{
  "abstract": "Objective To perform comprehensive validations of the integrative Box (iBox) system, a prediction model for long term risk of kidney allograft failure, for extension of its context of use in clinical trials as well as for its wider implementation in clinical practice.Design Extended validation study.Setting Paris Transplant Group database (comprising kidney recipients with transplantations between 1 January 2005 and 1 January 2014) and European, North American, and South American hospitals (comprising recipients of kidneys transplanted beween 1 January 2000 and 1 January 2022). Patients were followed until 1 November 2024.Participants 12 683 kidney tranplant recipients from 21 academic centres in Europe, North America, and South America; 4000 patients in the derivation cohort and 8683 in the validation cohorts.Main outcome measures Performance of the iBox, including flexible iBox versions in specific clinical contexts (race-free estimated glomerular filtration rate (eGFR) equations (ie, without including race as a factor in the calculation), in specific clinical contexts (initial nephropathy recurrence, BK virus associated nephropathy, and different immunosuppressive strategies), and over-extended follow-up periods. Predictive performance was assessed by discrimination, calibration, overall fit, and clinical utility.Results 12 683 kidney transplant recipients were included in the study (n=4000 in the derivation cohort and n=8683 in the validation cohorts). Median follow-up time after risk evaluation was 5.78 years (interquartile range (IQR) 3.51-7.00) in the derivation cohort and 4.68 years (2.48-7.00) in the validation cohorts. 549 (13.7%) and 991 (11.4%) patients had graft loss in the derivation and validation cohorts, respectively. All versions of the iBox algorithm maintained good discrimination and overall fit performance in the derivation and validation cohorts (C index range 0.79-0.87, Brier scores 0.08-0.11). Calibration was adequate in some but not all external validation cohorts, with trends toward overestimation or underestimation of predicted risks. Decision curve analysis showed positive and comparable net benefit for all iBox algorithms across decision thresholds up to 40% in the derivation cohort (net benefit 0.07-0.08 at 20% threshold) and validation cohorts (net benefit 0.03-0.11 at 20% threshold). Accounting for the competing risk of death with a functioning graft resulted in similar performance, except for calibration which varied across cohorts, without any model consistently outperforming any other model. The model performed well with different race-free eGFR equations (C index 0.81), in various clinical scenarios, including disease recurrence and BK virus nephropathy, with different immunosuppressive strategies, such as calcineurin inhibitors and mTOR (mechanistic target of rapamycin) inhibitors (C index range 0.74-0.87), and when extending the prediction period to 10 years after risk evaluation (C index 0.79). The iBox predictive performance was not modified when various histological indices were used. The iBox was also superior to eGFR slope (C index 0.81 v 0.62) and circulating anti-HLA donor specific antibodies (C index 0.81 v 0.57) in its predictive ability.Conclusions In this study, the robust predictive performance of the iBox system across diverse real world settings and clinical scenarios was shown. These results highlight the versatility and reliability of the iBox system, and support its use for risk stratification in routine clinical practice and as a surrogate endpoint for clinical trials.",
  "authors": [
    {
      "affiliations": [
        "Université de Paris Cité, INSERM, PARCC U970, Paris Institute for Transplantation and Organ Regeneration (PITOR), Paris, France"
      ],
      "name": "Marc Raynaud"
    },
    {
      "affiliations": [
        "Université de Paris Cité, INSERM, PARCC U970, Paris Institute for Transplantation and Organ Regeneration (PITOR), Paris, France"
      ],
      "name": "Agathe Truchot"
    },
    {
      "affiliations": [
        "Université de Paris Cité, INSERM, PARCC U970, Paris Institute for Transplantation and Organ Regeneration (PITOR), Paris, France"
      ],
      "name": "Sofia Naser"
    },
    {
      "affiliations": [
        "Kidney Transplant Department, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France"
      ],
      "name": "Olivier Aubert"
    },
    {
      "affiliations": [
        "Université de Paris Cité, INSERM, PARCC U970, Paris Institute for Transplantation and Organ Regeneration (PITOR), Paris, France",
        "Kidney Transplant Department, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France"
      ],
      "name": "Gillian Divard"
    },
    {
      "affiliations": [
        "Université de Paris Cité, INSERM, PARCC U970, Paris Institute for Transplantation and Organ Regeneration (PITOR), Paris, France"
      ],
      "name": "Thibaut Thalamas"
    },
    {
      "affiliations": [
        "Université de Paris Cité, INSERM, PARCC U970, Paris Institute for Transplantation and Organ Regeneration (PITOR), Paris, France",
        "Department of Nephrology, Tenon Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France"
      ],
      "name": "Yannis Lombardi"
    },
    {
      "affiliations": [
        "Kidney Transplant Department, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France"
      ],
      "name": "Christophe Legendre"
    },
    {
      "affiliations": [
        "Nephrology and Immunology Department, Bretonneau Hospital, Tours, France"
      ],
      "name": "Elodie Bailly"
    },
    {
      "affiliations": [
        "Nephrology and Immunology Department, Bretonneau Hospital, Tours, France"
      ],
      "name": "Mathias Buchler"
    },
    {
      "affiliations": [
        "Department of Nephrology, Hospital del Mar, Barcelona, Spain"
      ],
      "name": "Marta Crespo"
    },
    {
      "affiliations": [
        "Department of Nephrology, Hospital del Mar, Barcelona, Spain"
      ],
      "name": "Dolores Redondo"
    },
    {
      "affiliations": [
        "Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA",
        "Department of Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA"
