Graft-derived cell-free DNA, a noninvasive early rejection and graft damage marker in liver transplantation: A prospective, observational, multicenter cohort study
Graft-derived cell-free DNA (GcfDNA), which is released into the blood stream by necrotic and apoptotic cells, is a promising noninvasive organ integrity biomarker. In liver transplantation (LTx), neither conventional liver function tests (LTFs) nor immunosuppressive drug monitoring are very effecti...
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| creator | Schütz, Ekkehard Fischer, Anna Beck, Julia Harden, Markus Koch, Martina Wuensch, Tilo Stockmann, Martin Nashan, Björn Kollmar, Otto Matthaei, Johannes Kanzow, Philipp Walson, Philip D Brockmöller, Jürgen Oellerich, Michael |
| description | Graft-derived cell-free DNA (GcfDNA), which is released into the blood stream by necrotic and apoptotic cells, is a promising noninvasive organ integrity biomarker. In liver transplantation (LTx), neither conventional liver function tests (LTFs) nor immunosuppressive drug monitoring are very effective for rejection monitoring. We therefore hypothesized that the quantitative measurement of donor-derived cell-free DNA (cfDNA) would have independent value for the assessment of graft integrity, including damage from acute rejection.
Traditional LFTs were performed and plasma GcfDNA was monitored in 115 adults post-LTx at three German transplant centers as part of a prospective, observational, multicenter cohort trial. GcfDNA percentage (graft cfDNA/total cfDNA) was measured using droplet digital PCR (ddPCR), based on a limited number of predefined single nucleotide polymorphisms, enabling same-day turn-around. The same method was used to quantify blood microchimerism. GcfDNA was increased >50% on day 1 post-LTx, presumably from ischemia/reperfusion damage, but rapidly declined in patients without graft injury within 7 to 10 d to a median |
| doi_str_mv | 10.1371/journal.pmed.1002286 |
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Traditional LFTs were performed and plasma GcfDNA was monitored in 115 adults post-LTx at three German transplant centers as part of a prospective, observational, multicenter cohort trial. GcfDNA percentage (graft cfDNA/total cfDNA) was measured using droplet digital PCR (ddPCR), based on a limited number of predefined single nucleotide polymorphisms, enabling same-day turn-around. The same method was used to quantify blood microchimerism. GcfDNA was increased >50% on day 1 post-LTx, presumably from ischemia/reperfusion damage, but rapidly declined in patients without graft injury within 7 to 10 d to a median <10%, where it remained for the 1-y observation period. Of 115 patients, 107 provided samples that met preestablished criteria. In 31 samples taken from 17 patients during biopsy-proven acute rejection episodes, the percentage of GcfDNA was elevated substantially (median 29.6%, 95% CI 23.6%-41.0%) compared with that in 282 samples from 88 patients during stable periods (median 3.3%, 95% CI 2.9%-3.7%; p < 0.001). Only slightly higher values (median 5.9%, 95% CI 4.4%-10.3%) were found in 68 samples from 17 hepatitis C virus (HCV)-positive, rejection-free patients. LFTs had low overall correlations (r = 0.28-0.62) with GcfDNA and showed greater overlap between patient subgroups, especially between acute rejection and HCV+ patients. Multivariable logistic regression modeling demonstrated that GcfDNA provided additional LFT-independent information on graft integrity. Diagnostic sensitivity and specificity were 90.3% (95% CI 74.2%-98.0%) and 92.9% (95% CI 89.3%-95.6%), respectively, for GcfDNA at a threshold value of 10%. The area under the receiver operator characteristic curve was higher for GcfDNA (97.1%, 95% CI 93.4%-100%) than for same-day conventional LFTs (AST: 95.7%; ALT: 95.2%; γ-GT: 94.5%; bilirubin: 82.6%). An evaluation of microchimerism revealed that the maximum donor DNA in circulating white blood cells was only 0.068%. GcfDNA percentage can be influenced by major changes in host cfDNA (e.g., due to leukopenia or leukocytosis). One limitation of our study is that exact time-matched GcfDNA and LFT samples were not available for all patient visits.
