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Optimizing Detection of Kidney Transplant Injury by Assessment of Donor-Derived Cell-Free DNA via Massively Multiplex PCR

Standard noninvasive methods for detecting renal allograft rejection and injury have poor sensitivity and specificity. Plasma donor-derived cell-free DNA (dd-cfDNA) has been reported to accurately detect allograft rejection and injury in transplant recipients and shown to discriminate rejection from...

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Autores principales: Sigdel, Tara K., Archila, Felipe Acosta, Constantin, Tudor, Prins, Sarah A., Liberto, Juliane, Damm, Izabella, Towfighi, Parhom, Navarro, Samantha, Kirkizlar, Eser, Demko, Zachary P., Ryan, Allison, Sigurjonsson, Styrmir, Sarwal, Reuben D., Hseish, Szu-Chuan, Chan-On, Chitranon, Zimmermann, Bernhard, Billings, Paul R., Moshkevich, Solomon, Sarwal, Minnie M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352163/
https://www.ncbi.nlm.nih.gov/pubmed/30583588
http://dx.doi.org/10.3390/jcm8010019
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author Sigdel, Tara K.
Archila, Felipe Acosta
Constantin, Tudor
Prins, Sarah A.
Liberto, Juliane
Damm, Izabella
Towfighi, Parhom
Navarro, Samantha
Kirkizlar, Eser
Demko, Zachary P.
Ryan, Allison
Sigurjonsson, Styrmir
Sarwal, Reuben D.
Hseish, Szu-Chuan
Chan-On, Chitranon
Zimmermann, Bernhard
Billings, Paul R.
Moshkevich, Solomon
Sarwal, Minnie M.
author_facet Sigdel, Tara K.
Archila, Felipe Acosta
Constantin, Tudor
Prins, Sarah A.
Liberto, Juliane
Damm, Izabella
Towfighi, Parhom
Navarro, Samantha
Kirkizlar, Eser
Demko, Zachary P.
Ryan, Allison
Sigurjonsson, Styrmir
Sarwal, Reuben D.
Hseish, Szu-Chuan
Chan-On, Chitranon
Zimmermann, Bernhard
Billings, Paul R.
Moshkevich, Solomon
Sarwal, Minnie M.
author_sort Sigdel, Tara K.
collection PubMed
description Standard noninvasive methods for detecting renal allograft rejection and injury have poor sensitivity and specificity. Plasma donor-derived cell-free DNA (dd-cfDNA) has been reported to accurately detect allograft rejection and injury in transplant recipients and shown to discriminate rejection from stable organ function in kidney transplant recipients. This study used a novel single nucleotide polymorphism (SNP)-based massively multiplexed PCR (mmPCR) methodology to measure dd-cfDNA in various types of renal transplant recipients for the detection of allograft rejection/injury without prior knowledge of donor genotypes. A total of 300 plasma samples (217 biopsy-matched: 38 with active rejection (AR), 72 borderline rejection (BL), 82 with stable allografts (STA), and 25 with other injury (OI)) were collected from 193 unique renal transplant patients; dd- cfDNA was processed by mmPCR targeting 13,392 SNPs. Median dd-cfDNA was significantly higher in samples with biopsy-proven AR (2.3%) versus BL (0.6%), OI (0.7%), and STA (0.4%) (p < 0.0001 all comparisons). The SNP-based dd-cfDNA assay discriminated active from non-rejection status with an area under the curve (AUC) of 0.87, 88.7% sensitivity (95% CI, 77.7–99.8%) and 72.6% specificity (95% CI, 65.4–79.8%) at a prespecified cutoff (>1% dd-cfDNA). Of 13 patients with AR findings at a routine protocol biopsy six-months post transplantation, 12 (92%) were detected positive by dd-cfDNA. This SNP-based dd-cfDNA assay detected allograft rejection with superior performance compared with the current standard of care. These data support the feasibility of using this assay to detect disease prior to renal failure and optimize patient management in the case of allograft injury.
