Alkalosis-induced hypoventilation in cystic fibrosis: the importance of effective renal adaptation

Importance

In conditions where our blood undergoes alkalosis, a pronounced renal response is initiated, causing a marked increase in the excretion of the urinary base. We recently uncovered the cell physiology of it, which utilizes rapid activation of β-intercalated cells secreting collecting duct bases. This function is entirely dependent on the cystic fibrosis transmembrane conductance regulator (CFTR), the defective anion channel in cystic fibrosis. Therefore, CF patients and mice cannot effectively excrete an acute basal load. Here we find that the inability for rapid urinary base elimination 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 essential organs in the regulation of acid-base homeostasis in the body. In cystic fibrosis (CF), impaired renal ability to excrete excessive amounts of HCO3 in the urine leads to metabolic alkalosis [P. Berg et al., J. Am. Soc. Nephrol. 31, 1711–1727 (2020); F. Al-Ghimlas, M. E. Faughnan, E. Tullis, Open Respir. Med. J. 6, 59–62 (2012)]. This is caused by a faulty HCO3 secretion into β-intercalated cells of the collecting duct which requires both the cystic fibrosis transmembrane conductance regulator (CFTR) and pendrin for normal function [P. Berg et al., J. Am. Soc. Nephrol. 31, 1711–1727 (2020)]. We investigated the ventilatory consequences of acute oral basal load in normal, pendrin knockout (KO) and CFTR KO mice. In wild-type mice, oral basal load induces dose-dependent metabolic alkalosis, rapid urinary elimination of base, and moderate basal load does not impair ventilation. In contrast, CFTR and pendrin KO mice, which are unable to rapidly excrete excess base in the urine, developed marked and transient depression of ventilation when subjected to the same base load. Therefore, the rapid elimination of the renal base in response to an acute oral basal load is a necessary physiological function to avoid ventilatory depression. It is suggested that transient urinary alkalinization in the postprandial state evolved to proactively avoid hypoventilation. In cystic fibrosis, metabolic alkalosis may contribute to the generally reduced lung function via a suppression of ventilatory drive.

Footnotes

    • Accepted January 13, 2022.
  • Author contributions: research designed by PB, JFA, TW, HM and JL; PB, JFA and MVS conducted research; HM provided new analytical reagents/tools; PB, JFA, MVS, TW and HM analyzed the data; and PB, JFA and JL wrote the article.

  • The authors declare no competing interests.

  • This article is a direct PNAS submission.

  • This article contains additional information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2116836119/-/DCSupplemental.

Data availability

All study data is included in the article and/or IS Annex.

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