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Development of a multivariable geneexpression signature targeting T-cell-mediated rejection in peripheral blood of kidney transplant recipients validated in crosssectional and longitudinal samples

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Development of a multivariable geneexpression signature targeting T-cell-mediated rejection in peripheral blood of kidney transplant recipients validated in crosssectional and longitudinal samples. / Christakoudi, Sofia; Runglall, Manohursingh; Mobillo, Paula Andrea; Tsui, Tjir-Li; Duff, Claire; Domingo Vila, Clara; Kamra, Yogesh Kishore; Delaney, Florence; Montero , Rosa; Spiridou , Anastasia; Kassimatis, Theodoros; Phin Kon, Sui; Tucker, Beatriz; Farmer, Christopher; Strom, Terry B.; Lord, Graham M.; Rebollo-Mesa, Irene; Stahl, Daniel; Sacks, Steven; Hernandez-Fuentes, Maria P; Chowdhury, Paramit.

In: EBioMedicine, Vol. 41, 01.03.2019, p. 571-583.

Research output: Contribution to journalArticle

Harvard

Christakoudi, S, Runglall, M, Mobillo, PA, Tsui, T-L, Duff, C, Domingo Vila, C, Kamra, YK, Delaney, F, Montero , R, Spiridou , A, Kassimatis, T, Phin Kon, S, Tucker, B, Farmer, C, Strom, TB, Lord, GM, Rebollo-Mesa, I, Stahl, D, Sacks, S, Hernandez-Fuentes, MP & Chowdhury, P 2019, 'Development of a multivariable geneexpression signature targeting T-cell-mediated rejection in peripheral blood of kidney transplant recipients validated in crosssectional and longitudinal samples', EBioMedicine, vol. 41, pp. 571-583. https://doi.org/10.1016/j.ebiom.2019.01.060

APA

Christakoudi, S., Runglall, M., Mobillo, P. A., Tsui, T-L., Duff, C., Domingo Vila, C., ... Chowdhury, P. (2019). Development of a multivariable geneexpression signature targeting T-cell-mediated rejection in peripheral blood of kidney transplant recipients validated in crosssectional and longitudinal samples. EBioMedicine, 41, 571-583. https://doi.org/10.1016/j.ebiom.2019.01.060

Vancouver

Christakoudi S, Runglall M, Mobillo PA, Tsui T-L, Duff C, Domingo Vila C et al. Development of a multivariable geneexpression signature targeting T-cell-mediated rejection in peripheral blood of kidney transplant recipients validated in crosssectional and longitudinal samples. EBioMedicine. 2019 Mar 1;41:571-583. https://doi.org/10.1016/j.ebiom.2019.01.060

Author

Christakoudi, Sofia ; Runglall, Manohursingh ; Mobillo, Paula Andrea ; Tsui, Tjir-Li ; Duff, Claire ; Domingo Vila, Clara ; Kamra, Yogesh Kishore ; Delaney, Florence ; Montero , Rosa ; Spiridou , Anastasia ; Kassimatis, Theodoros ; Phin Kon, Sui ; Tucker, Beatriz ; Farmer, Christopher ; Strom, Terry B. ; Lord, Graham M. ; Rebollo-Mesa, Irene ; Stahl, Daniel ; Sacks, Steven ; Hernandez-Fuentes, Maria P ; Chowdhury, Paramit. / Development of a multivariable geneexpression signature targeting T-cell-mediated rejection in peripheral blood of kidney transplant recipients validated in crosssectional and longitudinal samples. In: EBioMedicine. 2019 ; Vol. 41. pp. 571-583.

