Aberrant IgA1 Glycosylation in IgA Nephropathy: A Systematic Review

Abstract

ObjectiveGalactose-deficient IgA1 was evaluated in patients with IgA nephropathy(IgAN) and controls in order to determine the predictive value of galactose-deficient IgA1 in cases of IgA nephropathy.MethodsPubMed, EMBASE, Cochrane central register of controlled trials, CNKI, CBM disc, and VIP database were searched to identify eligible studies that evaluated a difference in aberrant IgA1 glycosylation in IgAN patients compared with controls. A meta-analysis was conducted to evaluate the impact of galactose-deficient IgA1(Gd-IgA1) levels in different groups.ResultsA total of 22 studies (n = 1657) met inclusion criteria. The mean Newcastle-Ottawa Scale (NOS) score was 7.2 and ranged from 6 to 8. The standard mean difference(SMD) in the meta-analysis of 20 studies of the level of Gd-IgA1 in the serum and/or supernatant of cultured cells was higher in the IgAN group compared with healthy controls as well as in those with other renal diseases (SMD = 1.76, 95% CI = 1.18–2.34, P<0.00001; SMD = 1.05, 95% CI = 0.05–2.04, P = 0.04). The data synthesis suggested that IgAN patients had similar levels of serum Gd-IgA1, with no significant differences, compared with first-degree relatives and Henoch-Schonlein purpura nephritis (HSPN) patients (MD = 0.04, 95% CI = 0.00–0.08, P = 0.05; MD = -46.03, 95% CI = -217.70–125.64, P = 0.60). In addition, the combined MD of 5 studies indicated that there were no significant differences in Gd-IgA1 levels among patients with varying severities of IgAN (MD = 0.02, 95% CI = -0.02–0.05, P = 0.28).ConclusionsThe pooled evidence suggests that the level of Gd-IgA1 in the serum or supernatant of cultured cells from peripheral blood or tonsils may be a useful biomarker for predicting IgA nephropathy, though the level of Gd-IgA1 was not significantly associated with disease severity.

The Role of IgA in the Pathogenesis of IgA Nephropathy

“…It found no significant differences in the level of serum Gd-IgA1 between IgAN patients and their first-degree relatives. However, the level of serum Gd-IgA1 was found significantly higher in IgAN patients than in healthy controls or patients with other renal diseases, but the level of serum Gd-IgA1 was not associated with the disease severity [51].…”

Mesangial C4d Deposits in Early IgA Nephropathy

“…At present, these conditions have not been yet identified. Experimental evidence indicates that only degalactosylated IgA is able to activate the MBL pathway (10)(11)(12). This raises the hypothesis that both MBL deposits and activation of the complement via this pathway (and the ensuing C4d deposits) could be related to the degree of IgA1 glycosylation.…”

“…The current working model for the pathogenesis of IgAN indicates that, after mesangial deposition of galactose-deficient IgA1, IgA1/IgG, or IgA/IgA immune complexes, these deposits (via interaction with specific mesangial receptors or via direct activation of complement) induce activation, proliferation, increased mesangial matrix synthesis, and eventually, cell injury. Several studies have shown that mesangial IgA deposits can activate complement via two pathways that are not mutually exclusive (1,(8)(9)(10). In the majority of patients, the presence of mesangial IgA deposits colocalizes with C3 but not with IgG or C1q deposits, suggesting that activation occurs through the alternative pathway.…”

A cross-sectional analysis of clinicopathologic similarities and differences between Henoch-Schönlein purpura nephritis and IgA nephropathy

“…Histopathologically, IgAN is characterized by mesangial cell proliferation with IgA-IC deposition in the glomerular mesangium, which is indistinguishable from pathologic findings of HSPN [2,12,14]. Regarding the pathogenesis of IgAN, several studies that investigated aberrant IgA1 O-glycosylation indicated that galactose-deficient IgA1 (Gd-IgA1) plays a pivotal role in the progression of IgAN [15][16][17][18][19][20][21][22][23]. According to these studies, patients with IgAN have aberrant IgA1 molecules with a Gal deficiency of O-linked glycans in the hinge region, which indicates that Gd-IgA1 consists of terminal N-acetyl-galactosamine (GalNAc) or sialylated GalNAc [20][21][22][23].…”