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 leap combining 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.
Highlights
Membranous nephropathy (MN) is a rare disease affecting the glomerular capillary wall, which plays a key role in controlling permeability to proteins
The STARMEN trial [8] is a European randomized clinical trials (RCTs) that compared the efficacy of a sequential therapy with tacrolimus and rituximab to that of a cyclical alternating treatment with a modified Ponticelli protocol in inducing persistent clinical remission
This open-label controlled trial enrolled 86 patients with primary MN and persistent nephrotic syndrome after a run-in period of six-months.Patients had at least 4 g/day of proteinuria and anestimated glomerular filtration rate(eGFR) > 45 mL/min/1.73 m2
Summary
The combination of corticosteroids and an alkylating agent is the only therapy so far shown to preserve kidney function in the long-term [2,3], anti-CD20 biotherapy, rituximab [4], has become increasingly popular as first line therapy because of the toxicity of the alkylating agents and the long-term renal toxicity of calcineurin inhibitors (CNIs) and the high risk of relapsewhen they are used as monotherapy with or without prednisone. In the follow-up period after the first 6 months, in which the difference was not significant, the remission rate in terms of proteinuria was of 65% in the rituximab group, compared to 34% in the control group. Anti-PLA2R antibody titers were significantly reduced as early as three months in the rituximab group. This confirmed that a reduction in antibody titers precedes the reduction in proteinuria and suggested that monitoring of titers could be used to predict the need for a repeat infusion. At the end of the study more cyclosporine-treated patients suffered ≥50% decline in creatinine clearance compared to the rituximab group.Both agents were comparably safe and well tolerated
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