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Mass Spectrometry-based Proteomics in Microvascular Inflammation Diagnosis in Kidney Transplantation. (TranSpec)

Primary Purpose

Kidney Transplantation, Graft Rejection, Humoral Immunity

Status

Recruiting

Phase

Not Applicable

Locations

France

Study Type

Interventional

Intervention

Mass spectrometry-based proteomics of FFPE biopsies and urine samples

About this trial

This is an interventional diagnostic trial for Kidney Transplantation focused on measuring Antibody-mediated rejection, microvascular inflammation, proteomics, kidney transplantation

Eligibility Criteria

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

Inclusion Criteria:

Kidney transplant recipients
Diagnosis based on the 2019 Banff classification (polyomavirus nephropathy, T cell-mediated rejection, borderline changes)
Renal allograft biopsy allowing inclusion with at least 7 permeable glomeruli
The microvascular inflammation group with anti-HLA DSA is defined as follows:
- At least moderate microvascular inflammation: g + ptc > 2
- At least one anti-HLA DSA in the serum at the time of biopsy, with a Mean Fluorescence Intensity (MFI) > 3000 for the immunodominant DSA or the sum of the DSA
The microvascular inflammation group without anti-HLA DSA is defined as follows:
- At least moderate microvascular inflammation: g + ptc > 2
- No historical anti-HLA DSA or at the time of biopsy, MFI < 500
The stable graft recipients group is defined as follows:
- Glomerual Filtration Rate > 40ml/min, without clinical proteinuria
- No detectable DSA
- Protocol biopsy at 1 year posttransplantation without specific lesion or nonspecific severe lesion
The chronic nonspecific graft changes group is defined as follows:
- Moderate to severe interstitial fibrosis and tubular atrophy, in the absence of specific lesions: active rejection (antibody-mediated or T cell-mediated), borderline lesions, recurrent or de novo nephropathy, polyomavirus associated nephropathy.
- No C4d deposits on peritubular capillaries
- No detectable anti-HLA DSA at the time of biopsy.
The ischemic acute tubular injuries group is defined as :
- Histological lesions of tubular injuries in the absence of significant microvascular inflammation or C4d deposits
- No detectable anti-HLA DSA at the time of biopsy

Exclusion Criteria:

Minor patients
Mixed rejection (antibody-mediated and T cell-mediated)
Recurrent or de novo nephropathy
Specific treatment of rejection (T cell-mediated or antibody-mediated) in the last 6 months, excluding induction and
Baseline immunosuppressive treatment.

Sites / Locations

Hôpital PellegrinRecruiting
Hôpital Edouard Herriot
Hôpital Necker

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Experimental

Arm Description

Outcomes

Primary Outcome Measures

Assessing diagnostic performance of tissue protein signature

The primary outcome is the sensitivity and specificity of tissue protein signature in the diagnosis of microvascular inflammation (MVI) in kidney transplantation, the diagnostic reference standard being based on the 2019 Banff classification (histological and biological criteria). This primary outcome is based on FFPE kidney allograft biopsies.

Secondary Outcome Measures

Assessing the diagnostic performance of urine protein signatures

Sensitivity and specificity of the urinary protein signature in the diagnosis of MVI in kidney transplantation, compared to the reference standard (2019 Banff classification)

Assessing the performance of tissue proteomic signature

Sensitivity and specificity of tissue proteomic analysis in the prediction of the MVI subtype (anti-HLA DSA or not)

Assessing the performance of urine proteomic signature

Sensitivity and specificity of urine proteomic analysis in the prediction of the MVI subtype (anti-HLA DSA or not)

Compare protein profiles observed within different phenotypes of MVI in kidney transplantation

To describe and compare protein profiles observed within different phenotypes of MVI in kidney transplantation, at tissue and urine protein level according to Banff 2019 (with and without anti-HLA DSA).

