Antibodies Against M-Type Phospholipase Receptor and Prediction of Outcome in Membranous Nephropathy: We are Not There Yet

In 2009, Beck et al. [1] identified the M-type phospholipase receptor (PLA2R) as major antigen involved in membranous nephropathy. Antibodies against this protein, which is expressed on podocytes, were present in 70% of patients with idiopathic membranous nephropathy. The role of PLA2R was supported by a genome-wide association study that found an association between the PLA2R gene and the development of membranous nephropathy. However, proof of the pathogenicity of PLA2Rantibodies (PLA2Rab) is lacking in the absence of an appropriate animal model (mice and rats do not express PLA2R on podocytes). Still, the discovery of PLA2Rab and the subsequent development of a commercial qualitative immunofluorescence test (IFT) boasted clinical research. Many studies confirmed the presence of PLA2Rab in up to 80% of patients with membranous nephropathy. The presence of PLA2Rab is very specific for membranous nephropathy, thus allowing to diagnose membranous nephropathy without the need for kidney biopsy [2]. The development of quantitative ELISA assays (in house and commercial) stimulated studies that evaluated the role of antibody levels in predicting disease outcome. The data were promising and indeed suggested that measurement of PLA2Rab might be of added value. Patients with high antibody levels at baseline were unlikely to develop spontaneous remission [3]. Similarly, in a study of rituximab treatment high antibody levels were associated with poor response [4]. Many studies provided support for the notion that PLA2Rab levels could predict outcome. Unfortunately, most studies were retrospective, biased, and of limited size. Zhang et al. [5] evaluated the value of the presence and the level of PLA2Rab to predict disease outcome in a large patient cohort, who were followed up at Peking University first Hospital. The study included 359 patients, recruited in the period from January 2004 to December 2016. The authors conclude that both the presence as well as the level of PLA2Rab were independent predictors of remission. At first sight, these data derived from an unprecedented large patient cohort support implementation of quantitative measurement of PLA2Rab in clinical practice. However, a cautious note is needed, and early conclusions are not allowed. The manuscript clearly illustrates the difficulties of PLA2Rab predictor studies in membranous nephropathy.