Phospholipase A2 receptor antibodies in membranous nephropathy: unresolved issues.

The discovery of theM-type phospholipase A2 receptor (PLA2R) as a major antigen in idiopathic membranous nephropathy (iMN) was a breakthrough and established iMN as an autoimmune disease.1 Subsequent studies confirmed that antibodies against PLA2R were present in approximately 70% of incident iMN patients (reviewed by Hofstra and Wetzels2). The potential role ofmeasuring PLA2R antibodies for clinical practice was suggested by studies showing that the presence of PLA2R antibodies supported a diagnosis of iMN,2–4 changes in antibody levels paralleled clinical disease activity,5 disappearance of antibodies preceded and predicted subsequent decrease of proteinuria,6 and high titers of antibodies were associated with a low likelihood of spontaneous remission.7 In this issue of JASN, Hoxha et al. report their findings in a large cohort of 163 patients with MN.8 PLA2R antibodies (both IgG and IgG4) were measured in serum obtained within 6 months from kidney biopsy. The authors used an ELISA assay and immunofluorescence testing (IFT) (both commercially available in Europe).9 PLA2R antibodies were detected in 133 patients (82%). The median follow-up was 12 months, and the majority of patients (101 of 133) started immunosuppressive therapy within 3 months after presentation. Hoxha et al. show that PLA2R antibodies decreased during follow-up. The decrease in PLA2R antibodies preceded the decrease in proteinuria. The authors concluded that “there was a remarkable time lag between the rather rapid fall in antibody levels at 3 months and the protracted reduction in proteinuria.”8 These data confirm earlier findings and indicate that an immunologic remission precedes clinical remission in patients with iMN.6,10 Although no PLA2R antibodies were found in patients with complete remission, PLA2R antibodies were still present in a low titer in 50% of patients with a partial remission. These data indicate that a partial remission may not always reflect the absence of disease activity. The authors next analyzed the association between antibody levels at baseline and remission at 12 months after presentation. PLA2R antibody levels were significantly higher in 28 patients without remission than in 39 patients with remission. The median time to remission was significantly longer in patients with antibody levels above versus below the median (15 versus 9 months). The authors concluded that the PLA2R antibody level was “an independent risk factor for not achieving remission.”8 Such a conclusion, if valid and applicable to untreated patients, could improve individualized patient care. However, the data from the study by Hoxha et al. do not allow to conclude that antibody levels can help to accurately identify patients whowill develop a spontaneous remission because most of Hoxha’s patients were treated. Moreover, because treated patients nearly all developed a remission, the antibody levels merely predicted the time to remission. Although their patient cohort is large, the study by Hoxha et al. is limited because of the relatively short follow-up period, the use of various immunosuppressive treatment regimens, and the unnecessary early start of immunosuppressive therapy in many patients. The reported findings cannot change current guidelines for diagnosis and treatment of patients with iMN. Evidently, more rigid study protocols are needed to reliably answer the most relevant questions. Certainly, Hoxha et al. could perform additional analyses to answer some of the following unresolved questions.