The kSORT assay to detect renal transplant patients at high risk for acute rejection: results of the multicenter AART study

Abstract Background: Development of noninvasive molecular assays to improve disease diagnosis and patient monitoring is a critical need. In renal transplantation, acute rejection (AR) increases the risk for chronic graft injury and failure. Noninvasive diagnostic assays to improve current late and n...

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Authors: Roedder, Silke, Sigdel, Tara K., Salomonis, Nathan, Hsieh, Sue, Dai, Hong, Bestard Matamoros, Oriol, Metes, Diana, Zeevi, Andrea, Gritsch, Albin, Cheeseman, Jennifer, Macedo, Camila, Peddy, Ram, Medeiros, Mara, Vincenti, Flavio, Asher, Nancy, Salvatierra, Oscar, Shapiro, Ron, Kirk, Allan, Reed, Elaine, Sarwal, Minnie M.
Format: article
Status:Published version
Publication Date:2014
Country:España
Institution:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repository:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/125745
Online Access:https://hdl.handle.net/2445/125745
Access Level:Open access
Keyword:Nefrologia
Malalties del ronyó
Trasplantament renal
Nephrology
Kidney diseases
Kidney transplantation
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spelling The kSORT assay to detect renal transplant patients at high risk for acute rejection: results of the multicenter AART studyRoedder, SilkeSigdel, Tara K.Salomonis, NathanHsieh, SueDai, HongBestard Matamoros, OriolMetes, DianaZeevi, AndreaGritsch, AlbinCheeseman, JenniferMacedo, CamilaPeddy, RamMedeiros, MaraVincenti, FlavioAsher, NancySalvatierra, OscarShapiro, RonKirk, AllanReed, ElaineSarwal, Minnie M.NefrologiaMalalties del ronyóTrasplantament renalNephrologyKidney diseasesKidney transplantationAbstract Background: Development of noninvasive molecular assays to improve disease diagnosis and patient monitoring is a critical need. In renal transplantation, acute rejection (AR) increases the risk for chronic graft injury and failure. Noninvasive diagnostic assays to improve current late and nonspecific diagnosis of rejection are needed. We sought to develop a test using a simple blood gene expression assay to detect patients at high risk for AR. Methods and Findings: We developed a novel correlation-based algorithm by step-wise analysis of gene expression data in 558 blood samples from 436 renal transplant patients collected across eight transplant centers in the US, Mexico, and Spain between 5 February 2005 and 15 December 2012 in the Assessment of Acute Rejection in Renal Transplantation (AART)study. Gene expression was assessed by quantitative real-time PCR (QPCR) in one center. A 17-gene set the Kidney Solid Organ Response Test (kSORT) was selected in 143 samples for AR classification using discriminant analysis (area under the receiver operating characteristic curve [AUC] = 0.94; 95% CI 0.91-0.98), validated in 124 independent samples (AUC = 0.95; 95% CI 0.88-1.0) and evaluated for AR prediction in 191 serial samples, where it predicted AR up to 3 mo prior to detection by the current gold standard (biopsy). A novel reference-based algorithm (using 13 12-gene models) was developed in 100 independent samples to provide a numerical AR risk score, to classify patients as high risk versus low risk for AR. kSORT was able to detect AR in blood independent of age, time post-transplantation, and sample source without additional data normalization; AUC = 0.93 (95% CI 0.86-0.99). Further validation of kSORT is planned in prospective clinical observational and interventional trials. Conclusions: The kSORT blood QPCR assay is a noninvasive tool to detect high risk of AR of renal transplants.Public Library of Science (PLoS)2018201820142018info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/125745Articles publicats en revistes (Ciències Clíniques)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1371/journal.pmed.1001759PLoS Medicine, 2014, vol. 11, num. 11, p. e1001759https://doi.org/10.1371/journal.pmed.1001759cc-by (c) Roedder, Silke et al., 2014http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:recercat.cat:2445/1257452026-05-29T05:05:01Z
dc.title.none.fl_str_mv The kSORT assay to detect renal transplant patients at high risk for acute rejection: results of the multicenter AART study
title The kSORT assay to detect renal transplant patients at high risk for acute rejection: results of the multicenter AART study
spellingShingle The kSORT assay to detect renal transplant patients at high risk for acute rejection: results of the multicenter AART study
Roedder, Silke
Nefrologia
Malalties del ronyó
Trasplantament renal
Nephrology
Kidney diseases
Kidney transplantation
title_short The kSORT assay to detect renal transplant patients at high risk for acute rejection: results of the multicenter AART study
title_full The kSORT assay to detect renal transplant patients at high risk for acute rejection: results of the multicenter AART study
title_fullStr The kSORT assay to detect renal transplant patients at high risk for acute rejection: results of the multicenter AART study
title_full_unstemmed The kSORT assay to detect renal transplant patients at high risk for acute rejection: results of the multicenter AART study
title_sort The kSORT assay to detect renal transplant patients at high risk for acute rejection: results of the multicenter AART study
dc.creator.none.fl_str_mv Roedder, Silke
Sigdel, Tara K.
