Using only an age-dependent threshold of estimated glomerular filtration rate (eGFR) — a marker of kidney function — indicating mild-to-moderate kidney disease is insufficient to effectively screen for undiagnosed Fabry disease patients among the general population, a study shows.
The findings suggest that appropriate screening likely wil require evidence of moderate-to-severe kidney disease, along with other Fabry symptoms or biomarkers, the researchers noted.
Fabry disease is caused by mutations in the GLA gene, located in the X chromosome (one of the two sex chromosomes). This results in absent or markedly reduced activity of the alpha-galactosidase A (Gal A) enzyme, leading to the toxic accumulation of two fat molecules — Gb3 and lyso-Gb3 — in the heart, kidneys, nervous system, eyes, and skin.
These patients often have progressive kidney impairment, which can lead to kidney failure (end-stage renal disease, or ESRD).
Since men have only one X chromosome, those who inherit a mutated GLA gene will develop the disease and typically present more severe symptoms than women, who have two X chromosomes and can compensate, to a certain extent, the mutated copy with a healthy one.
This compensation process varies significantly among women carrying GLA mutations, resulting in considerably different disease types, severity, and age of onset.
Fabry disease is estimated to affect one in 40,000 to 60,000 men worldwide, with a much less-known frequency among women. Still, evidence suggests that the overall frequency may be much higher (up to one in 4,600 people), depending on the inclusion of late-onset cases, women with a large range of symptoms, or mutations of unknown significance.
Notably, while 0.1–0.7% of people with ESRD are estimated to have Fabry disease, its frequency among people with earlier stages of kidney disease (not under the care of specialist kidney physicians) remains undetermined.
To fill this knowledge gap, researchers in the U.K. evaluated whether abnormal results in the eGFR test — done routinely to assess kidney function — could be used to identify potential Fabry disease patients in the general population and provide an estimate of the disease’s frequency among people with mild-to-moderate kidney disease.
This study was part of the PATHFINDER project, which builds on the premise of using routine laboratory results to identify people who should be tested for inherited metabolic diseases, such as Fabry disease.
The researchers analyzed electronic laboratory databases comprising patients from primary care and non-specialist secondary care in nine U.K. hospitals to identify those with reduced eGFR activity, but no ESRD.
They defined three age-specific eGFR thresholds: 15–54 milliliters per minute per square meter (mL/min/1.83m2) for those age 20–49 years, 15–29 mL/min/1.83m2 for those age 50–59, and 15–39 mL/min/1.83m2 for those age 60–69.
The analysis identified 1,084 patients (579 women and 505 men) with reduced kidney function, who were asked to provide a blood sample for additional tests assessing Gal A activity in men and Gal A activity and lyso-Gb3 levels in women.
Of note, women with Fabry disease may have normal Gal A activity levels, so an additional biomarker test is required to support a suspicion of Fabry disease, which then must be confirmed through genetic testing.
Results showed that one woman had lower-than-normal levels of Gal A activity and higher-than-normal lyso-Gb3 levels. Genetic testing confirmed that she carried a mutation in one of the GLA gene copies (c.898C>T), which was considered likely disease-causative.
It was later confirmed that her mother had Fabry disease, but she had not been contacted for family screening. None of the men were found to have Fabry disease.
“A single-point eGFR screening threshold of up to 55ml/min (age-dependent) did not identify any previously unsuspected cases of [Fabry disease],” the researchers wrote.
“The study was underpowered to detect significant numbers of cases, but the lack of cases identified shows that screening without significant [kidney] disease or other [Fabry disease] features is not useful,” they added.
Viable Fabry disease screening must likely include a stricter eGFR threshold (lower than 45 mL/min/1.73m2) indicating moderate-to-severe kidney disease, confirmed through multiple tests over time, combined with additional biomarkers and/or symptoms, the researchers noted.
They also emphasized the importance of findings ways to identify Fabry patients early on, because early treatment is key to prevent kidney disease progression and kidney failure.
The study was supported by Sanofi Genzyme Therapeutics — the developer of Fabrazyme, the first disease-specific therapy approved for Fabry disease — and research nurses were funded by the U.K.’s National Institute for Health Research.
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