Bicarbonate Excretion in Urine May Be Useful Test of CFTR Function
Test can be used to determine severity of genetic dysfunction in CF patients
A new test that measures the excretion of bicarbonate in urine may be used to assess the effectiveness of treatments for cystic fibrosis (CF), according to a new study.
“The goal is for the urine test to be used as a clinical tool to determine both the severity of the genetic dysfunction and the medicine’s restorative effect in individual patients with cystic fibrosis,” Jens Leipziger, MD, a professor at Aarhus University and co-author of the study, said in a press release.
Results from the study also suggest that the CFTR modulator Trikafta can improve kidney function in CF patients.
The study, “Challenged Urine Bicarbonate Excretion as a Measure of Cystic Fibrosis Transmembrane Conductance Regulator Function in Cystic Fibrosis,” was published in the journal Annals of Internal Medicine.
Dysfunctional CFTR protein can cause issues in the kidneys
CF is caused by mutations that impair the functionality of the CFTR protein, which acts like a gate on the surface of certain cells, regulating the flow of water and salt molecules in and out of the cell. This results in the production of thick sticky mucus, which is mainly responsible for the symptoms of CF.
Dysfunctional CFTR protein can also cause issues in the kidneys, which regulate the balance of salts in the body. Prior research has shown that CF patients have markedly reduced ability to increase the excretion of bicarbonate, which is used in the body to help regulate the acid-base balance. Bicarbonate is well-known as a component of baking soda (sodium bicarbonate).
In the study, a team led by scientists in Denmark evaluated whether measuring bicarbonate excretion in urine might be useful as a clinical metric for CF patients. The team suggested that urine tests could be useful as an alternative to sweat chloride tests, which are more time-consuming and require substantial expertise to carry out.
“The management of cystic fibrosis has changed with the recent introduction of treatments targeting the disease-causing mechanism. As the new treatments aim to improve the functioning of CFTR, the urine test can provide a measurement of whether a given treatment is effective,” said Leipziger, who is co-inventor on a patent application for the use of bicarbonate excretion as a biomarker in CF that was submitted by Aarhus University.
The study included 50 CF patients who were starting on treatment with Kaftrio (elexacaftor/tezacaftor/ivacaftor), a triple-combination CFTR modulator therapy that can boost the functionality of the CFTR protein in people with specific CF-causing mutations. Kaftrio is marketed as Trikafta in the U.S.
Prior to starting treatment (baseline), all patients underwent a challenged urine bicarbonate excretion assessment — meaning they consumed a standardized dose of sodium bicarbonate, and then the amount of bicarbonate excreted in their urine was measured. The testing was then repeated after patients had been on Trikafta for six months.
At baseline, patients with higher bicarbonate excretion in their urine tended to have better lung function, better pancreas function, and a lower risk of infection with the bacteria Pseudomonas aeruginosa. Baseline bicarbonate excretion was generally higher in patients with mutations that don’t fully impair the functionality of the CFTR protein.
After half a year on Trikafta, the average bicarbonate excretion increased by 3.9 millimoles/three hours, reaching about 70% of levels seen in individuals without CF.
the urine test can provide a measurement of whether a given treatment is effective
Trikafta partially restores kidney CFTR function in patients
The scientists concluded that Trikafta “partially restores renal [kidney] CFTR function in patients with CF, likely resulting in decreased risk for electrolyte disorders and metabolic alkalosis.” Of note, electrolyte disorders occur when certain mineral levels in the blood get too high or too low, whereas metabolic alkalosis occurs when there’s excessive bicarbonate in body fluids.
The team noted that this study is limited because it was conducted at a single center without a placebo group as a control.
“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,” the researchers wrote.
Leipziger said: “We know that the medicine is absorbed, metabolized and excreted differently from person to person. If, with a simple test, we can monitor the effects of the medicine for the individual patient, then we expect that patients will be able to achieve a better treatment result.”
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