Significance of glomerular IgG3 deposition in patients with primary membranous nephropathy

Primary membranous nephropathy (pMN) is an autoimmune glomerular disease characterized by subepithelial immune complex deposition, involving IgG4 dominant autoantibodies targeting podocyte antigens. Although glomerular IgG3 deposition has been identified in some cases of pMN, its clinical significance remains unclear. This was a retrospective cohort study. One hundred and eighty-nine patients with biopsy-proven pMN from Tianjin Medical University General Hospital between July 2021 and December 2022 were retrospectively enrolled. Clinical, laboratory, pathological features, and treatment outcomes were compared between patients with and without glomerular IgG3 deposition. The primary endpoint of this study was the remission of proteinuria, including complete remission (CR) and partial remission (PR). The deposition of IgG3 was detected by direct immunofluorescence. Among the 189 patients with pMN, glomerular IgG subclasses were observed as follows: IgG1 in 167 patients (88.4%), IgG2 in 25 (13.2%), IgG3 in 44 (23.3%) patients, and IgG4 in 185 (97.9%) patients. Compared to those without glomerular IgG3 deposition, patients with IgG3 deposition were significantly younger, exhibited a lower level of anti-phospholipase A2 receptor (PLA2R) antibodies and a lower level of urinary protein. Pathologically, they showed less glomerular segmental sclerosis, less IgG1 deposition and a lower positivity rate of PLA2R expression. During a median follow-up of 20 months, Kaplan-Meier analysis showed that patients with IgG3 deposition achieved higher rates of both renal remission (log-rank, P = 0.005) and complete remission (log-rank, P = 0.011), particularly among those with stronger IgG3 staining. Multivariate Cox analysis identified IgG3 deposition was associated with cumulative remission (HR = 1.998, P = 0.020) and complete remission (HR = 1.065, P = 0.002), with high anti-PLA2R antibody level, and urinary protein identified as independent risk factors. Compared with patients without renal IgG3 deposition, patients with renal IgG3 deposition had higher levels of total IgG3 and IgG3 subclass anti-PLA2R antibodies in blood, but lower levels of total IgG1 and IgG1 subclass anti-PLA2R antibodies. The ability of blood anti-PLA2R antibodies to activate complement was slightly higher but without statistical significance. Within the cohort of the current study, patients with pMN with renal IgG3 deposition did not show more severe clinical manifestations, which might be related to the lower total autoantibody levels in the blood.