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

doi:10.1016/j.ebiom.2020.102899

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

EBioMedicine. 2020 Aug:58:102899. doi: 10.1016/j.ebiom.2020.102899. Epub 2020 Jul 21.

Authors

Sofia Christakoudi¹, Manohursingh Runglall², Paula Mobillo³, Irene Rebollo-Mesa⁴, Tjir-Li Tsui⁵, Estefania Nova-Lamperti³, Catharine Taube³, Sonia Norris³, Yogesh Kamra³, Rachel Hilton⁶, Titus Augustine⁷, Sunil Bhandari⁸, Richard Baker⁹, David Berglund¹⁰, Sue Carr¹¹, David Game⁶, Sian Griffin¹², Philip A Kalra¹³, Robert Lewis¹⁴, Patrick B Mark¹⁵, Stephen D Marks¹⁶, Iain MacPhee¹⁷, William McKane¹⁸, Markus G Mohaupt¹⁹, Estela Paz-Artal²⁰, Sui Phin Kon²¹, Daniel Serón²², Manish D Sinha²³, Beatriz Tucker²¹, Ondrej Viklický²⁴, Daniel Stahl²⁵, Robert I Lechler²⁶, Graham M Lord²⁷, Maria P Hernandez-Fuentes²⁶

Affiliations

¹ 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. Electronic address: s.christakoudi@imperial.ac.uk.
² NIHR Biomedical Research Centre at Guy's & St Thomas' NHS Foundation Trust and King's College London, Great Maze Pond, London SE1 9RT, UK.
³ MRC Centre for Transplantation, King's College London, Great Maze Pond, London SE1 9RT, UK.
⁴ 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.
⁵ 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.
⁶ Guy's and St Thomas' NHS Foundation Trust, Great Maze Pond, London SE1 9RT, UK.
⁷ Manchester Royal Infirmary, Oxford Rd, Manchester M13 9WL, UK.
⁸ Hull University Teaching Hospitals NHS Trust, Anlaby Rd, Hull HU3 2JZ, UK.
⁹ St James's University Hospital, Beckett St, Leeds LS9 7TF, UK.
¹⁰ Department of Immunology, Genetics and Pathology, Uppsala University, Rudbecklaboratoriet, 751 85 Uppsala, Sweden.
¹¹ Leicester General Hospital, Gwendolen Rd, Leicester LE5 4PW, UK.
¹² Cardiff and Vale University Health Board, Cardiff CF14 4XW, UK.
¹³ Salford Royal NHS Foundation Trust, Stott Ln, Salford M6 8HD, UK.
¹⁴ Queen Alexandra Hospital, Southwick Hill Rd, Cosham, Portsmouth PO6 3LY, UK.
¹⁵ University of Glasgow, University Avenue, Glasgow G12 8QQ, UK.
¹⁶ 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.
¹⁷ 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.
¹⁸ Northern General Hospital, Herries Rd, Sheffield S5 7AU, UK.
¹⁹ Internal Medicine, Lindenhofgruppe Berne, Switzerland; University of Bern, Berne, Switzerland; School of Medicine, University of Nottingham, Nottingham NG5 1PB, UK.
²⁰ Department of Immunology and imas12 Research Institute, University Hospital 12 de Octubre, Madrid, Spain.
²¹ King's College Hospital NHS Foundation Trust, Denmark Hill, London SE5 9RS, UK.
²² Hospital Universitario Vall d'Hebrón, Passeig de la Vall d'Hebron, 119-129, 08035 Barcelona, Spain.
²³ 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.
²⁴ Transplantační laboratoř, Institut klinické a experimentální medicíny (IKEM), Vídeňská 1958/9, 140 21 Praha 4, Czech Republic.
²⁵ Biostatistics and Health Informatics Department, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 16 De Crespigny Park, London SE5 8AF, UK.
²⁶ 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.
²⁷ 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.

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].

Keywords: Biomarkers; Immunosuppressive Drugs; Kidney; Operational Tolerance; RT-qPCR; Transplantation.

Publication types

Comparative Study

MeSH terms

Adult
Aged
Case-Control Studies
Consensus
Female
Gene Expression Profiling / methods*
Gene Regulatory Networks* / drug effects
Graft Rejection / genetics
Graft Rejection / prevention & control*
Humans
Immunosuppressive Agents / pharmacology
Immunosuppressive Agents / therapeutic use*
Kidney Transplantation / adverse effects
Logistic Models
Male
Middle Aged
Real-Time Polymerase Chain Reaction
Transplantation Tolerance*

Substances

Immunosuppressive Agents

Grants and funding

MR/J006742/1/MRC_/Medical Research Council/United Kingdom