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The kSORT Assay to Detect Renal Transplant Patients at High Risk for Acute Rejection: Results of the Multicenter AART Study

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 nonspecifi...

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Autores principales: Roedder, Silke, Sigdel, Tara, Salomonis, Nathan, Hsieh, Sue, Dai, Hong, Bestard, 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4227654/
https://www.ncbi.nlm.nih.gov/pubmed/25386950
http://dx.doi.org/10.1371/journal.pmed.1001759
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author Roedder, Silke
Sigdel, Tara
Salomonis, Nathan
Hsieh, Sue
Dai, Hong
Bestard, 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_facet Roedder, Silke
Sigdel, Tara
Salomonis, Nathan
Hsieh, Sue
Dai, Hong
Bestard, 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_sort Roedder, Silke
collection PubMed
description 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. Please see later in the article for the Editors' Summary
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spelling pubmed-42276542014-11-18 The kSORT Assay to Detect Renal Transplant Patients at High Risk for Acute Rejection: Results of the Multicenter AART Study Roedder, Silke Sigdel, Tara Salomonis, Nathan Hsieh, Sue Dai, Hong Bestard, 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. PLoS Med Research Article 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. Please see later in the article for the Editors' Summary Public Library of Science 2014-11-11 /pmc/articles/PMC4227654/ /pubmed/25386950 http://dx.doi.org/10.1371/journal.pmed.1001759 Text en © 2014 Roedder et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Roedder, Silke
Sigdel, Tara
Salomonis, Nathan
Hsieh, Sue
Dai, Hong
Bestard, 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.
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
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_short The kSORT Assay to Detect Renal Transplant Patients at High Risk for Acute Rejection: Results of the Multicenter AART Study
title_sort ksort assay to detect renal transplant patients at high risk for acute rejection: results of the multicenter aart study
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4227654/
https://www.ncbi.nlm.nih.gov/pubmed/25386950
http://dx.doi.org/10.1371/journal.pmed.1001759
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