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spelling pubmed-63521632019-02-01 Optimizing Detection of Kidney Transplant Injury by Assessment of Donor-Derived Cell-Free DNA via Massively Multiplex PCR Sigdel, Tara K. Archila, Felipe Acosta Constantin, Tudor Prins, Sarah A. Liberto, Juliane Damm, Izabella Towfighi, Parhom Navarro, Samantha Kirkizlar, Eser Demko, Zachary P. Ryan, Allison Sigurjonsson, Styrmir Sarwal, Reuben D. Hseish, Szu-Chuan Chan-On, Chitranon Zimmermann, Bernhard Billings, Paul R. Moshkevich, Solomon Sarwal, Minnie M. J Clin Med Article Standard noninvasive methods for detecting renal allograft rejection and injury have poor sensitivity and specificity. Plasma donor-derived cell-free DNA (dd-cfDNA) has been reported to accurately detect allograft rejection and injury in transplant recipients and shown to discriminate rejection from stable organ function in kidney transplant recipients. This study used a novel single nucleotide polymorphism (SNP)-based massively multiplexed PCR (mmPCR) methodology to measure dd-cfDNA in various types of renal transplant recipients for the detection of allograft rejection/injury without prior knowledge of donor genotypes. A total of 300 plasma samples (217 biopsy-matched: 38 with active rejection (AR), 72 borderline rejection (BL), 82 with stable allografts (STA), and 25 with other injury (OI)) were collected from 193 unique renal transplant patients; dd- cfDNA was processed by mmPCR targeting 13,392 SNPs. Median dd-cfDNA was significantly higher in samples with biopsy-proven AR (2.3%) versus BL (0.6%), OI (0.7%), and STA (0.4%) (p < 0.0001 all comparisons). The SNP-based dd-cfDNA assay discriminated active from non-rejection status with an area under the curve (AUC) of 0.87, 88.7% sensitivity (95% CI, 77.7–99.8%) and 72.6% specificity (95% CI, 65.4–79.8%) at a prespecified cutoff (>1% dd-cfDNA). Of 13 patients with AR findings at a routine protocol biopsy six-months post transplantation, 12 (92%) were detected positive by dd-cfDNA. This SNP-based dd-cfDNA assay detected allograft rejection with superior performance compared with the current standard of care. These data support the feasibility of using this assay to detect disease prior to renal failure and optimize patient management in the case of allograft injury. MDPI 2018-12-23 /pmc/articles/PMC6352163/ /pubmed/30583588 http://dx.doi.org/10.3390/jcm8010019 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sigdel, Tara K.
Archila, Felipe Acosta
Constantin, Tudor
Prins, Sarah A.
Liberto, Juliane
Damm, Izabella
Towfighi, Parhom
Navarro, Samantha
Kirkizlar, Eser
Demko, Zachary P.
Ryan, Allison
Sigurjonsson, Styrmir
Sarwal, Reuben D.
Hseish, Szu-Chuan
Chan-On, Chitranon
Zimmermann, Bernhard
Billings, Paul R.
Moshkevich, Solomon
Sarwal, Minnie M.
Optimizing Detection of Kidney Transplant Injury by Assessment of Donor-Derived Cell-Free DNA via Massively Multiplex PCR
title Optimizing Detection of Kidney Transplant Injury by Assessment of Donor-Derived Cell-Free DNA via Massively Multiplex PCR
title_full Optimizing Detection of Kidney Transplant Injury by Assessment of Donor-Derived Cell-Free DNA via Massively Multiplex PCR
title_fullStr Optimizing Detection of Kidney Transplant Injury by Assessment of Donor-Derived Cell-Free DNA via Massively Multiplex PCR
title_full_unstemmed Optimizing Detection of Kidney Transplant Injury by Assessment of Donor-Derived Cell-Free DNA via Massively Multiplex PCR
title_short Optimizing Detection of Kidney Transplant Injury by Assessment of Donor-Derived Cell-Free DNA via Massively Multiplex PCR
title_sort optimizing detection of kidney transplant injury by assessment of donor-derived cell-free dna via massively multiplex pcr
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352163/
https://www.ncbi.nlm.nih.gov/pubmed/30583588
http://dx.doi.org/10.3390/jcm8010019
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