Development and validation of the first consensus gene-expression signature of operational tolerance in kidney transplantation, incorporating adjustment for immunosuppressive drug therapy

Christakoudi, S. et al. (2020) Development and validation of the first consensus gene-expression signature of operational tolerance in kidney transplantation, incorporating adjustment for immunosuppressive drug therapy. EBioMedicine, 58, 102899. (doi: 10.1016/j.ebiom.2020.102899)

Abstract

Background: Kidney transplant recipients (KTRs) with “operational tolerance” (OT) maintain a functioning graft without immunosuppressive (IS) drugs, thus avoiding treatment complications. Nevertheless, IS drugs can influence gene-expression signatures aiming to identify OT among treated KTRs. Methods: We compared five published signatures of OT in peripheral blood samples from 18 tolerant, 183 stable, and 34 chronic rejector KTRs, using gene-expression levels with and without adjustment for IS drugs and regularised logistic regression. Findings: IS drugs explained up to 50% of the variability in gene-expression and 20–30% of the variability in the probability of OT predicted by signatures without drug adjustment. We present a parsimonious consensus gene-set to identify OT, derived from joint analysis of IS-drug-adjusted expression of five published signature gene-sets. This signature, including CD40, CTLA4, HSD11B1, IGKV4–1, MZB1, NR3C2, and RAB40C genes, showed an area under the curve 0⋅92 (95% confidence interval 0⋅88–0⋅94) in cross-validation and 0⋅97 (0⋅93–1⋅00) in six months follow-up samples. Interpretation: We advocate including adjustment for IS drug therapy in the development stage of gene-expression signatures of OT to reduce the risk of capturing features of treatment, which could be lost following IS drug minimisation or withdrawal. Our signature, however, would require further validation in an independent dataset and a biomarker-led trial.

• Item Type: Articles
• Additional Information: The authors acknowledge financial support from FP7-HEALTH-2012-INNOVATION-1 (project number 305147: BIO-DrIM); Medical Research Council MRC grants to Maria P. Hernandez-Fuentes [G0801537/ID: 88245] and to MRC Centre for Transplantation [MRC grant no. MR/J006742/1]); Guy's and St Thomas’ Charity [grants R080530 and R090782]; NIHR-BRC School for Translational and Experimental Medicine/Cluster 4 Early Career Award in Translational Science to Sofia Christakoudi. Sofia Christakoudi, Irene Rebollo-Mesa, Paula Mobillo, and Daniel Stahl were also funded by the EU project BIO-DrIM. Estefania Nova-Lamperti was funded by a scholarship from CONICYT Bicentennial Becas-Chile, Chile. Maria P. Hernandez-Fuentes has also received funding from the European Union, Seventh Framework Programme [FP7/2007–2013], under grant agreement [No HEALTH-F5–2010–260687: The ONE Study]. Ondrej Viklický received funding from the Czech Ministry of Health [grant number NV19–06–00031]. The research was funded/supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Mark, Professor Patrick
• Authors: Christakoudi, S., Runglall, M., Mobillo, P., Rebollo-Mesa, I., Tsui, T.-L., Nova-Lamperti, E., Taube, C., Norris, S., Kamra, Y., Hilton, R., Augustine, T., Bhandari, S., Baker, R., Berglund, D., Carr, S., Game, D., Griffin, S., Kalra, P. A., Lewis, R., Mark, P. B., Marks, S. D., MacPhee, I., McKane, W., Mohaupt, M. G., Paz-Artal, E., Kon, S. P., Serón, D., Sinha, M. D., Tucker, B., Viklický, O., Stahl, D., Lechler, R. I., Lord, G. M., and Hernandez-Fuentes, M. P.
• College/School: College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: EBioMedicine
• Publisher: Elsevier
• ISSN: 2352-3964
• ISSN (Online): 2352-3964
• Published Online: 21 July 2020
• Copyright Holders: Copyright © 2020 The Authors
• First Published: First published in EBioMedicine 58:102899
• Publisher Policy: Reproduced under a Creative Commons License