IgA nephropathy

Definition: IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide, but its etiologic mechanisms are still poorly understood.

Synopsis

 focal mesangial cells hyperplasia (focal areas of increased cell proliferation in mesangium)

• minimal increase in mesangial matrix and cells
• moderate diffuse mesangial expansion
• mesangial enlargement (excess of matrix and mesangial hypercellularity)

 glomerular segmental sclerosis
 membrano-proliferative glomerulonephritis
 necrotizing alterations of glomerular tuft with segmental extracapillary proliferation (similar to capillaritis of Henoch-Schonlein purpura and ANCA associated vasculitis)
 tubulo-interstitial lesions

• leukocyte infiltration
• intersitial fibrosis

 IgA deposits in the mesangium

• mesangial and/or mesangioparietal deposition of IgA as the predominant or sole immunoglobulin

Ultrastructure

 mesangial electron dense deposits
 increased mesangial matrix
 increased mesangial cellularity

Differential diagnosis

 Henoch-Schönlein purpura

• crescents are more frequent in biopsied Henoch-Schönlein purpura than in IgA nephropathy

Susceptibility

IgAN is associated with variants near genes involved in innate immunity and inflammation.

 locus IGAN1 at 6q22-23
 locus at 4q26-31 (17186473)
 locus at 17q12-22 (17186473)

 17p13 (rs3803800)
 8p23 (rs2738048) (implicated the genes encoding tumor necrosis factor (TNFSF13) and α-defensin (DEFA) as susceptibility genes).
 multiple associations in the major histocompatibility complex (MHC) region (rs660895, rs1794275, rs2523946)
 22q12 (rs12537).
 rs660895 is associated with clinical subtypes of IgAN, proteinuria and IgA levels.

Reviews

 Lai AS, Lai KN. Molecular basis of IgA nephropathy. Curr Mol Med. 2005 Aug;5(5):475-87. PMID: 16101476

 Donadio JV, Grande JP. IgA nephropathy.
N Engl J Med. 2002 Sep 5;347(10):738-48. PMID: 12213946

 Monteiro RC, Moura IC, Launay P, Tsuge T, Haddad E, Benhamou M, Cooper MD, Arcos-Fajardo M. Pathogenic significance of IgA receptor interactions in IgA nephropathy. Trends Mol Med. 2002 Oct;8(10):464-8. PMID: 12383768

 Ferrario F, Rastaldi MP, Napodano P. Morphological features in IgA nephropathy. Ann Med Interne (Paris). 1999 Feb;150(2):108-16. PMID: 10392259

References

 A genome-wide association study in Han Chinese identifies multiple susceptibility loci for IgA nephropathy. Yu XQ, Li M, Zhang H, Low HQ, Wei X, Wang JQ, Sun LD, Sim KS, Li Y, Foo JN, Wang W, Li ZJ, Yin XY, Tang XQ, Fan L, Chen J, Li RS, Wan JX, Liu ZS, Lou TQ, Zhu L, Huang XJ, Zhang XJ, Liu ZH, Liu JJ. Nat Genet. 2011 Dec 25. PMID: 22197929

 Bisceglia L, Cerullo G, Forabosco P, Torres DD, Scolari F, Di Perna M, Foramitti M, Amoroso A, Bertok S, Floege J, Mertens PR, Zerres K, Alexopoulos E, Kirmizis D, Ermelinda M, Zelante L, Schena FP; European IgAN Consortium.Genetic heterogeneity in Italian families with IgA nephropathy: suggestive linkage for two novel IgA nephropathy loci.Am J Hum Genet. 2006 Dec;79(6):1130-4. PMID: 17186473