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Donor-specific Cell-free DNA as a Biomarker in Solid Organ Transplantation. A Systematic Review

Knight, Simon Robert, MChir1,2; Thorne, Adam, BSc1; Lo Faro, Maria Letizia, PhD1

doi: 10.1097/TP.0000000000002482

Background There is increasing interest in the use of noninvasive biomarkers to reduce the risks posed by invasive biopsy for monitoring of solid organ transplants (SOTs). One such promising marker is the presence of donor-derived cell-free DNA (dd-cfDNA) in the urine or blood of transplant recipients.

Methods We systematically reviewed the published literature investigating the use of cfDNA in monitoring of graft health after SOT. Electronic databases were searched for studies relating cfDNA fraction or levels to clinical outcomes, and data including measures of diagnostic test accuracy were extracted. Narrative analysis was performed.

Results Ninety-five articles from 47 studies met the inclusion criteria (18 kidneys, 7 livers, 11 hearts, 1 kidney-pancreas, 5 lungs, and 5 multiorgans). The majority were retrospective and prospective cohort studies, with 19 reporting diagnostic test accuracy data. Multiple techniques for measuring dd-cfDNA were reported, including many not requiring a donor sample. dd-cfDNA falls rapidly within 2 weeks, with baseline levels varying by organ type. Levels are elevated in the presence of allograft injury, including acute rejection and infection, and return to baseline after successful treatment. Elevation of cfDNA levels is seen in advance of clinically apparent organ injury. Discriminatory power was greatest for higher grades of T cell–mediated and antibody-mediated acute rejection, with high negative predictive values.

Conclusions Cell-free DNA is a promising biomarker for monitoring the health of SOTs. Future studies will need to define how it can be used in routine clinical practice and determine clinical benefit with routine prospective monitoring.

The authors systematically review the published literature on the use of donor-derived cell-free DNA in the urine or blood of transplant recipients as a noninvasive biomarker for monitoring solid organ transplant recipient and its possible use as an alternative to biopsy of the allograft.

1 Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom.

2 Centre for Evidence in Transplantation, Clinical Effectiveness Unit, Royal College of Surgeons of England, London, United Kingdom.

Received 10 August 2018. Revision received 22 September 2018.

Accepted 29 September 2018.

The authors declare no funding or conflicts of interest.

S.K. conceived the study, authored the study protocol, developed and performed literature searches, screened references, analyzed the data, and wrote the article. A.T. participated in study design, screened references, analyzed the data, and participated in the writing of the article. M.L.F. participated in study design and participated in the writing of the article.

Correspondence: Simon R. Knight, Oxford Transplant Centre, Nuffield Department of Surgical Sciences, Churchill Hospital, Old Rd, Headington OX3 7LE, United Kingdom. (

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