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.

Successful treatment of patients with refractory idiopathic membranous nephropathy with low-dose Rituximab: A single-center experience

“…Therefore, effective and safe therapeutic strategies for refractory IMN must be explored. In the past decade, significant advances in understanding of IMN have established that it is an autoantibody-driven disease[ 21 , 22 ]. As a result, there is a clear choice for treating B-cell depletion.…”

Rituximab in patients with membranous nephropathy and kidney insufficiency

“…Except for the above factors, there are several factors including serum RTX levels, the existence of anti- RTX antibodies, Th17-mediated inflammation and so on that have been demonstrated to influence the efficacy of RTX in the treatment of membranous nephropathy ( Teisseyre et al, 2022 ). Studies have confirmed that low RTX levels at month 3 correlate with poor B-cell depletion at months 3 and 6, with high anti-PLA2R antibody titer at months 3, 6 and 12, and with proteinuria at months 3, 6 and 12.…”

Disease-Specific Treatment For Primary Membranous Nephropathy: The Role of Monoclonal Antibodies

“…Nanoparticles with autoimmune disease-relevant peptides bound to major histocompatibility complex class II molecules could also be used to induce antigen-specific Tregs that promote the differentiation of B-cells into disease-suppressing regulatory B-cells 192 . Whether these new biotechnologies may have a role in the treatment of refractory PMN is therefore worth investigating 193 .…”