Coexistence of Different Circulating Anti-Podocyte Antibodies in Membranous Nephropathy

Abstract

SummaryBackground and objectives The discovery of different podocyte autoantibodies in membranous nephropathy (MN) raises questions about their pathogenetic and clinical meaning. This study sought to define antibody isotypes and correlations; to compare levels in MN, other glomerulonephritides, and controls; and to determine their association with clinical outcomes.Design, setting, participants, & measurements Serum IgG 1 , IgG 3 , and IgG 4 against aldose reductase (AR), SOD2, and a-enolase (aENO) were measured at diagnosis in 186 consecutive MN patients, in 96 proteinuric controls (36 with FSGS, and 60 with IgA nephropathy), and in 92 healthy people recruited in four Italian nephrology units. Anti-phospholipase A2 receptor (PLA2r) and anti-neutral endopeptidase (NEP) IgG 4 were titrated in the same specimens. Association with 1-year follow-up clinical parameters was studied in 120 patients.Results IgG 4 was the most common isotype for all antibodies; IgG 1 and IgG 3 were nearly negligible. IgG 4 levels were positive in a significant proportion of MN patients (AR, 34%; SOD2, 28%; aENO, 43%). Antibody titers were higher in MN than in healthy and pathologic controls (P,0.005). Anti-NEP IgG 4 did not differ from normal controls (P=0.12). Anti-PLA2r IgG 4 was detected in 60% of patients and correlated with anti-AR, anti-SOD2, and anti-aENO IgG 4 (P,0.001). In MN patients negative for the whole antibody panel (20%), 1-year proteinuria was lower compared with patients with at least one antibody positivity (P,0.05).Conclusions Our data suggest that IgG 4 is the prevalent isotype for antibodies against cytoplasmic antigens of podocytes (AR, SOD2, aENO). Their levels were higher than in other proteinuric glomerulonephritides and in normal controls and were correlated with anti-PLA2r. Only baseline negativity for all known antibodies predicted lower 1-year proteinuria.

IgG subclass staining in renal biopsies with membranous glomerulonephritis indicates subclass switch during disease progression

“…[2][3][4] However, other potential antigens in primary/idiopathic membranous glomerulonephritis may also evoke an IgG4 response. [5][6][7][8] Also, one has to consider that the presence of an underlying condition, that can be associated with membranous glomerulonephritis, does not necessarily exclude the possibility of a primary membranous glomerulonephritis, particularly if the glomerular capillary deposits are IgG4 dominant (eg, a person with a malignancy or hepatitis B or C virus infection can have membranous glomerulonephritis independent of these conditions). Our data confirmed the already known fact that, in most biopsies with primary membranous glomerulonephritis, the glomerular deposits are IgG4 dominant.…”

“…3,4 However, PLA2R may not be the only target antigen in idiopathic membranous glomerulonephritis, because other recent studies described potential target antigens such as aldose reductase, superoxide dismutase, 5 aenolase 6 and bovine serum albumin, 7 however, with less prevalence. 8 Many patients with primary membranous glomerulonephritis have several types of circulating anti-podocyte antibodies at the same time but, among these antibodies, anti-PLA2R antibodies are the most prevalent. 8 These antibodies are primarily of the IgG4 subclass, which is consistent with the well-known finding that, in idiopathic membranous glomerulonephritis, the subepithelial immune complexes contain mostly IgG4.…”

“…8 Many patients with primary membranous glomerulonephritis have several types of circulating anti-podocyte antibodies at the same time but, among these antibodies, anti-PLA2R antibodies are the most prevalent. 8 These antibodies are primarily of the IgG4 subclass, which is consistent with the well-known finding that, in idiopathic membranous glomerulonephritis, the subepithelial immune complexes contain mostly IgG4. In contrast, several papers indicate that in secondary forms of membranous glomerulonephritis, the IgG subclass distribution is different from the primary form, and the deposits are frequently not IgG4 dominant.…”

Rituximab-based novel strategies for the treatment of immune-mediated glomerular diseases

“…There is also evidence that additional podocyte antigens, such as neutral endopeptidase (NEP) , aldose reductase (AR), SOD2 and α-enolase (α-ENO) may be the target of pathologic auto-antibodies in idiopathic membranous nephropathy [67], [68], [69] and [70]. A recent study examined the auto-antibody profile of 186 consecutive patients diagnosed with idiopathic membranous nephropathy [71], as well as of healthy controls and patients with other proteinuric diseases (FSGS and IgA nephropathy). Among patients with membranous nephropathy, 34% were positive for anti-AR, 28% for SOD2 and 43% for α-ENO (P < 0.001 for all comparisons).…”

Anti-phospholipase A2 receptor antibody in membranous nephropathy; an Indian experience

“…Lower prevalence in our study may be explained by the fact that we included patients with relapse and refractory disease in our study group. The anti-PLA 2 R negativity in these patients can be explained by the possible presence of other target antigens implicated in pathogenesis of idiopathic MN such as non-PLA 2 R podocyte antigens (25). Anti-PLA 2 R was negative in five patients with secondary MN, majority with SLE as the secondary cause.…”