To our knowledge, this is the first reported case of PLA2R-positive MN which subsequently developed IgG4-RD. It is quite difficult to distinguish whether this patient’s renal disease is primary MN or secondary MN related to IgG4-RD. It may simply be primary MN complicated later by IgG4-RD, which might suggest the presence of a common pathology between primary MN and IgG4-RD. Alternatively, it may be renal involvement that precedes other manifestations of IgG4-RD. In this regard, this case showed an atypical course for IgG4-related secondary MN in the following two respects: 1) glomerular staining for PLA2R was positive; and 2) MN alone preceded other manifestations of IgG4-RD.

At the onset of nephrotic syndrome, both the clinical course without extrarenal diseases and renal biopsy findings of PLA2R-positive MN without TIN strongly suggested a diagnosis of primary MN [8, 13]. Predominant deposition of IgG4 followed by IgG1 in IgG subclass staining was consistent with both primary MN and IgG4-related secondary MN [14]. The clinical course after the initial renal biopsy that showed partial remission of nephrotic syndrome with losartan may be explained by the effect of ARB, but it could be due to spontaneous resolution of primary MN.

Positive glomerular PLA2R staining is highly specific for the diagnosis of primary MN [8, 9], and actually, most cases of MN in the setting of IgG4-RD have been reported to be negative for PLA2R [6]. However, five cases have been reported to date in which PLA2R-positive MN developed during the course of IgG4-RD (Table 2) [14,15,16,17,18]. Although some of these cases may actually be PLA2R-associated primary MN unrelated to IgG4-RD, some features of these cases are uncommon for primary MN. For example, the presence of subendothelial and mesangial deposits on EM, observed in Case 5, is atypical for primary MN (Table 2) [9, 18]. Moreover, the favorable response of MN to steroid treatment for IgG4-RD observed in Case 5 and our case suggests that these are more likely to be IgG4-related secondary MN rather than primary MN. In fact, a certain number of PLA2R-positive cases are reported in secondary MN due to other diseases, including hepatitis B, hepatitis C, and sarcoidosis, possibly via inducing immune response to PLA2R [19]. For example, in sarcoidosis, a related disease of IgG4-RD, PLA2R-positive MN is frequently observed in active sarcoidosis, which suggests the existence of a causal relationship in which the immunological status of sarcoidosis may induce immunization against PLA2R [20]. As is the case with secondary MN associated with sarcoidosis, the possibility cannot be ruled out that there is PLA2R-positive secondary MN associated with IgG4-RD. Positive PLA2R on the second renal biopsy after the onset of IgG4-RD may suggest the possibility of PLA2R-positive secondary MN related to IgG4-RD.

Furthermore, this case of PLA2R positivity on both the initial and second renal biopsy suggests that renal damage at either time point has a common etiology. Regarding the onset of IgG4-related secondary MN, there have been several reports of rare cases in which the onset of MN precedes the onset of other symptoms of IgG4-RD, suggesting that MN can be an initial manifestation of IgG4-RD (Table 3) [21,22,23]. All three cases reported so far are predominantly positive for IgG4 by tissue staining and negative for PLA2R by serum or tissue staining, consistent with the characteristics of IgG4-related secondary MN. In these cases, time interval from the onset of MN to the onset of IgG4-RD ranges from 1 to 3 years, which is similar in this case. The clinical course of this case, in which the second biopsy showed worsening MN and new development of TIN compared with the first one, has been observed in Case 3 (Table 3). These three cases suggest that IgG4-RD may contribute to the pathogenesis of MN through some mechanism, even at a subclinical status.

The predominant subclass of antibodies to PLA2R is IgG4 and predominant deposition of IgG4 in the GBM is a well-known feature of PLA2R-associated primary MN. Although IgG4 anti-PLA2R antibodies have not been proven to be responsible for MN, recent studies have suggested the possible mechanisms of podocyte injury mediated by anti-PLA2R antibodies [24, 25]. IgG4-producing plasma cells by IgG4-RD may promote PLA2R antibody production, thereby contributing to the pathogenesis of PLA2R-associated MN.

In situations where PLA2R-positive MN and IgG4-RD coexist, given the possible involvement of IgG4-RD in the pathogenesis of PLA2R-associated primary MN, it is particularly difficult to completely discern whether MN is “primary” MN without any contribution form IgG4-RD or PLA2R-positive “secondary” MN contributed by IgG4-RD. When the responsiveness to steroid treatment suggests the contribution of IgG4-RD to the pathology of MN, as in this case, it may be necessary to perform maintenance therapy for assuming the contribution of IgG4-RD, even if PLA2R is positive.

In summary, the present case of PLA2R-positive MN preceding the onset of IgG4-RD highlighted the difficulty of distinguishing between primary and secondary MN in the presence of IgG4-RD. Although further studies are needed to clarify the relationship between PLA2R-positive MN and IgG4-RD, it may be worth keeping in mind that predisposition to IgG4-RD may be hidden in the background of a diagnosis of PLA2R-positive primary MN.