Carboxymethyl-lysine is a Prominent Target of Circulating IgA in IgA Nephropathy
Introduction: IgA nephropathy (IgAN), the most prevalent glomerular disease worldwide, carries a significant risk of kidney failure. Its pathogenesis involves the presence of elevated levels of IgA and galactose-deficient IgA (Gd-IgA), deposition of these antibodies in the kidney mesangium, and comp...
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Elsevier
2025-07-01
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| Series: | Kidney International Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2468024925002335 |
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| author | Sara Alibrandi Talita Aguiar Mattea Ausmeier Paolo Molinari Enrico Fiaccadori Umberto Maggiore Nicholas Chun Maria Lanau Mario Perez-Arnedo Joaquin Manrique Paolo Cravedi Emmanuel Zorn |
| author_facet | Sara Alibrandi Talita Aguiar Mattea Ausmeier Paolo Molinari Enrico Fiaccadori Umberto Maggiore Nicholas Chun Maria Lanau Mario Perez-Arnedo Joaquin Manrique Paolo Cravedi Emmanuel Zorn |
| author_sort | Sara Alibrandi |
| collection | DOAJ |
| description | Introduction: IgA nephropathy (IgAN), the most prevalent glomerular disease worldwide, carries a significant risk of kidney failure. Its pathogenesis involves the presence of elevated levels of IgA and galactose-deficient IgA (Gd-IgA), deposition of these antibodies in the kidney mesangium, and complement-mediated glomerular injury, leading to progressive renal function loss. The source and specificity of IgA in this disease remain unclear. We hypothesized that pathogenic IgA results from an immune response to abnormal protein modifications. Methods: We used an advanced enzyme-linked immunosorbent assay (ELISA) platform to assess serum IgA and Gd-IgA reactivity to 93 posttranslational modifications and other chemical adducts in 28 patients with biopsy-proven IgAN and 22 healthy controls. Results: Carboxymethyl-lysine (CML) was identified as the dominant target of IgA and Gd-IgA, but not IgG in patients with IgAN. This finding was validated in an independent cohort of 15 IgAN cases and 15 controls. In addition, a positive correlation was found between serum CML concentration and IgA reactivity in patients with IgAN, alongside albuminuria. Lastly, immunofluorescence staining observed elevated CML deposition in glomeruli of patients with IgAN than in controls. Conclusion: Our studies identify CML as a primary target of circulating IgA in IgAN, suggesting that aberrant responses to this modified self-antigen contribute to disease pathophysiology. |
| format | Article |
| id | doaj-art-158e4e123e0f4dd4b654c582b9fdf92a |
| institution | Kabale University |
| issn | 2468-0249 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Kidney International Reports |
| spelling | doaj-art-158e4e123e0f4dd4b654c582b9fdf92a2025-08-20T03:24:16ZengElsevierKidney International Reports2468-02492025-07-011072414242310.1016/j.ekir.2025.04.016Carboxymethyl-lysine is a Prominent Target of Circulating IgA in IgA NephropathySara Alibrandi0Talita Aguiar1Mattea Ausmeier2Paolo Molinari3Enrico Fiaccadori4Umberto Maggiore5Nicholas Chun6Maria Lanau7Mario Perez-Arnedo8Joaquin Manrique9Paolo Cravedi10Emmanuel Zorn11Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Department of Medicine and Surgery, University of Parma, Parma, Italy; Nephrology Unit, University Hospital of Parma, Parma, ItalyColumbia Center for Translational Immunology, Columbia University Medical Center, New York, New York, USAColumbia Center for Translational Immunology, Columbia University Medical Center, New York, New York, USA; Institute of Anatomy and Cell Biology, Faculty of Medicine, Martin Luther University of Halle-Wittenberg, Halle (Saale), GermanyTranslational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Department of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca' Grande Ospedale Policlinico, Milan, ItalyDepartment of Medicine and Surgery, University of Parma, Parma, Italy; Nephrology Unit, University Hospital of Parma, Parma, ItalyDepartment of Medicine and Surgery, University of Parma, Parma, Italy; Nephrology Unit, University Hospital of Parma, Parma, ItalyTranslational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USANephrology Department, Hospital Universitario de Navarra. Pamplona SpainNephrology Department, Hospital Universitario de Navarra. Pamplona SpainNephrology Department, Hospital Universitario de Navarra. Pamplona SpainTranslational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Correspondence: Paolo Cravedi, Department of Medicine, Icahn School of Medicine at Mount Sinai, 1 Levy G Pl, New York, New York 10029, USA.Columbia Center for Translational Immunology, Columbia University Medical Center, New York, New York, USAIntroduction: IgA nephropathy (IgAN), the most prevalent glomerular disease worldwide, carries a significant risk of kidney failure. Its pathogenesis involves the presence of elevated levels of IgA and galactose-deficient IgA (Gd-IgA), deposition of these antibodies in the kidney mesangium, and complement-mediated glomerular injury, leading to progressive renal function loss. The source and specificity of IgA in this disease remain unclear. We hypothesized that pathogenic IgA results from an immune response to abnormal protein modifications. Methods: We used an advanced enzyme-linked immunosorbent assay (ELISA) platform to assess serum IgA and Gd-IgA reactivity to 93 posttranslational modifications and other chemical adducts in 28 patients with biopsy-proven IgAN and 22 healthy controls. Results: Carboxymethyl-lysine (CML) was identified as the dominant target of IgA and Gd-IgA, but not IgG in patients with IgAN. This finding was validated in an independent cohort of 15 IgAN cases and 15 controls. In addition, a positive correlation was found between serum CML concentration and IgA reactivity in patients with IgAN, alongside albuminuria. Lastly, immunofluorescence staining observed elevated CML deposition in glomeruli of patients with IgAN than in controls. Conclusion: Our studies identify CML as a primary target of circulating IgA in IgAN, suggesting that aberrant responses to this modified self-antigen contribute to disease pathophysiology.http://www.sciencedirect.com/science/article/pii/S2468024925002335biomarkerbiopsychemical adductIgA nephropathykidney diseaseproteinuria |
| spellingShingle | Sara Alibrandi Talita Aguiar Mattea Ausmeier Paolo Molinari Enrico Fiaccadori Umberto Maggiore Nicholas Chun Maria Lanau Mario Perez-Arnedo Joaquin Manrique Paolo Cravedi Emmanuel Zorn Carboxymethyl-lysine is a Prominent Target of Circulating IgA in IgA Nephropathy Kidney International Reports biomarker biopsy chemical adduct IgA nephropathy kidney disease proteinuria |
| title | Carboxymethyl-lysine is a Prominent Target of Circulating IgA in IgA Nephropathy |
| title_full | Carboxymethyl-lysine is a Prominent Target of Circulating IgA in IgA Nephropathy |
| title_fullStr | Carboxymethyl-lysine is a Prominent Target of Circulating IgA in IgA Nephropathy |
| title_full_unstemmed | Carboxymethyl-lysine is a Prominent Target of Circulating IgA in IgA Nephropathy |
| title_short | Carboxymethyl-lysine is a Prominent Target of Circulating IgA in IgA Nephropathy |
| title_sort | carboxymethyl lysine is a prominent target of circulating iga in iga nephropathy |
| topic | biomarker biopsy chemical adduct IgA nephropathy kidney disease proteinuria |
| url | http://www.sciencedirect.com/science/article/pii/S2468024925002335 |
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