Advances in Membranous Nephropathy

Abstract

Membranous nephropathy (MN) is a rare auto-immune disease where the glomerulus is targeted by circulating auto-antibodies mostly against podocyte antigens, which results in the formation of electron-dense immune complexes, activation of complement and massive proteinuria. MN is the most common cause of nephrotic syndrome in adults leading to severe thrombotic complications and kidney failure. This review is focused on the recent therapeutic and pathophysiological advances that occurred in the last two years. For a long time, we were lacking a head-to-head comparison between cyclophosphamide considered as the gold standard therapy and other medications, notably rituximab. Substantial progress has been achieved owing to three randomized controlled trials. MENTOR (Membranous Nephropathy Trial of Rituximab) and STARMEN (Sequential Therapy with Tacrolimus and Rituximab in Primary Membranous Nephropathy) conclusively established that calcineurin inhibitor-based regimens are slower to result in an immunologic response than rituximab or cyclophosphamide, achieve fewer complete clinical remissions, and are less likely to maintainremission. Rituximab Versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy (RI-CYCLO) suggested that competition between cyclophosphamide and rituximab remains open. Given the technological leapcombining laser microdissection of glomeruli and mass spectrometry of solubilized digested proteins, four “new antigens” were discovered including NELL-1 and Semaphorin 3B in so-called primary MN, and exostosins 1 and 2 and NCAM 1 in lupus MN. NELL-1 is associated with about 8% of primary MN and is characterized by segmental immune deposits and frequent association with cancer (30%). Semaphorin 3B-associated MN usually occurs in children, often below the age of two years, where it is the main antigen, representing about 16% of non-lupus MN in childhood. Exostosins 1/2 and NCAM 1 are associated with 30% and 6% of lupus MN, respectively. Exostosins 1/2 (EXT1/2) staining is associated with a low rate of end-stage kidney disease (ESKD) even in mixed classes III/IV+V. These findings already lead to revisiting the diagnostic and therapeutic algorithms toward more personalized medicine.

Helper T Cells in Idiopathic Membranous Nephropathy

“…In 2009, Beck et al (1) discovered the podocyte autoantigen, i.e., M-type receptor of secretory phospholipase A2 1 (PLA2R1), in the immune deposits of IMN, providing a key evidence of IMN as an autoimmune disease. Later, in addition to PLA2R, more IMN antigens were identified, including thrombospondin type-1 domain-containing 7A (THSD7A), neural epidermal growth factor-like 1 protein (Nell-1), and semaphorin 3B (sema3B), which were all self-components of podocytes (2). In recent years, the incidence of IMN has been increasing year by year, making it the most common primary glomerular disease (3).…”

A Fresh Perspective on Monoclonal Gammopathies of Renal Significance

“…To this point, anti-CD20 antibodies or proteasome inhibitors have shown efficacy in treating a variety of autoimmune conditions in which the disease-causing antibodies are polyclonal, such as membranous nephropathy, lupus nephritis, and refractory immune-mediated thrombocytopenic purpura. 44 , 45 Optimal evidence of the indisputable monoclonal nature of Ig deposits is definitely a prerequisite to guide therapy in MGRS, at least in the absence of a corresponding circulating monoclonal Ig. A crucial issue remains whether the pathogenic clone is truly malignant or emerges secondarily as part of an initially adaptive immune response to virus or other pathogens, immunodeficiency state, autoimmunity, or other immunologic challenge.…”

A Review of Therapy for Primary Membranous Nephropathy Post-MENTOR

“…Primary membranous nephropathy (PMN) is the most common cause of nephrotic syndrome in adults, accounting for 20-40% of all cases. It is an autoimmune disease with an incidence rate of 1.2 per 100,000 persons per year, and a male to female ratio of 2:1 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. The discovery of autoantibodies to phospholipase A2 receptor (PLA2R) by Beck and Salant in 2009 revolutionized our understanding of the pathophysiology of this unique disease [2].…”

“…PLA2R, a normal molecule in the podocyte structure, serves as the target antigen for PLA2R antibodies, causing an immunological response that results in the clinical signs of proteinuria and hypoalbuminemia [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. Furthermore, the identification of this antigen and antibody has had a significant impact on the treatment approach.…”

“…Furthermore, the identification of this antigen and antibody has had a significant impact on the treatment approach. A serological approach involving evaluation of the PLA2R antibody levels has been proposed, which serve not only as a marker of disease evolution, but also as a determining factor for treatment [11,12].…”