Background: Immunoglobulin A nephropathy (IgAN) can exist as a primary glomerulonephritis (GN) or in association with various clinical conditions, suggesting that it could include several heterogeneous disorders. The familial form of IgAN has been increasingly recognized, supporting the suggestion that genetic factors could be involved in the disease pathogenesis, although it remains unclear whether the familial form is itself heterogeneous.
Methods: This study included 24 patients with a biopsy-proven IgAN from 11 unrelated families coming from five geographically distinct regions of Italy, and 90 of their relatives investigated for the presence of nephritis. Families were included in a genome-wide linkage analysis to identify loci responsible for the disease.
Results: Liver or systemic disease was not found in any case, and no hearing loss or ocular alterations were detected. Renal biopsy showed mesangial expansion at light microscopy, with glomerular sclerosis involving from 11 to 35% of glomeruli in eight patients. Ultrastructural examination revealed mesangial electron dense deposits along with a diffuse glomerular basement membrane (GBM) thinning typical of thin basement membrane disease (TBMD) in eight patients belonging to six families. Of the 90 relatives, 12 had "suspected IgAN", 73 were defined as "unaffected" and five as "probably unaffected". Families with co-existent TBMD failed to link to the IGAN1 locus. After a follow-up of 3-19 yrs, nine patients (37%) showed a progressive reduction in renal function and five of them reached end-stage renal disease (ESRD).
Conclusion: These data demonstrate that familial IgAN is present outside geographically confined regions of Italy. Co-aggregation of IgAN with TBMD suggests that familial IgAN itself is a heterogeneous disorder and that inherited GBM abnormalities could be the first alteration, in some cases.