An easy-to-administer electrolyte test could offer new insight into response to treatment and disease progression for patients with cystic fibrosis.
In a new study, researchers found that urine bicarbonate excretion is a potential marker for the function of the cystic fibrosis transmembrane conductance regulator (CFTR), an ion channel that, when defective, causes mucous obstruction, infection, chronic inflammation, and fibrosis.
The prospective, observational study, published October 31 in the Annals of Internal Medicine, investigated the association of urine bicarbonate excretion with disease severity and response to treatment with elexacaftor/tezacaftor/ivacaftor (ETI) in 50 Danish adults with CF (39 of whom completed the 6-month protocol).
ETI has significantly altered CF care by its ability to restore CFTR function to almost normal. This leads to improvement in lung function and quality of life while reducing pulmonary exacerbations and hospitalization. The study suggests that increased excretion of bicarbonate by the kidneys appears to reflect that improvement, according to the researchers.
"Renal disease related to CF is a field of emerging knowledge," according to the authors, who note that "patients with CF have a markedly reduced ability to increase renal base excretion after oral sodium bicarbonate loading."
In the study, two oral bicarbonate challenges, one before treatment and one 6 months after, showed that low excretion of bicarbonate was associated with CF characteristics, but the marker rose significantly with ETI.
Higher excretion of bicarbonate was associated with improved lung function, pancreatic sufficiency, and a lower risk for developing chronic pseudomonas infections, the researchers report. Bicarbonate excretion increased to about 70% of that seen in healthy control persons ― near normal ― with the treatment. (ETI's effect on bicarbonate excretion was less pronounced in patients with minimal function mutations and residual function mutations, the researchers note.)
"With an increasing number of CFTR modulator treatments available, sensitive biomarkers to validate and quantify treatment response are required," the authors write.
The current gold standard for measuring the CF protein's function is the sweat chloride test. But that test should be performed only at accredited centers, according to Natalie West, MD, MHS, a pulmonary specialist at John Hopkins University, in Baltimore, who was not involved in the new study. Results of tests of sweat chloride from these centers and those from outside labs can be "vastly different," she said. As a result, some patients may have to travel to be tested. Johns Hopkins is the only accredited center in Maryland, she said.
By comparison, "any lab can run" a test for urine bicarbonate, West said. "It doesn't require such specialized expertise." And while the sweat chloride test isn't particularly expensive, costing around $250, the cost of the urine bicarbonate test is comparable if not less.
At baseline, the study also confirmed that bicarbonate excretion correlates with other measures of CF severity, including the type of gene mutation, lung function, pancreatic sufficiency, and risk for chronic pseudomonas infection.
"I think that's the thing I found most promising," West said of the proposed marker's link to the disease, because "sweat chloride has not been shown to associate quite well with some of those markers."
The findings also suggest that ETI therapy reduces the risk for renal complications such as electrolyte disorders and metabolic alkalosis, for which CF patients are at higher risk, the researchers write.
Urine bicarbonate is not likely to replace sweat chloride, West added. Nor would it be used during routine medical visits, since CF patients already undergo testing of lung function at every visit. But she does see it being used with sweat chloride to better understand how an individual's CFTR is working, especially in cases in which patients don't respond as expected to ETI or in cases in which a physician wants to monitor ETI tolerance over time.
As a specialist in adult pulmonology, West said bicarbonate excretion also could be valuable in diagnosis. Some patients with milder disease are not diagnosed with CF until adulthood. And in some of these cases, sweat chloride is almost normal. Urine bicarbonate could offer another, simple diagnostic tool alongside genetic testing, she said.
The new study only included 39 participants, all from a single center, and there was no placebo-control group. The participants' average lung function was 79% (70% or higher is considered mild disease). Few people with severe diseases were included in the analysis. "It definitely was a healthier group," West said.
West said she would need to see results from a larger study before she adopted the bicarbonate test in her practice. But it has the potential to become "another check," and it is a practical way to measure "how our patients are or are not responding to CFTR modulators," she said.
Funding for the study came from the Danish Regions Medication and Treatment Research Fund and the Innovation Fund Denmark. West has received funding from the Cystic Fibrosis Foundation and Cystic Fibrosis Foundation Therapeutics, Inc.
Ann Intern Med. Published online October 31, 2022.
Donavyn Coffey is a Kentucky-based journalist reporting on healthcare, the environment, and anything that affects the way we eat. She has a master's degree from NYU's Arthur L. Carter Journalism Institute and a master's degree in molecular nutrition from Aarhus University in Denmark. You can see more of her work in Wired, Scientific American, Popular Science, and elsewhere.
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Image 1: Dr Natalie West
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