Anti-phospholipase A2 Receptor Antibody and Immunosuppression in Membranous Nephropathy: More Evidence for Pathogenicity of Anti-phospholipase A2 Receptor Autoantibodies.

In the 6 years since the discovery of anti-phospholipase A2 receptor (anti-PLA2R) antibodies in the majority of patients with primary membranous nephropathy (MN),1 our understanding of the role of anti-PLA2R in clinical disease has evolved rapidly. The initial small retrospective clinical studies indicated that anti-PLA2R levels could be modulated by immunosuppression.1,2 Levels decreased in advance of levels of proteinuria, with most patients becoming anti-PLA2R seronegative over 6–9 months followed by remission of proteinuria over 12–24months. The EuropeanMN cohort study showed an association between high levels of anti-PLA2R and active disease at presentation with less chance of experiencing spontaneous remission.3 The Manchester study reported high anti–PLA2R levels linked to poor clinical outcome at 5 years.4 Using a standard immunosuppression protocol, Bech et al.5 have shown that failure to render patients anti-PLA2R seronegative by immunosuppression therapy is associated with high risk of relapse. Amulticenter study from Germany clearly confirms anti-PLA2R levels as an independent risk factor for not achieving remission of proteinuria.6 Importantly, delay in treatment to reduce anti-PLA2R may risk decline in renal function.7 These studies have benefited from ELISA assays4,8 developed in the last 3 years to provide sensitive, specific, and quantitative assays of anti-PLA2R, which are more appropriate than Western blotting for routine clinical assay. The major therapy for MN over the last 25 years has been nonspecific immunosuppression empiricallydeterminedusing combinations of cyclophosphamide and steroids. Because of a lack of a relevant biomarker of the immunopathology, remissionofproteinuria isused as thedominantoutcomemeasure. Although these potent nonspecific drugs may be effective in preventing disease progression in 60%–80% of patients, this comes at the cost of significant morbidity and mortality because of increased risks of infection, malignancy, and cardiovascular events. Most patients experience a remitting/relapsing disease, commonly requiring several courses of immunosuppression, with a subset of patients displaying resistance to immunosuppressive therapy. This experience indicates the need for improved treatment with targeted drugs and better therapy management on the basis of a relevant biomarker. Rituximab, a specific CD20 B cell–depleting mAb, is the first agent representing a new generation of targeted immunosuppressive therapy that has shown promising results in small studies in induction of remission of nephrotic syndrome in two thirds of patients with primary MN. The paper in this issue of JASN by Ruggenenti et al.9 is important, because it describes rituximab immunosuppression in a large series of 101 patients withMN treated in a standardizedway in a single center in the context of anti-PLA2R classification and monitoring. In this study by Ruggenenti et al.,9 outcomes of patients with or without detectable anti-PLA2Rs at baseline were similar. Current evidence suggests that anti-PLA2R antibodies are of high affinity.10 Can this property explain the outcome of patients who are seronegative? As anti-PLA2Rs are secreted and enter the blood circulation, they will bind to target receptors on podocytes and are effectively affinity adsorbed out of the circulation. In patients where the rate of anti-PLA2R production is low, it is possible that all anti-PLA2Rs are adsorbed by podocytes in this way to initiate MN pathology and proteinuria, but the patients seem to be seronegative for antiPLA2Rs. Only when the rate of kidney sequestration is less than the rate of anti-PLA2R productionwill the patient become seropositive. Previous studies have identified that almost 50% of patients with primary MN who are seronegative for antiPLA2Rs show PLA2R antigen in the glomerular basement membrane immune deposits.11 In this paper, Ruggenenti et al.9 did not classify kidney biopsy status for PLA2R, but this explanation may account for some patients who were seronegative and explain the patient who was originally seronegative but became seropositive postrelapse. Recently, another MN antigen, thrombospondin type 1 domain containing 7A insert, has been described that invokes an anti-thrombospondin type 1 domain containing 7A insert antibody that circulates in the blood that can be eluted from kidney biopsies and may Published online ahead of print. Publication date available at www.jasn.org.