Optimizing α-galactosidase A enzyme cutoff for Fabry disease screening in chronic kidney disease patients: a single-center reassessment of diagnostic yield and cost-effectiveness

Abstract

Fabry disease has been increasingly recognized in patients with chronic kidney disease (CKD). While dried blood spot (DBS) testing for α-galactosidase A (α-Gal A) activity is a common screening method, the optimal cutoff value for enzyme activity in this population remains uncertain. We retrospectively analyzed data from a Fabry disease screening program conducted between October 1, 2018, and September 31, 2023, at Taichung Veterans General Hospital. Male patients with CKD or ESKD underwent DBS α-Gal A enzyme activity testing. Patients with enzyme activity <2.0 μmol/L/hr were referred for confirmatory genetic testing. We assessed the diagnostic yield, baseline characteristics of true positive, false positive, and true negative cases, and performed receiver operating characteristic (ROC) analysis to identify the optimal diagnostic threshold. Among 1,654 screened patients, 35 had enzyme activity <2.0 μmol/L/hr, of whom 6 (0.36%) were genetically confirmed as having Fabry disease. Broadening the screening threshold from 1.2 to 2.0 μmol/L/hr enabled the identification of two additional cases. ROC analysis identified an optimal cutoff value of 1.96 μmol/L/hr (AUROC 0.996, 95%CI: 0.991–1.000), yielding a sensitivity of 98.3% (95CI%: 0.9769–0.9891) and specificity of 100% (95%CI:1-1). Patients with false-positive results had significantly lower leukocyte counts than true-positive cases. The incremental cost to detect two additional Fabry patients was $8,010 USD, representing acceptable cost-effectiveness under Taiwan’s healthcare framework. Expanding α-Gal A enzyme activity cutoff value from 1.2 to 2.0 μmol/L/hr improved the diagnostic performance of Fabry disease screening in CKD patients and proved to be cost-effective.