The evolution of the therapeutic approach to membranous nephropathy.

Primary membranous nephropathy (MN) is a frequent cause of nephrotic syndrome (NS) in adults. In untreated patients, the outcome is variable, with one-third of the patients entering remission while the remaining ones show persisting proteinuria or progression to end-stage renal disease. Randomized clinical trials reported the efficacy of a 6-month regimen alternating intravenous and oral glucocorticoids with an alkylating agent every other month. The potential side effects of this regimen were limited by the fact that the use of glucocorticoids and alkylating agent did not exceed 3 months each. Two randomized trials with follow-ups (FU) up to 10 years provided assurance about the long-term efficacy and safety of this cyclical therapy. Calcineurin inhibitors have also been used successfully. However, in most responders, NS relapsed after the drug was withdrawn. Conflicting results have been reported with mycophenolate salts and adrenocorticotropic hormone. Observational studies reported good results with rituximab (RTX). Two controlled trials demonstrated the superiority of RTX over antiproteinuric therapy alone and cyclosporine. However, the FUs were relatively short and no randomized trial has been published against cyclical therapy. The available results, together with the discovery that most patients with MN have circulating antibodies against the phospholipase A2 receptor 1, support the use of cytotoxic drugs or RTX in MN. It is difficult to choose between these two different treatments. RTX is easier to use, but the FUs of the available studies are short, thus doubts remain about the long-term risk of relapses and the safety of repeated administrations of RTX.