Development of Urinary Diagnostic Biomarker for IgA Nephropathy by Lectin Microarray

Abstract

<b><i>Introduction:</i></b> 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. <b><i>Methods:</i></b> We conducted a retrospective study enrolling 493 patients who underwent renal biopsy at Okayama University Hospital between December 2010 and September 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 were improved by adding the urinary glycan intensity. <b><i>Results:</i></b> Among 45 lectins, 3 lectins showed a significant improvement of the models: <i>Amaranthus caudatus</i> lectin (ACA) with the difference of c-statistics 0.038 (95% CI: 0.019–0.058, <i>p</i> < 0.001), <i>Agaricus bisporus</i> lectin (ABA) 0.035 (95% CI: 0.015–0.055, <i>p</i> < 0.001), and <i>Maackia amurensis</i> lectin (MAH) 0.035 (95% CI: 0.015–0.054, <i>p</i> < 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 the reference standard at the predefined threshold probability of 40%. <b><i>Conclusions:</i></b> 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 a useful and robust noninvasive strategy for the diagnosis of IgAN.

Increased Urinary IgA in Paediatric IgA Vasculitis Nephritis

“…This was also replicated in a Chinese study which described an incidence of 73% for IgAVN in hospitalised children with a urinary gd-IgA1/Cr ratio ≥ 105.74 U/mL during the six-month follow up [ 14 ]. Similar findings have been reported for IgAN, with some specificity of urinary gd-IgA1 to differentiate it from other kidney diseases [ 12 , 13 , 15 ].…”

“…Despite these limitations, this study, alongside existing evidence, opens up new areas for future work. Combining biomarkers such as urinary IgA with other novel markers or existing monitoring regimens that may be focused on urine dipstick findings may allow better information to identify children developing nephritis, and further scientific studies may utilise extracting IgA from urine to explore the IgA glycan profiles and better characterise this disease [ 15 , 19 , 20 ].…”