The pathogenesis of IgA nephropathy: what is new and how does it change therapeutic approaches?

Abstract

Immunoglobulin A (IgA) nephropathy is the most common glomerulonephritis worldwide. For example, in Japan, full-blown IgA nephropathy has been detected in ~1.5% of all allograft kidneys at the time of transplant. Genetic and environmental modifiers, as well as generic progression factors (eg, hypertension), must have a major role in determining who will become clinically overt and who will experience progression. In patients with clinically overt IgA nephropathy and/or progressive disease, it now is relatively well established that the pathogenesis involves 6 major steps: (1) Increased occurrence of IgA1 with poor galactosylation in the circulation. This might relate to the migration of mucosal B cells to bone marrow, where they produce "correct" poorly galactosylated IgA. Modulation of mucosal immunity may offer new therapeutic options. (2) Generation of IgG antibodies against poorly galactosylated IgA1. This could lay the foundation for immunosuppression, whereas detection of such IgG autoantibodies may accommodate the noninvasive monitoring of IgA nephropathy. (3) Mesangial deposition and/or formation of IgG-IgA1 or IgA1-IgA1 complexes. (4) Activation of mesangial IgA receptors and/or complement; both lend themselves to therapeutic interference. (5) Mesangial cell damage and activation of secondary pathways, such as overproduction of platelet-derived growth factor, which can be targeted specifically. (6) Activation of pathomechanisms that are not specific for IgA nephropathy and that drive glomerulosclerosis and tubulointerstitial fibrosis. Although at present our therapeutic armamentarium is still limited largely to supportive care and immunosuppression in some instances, these new insights can be expected to yield novel, perhaps individualized, therapeutic options in primary and recurrent IgA nephropathy.