      ],
      "name": "Brad C Astor"
    },
    {
      "affiliations": [
        "Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA",
        "Department of Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA"
      ],
      "name": "Didier Mandelbrot"
    },
    {
      "affiliations": [
        "Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA",
        "Department of Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA"
      ],
      "name": "Sandesh Parajuli"
    },
    {
      "affiliations": [
        "Université de Paris Cité, INSERM, PARCC U970, Paris Institute for Transplantation and Organ Regeneration (PITOR), Paris, France",
        "Department of Nephrology, Arterial Hypertension, Dialysis and Transplantation, University Hospital Centre Zagreb, School of Medicine, University of Zagreb, Zagreb, Croatia"
      ],
      "name": "Ivana Juric"
    },
    {
      "affiliations": [
        "Department of Nephrology, Arterial Hypertension, Dialysis and Transplantation, University Hospital Centre Zagreb, School of Medicine, University of Zagreb, Zagreb, Croatia"
      ],
      "name": "Nikolina Basic-Jukic"
    },
    {
      "affiliations": [
        "Department of Transplantation and Liver Surgery, Helsinki University Central Hospital, Helsinki, Finland"
      ],
      "name": "Ilkka Helanterä"
    },
    {
      "affiliations": [
        "Centre for Kidney and Bladder Health, University College London, Royal Free Hospital, London, UK"
      ],
      "name": "Rhys D R Evans"
    },
    {
      "affiliations": [
        "Centre for Kidney and Bladder Health, University College London, Royal Free Hospital, London, UK"
      ],
      "name": "Aruna Sanghera"
    },
    {
      "affiliations": [
        "Centre for Kidney and Bladder Health, University College London, Royal Free Hospital, London, UK"
      ],
      "name": "Maryam Javed"
    },
    {
      "affiliations": [
        "Department of Internal Medicine, Division of Nephrology and Hypertension, Spencer Fox Eccles School of Medicine at the University of Utah, Salt Lake City, Utah, USA"
      ],
      "name": "Miklos Z Molnar"
    },
    {
      "affiliations": [
        "Department of Internal Medicine, Division of Nephrology and Hypertension, Spencer Fox Eccles School of Medicine at the University of Utah, Salt Lake City, Utah, USA"
      ],
      "name": "Junji Yamauchi"
    },
    {
      "affiliations": [
        "Department of Surgery, Division of Transplantation and Advanced Hepatobiliary Surgery, Spencer Fox Eccles School of Medicine at the University of Utah, Salt Lake City, Utah, USA"
      ],
      "name": "Katalin Fornadi"
    },
    {
      "affiliations": [
        "Universidade Federal de Sao Paulo, Hospital do Rim, Escola Paulista de Medicina, Sao Paulo, Brazil"
      ],
      "name": "Kamilla Linhares"
    },
    {
      "affiliations": [
        "Association \"Le Flambeau de la Vie”, Paris, France"
      ],
      "name": "Michel Baujard"
    },
    {
      "affiliations": [
        "The Voice of the Patient, Saint Louis, Missouri, USA"
      ],
      "name": "Kevin J Fowler"
    },
    {
      "affiliations": [
        "Albert Einstein College of Medicine, Renal Division Montefiore Medical Center, Kidney Transplantation Program, Bronx, New York, New York, USA"
      ],
      "name": "Enver Akalin"
    },
    {
      "affiliations": [
        "Division of Nephrology, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA"
      ],
      "name": "Gaurav Gupta"
    },
    {
      "affiliations": [
        "Unidad de Trasplante Renopancreas, Centro de Educacion Medica e Investigaciones Clinicas, Buenos Aires, Argentina"
      ],
      "name": "Gervacio Soler Pujol"
    },
    {
      "affiliations": [
        "Universidade Federal de Sao Paulo, Hospital do Rim, Escola Paulista de Medicina, Sao Paulo, Brazil"
      ],
      "name": "Helio Tedesco-Silva"
    },
    {
      "affiliations": [
        "NYU Grossman School of Medicine, Departments of Surgery and Medicine, New York, New York, USA"
      ],
      "name": "Babak J Orandi"
    },
    {
      "affiliations": [
        "Department of Microbiology, Immunology, and Transplantation, KU Leuven, Leuven, Belgium"
      ],
      "name": "Maarten Naesens"
    },
    {
      "affiliations": [
        "Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany"
      ],
      "name": "Klemens Budde"
    },
    {
      "affiliations": [
        "Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany"
      ],
      "name": "Marcel Naik"
    },
    {
      "affiliations": [
        "Department of Transplantation, Nephrology, and Clinical Immunology, Foch Hospital, Suresnes, France"
      ],
      "name": "Alexandre Hertig"
    },
    {
      "affiliations": [
        "Kidney Transplant Department, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France"
      ],
      "name": "Dany Anglicheau"
    },
    {
      "affiliations": [
        "Department of Nephrology and Organ Transplantation, Toulouse Rangueil University Hospital, INSERM UMR 1291, Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), University Paul Sabatier, Toulouse, France"
      ],
      "name": "Nassim Kamar"
    },
    {
      "affiliations": [
        "NYU Grossman School of Medicine, Departments of Surgery and Population Health, New York, New York, USA"
      ],
      "name": "Dorry L Segev"
    },
    {
      "affiliations": [
        "Université de Paris Cité, INSERM, PARCC U970, Paris Institute for Transplantation and Organ Regeneration (PITOR), Paris, France",
        "Kidney Transplant Department, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France"
      ],
      "name": "Carmen Lefaucheur"
    },
    {
      "affiliations": [
        "Université de Paris Cité, INSERM, PARCC U970, Paris Institute for Transplantation and Organ Regeneration (PITOR), Paris, France",
        "Kidney Transplant Department, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France"
      ],
      "name": "Alexandre Loupy"
    }
  ],
  "title": "Qualified prediction system for allograft failure in real world settings: extended validation study",
  "uid": "ef4cc863-0800-59ee-8631-47e269ef53dd"
}