In this study, determination of GcfDNA in plasma by ddPCR allowed for earlier and more sensitive discrimination of acute rejection in LTx patients as compared with conventional LFTs. Potential blood microchimerism was quantitatively low and had no significant influence on GcfDNA value. Further research, which should ideally include protocol biopsies, will be needed to establish the practical value of GcfDNA measurements in the management of LTx patients.</description><identifier>ISSN: 1549-1676</identifier><identifier>ISSN: 1549-1277</identifier><identifier>EISSN: 1549-1676</identifier><identifier>DOI: 10.1371/journal.pmed.1002286</identifier><identifier>PMID: 28441386</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adult ; Aged ; Analysis ; Area Under Curve ; Biology and Life Sciences ; Biomarkers ; Biomarkers - blood ; Biopsy ; Blood circulation ; Chimerism ; Cohort analysis ; Deoxyribonucleic acid ; DNA ; DNA - blood ; DNA methylation ; Female ; Genetic aspects ; Genomes ; Germany ; Graft rejection ; Graft Rejection - blood ; Graft Rejection - diagnosis ; Grafting ; Health aspects ; Hepacivirus ; Humans ; Immunology ; Immunosuppression ; Leukocytes - metabolism ; Leukopenia ; Liver ; Liver Function Tests ; Liver Transplantation ; Liver transplants ; Logistic Models ; Male ; Medicine and Health Sciences ; Middle Aged ; Open access publishing ; Patients ; Pharmacology ; Plasma ; Prospective Studies ; ROC Curve ; Single nucleotide polymorphisms ; Surgery ; Therapeutic drug monitoring ; Transplants & implants ; Viruses</subject><ispartof>PLoS medicine, 2017-04, Vol.14 (4), p.e1002286</ispartof><rights>COPYRIGHT 2017 Public Library of Science</rights><rights>2017 Public Library of Science. 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 credited: Schütz E, Fischer A, Beck J, Harden M, Koch M, Wuensch T, et al. (2017) Graft-derived cell-free DNA, a noninvasive early rejection and graft damage marker in liver transplantation: A prospective, observational, multicenter cohort study. PLoS Med 14(4): e1002286. https://doi.org/10.1371/journal.pmed.1002286</rights><rights>2017 Schütz et al 2017 Schütz et al</rights><rights>2017 Public Library of Science. 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 credited: Schütz E, Fischer A, Beck J, Harden M, Koch M, Wuensch T, et al. (2017) Graft-derived cell-free DNA, a noninvasive early rejection and graft damage marker in liver transplantation: A prospective, observational, multicenter cohort study. PLoS Med 14(4): e1002286. https://doi.org/10.1371/journal.pmed.1002286</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c731t-4a57e16b6944db0b1fd8548ac9613e52d4653a26226909ed7d10f242cce777073</citedby><cites>FETCH-LOGICAL-c731t-4a57e16b6944db0b1fd8548ac9613e52d4653a26226909ed7d10f242cce777073</cites><orcidid>0000-0002-8854-1340 ; 0000-0002-2169-561X ; 0000-0001-8151-422X ; 0000-0001-8118-0717</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5404754/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5404754/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28441386$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Schütz, Ekkehard</creatorcontrib><creatorcontrib>Fischer, Anna</creatorcontrib><creatorcontrib>Beck, Julia</creatorcontrib><creatorcontrib>Harden, Markus</creatorcontrib><creatorcontrib>Koch, Martina</creatorcontrib><creatorcontrib>Wuensch, Tilo</creatorcontrib><creatorcontrib>Stockmann, Martin</creatorcontrib><creatorcontrib>Nashan, Björn</creatorcontrib><creatorcontrib>Kollmar, Otto</creatorcontrib><creatorcontrib>Matthaei, Johannes</creatorcontrib><creatorcontrib>Kanzow, Philipp</creatorcontrib><creatorcontrib>Walson, Philip D</creatorcontrib><creatorcontrib>Brockmöller, Jürgen</creatorcontrib><creatorcontrib>Oellerich, Michael</creatorcontrib><title>Graft-derived cell-free DNA, a noninvasive early rejection and graft damage marker in liver transplantation: A prospective, observational, multicenter cohort study</title><title>PLoS medicine</title><addtitle>PLoS Med</addtitle><description>Graft-derived cell-free DNA (GcfDNA), which is released into the blood stream by necrotic and apoptotic cells, is a promising noninvasive organ integrity biomarker. In liver transplantation (LTx), neither conventional liver function tests (LTFs) nor immunosuppressive drug monitoring are very effective for rejection monitoring. We therefore hypothesized that the quantitative measurement of donor-derived cell-free DNA (cfDNA) would have independent value for the assessment of graft integrity, including damage from acute rejection.
