IgA vasculitis with nephritis: update of pathogenesis with clinical implications

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.

Keywords: Children; Henoch-Schönlein purpura; IgA vasculitis; IgA1 glycoforms; IgAVN; Progression.

Fig. 1. Hypothesis for the pathogenesis of IgAN and IgAVN

IgAN and IgAVN appear to share the same pathogenesis, i.e., aberrantly glycosylated IgA1 (galactose-deficient in some hinge-region O-glycans; Gd-IgA1) is an autoantigen recognized by IgG autoantibodies, resulting in the formation of circulating pathogenic immune complexes. Some of these complexes, in turn, deposit in the kidney and induce glomerular injury. Figure modified from [137], used with permission.