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, 2020 Aug.
Article
em En
| MEDLINE
| ID: mdl-32707447
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 0â 92 (95% confidence interval 0â 88-0â 94) in cross-validation and 0â 97 (0â 93-1â 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 [305147BIO-DrIM] (SC,IR-M,PM,DSt); MRC [G0801537/ID88245] (MPH-F); MRC [MR/J006742/1] (IR-M); Guy's&StThomas' Charity [R080530]&[R090782]; CONICYT-Bicentennial-Becas-Chile (EN-L); EUFP7/2007-2013 [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 [portfolio7521].Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Perfilação da Expressão Gênica
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Tolerância ao Transplante
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Redes Reguladoras de Genes
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Rejeição de Enxerto
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Imunossupressores
Tipo de estudo:
Guideline
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Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Adult
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Aged
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
EBioMedicine
Ano de publicação:
2020
Tipo de documento:
Article