What Predicts Allograft Failure in Lung Transplantation?

Allograft failure in individuals who receive lung transplants can be predicted by measuring donor-derived cell-free DNA (%ddcfDNA) for allograft injury, according to a study recently published in EBioMedicine. This could partially explain the prevalence of chronic lung allograft dysfunction in patients who receive lung transplants.

This prospective, multicenter study included 106 individuals who enrolled while waiting for lung transplants. The primary outcome of the study was the time from lung transplantation to allograft failure, which included retransplantation, mortality as a result of respiratory failure, and/or acute chronic lung allograft dysfunction. Exclusion criteria included a lack of plasma samples for %ddcfDNA analysis or mortality within 3 months of lung transplant. Shotgun sequencing was used to measure %ddcfDNA in plasma samples for the initial 3 months following lung transplants. Cox regression analysis was used to examine the relationship between allograft failure and average ddcfDNA levels during the 3-month period of plasma sample collection.

A total of 43.5% of participants achieved the primary outcome; 27 died from respiratory problems, 14 experienced chronic lung allograft dysfunction, and 5 underwent retransplantation. There was significant variability in average ddcfDNA throughout the population, with median values of 3.6% in the upper tertile, 1.6% in the middle tertile, and 0.7% in the lower tertile. Being in the upper tertile was associated with a 6.6 times greater likelihood of allograft failure (95% CI, 1.6-19.9; P =.007), clinically silent %ddcfDNA spikes that occurred more frequently, and reduced peak forced expiratory volumes in 1 second. Just after lung transplantation, %ddcfDNA was elevated and followed a 2-step logarithmic decay. Higher average ddcfDNA correlated with pretransplant factors such as obesity, age of donor, lung allocation score, and age of recipient.

Limitations to this study included a lack of chronic lung allograft dysfunction assessment in very ill participants, a low relative survival rate, and potential bias caused by highly variable samples per participant.

The researchers proposed “[average] %ddcfDNA as a predictive marker for allograft failure and premature death. …These underlying events, uncovered through our analysis of %ddcfDNA, may help to explain the unacceptably high rate of [chronic lung allograft dysfunction] that remains the Achilles heel of lung transplantation.”

Reference

Agbor-Enoh S, Wang Y, Tunc I, et al. Donor-derived cell-free DNA predicts allograft failure and mortality after lung transplantation [published online January 26, 2019]. EBioMedicine. doi:10.1016/j.ebiom.2018.12.029