Background

Patients with cystic fibrosis (CF) do not respond with increased urinary HCO₃^– excretion after stimulation with secretin and often present with metabolic alkalosis.

Methods

By combining RT-PCR, immunohistochemistry, isolated tubule perfusion, in vitro cell studies, and in vivo studies in different mouse models, we elucidated the mechanism of secretin-induced urinary HCO₃^– excretion. For CF patients and CF mice, we developed a HCO₃^- drinking test to assess the role of the cystic fibrosis transmembrane conductance regulator (CFTR) in urinary HCO₃^-excretion and applied it in the patients before and after treatment with the novel CFTR modulator drug, lumacaftor-ivacaftor.

Results

β-Intercalated cells express basolateral secretin receptors and apical CFTR and pendrin. In vivo application of secretin induced a marked urinary alkalization, an effect absent in mice lacking pendrin or CFTR. In perfused cortical collecting ducts, secretin stimulated pendrin-dependent Cl^–/HCO₃^– exchange. In collecting ducts in CFTR knockout mice, baseline pendrin activity was significantly lower and not responsive to secretin. Notably, patients with CF (F508del/F508del) and CF mice showed a greatly attenuated or absent urinary HCO₃^–-excreting ability. In patients, treatment with the CFTR modulator drug lumacaftor-ivacaftor increased the renal ability to excrete HCO₃^–.

Conclusions

These results define the mechanism of secretin-induced urinary HCO₃^– excretion, explain metabolic alkalosis in patients with CF, and suggest feasibility of an in vivo human CF urine test to validate drug efficacy.