Evidence for genetic factors in the development and progression of IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is the most common glomerulonephritis in the world among patients undergoing renal biopsy. Once considered a relatively benign condition, longitudinal follow-up studies have revealed that in fact 9 to 50% of patients progress to end-stage renal disease within 20 years of disease onset. In the three decades since its first description by Jean Berger and Nicole Hinglais, clinical, epidemiologic, and immunologic studies of the pathogenesis of primary (idiopathic) mesangial glomerulonephritis with predominant IgA deposits have characterized the features of IgAN as a distinct glomerular disease entity. However, the basic molecular mechanism(s) underlying abnormal IgA deposition in the mesangium with ensuing extracellular matrix expansion and mesangial cell proliferation remains poorly understood. The task of elucidating the molecular basis of IgAN is made especially challenging by the fact that both environmental and genetic components likely contribute to the development and progression of IgAN. METHODS AND RESULTS: We review here the evidence for genetic factors in the development and progression of IgAN, including a reappraisal of earlier conflicting results from small immunogenetic case-control studies, the evidence for racial differences in the prevalence of IgAN, a detailed summary of all reported occurrences of familial IgAN worldwide, and an exhaustive review of new insights gained through the study of two murine models of hereditary IgAN: the ddY and the uteroglobin-deficient mouse. CONCLUSIONS: With the development of powerful molecular genetic approaches to the study of both Mendelian and complex human genetic diseases, and the successful efforts of investigators to identify and clinically characterize large IgAN multiplex families, we propose that genetic analysis of familial IgAN is the most promising approach to the identification of IgAN disease/susceptibility genes. Alternatively, if the case-control study design is employed to identify associations between particular candidate genes or markers and the development of IgAN, spurious associations caused by the effects of population stratification should be ruled out by confirming the findings using powerful and sensitive family-based methodologies such as the transmission/dysequilibrium test (TDT).

IgG antineutrophil cytoplasmic antibodies in IgA nephropathy: a clinical variant?

Anti-neutrophil cytoplasmic antibodies (ANCAs) of the immunoglobulin (Ig) G isotype are associated with rapidly progressive glomerulonephritis. These have been detected rarely in patients with Henoch-Schönlein purpura (HSP) and have only been previously reported once in a patient with IgA nephropathy (IgAN). In contrast, IgA-ANCAs have been detected in patients with HSP or IgAN, although further verification of this finding by various investigators has yielded conflicting results. We report a case of biopsy-proven IgAN in which the patient developed a rapidly progressive glomerulonephritis and was determined to have ANCAs of both IgA and IgG isotypes. This report suggests an association between fulminant IgAN and ANCA-associated disease and that ANCAs may be underdetected in children with previously diagnosed IgAN. Identification of these antibodies may guide further management of these patients.