Glomerular diseases: membranous nephropathy--a modern view

Abstract

Membranous nephropathy (MN) is an autoimmune disease usually associated with a nephrotic syndrome and it may progress to ESRD in the long term. Its etiology is often unknown (idiopathic MN), whereas other cases have a recognizable etiology (secondary MN). In idiopathic MN, the glomerular lesions are mainly caused by autoantibodies against a podocyte membrane protein, the M-type of phospholipase A2 receptor 1. The natural course of idiopathic MN is quite varied with spontaneous complete or partial remissions a relatively common occurrence. Patients with asymptomatic non-nephrotic proteinuria seldom progress and need only conservative management. Those with persistent full-blown nephrotic syndrome and those with declining renal function are candidates for specific treatment with any of several regimens. Cyclical therapy with alternating monthly intravenous and oral glucocorticoids combined with a cytotoxic agent can induce remission and preserve renal function in the long term. Cyclosporine or tacrolimus can induce remission, but relapses are frequent after the drug withdrawal. Mycophenolate mofetil monotherapy seems to be ineffective, but may be beneficial when administered together with steroids. The experience with adrenocorticotropic hormone, natural or synthetic, is limited to a few studies with short-term follow-up, but high rates of remission can be seen after prolonged treatment. A high rate of remission and good tolerance have also been reported with rituximab. Patients with moderate renal insufficiency may also benefit from treatment, but at a price of frequent and serious side effects. With these limitations in mind, idiopathic MN may be considered a treatable disease in many patients.

Figure 1.

A personal hypothetical mechanistic interpretation of idiopathic MN. In genetically predisposed patients, a polymorphism of PLA2R1 may create a unique conformational variant. Alternatively endogenous or exogenous injuries (viral attack?) may cause structural alterations of PLA2R1 or lead to podocyte injury with exposure of some “hidden” epitopes of PLA2R1. It is possible that these abnormal molecular patterns are recognized as danger signals by the receptors of innate immunity with consequent recruitment of inflammatory cells. In this inflammatory microenvironment, the dendritic cells would become mature, intercept the epitopes of PLA2R1 expressed on the glomerular podocyte surface, and migrate to lymph nodes where they present the antigen to the cells of the adaptive immunity. The B cells would differentiate into plasma cells that secrete specific hypogalactosylated IgG4. These antibodies attack the epitopes of PLA2R1 on podocyte surface, with formation of subepithelial immune complexes and consequent production of ROS, and inflammation. The hypogalactosylated IgG4 activates the complement system through the lectin pathway which initiates the complement cascade, with the final production of the cytolytic C5b-C9 complex, also called the membrane attack complex. As a consequence, there is an increased damage of podocytes, alteration of the actin cytoskeleton, loss of the glomerular barrier permselectivity, and proteinuria. MN, membranous nephropathy; PLA2R1, phospholipase A2 receptor 1; ROS, reactive oxygen species.