EBioMedicine (Aug 2020)
Development and validation of the first consensus gene-expression signature of operational tolerance in kidney transplantation, incorporating adjustment for immunosuppressive drug therapy
- Sofia Christakoudi,
- Manohursingh Runglall,
- Paula Mobillo,
- Irene Rebollo-Mesa,
- Tjir-Li Tsui,
- Estefania Nova-Lamperti,
- Catharine Taube,
- Sonia Norris,
- Yogesh Kamra,
- Rachel Hilton,
- Titus Augustine,
- Sunil Bhandari,
- Richard Baker,
- David Berglund,
- Sue Carr,
- David Game,
- Sian Griffin,
- Philip A. Kalra,
- Robert Lewis,
- Patrick B. Mark,
- Stephen D. Marks,
- Iain MacPhee,
- William McKane,
- Markus G. Mohaupt,
- Estela Paz-Artal,
- Sui Phin Kon,
- Daniel Serón,
- Manish D. Sinha,
- Beatriz Tucker,
- Ondrej Viklický,
- Daniel Stahl,
- Robert I. Lechler,
- Graham M. Lord,
- Maria P. Hernandez-Fuentes
Affiliations
- Sofia Christakoudi
- MRC Centre for Transplantation, King's College London, Great Maze Pond, London SE1 9RT, UK; Biostatistics and Health Informatics Department, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 16 De Crespigny Park, London SE5 8AF, UK; Correspondence to: Present address. Epidemiology and Biostatistics Department, Imperial College London, Norfolk Place, St Mary's Campus, London W2 1PG, UK.
- Manohursingh Runglall
- NIHR Biomedical Research Centre at Guy's & St Thomas’ NHS Foundation Trust and King's College London, Great Maze Pond, London SE1 9RT, UK
- Paula Mobillo
- MRC Centre for Transplantation, King's College London, Great Maze Pond, London SE1 9RT, UK
- Irene Rebollo-Mesa
- MRC Centre for Transplantation, King's College London, Great Maze Pond, London SE1 9RT, UK; Biostatistics and Health Informatics Department, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 16 De Crespigny Park, London SE5 8AF, UK
- Tjir-Li Tsui
- MRC Centre for Transplantation, King's College London, Great Maze Pond, London SE1 9RT, UK; Guy's and St Thomas’ NHS Foundation Trust, Great Maze Pond, London SE1 9RT, UK
- Estefania Nova-Lamperti
- MRC Centre for Transplantation, King's College London, Great Maze Pond, London SE1 9RT, UK
- Catharine Taube
- MRC Centre for Transplantation, King's College London, Great Maze Pond, London SE1 9RT, UK
- Sonia Norris
- MRC Centre for Transplantation, King's College London, Great Maze Pond, London SE1 9RT, UK
- Yogesh Kamra
- MRC Centre for Transplantation, King's College London, Great Maze Pond, London SE1 9RT, UK
- Rachel Hilton
- Guy's and St Thomas’ NHS Foundation Trust, Great Maze Pond, London SE1 9RT, UK
- Titus Augustine
- Manchester Royal Infirmary, Oxford Rd, Manchester M13 9WL, UK
- Sunil Bhandari
- Hull University Teaching Hospitals NHS Trust, Anlaby Rd, Hull HU3 2JZ, UK
- Richard Baker
- St James's University Hospital, Beckett St, Leeds LS9 7TF, UK
- David Berglund
- Department of Immunology, Genetics and Pathology, Uppsala University, Rudbecklaboratoriet, 751 85 Uppsala, Sweden
- Sue Carr
- Leicester General Hospital, Gwendolen Rd, Leicester LE5 4PW, UK
- David Game
- Guy's and St Thomas’ NHS Foundation Trust, Great Maze Pond, London SE1 9RT, UK
- Sian Griffin
- Cardiff and Vale University Health Board, Cardiff CF14 4XW, UK
- Philip A. Kalra
