Continuous indices to assess the phenotypic spectrum of kidney transplant rejection

Thibaut Vaulet, Priyanka Koshy, Karolien Wellekens, Olivier Aubert, Charlotte Bottomley, Jasper Callemeyn, Evert Cleenders, Maarten Coemans, Lynn Cornell, Aiko P. J. de Vries, Gillian Divard, Marie-Paule Emonds, Sandrine Florquin, Mark Haas, Philip F. Halloran, Jesper Kers, Dirk Kuypers, Thangamani Muthukumar, Angelica Pagliazzi, Steven Salvatore, Olivier Thaunat, Surya V. Seshan, Elisabet Van Loon, Thomas Vanhoutte, Georg A. Böhmig, Friedrich A. von Samson-Himmelstjerna, Michelle Willicombe, Aravind Cherukuri, Alexandre Loupy, Candice Roufosse and Maarten Naesens ()
Additional contact information
Thibaut Vaulet: KU Leuven, Nephrology and Renal Transplantation Research Group, Department of Microbiology, Immunology and Transplantation
Priyanka Koshy: KU Leuven, Nephrology and Renal Transplantation Research Group, Department of Microbiology, Immunology and Transplantation
Karolien Wellekens: KU Leuven, Nephrology and Renal Transplantation Research Group, Department of Microbiology, Immunology and Transplantation
Olivier Aubert: Necker Enfants Malades Institute (INEM), Université Paris Cité, Inserm UMR1151
Charlotte Bottomley: Imperial College, Department of Immunology and Inflammation
Jasper Callemeyn: KU Leuven, Nephrology and Renal Transplantation Research Group, Department of Microbiology, Immunology and Transplantation
Evert Cleenders: KU Leuven, Nephrology and Renal Transplantation Research Group, Department of Microbiology, Immunology and Transplantation
Maarten Coemans: KU Leuven, Nephrology and Renal Transplantation Research Group, Department of Microbiology, Immunology and Transplantation
Lynn Cornell: Department of Pathology & Laboratory Medicine and Department of Medicine at the University of Calgary
Aiko P. J. de Vries: Leiden University Medical Center, Division of Nephrology, Department of Medicine
Gillian Divard: Paris Institute for Transplantation and Organ Regeneration, Université Paris Cité, INSERM U970 PARCC
Marie-Paule Emonds: Belgian Red Cross-Flanders, Histocompatibility and Immunogenetics Laboratory
Sandrine Florquin: Dept. of Pathology, Amsterdam UMC, University of Amsterdam
Mark Haas: Cedars-Sinai Medical Center, Department of Pathology and Laboratory Medicine
Philip F. Halloran: University of Alberta, Department of Medicine
Jesper Kers: Leiden University Medical Center, Division of Nephrology, Department of Medicine
Dirk Kuypers: KU Leuven, Nephrology and Renal Transplantation Research Group, Department of Microbiology, Immunology and Transplantation
Thangamani Muthukumar: Weill Cornell Medicine, Division of Nephrology and Hypertension
Angelica Pagliazzi: KU Leuven, Nephrology and Renal Transplantation Research Group, Department of Microbiology, Immunology and Transplantation
Steven Salvatore: Weill Cornell Medicine, Department of Pathology and Laboratory Medicine
Olivier Thaunat: Univ. Lyon, CIRI, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon
Surya V. Seshan: Weill Cornell Medicine, Department of Pathology and Laboratory Medicine
Elisabet Van Loon: KU Leuven, Nephrology and Renal Transplantation Research Group, Department of Microbiology, Immunology and Transplantation
Thomas Vanhoutte: KU Leuven, Nephrology and Renal Transplantation Research Group, Department of Microbiology, Immunology and Transplantation
Georg A. Böhmig: Medical University of Vienna, Division of Nephrology and Dialysis, Department of Medicine III
Friedrich A. von Samson-Himmelstjerna: University Hospital Schleswig-Holstein—Campus Kiel, Department of Nephrology and Hypertension
Michelle Willicombe: Imperial College, Department of Immunology and Inflammation
Aravind Cherukuri: University of Pittsburgh, Thomas E. Starzl Transplantation Institute
Alexandre Loupy: Paris Institute for Transplantation and Organ Regeneration, Université Paris Cité, INSERM U970 PARCC
Candice Roufosse: Imperial College, Department of Immunology and Inflammation
Maarten Naesens: KU Leuven, Nephrology and Renal Transplantation Research Group, Department of Microbiology, Immunology and Transplantation

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract The Banff classification for kidney transplant pathology dichotomizes the rejection continuum into distinct diagnostic categories, introducing artificial cutoff points and threshold effects. To better reflect the underlying disease spectrum, in this cohort study of 19,500 biopsies from 8873 patients across 10 centers worldwide, we developed two indices for quantifying antibody-mediated rejection/microvascular inflammation and T-cell-mediated rejection/tubulointerstitial inflammation from histological lesion scores and calculated indices for overall activity and chronicity. These indices demonstrate excellent discrimination for the main diagnostic categories of rejection (AUCs from 0.95 to 0.99), with consistent performance across derivation and validation datasets. These indices strictly confine intermediate phenotypes to low index values and are associated to graft failure even within the diagnostic categories, thus reflecting the underlying rejection continuum. In this work, we demonstrate that four continuous indices provide implementable and interpretable global evaluation of kidney transplant histology that align with the continuous nature of the rejection process regardless of the underlying disease cause.

Date: 2025
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DOI: 10.1038/s41467-025-65153-9

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