Key Points

This study developed a urine acid/base score to assess tubular acid excretion capacity and identify early acid retention in CKD.The results show that early signs of acid retention (a low acid/base score) are associated with a higher risk for CKD progression.Future research should address if a low urine acid/base score can be improved and if this translates into clinically meaningful effects.

Background

Acidosis is associated with exacerbated loss of kidney function in CKD. Currently, acid/base status is assessed by plasma measures, although organ-damaging covert acidosis, subclinical acidosis, may be present before reflected in plasma. Low urine NH4+ excretion associates with poor kidney outcomes in CKD and is proposed as a marker for subclinical acidosis. However, low NH4+ excretion could result from either a low capacity or a low demand for acid excretion. We hypothesized that a urine acid/base score reflecting both the demand and capacity for acid excretion would better predict CKD progression.

Methods

Twenty-four–hour urine collections were included from three clinical studies of patients with CKD stage 3 and 4: a development cohort (N=82), a variation cohort (N=58), and a validation cohort (N=73). A urine acid/base score was derived and calculated from urinary pH and [NH4+]. Subclinical acidosis was defined as an acid/base score below the lower limit of the 95% prediction interval of healthy controls. The main outcomes were change in measured GFR after 18 months and CKD progression (defined as ≥50% decline in eGFR, initiation of long-term dialysis, or kidney transplantation) during up to 10 years of follow-up.

Results

Subclinical acidosis was prevalent in all cohorts (n=54/82, 48/73, and 40/58, respectively, approximately 67%). Subclinical acidosis was associated with an 18% (95% confidence interval [CI], 2 to 32) larger decrease of measured GFR after 18 months. During a median follow-up of 6 years, subclinical acidosis was associated with a higher risk of CKD progression. Adjusted hazard ratios were 9.88 (95% CI, 1.27 to 76.7) in the development cohort and 11.1 (95% CI, 2.88 to 42.5) in the validation cohort. The acid/base score had a higher predictive value for CKD progression than NH4+ excretion alone.

Conclusions

Subclinical acidosis, defined by a new urine acid/base score, was associated with a higher risk of CKD progression in patients with CKD stage 3 and 4.