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About the Authors:
Ekkehard Schütz
Affiliation: Chronix Biomedical, Göttingen, Germany
Anna Fischer
Affiliation: Department of Clinical Pharmacology, University Medical Center Göttingen, Göttingen, Germany
Julia Beck
Affiliation: Chronix Biomedical, Göttingen, Germany
Markus Harden
Affiliation: Department of Medical Statistics, University Medical Center Göttingen, Göttingen, Germany
Martina Koch
Affiliation: Department of Hepatobiliary Surgery and Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Tilo Wuensch
Affiliation: Department of Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany
Martin Stockmann
Affiliation: Department of Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany
Björn Nashan
Affiliation: Department of Hepatobiliary Surgery and Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Otto Kollmar
Affiliation: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany
Johannes Matthaei
Affiliation: Department of Clinical Pharmacology, University Medical Center Göttingen, Göttingen, Germany
ORCID http://orcid.org/0000-0001-8118-0717
Philipp Kanzow
Affiliation: Department of Clinical Pharmacology, University Medical Center Göttingen, Göttingen, Germany
ORCID http://orcid.org/0000-0002-2169-561X
Philip D. Walson
Affiliation: Department of Clinical Pharmacology, University Medical Center Göttingen, Göttingen, Germany
Jürgen Brockmöller
Affiliation: Department of Clinical Pharmacology, University Medical Center Göttingen, Göttingen, Germany
ORCID http://orcid.org/0000-0002-8854-1340
Michael Oellerich
* E-mail: [email protected]
Affiliation: Department of Clinical Pharmacology, University Medical Center Göttingen, Göttingen, GermanyAbstract
Background
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.
Methods and findings
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...