A Randomized Trial Comparing the Safety, Adherence, and Pharmacodynamics Profiles of Two Doses of Sodium Bicarbonate in CKD: the BASE Pilot Trial
Authors: Raphael Kalani L. , Isakova Tamara , Ix Joachim H. , Raj Dominic S. , Wolf Myles , Fried Linda F. , Gassman Jennifer J. , Kendrick Cynthia , Larive Brett , Flessner Michael F. , Mendley Susan R. , Hostetter Thomas H. , Block Geoffrey A. , Li Ping , Middleton John P. , Sprague Stuart M. , Wesson Donald E. , Cheung Alfred K. 
Published: December 2019

Significance Statement
Oral sodium bicarbonate supplementation may preserve kidney function in patients with CKD. However, the best dose to use in phase-3 trials testing this hypothesis is uncertain. The authors conducted a multicenter pilot study to assess the safety, tolerability, adherence, and pharmacodynamics of two doses of sodium bicarbonate, 0.8 and 0.5 meq/kg of lean body wt per day, over 28 weeks. They showed that the higher dose of sodium bicarbonate was well tolerated, reduced urinary ammonium excretion, and raised serum bicarbonate more than the lower dose, but it modestly increased urinary albumin excretion. These findings contribute to understanding the pharmacodynamic effects and patient acceptance of sodium bicarbonate in CKD.

Background
Oral sodium bicarbonate (NaHCO3) may preserve kidney function in CKD, even if initiated when serum bicarbonate concentration is normal. Adequately powered trials testing this hypothesis have not been conducted, partly because the best dose for testing is unknown.

Methods
This multicenter pilot trial assessed the safety, tolerability, adherence, and pharmacodynamics of two doses of NaHCO3 over 28 weeks in adults with eGFR 20–44 or 45–59 ml/min per 1.73 m2 with urinary albumin/creatinine (ACR) ≥50 mg/g and serum bicarbonate 20–28 meq/L. We randomly assigned 194 participants from ten clinical sites to receive higher-dose (HD-NaHCO3; 0.8 meq/kg of lean body wt per day; n=90) or lower-dose (LD-NaHCO3; 0.5 meq/kg of lean body wt per day; n=52) NaHCO3 or matching placebo (n=52). The dose was adjusted depending on side effects. The prescribed dose at week 28 was the primary outcome; a dose was considered acceptable for a full-scale trial if ≥67% of participants were on full-dose and ≥80% were on ≥25% of the per-protocol dose.

Results
Mean±SD baseline eGFR was 36±9 ml/min per 1.73 m2, serum bicarbonate was 24±2 meq/L, and median (IQR) ACR was 181 (25–745) mg/g. Both doses were well tolerated without significant changes in BP, weight, or serum potassium. The proportions of adverse events and hospitalizations were similar across the groups. Consequently, 87% in HD-NaHCO3, 96% in LD-NaHCO3, and 87% in placebo were on full dose at week 28; and 91% in HD-NaHCO3, 98% in LD-NaHCO3, and 92% in placebo were on ≥25% of the per-protocol dose. Mean urinary ammonium excretion was 25% lower and serum bicarbonate concentration was 1.3 meq/L higher in HD-NaHCO3 compared with LD-NaHCO3 at week 28. However, mean ACR increased by 12% in the lower-dose group and 30% in the higher-dose group.

Conclusions
Both NaHCO3 doses were well tolerated over 28 weeks with no significant difference in adverse events or hospitalization compared with placebo. The higher dose lowered urinary ammonium excretion and increased serum bicarbonate more than the lower dose but was associated with a greater increase in ACR. The higher 0.8 meq/kg of lean body wt per day dose of NaHCO3 may be a reasonable choice for future trials.