Alkylating agents in membranous nephropathy: efficacy proven beyond doubt.

Idiopathic membranous nephropathy (iMN) is one of the most common causes of the nephrotic syndrome in adults. The clinical course of patients with iMN is quite variable. Untreated, ∼40–50% of patients with iMN and nephrotic proteinuria will develop end-stage renal disease (ESRD) [1]. According to data of registries in the USA, Europe, and Australia and New Zealand, MN was the cause of ESRD in 0.47–1.71% of patients who started renal replacement therapy in the period 1980–94 [2]. The treatment of iMN is heavily debated. Although several studies have claimed success of immunosuppressive therapy [3–6], a meta-analysis and Cochrane review published in 2004 concluded that there is insufficient evidence of the efficacy of immunosuppressive therapy [7]. The perception that immunosuppressive therapy is of limited benefit is fostered by recent reviews and research articles which explicitly state that the prognosis of membranous nephropathy has hardly improved in recent years with up to 40% of patients reaching ESRD [8–10]. This ongoing debate may lead to therapeutic nihilism. The uncertainty on the use of immunosuppressive therapy in patients with iMN is reflected in our recent study, in which we evaluated by questionnaire the immunosuppressive strategies that had been used in 45 patients with iMN who started renal replacement therapy in the period 2000–05 [11]. The majority of patients (23; 52%) had not received any immunosuppressive therapy, initial immunosuppressive treatment consisted of prednisone monotherapy in seven patients (16%), cyclosporine and prednisone in f ive patients (11%), cyclophosphamide and prednisone in another five patients (11%), chlorambucil and prednisone in three patients (7%), and azathioprine and prednisone in one patient (2%). We summarize the evidence that immunosuppressive therapy using alkylating agents is effective in iMN and improves renal survival. We discuss the risks associated with this treatment and touch upon areas of uncertainty. The introduction of new immunosuppressive agents and biologicals has provided hope for effective and safer treatment of patients with iMN. These new agents must be evaluated in randomized trials. Since alkylating agents are proven effective, these agents should be considered the golden standard of therapy and used as comparator drug in such trials.