Although we do not fully understand the pathogenesis of these diseases, our understanding is improving. Both IgAN and C3G could be described as diseases that have autoimmune components that manifest, in part, based on genetic susceptibility. In IgAN, the “4-hit” hypothesis provides a conceptual framework for the pathogenesis (Table). As described by Suzuki et al, this model begins with Hit 1, which is the production of galactose-deficient immunoglobulin A1 (Gd-IgA1).

Abbreviations: Gd-IgA1, galactose-deficient immunoglobulin A1; IgA1, immunoglobulin A1; IgAN, immunoglobulin A nephropathy.

The cause of Hit 1 is unknown, but there are several theories extending from the key role of IgA in mucosal immunity, along with observed differences in IgAN incidence by ancestry (eg, East Asian, European, African). Blood levels of Gd-IgA1 are a heritable trait, and approximately 75% of patients with IgAN and 30% to 40% of their first-degree relatives have a serum Gd-IgA1 that is above the 90th percentile for healthy persons. Interestingly, it is theorized that some of the genetic findings that are associated with IgAN may be the result of evolution. For instance, as people migrated from Africa to East Asia and were exposed to new intestinal pathogens, genetic variants may have allowed for a more robust immune defense directed at these pathogens. This provided a survival advantage in that context, but it also set people up for IgAN in the longer-term.

Hit 2 is the formation of circulating antibodies directed against Gd-IgA1. Hit 3 is the formation of pathogenic immune complexes in the circulation that ultimately leads to Hit 4 (ie, the mesangial deposition of IgA1-containing immune complexes, which sets the stage for inflammation and progressive glomerular injury). 

Several genome-wide association studies have been conducted in patients with IgAN who have different ancestries, and numerous susceptibility loci have been identified. HLA variants and the complement-related genes are notable among those that are associated with an increased risk of IgAN. It has been shown in both animal models and human studies that patients with IgAN have evidence of complement pathway activation, which correlates with disease activity. 

C3G represents a spectrum of related kidney disorders with autoimmune and genetic causes. Again, we are still learning about the pathophysiology, and this disease is quite heterogeneous; however, C3 nephritic factors may be involved in some cases. C3 nephritic factors can be described as a group of autoantibodies that permit the continuous overactivation of the alternative complement pathway. They may be found in approximately 50% of patients with C3G and are linked to a variety of clinical diseases, including various nephropathies and partial lipodystrophy, as well as retinal changes and infections. C3G cases with autoantibodies to CFB, CFH, and C3 have been more recently described, and C3 convertase antibodies have been detected in patients with C3G and C3G with dense deposit disease patterns. 

While autoantibodies to the C3 and complement 5 convertases of complement are the most commonly detected drivers of complement dysregulation in C3G, genetic mutations in complement genes can also be found. It has been estimated that approximately 25% of patients with C3G carry rare variants or genomic rearrangements in complement genes that are disease associated. The genetic causes of C3G involve variants of complement genes, such as those coding for the components of C3 convertase, C3, CFB, and the regulator CFH.