Personalized Treatment Protocol for Membranous Nephropathy

At the 61st European Renal Association Congress, Vesna Brglez and others reported on the efficacy of a personalized treatment protocol for membranous nephropathy (MN) versus the rituximab protocol established by the GEMRITUX study.

MN is a rare but serious autoimmune disease that affects kidney glomeruli. In 50% to 70% of cases, the major autoantigen is phospholipase A2 receptor 1 (PLA2R1) protein. In some cases, patients present antibodies against a single immunodominant cystine-rich domain, but in other instances they develop additional antibodies against C-type lectin domains (CTLDs) CTLD1, CTLD7, and/or CTLD8 of PLA2R1, defining a cascade immunization or epitope spreading. This epitope spreading can strengthen immune response to destroy a pathogen or may be associated with spurring autoantibody-mediated autoimmune pathologies.

An initial study by Brglez et al found that single domain recognition (nonspreader patients) is associated with higher odds for spontaneous remission of MN (45.00% vs 0.05% in GEMRITUX cohort) and a more positive response to treatment (100% of remission regardless of rituximab dose). Alternately, patients with multidomain recognition (spreader patients) of CTLD1 and/or CTLD7 domains have poorer prognoses, are less likely to achieve remission, and require a high dose of rituximab. Thus, the researchers proposed a more individualized protocol based on a patient’s PLA2R1 epitope spreading status. The current study evaluated the efficacy of this treatment protocol versus the GEMRITUX protocol.

The researchers assigned 64 patients with PLA2R1-related MN from 12 French hospitals to either a control group that followed the GEMRITUX protocol (symptomatic treatment for 6 months, two infusions of rituximab 375 mg/m² at month 6 in case of persistent nephrotic syndrome [NS]) or a personalized treatment protocol group (PMMN). Patients without epitope spreading at 0 months were treated with the GEMRITUX protocol; those with epitope spreading at 0 or 6 months with ongoing NS received immediate treatment with infusions of rituximab 1 g. Age, gender, albumin, urine protein-to-creatinine ratio (UPCR), anti-PLA2R1 titer, and the rate of PLA2R1 epitope spreading at baseline did not vary between the two groups. Three patients were omitted from the final analyses.

The primary outcome was rate of clinical remission at 12 months; secondary outcomes included complete and partial remission, immunological remission, serum creatinine, proteinuria, albuminuria, and PLA2R1 antibody titer. At 12 months, 34% of the GEMRITUX group and 69% of the PMMN group achieved partial remission (P=.0105; UPCR <3.5 g/g with a decrease greater than 50% from baseline), improved or normalized serum albumin, and increase of serum creatinine lower than 20%.

There was no difference in the remission rate of the GEMRITUX versus the PMMN group for nonspreader patients (38% vs 50%; P=.7107), but spreader patients were more likely to reach remission with the personalized protocol (36% vs 87%; P=.0078). The total clinical remission rate (UPCR <0.3 g/g and normal albumin) was nearly statistically significant for both the GEMRITUX and PMMN groups (0% vs 16%; P=.0538).

In conclusion, the study authors found that a personalized treatment protocol based on epitope spreading status was better at achieving remission at 12 months for patients with PLA2R1-related MN than standard GEMRITUX therapy. They recommend that patients with multiple domain recognition be treated immediately with high doses of rituximab to boost their odds of remission.

Source: Brglez V, Teisseyre M, Moranne O, et al. Protocol based on PLA2R1 epitope recognition is superior to standard protocol in achieving remission in PLA2R1-associated membranous nephropathy. Abstract #992. Presented at the 61st European Renal Association Congress; May 23-26, 2024; Stockholm, Sweden.