Traditional LFTs were performed and plasma GcfDNA was monitored in 115 adults post-LTx at three German transplant centers as part of a prospective, observational, multicenter cohort trial. GcfDNA percentage (graft cfDNA/total cfDNA) was measured using droplet digital PCR (ddPCR), based on a limited number of predefined single nucleotide polymorphisms, enabling same-day turn-around. The same method was used to quantify blood microchimerism. GcfDNA was increased >50% on day 1 post-LTx, presumably from ischemia/reperfusion damage, but rapidly declined in patients without graft injury within 7 to 10 d to a median <10%, where it remained for the 1-y observation period. Of 115 patients, 107 provided samples that met preestablished criteria. In 31 samples taken from 17 patients during biopsy-proven acute rejection episodes, the percentage of GcfDNA was elevated substantially (median 29.6%, 95% CI 23.6%-41.0%) compared with that in 282 samples from 88 patients during stable periods (median 3.3%, 95% CI 2.9%-3.7%; p < 0.001). Only slightly higher values (median 5.9%, 95% CI 4.4%-10.3%) were found in 68 samples from 17 hepatitis C virus (HCV)-positive, rejection-free patients. LFTs had low overall correlations (r = 0.28-0.62) with GcfDNA and showed greater overlap between patient subgroups, especially between acute rejection and HCV+ patients. Multivariable logistic regression modeling demonstrated that GcfDNA provided additional LFT-independent information on graft integrity. Diagnostic sensitivity and specificity were 90.3% (95% CI 74.2%-98.0%) and 92.9% (95% CI 89.3%-95.6%), respectively, for GcfDNA at a threshold value of 10%. The area under the receiver operator characteristic curve was higher for GcfDNA (97.1%, 95% CI 93.4%-100%) than for same-day conventional LFTs (AST: 95.7%; ALT: 95.2%; γ-GT: 94.5%; bilirubin: 82.6%). An evaluation of microchimerism revealed that the maximum donor DNA in circulating white blood cells was only 0.068%. GcfDNA percentage can be influenced by major changes in host cfDNA (e.g., due to leukopenia or leukocytosis). One limitation of our study is that exact time-matched GcfDNA and LFT samples were not available for all patient visits.
In this study, determination of GcfDNA in plasma by ddPCR allowed for earlier and more sensitive discrimination of acute rejection in LTx patients as compared with conventional LFTs. Potential blood microchimerism was quantitatively low and had no significant influence on GcfDNA value. Further research, which should ideally include protocol biopsies, will be needed to establish the practical value of GcfDNA measurements in the management of LTx patients.</description><subject>Adult</subject><subject>Aged</subject><subject>Analysis</subject><subject>Area Under Curve</subject><subject>Biology and Life Sciences</subject><subject>Biomarkers</subject><subject>Biomarkers - blood</subject><subject>Biopsy</subject><subject>Blood circulation</subject><subject>Chimerism</subject><subject>Cohort analysis</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA - blood</subject><subject>DNA methylation</subject><subject>Female</subject><subject>Genetic aspects</subject><subject>Genomes</subject><subject>Germany</subject><subject>Graft rejection</subject><subject>Graft Rejection - blood</subject><subject>Graft Rejection - diagnosis</subject><subject>Grafting</subject><subject>Health aspects</subject><subject>Hepacivirus</subject><subject>Humans</subject><subject>Immunology</subject><subject>Immunosuppression</subject><subject>Leukocytes - metabolism</subject><subject>Leukopenia</subject><subject>Liver</subject><subject>Liver Function Tests</subject><subject>Liver Transplantation</subject><subject>Liver transplants</subject><subject>Logistic Models</subject><subject>Male</subject><subject>Medicine and Health Sciences</subject><subject>Middle Aged</subject><subject>Open access publishing</subject><subject>Patients</subject><subject>Pharmacology</subject><subject>Plasma</subject><subject>Prospective Studies</subject><subject>ROC Curve</subject><subject>Single nucleotide polymorphisms</subject><subject>Surgery</subject><subject>Therapeutic drug monitoring</subject><subject>Transplants & 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Ekkehard</au><au>Fischer, Anna</au><au>Beck, Julia</au><au>Harden, Markus</au><au>Koch, Martina</au><au>Wuensch, Tilo</au><au>Stockmann, Martin</au><au>Nashan, Björn</au><au>Kollmar, Otto</au><au>Matthaei, Johannes</au><au>Kanzow, Philipp</au><au>Walson, Philip D</au><au>Brockmöller, Jürgen</au><au>Oellerich, Michael</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Graft-derived cell-free DNA, a noninvasive early rejection and graft damage marker in liver transplantation: A prospective, observational, multicenter cohort study</atitle><jtitle>PLoS medicine</jtitle><addtitle>PLoS Med</addtitle><date>2017-04-25</date><risdate>2017</risdate><volume>14</volume><issue>4</issue><spage>e1002286</spage><pages>e1002286-</pages><issn>1549-1676</issn><issn>1549-1277</issn><eissn>1549-1676</eissn><abstract>Graft-derived cell-free DNA (GcfDNA), which is released into the blood stream by necrotic and apoptotic cells, is a promising noninvasive organ integrity biomarker. In liver transplantation (LTx), neither conventional liver function tests (LTFs) nor immunosuppressive drug monitoring are very effective for rejection monitoring. We therefore hypothesized that the quantitative measurement of donor-derived cell-free DNA (cfDNA) would have independent value for the assessment of graft integrity, including damage from acute rejection.