Bibtex Download

@article{4841400b025d47c2bcdd9f99d0d901b4,
title = "Development of a multivariable geneexpression signature targeting T-cell-mediated rejection in peripheral blood of kidney transplant recipients validated in crosssectional and longitudinal samples",
abstract = "Background: Acute T-cell mediated rejection (TCMR) is usually indicated by alteration in serum-creatinine measurements when considerable transplant damage has already occurred. There is, therefore, a need for non-invasive early detection of immune signals that would precede the onset of rejection, prior to transplant damage. Methods: We examined the RT-qPCR expression of 22 literature-based genes in peripheral blood samples from 248 patients in the Kidney Allograft Immune Biomarkers of Rejection Episodes (KALIBRE) study. To account for post-transplantation changes unrelated to rejection, we generated time-adjusted gene-expression residuals from linear mixed-effects models in stable patients. To select genes, we used penalised logistic regression based on 27 stable patients and 27 rejectors with biopsy-proven T-cell-mediated rejection, fulfilling strict inclusion/exclusion criteria. We validated this signature in i) an independent group of stable patients and patients with concomitant T-cell and antibody-mediated-rejection, ii) patients from an independent study, iii) cross-sectional pre-biopsy samples from non-rejectors and iv) longitudinal follow-up samples covering the first post-transplant year from rejectors, non-rejectors and stable patients. Findings: A parsimonious TCMR-signature (IFNG, IP-10, ITGA4, MARCH8, RORc, SEMA7A, WDR40A) showed cross-validated area-under-ROC curve 0.84 (0.77–0.88) (median, 2.5 th –97.5 th centile of fifty cross-validation cycles), sensitivity 0.67 (0.59–0.74) and specificity 0.85 (0.75–0.89). The estimated probability of TCMR increased seven weeks prior to the diagnostic biopsy and decreased after treatment. Gene expression in all patients showed pronounced variability, with up to 24{\%} of the longitudinal samples in stable patients being TCMR-signature positive. In patients with borderline changes, up to 40{\%} of pre-biopsy samples were TCMR-signature positive. Interpretation: Molecular marker alterations in blood emerge well ahead of the time of clinically overt TCMR. Monitoring a TCMR-signature in peripheral blood could unravel T-cell-related pro-inflammatory activity and hidden immunological processes. This additional information could support clinical management decisions in cases of patients with stable but poor kidney function or with inconclusive biopsy results.",
author = "Sofia Christakoudi and Manohursingh Runglall and Mobillo, {Paula Andrea} and Tjir-Li Tsui and Claire Duff and {Domingo Vila}, Clara and Kamra, {Yogesh Kishore} and Florence Delaney and Rosa Montero and Anastasia Spiridou and Theodoros Kassimatis and {Phin Kon}, Sui and Beatriz Tucker and Christopher Farmer and Strom, {Terry B.} and Lord, {Graham M.} and Irene Rebollo-Mesa and Daniel Stahl and Steven Sacks and Hernandez-Fuentes, {Maria P} and Paramit Chowdhury",
year = "2019",
month = "3",
day = "1",
doi = "10.1016/j.ebiom.2019.01.060",
language = "English",
volume = "41",
pages = "571--583",
journal = "EBioMedicine",
issn = "2352-3964",
publisher = "Elsevier BV",

}

RIS (suitable for import to EndNote) Download

TY - JOUR

T1 - Development of a multivariable geneexpression signature targeting T-cell-mediated rejection in peripheral blood of kidney transplant recipients validated in crosssectional and longitudinal samples

AU - Christakoudi, Sofia

AU - Runglall, Manohursingh

AU - Mobillo, Paula Andrea

AU - Tsui, Tjir-Li

AU - Duff, Claire

AU - Domingo Vila, Clara

AU - Kamra, Yogesh Kishore

AU - Delaney, Florence

AU - Montero , Rosa

AU - Spiridou , Anastasia

AU - Kassimatis, Theodoros

AU - Phin Kon, Sui

AU - Tucker, Beatriz

AU - Farmer, Christopher

AU - Strom, Terry B.

AU - Lord, Graham M.

