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Alkalosis-induced hypoventilation in cystic fibrosis: The importance of efficient renal adaptation

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Significance statement: In conditions when our blood experiences alkalosis, a pronounced kidney response is initiated causing a marked increase of urine base excretion. We recently discovered the cellular physiology of this, which employs fast activation of the base-secreting β-intercalated cells of the collecting duct. This function is fully dependent on the cystic fibrosis transmembrane conductance regulator (CFTR), the anion channel defective in CF. Hence, CF patients and mice cannot efficiently excrete an acute base load. Here, we find that the inability of fast urinary base removal in the CF mouse model causes a marked inhibition of ventilation. This study provides physiological insights into acid–base regulation and may have important implications for CF patients who are already burdened with reduced lung function.

Abstract: The lungs and kidneys are pivotal organs in the regulation of body acid–base homeostasis. In cystic fibrosis (CF), the impaired renal ability to excrete an excess amount of HCO3− into the urine leads to metabolic alkalosis. This is caused by defective HCO3− secretion in the β-intercalated cells of the collecting duct that requires both the cystic fibrosis transmembrane conductance regulator (CFTR) and pendrin for normal function. We studied the ventilatory consequences of acute oral base loading in normal, pendrin knockout (KO), and CFTR KO mice. In wild-type mice, oral base loading induced a dose-dependent metabolic alkalosis, fast urinary removal of base, and a moderate base load did not perturb ventilation. In contrast, CFTR and pendrin KO mice, which are unable to rapidly excrete excess base into the urine, developed a marked and transient depression of ventilation when subjected to the same base load. Therefore, swift renal base elimination in response to an acute oral base load is a necessary physiological function to avoid ventilatory depression. The transient urinary alkalization in the postprandial state is suggested to have evolved for proactive avoidance of hypoventilation. In CF, metabolic alkalosis may contribute to the commonly reduced lung function via a suppression of ventilatory drive.
Original languageDanish
Article numbere2116836119
JournalPNAS (Proceedings of the National Academy of Sciences of the United States of America)
Number of pages7
Publication statusPublished - Feb 2022

    Research areas

  • Acid–base, CFTR, Cystic fibrosis, Hypoventilation, Kidney

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