Impaired Renal HCO3- Excretion in Cystic Fibrosis

J Am Soc Nephrol. 2020 Aug;31(8):1711-1727. doi: 10.1681/ASN.2020010053. Epub 2020 Jul 23.


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.

Keywords: cystic fibrosis; ion transport; kidney tubule; renal tubular acidosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bicarbonates / metabolism*
  • Cyclic AMP / physiology
  • Cystic Fibrosis / metabolism*
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / physiology
  • Humans
  • Kidney / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Rats, Inbred F344
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / physiology
  • Receptors, Gastrointestinal Hormone / genetics
  • Receptors, Gastrointestinal Hormone / physiology
  • Secretin / pharmacology


  • Bicarbonates
  • Receptors, G-Protein-Coupled
  • Receptors, Gastrointestinal Hormone
  • secretin receptor
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Secretin
  • Cyclic AMP