Molecular microscope strategy to improve risk stratification in early antibody-mediated kidney allograft rejection.
Antibody-mediated rejection (ABMR) is the leading cause of kidney allograft loss. We investigated whether the addition of gene expression measurements to conventional methods could serve as a molecular microscope to identify kidneys with ABMR that are at high risk for failure. We studied 939 consecutive kidney recipients at Necker Hospital (2004-2010; principal cohort) and 321 kidney recipients at Saint Louis Hospital (2006-2010; validation cohort) and assessed patients with ABMR in the first 1 year post-transplant. In addition to conventional features, we assessed microarray-based gene expression in transplant biopsy specimens using relevant molecular measurements: the ABMR Molecular Score and endothelial donor-specific antibody-selective transcript set. The main outcomes were kidney transplant loss and progression to chronic transplant injury. We identified 74 patients with ABMR in the principal cohort and 54 patients with ABMR in the validation cohort. Conventional features independently associated with failure were donor age and humoral histologic score (g+ptc+v+cg+C4d). Adjusting for conventional features, ABMR Molecular Score (hazard ratio [HR], 2.22; 95% confidence interval [95% CI], 1.37 to 3.58; P=0.001) and endothelial donor-specific antibody-selective transcripts (HR, 3.02; 95% CI, 1.00 to 9.16; P<0.05) independently associated with an increased risk of graft loss. The results were replicated in the independent validation group. Adding a gene expression assessment to a traditional risk model improved the stratification of patients at risk for graft failure (continuous net reclassification improvement, 1.01; 95% CI, 0.57 to 1.46; P<0.001; integrated discrimination improvement, 0.16; P<0.001). Compared with conventional assessment, the addition of gene expression measurement in kidney transplants with ABMR improves stratification of patients at high risk for graft loss.
Paris Descartes University and Hôpital Necker and Paris Translational Research Center for Organ Transplantation, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-S970, Paris, France;
Alexandre
A
Loupy
Paris Translational Research Center for Organ Transplantation, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-S970, Paris, France; Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris, Paris, France;
Carmen
C
Lefaucheur
Paris Translational Research Center for Organ Transplantation, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-S970, Paris, France; Unit 3181, University Hospital of Besançon, France;
Dewi
D
Vernerey
Alberta Transplant Applied Genomics Centre, Edmonton, Alberta, Canada;
Jessica
J
Chang
Alberta Transplant Applied Genomics Centre, Edmonton, Alberta, Canada; Department of Laboratory Medicine and Pathology and.
Luis G
LG
Hidalgo
Paris Translational Research Center for Organ Transplantation, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-S970, Paris, France;
Thibaut
T
Beuscart
Department of Pathology, Saint Louis Hospital, Paris, France;
Jerome
J
Verine
Paris Translational Research Center for Organ Transplantation, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-S970, Paris, France;
Olivier
O
Aubert
Pateforme Centres de Resources Biologiques, Institut Gustave Roussy, Villejuif, France; and.
Sébastien
S
Dubleumortier
Paris Descartes University and Hôpital Necker and Paris Translational Research Center for Organ Transplantation, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-S970, Paris, France; Department of Pathology, Necker Hospital, Paris, France.
Jean-Paul
JP
Duong van Huyen
Paris Translational Research Center for Organ Transplantation, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-S970, Paris, France;
Xavier
X
Jouven
Paris Translational Research Center for Organ Transplantation, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-S970, Paris, France; Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris, Paris, France;
Denis
D
Glotz
Paris Descartes University and Hôpital Necker and Paris Translational Research Center for Organ Transplantation, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-S970, Paris, France;
Christophe
C
Legendre
Alberta Transplant Applied Genomics Centre, Edmonton, Alberta, Canada; Department of Medicine, Division of Nephrology and Transplant Immunology, University of Alberta, Edmonton, Alberta, Canada; phil.halloran@ualberta.ca.
Philip F
PF
Halloran
D000328:Adult; D000368:Aged; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D018570:Risk Assessment; D019737:Transplants / Q000378:metabolism*