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.