Anti–Phospholipase A2 Receptor 1 and Anti–Cysteine Rich Antibodies, Domain Recognition and Rituximab Efficacy in Membranous Nephropathy: A Prospective Cohort Study

Rationale & Objective Proteinuria and anti–phospholipase A2 receptor 1 (anti-PLA2R1) antibody titers are associated with primary membranous nephropathy (MN) outcomes. We evaluated the association of antibodies against the cysteine-rich (CysR) and C-type lectin 1, 7, and 8 (CTLD1, CTLD7, and CTLD8) domains of PLA2R1 with MN outcomes. Study Design Prospective cohort study. Setting & Participants One-hundred-thirteen consecutive, consenting patients referred to the Nephology Unit of the Azienda-Socio-Sanitaria-Territoriale (ASST) Papa Giovanni XXIII (Bergamo, Italy) with PLA2R1-related, biopsy-proven MN whose persistent nephrotic syndrome (NS) was managed conservatively for >6 months and were monitored with serial evaluations of proteinuria, autoantibodies (by enzyme-linked immunosorbent assay), and clinical outcomes. Exposure Rituximab. Outcome Complete (proteinuria < 0.3 g/24 h) or partial (proteinuria ≥ 0.3 g/24 h and < 3.0 g/24 h with >50% reduction vs basal) NS remission. Analytical Approach Univariable and multivariable Cox regression analyses. Results All patients had anti-CysR antibodies; 62 (54.9%) were multidomain recognizers. Anti-PLA2R1 and anti-CysR antibody titers were strongly correlated at baseline (P < 0.001, r = 0.934), 6 months (P < 0.001, r = 0.964), and 12 months (P < 0.001, r = 0.944). During a median follow-up of 37.1 (IQR, 20.3-56.9) months, 71 patients (62.8%) achieved either complete or partial remission of their NS. Lower baseline anti-PLA2R1 (HR, 0.997 [95% CI, 0.996-0.999], P = 0.002) and anti-CysR [HR, 0.996 [95% CI, 0.993-0.998], P = 0.001) titers were associated with a higher probability of remission, along with female sex, lower proteinuria, and lower serum creatinine levels (P < 0.05 for all comparisons). Anti-CTLD antibodies were not associated with outcomes. At 6 and 12 months, compared to baseline, anti-PLA2R1 and anti-CysR antibody titers decreased more in patients progressing to partial or complete remission than in those without remission (P < 0.05 for all comparisons). Limitations Observational design. Conclusions In PLA2R1-related MN, anti-PLA2R1 and anti-CysR antibodies similarly predict rituximab efficacy independent of PLA2R1 domain recognition. The choice between these tests should be dictated by feasibility and costs. Evaluating anti-CTLD antibodies appears unnecessary. Plain-Language Summary Primary membranous nephropathy (MN), a leading cause of nephrotic syndrome (NS) in adults, is an autoimmune disease caused by autoantibodies binding to the podocyte antigen phospholipase A2 receptor 1 (PLA2R1). We assessed whether the effects of anti-CD20 cytolytic therapy with the monoclonal antibody rituximab are associated with detection rates and levels of anti-PLA2R1 antibodies and antibodies against PLA2R1 domains such as cysteine-rich (CysR), and C-type lectin 1, 7, and 8 (CTLD1, 7, and 8), in patients with PLA2R1-related MN and persistent NS. The probability of rituximab-induced complete or partial NS remission was associated with baseline anti-PLA2R1 and anti-CysR antibody titers, but not with anti-CTLD1, 7 and 8 antibodies or multidomain recognition. Integrated evaluation of anti-PLA2R1 or anti-CysR antibodies with proteinuria and kidney function may play a role in monitoring the effects of rituximab in patients with PLA2R1-related NS and MN. Proteinuria and anti–phospholipase A2 receptor 1 (anti-PLA2R1) antibody titers are associated with primary membranous nephropathy (MN) outcomes. We evaluated the association of antibodies against the cysteine-rich (CysR) and C-type lectin 1, 7, and 8 (CTLD1, CTLD7, and CTLD8) domains of PLA2R1 with MN outcomes. Prospective cohort study. One-hundred-thirteen consecutive, consenting patients referred to the Nephology Unit of the Azienda-Socio-Sanitaria-Territoriale (ASST) Papa Giovanni XXIII (Bergamo, Italy) with PLA2R1-related, biopsy-proven MN whose persistent nephrotic syndrome (NS) was managed conservatively for >6 months and were monitored with serial evaluations of proteinuria, autoantibodies (by enzyme-linked immunosorbent assay), and clinical outcomes. Rituximab. Complete (proteinuria < 0.3 g/24 h) or partial (proteinuria ≥ 0.3 g/24 h and < 3.0 g/24 h with >50% reduction vs basal) NS remission. Univariable and multivariable Cox regression analyses. All patients had anti-CysR antibodies; 62 (54.9%) were multidomain recognizers. Anti-PLA2R1 and anti-CysR antibody titers were strongly correlated at baseline (P < 0.001, r = 0.934), 6 months (P < 0.001, r = 0.964), and 12 months (P < 0.001, r = 0.944). During a median follow-up of 37.1 (IQR, 20.3-56.9) months, 71 patients (62.8%) achieved either complete or partial remission of their NS. Lower baseline anti-PLA2R1 (HR, 0.997 [95% CI, 0.996-0.999], P = 0.002) and anti-CysR [HR, 0.996 [95% CI, 0.993-0.998], P = 0.001) titers were associated with a higher probability of remission, along with female sex, lower proteinuria, and lower serum creatinine levels (P < 0.05 for all comparisons). Anti-CTLD antibodies were not associated with outcomes. At 6 and 12 months, compared to baseline, anti-PLA2R1 and anti-CysR antibody titers decreased more in patients progressing to partial or complete remission than in those without remission (P < 0.05 for all comparisons). Observational design. In PLA2R1-related MN, anti-PLA2R1 and anti-CysR antibodies similarly predict rituximab efficacy independent of PLA2R1 domain recognition. The choice between these tests should be dictated by feasibility and costs. Evaluating anti-CTLD antibodies appears unnecessary.