Impaired renal HCO₃^- secretion in CFTR deficient mice causes metabolic alkalosis during chronic base-loading

Cystic fibrosis patients have an increased risk of developing metabolic alkalosis presumably as a result of altered renal HCO₃^- handling. In this study, we directly assess the kidneys' ability to compensate for a chronic base-load in the absence of functional CFTR.

Comprehensive urine and blood acid-base analyses were done in anaesthetized WT mice or mice lacking either CFTR or pendrin, with or without 7 days of oral NaHCO₃ loading. The in vivo experiments were complemented by a combination of immunoblotting and experiments with perfused isolated mouse cortical collecting ducts (CCD).

Base-loaded WT mice maintained acid-base homeostasis by elevating urinary pH and HCO₃^- excretion and decreasing urinary net acid excretion. In contrast, pendrin KO mice and CFTR KO mice were unable to increase urinary pH and HCO₃^- excretion and unable to decrease urinary net acid excretion sufficiently and thus developed metabolic alkalosis in response to the same base-load. The expression of pendrin was increased in response to the base-load in WT mice with a paralleled increased pendrin function in the perfused CCD. In CFTR KO mice, 7 days of base-loading did not upregulate pendrin expression and apical Cl^- /HCO₃^- exchange function was strongly blunted in the CCD.

CFTR KO mice develop metabolic alkalosis during a chronic base-load because they are unable to sufficiently elevate renal HCO₃^- excretion. This can be explained by markedly reduced pendrin function in the absence of CFTR.