Kidney Week

Abstract: FR-PO573

Elexacaftor/Tezacaftor/Ivacaftor (ETI) Treatment Corrects the Salt-Losing Phenotype in People with Cystic Fibrosis

Session Information

• Fluid, Electrolyte, and Acid-Base Disorders: Basic
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Fluid, Electrolytes, and Acid-Base Disorders

• 1101 Fluid, Electrolyte, and Acid-Base Disorders: Basic

Authors

• Leipziger, Jens G., Aarhus Universitet, Aarhus, Midtjylland, Denmark

Jens G. Leipziger, MD, DrMed

• Svendsen, Samuel L.C., Aarhus Universitet, Aarhus, Midtjylland, Denmark

Samuel L.C. Svendsen, MD, PhD

• Rousing, Amalie Quist, Aarhus Universitet, Aarhus, Midtjylland, Denmark

Amalie Quist Rousing

• Bandulik, Sascha, Universitat Regensburg, Regensburg, Bayern, Germany

Sascha Bandulik

• Warth, Richard, Universitat Regensburg, Regensburg, Bayern, Germany

Richard Warth

• Sorensen, Mads Vaarby, Aarhus Universitet, Aarhus, Midtjylland, Denmark

Mads Vaarby Sorensen, PhD

• Jeppesen, Majbritt, Aarhus Universitetshospital, Aarhus, Denmark

Majbritt Jeppesen, MD

• Berg, Peder, Aarhus Universitet, Aarhus, Midtjylland, Denmark

Peder Berg, MD

Background

PwCF have an increased risk for fluid and electrolyte imbalances caused by fluid and salt loss. Congruently, guidelines advocate increased salt intake. In this study, we investigate the effect of ETI treatment on blood pressure and fluid- and electrolyte homeostasis in pwCF.

Methods

We quantified the effect of 6 months ETI treatment in pwCF (n=45) on blood pressure; electrolyte- and acid-base balance; aldosterone levels; and the diuretic response to an oral NaHCO₃ loading test. Furthermore, to explore sweat-independent pathophysiological mechanisms contributing to the phenotype of pwCF, we NaCl-depleted CF, pendrin KO, and WT mice for 7 days. Hereafter, the renal adaptation and systemic electrolyte and acid-base homeostasis were assessed.

Results

In pwCF, ETI treatment increased: blood pressure, venous Na⁺, and the diuretic response to oral NaHCO₃-loading. Congruently, treatment markedly decreased heart rate, aldosterone levels, venous tCO₂ and the proportion of pwCF with low Na⁺ levels. In CF mice, NaCl depletion caused lower Na⁺, K⁺, and Cl^- levels while HCO₃^- and aldosterone levels were increased. Interestingly, CF mice failed to increase renal pendrin protein abundance. During NaCl depletion, pendrin KO mice developed severe hyponatremia, hypochloremia, hypokalemia, metabolic alkalosis, and weight loss.

Conclusion

In pwCF, ETI treatment improves NaCl and fluid conservation. CF mice have an impaired ability to retain salt and fluid when NaCl-depleted, which is explained by insufficient renal pendrin regulation. Hence, part of the treatment effect in pwCF is likely attributed to correction of renal CFTR. Salt repletion appears less necessary in ETI-treated pwCF.

Funding

• Private Foundation Support