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Immunopathological Analysis in a French National Cohort of Membranous Nephropathy (IHMN)

Primary Purpose

Membranous Nephropathy

Status
Not yet recruiting
Phase
Not Applicable
Locations
Study Type
Interventional
Intervention
Blood sample
Sponsored by
Centre Hospitalier Universitaire de Nice
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional screening trial for Membranous Nephropathy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Age 18 years or more
  • Biopsy on a native kidney consistent with MN and/or positivity for serum anti-PLA2R1 and/or anti-THSD7A antibodies
  • Signed informed consent

Exclusion Criteria:

  • Diagnosis error based on the kidney biopsy staining or on serology analyses for the positivity for anti-PLA2R1 and/or anti-THSD7A
  • Patients unable to give an informed consent
  • Patients withdrawing an informed consent

Sites / Locations

    Arms of the Study

    Arm 1

    Arm Type

    Other

    Arm Label

    Cohort

    Arm Description

    All patients included will have to be taken blood samples

    Outcomes

    Primary Outcome Measures

    To determine the incidence of Membranous Nephropathy (MN) and its evolution
    as either complete remission (UPCR < 0.3 g/g, serum albumin > 35 g/L, eGFR > 60 ml/min/1.73 m²) or partial remission (UPCR < 3.5 g/g and reduction of at least 50% from baseline, < 20% increase of serum creatinin from baseline) or persistent nephrotic syndrome (UPCR > 3.5 g/g, serum albumin < 30 g/L)

    Secondary Outcome Measures

    Determination of incidence of primary and secondary forms of MN
    Identification of environmental factors associated with the onset of MN
    Thanks to a specific questionnaire data on medical history, lifestyle, demography and profession will be collected Medical history: prior diagnosis of any autoimmune disease, cancer, infection or other, infection in the month before the diagnosis of MN, thrombosis, drugs taken at the moment of diagnosis, allergies and type of symptomes Emotional state: emotional state at diagnosis, stressful or destabilizing event in the year preceding diagnosis of MN
    Description of the standard of care for patients with MN in France
    Treatment names and their duration (in weeks) will be collected
    the prognostic value of epitope spreading in patients with PLA2R1-associated MN
    Epitope spreading status is determined by measuring the positivity to anti-CysR, anti-CTLD1 and CTLD7 antibodies in the serum, by the means of ELISA and expressed as RU/mL. The patients with antibodies targetting CysR only are considered as non-spreaders, while the patients additionnaly targetting either CTLD1 and/or CTLD7 are considered as spreaders. Epitope spreading status (non-spreader or spreader) will be correlated to clinical outcome (complete remission, partial remission or persistent nephrotic syndrome, as defined under primary outcome measures) one year after inclusion.
    Characterization of HLA typing of MN patients
    Isolation of DNA and genotyping will be performed with the use of standard procedures of Next Generation Sequencing
    Prognostic value of tissue staining for glomerular deposit of PLA2R1, THSD7A, as welle as of different IgG subclasses
    Positivity for PLA2R1, THSD7A and NELL-1 antigens will be determined using immunostaining with antibodies against PLA2R1, THSD7A and NELL-1, and Positivity for IgG1 IgG2, IgG3 and IgG4 subclasses will be determined using immunostaining with antibodies against IgG1 IgG2, IgG3 and IgG4, respectively, in glomeruli of kidney biopsy at inclusion. The positivity of tissue staining for PLA2R1, THSD7A and NELL-1or Ig subclasses will be correlated to the patient's clinical outcome one year after inclusion (complete remission, partial remission or persistent nephrotic syndrome, as defined under primary outcome measures).

    Full Information

    First Posted
    December 26, 2019
    Last Updated
    April 3, 2020
    Sponsor
    Centre Hospitalier Universitaire de Nice
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    1. Study Identification

    Unique Protocol Identification Number
    NCT04326218
    Brief Title
    Immunopathological Analysis in a French National Cohort of Membranous Nephropathy
    Acronym
    IHMN
    Official Title
    Immunopathological Analysis in a French National Cohort of Membranous Nephropathy (IHMN)
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    March 2020
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    July 1, 2020 (Anticipated)
    Primary Completion Date
    July 1, 2024 (Anticipated)
    Study Completion Date
    July 1, 2024 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Centre Hospitalier Universitaire de Nice

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    No

    5. Study Description

    Brief Summary
    National cohort of all cases of membranous nephropathy (MN) during a 1 year period in France, based on a pathological and/or serological diagnostic, collecting the data on: incidence of MN prevalence of anti-PLA2R1 and anti-THSD7A clinical outcome one year after diagnosis or after relapse (complete remission, partial remission or persistent nephrotic syndrome) environmental risk factors for the onset of MN HLA markers patient care status in France
    Detailed Description
    Membranous nephropathy is a rare auto-immune disease, yet a major cause of nephrotic syndrome in adults. It is characterised by the deposition of antigen-antibody complexes on the glomerular basement membrane, leading to a decreased filtration rate and eventually kidney failure. About one third of cases have a favourable outcome without any treatment, another third requires a long term symptomatic treatment to manage their symptoms, and the last third of patients advances to end stage renal failure, requiring dialysis and kidney graft. MN can be associated with cancer, infections, other auto-immune diseases and with certain drugs (secondary MN), but most often it is idiopathic. In the latter form two antigens have been identified, PLA2R1 and THSD7A, with corresponding auto-antibodies in 70% and 2% of MN patients, respectively. GWAS studies identified several alleles associated with a higher risk of developing MN, however, since these are common variants they cannot explain the onset of MN in the vast majority of cases. Since MN is a rare disease, the number of new cases per each center is low, and nation-wide studies are needed to correctly evaluate its incidence and risk factors for the onset of MN, as well as validate previously published findings in monocentric studies on the prognostic value of PLA2R1 epitope spreading (immunisation against multiple domains of PLA2R1). This study aims to establish a French national cohort of all cases of MN in a one year period in France. The inclusion will last one year with one additional year of follow-up, for a total of 2 years. In the first year, nephrologists of each associate centers in France will propose the study to each of their patients diagnosed with MN. In addition, clinical information will be collected, as well as a survey on patients' lifestyle habits. Serum samples will be sent for centralised analyses in Nice. This study will help to clarify the results from single center studies, such as the prognostic value of epitope spreading. The information acquired on environmental risk factors will help us understand the pathophysiological mechanisms leading to the onset of MN et, by association, to other auto-immune diseases. With this knowledge, measures could be put in place to protect the population at risk.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Membranous Nephropathy

