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

Abstract

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.

Keywords: KDIGO (Kidney Disease: Improving Global Outcomes); PLA2R1 autoantibodies; autoimmunity; immunomonitoring; immunosuppressive therapy; membranous nephropathy; nephrotic syndrome; rituximab.

Figure 1

Risk of disease progression in membranous nephropathy. PLA2R1, phospholipase A2 receptor type 1. Th2 and Th17 pro-inflammatory cytokines are increased in patients with pMN (13, 14). High anti-PLA2R1 antibody titer, positive epitope spreading, antibodies to intracellular antigens, high proteinuria despite optimal supportive care and deterioration of kidney function are associated with the risk of disease progression. Urine low-molecular-weight proteins and urinary IgG excretion have been shown to correlate with disease progression in patients with pMN, but these markers are rarely used in daily practice. Figure created with BioRender.com.

Figure 2

Main causes of rituximab resistance in membranous nephropathy. ADAs, anti-drug antibodies; FcRN, neonatal Fc receptor for IgG; PLA2R1, phospholipase A2 receptor type 1; RTX, rituximab. Figure created with BioRender.com.

Figure 3

Treatment of primary membranous nephropathy based on risk assessment of disease progression and rituximab immunomonitoring. CNIs, calcineurin inhibitors; M3, month-3 (3 months after rituximab infusion); M6, month-6 (six months after rituximab infusion); NS, nephrotic syndrome; pMN, primary membranous nephropathy; PLA2R1, phospholipase A2 receptor type 1; RTX, rituximab; UPCR, urine protein/creatinine ratio. *Low to moderate risk of disease progression: negative epitope spreading and anti-PLA2R1 titer < 150 RU/ml, and no severe complication related to NS, and reduction of proteinuria under optimal supportive care and no deterioration of kidney function. High to very high risk of disease progression: positive epitope spreading, and/or anti-PLA2R1 titer > 150 RU/ml, and/or severe complication related to NS, and/or high proteinuria (> 8 g/d) despite optimal supportive care and/or deterioration of kidney function. Urine low-molecular-weight proteins and urinary IgG excretion have been shown to correlate with disease progression in patients with pMN, but these markers are rarely used in daily practice. Serum rituximab level analyzed by ELISA (LISA-TRACKER Duo Rituximab, Theradiag ^© Croissy Beaubourg, France) three months after the last injection. The limit of detection defined by the manufacturer is 2 µg/ml.

Figure 4

Algorithm for management of patients with treatment-resistant primary membranous nephropathy. CNIs, calcineurin inhibitors; GFR, glomerular filtration rate; pMN, primary membranous nephropathy. *directly related to membranous nephropathy. To date, the alkylating agents (e.g. cyclophosphamide) are the only treatment with proven efficacy to prevent end stage kidney disease (ESKD) and death.

Figure 5

Algorithm for management of patients with relapsing primary membranous nephropathy. CNIs, calcineurin inhibitors; pMN, primary membranous nephropathy.