Kaftrio may reduce need for salt supplementation in CF, study suggests
Treatment restored electrolyte balance, reduced blood carbon dioxide levels
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Treatment with Kaftrio may reduce the need for salt supplementation to treat salt wasting, the excessive loss of sodium and chloride in sweat that occurs in people with cystic fibrosis (CF), a new study reports.
Kaftrio (elexacaftor/tezacaftor/ivacaftor), sold as Trikafta in the U.S., restored electrolyte (salt) balance, as indicated by higher blood sodium levels and greater urinary excretion of water and sodium. Treatment also reduced blood carbon dioxide levels and the risk of alkalosis, a condition in which the body’s fluids become too alkaline, raising the blood pH. It also reduced blood levels of aldosterone, a blood pressure hormone.
“Increased awareness is warranted when [sodium chloride] replacement therapy is considered in [people with CF] treated with [Kaftrio],” researchers wrote.
The study, “Elexacaftor/tezacaftor/ivacaftor corrects salt-wasting in cystic fibrosis,” was published in the Journal of Cystic Fibrosis.
Dysfunction in key protein leads to salt wasting in CF
CF is caused by defects in CFTR, a protein that normally controls the flow of chloride ions, negatively charged salt particles, across cell membranes. Without sufficient CFTR activity, cells cannot properly hydrate cell surfaces, leading to the production of thick, sticky mucus that characterizes the disease.
CFTR dysfunction also causes salt wasting, an excessive loss of sodium and chloride through sweat, particularly during hot weather or exercise. This can lead to electrolyte imbalances (salts), hyponatremia (low sodium), and dehydration. As a result, it’s recommended that people with CF supplement with salt, particularly before exercise and during periods of higher temperatures.
Normally, excess dietary salt can raise blood pressure, which in turn increases the risk of cardiovascular disease. Moreover, people with CF have elevated blood levels of aldosterone. This hormone causes the kidneys to retain sodium and water while excreting excess potassium, which helps regulate blood pressure. Nevertheless, CF patients have a low risk of developing high blood pressure, likely due to salt wasting.
In this study, researchers in Denmark and Germany sought to assess the effects of Kaftrio, a CFTR modulator, on electrolyte balance and blood pressure in people with CF. Kaftrio boosts CFTR’s function in patients with certain CF-causing mutations.
The team analyzed urine and blood samples from 50 people with CF, ages 25 to 34, before and after nine months of treatment with Kaftrio. Urine samples from 28 healthy individuals were also tested.
Pretreatment urine tests showed no signs of kidney problems among CF patients, as indicated by creatinine levels comparable to those of controls. Still, CF patients excreted approximately twice as much sodium, potassium, calcium, and chloride as healthy individuals, as indicated by a higher salt-to-creatinine ratio.
“The increased excretion of several electrolytes in [CF patients] could reflect renal wasting but must also indicate increased oral intake or associated increased intestinal absorption,” the team noted.
Kaftrio treatment increased blood sodium levels
Before treatment, about one-fourth (26%) of CF patients had low blood sodium levels, which increased with Kaftrio treatment. Treatment also lowered blood carbon dioxide levels, thereby reducing the risk of alkalosis, a common CF complication. While sweat chloride concentration decreased with treatment, no changes were noted in blood levels of calcium, potassium, or magnesium.
Kaftrio treatment led to modest increases in blood pressure and a decrease in heart rate, with these changes becoming evident within four weeks. Body weight also increased by about 4 kg (8.8 lbs), most rapidly during the first 4 to 6 weeks of treatment. On average, blood aldosterone levels dropped substantially — especially in those with higher pretreatment levels.
“We propose that the mechanism of [Kaftrio]-induced elevation of blood pressure is not a pharmacological adverse effect, rather it is the expected physiological response to cessation of salt-wasting and increased salt and water retention,” the researchers wrote.
Overall, treatment effects were similar in male and female patients, with no consistent differences across different CF-causing mutations.
The salt-wasting [characteristic] and the state of volume contraction in [people with CF] are significantly improved after treatment with [Kaftrio].
Because CF patients have markedly reduced bicarbonate secretion, which the body uses to regulate acid-base balance, participants underwent an oral bicarbonate challenge. That is, they received a standardized dose of sodium bicarbonate (baking soda), and the amount of salts and water excreted in their urine was measured.
Results showed that Kaftrio treatment increased urine (diuresis) and sodium (natriuresis) excretion to levels comparable to those of healthy controls. Again, no differences were observed between male and female patients and between those with various CF-causing mutations.
“The salt-wasting [characteristic] and the state of volume contraction in [people with CF] are significantly improved after treatment with [Kaftrio],” the researchers concluded. “Salt repletion appears unnecessary in [Kaftrio]-treated [people with CF].”
