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Abstract: FR-OR080

Membranous Nephropathy: Response to Rituximab Is Dependent on Anti-PLA2R1 Epitope Spreading and Gender

Session Information

Category: Glomerular Diseases

  • 1203 Glomerular Diseases: Clinical, Outcomes, and Trials

Authors

  • Brglez, Vesna, Université Côte d’Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Valbonne, France
  • Ruggenenti, Piero Luigi, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
  • Ruggiero, Barbara, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Ranica (Bergamo), Italy
  • Perico, Luca, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Ranica (Bergamo), Italy
  • Gennarini, Alessia, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
  • Payre, Christine, Université Côte d’Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Valbonne, France
  • Dolla, Guillaume, Université Côte d’Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Valbonne, France
  • Seitz-Polski, Barbara, Université Côte d’Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Valbonne, France
  • Benigni, Ariela, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Ranica (Bergamo), Italy
  • Lambeau, Gerard J., Université Côte d’Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Valbonne, France
  • Remuzzi, Giuseppe, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
Background

Membranous nephropathy (MN) is a rare autoimmune kidney disease, yet one of the leading causes of nephrotic syndrome (NS) in adults. Clinical evolution is complex and treatment controversial. There is a need for better biomarkers to identify patients at risk of severe disease and orient therapy. Phospholipase A2 receptor 1 (PLA2R1) was identified as the major autoantigen in 70% of patients with MN. Proteinuria and PLA2R1 antibody titer predict outcome in PLA2R1-related MN.

Methods

We evaluated the additional predictive role of PLA2R1 epitope spreading from the immunodominant CysR domain to CTLD1 and CTLD7 domains in 117 consecutive, rituximab- treated patients with PLA2R1-related MN and nephrotic syndrome. Primary outcome was complete (proteinuria <0.3 g/24h) or partial remission (proteinuria <3.0 g/24h and >50% reduction vs basal). Non-spreaders had antibodies restricted to the CysR domain while spreaders had additional antibodies to CTLD1 and/or CTLD7 domains.

Results

Higher basal anti-PLA2R1 titer associated with higher probability of spreading. All patients with titer >400 RU/ml were spreaders. Fifteen of the 79 spreaders (19%) were females vs 16 of the 38 non-spreaders (42%; p=0.008), and 15 of 31 females (48%) were spreaders vs 64 of 86 males (74%; p<0.01). During a median (IQR) follow-up of 32.2 (16.4-50.5) months, 77 patients (66%) achieved the combined endpoint of complete or partial remission. Female gender (p=0.004), shorter duration of proteinuria (p=0.004), lower proteinuria (p=0.004), lower antibody titer (p=0.036), and no epitope spreading (p=0.009) predicted remission. Compared to spreader males, the HR (95% CI) for the endpoint was 5.15 (2.73-9.70; p<0.0001) in non-spreader females, 2.09 (1.16-3.77, p=0.014) in spreader females, and 1.85 (0.95-2.59, p=0.069) in non-spreader males.

Conclusion

In MN, anti-PLA2R1 titer and epitope spreading monitoring help to predict response to rituximab. Better response of females could be explained, at least partially, by protection against PLA2R1 epitope spreading.

VB and PR contributed equally as first authors, GL and GR contributed equally as last authors.

Funding

  • Private Foundation Support