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.

Automated summary

In patients with chronic kidney disease, covert acid stress is associated with disease progression. This study found that urinary citrate (UcitV) can better identify dietary acid load, while ammonium (UNH4+V) can better indicate H+ retention. However, further research is needed to establish a clinically useful diagnostic method.