Early PLA2R Status in Severe Anti-PLA2R-mediated Membranous Nephropathy and Long Term Kidney Outcome. (EPSILON)

This is a multicentric retrospective observational cohort study. The aim of this study is to evaluate, during the initial phase of immunosuppressive treatment for severe PLA2R-positive membranous nephropathy, the independent association between anti-PLA2R antibody trajectories and the occurrence of long-term major kidney events (within 10 years after treatment initiation).

The secondary objectives are :

To assess the association between the initial anti-PLA2R antibody trajectory (between 0 and 6 ± 3 months after treatment, before any potential re-treatment) and the occurrence of nephrological remission.

To assess the association between the initial anti-PLA2R antibody trajectory (between 0 and 6 ± 3 months after treatment, before any potential re-treatment) and the occurrence of immunological remission.

To evaluate, in real-world practice, the safety of immunosuppressive therapies in the treatment of severe PLA2R-positive membranous nephropathy.

Study Overview

• Status: Not yet recruiting
• Conditions: Membranous Nephropathy; Major Adverse Kidney Events

Detailed Description

Membranous nephropathy (MN) is the leading cause of nephrotic syndrome in non-diabetic Caucasian adults, with a highly variable disease course. One-third of patients achieve spontaneous remission, one-third develop chronic kidney disease, and another third progress to end-stage renal disease (ESRD). This variability necessitates early risk assessment to prevent both overtreatment and disease progression.

Anti-PLA2R antibodies, detected in 60-65% of cases, are crucial for diagnosis and disease monitoring. High antibody levels are associated with a low likelihood of spontaneous remission, often justifying early immunosuppressive therapy. However, the precise predictive value and threshold levels of these antibodies remain unclear.

Among available immunosuppressive treatments, rituximab is favored for its efficacy and low toxicity, making it the standard therapy for MN. However, only 30-35% of patients achieve complete remission within two years, while two-thirds of those without complete remission remain at risk of progression to ESRD.

This variability in response to rituximab is likely influenced by several factors, including excessive urinary drug loss, immune resistance, genetic predispositions, and comorbidities such as obesity and vitamin D deficiency. Although personalized therapeutic approaches are under investigation, large-scale validation is needed.

In conclusion, despite significant advancements, particularly with anti-PLA2R antibodies and rituximab, multicenter studies are required to refine therapeutic strategies and improve long-term outcomes in anti-PLA2R+ MN by promoting a more personalized approach to treatment.

• Study Type: Observational
• Enrollment (Estimated): 250

Contacts and Locations

• Study Contact: Name: Romain BROUSSE, MD, PhD student; Phone Number: +33156017043; Email: Romain.brousse@aphp.fr
• Study Contact Backup: Name: Karine DAHAN, MD; Email: Karine.dahan@aphp.fr

Study Locations

• France
  • Paris, France, 75020
    • Néphrologie & Dialyses department, Tenon Hospital
    • Contact: Romain BROUSSE, MD, PhD student; Phone Number: +33156017043; Email: Romain.brousse@aphp.fr
    • Contact: Karine DAHAN, MD; Email: Karine.dahan@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients with antiPLA2R positive membranous nephropathy will be obtained from the immunology laboratories of Saint Antoine Hospital and Mondor Hospital (performing all antiPLA2R analysis in Paris).

Description

Inclusion Criteria:

• Patient followed in 8 nephrology departments of AP-HP between 01/01/2017 and 12/31/2026
• Age > 6 years
• With serodiagnosis of MN via identification of anti-PLA2R antibodies
• Treatment with an immunosuppressive drug.

Exclusion Criteria:

• Diagnosis of MN without testing for anti-PLA2R antibodies
• Refusal to use the data
• Occurrence of the primary endpoint at the time of disease diagnosis (diagnosis of membranous nephropathy at the stage of end-stage kidney disease)
• Lack of patient follow-up at the centers participating in the study
• Lack of reassessment of anti-PLA2R antibody titers within 12 months after initiation of immunosuppressive therapy

Study Plan

How is the study designed?

Design Details

• Observational Models: COHORT
• Time Perspectives: RETROSPECTIVE

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of a major nephrological event within 10 years following immunosuppressive treatment for anti-PLA2R-positive membranous nephropathy	Major adverse kidney event (MAKE) - Composite variable defined by one of the following event: Initiation of chronic dialysis (duration > 3 months).; Kidney transplantation.; Chronic kidney disease with a sustained estimated GFR < 15 ml/min/1.73m², confirmed by two measurements at least 28 days apart.; Sustained decline of > 50% in GFR from baseline at diagnosis, confirmed by two measurements at least 28 days apart.	between diagnostic and last follow-up, up to 10 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Association between the initial trajectory (defined as the percentage change ((M6 - M0)/M0) in the anti-PLA2R antibody titer	Association between the initial trajectory (defined as the percentage change ((M6 - M0)/M0) in the anti-PLA2R antibody titer, quantified using the ELISA technique, between the titer at the time of initiation of immunosuppressive therapy (D0) and the titer from the first anti-PLA2R measurement performed at 6 ± 3 months after initiation of immunosuppressive therapy (M6 ± 3)) of anti-PLA2R antibodies (from 0 to 6+/-3 months post-treatment) and the occurrence of nephrological response (either complete and/or partial). Nephrological relapse is defined as : The occurrence of proteinuria >3 g/g in a patient who had previously achieved complete or partial remission.; The occurrence of a clinically significant relapse, defined as a relapse warranting immunosuppressive therapy in any of specifics situations	between diagnostic and last follow-up, , up to 10 years
Association between the initial trajectory of anti-PLA2R antibodies (from 0 to 6 +/- 3 months post-treatment) and the occurrence of immune response	Immunological relapse is defined as reappearance of detectable anti-PLA2R antibodies by ELISA after achieving anti-PLA2R antibody negativity during treatment.	between diagnostic and last follow-up, , up to 10 years
Safety of immunosuppressive drugs	Reporting of all adverse event recorded in patients' medical record during follow up. Scoring performed according to the CTCAE v5.0.	between diagnostic and last follow-up, , up to 10 years

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Romain BROUSSE, MD, PhD student, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Estimated): November 1, 2026
• Primary Completion (Estimated): November 1, 2027
• Study Completion (Estimated): November 1, 2027

Study Registration Dates

• First Submitted: November 5, 2026
• First Submitted That Met QC Criteria: November 5, 2026
• First Posted (Actual): November 12, 2026

Study Record Updates

• Last Update Posted (Actual): November 12, 2026
• Last Update Submitted That Met QC Criteria: November 5, 2026
• Last Verified: November 1, 2026

More Information

Terms related to this study

• Keywords: trajectories; major adverse kidney events; antiPLA2R antibodies
• Additional Relevant MeSH Terms: Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Autoimmune Diseases; Immune System Diseases; Glomerulonephritis; Nephritis; Glomerulonephritis, Membranous
• Other Study ID Numbers: APHP251555

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No