**4. Discussion**

IgAV is the most common vasculitis in children but it can also occur in adults. IgAV spontaneously resolves in about 94% of children and 89% of adults [13], although some IgAV patients exhibit kidney involvement (IgAVN). The disease mechanisms of IgAVN and IgAN are thought to be closely related [6,9]. Both diseases exhibit glomerular IgA immunodeposits with co-deposits of complement C3 [13–18]. The IgA immunodeposits are of the IgA1 subclass [18–20].

Pathogenesis of both IgAN and IgAVN is thought to occur through a multi-hit process [5]. This process includes the production of galactose-deficient IgA1 (Gd-IgA1) [21–29], generation of circulating IgG autoantibodies specific for Gd-IgA1 [29–34], formation of pathogenic Gd-IgA1-containing immune complexes [30,35–43], and the subsequent mesangial deposition of these immune complexes resulting in glomerular injury [34,44]. These conclusions are supported by multiple lines of evidence. For example, serum levels of Gd-IgA1 and the corresponding IgG autoantibodies are associated with a faster decline in kidney function in patients with IgAN [45–47]. Moreover, IgA-containing glomerular immunodeposits are enriched for Gd-IgA1 glycoforms [48,49] and the corresponding IgG autoantibodies [33]. In both IgAN and IgAVN, Gd-IgA1 is produced by IgA1-secreting cells due to dysregulation of key glycosyltransferases [29,50,51].

Circulating levels of Gd-IgA1 and Gd-IgA1-specific IgG autoantibodies are elevated in patients with IgAVN but not in patients with IgAV [29], supporting the hypothesis that IgAVN and IgAN share pathogenetic components. IgAVN patients have the onset of disease defined by purpura, with kidney involvement developing with 4–6 weeks later [5,13,17]. However, there is a limited information about histopathologic disease severity in relation to disease onset.

In this study of 110 adult patients with IgAVN, we assessed histopathologic disease severity based on interval between purpura onset and diagnostic kidney biopsy and correlated the findings with clinical and laboratory data. IgAVN patients biopsied <1 month since the onset of purpura more commonly had glomerular leukocytes and had the highest percentage of neutrophils among peripheral-blood leukocytes. These findings are consistent with an acute-onset inflammatory reaction in patients with IgAVN who were biopsied <1 month after the onset of purpura. Moreover, serum total IgA concentration correlated with the glomerular mesangial proliferation score.

A limitation of this study is the relatively small number of patients from a single center who were of single ethnicity. The patients were followed regularly for up to 6 months after the appearance of purpura at their respective local-area hospitals. However, these data were not been available for this study. This limitation implies that these findings need to be assessed in other cohorts and different ethnic groups, ideally with regular follow-up after the onset of purpura until biopsy as well as after biopsy.

Our study demonstrates a chronological association between leukocytic infiltration and glomeruloproliferative responses in IgAVN patients. These findings raise a question whether patients with IgAV should be followed frequently after the onset of purpura to detect nephritis in the early stages and whether assessment of biomarkers, such as Gd-IgA1- and Gd-IgA1-specific IgG autoantibodies, should be included.

**Author Contributions:** Conceptualization, L.L., C.H., J.N., B.A.J. and L.N.; data generation, L.L., S.L. and L.N.; statistical analyses, L.L., M.A., S.H. and L.N.; writing—original draft manuscript, L.L. and L.N.; writing—review and editing, L.L., J.N., B.A.J. and L.N. All authors have read and agreed to the published version of the manuscript.

**Funding:** Supported by NIH grants DK078244 and DK082753 and a gift from the IGA Nephropathy Foundation of America.

**Institutional Review Board Statement:** The study was conducted according to the guidelines of the Declaration of Helsinki, and was approved by ethics board of Huashan Hospital, Fudan University, Shanghai, China.

**Informed Consent Statement:** Not Applicable.

**Data Availability Statement:** Not Applicable.

**Conflicts of Interest:** B.A.J. and J.N. are co-inventors on US patent application 14/318,082 (assigned to UAB Research Foundation). B.A.J. and J.N. are co-founders and co-owners of and consultants for Reliant Glycosciences, LLC.
