Advances in the Management of Primary Membranous Nephropathy and Rituximab-Refractory Membranous Nephropathy

Primary membranous nephropathy (pMN) is an auto-immune disease characterized by auto-antibodies targeting podocyte antigens resulting in activation of complement and damage to the glomerular basement membrane. pMN is the most common cause of nephrotic syndrome in adults without diabetes. Despite a very heterogeneous course of the disease, the treatment of pMN has for many years been based on uniform management of all patients regardless of the severity of the disease. The identification of prognostic markers has radically changed the vision of pMN and allowed KDIGO guidelines to evolve in 2021 towards a more personalized management based on the assessment of the risk of progressive loss of kidney function. The recognition of pMN as an antibody-mediated autoimmune disease has rationalized the use immunosuppressive drugs such as rituximab. Rituximab is now a first line immunosuppressive therapy for patients with pMN with proven safety and efficacy achieving remission in 60-80% of patients. For the remaining 20-40% of patients, several mechanisms may explain rituximab resistance: (i) decreased rituximab bioavailability; (ii) immunization against rituximab; and (iii) chronic glomerular damage. The treatment of patients with rituximab-refractory pMN remains controversial and challenging. In this review, we provide an overview of recent advances in the management of pMN (according to the KDIGO 2021 guidelines), in the understanding of the pathophysiology of rituximab resistance, and in the management of rituximab-refractory pMN. We propose a treatment decision aid based on immunomonitoring to identify failures related to underdosing or immunization against rituximab to overcome treatment resistance.

Automated summary

Primary membranous nephropathy (pMN) is an autoimmune disease characterized by damage to the glomerular basement membrane due to auto-antibodies. The conventional treatment approach for pMN involves uniform management, regardless of disease severity. However, recent advances have led to a more personalized management based on prognostic markers. Rituximab, an immunosuppressive drug, has shown to be effective in achieving remission in a majority of patients with pMN. However, there are cases of rituximab resistance, which pose challenges to treatment. Immunomonitoring may aid in overcoming treatment resistance by identifying possible causes and adjusting the treatment accordingly.