IgG4-Related Kidney Disease

The term “IgG4-related disease” was recently coined to identify a rare systemic disorder hallmarked by fibro-inflammatory, tumor-like masses possibly affecting almost any organ. Pathologic tissues are characterized by dense, polyclonal, lymphoplasmacytic infiltrates, rich in IgG4-positive plasma cells on a background of fibrosis, which often has a storiform pattern; obliterative phlebitis and tissue eosinophilia often coexist. About two thirds of patients display high serum IgG4 levels, whereas in the remaining third, even in the presence of typical clinical and histopathologic features and before any therapy has been initiated, serum IgG4 levels are normal. The etiology of IgG4-related disease is still unclear. Given its association with HLA variants, its overlap with other autoimmune diseases, and its sensitivity to glucocorticoids and immunosuppressants, it is reasonable to consider this condition as a systemic immune-mediated disorder. However, only a few antigens capable of triggering the immune response have been identified, most of which are restricted to specific disease manifestations, possibly reflecting the wide heterogeneity of clinical phenotypes. Several cell-mediated immune mechanisms leading to tissue damage have been clarified, with T and B cells being also capable of inducing tissue fibrosis. On the other hand, it is still debated whether IgG4 actually play a role in disease pathogenesis. This controversy arises as IgG4 typically display an anti-inflammatory activity and only weakly activate the complement system. Moreover, an increase in IgG4 is not specific for the diagnosis of IgG4-related disease because high IgG4 serum levels can be found in several other inflammatory, allergic, and neoplastic diseases. Hence, IgG4 serum levels are believed to reflect an abnormal systemic inflammatory reaction, probably representing an epiphenomenon rather than an actual driver of IgG4-related disease.