Clin Chem Lab Med. 2026 Feb 2. doi: 10.1515/cclm-2025-1499. Online ahead of print.
ABSTRACT
OBJECTIVES: Diagnosing atypical IgG4-mediated anti-glomerular basement membrane (anti-GBM) disease is challenging because conventional serological assays poorly detect IgG4 antibodies. Here we study which commercial assays are affected and we describe proof-of-concept of improved IgG4 anti-GBM detection.
METHODS: To investigate the scope of the diagnostic dilemma detecting IgG4 anti-GBM antibodies, serum from a patient with atypical IgG4-mediated anti-GBM was distributed to 36 laboratories participating in the Dutch External Quality Assessment (EQA) program. To improve IgG4 anti-GBM detection in the fluorescent enzyme immunoassay (FEIA), the standard anti-IgG conjugate was replaced with anti-IgG4 conjugate.
RESULTS: We report the diagnostic delay of a patient with atypical anti-GBM disease who presented with an indolent disease course. Histopathology comprised hallmarks of classic anti-GBM disease including bright linear IgG deposits along the GBM but without the typical findings of diffuse crescentic and necrotizing glomerulonephritis. IgG anti-GBM test results were repeatedly negative. Histopathological subclass analysis demonstrated that the linear IgG deposits were predominantly IgG4. All 36 Dutch EQA-participants reported negative anti-GBM test results, demonstrating that the diagnostic challenge of detecting IgG4 anti-GBM is broadly applicable across multiple diagnostic assays. A minor modification to the manufacturer’s standard protocol of the FEIA anti-GBM dramatically improved the assay’s performance for measuring antibodies of the IgG4 isotype. Using the modified IgG4-GBM test, we were able to diagnose and monitor one more patient with atypical IgG4-mediated anti-GBM disease.
CONCLUSIONS: Here we demonstrate proof-of-concept of a modified IgG4 anti-GBM blood test allowing serological confirmation of atypical anti-GBM disease and sensitive monitoring of therapy response.
PMID:41620942 | DOI:10.1515/cclm-2025-1499