The four-hit hypothesis

In IgA nephropathy, there is an increase in poorly galactosylated IgA1 (galactose-deficient-IgA1 or Gd-IgA1) in the circulation (Hit 1), believed to be derived from a mucosal source. Autoantibodies are formed that recognize Gd-IgA1 (Hit 2), leading to immune complex formation (Hit 3), and their subsequent mesangial deposition (Hit 4), triggering mesangial cell activation and proliferation, cytokine release, complement activation, podocyte injury, and downstream kidney injury and fibrosis.