Abstract: FR-PO902
Novel Serodiagnostic Biomarkers for IgA Nephropathy Using Matrix-Assisted Laser Desorption Ionization-Time of Flight (MALDI-TOF) Mass Spectrometry Glycoprofiling of IgA1
Session Information
- IgA Nephropathy: Clinical, Outcomes, and Therapeutics
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1402 Glomerular Diseases: Clinical, Outcomes, and Therapeutics
Authors
- Nakazawa, Shigeaki, Osaka Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Suita, Osaka, Japan
- Novak, Jan, The University of Alabama at Birmingham, Birmingham, Alabama, United States
- Nonomura, Norio, Osaka Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Suita, Osaka, Japan
- Kakuta, Yoichi, Osaka Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Suita, Osaka, Japan
Background
IgA nephropathy (IgAN) is one of the most common primary glomerulonephritides worldwide, with many patients progressing to kidney failure. IgAN is characterized by IgA1 glomerular immunodeposits enriched for galactose-deficient IgA1 glycoforms (Gd-IgA1). Human IgA1 hinge region contains 3-6 clustered O-glycans, and patients with IgAN have elevated serum levels of Gd-IgA1. Gd-IgA1 glycoforms have N-acetylgalactosamine (GalNAc) residues exposed and available for binding by a GalNAc-specific lectin (e.g., from Helix pomatia; HPA). These Gd-IgA1 glycoforms can be also recognized by autoantibodies specific for Gd-IgA1, resulting in the formation of nephritogenic immune complexes. Previously, we comprehensively analyzed IgA1 O-glycan profiles using MALDI-TOF mass spectrometry (MS). We determined that IgAN patients have elevated serum levels of Gd-IgA1 and that these glycoforms have reduced number of Gal residues. In this study, we assessed whether the IgA1 O-glycan profiling can provide diagnostic-level data for IgAN.
Methods
Kidney-transplant recipients who underwent transplantation at Osaka University Transplant Group from 2013 to 2024 were recruited, with kidney donors serving as controls. The volunteers were divided into two cohorts: a discovery cohort (n=85) and a validation cohort (n=46). Serum IgA was isolated, digested with trypsin, and the released IgA1 hinge-region glycopeptides were isolated and analyzed by MALDI-TOF MS on a BRUKER Ultraflex instrument. An IgAN-MS index was calculated using multiple regression analysis based on the relative representation of specific glycoforms of IgA1 hinge-region glycopeptides. A cut-off value was determined by ROC curve analysis in the discovery cohort, and the diagnostic ability was tested in the validation cohort.
Results
In the discovery cohort, setting a cut-off value of 0.38 yielded a high diagnostic performance with an AUC of 0.89. This diagnostic performance was confirmed using the validation cohort, with a sensitivity of 72% and specificity of 68%.
Conclusion
In summary, analysis of IgA1 O-glycoforms by MALDI-TOF MS represents a novel, noninvasive biomarker for IgAN that can provide another level of information in addition to kidney-biopsy evaluation.