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Development of a multivariable gene-expression signature targeting T-cell-mediated rejection in peripheral blood of kidney transplant recipients validated in cross-sectional and longitudinal samples

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العنوان: Development of a multivariable gene-expression signature targeting T-cell-mediated rejection in peripheral blood of kidney transplant recipients validated in cross-sectional and longitudinal samples
المؤلفون: Christakoudi, S, Runglall, M, Mobillo, P, Tsui, T-L, Duff, C, Domingo-Vila, C, Kamra, Y, 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
المصدر: 583 ; 571
بيانات النشر: Elsevier
سنة النشر: 2019
المجموعة: Imperial College London: Spiral
مصطلحات موضوعية: Science & Technology, Life Sciences & Biomedicine, Medicine, General & Internal, Research & Experimental, General & Internal Medicine, Research & Experimental Medicine, POLYOMAVIRUS, INFECTION, Adolescent, Adult, Aged, Antigens, CD, Area Under Curve, Cross-Sectional Studies, Female, GPI-Linked Proteins, Graft Rejection, Humans, Interferon-gamma, Kidney Transplantation, Longitudinal Studies, Male, Middle Aged, Nuclear Receptor Subfamily 1, Group F, Member 3, ROC Curve, Semaphorins
جغرافية الموضوع: Netherlands
الوصف: 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, 2.5th-97.5th 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 ...
نوع الوثيقة: article in journal/newspaper
اللغة: English
تدمد: 2352-3964
العلاقة: EBioMedicine; http://hdl.handle.net/10044/1/67588Test; https://doi.org/10.1016/j.ebiom.2019.01.060Test
DOI: 10.1016/j.ebiom.2019.01.060
الإتاحة: https://doi.org/10.1016/j.ebiom.2019.01.060Test
http://hdl.handle.net/10044/1/67588Test
حقوق: © 2019 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0Test/).
رقم الانضمام: edsbas.CBCE4BBE
قاعدة البيانات: BASE
الوصف
تدمد:23523964
DOI:10.1016/j.ebiom.2019.01.060