Molecular Insights into the Pathogenesis of IgA Nephropathy

Immunoglobulin IgA nephropathy (IgAN) is the leading form of primary glomerulonephritis associated with end-stage renal failure, requiring either dialysis or renal transplantation. Microscopic hematuria and proteinuria are the most common presentations, and mesangial cell proliferation with IgA deposition are found in renal biopsies. There is growing evidence that IgAN is an immune complex (IC)-mediated disease. To date, three key molecules have been implicated in IC formation, correlating with disease progression/recurrence after transplantation: galactose-deficient IgA1 (Gd-IgA1), IgG anti-Gd-IgA1 antibodies, and soluble CD89 (an Fc receptor for IgA). This review examines recent data on the role of these molecular players in IgAN. Understanding these factors is essential because such knowledge could lead to improved strategies for the future management of patients with IgAN.

TrendsThree key immunologic molecules are found in the circulating immune complex (CIC): Gd-IgA1, IgG antibody anti-Gd-IgA1, and soluble CD89. At diagnosis, soluble CD89 and IgG anti-Gd-IgA1 antibodies in IgAN patient serum are strong candidate markers of disease activity and severity. They might also predict the risk for disease progression and recurrence after renal transplantation.CD89 has been implicated in IgAN pathophysiology. It participates in humoral aggression of the kidney through CICs containing CD89. In addition, kidney infiltration by circulating monocytes can result from activation of ITAM-bearing CD89 bound to Gd-IgA1 complexes.Glomerular damage can be mediated through fixation of CIC upon transferrin receptor (CD71) protein overexpression in the renal mesangium. The presence of CICs is amplified by surface expression of mesangial tranglutaminase 2 leading to mesangial cell activation and disturbing mesangial–podocyte interactions. This can lead to rupture of the glomerular barrier homeostasis with proteinuria and hematuria.Local complement activation via C3a and C5a anaphylatoxins has more impact on glomerular inflammation than systemic activation in IgAN pathogenesis. Inhibition of C3a/C3aR or C5a/C5aR interactions or membrane attack complex formation may be useful in aggressive IgAN with an unsatisfactory response to traditional immunosuppression treatment.Risk loci for IgAN have been recently linked to genes involved in immunity against intestinal pathogens. Indeed, the geographical breakdown of risk loci suggests an environmental influence of host–pathogen interactions through intestinal microbiota.Immune responses against particular food and pathogen antigens can contribute to CIC formation, with exacerbated nephritogenic properties and hematuria; mucosal infection can frequently trigger episodes of glomerulonephritis in IgAN.