Salomonis, Nathan
Hsieh, Sue
Dai, Hong
Bestard Matamoros, Oriol
Metes, Diana
Zeevi, Andrea
Gritsch, Albin
Cheeseman, Jennifer
Macedo, Camila
Peddy, Ram
Medeiros, Mara
Vincenti, Flavio
Asher, Nancy
Salvatierra, Oscar
Shapiro, Ron
Kirk, Allan
Reed, Elaine
Sarwal, Minnie M.
author Roedder, Silke
author_facet Roedder, Silke
Sigdel, Tara K.
Salomonis, Nathan
Hsieh, Sue
Dai, Hong
Bestard Matamoros, Oriol
Metes, Diana
Zeevi, Andrea
Gritsch, Albin
Cheeseman, Jennifer
Macedo, Camila
Peddy, Ram
Medeiros, Mara
Vincenti, Flavio
Asher, Nancy
Salvatierra, Oscar
Shapiro, Ron
Kirk, Allan
Reed, Elaine
Sarwal, Minnie M.
author_role author
author2 Sigdel, Tara K.
Salomonis, Nathan
Hsieh, Sue
Dai, Hong
Bestard Matamoros, Oriol
Metes, Diana
Zeevi, Andrea
Gritsch, Albin
Cheeseman, Jennifer
Macedo, Camila
Peddy, Ram
Medeiros, Mara
Vincenti, Flavio
Asher, Nancy
Salvatierra, Oscar
Shapiro, Ron
Kirk, Allan
Reed, Elaine
Sarwal, Minnie M.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Nefrologia
Malalties del ronyó
Trasplantament renal
Nephrology
Kidney diseases
Kidney transplantation
topic Nefrologia
Malalties del ronyó
Trasplantament renal
Nephrology
Kidney diseases
Kidney transplantation
description Abstract Background: Development of noninvasive molecular assays to improve disease diagnosis and patient monitoring is a critical need. In renal transplantation, acute rejection (AR) increases the risk for chronic graft injury and failure. Noninvasive diagnostic assays to improve current late and nonspecific diagnosis of rejection are needed. We sought to develop a test using a simple blood gene expression assay to detect patients at high risk for AR. Methods and Findings: We developed a novel correlation-based algorithm by step-wise analysis of gene expression data in 558 blood samples from 436 renal transplant patients collected across eight transplant centers in the US, Mexico, and Spain between 5 February 2005 and 15 December 2012 in the Assessment of Acute Rejection in Renal Transplantation (AART)study. Gene expression was assessed by quantitative real-time PCR (QPCR) in one center. A 17-gene set the Kidney Solid Organ Response Test (kSORT) was selected in 143 samples for AR classification using discriminant analysis (area under the receiver operating characteristic curve [AUC] = 0.94; 95% CI 0.91-0.98), validated in 124 independent samples (AUC = 0.95; 95% CI 0.88-1.0) and evaluated for AR prediction in 191 serial samples, where it predicted AR up to 3 mo prior to detection by the current gold standard (biopsy). A novel reference-based algorithm (using 13 12-gene models) was developed in 100 independent samples to provide a numerical AR risk score, to classify patients as high risk versus low risk for AR. kSORT was able to detect AR in blood independent of age, time post-transplantation, and sample source without additional data normalization; AUC = 0.93 (95% CI 0.86-0.99). Further validation of kSORT is planned in prospective clinical observational and interventional trials. Conclusions: The kSORT blood QPCR assay is a noninvasive tool to detect high risk of AR of renal transplants.
publishDate 2014
dc.date.none.fl_str_mv 2014
2018
2018
2018
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/125745
url https://hdl.handle.net/2445/125745
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1371/journal.pmed.1001759
PLoS Medicine, 2014, vol. 11, num. 11, p. e1001759
https://doi.org/10.1371/journal.pmed.1001759
dc.rights.none.fl_str_mv cc-by (c) Roedder, Silke et al., 2014
http://creativecommons.org/licenses/by/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Roedder, Silke et al., 2014
http://creativecommons.org/licenses/by/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Public Library of Science (PLoS)
publisher.none.fl_str_mv Public Library of Science (PLoS)
dc.source.none.fl_str_mv Articles publicats en revistes (Ciències Clíniques)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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