- Salford Royal NHS Foundation Trust, Stott Ln, Salford M6 8HD, UK
- Robert Lewis
- Queen Alexandra Hospital, Southwick Hill Rd, Cosham, Portsmouth PO6 3LY, UK
- Patrick B. Mark
- University of Glasgow, University Avenue, Glasgow G12 8QQ, UK
- Stephen D. Marks
- Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, London WC1N 3JH, UK; University College London Great Ormond Street Institute of Child Health, NIHR Great Ormond Street Hospital Biomedical Research Centre, London WC1N 1EH, UK
- Iain MacPhee
- St George's Hospital, Blackshaw Rd, London SW17 0QT, UK & Institute of Medical and Biomedical Education, St George's, University of London, Cranmer Terrace, London SW17 0RE
- William McKane
- Northern General Hospital, Herries Rd, Sheffield S5 7AU, UK
- Markus G. Mohaupt
- Internal Medicine, Lindenhofgruppe Berne, Switzerland; University of Bern, Berne, Switzerland; School of Medicine, University of Nottingham, Nottingham NG5 1PB, UK
- Estela Paz-Artal
- Department of Immunology and imas12 Research Institute, University Hospital 12 de Octubre, Madrid, Spain
- Sui Phin Kon
- King's College Hospital NHS Foundation Trust, Denmark Hill, London SE5 9RS, UK
- Daniel Serón
- Hospital Universitario Vall d'Hebrón, Passeig de la Vall d'Hebron, 119-129, 08035 Barcelona, Spain
- Manish D. Sinha
- Evelina London Children's Hospital, Westminster Bridge Rd, Lambeth, London SE1 7EH, UK; Guy's and St Thomas’ NHS Foundation Trust, Great Maze Pond, London SE1 9RT, UK; King's Health Partners, Guy's Hospital, London SE1 9RT, UK
- Beatriz Tucker
- King's College Hospital NHS Foundation Trust, Denmark Hill, London SE5 9RS, UK
- Ondrej Viklický
- Transplantační laboratoř, Institut klinické a experimentální medicíny (IKEM), Vídeňská 1958/9, 140 21 Praha 4, Czech Republic
- Daniel Stahl
- Biostatistics and Health Informatics Department, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 16 De Crespigny Park, London SE5 8AF, UK
- Robert I. Lechler
- MRC Centre for Transplantation, King's College London, Great Maze Pond, London SE1 9RT, UK; King's Health Partners, Guy's Hospital, London SE1 9RT, UK
- Graham M. Lord
- MRC Centre for Transplantation, King's College London, Great Maze Pond, London SE1 9RT, UK; NIHR Biomedical Research Centre at Guy's & St Thomas’ NHS Foundation Trust and King's College London, Great Maze Pond, London SE1 9RT, UK; Guy's and St Thomas’ NHS Foundation Trust, Great Maze Pond, London SE1 9RT, UK
- Maria P. Hernandez-Fuentes
- MRC Centre for Transplantation, King's College London, Great Maze Pond, London SE1 9RT, UK; King's Health Partners, Guy's Hospital, London SE1 9RT, UK
- Journal volume & issue
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Vol. 58
p. 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. Funding: FP7-HEALTH-2012-INNOVATION-1 [305147:BIO-DrIM] (SC,IR-M,PM,DSt); MRC [G0801537/ID:88245] (MPH-F); MRC [MR/J006742/1] (IR-M); Guy's&StThomas’ Charity [R080530]&[R090782]; CONICYT-Bicentennial-Becas-Chile (EN-L); EU:FP7/2007–2013 [HEALTH-F5–2010–260687: The ONE Study] (MPH-F); Czech Ministry of Health [NV19–06–00031] (OV); NIHR-BRC Guy's&StThomas' NHS Foundation Trust and KCL (SC); UK Clinical Research Networks [portfolio:7521].