Full Information

NCT ID

NCT04851145

First Posted

April 14, 2021

Last Updated

July 17, 2023

Sponsor

University Hospital, Bordeaux

1. Study Identification

Unique Protocol Identification Number

NCT04851145

Brief Title

Mass Spectrometry-based Proteomics in Microvascular Inflammation Diagnosis in Kidney Transplantation.

Acronym

TranSpec

Official Title

Diagnostic Value of Mass Spectrometry-based Proteomics in Microvascular Inflammation in Kidney Transplantation, the TranSpec Study.

Study Type

Interventional

2. Study Status

Record Verification Date

July 2023

Overall Recruitment Status

Recruiting

Study Start Date

November 8, 2021 (Actual)

Primary Completion Date

November 2023 (Anticipated)

Study Completion Date

November 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University Hospital, Bordeaux

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

Microvascular inflammation, the hallmark histological criteria of antibody-mediated rejection in kidney transplantation, remains an issue in routine practice, due to a lack of reproducibility in its recognition by pathologists and an incomplete comprehension of its pathophysiology, leading to a poor treatment efficacy. The main objective of this study is to assess the performances of tissue proteic signatures designed for the diagnosis of microvascular inflammation in kidney transplantation, from formalin-fixed and paraffin-embedded (FFPE) allograft biopsies analyzed by mass spectrometry-based proteomics.

Detailed Description

Antibody-mediated rejection (ABMR) is due to pathogenic antibodies produced by the donor (donor-specific antibodies, DSA) that are directed against Human Leukocyte Antigens (HLA) or other antigens (non HLA) of the graft. ABMR is currently the leading cause of long-term kidney allograft failure. Histological lesions of microvascular inflammation (MVI) are the hallmark criteria of ABMR according to the 2019 Banff classification. Lack of reproducibility in the scoring of MVI by pathologists is still an issue of the diagnosis of ABMR in routine practice, while the understood pathophysiological mechanisms of MVI (anti-HLA DSA, DSA against non HLA antigens and/or NK cell-mediated) are poorly assessed in practice, possibly explaining the wide variability of treatment efficacy. In a prior study, the investigators confirmed the value of mass spectrometry for the analysis of the glomerular proteome during ABMR, compared to the one of stable grafts, from FFPE biopsies. The investigators identified 82 proteins, particularly involved in leukocyte activation and the interferons pathways, in accordance with transcriptomic approaches. Five proteins were validated by immunohistochemistry. The investigators now propose to analyze kidney allograft FFPE biopsies of 92 patients by mass spectrometry, including 32 with MVI (with and without anti-HLA DSA) and 60 with relevant differential diagnoses. The main objective is to assess the diagnostic performances of tissue proteic signatures designed by machine-learning methods for the diagnosis of microvascular inflammation, the reference standard being the 2019 Banff classification. One of the secondary objectives includes the comparison of the protein profile of MVI with and without anti-HLA DSA, but also the proteomic analysis of 60 urine samples from the same population, in order to assess the performances of mass spectrometry in the non-invasive diagnosis of MVI in kidney transplantation.

6. Conditions and Keywords

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

Kidney Transplantation, Graft Rejection, Humoral Immunity, Proteomics

Keywords

Antibody-mediated rejection, microvascular inflammation, proteomics, kidney transplantation

7. Study Design

Primary Purpose

Diagnostic

Study Phase

Not Applicable

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

92 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Experimental

Arm Type

Experimental

Intervention Type

Diagnostic Test

Intervention Name(s)

Mass spectrometry-based proteomics of FFPE biopsies and urine samples

Intervention Description

The biopsy and urine samples will be processed by the OncoProt platform (University of Bordeaux) for proteomic analysis by tandem mass spectrometry (label-free quantification) as follows: Biopsies: laser microdissection of the renal cortex, fixation reversion, protein extraction and electrophoretic migration, tryptic digestion. Urines: samples concentration by centrifugation/filtration and tryptic digestion according to a protocol adapted from the FASP method (Filter-Aided Sample Preparation)

Primary Outcome Measure Information:

Title

Assessing diagnostic performance of tissue protein signature

Description

Time Frame

18 months after inclusion

Secondary Outcome Measure Information:

