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

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 [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 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 [P. Berg et al., J. Am. Soc. Nephrol. 31, 1711–1727 (2020)]. 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.

CFTR-beyond the airways: Recent findings on the role of the CFTR channel in the pancreas, the intestine and the kidneys

“…This could be a factor contributing to CF lung disease. In fact, Berg et al convincingly demonstrated alkalosis-induced hypoventilation by loss of CFTR function in mice [62] . Thus, metabolic alkalosis may contribute to reduced lung function in CF, via a suppression of ventilatory drive.…”

Loss of the Secretin Receptor Impairs Renal Bicarbonate Excretion and Aggravates Metabolic Alkalosis in Mice during Acute Base-Loading

“…2,3 During alkalosis, physiological compensation includes hypoventilation to retain CO 2 and increased renal bicarbonate excretion. 1,2,[4][5][6] The appropriate renal response to an acute base load relies on the base-secreting b-ICs in the collecting duct 7,8 that secrete bicarbonate by the apical chloride-bicarbonate exchanger pendrin (SLC26A4). 8 Collecting duct base secretion depends on pendrin and the CFTR anion channel.…”

“…8 Collecting duct base secretion depends on pendrin and the CFTR anion channel. [4][5][6]9 Hence, loss of pendrin or CFTR impairs the ability for immediate elevation of renal bicarbonate excretion and leads to metabolic alkalosis. 4,5,7,[10][11][12] It is noteworthy that the insulin receptor kinase receptor (IRR), an orphan receptor tyrosine kinase receptor expressed in b-ICs, may be mediating the activation of collecting duct base secretion.…”

A latent reversible ratiometric optical pH sensing probe based on phenylboronic acid for alkaline pH detection and applications in test paper and alkalotic HK-2 cells

“…Based on the deprotonation/protonation and intramolecular charge transfer mechanism, rapid and sensitive optical test papers were successfully fabricated for alkaline pH analysis. Furthermore, as the kidneys stand as pivotal organs for maintaining the balance of body acid–base fluctuation, 29 the proposed platform was also effectively applied to monitor the pH in alkalotic HK-2 cells.…”