Glomerular diseases: emerging tests and therapies for IgA nephropathy

Abstract

The last decade has seen major progress in understanding the pathogenesis as well as the prognosis and treatment of patients with IgA nephropathy (IgAN). Although the diagnostic criterion of a kidney biopsy demonstrating dominant or codominant IgA deposition remains unchanged, much more is known about the genetic and environmental factors predisposing to disease development and progression. These advances have led to the identification of novel diagnostic and prognostic markers. Among the most promising clinically are genetic profiling, quantification of galactose-deficient IgA1 levels, and measurement of anti-IgA1 immunoglobulins. While targeted treatment for IgAN remains elusive, there is mounting evidence for therapeutic interventions that alter the disease course. The appropriate validation and integration of these discoveries into clinical care represent a major challenge, but one that holds tremendous promise for refining prognostication, guiding therapy, and improving the lives of patients with IgAN.

Figure 1.

Pathogenesis of IgA nephropathy: a proposed multistep model of IgA nephropathy, demonstrating the interaction of genetics, environmental factors, and both innate and acquired immunity. Step 1: Elevated circulating levels of galactose-deficient IgA1 (Gd-IgA1) are produced, probably due to genetic factors. Mis-trafficking of B cells from mucosal to systemic compartments may also be responsible, although this may also be influenced by genotype. Step 2: IgA or IgG antibodies directed against the underglycosylated hinge region of Gd-IgA1 (represented by the gray star) are produced, possibly driven by molecular mimicry. It is likely that these pathogenic antibodies are more likely to be produced in the setting of specific HLA haplotypes. Step 3: Immune complexes of Gd-IgA1 and antiglycan antibodies are formed. This may happen in the circulation (3a), or it may happen in situ against previously deposited IgA1 (3b). Step 4: The presence of immune complexes activates the complement cascade, induces mesangial cell proliferation and activation, and ultimately leads to the irreversible damage in the form of segmental or global glomerular sclerosis and interstitial fibrosis.