Antiphospholipase A2 receptor autoantibody guided diagnosis and treatment of membranous nephropathy: a new personalized medical approach.

Medical care is entering into a new phase of “personalized” medical care in which diagnosis and management are tailored to the specific aspects of individual patients. This approach is often guided by the results of sophisticated biomarkers of disease, prognosis, or treatment responsiveness. In this issue of CJASN, Bech and coworkers from the Radboud University Medical Center (Nijmegen, The Netherlands) and Manchester Institute of Nephrology (Manchester, UK) describe their findings from an observational, prospective study of the clinical utility of measurement of antiphospholipase A2 receptor autoantibody (aPLA2R) in a cohort of patients with presumed primary (idiopathic) membranous nephropathy (iMN) and nephrotic syndrome (1). This study builds on the nowwell known and ground-breaking studies that defined a pathogenic role of such autoantibodies in iMN, described by Beck et al. in 2009 (2). This new study is particularly timely because the US Food and Drug Administration recently approved the commercial sale of assays (indirect immunofluorescence assay [IFA] and ELISA, Euroimmun, Morris Plains, NJ) for circulating aPLA2R onMay 29 and June 27, 2014 (3). Similar assays have previously been approved for use in Europe. Thus, the stakes for resolving uncertainties regarding application ofmeasurements of aPLA2R in iMN have escalated considerably, and the pace of investigation in this arena of disease serology has dramatically quickened. Because of the novelty of this emerging area of study, it is not surprising that many questions surround the precise role of such aPLA2R measurements in patients with nephrotic syndrome in general and specifically in those with membranous nephropathy (MN), either idiopathic or secondary. Two authors of the current study have recently outlined the general nature of these uncertainties (4): (1)Which assay for aPLA2R is best? (2) Can an aPLA2R measurement be used to diagnose iMN without resort to renal biopsy? (3) Can an aPLA2R assay accurately separate iMN from secondary forms of MN? (4) Can quantification of aPLA2R predict outcome or guide the treatment of iMN? In addition, they address the potential value of combining aPLA2R measures and PLA2R antigen staining of renal biopsy specimens in the diagnosis of iMN. For the sake of completeness, another poorly understood issue that needs mention andmuch further study is the role of aPLA2R measurements in assessing the risk and the course of recurrence of iMN in renal allografts. Bech and colleagues’ study was sharply focused on the utility of preand post-treatment assays of aPLA2R on shortand long-term outcomes (mainly remissions andrelapsesofproteinuriaduringandafter treatmentwith alkylating agents [cyclophosphamide], mycophenolate mofetil [MMF], or rituximab) in iMN. It is noteworthy that none of the patients included in this study received calcineurin inhibitors, at least initially, perhaps because of the potential for adverse events in patients with reduced renal function. The study size was relatively small (48 patients), and most of the study sample consisted of “high-risk” patients with impaired renal function and/or high-grade proteinuria and severe nephrotic syndrome.Whether the results apply equally to patients with milder disease is unknown. However, the prolonged follow-up (up to 5 years) was a real strength of the study. An ELISA was used to quantify aPLA2R, so the relevance of these findings to results from the IFAwill need to be confirmed. Although there is generally a high degree of concordance between the ELISA and IFA results for aPLA2R, discordant results can occasionally be observed (5,6). The key findings of this preliminary but valuable study is that aPLA2R, while commonly found at the discovery of iMN (sensitivity of about 70%), does not reliably predict the initial response to treatment, regardless of the agent used, even though an alkylating agent regimenwasmore effective thanMMF in quickly reducing the aPLA2R levels. As in other studies, the authors confirmed that the aPLA2R levels decline before the development of remissions of proteinuria and that such remissions candevelopweeksormonths after the discontinuation of treatment (7–9). Perhaps most important, the level of aPLA2R at the end of treatment predicted the long-term outcomes. According to a Kaplan–Meier analysis, about 55% of patients who were PLA2R negative at the completion of therapy remained in remission for 5 years, compared with none in remission at 2 years after completion of treatment in the aPLA2R-positive group (see Figure 2 in Bech and colleagues’ paper). Department of Medicine, Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California