Intro: Cystic fibrosis (CF) is a lethal inherited multi-organ disease caused by loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. Respiratory insufficiency is the primary cause of mortality in CF, but additional complications such as alkalosis and a Bartter-like phenotype have been observed, potentially contributing to end-stage hypercapnic respiratory failure. The mechanism behind the development of alkalosis in CF has been unclear.

Methods: This study utilized various molecular techniques (immunoblotting, immunostainings, in vitro cell studies, etc.), ex vivo renal tubule perfusion, in vivo whole animal studies, and clinical investigations involving individuals with CF and healthy controls.

Results: The function of renal β-intercalated cells, which are responsible for physiological regulation of renal HCO₃^– excretion, is reliant on CFTR. Loss of CFTR function leads to dysfunctional pendrin regulation and impaired renal HCO₃^– excretion, resulting in exacerbated metabolic alkalosis and hypoventilation during acute base loading. Individuals with CF exhibit a significantly reduced ability to excrete an oral HCO₃^– load. The level of challenged urine HCO₃^– excretion correlates with important disease features such as lung function, pancreatic insufficiency, mutation type, and risk of persistent pulmonary infections. Treatment with the CFTR modulator drug Elexacaftor/Tezacaftor/Ivacaftor significantly improves urine HCO₃^– excretion. Furthermore, CFTR modulator therapy may restore pendrin function, reducing the risk of electrolyte disorders and metabolic alkalosis. This is highlighted by the correction of the salt-wasting phenotype in persons with CF following CFTR modulator treatment.

Conclusions: This research provides insights into the role of CFTR in renal HCO₃^– excretion and the development of alkalosis in CF. Mechanistically, Loss of CFTR causes dysfunctional pendrin regulation and CFTR is necessary for alkalosis-induced pendrin activation. Pendrin is the HCO₃^–-secretory pathway in the distal renal tubular system and is furthermore important for renal fluid and NaCl conservation. CFTR modulator therapy shows promise in improving urine HCO₃^– excretion and correcting electrolyte imbalances. Acute renal HCO₃^– excretion may serve as a useful measure of CFTR function and as a prognostic marker in persons with CF. The precise mechanism by which CFTR regulates pendrin function remains unresolved.