IgA nephropathy pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Ali Poyan Mehr, M.D. [2]Associate Editor(s)-in-Chief: Olufunmilola Olubukola M.D.[3]
Overview
IgA nephropathy is characterized by the presence of aberrant IgA1 immunoglobulins deposited on the glomerular mesangium. IgG and IgM may also be present to a much lower extent. On the other hand, serum IgA1 levels are elevated in patients with IgA nephropathy in 30-50% of cases. IgA1 subtypes contain galactose-deficient 3-6 O-glycans that may act as binding sites for anti-N-acetyl-galactosamine antibodies. These antibodies have been shown to be expressed following antigenic exposure to certain infectious agents. Currently, IgA nephropathy is believed to be a 4-hit process that eventually leads to IgA deposition on glomerular mesangium. Although mesangial deposition is most commonly seen in patients with IgA nephropathy, other pathological features might still be present.
Pathophysiology
IgA nephropathy is characterized by the presence of IgA1 deposits along the glomerular mesangium, in addition to complement C3, and properidin that are concomitantly present in almost all cases of IgA nephropathy.
The presence of increased IgA1 in IgA nephropathy has clear pathological implications due to the characteristic morphology of IgA1 subclass. Serum IgA1 levels are increased in 30-50% of patients with IgA nephropathy. The elevated serum levels of IgA1 in such patients is currently believed to be genetically determined. IgA1 contains a unique hinge region at a location of the immunoglobulin heavy chain between the first and second constant region domains.[1] The location is described to be rich in serine and threonine; the abundance of these amino acids at the specific site is likely to facilitate the attachment of 3-6 O-glycans, deficient in galactose, to the IgA.[1][2][3][4] Nonetheless, genetic predisposition and aberrant glycosylation do not seem to sufficiently cause IgA nephropathy alone. In fact, J chain-containing IgA, IgM, and IgG antibodies against the galactose-deficient IgA1 are also needed for the pathogenesis of IgA.[1][5] These antibodies bind specifically to the N-acetylgalactosamine (GalNAc) residues of the IgA1 antibodies at the O-linked glycans of the hinge region in the heavy chain. This process is then followed by the accumulation of the formed immune complexes in the mesangial cells.[1] Finally, activated mesangial cells induce renal injury by the production and secretion of extracellular matrix, and pro-inflammatory cytokines and chemokines.[1]
Several organisms and viruses may produce GalNAc on their surface, which may be the underlying etiology to the development of anti-GalNAc antibodies.[5] Respiratory-syncitial virus (RSV), Epstein-Barr virus (EBV), Herpes virus, and several strains of streptococci are all examples of infectious agents that express GalNAc epitopes. Induced antibodies released during an active infection most likely recognizes and reacts with GalNac terminals found at O-linked glycans of IgA1 antibodies in the galactose-deficient hinge region.[5]
The pathogenesis of IgA nephropathy is thus described by Suzuki and colleagues[1] as a 4-hit hypothesis that is summarized in the image below:
(Adapted from Suzuki H, Kiryluk K, Novak J, et al. The pathophysiology of IgA nephropathy. J Am Soc Nephrol. 2011; 22(10):1795-803)
The presence of IgG and/or IgM deposits has been observed to be frequently present[6], whereas complement C4, C4d[7], mannose-binding lectin[8], and C5b-C9[9] have also been detected to a much less extent.
Ultimately, IgA nephropathy may have any of the following 6 findings on light microscopy (in increasing order of severity):
- Normal appearing biopsy
- Focal mesangial hypercellularity
- Diffuse mesangial hypercellularity
- Focal proliferative glomerulonephritis
- Diffuse proliferative glomerulonephritis
- Chronic sclerosing glomerulonephritis
On electron microscopy, mesangial deposits are most commonly seen. However, depositions on capillary walls are possible; they herald worse prognosis.
