Background. Metabolic acidosis, usually manifested by low serum bicarbonate level, is common in chronic kidney disease (CKD) and appears to be associated with higher mortality in dialysis patients. It is not known whether a similar association is present in patients with non-dialysis-dependent CKD (NDD-CKD).

Methods. We used multivariable-adjusted Cox models to examine the association between baseline and time-variable serum bicarbonate (measured as total CO₂) with the outcomes of all-cause mortality and the composite of pre-dialysis mortality or end-stage renal disease in 1240 male patients with moderate and advanced NDD-CKD.

Results. Serum bicarbonate showed a significant U-shaped association with all-cause mortality, with the highest mortality rate observed in patients with baseline serum bicarbonate levels <22 mmol/L [multivariable-adjusted hazard ratio (95% confidence interval) for patients with serum bicarbonate <22 mmol/L versus ≥22 mmol/L: 1.33 (1.05–1.69), P = 0.02] and the lowest mortality observed in patients with baseline serum bicarbonate of 26–29 mmol/L. The associations between lower serum bicarbonate level and mortality were more accentuated in subgroups of patients with better nutritional status and lower inflammation.

Conclusions. Both lower and higher serum bicarbonates are associated with increased all-cause mortality in patients with moderate and advanced NDD-CKD. Clinical trials are needed to determine if therapeutic interventions aimed at optimizing serum bicarbonate can result in improved outcomes in this population.