IgA Nephropathy: Current Understanding and Perspectives on Pathogenesis and Targeted Treatment

Abstract

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, with varied clinical and histopathological features between individuals, particularly across races. As an autoimmune disease, IgAN arises from consequences of increased circulating levels of galactose-deficient IgA1 and mesangial deposition of IgA-containing immune complexes, which are recognized as key events in the widely accepted "multi-hit" pathogenesis of IgAN. The emerging evidence further provides insights into the role of genes, environment, mucosal immunity and complement system. These developments are paralleled by the increasing availability of diagnostic tools, potential biomarkers and therapeutic agents. In this review, we summarize current evidence and outline novel findings in the prognosis, clinical trials and translational research from the updated perspectives of IgAN pathogenesis.

Keywords: Gd-IgA1; clinical trials; complement dysregulation; immunoglobulin A nephropathy; microbiota; mucosa-associated lymphoid tissue; mucosal immunity; prognosis; translational researches.

Figure 1

The pathophysiology of IgAN. IgAN usually presents with episodic gross hematuria and a concurrent upper respiratory tract infection or gastrointestinal disorder. Individuals with genetic susceptibility to IgAN develop aberrant mucosal immune responses to persistent antigenic stimulus, pathogenic microbiota and microbial metabolites. Antigen-presenting cells thereby activate and facilitate B-cells undergoing class switch and then differentiate into IgA+ ASCs in T-cell-dependent or T-cell-independent manners. Some mistrafficking ASCs take up residence in systemic sites, such as the bone marrow, NALT and GALT, leading to an increased circulating level of Gd-IgA1 and thus resulting in immune complex formation. The Gd-IgA1-containing immune complexes deposit in glomerular mesangium. Subsequently, complement activation (the alternative, lectin and terminal pathway) and intraglomerular inflammation together synergistically lead to kidney injuries, such as mesangial hypercellularity and fibrosis. ASC, antibody-secreting cell; CIC, circulating immune complex; DC, dendritic cell; NALT, nasal-associated lymphoid tissue; GALT, gut-associated lymphoid tissue; IgAN, IgA nephropathy.