Novel biomarker shows promise in assessing CFTR function in patients with cystic fibrosis

Challenged urine bicarbonate excretion provided a simple and safe quantification of cystic fibrosis transmembrane conductance regulator function among adults with cystic fibrosis, according to data published in Annals of Internal Medicine.

“This study is also the first to document elexacaftor/tezacaftor/ivacaftor-induced increases of [cystic fibrosis transmembrane conductance regulator (CFTR)] function in renal epithelium,” Peder Berg, MD, research assistant and PhD student the department of biomedicine at Aarhus University in Aarhus, Denmark, and fellow researchers wrote.

For the prospective observational study, Berg and colleagues aimed to assess a novel, noninvasive in vivo method to quantify CFTR function in humans at baseline and following 6 months of treatment.

Because renal base excretion is impaired in cystic fibrosis and urine bicarbonate excretion may be an in vivo biomarker of CFTR function, researchers used an oral sodium bicarbonate challenge test, during which individuals provided a sample of urine and then ingested 79 mg/kg of body weight of sodium bicarbonate dissolved in 200 mL of tap water, with urine then collected hourly for 3 hours. For the first 2 hours, an additional 200 mL of tap water was ingested hourly.

The single-center study included 50 adults (median age, 29 years; 56% women) with cystic fibrosis beginning CFTR modulator therapy with elexacaftor/tezacaftor/ivacaftor (Trikafta, Vertex Pharmaceuticals) from May 2020 to June 2021.

Baseline results indicated that 3-hour cumulated bicarbonate excretion (mmol/3 h) was linked to several cystic fibrosis disease characteristics.

Specifically, patients with residual function mutations demonstrated a 6.8 mmol/3h (95% CI, 2.6-10.9) higher bicarbonate excretion than patients homozygous for dF508.

Also, 1 mmol/3 h higher bicarbonate excretion was linked to a 33% (95% CI, 16%-53%) higher likelihood of pancreatic insufficiency, a 2.4% (95% CI, 1%-3.8%) higher percentage of predicted FEV₁ (ppFEV₁) and an 8.5% (95% CI, 2.3%-15%) lower relative risk for chronic Pseudomonas aeruginosa infections.

Thirty-nine patients completed the 6-month protocol.

Treatment with elexacaftor/tezacaftor/ivacaftor improved bicarbonate excretion by 3.9 mmol/3 h (95% CI, 1.6-6.1) and reached roughly 70% of that observed among 10 healthy control participants. This increase in bicarbonate excretion also related to an increase in ppFEV₁ of 9.4%.

“Although further studies are needed to address the performance and sensitivity of this approach, this early-stage evaluation shows that challenged urine bicarbonate excretion may offer a new, simple and safe quantification of CFTR function and the extent of its pharmacologic improvement,” Berg and colleagues wrote. “Elexacaftor/tezacaftor/ivacaftor partially restores renal CFTR function in patients with [cystic fibrosis], likely resulting in decreased risk for electrolyte disorders and metabolic alkalosis,” they continued.

The researchers added that challenged urine bicarbonate excretion “may help to guide decision-making to improve precision medicine and the development of novel CFTR modulator drugs.”