Title

Assessing the diagnostic performance of urine protein signatures

Description

Sensitivity and specificity of the urinary protein signature in the diagnosis of MVI in kidney transplantation, compared to the reference standard (2019 Banff classification)

Time Frame

18 months after inclusion

Title

Assessing the performance of tissue proteomic signature

Description

Sensitivity and specificity of tissue proteomic analysis in the prediction of the MVI subtype (anti-HLA DSA or not)

Time Frame

18 months after inclusion

Title

Assessing the performance of urine proteomic signature

Description

Sensitivity and specificity of urine proteomic analysis in the prediction of the MVI subtype (anti-HLA DSA or not)

Time Frame

18 months after inclusion

Title

Compare protein profiles observed within different phenotypes of MVI in kidney transplantation

Description

Time Frame

18 months after inclusion

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Kidney transplant recipients Diagnosis based on the 2019 Banff classification (polyomavirus nephropathy, T cell-mediated rejection, borderline changes) Renal allograft biopsy allowing inclusion with at least 7 permeable glomeruli The microvascular inflammation group with anti-HLA DSA is defined as follows: At least moderate microvascular inflammation: g + ptc > 2 At least one anti-HLA DSA in the serum at the time of biopsy, with a Mean Fluorescence Intensity (MFI) > 3000 for the immunodominant DSA or the sum of the DSA The microvascular inflammation group without anti-HLA DSA is defined as follows: At least moderate microvascular inflammation: g + ptc > 2 No historical anti-HLA DSA or at the time of biopsy, MFI < 500 The stable graft recipients group is defined as follows: Glomerual Filtration Rate > 40ml/min, without clinical proteinuria No detectable DSA Protocol biopsy at 1 year posttransplantation without specific lesion or nonspecific severe lesion The chronic nonspecific graft changes group is defined as follows: Moderate to severe interstitial fibrosis and tubular atrophy, in the absence of specific lesions: active rejection (antibody-mediated or T cell-mediated), borderline lesions, recurrent or de novo nephropathy, polyomavirus associated nephropathy. No C4d deposits on peritubular capillaries No detectable anti-HLA DSA at the time of biopsy. The ischemic acute tubular injuries group is defined as : Histological lesions of tubular injuries in the absence of significant microvascular inflammation or C4d deposits No detectable anti-HLA DSA at the time of biopsy Exclusion Criteria: Minor patients Mixed rejection (antibody-mediated and T cell-mediated) Recurrent or de novo nephropathy Specific treatment of rejection (T cell-mediated or antibody-mediated) in the last 6 months, excluding induction and Baseline immunosuppressive treatment.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Bertrand CHAUVEAU, Dr

Phone

5 56 72 21 24

Ext

+33

bertrand.chauveau@chu-bordeaux.fr

First Name & Middle Initial & Last Name or Official Title & Degree

Pierre MERVILLE, Pr

Phone

5 56 79 55 38

Ext

+33

pierre.merville@chu-bordeaux.fr

Facility Information:

Facility Name

Hôpital Pellegrin

City

Bordeaux

ZIP/Postal Code

33000

Country

France

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Bertrand CHAUVEAU, Dr

Phone

5 56 72 21 24

Ext

+33

bertrand.chauveau@chu-bordeaux.fr

First Name & Middle Initial & Last Name & Degree

Pierre MERVILLE, Pr

Phone

5 56 79 55 38

Ext

+33

pierre.merville@chu-bordeaux.fr

Facility Name

Hôpital Edouard Herriot

City

Lyon

ZIP/Postal Code

69003

Country

France

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Olivier THAUNAT, Pr

olivier.thaunat@chu-lyon.fr

Facility Name

Hôpital Necker

City

Paris

ZIP/Postal Code

75015

Country

France

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Dany ANGLICHEAU, Pr

dany.anglicheau@aphp.fr

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

Mass Spectrometry-based Proteomics in Microvascular Inflammation Diagnosis in Kidney Transplantation.

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