether treatment with sodium bicarbonate improves muscle and bone outcomes. Results of the trial were reported in the American Journal of Kidney Disease [2020;75(2):225-234].

Of 283 patients assessed for study eligibility, 149 met inclusion criteria and were randomly assigned to either sodium bicarbonate 0.4 mEq per kg of ideal body weight per day n=74) or identical appearing placebo (n=75). The dual primary outcomes of interest were muscle function assessed using sit-to-stand test and bone mineral density. Muscle biopsies were conducted at baseline and 2 months. Participants were seen at baseline and 2, 6, 12, and 24 months.

Mean age of the study cohort was 61 years, 54% were women, 58% were non-Hispanic blacks, 27% were non-Hispanic whites, and 13% were Hispanics. At baseline, 93% of participants had hypertension and 62% had diabetes mellitus. Mean baseline serum bicarbonate level was 24.0 mEq/L and mean baseline estimated glomerular filtration rate (eGFR) was 36.3 mL/min/1.73 m2. There were no statistically significant differences in baseline characteristics between the intervention group and the placebo group.

Mean follow up was 1.35 years; there was no difference between the two study arms in mean follow-up time (1.29 years for intervention arm vs 1.42 for placebo arm). In the placebo arm, follow-up represented 106 person-years and in the intervention arm, follow-up represented 92 person-years on sodium bicarbonate treatment. During the course of the study, a total of 45 participants dropped out.

At baseline, serum bicarbonate levels were similar between the two arms. Subsequently, levels in participants in the sodium bicarbonate treatment arm increased significantly (P<.001). At 2, 6, 12, and 24 months, mean serum bicarbonate levels in the intervention arm were 26.4, 25.5, 25.6, and 24.4 mEq/L. In the intervention arm, 44 participants achieved a >3 mEq/l increase in serum bicarbonate level at any follow-up time compared with 20 participants in the placebo arm (P<.001). Sodium bicarbonate treatment caused a decrease in serum potassium levels by ~0.1 mEq/L compared with placebo; this difference had borderline statistical significance (P=.05). There were no  differences in eGFR between the two arms.

Participants in the intervention arm had similar bone density at 24 months compared with those in the placebo arm. In both groups, bone density at 24 months decreased from baseline (P=.03). The two groups were also similar in hand grip strength; over time, hand grip strength decreased in the placebo group and increase slightly in the intervention arm, but the difference was not statistically significant. During follow-up, sit-to-stand times decreased in both arms (P<.001), but there was no difference in rate of change. The two groups were similar in weight, blood pressure, physical function, physical composite score, or any other quality-of-life measurements.

A total of 12 participants underwent muscle biopsy (five in the intervention arm and seven in the placebo arm). Between baseline and the 2-month muscle biopsy, the median change in serum bicarbonate levels was +1 mEq/L in the intervention arm and –1 mEq/L in the placebo arm. There were no significant effects of sodium bicarbonate supplementation on insulin signaling (based on Western blotting of phosphorylated protein kinease B [Akt] and total Akt), an indicator of muscle protein breakdown, proteolysis mediators, or markers of inflammation.

There were no statistically significant differences between the two arms in the number of serious adverse events. During the course of the study, 14 patients in the intervention arm had a potassium level >5.0 mEq/L compared with 30 in the placebo arm (P=.006; odds ratio, 0.35; 95% confidence interval, 0.17-0.74). Participants in the sodium bicarbonate group experienced slightly more total adverse events compared with participants in the placebo arm (45% vs 32%, respectively). There were no other differences in adverse events.

The researchers cited some limitations to the study, including the inability to evaluate kidney function outcomes, the greater than expected number of participants who dropped out during the study, and the bicarbonate levels of the two groups not achieving consistently large separation during the 24-month study period. The participants also had fairly normal serum bicarbonate levels at baseline, possibly limiting the effect of the intervention.

In conclusion, the researchers said, “In this multicenter randomized placebo-controlled trial of sodium bicarbonate in participants with CKD stages 3 and 4, there was no significant difference between the randomly assigned groups in muscle function, as measured using sit-to-stand test, or bone mineral density. Although not powered for the outcome, there were no differences in kidney function over the 2 years. A larger randomized clinical trial of sodium bicarbonate therapy, possible with a larger dose of sodium bicarbonate, is required to evaluate whether treatment with sodium bicarbonate is beneficial for kidney function.”

Takeaway Points

  1. Results of a randomized, placebo-controlled clinical trial to determine whether treatment with sodium bicarbonate improves muscle and bone outcomes in patients with chronic kidney disease stages 3 and 4.
  2. Participants were randomized to either sodium bicarbonate 0.4 mEq/L per kg of ideal body weight per day (intervention arm) or placebo.
  3. During 24 months of follow-up, mean sodium bicarbonate levels in the intervention arm were significantly higher than in the placebo arm (P<.001).