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

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 (SOT). 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 following SOT. Electronic databases were searched for studies relating cfDNA fraction or levels to clinical outcomes, and data including measures of diagnostic test accuracy (DTA) were extracted. Narrative analysis was performed.

RESULTS: 95 manuscripts from 47 studies met the inclusion criteria (18 kidney, 7 liver, 11 heart, 1 kidney-pancreas, 5 lung, and 5 multiorgan). The majority were retrospective and prospective cohort studies, with 19 reporting DTA 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 (AR) and infection, and return to baseline following successful treatment. Elevation of cfDNA levels are seen in advance of clinically apparent organ injury. Discriminatory power was greatest for higher grades of T cell mediated and antibody-mediated AR, with high negative predictive values.

CONCLUSIONS: cfDNA is a promising biomarker for monitoring the health of solid-organ transplants. Future studies will need to define how it can be used in routine clinical practice and determine clinical benefit with routine prospective monitoring.