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Impaired Renal HCO3- Excretion in Cystic Fibrosis

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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.
OriginalsprogEngelsk
Artikelnummer31
TidsskriftJournal of the American Society of Nephrology
Vol/bind31
Nummer8
Sider (fra-til)1711-1727
Antal sider17
ISSN1046-6673
DOI
StatusUdgivet - 2020

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