Development of Urinary Diagnostic Biomarker for IgA Nephropathy by Lectin Microarray

Introduction. The pathogenic roles of aberrantly glycosylated IgA1 have been reported. However, it is unexplored whether the profiling of urinary glycans contributes to the diagnosis of IgAN.
Methods. We conducted the retrospective study enrolling 493 patients who underwent renal biopsy at Okayama University Hospital between Dec. 2010 and Sep. 2017. We performed lectin microarray in urine samples and investigated whether c-statistics of the reference standard diagnosis model employing hematuria, proteinuria, and serum IgA was improved by adding the urinary glycan intensity.
Results. Among 45 lectins, 3 lectins showed a significant improvement of the models: Amaranthus caudatus lectin (ACA) with the difference of c-statistics 0.038 [95%CI, 0.019 - 0.058, P < 0.001], Agaricus bisporus lectin (ABA) 0.035 [95%CI, 0.015 - 0.055, P < 0.001], Maackia amurensis lectin (MAH) 0.035 [95%CI, 0.015 - 0.054, P < 0.001]. In 3 lectins, each signal plus reference standard showed good reclassification (category free NRI and relative IDI) and good model fitting associated with the improvement of AIC and BIC. Stratified by eGFR, the discriminatory ability of ACA plus reference standard was maintained, suggesting the robust renal function-independent diagnostic performance of ACA. By decision curve analysis, there was a 3.45% net benefit by adding urinary glycan intensity of ACA to reference standard at the pre-defined threshold probability of 40%. Conclusions. The reduction of Gal(β1-3)GalNAc (T-antigen), Sia(α2-3)Gal(β1-3)GalNAc (Sialyl T), and Sia(α2-3)Gal(β1-3)Sia(α2-6)GalNAc (disialyl-T) was suggested by binding specificities of 3 lectins. C1GALT1 and COSMC were responsible for the biosynthesis of these glycans, and they were known to be downregulated in IgAN. The urinary glycan analysis by ACA is useful and robust non-invasive strategy for the diagnosis of IgAN.

This is an Accepted Manuscript published by S. Karger AG.