Impaired Renal HCO₃^- Excretion in Cystic Fibrosis.

Abstract

Patients with cystic fibrosis (CF) do not respond with increased urinary HCO₃^- excretion after stimulation with secretin and often present with metabolic alkalosis. By combining RT-PCR, immunohistochemistry, isolated tubule perfusion, <i>in vitro</i> cell studies, and <i>in vivo</i> 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. <i>β</i>-Intercalated cells express basolateral secretin receptors and apical CFTR and pendrin. <i>In vivo</i> 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^-. These results define the mechanism of secretin-induced urinary HCO₃^- excretion, explain metabolic alkalosis in patients with CF, and suggest feasibility of an <i>in vivo</i> human CF urine test to validate drug efficacy.