Precision Risk Stratification in Kidney Transplant Patients - EU-TRAIN
Condition: Kidney Transplant Rejection; Kidney Transplantation; Risk Stratification; Prognosis
Study type: Observational

Summary: 
      Main objective: To design a precision risk stratification system that predicts individual
      risk of rejection
    

Detailed description: 
      Allograft rejection is still a major threat to allografts with thousands of allografts
      failing every year worldwide due to organ rejection, with immediate consequences for the
      patients in terms of mortality and morbidity. With a prevalence around 20% in the first-year
      post transplant, rejection also carries high economic impact representing a 72% increase in
      transplantation price and downstream cost because of return on dialysis (60,000€ health care
      increase per patient). The rough estimates from 200,000 kidney allograft failures per year
      equals to 12 billion extra cost for the health care system per year.

      Various explanations may be involved: 1) The current stratification system relies on various
      elements of the follow up of standard of care after kidney transplantation (histology,
      immunology) taken separately and, 2) Current therapeutic strategy is a "one fit for all"
      approach. Literature data show that therapeutics are not individualized, with 98% of patients
      having the same immunosuppressive regimens without analysis of response to therapy; 3) Lack
      of integration of omics in the stratification process. Today, the only approaches used to
      monitor the advent of immune-mediated allograft damage are nonspecific markers such as serum
      creatinine level and proteinuria which are not integrated in a dynamic approach. Some kidney
      transplant programs have implemented surveillance allograft biopsies, but they lack
      specificity and sensitivity and do not provide etiopathology of the underlying process. This
      impairs the risk stratification process.

      In this project, leading European scientific teams, which have created relevant population
      cohorts and expertise, have joined forces to allow for large-scale (>5,000 patients) risk
      prediction studies in the field of kidney transplantation. The overall goal of the EUropean
      TRAnsplantation and INnovation consortium (EU-TRAIN) is to prevent kidney allograft failure
      and improve allograft survival by informing clinical decision and delivering optimised
      interventions to patients at individual level. The project aims to improve the current gold
      standard for risk stratification and prognosis among kidney transplant recipients.

      The members of the EU-TRAIN consortium have invested heavily in the last decade to create
      large highly detailed European kidney transplant cohorts and to achieve best level scientific
      expertise in the assessment of innovative biomarkers and rejection reclassification on the
      basis of disease mechanism using gene expression. Ground-breaking concrete results have
      already been obtained that have changed patient care and transplant medicine guidelines: This
      is underlined by highly cited publications in the leading specialised journals and also in
      journals aimed at a popular audience that underlines the systemic nature of this approach,
      (NEJM (n=10), Lancet (n=2), BMJ (n=1), JASN (n=18)). Using this approach, the investigators
      have recently identified new forms of allograft rejection, resulting in changes in the most
      recent international allograft Banff classification and reclassifying rejection diagnosis and
      disease stage. This research strategy also led to recently demonstrate the clinical relevance
      of new non-invasive biomarkers for defining the pathogenicity of anti-HLA antibodies and
      allograft loss risk assessment and incorporate gene expression measurements in allograft
      rejection risk stratification.

      The EU-TRAIN project will further elevate these cohorts synergistically by adding data on
      novel biomarkers, so far underdeveloped in kidney transplant research, in particular genomics
      and immunological data. A comprehensive integration strategy of these exceptionally large and
      complete cohorts constitutes a quantum leap in transplant research, and offers a unique
      opportunity, out of reach so far, to design strategies for truly personalised medicine.

      The expected benefit for participants and society will be to reduce the financial burden of
      graft rejection for society.

      500 new transplanted patients in the 7 clinical transplant sites will be included in the
      prospective multicentre EU-TRAIN cohort with centralised analysis of samples in CHUN (blood
      mRNA), ICS (blood cellular assays), Charité (non-HLA antibodies and blood endothelial
      targets), AP-HP (blood anti-HLA DSA), and INSERM (Biopsy mRNA).

      Vulnerable participants excluded.

      Schedule for the study:

        -  inclusion period: 12 months

        -  participation period (treatment - follow-up): 12 months

        -  total duration of the study: 24 months

      Exclusion period for participation in other studies, and justification: the participation to
      other minimal risks and constraints studies and observational non-interventional studies is
      allowed during this study. There is no exclusion period at the end of study. The
      participation to other interventional and observational non-interventional studies is allowed
      after the end of the study.

      Number of enrolments expected per site and per month :

        -  Necker Hospital, Paris: 10 patients / month

        -  Saint-Louis Hospital, Paris: 6 patients / month

        -  CHU Nantes: 10 patients / month

        -  Charité-Universitätsmedizin, Campus Virchow Klinikum, Berlin: 4 patients / month

        -  Charité-Universitätsmedizin, Campus Mitte, Berlin: 3 patients / month

        -  Bellvitge University Hospital, Barcelona: 7 patients / month

        -  Geneva University Hospitals, Geneva: 2 patients / month

        -  Vall d'Hebron Hospital, Barcelona : 6 patients / month

        -  Kremlin Bicêtre Hospital, Paris : 4 patients / month
    

Intervention name(s): kidney transplantation
Intervention type(s): Procedure
Intervention description(s): samples additional to the standard of care' (SOC)will be taken at each visit (Day 0, Month 3, Month12, clinical indication)
Other intervention name(s): Gene expression analysis in the biopsy; Non-HLA antibody analysis in the blood; Protein biomarker analysis in the blood; T and B cell analyses in the blood; mRNA in the blood
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        New kidney transplants patients
      
Biospecimen description: 
      blood samples, kidney biopsy samples for these analysis : Transcriptomics analysis
      Characteristics of anti HLA DSA analysis on endothelial targets Non-HLA antibodies analysis
      Omics blood analysis T and B cell analyses (ELISPOT) Blood mRNA
    
Keywords: Kidney; Allogenic transplantation; Cohort study; Rejection; Biomarkers; Response to treatment; Integrative medicine