New-onset IgA nephropathy following COVID-19 vaccination

Abstract

Coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused significant economic and health damage worldwide. Rapid vaccination is one of the key strategies to curb severe illness and death due to SARS-CoV-2 infection. Hundreds of millions of people worldwide have received various COVID-19 vaccines, including mRNA vaccines, inactivated vaccines and adenovirus-vectored vaccines, but the side effects and efficacy of most vaccines have not been extensively studied. Recently, there have been increasing reports of immunoglobulin A nephropathy (IgAN) after COVID-19 vaccination, however, whether their relationship is causal or coincidental remains to be verified. Here, we summarize the latest clinical evidence of IgAN diagnosed by renal biopsy associated with the COVID-19 vaccine published by 10 July 2022 with the largest sample size, and propose a hypothesis for the pathogenesis between them. At the same time, the new opportunity presented by COVID-19 vaccine allows us to explore the mechanism of IgAN recurrence for the first time. Indeed, we recognize that large-scale COVID-19 vaccination has enormous benefits in preventing COVID-19 morbidity and mortality. The purpose of this review is to help guide the clinical assessment and management of IgA nephropathy post-COVID-19 vaccination and to enrich the 'multi-hit' theory of IgA nephropathy.

Figure 1.

Mucosal immune anatomy of IgA responses and the ‘multi-hit’ model of IgAN. IgA is the most abundant antibody isotype in the body, with the majority of IgA found in mucosal secretions. Mucosal IgA production is induced by T-cell-dependent and T-cell-independent mechanisms. In individuals with a genetic predisposition to IgA nephropathy, chronic bacterial infection and gut dysbiosis initiate T-cell-independent pathways that trigger the expression of TLRs on antigen-presenting cells that recognize pathogens and release a variety of lymphocyte inflammatory cytokines, such as IL-6, IL-10, IL-21, BAFF, TGF-β and APRIL, stimulate B-cell differentiation and proliferation, have class switching from IgM to IgA1. IgA-secreting plasma cells migrate to lamina propria, where they release dimeric IgA1 (dIgA1). The dimers are formed through an interaction of two IgA1 molecules with a joining chain (J-chain), which is synthesized by plasma cells. IgA1 dimers can bind to the polymeric Ig receptor (pIgR) on the basolateral surface of the mucosal epithelium and undergo transcytosis to the apical surface, where they dissociate from pIgR and are secreted into the lumen carrying the secretory component of the receptor. In the T-cell-dependent pathway, B-cell type switching occurs after antigen-specific T-cell activation. The level of IgA1 bearing galactose-deficient O-glycans (Gd-IgA1) is increased in the circulation of patients with IgA nephropathy (hit 1). These IgA1 glycoforms are recognized as autoantigens by antiglycan autoantibodies (anti-Gd-IgA1 autoantibodies; hit 2), resulting in the formation of nephritogenic immune complexes (hit 3), some of which deposit in the kidney and activate mesangial cells (hit 4). Mesangial cells start to proliferate and overproduce components of extracellular matrix, cytokines and chemokines. Some of these cytokines can then cause podocyte injury and induce proteinuria. The figure refers to the pathogenesis of IgAN by Gesualdo et al.

Figure 2.

Hypothesis of IgAN caused by COVID-19 vaccination. The most common systemic symptoms in IgAN patients caused by COVID-19 vaccination were fever, fatigue and pain, and renal symptoms were GH, proteinuria and AKI. COVID-19 vaccination stimulates antigen-presenting cells (APCs), eliciting innate and subsequent adaptive immune responses. The first hypothesis for the development of IgAN in patients is the production of multiple antiglycan antibodies that cross-react with pre-existing galactose-deficient O-glycans (Gd-IgA1, A). The second hypothesis is an increase in pathogenic IgA production similar to influenza vaccine (B). The third hypothesis is that the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein (S) acts as a superantigen, causing cytokine storms (C). The data indicated that the COVID-19 mRNA vaccine was effective in inducing spike antigen-specific IgA and IgG production and, after the second vaccination, elicited strong CD4+ T-cell and CD8+ T-cell responses and a strong antibody response. The CD4+ T-cell response is mainly of helper T-cell type 1, producing IFN-c, TNF-α and IL-2. The main responses of CD8+ T cells are IFN-γ and TNF.