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

TY - JOUR

T1 - Alkalosis-induced hypoventilation in cystic fibrosis

T2 - The importance of efficient renal adaptation

AU - Berg, Peder

AU - Andersen, Jesper Frank

AU - Sørensen, Mads Vaarby

AU - Wang, Tobias

AU - Malte, Hans

AU - Leipziger, Jens

PY - 2022/2

Y1 - 2022/2

N2 - 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 HCO 3 2 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 HCO 3 2 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.

AB - 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 HCO 3 2 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 HCO 3 2 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.

KW - Acid–base

KW - CFTR

KW - Cystic fibrosis

KW - Hypoventilation

KW - Kidney

KW - Lung/metabolism

KW - Cystic Fibrosis/complications

KW - Mice, Inbred C57BL

KW - Alkalosis/metabolism

KW - Male

KW - Renal Reabsorption/physiology

KW - Hypoventilation/etiology

KW - Kidney/metabolism

KW - Mice, Knockout

KW - Renal Elimination

KW - Cystic Fibrosis Transmembrane Conductance Regulator/genetics

KW - Animals

KW - Chloride-Bicarbonate Antiporters

KW - Bicarbonates/metabolism

KW - Female

KW - Ion Transport

KW - Mice

KW - Acid-Base Equilibrium/physiology

KW - Disease Models, Animal

U2 - 10.1073/pnas.2116836119

DO - 10.1073/pnas.2116836119

M3 - Journal article

C2 - 35173044

SN - 0027-8424

VL - 119

JO - Proceedings of the National Academy of Sciences (PNAS)

JF - Proceedings of the National Academy of Sciences (PNAS)

IS - 8

M1 - e2116836119

ER -