Biomarkers of covert acid stress in patients with CKD: A cross-sectional study

Introduction: Like metabolic acidosis, earlier stages of acid (H+) stress, including an ongoing H+ challenge in the form of dietary H+, without or with steady-state H+ accumulation but with normal plasma total CO2 (PTCO2) (the latter state known as eubicarbonatemic acidosis), are associated with augmented progression of chronic kidney disease (CKD) but diagnosis of this covert H+ stress is clinically problematic. Prior published studies to identify clinically practical biomarkers of covert H+ stress did not include assessments of either dietary H+ or H+ retention. Methods: We tested plasma pH (PpH), 8-hour urine excretion of citrate (UcitV) or ammonium (UNH4+V) as biomarkers of dietary H+ assessed as potential renal acid load (PRAL) and of steady-state H+ retention by comparing observed to expected PTCO2 increase two hours after an oral NaHCO3 bolus. We recruited 313 non-diabetic participants with PTCO2 >= 22 mM to exclude participants with metabolic acidosis and with eGFR [mean (SD), ml/min/1.73 m2] stages G1 [n=62, 99.2 (7.3)], G2 [n=167, 73.8 (6.3)], and G3 [n=84, 39.9 (6.7)]. We performed linear regressions (LR) between H+ retention or PRAL (dependent variables) and PpH, UcitV or UNH4+V (independent variables) after adjusting for eGFR.Results: Steady-state H+ retention [mean (SD), mmol] increased with stage [G1=3.8 (12.5), G2=18.2 (12.4), and G3=25.6 (9.0)]. PpH was not significantly associated with PRAL in any group and its association with H+ retention was significant only for G3 (p<0.01). UcitV association with PRAL was significant for only G1 (p<0.01) but not for G2 (p=0.65) or G3 (p=0.11). UcitV association with H+ retention was negative for both G2 (p<0.01) and G3 (p<0.01) but was not significant for G1 (p=0.50). Adding UNH4+V to UcitV as a regressor for H+ retention increased r2 only marginally for G2 (0.61 to 0.63) and G3 (0.75 to 0.79). UNH4+V association with PRAL was positive (p<0.01) for G1 and G2 but was not significant for G3 (p=0.46). UNH4+V association with H+ retention was significant for both G2 (p<0.04) and G3 (p<0.01) but diverged directionally, being positive for G2 but negative for G3. Discussion/Conclusions: Among patients with CKD at risk for covert H+ stress, lower UcitV better identified eubicarbonatemic acidosis than UNH4+V because the UNH4+V vs. H+ retention relationship diverged between G2 and G3. Neither test identified eubicarbonatemic acidosis with certainty, indicating need for further work to establish a clinically useful test. On the other hand, UNH4+V had better utility identifying increased dietary H+ assessed as PRAL in G1 and G2.