A Randomized Controlled Trial of Rituximab Versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy

Idiopathic Membranous nephropathy (IMN) is an immune-mediated glomerular disease characterized by deposition of IgG4 antibodies in the subepithelial area of the glomerular basement membrane (GBM). Proteinuria is the hallmark of the disease. The commonest presentation of IMN is nephrotic syndrome with preserved kidney function. The natural course of the disease can be variable and may be punctuated with spontaneous remissions and relapses. In about 20% of patients, there is spontaneous complete remission of the nephrotic syndrome, and another 15-20% undergo partial remission; about 30% of patients may remain with fluctuating proteinuria and about 30% may progress to end-stage renal disease (ESRD). However, data from natural history studies and placebo arms of intervention studies with follow-up lasting more than 10 years show that about 30-40% of the untreated patients with persistent nephrotic syndrome progress to ESRD.

Complete remission of nephrotic syndrome predicts excellent long-term kidney and patient survival, and partial remission also significantly reduces the risk of progression to ESRD. Therefore, persisting remission of the nephrotic state is an acceptable surrogate end-point to assess efficacy of treatment. The primary aims of treatment, therefore, are to induce a lasting reduction in proteinuria. The best-validated regimen is combination therapy with corticosteroids and cyclophosphamide ("Ponticelli" regimen). This treatment is superior to supportive therapy alone in inducing remissions and preventing long-term decline of kidney function in patients with idiopathic MN and persisting nephrotic syndrome. However, there are concerns about the use of cyclophosphamide, since its use may be associated with adverse events, leading to treatment interruption in about 9% of patients. These adverse events include bone marrow suppression, gonadal toxicity, infections and oncogenic effects.

Thus, the availability of alternative therapies highly effective but with a greater safety profile is desirable.

Recent human studies confirmed that MN is an autoimmune disease, suggesting that the disease may be triggered by isotype specific autoantibodies directed against podocyte enzymes and podocyte receptors that are recognized as antigens, including M-type phospholipase-2 receptors(PLA2R1) and thrombospondin type 1 domain-containing 7A (THSD7A). The podocyte expression of these autoantigens can trigger the production of specific antibodies and in situ deposits of immune complexes, with consequent activation of complement cascade, oxygen radicals, and other inflammatory pathways leading to tissue injury and fibrosis. Additional autoantibodies, directed to podocyte neo-expressed cytoplasm proteins have been described, including aldose reductase (AR), Mn-superoxide dismutase (SOD2) and alpha-enolase (alpha-ENO).

However, the mechanisms eliciting the expression of these neoantigens on podocytes and regulating the deposition of the auto-antibodies on the subepithelial surface of the glomerular basement membrane is not known.