Development and validation of a peripheral blood mRNA assay for the assessment of antibody-mediated kidney allograft rejection: A multicentre, prospective studyResearch in context
Elisabet Van Loon,
Stéphane Gazut,
Saleh Yazdani,
Evelyne Lerut,
Henriette de Loor,
Maarten Coemans,
Laure-Hélène Noël,
Lieven Thorrez,
Leentje Van Lommel,
Frans Schuit,
Ben Sprangers,
Dirk Kuypers,
Marie Essig,
Wilfried Gwinner,
Dany Anglicheau,
Pierre Marquet,
Maarten Naesens
Affiliations
Elisabet Van Loon
Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, Leuven, Belgium; University Hospitals Leuven, Department of Nephrology and Renal Transplantation, Leuven, Belgium
Stéphane Gazut
CEA, LIST, Laboratory for Data Analysis and Systems' Intelligence, Gif-sur-Yvette, France
Saleh Yazdani
Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, Leuven, Belgium
Evelyne Lerut
University Hospitals Leuven, Department of Morphology and Molecular Pathology, Leuven, Belgium
Henriette de Loor
Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, Leuven, Belgium
Maarten Coemans
Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, Leuven, Belgium
Laure-Hélène Noël
Necker-Enfants Malades Institute, French National Institute of Health and Medical Research U1151, France
Lieven Thorrez
KU Leuven Department of Development and Regeneration, campus KULAK, Kortrijk, Belgium
Leentje Van Lommel
KU Leuven Gene Expression Unit, Department of Cellular and Molecular Medicine, Leuven, Belgium
Frans Schuit
KU Leuven Gene Expression Unit, Department of Cellular and Molecular Medicine, Leuven, Belgium
Ben Sprangers
Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, Leuven, Belgium; University Hospitals Leuven, Department of Nephrology and Renal Transplantation, Leuven, Belgium; KU Leuven Laboratory of Molecular Immunology, Rega Institute, Leuven, Belgium
Dirk Kuypers
Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, Leuven, Belgium; University Hospitals Leuven, Department of Nephrology and Renal Transplantation, Leuven, Belgium
Marie Essig
CHU Limoges, Department of Nephrology, Dialysis and Transplantation, Univ. Limoges, U850 INSERM, Limoges, France
Wilfried Gwinner
Department of Nephrology, Hannover Medical School, Hannover, Germany
Dany Anglicheau
Paris Descartes, Sorbonne Paris Cité University, INSERM U1151, Paris, France; Department of Nephrology and Kidney Transplantation, RTRS Centaure, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
Pierre Marquet
CHU Limoges, Univ. Limoges, U850 INSERM, Limoges, France
Maarten Naesens
Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, Leuven, Belgium; University Hospitals Leuven, Department of Nephrology and Renal Transplantation, Leuven, Belgium; Corresponding author at: Department of Microbiology, Immunology and Transplantation, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
Background: Antibody-mediated rejection, a leading cause of renal allograft graft failure, is diagnosed by histological assessment of invasive allograft biopsies. Accurate non-invasive biomarkers are not available. Methods: In the multicentre, prospective BIOMARGIN study, blood samples were prospectively collected at time of renal allograft biopsies between June 2011 and August 2016 and analyzed in three phases. The discovery and derivation phases of the study (N = 117 and N = 183 respectively) followed a case-control design and included whole genome transcriptomics and targeted mRNA expression analysis to construct and lock a multigene model. The primary end point was the diagnostic accuracy of the locked multigene assay for antibody-mediated rejection in a third validation cohort of serially collected blood samples (N = 387). This trial is registered with ClinicalTrials.gov, number NCT02832661. Findings: We identified and locked an 8-gene assay (CXCL10, FCGR1A, FCGR1B, GBP1, GBP4, IL15, KLRC1, TIMP1) in blood samples from the discovery and derivation phases for discrimination between cases with (N = 49) and without (N = 134) antibody-mediated rejection. In the validation cohort, this 8-gene assay discriminated between cases with (N = 41) and without antibody-mediated rejection (N = 346) with good diagnostic accuracy (ROC AUC 79·9%; 95% CI 72·6 to 87·2, p < 0·0001). The diagnostic accuracy of the 8-gene assay was retained both at time of stable graft function and of graft dysfunction, within the first year and also later after transplantation. The 8-gene assay is correlated with microvascular inflammation and transplant glomerulopathy, but not with the histological lesions of T-cell mediated rejection. Interpretation: We identified and validated a novel 8-gene expression assay that can be used for non-invasive diagnosis of antibody-mediated rejection. Funding: The Seventh Framework Programme (FP7) of the European Commission. Keywords: Kidney transplantation, Antibody-mediated rejection, Biomarker
