Donor-derived cell-free DNA predicts allograft failure and mortality after lung transplantation

Abstract

BackgroundAllograft failure is common in lung-transplant recipients and leads to poor outcomes including early death. No reliable clinical tools exist to identify patients at high risk for allograft failure. This study tested the use of donor-derived cell-free DNA (%ddcfDNA) as a sensitive marker of early graft injury to predict impending allograft failure.MethodsThis multicenter, prospective cohort study enrolled 106 subjects who underwent lung transplantation and monitored them after transplantation for the development of allograft failure (defined as severe chronic lung allograft dysfunction [CLAD], retransplantation, and/or death from respiratory failure). Plasma samples were collected serially in the first three months following transplantation and assayed for %ddcfDNA by shotgun sequencing. We computed the average levels of ddcfDNA over three months for each patient (avddDNA) and determined its relationship to allograft failure using Cox-regression analysis.FindingsavddDNA was highly variable among subjects: median values were 3·6%, 1·6% and 0·7% for the upper, middle, and low tertiles, respectively (range 0·1%–9·9%). Compared to subjects in the low and middle tertiles, those with avddDNA in the upper tertile had a 6·6-fold higher risk of developing allograft failure (95% confidence interval 1·6–19·9, p = 0·007), lower peak FEV1 values, and more frequent %ddcfDNA elevations that were not clinically detectable.InterpretationLung transplant patients with early unresolving allograft injury measured via %ddcfDNA are at risk of subsequent allograft injury, which is often clinically silent, and progresses to allograft failure.FundNational Institutes of Health.

Donor-derived, cell-free DNA levels by next-generation targeted sequencing are elevated in allograft rejection after lung transplantation

“…To date, the International Society for Heart and Lung Transplantation (ISHLT) Thoracic Transplant Registry has accrued data on more than 69 200 adult lung transplants ( Donor-derived cell free-DNA (dd-cfDNA) has been extensively investigated as a biomarker of "allograft injury" and has been validated for differentiation of acute cellular (ACR), antibody-mediated rejection (AMR), and quiescence after renal and cardiac transplantation [3][4][5]. After LT, Agbor-Enoh et al, while utilizing shotgun sequencing methods, described elevated dd-cfDNA levels during ACR and AMR; while the highest tertile dd-cfDNA during the initial 3-months portended a 6.6-fold increased risk for subsequent allograft failure [6,7].…”

Plasma Donor-derived Cell-free DNA Levels Are Increased During Acute Cellular Rejection After Lung Transplant: Pilot Data

“…Previous single-center studies after LT that used “shotgun” sequencing techniques and required genomic material from both donor and recipient have described utility of donor-derived cell-free DNA (dd-cfDNA) for detection of acute cellular rejection (ACR) and antibody-mediated allograft rejection (AMR). 1 - 3 However, these techniques are not readily applicable to routine clinical implementation for surveillance. Therefore, we assessed utility of a clinical-grade “next-generation sequencing” (NGS) dd-cfDNA assay that interrogates a panel of single-nucleotide polymorphisms with a distinct advantage that it does not require a donor genomic specimen.…”

New Clue: Prediction from Cell-Free DNA

“…cfDNA can be found in many tissues, including blood, which is thought that cfDNA is a reflection of a person’s health and disease [ 8 ]. Recently, donor-derived cell-free DNA (dd-cfDNA) has been used as a noninvasive diagnostic test; the measurement of dd-cfDNA as a fraction of the total cfDNA can detect rejection in heart, lung, liver and kidney allografts [ 9 , 10 ]. Some studies indicated that cfDNA combined with other markers could improve the diagnosis of CLAD significantly [ 11 ].…”