Prospective Associations between the CKD-Mineral Bone Disorder and Metabolic Acidosis

Abstract Background Although the mineral bone disorder of CKD (CKD-MBD) and metabolic acidosis share some biochemical features that may be related to acidosis effects on bone and kidney, associations between the CKD-MBD and metabolic acidosis are not well studied. Methods In this post-hoc analysis of 1,993 CAN AIM TO PREVENt Trial participants with stage 3/4 CKD followed for 2.86 years per participant, mixed-effects linear and logistic regression were used to evaluate prospective associations between phosphate, calcium, 25(OH)D, PTH, and FGF-23 with 1) declining plasma bicarbonate, 2) subclinical metabolic acidosis (bicarbonate 22–24 mmol/L), and 3) clinical metabolic acidosis (bicarbonate < 22 mmol/L). Results Each mmol/L increase in phosphate predicted a lower bicarbonate (-1.29 mmol/L (95% CI: -1.61, -0.98; p < 0.001)), and increased odds for subclinical (OR 1.92 (1.32, 2.79); p = 0.001) and clinical metabolic acidosis (OR 5.03 (3.16, 7.93); p < 0.001). Each mmol/L increase in calcium predicted a higher bicarbonate (2.70 mmol/L (2.11, 3.30; p < 0.001)), and decreased odds for subclinical (OR 0.23 (0.11, 0.46); p < 0.001) and clinical metabolic acidosis (OR 0.15 (0.06, 0.37); p < 0.001). Each unit increase in log-transformed 25(OH)D predicted a higher bicarbonate (0.38 mmol/L (0.23, 0.53); p < 0.001)), and decreased odds for subclinical (OR 0.67 (0.56, 0.80); p < 0.001) and clinical metabolic acidosis (OR 0.65 (0.50, 0.82); p < 0.001). Log-PTH exhibited a non-linear relationship with acidosis risk: moderate elevations were associated with reduced acidosis risk (OR 0.60 (0.40, 0.90); p = 0.013) while higher levels predicted an increased risk for subclinical (OR 1.42 (1.02, 1.98); p = 0.041) but not clinical metabolic acidosis (OR 1.44 (0.93, 2.24); p = 0.103). No significant associations were found between log-FGF-23 and acidosis risk (OR 1.02 (0.88, 1.19); p = 0.767). Conclusions Key elements of the CKD-MBD were independently and prospectively associated with the development of metabolic acidosis. Future studies could examine mechanisms and determine if a causal relationship exists between progressive metabolic acidosis and the CKD-MBD.