    7. Study Design

    Primary Purpose
    Screening
    Study Phase
    Not Applicable
    Interventional Study Model
    Single Group Assignment
    Model Description
    Descriptive analysis of patient cohort who will be subjected to specific samples related to the study
    Masking
    None (Open Label)
    Allocation
    N/A
    Enrollment
    400 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Cohort
    Arm Type
    Other
    Arm Description
    All patients included will have to be taken blood samples
    Intervention Type
    Other
    Intervention Name(s)
    Blood sample
    Intervention Description
    Serum samples will be sent for centralised analyses in Nice. On these samples, different analysis will be performed : anti-PLA2R1 and anti-THSD7A antibodies anti-PLA2R1 and anti-THSD7A epitopes HLA typing
    Primary Outcome Measure Information:
    Title
    To determine the incidence of Membranous Nephropathy (MN) and its evolution
    Description
    as either complete remission (UPCR < 0.3 g/g, serum albumin > 35 g/L, eGFR > 60 ml/min/1.73 m²) or partial remission (UPCR < 3.5 g/g and reduction of at least 50% from baseline, < 20% increase of serum creatinin from baseline) or persistent nephrotic syndrome (UPCR > 3.5 g/g, serum albumin < 30 g/L)
    Time Frame
    one year after inclusion
    Secondary Outcome Measure Information:
    Title
    Determination of incidence of primary and secondary forms of MN
    Time Frame
    24 months
    Title
    Identification of environmental factors associated with the onset of MN
    Description
    Thanks to a specific questionnaire data on medical history, lifestyle, demography and profession will be collected Medical history: prior diagnosis of any autoimmune disease, cancer, infection or other, infection in the month before the diagnosis of MN, thrombosis, drugs taken at the moment of diagnosis, allergies and type of symptomes Emotional state: emotional state at diagnosis, stressful or destabilizing event in the year preceding diagnosis of MN
    Time Frame
    24 months
    Title
    Description of the standard of care for patients with MN in France
    Description
    Treatment names and their duration (in weeks) will be collected
    Time Frame
    24 months
    Title
    the prognostic value of epitope spreading in patients with PLA2R1-associated MN
    Description
    Epitope spreading status is determined by measuring the positivity to anti-CysR, anti-CTLD1 and CTLD7 antibodies in the serum, by the means of ELISA and expressed as RU/mL. The patients with antibodies targetting CysR only are considered as non-spreaders, while the patients additionnaly targetting either CTLD1 and/or CTLD7 are considered as spreaders. Epitope spreading status (non-spreader or spreader) will be correlated to clinical outcome (complete remission, partial remission or persistent nephrotic syndrome, as defined under primary outcome measures) one year after inclusion.
    Time Frame
    24 months
    Title
    Characterization of HLA typing of MN patients
    Description
    Isolation of DNA and genotyping will be performed with the use of standard procedures of Next Generation Sequencing
    Time Frame
    12 months
    Title
    Prognostic value of tissue staining for glomerular deposit of PLA2R1, THSD7A, as welle as of different IgG subclasses
    Description
    Positivity for PLA2R1, THSD7A and NELL-1 antigens will be determined using immunostaining with antibodies against PLA2R1, THSD7A and NELL-1, and Positivity for IgG1 IgG2, IgG3 and IgG4 subclasses will be determined using immunostaining with antibodies against IgG1 IgG2, IgG3 and IgG4, respectively, in glomeruli of kidney biopsy at inclusion. The positivity of tissue staining for PLA2R1, THSD7A and NELL-1or Ig subclasses will be correlated to the patient's clinical outcome one year after inclusion (complete remission, partial remission or persistent nephrotic syndrome, as defined under primary outcome measures).
    Time Frame
    12 months

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Age 18 years or more Biopsy on a native kidney consistent with MN and/or positivity for serum anti-PLA2R1 and/or anti-THSD7A antibodies Signed informed consent Exclusion Criteria: Diagnosis error based on the kidney biopsy staining or on serology analyses for the positivity for anti-PLA2R1 and/or anti-THSD7A Patients unable to give an informed consent Patients withdrawing an informed consent
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Barbara SEITZ-POLSKI, MD
    Phone
    +33 4 92 03 55 02
    Email
    seitz-polski.b@chu-nice.fr

    12. IPD Sharing Statement

    Plan to Share IPD
    No
    IPD Sharing Plan Description
    No data will be shared
    Citations:
    PubMed Identifier
    36283759
    Citation
    Cremoni M, Agbekodo S, Teisseyre M, Zorzi K, Brglez V, Benzaken S, Esnault V, Planchard JH, Seitz-Polski B. Toxic Occupational Exposures and Membranous Nephropathy. Clin J Am Soc Nephrol. 2022 Nov;17(11):1609-1619. doi: 10.2215/CJN.02930322. Epub 2022 Oct 25.
    Results Reference
    derived

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    Immunopathological Analysis in a French National Cohort of Membranous Nephropathy

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