Multi-hit Pathogenesis of IgA Nephropathy

Abstract

　IgA nephropathy (IgAN) is characterised by the deposition of IgA in the glomerular mesangium and is the most commonly reported primary glomerulonephritis worldwide. Thirty to forty percent of patients with IgAN develop progressive renal function decline, requiring renal replacement therapy within two decades of diagnosis. Development of a curative treatment and strategies for early diagnosis and treatment are necessary. Renal biopsy is the gold standard for the diagnosis and assessment of disease activity. Therefore, reliable biomarkers are needed for the non-invasive diagnosis of this disease and to more fully delineate the risk for progression. For the pathogenesis of IgAN, it is now widely accepted that multi-hit hypothesis, including production of galactose-deficient IgA1 (Gd-IgA1)(1st hit), and IgG autoantibodies that recognize Gd-IgA1 (2nd hit) and their subsequent immune complex formation (3rd hit) and glomerular deposition (4th hit). Although the prognostic values of several biomarkers have been discussed, we recently developed a highly sensitive and specific diagnostic method by measuring serum levels of Gd-IgA1 and Gd-IgA1 contained immune complexes. In addition, urinary Gd-IgA1 may represent a disease-specific biomarker of IgAN. We also confirmed a significant correlation between serum levels of these effector molecules and disease activity, suggesting that each can be considered as a practical surrogate marker of therapeutic response. A better understanding of the molecular basis of the pathogenesis of IgAN will likely result in disease-specific serum and urinary biomarkers. Thus, these disease-oriented specific biomarkers may be useful for screening of potential IgAN with isolated hematuria, earlier diagnosis, disease activity, and eventually, response to treatment.