Identification and Cross-Platform Validation of Sparse Molecular Classifiers for Antibody-Mediated and T-Cell–Mediated Rejection After Kidney Transplantation
Kidney International Reports, vol. 10, pp. 1806–1818
Abstract
Introduction Molecular classifiers are a promising tool to refine the diagnosis of antibody-mediated rejection (ABMR) and T-cell–mediated rejection (TCMR) after kidney transplantation. Despite this potential, the integration of molecular classifiers in transplant clinics has been slow, in part because of the complexity of current assays and lack of a consensus platform. Herein, we aimed to develop and validate sparse molecular classifiers for ABMR and TCMR using allograft tissue. Methods In a discovery cohort of 224 kidney transplant biopsies, lasso regression was applied on microarray gene expression data to derive a molecular classifier for ABMR and TCMR, respectively. Results A 2-gene classifier for ABMR ( PLA1A , GNLY) and a 2-gene classifier for TCMR ( IL12RB1 , ARPC1B) were identified. External validation ( n = 403 biopsies) demonstrated preserved diagnostic accuracy for ABMR (area under the receiver operating characteristic curve [ROC-AUC]: 0.80, 95% confidence interval [CI]: 0.75–0.85) and TCMR (ROC-AUC: 0.83, 95% CI: 0.77–0.89), with the possibility to discriminate between pure and mixed rejection phenotypes. Complementary to their diagnostic potential, the molecular classifiers associated with accelerated graft loss in a second validation cohort ( n = 282 biopsies) and identified allografts at risk for failure with histological lesions that did not reach the Banff thresholds for rejection. The computational approach was further validated using the Banff Human Organ Transplant (B-HOT) gene panel in 2 independent biopsy cohorts that were analyzed on the Nanostring nCounter platform ( n = 66 and n = 80, respectively). Conclusion Rigid variable selection strategies can yield sparse molecular classifiers for allograft rejection phenotypes with preserved accuracy and prognostic value across different molecular diagnostic platforms, which may facilitate their interpretation and clinical implementation.
Authors 23
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Universitair Ziekenhuis Leuven · KU Leuven
Affiliation as printed
Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
Nephrology and Renal Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
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Center for Information Services and High Performance Computing · Technische Universität Dresden · Universidad Nacional Autónoma de México
Affiliation as printed
Department of Mathematics, Faculty of Sciences, Universidad Nacional Autónoma de México, Mexico City, Mexico
Zentrum für Informationsdienste und Hochleistungsrechnen, Innovative Methods of Computing, Technische Universität Dresden, Dresden, Germany
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Hôpital Necker-Enfants Malades · Inserm · Université Paris Cité · Institut Necker Enfants Malades · Assistance Publique – Hôpitaux de Paris
Affiliation as printed
Department of Nephrology and Kidney Transplantation, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
Institut Necker-Enfants Malades, INSERM U1151, Paris, France
Université de Paris, Paris, France
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Affiliation as printed
Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College, London, UK
Imperial College Renal and Transplant Centre, Imperial College NHS Trust, London, UK
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Medizinische Hochschule Hannover
Affiliation as printed
Nephropathology Unit, Institute of Pathology, Hannover Medical School, Hannover, Germany
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Erasmus MC · Universitätsklinikum Aachen · Erasmus MC Transplant Institute · RWTH Aachen University
Affiliation as printed
Department of Medicine 2, Medical Faculty, RWTH Aachen University Hospital, Aachen, Germany
Department of Pathology and Clinical Bioinformatics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
Erasmus MC Transplant Institute, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
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Erasmus MC · Erasmus MC Transplant Institute
Affiliation as printed
Department of Pathology and Clinical Bioinformatics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
Erasmus MC Transplant Institute, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
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Affiliation as printed
Nephrology and Renal Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
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Center for Information Services and High Performance Computing · Technische Universität Dresden
Affiliation as printed
Zentrum für Informationsdienste und Hochleistungsrechnen, Innovative Methods of Computing, Technische Universität Dresden, Dresden, Germany
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Assistance Publique – Hôpitaux de Paris · Hôpital Ambroise-Paré
Affiliation as printed
AP-HP Paris Saclay, Ambroise Pare Hospital, Department of Nephrology, Boulogne Billancourt, France
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Medizinische Hochschule Hannover
Affiliation as printed
Nephrology, Internal Medicine, Hannover Medical School, Hannover, Germany
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Affiliation as printed
Department of Medicine, Division of Nephrology and Transplant Immunology, University of Alberta, Edmonton, Alberta, Canada
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Erasmus MC · Erasmus MC Transplant Institute
Affiliation as printed
Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, The Netherlands
Erasmus MC Transplant Institute, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
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Universitair Ziekenhuis Leuven
Affiliation as printed
Department of Morphology and Molecular Pathology, University Hospitals Leuven, Leuven, Belgium
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Universitair Ziekenhuis Leuven · KU Leuven
Affiliation as printed
Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
Nephrology and Renal Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
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Universitair Ziekenhuis Leuven
Affiliation as printed
Department of Morphology and Molecular Pathology, University Hospitals Leuven, Leuven, Belgium
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Inserm · Centre Hospitalier Universitaire de Limoges · Université de Limoges
Affiliation as printed
Pharmacology and Transplantation, INSERM U1248, CHU Limoges, Université de Limoges, Limoges, France
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Erasmus MC · Erasmus MC Transplant Institute
Affiliation as printed
Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
Erasmus MC Transplant Institute, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
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North West London Pathology · Imperial College London
Affiliation as printed
Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College, London, UK
Department of Cellular Pathology, North West London Pathology, London, UK
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Universitair Ziekenhuis Leuven · KU Leuven
Affiliation as printed
Department of Microbiology and Immunology, Laboratory of Molecular Immunology, Rega Institute, KU Leuven, Leuven, Belgium
Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
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Universitair Ziekenhuis Leuven · KU Leuven
Affiliation as printed
Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
Nephrology and Renal Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
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Khalifa University of Science and Technology · Helmholtz Centre for Infection Research · Center for Information Services and High Performance Computing · Technische Universität Dresden
Affiliation as printed
Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany
Mathematics Department, Khalifa University, Abu Dhabi, United Arab Emirates
Zentrum für Informationsdienste und Hochleistungsrechnen, Innovative Methods of Computing, Technische Universität Dresden, Dresden, Germany
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Maarten Naesens corresponding
Universitair Ziekenhuis Leuven · KU Leuven
Affiliation as printed
Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
Nephrology and Renal Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
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