Impaired Renal HCO3 - Excretion in Cystic Fibrosis

Significance Statement Cystic fibrosis (CF) is a multi-system disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator CFTR, an epithelial chloride channel. Patients with CF do not respond with increased urinary HCO 3 - excretion after stimulation with secretin and often present with metabolic alkalosis. Based on studies with several knockout (KO) mouse models, patients with CF, and cell studies, this paper defines the role of CFTR in renal HCO 3 - excretion. Secretin-induced renal HCO 3 - excretion occurs in the collecting duct and is pendrin- and CFTR-dependent. The study explains metabolic alkalosis in CF and suggests the feasibility of developing a test of urinary HCO 3 - excretion in CF patients who have two copies of the F508del mutation to assess CFTR function and response to drug treatment. Background Patients with cystic fibrosis (CF) do not respond with increased urinary HCO 3 − 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 HCO 3 − excretion. For CF patients and CF mice, we developed a HCO 3 - drinking test to assess the role of the cystic fibrosis transmembrane conductance regulator (CFTR) in urinary HCO 3 - 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 − /HCO 3 − 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 HCO 3 − -excreting ability. In patients, treatment with the CFTR modulator drug lumacaftor-ivacaftor increased the renal ability to excrete HCO 3 − . Conclusions These results define the mechanism of secretin-induced urinary HCO 3 − excretion, explain metabolic alkalosis in patients with CF, and suggest feasibility of an in vivo human CF urine test to validate drug efficacy.