The following variations may also be found; but they are not exclusive of IgA nephropathy[10]:
- Segmental endocapillary proliferation
- Segmental Glomerulosclerosis and adhesions
- Tubular atrophy and interstitial fibrosis
- Glomerular crescent surrounding the glomerular tuft
IgA frequently recurs following transplantation whereas IgA deposits in donor kidneys tend to usually resolve following recipient engraftment.[11] Both phenomena raise the suspicion of IgA nephropathy being in fact a systemic disease with renal manifestations than an isolated renal disease.[10]
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Suzuki H, Kiryluk K, Novak J, Moldoveanu Z, Herr AB, Renfrow MB; et al. (2011). "The pathophysiology of IgA nephropathy". J Am Soc Nephrol. 22 (10): 1795–803. doi:10.1681/ASN.2011050464. PMID 21949093.
- ↑ Allen AC, Harper SJ, Feehally J (1995). "Galactosylation of N- and O-linked carbohydrate moieties of IgA1 and IgG in IgA nephropathy". Clin Exp Immunol. 100 (3): 470–4. PMC 1534466. PMID 7774058.
- ↑ Odani H, Yamamoto K, Iwayama S, Iwase H, Takasaki A, Takahashi K; et al. (2010). "Evaluation of the specific structures of IgA1 hinge glycopeptide in 30 IgA nephropathy patients by mass spectrometry". J Nephrol. 23 (1): 70–6. PMID 20091489.
- ↑ Novak J, Julian BA, Mestecky J, Renfrow MB (2012). "Glycosylation of IgA1 and pathogenesis of IgA nephropathy". Semin Immunopathol. 34 (3): 365–82. doi:10.1007/s00281-012-0306-z. PMID 22434325.
- ↑ 5.0 5.1 5.2 Tomana M, Novak J, Julian BA, Matousovic K, Konecny K, Mestecky J (1999). "Circulating immune complexes in IgA nephropathy consist of IgA1 with galactose-deficient hinge region and antiglycan antibodies". J Clin Invest. 104 (1): 73–81. doi:10.1172/JCI5535. PMC 408399. PMID 10393701.
- ↑ Berthoux F, Suzuki H, Thibaudin L, Yanagawa H, Maillard N, Mariat C; et al. (2012). "Autoantibodies targeting galactose-deficient IgA1 associate with progression of IgA nephropathy". J Am Soc Nephrol. 23 (9): 1579–87. doi:10.1681/ASN.2012010053. PMC 3431415. PMID 22904352.
- ↑ Espinosa M, Ortega R, Gómez-Carrasco JM, López-Rubio F, López-Andreu M, López-Oliva MO; et al. (2009). "Mesangial C4d deposition: a new prognostic factor in IgA nephropathy". Nephrol Dial Transplant. 24 (3): 886–91. doi:10.1093/ndt/gfn563. PMID 18842673.
- ↑ Roos A, Rastaldi MP, Calvaresi N, Oortwijn BD, Schlagwein N, van Gijlswijk-Janssen DJ; et al. (2006). "Glomerular activation of the lectin pathway of complement in IgA nephropathy is associated with more severe renal disease". J Am Soc Nephrol. 17 (6): 1724–34. doi:10.1681/ASN.2005090923. PMID 16687629.
- ↑ Miyamoto H, Yoshioka K, Takemura T, Akano N, Maki S (1988). "Immunohistochemical study of the membrane attack complex of complement in IgA nephropathy". Virchows Arch A Pathol Anat Histopathol. 413 (1): 77–86. PMID 3131958.
- ↑ 10.0 10.1 Wyatt RJ, Julian BA (2013). "IgA nephropathy". N Engl J Med. 368 (25): 2402–14. doi:10.1056/NEJMra1206793. PMID 23782179.
- ↑ Silva FG, Chander P, Pirani CL, Hardy MA (1982). "Disappearance of glomerular mesangial IgA deposits after renal allograft transplantation". Transplantation. 33 (2): 241–6. PMID 7036478.