Donor-Derived, Cell-Free DNA May Predict Lung Transplant Rejection

Elevated donor-derived, cell-free DNA (ddcfDNA) in the 3 months post-lung transplant can identify clinically silent allograft injury and predict progression to chronic rejection, according to a proof-of-concept study published Jan. 26 in EBioMedicine. Early identification of patients at risk for developing allograft failure could provide a window of opportunity to address immunologic mechanisms that left unaddressed could progress to transplant rejection.

“This is the first report of a method to detect and quantify clinically silent, but likely pathological, events preceding allograft failure,” write the authors led by Sean Agbor-Enoh, M.D., Ph.D., from the National Heart, Lung and Blood Institute in Bethesda, Md. “These underlying events, uncovered through our analysis of [levels of] ddcfDNA, may help to explain the unacceptably high rate of chronic lung allograft dysfunction that remains the Achilles heel of lung transplantation.”

It is estimated that half of all lung transplants fail within 5 years due to chronic rejection, a rate higher than for other solid organ transplants. This failure, called chronic lung allograft dysfunction (CLAD), includes bronchiolitis obliterans syndrome (BOS), which is the most common subtype. Despite these high rates of transplantation failure, there is no current predictor for which patients are at risk for developing BOS and chronic lung transplant rejection. Yet, prior research shows that fragments of ddcfDNA result from cell injury and cell death and are detectable in the blood of transplant recipients.

The researchers prospectively monitored 106 subjects who underwent lung transplantation at multiple institutions for allograft failure. A total of 1,145 plasma samples (9.7 samples per patient) were collected serially in the first three months following transplantation and assayed for percent ddcfDNA using shotgun sequencing. Average levels of ddcfDNA (avddDNA) over the three months were calculated for each patient.

The researchers found that all three groups for average levels of ddcfDNA (low, middle, and upper tertiles) showed high immediate post-transplant ddcfDNA levels with variable levels of ddcfDNA decay. Median values for avddDNA were highly variable (range 0.1 percent to 9.9 percent)— 3.6 percent for the upper, 1.6 percent for the middle, and 0.7 percent for the low tertile.

Overall, a 1 percent increase in avddDNA increased the risk of allograft failure 1.4-fold, the risk of CLAD or death by 1.5-fold, and all-cause death by 1.5-fold. However, those in the upper tertile had a 6.6-fold higher risk of developing allograft failure, a 7.8-fold higher risk of CLAD or death, and a 3.9-fold higher risk of all-cause mortality compared to the subjects in the low avddDNA tertile.

“Only one-third of these elevated %ddcfDNA episodes were associated with acute rejection or clinical infection,” explain the authors. “The remainder were not coincident to any signs detectable by histopathology, spirometry, clinical examination, or by any other clinical tests. These episodes of clinically silent elevations in %ddcfDNA could represent early detection of injury that progresses to pathologically overt changes.”

While experts are optimistic that with further validation ddcfDNA may be a clinically relevant, noninvasive marker of early allograft injury, particularly for lung transplant recipients, there is some concern that options to intervene remain limited.

“While this assay provides an early detection for BOS, there currently are no therapeutic modalities to prevent or cure chronic lung rejection once it is established,” writes Sandhya Bansal, Ph.D., the coauthor of a related commentary published Feb. 5. “However, this method for early detection of BOS does allow researchers to evaluate changes in immune modulatory molecules and T regulatory cells that may prove to be important in developing novel treatment strategies.”

Takeaway: Elevated levels of ddcfDNA in the early months post-lung transplant may be able to predict long-term outcomes, including progression to chronic rejection, even in the absence of traditionally detectable clinical signs of rejection.