AU - Rebollo-Mesa, Irene

AU - Stahl, Daniel

AU - Sacks, Steven

AU - Hernandez-Fuentes, Maria P

AU - Chowdhury, Paramit

PY - 2019/3/1

Y1 - 2019/3/1

N2 - Background: Acute T-cell mediated rejection (TCMR) is usually indicated by alteration in serum-creatinine measurements when considerable transplant damage has already occurred. There is, therefore, a need for non-invasive early detection of immune signals that would precede the onset of rejection, prior to transplant damage. Methods: We examined the RT-qPCR expression of 22 literature-based genes in peripheral blood samples from 248 patients in the Kidney Allograft Immune Biomarkers of Rejection Episodes (KALIBRE) study. To account for post-transplantation changes unrelated to rejection, we generated time-adjusted gene-expression residuals from linear mixed-effects models in stable patients. To select genes, we used penalised logistic regression based on 27 stable patients and 27 rejectors with biopsy-proven T-cell-mediated rejection, fulfilling strict inclusion/exclusion criteria. We validated this signature in i) an independent group of stable patients and patients with concomitant T-cell and antibody-mediated-rejection, ii) patients from an independent study, iii) cross-sectional pre-biopsy samples from non-rejectors and iv) longitudinal follow-up samples covering the first post-transplant year from rejectors, non-rejectors and stable patients. Findings: A parsimonious TCMR-signature (IFNG, IP-10, ITGA4, MARCH8, RORc, SEMA7A, WDR40A) showed cross-validated area-under-ROC curve 0.84 (0.77–0.88) (median, 2.5 th –97.5 th centile of fifty cross-validation cycles), sensitivity 0.67 (0.59–0.74) and specificity 0.85 (0.75–0.89). The estimated probability of TCMR increased seven weeks prior to the diagnostic biopsy and decreased after treatment. Gene expression in all patients showed pronounced variability, with up to 24% of the longitudinal samples in stable patients being TCMR-signature positive. In patients with borderline changes, up to 40% of pre-biopsy samples were TCMR-signature positive. Interpretation: Molecular marker alterations in blood emerge well ahead of the time of clinically overt TCMR. Monitoring a TCMR-signature in peripheral blood could unravel T-cell-related pro-inflammatory activity and hidden immunological processes. This additional information could support clinical management decisions in cases of patients with stable but poor kidney function or with inconclusive biopsy results.

AB - Background: Acute T-cell mediated rejection (TCMR) is usually indicated by alteration in serum-creatinine measurements when considerable transplant damage has already occurred. There is, therefore, a need for non-invasive early detection of immune signals that would precede the onset of rejection, prior to transplant damage. Methods: We examined the RT-qPCR expression of 22 literature-based genes in peripheral blood samples from 248 patients in the Kidney Allograft Immune Biomarkers of Rejection Episodes (KALIBRE) study. To account for post-transplantation changes unrelated to rejection, we generated time-adjusted gene-expression residuals from linear mixed-effects models in stable patients. To select genes, we used penalised logistic regression based on 27 stable patients and 27 rejectors with biopsy-proven T-cell-mediated rejection, fulfilling strict inclusion/exclusion criteria. We validated this signature in i) an independent group of stable patients and patients with concomitant T-cell and antibody-mediated-rejection, ii) patients from an independent study, iii) cross-sectional pre-biopsy samples from non-rejectors and iv) longitudinal follow-up samples covering the first post-transplant year from rejectors, non-rejectors and stable patients. Findings: A parsimonious TCMR-signature (IFNG, IP-10, ITGA4, MARCH8, RORc, SEMA7A, WDR40A) showed cross-validated area-under-ROC curve 0.84 (0.77–0.88) (median, 2.5 th –97.5 th centile of fifty cross-validation cycles), sensitivity 0.67 (0.59–0.74) and specificity 0.85 (0.75–0.89). The estimated probability of TCMR increased seven weeks prior to the diagnostic biopsy and decreased after treatment. Gene expression in all patients showed pronounced variability, with up to 24% of the longitudinal samples in stable patients being TCMR-signature positive. In patients with borderline changes, up to 40% of pre-biopsy samples were TCMR-signature positive. Interpretation: Molecular marker alterations in blood emerge well ahead of the time of clinically overt TCMR. Monitoring a TCMR-signature in peripheral blood could unravel T-cell-related pro-inflammatory activity and hidden immunological processes. This additional information could support clinical management decisions in cases of patients with stable but poor kidney function or with inconclusive biopsy results.

UR - http://www.scopus.com/inward/record.url?scp=85062221059&partnerID=8YFLogxK

U2 - 10.1016/j.ebiom.2019.01.060

DO - 10.1016/j.ebiom.2019.01.060

M3 - Article

VL - 41

SP - 571

EP - 583

JO - EBioMedicine

JF - EBioMedicine

SN - 2352-3964

ER -

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