A Urine pH-Ammonium Acid/Base Score and CKD Progression.

INTRODUCTION: Acidosis is associated with exacerbated loss of kidney function in chronic kidney disease (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: 24-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. 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, ∼67%). Subclinical acidosis was associated with an 18% (95% CI: 2-32) larger decrease of measured GFR after 18 months. During a median follow-up of 6 years, subclinical acidosis was associated with a markedly higher risk for CKD progression. Adjusted hazard ratios were 9.88 (95% CI 1.27-76.7) in the development cohort and 11.1 in the validation cohort (95% CI: 2.88-42.5). 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.

Trimethoprim inhibits renal H+-K+-ATPase in states of K+ depletion.

There is growing consensus that under physiological conditions, collecting duct H+ secretion is independent of epithelial Na+ channel (ENaC) activity. We have recently shown that the direct ENaC inhibitor benzamil acutely impairs H+ excretion by blocking renal H+-K+-ATPase. However, the question remains whether inhibition of ENaC per se causes alterations in renal H+ excretion. To revisit this question, we studied the effect of the antibiotic trimethoprim (TMP), which is well known to cause K+ retention by direct ENaC inhibition. The acute effect of TMP (5 µg/g body wt) was assessed in bladder-catheterized mice, allowing real-time measurement of urinary pH, electrolyte, and acid excretion. Dietary K+ depletion was used to increase renal H+-K+-ATPase activity. In addition, the effect of TMP was investigated in vitro using pig gastric H+-K+-ATPase-enriched membrane vesicles. TMP acutely increased natriuresis and decreased kaliuresis, confirming its ENaC-inhibiting property. Under control diet conditions, TMP had no effect on urinary pH or acid excretion. Interestingly, K+ depletion unmasked an acute urine alkalizing effect of TMP. This finding was corroborated by in vitro experiments showing that TMP inhibits H+-K+-ATPase activity, albeit at much higher concentrations than benzamil. In conclusion, under control diet conditions, TMP inhibited ENaC function without changing urinary H+ excretion. This finding further supports the hypothesis that the inhibition of ENaC per se does not impair H+ excretion in the collecting duct. Moreover, TMP-induced urinary alkalization in animals fed a low-K+ diet highlights the importance of renal H+-K+-ATPase-mediated H+ secretion in states of K+ depletion.NEW & NOTEWORTHY The antibiotic trimethoprim (TMP) often mediates K+ retention and metabolic acidosis. We suggest a revision of the underlying mechanism that causes metabolic acidosis. Our results indicate that TMP-induced metabolic acidosis is secondary to epithelial Na+ channel-dependent K+ retention. Under control dietary conditions, TMP does not per se inhibit collecting duct H+ secretion. These findings add further argument against a physiologically relevant voltage-dependent mechanism of collecting duct H+ excretion.

Challenged Urine Bicarbonate Excretion as a Measure of Cystic Fibrosis Transmembrane Conductance Regulator Function in Cystic Fibrosis.

BACKGROUND: In cystic fibrosis (CF), renal base excretion is impaired. Accordingly, challenged urine bicarbonate excretion may be an in vivo biomarker of cystic fibrosis transmembrane conductance regulator (CFTR) function. OBJECTIVE: To evaluate the association between challenged bicarbonate excretion and clinical characteristics at baseline, quantify the CFTR modulator drug elexacaftor/tezacaftor/ivacaftor-induced changes of challenged bicarbonate excretion after 6 months of treatment, and characterize the intraindividual variation in healthy adults. DESIGN: Prospective observational study. SETTING: Cystic fibrosis clinic, Aarhus University Hospital, Denmark. PATIENTS: Fifty adult patients with CF starting CFTR modulator therapy with elexacaftor/tezacaftor/ivacaftor between May 2020 and June 2021. MEASUREMENTS: Quantification of urine bicarbonate excretion after an acute oral sodium bicarbonate challenge before and 6 months after elexacaftor/tezacaftor/ivacaftor treatment. RESULTS: At baseline, challenged urine bicarbonate excretion was associated with several CF disease characteristics. Bicarbonate excretion was higher in patients with residual function mutations. A higher bicarbonate excretion was associated with better lung function, pancreatic sufficiency, and lower relative risk for chronic pseudomonas infections. Elexacaftor/tezacaftor/ivacaftor treatment increased bicarbonate excretion by 3.9 mmol/3 h (95% CI, 1.6 to 6.1 mmol/3 h), reaching about 70% of that seen in healthy control participants. In healthy control participants, individual bicarbonate excretion at each visit correlated with the individual mean bicarbonate excretion. The median coefficient of variation was 31%. LIMITATION: Single-center study without a placebo-controlled group. CONCLUSION: Although further studies are needed to address the performance and sensitivity of this approach, this early-stage evaluation shows that challenged urine bicarbonate excretion may offer a new, simple, and safe quantification of CFTR function and the extent of its pharmacologic improvement. Elexacaftor/tezacaftor/ivacaftor partially restores renal CFTR function in patients with CF, likely resulting in decreased risk for electrolyte disorders and metabolic alkalosis. PRIMARY FUNDING SOURCE: Innovation Fund Denmark.