Combined evaluation of glomerular phospholipase A2 receptor and immunoglobulin G subclass in membranous nephropathy

Abstract

Background: Phospholipase A2 receptor (PLA2R) is a major target antigen in idiopathic membranous nephropathy (MN). Anti-PLA2R antibodies are mainly of the immunoglobulin G (IgG) subclass IgG4, although other IgG subclass depositions in glomeruli may also be detected. However, the importance of the subclass of the IgG deposit has not been proven. Thus we investigated clinical findings from patients with idiopathic MN in relation to glomerular PLA2R deposition and IgG subclass.

Methods: We enrolled 132 Japanese patients with biopsy-proven idiopathic MN in a multicentre retrospective observational study. We investigated the complete remission rate as the primary outcome and the development of end-stage kidney disease (ESKD) as the secondary outcome in relation to glomerular PLA2R deposition. Moreover, we evaluated prognostic factors, including glomerular IgG subclass, in the PLA2R-positive group.

Results: The percentage of cases with glomerular PLA2R deposition was 76.5% (n = 101). The first complete remission rate of the PLA2R-positive group was worse than that of the PLA2R-negative group (logrank test P < .001). ESKD incidence did not significantly differ between the glomerular PLA2R-negative and PLA2R-positive MN groups (logrank test P = .608). In the PLA2R-positive group, higher PLA2R intensities and IgG2 staining were associated with a poorer first complete remission rate (logrank test P < .001 and P = .032, respectively). Cox proportional hazards analysis also showed that strong PLA2R deposition and positive IgG2 staining were significantly associated with a failure to reach complete remission [hazard ratio 2.09 (P = .004) and 1.78 (P = .030), respectively].

Conclusions: Our results suggest that intense glomerular PLA2R and IgG2 positivity predict a poor proteinuria remission rate in idiopathic MN.

Keywords: complement; immunoglobulin G subclass; membranous nephropathy; oligosaccharide; phospholipase A2 receptor.

Graphical Abstract

Figure 1:

Confocal light microscopy images demonstrating the co-localization of PLA2R with total IgG and specific IgG subclasses. (A–D) Images show co-localization of PLA2R and whole IgG: (A) DAPI, (B) IgG, (C) PLA2R, (D) Merge. (E–H) Images show co-localization of PLA2R and IgG1: (E) DAPI, (F) IgG1, (G) PLA2R, (H) Merge. (I–L) Images show co-localization of PLA2R and IgG2: (I) DAPI, (J) IgG2, (K) PLA2R, (L) Merge. (M–P) Images show co-localization of PLA2R and IgG3: (M) DAPI, (N) IgG3, (O) PLA2R, (P) Merge. (Q–T) Images show co-localization of PLA2R and IgG4: (Q) DAPI, (R) IgG4, (S) PLA2R, (T) Merge. DAPI: 4′,6-diamidino-2-phenylindole.

Figure 2:

Differences in remission rate according to the presence of glomerular PLA2R staining. (A) Kaplan–Meier analysis of the first complete remission rates of the glomerular PLA2R-positive MN group and the glomerular PLA2R-negative MN group. (B) The bar chart shows the rates of partial and complete remission at 1 month, 6 months, 1 year, 3 years and 5 years after renal biopsy for the PLA2R-negative and PLA2R-positive MN groups. CR: complete remission; PR: partial remission; NR: no remission.

Figure 3:

Association between glomerular PLA2R staining intensity and proteinuria remission rate. (A) Kaplan–Meier analysis of the first complete remission rates in each group with negative, 1+ and ≥2 glomerular PLA2R intensity. (B) The bar chart shows the rates of partial and complete remission for the entire observation period stratified by the intensity of glomerular PLA2R staining. (C) The bar chart shows the distribution of the evaluations of PLA2R intensity for each of the three observers in the interobserver reproducibility analysis. CR: complete remission; PR: partial remission; NR: no remission.

Figure 4:

Difference in urinary protein remission rate according to IgG subclass staining in patients with glomerular PLA2R-positive MN. (A) In the glomerular PLA2R-positive MN group, Kaplan–Meier analysis of the first complete remission rates of the glomerular IgG2-negative and positive MN groups. (B) In the glomerular PLA2R-positive MN group, Kaplan–Meier analysis of the first complete remission rates of the glomerular IgG3-negative and positive MN groups.