Traditional LFTs were performed and plasma GcfDNA was monitored in 115 adults post-LTx at three German transplant centers as part of a prospective, observational, multicenter cohort trial. GcfDNA percentage (graft cfDNA/total cfDNA) was measured using droplet digital PCR (ddPCR), based on a limited number of predefined single nucleotide polymorphisms, enabling same-day turn-around. The same method was used to quantify blood microchimerism. GcfDNA was increased >50% on day 1 post-LTx, presumably from ischemia/reperfusion damage, but rapidly declined in patients without graft injury within 7 to 10 d to a median <10%, where it remained for the 1-y observation period. Of 115 patients, 107 provided samples that met preestablished criteria. In 31 samples taken from 17 patients during biopsy-proven acute rejection episodes, the percentage of GcfDNA was elevated substantially (median 29.6%, 95% CI 23.6%-41.0%) compared with that in 282 samples from 88 patients during stable periods (median 3.3%, 95% CI 2.9%-3.7%; p < 0.001). Only slightly higher values (median 5.9%, 95% CI 4.4%-10.3%) were found in 68 samples from 17 hepatitis C virus (HCV)-positive, rejection-free patients. LFTs had low overall correlations (r = 0.28-0.62) with GcfDNA and showed greater overlap between patient subgroups, especially between acute rejection and HCV+ patients. Multivariable logistic regression modeling demonstrated that GcfDNA provided additional LFT-independent information on graft integrity. Diagnostic sensitivity and specificity were 90.3% (95% CI 74.2%-98.0%) and 92.9% (95% CI 89.3%-95.6%), respectively, for GcfDNA at a threshold value of 10%. The area under the receiver operator characteristic curve was higher for GcfDNA (97.1%, 95% CI 93.4%-100%) than for same-day conventional LFTs (AST: 95.7%; ALT: 95.2%; γ-GT: 94.5%; bilirubin: 82.6%). An evaluation of microchimerism revealed that the maximum donor DNA in circulating white blood cells was only 0.068%. GcfDNA percentage can be influenced by major changes in host cfDNA (e.g., due to leukopenia or leukocytosis). One limitation of our study is that exact time-matched GcfDNA and LFT samples were not available for all patient visits.
In this study, determination of GcfDNA in plasma by ddPCR allowed for earlier and more sensitive discrimination of acute rejection in LTx patients as compared with conventional LFTs. Potential blood microchimerism was quantitatively low and had no significant influence on GcfDNA value. Further research, which should ideally include protocol biopsies, will be needed to establish the practical value of GcfDNA measurements in the management of LTx patients.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>28441386</pmid><doi>10.1371/journal.pmed.1002286</doi><orcidid>https://orcid.org/0000-0002-8854-1340</orcidid><orcidid>https://orcid.org/0000-0002-2169-561X</orcidid><orcidid>https://orcid.org/0000-0001-8151-422X</orcidid><orcidid>https://orcid.org/0000-0001-8118-0717</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1549-1676 |
| ispartof | PLoS medicine, 2017-04, Vol.14 (4), p.e1002286 |
| issn | 1549-1676 1549-1277 1549-1676 |
| language | eng |
| recordid | cdi_plos_journals_1899330206 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Public Library of Science (PLoS) |
| subjects | Adult Aged Analysis Area Under Curve Biology and Life Sciences Biomarkers Biomarkers - blood Biopsy Blood circulation Chimerism Cohort analysis Deoxyribonucleic acid DNA DNA - blood DNA methylation Female Genetic aspects Genomes Germany Graft rejection Graft Rejection - blood Graft Rejection - diagnosis Grafting Health aspects Hepacivirus Humans Immunology Immunosuppression Leukocytes - metabolism Leukopenia Liver Liver Function Tests Liver Transplantation Liver transplants Logistic Models Male Medicine and Health Sciences Middle Aged Open access publishing Patients Pharmacology Plasma Prospective Studies ROC Curve Single nucleotide polymorphisms Surgery Therapeutic drug monitoring Transplants & implants Viruses |
| title | Graft-derived cell-free DNA, a noninvasive early rejection and graft damage marker in liver transplantation: A prospective, observational, multicenter cohort study |
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