Fervenza, Fernando C.

ABSTRACT Background Membranous nephropathy (MN) is a leading cause of nephrotic syndrome (NS). Since the identification of anti–phospholipase A2 receptor (anti-PLA2R) antibodies in 2009, the use of laser microdissection and tandem mass spectrometry (LMD/MS) has allowed the discovery of several target antigens in MN. Methods In this retrospective cohort study, adult patients evaluated at the Division of Nephrology at Brotzu Hospital (Cagliari, Italy) with biopsy-proven MN and a negative serological test for anti-PLA2R antibody underwent LMD/MS, performed at the Department of Laboratory Medicine and Pathology of Mayo Clinic (Rochester, MN, USA). Results Twenty-four cases of biopsy-proven MN were available for antigen detection by LMD/MS studies. High total spectral counts of PLA2R were detected in 12 out of 24 (50%) cases. In addition, high spectral counts of THSD7A and NELL1 were detected in two cases each, and EXT1/EXT2 and NCAM1 in one case each. Five putative antigens have been detected: SULF1, PGLYRP, HYAL1, THBS and SEZ6L2. Conclusions Our study highlights at least two interesting considerations. First, the determination of PLA2R on renal tissue in the diagnosis of PLA2R-associated MN is emphasized since 50% of our cases were falsely diagnosed with PLA2R-negative MN based on the serum anti-PLA2R antibodies determination. Second, our study shows six patients with MN likely associated with putative antigens, two of them showing new antigens never described before in literature (HYAL1 and THBS1). This high prevalence of putative antigens in our cohort is not easily explainable and paves the way for evaluating specific factors in the Sardinian population that could explain this evidence.

Key Points In phospholipase A2 receptor-membranous nephropathy, clinical variables and antibody levels over 3 or 6 months of treatment were predictors of remission at 1 year. Prediction models at 3 and 6 months had similar performance predicting remission, with the 3-month model allowing for earlier assessment of response. The 3-month and 6-month prediction models could be applied in those treated with supportive therapy, rituximab, calcineurin inhibitors, or cyclophosphamide. Background In patients with antiphospholipase A2 receptor antibody–associated membranous nephropathy, there is currently no accepted method to predict an individual's probability of remission after treatment with immunosuppression or supportive therapy using changes in antibody levels and clinical variables during the first 3–6 months of therapy. Methods Using a cohort of 187 patients from the Glomérulopathie extramembraneuse rituximab, Membranous Nephropathy Trial of Rituximab, and Sequential Treatment with Tacrolimus and Rituximab Versus Alternating Corticosteroids and Cyclophosphamide in primary Membranous Nephropathy clinical trials with antibody levels at baseline ≥14 RU/ml, we derived logistic regression models to predict proteinuria remission at 12 months that can be used at baseline or after 3 or 6 months of treatment. Treatment exposures in the trials included supportive therapy, rituximab, calcineurin inhibitors, and cyclophosphamide. Predictors in the models included male sex and baseline and changes in serum albumin, proteinuria, and antibody levels, with or without changes in eGFR. Results Proteinuria remission at 12 months was achieved in 107 patients. Compared with the model at baseline, the 3-month and 6-month models had better model fit with lower Akaike information criterion (186/158 versus 225) and higher R 2 (52.7%/62.4% versus 25.8%), better discrimination with higher C-statistic (0.87 and 0.91 versus 0.75, P < 0.001), and better calibration with lower integrated calibration index (0.89%/2.22% versus 2.51%). The 3-month and 6-month models had no consistent difference in prediction performance, and decision curve analysis demonstrated similar net benefit for treatment decisions based on either model up to a threshold probability of 31%. Prediction performance was similar after internal validation using optimism correction. Prediction performance was maintained within subgroups of different treatment regimens, including supportive therapy, rituximab, calcineurin inhibitors, and cyclophosphamide. Conclusions Either the 3-month or 6-month models can be used in patients with antiphospholipase A2 receptor antibody associated membranous nephropathy after 3 or 6 months of treatment with a variety of immunosuppression or supportive therapy to predict remission status at 12 months.

Purpose of review Pioneering contributions in membranous nephropathy over the last decade have greatly enhanced our comprehension of its pathogenesis, diagnosis, and treatments, igniting renewed interest in this entity. This review provides an updated perspective on the diagnosis and therapeutic management of membranous nephropathy. Recent findings The identification of antiphospholipase A2 receptor (PLA2R) antibodies in 50–80% of membranous nephropathy patients was a key breakthrough. High or increasing PLA2R antibody levels are linked to persistent nephrotic syndrome and the need for targeted treatment. Given the high specificity of PLA2R antibodies, a kidney biopsy may not be required for pure nephrotic syndrome cases with no comorbidities. Over the years, various target antigens and associated conditions have been identified in membranous nephropathy patients, leading to a reclassification of membranous nephropathy. Treatment approaches vary based on baseline characteristics and changes in proteinuria and PLA2R titers. Rituximab has emerged as the first-line therapy for most patients without severe risk factors, with other emerging therapies under development. Summary Advances in the diagnosis and treatment of membranous nephropathy have moved the management towards a more precision-based approach, though further studies and new therapies are needed for a comprehensive management strategy.