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IgA vasculitis with nephritis: update of pathogenesis with clinical implications

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Abstract

IgA vasculitis with nephritis (IgAVN) shares many pathogenetic features with IgA nephropathy (IgAN). The purpose of this review is to describe our current understanding of the pathogenesis of pediatric IgAVN, particularly as it relates to the four-hit hypothesis for IgAN. These individual steps, i.e., hits, in the pathogenesis of IgAN are (1) elevated production of IgA1 glycoforms with some O-glycans deficient in galactose (galactose-deficient IgA1; Gd-IgA1), (2) generation of circulating IgG autoantibodies specific for Gd-IgA1, (3) formation of pathogenic circulating Gd-IgA1–containing immune complexes, and (4) kidney deposition of the Gd-IgA1-IgG immune complexes from the circulation and induction of glomerular injury. Evidence supporting the four-hit hypothesis in the pathogenesis of pediatric IgAVN is detailed. The genetics, pediatric outcomes, and kidney histopathologic features and the impact of these findings on future treatment and potential biomarkers are discussed. In summary, the evidence points to the critical roles of Gd-IgA1-IgG immune complexes and complement activation in the pathogenesis of IgAVN. Future studies are needed to characterize the features of the immune and autoimmune responses that enable progression of IgA vasculitis to IgAVN.

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Acknowledgements

The authors thank Bruce A. Julian for the critical reading of the manuscript.

Funding

This study was supported in part by NIH grants DK078244, DK082753, DK116690, and DK105124 and a gift from the IGA Nephropathy Foundation of America.

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Author notes

  1. M. Colleen Hastings and Dana V. Rizk contributed equally to this work.

Authors and Affiliations

  1. Division of Pediatric Nephrology and Hypertension, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA

    M. Colleen Hastings, Rima S. Zahr & Robert J. Wyatt

  2. Division of Nephrology, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA

    M. Colleen Hastings

  3. Children’s Foundation Research Institute at the Le Bonheur Children’s Hospital, Memphis, TN, USA

    M. Colleen Hastings, Rima S. Zahr & Robert J. Wyatt

  4. Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, Birmingham, AL, USA

    Dana V. Rizk

  5. Division of Nephrology, Department of Medicine, College of Physicians & Surgeons, Columbia University, New York, NY, USA

    Krzysztof Kiryluk

  6. Division of Pediatric Nephrology, Department of Pediatrics, University of Utah, Salt Lake City, UT, USA

    Raoul Nelson

  7. Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA

    Jan Novak

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DVR and JN are co-founders and co-owners of and consultants for Reliant Glycosciences, LLC. JN and RJW are co-inventors on US patent application 14/318,082 (assigned to UAB Research Foundation).

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Hastings, M.C., Rizk, D.V., Kiryluk, K. et al. IgA vasculitis with nephritis: update of pathogenesis with clinical implications. Pediatr Nephrol 37, 719–733 (2022). https://doi.org/10.1007/s00467-021-04950-y

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