A novel blood-based biomarker of lung transplant dysfunction in newly transplanted lungs could help identify patients at high risk for chronic rejection without a lung biopsy, researchers reported.
In what was characterized as a proof-of-concept study, researchers from the National Heart, Lung, and Blood Institute (NHLBI), Johns Hopkins School of Medicine, and several other institutions described how donor-derived cell-free DNA (%ddcfDNA) characterized "post-transplantation trends of lung-allograft injury that may lead to allograft failure and death."
"Our results demonstrate that the average %ddcfDNA in the early post-transplant period correlated with the development of allograft failure and all-cause mortality," wrote NHLBI researcher Hannah Valantine, MD, and colleagues, in the study online in .
Valantine said the test solves the long-standing problem of detecting hidden signs of rejection and transplant failure in lung transplant recipients with no outward signs of organ rejection.
"We showed for the first time that donor-derived DNA is a predictive marker for chronic lung rejection and death, and could provide critical time-points to intervene, perhaps preventing these outcomes," she said in a press statement. "Once rejection is detected early via this test, doctors would then have the option to increase the dosages of anti-rejection drugs, add new agents that reduce tissue inflammation, or take other measures to prevent or slow the progression."
Lung transplant patients have the shortest median survival of any solid organ transplant recipients due to the high incidence of chronic rejection, also known as chronic lung allograft dysfunction (CLAD).
Several biomarkers predictive of lung allograft failure have been identified, but their clinical usefulness has been limited by the requirement for bronchoscopy to acquire a sample, poor specificity or sensitivity, or other reasons.
Earlier research by Valantine and colleagues led to a sensitive genomic blood test designed to identify allograft injury from infection, acute rejection, and other complications.
In the new study, involving 106 lung transplant recipients, the researchers were able to determine the extent of clinically detected and clinically silent allograft injury in the early post-transplant period and determine its relationship to allograft failure.
The multicenter, prospective, cohort study included transplant recipients who were closely monitored for allograft failure after transplant. Endpoints included CLAD, retransplantation, and/or death from respiratory failure.
Plasma samples were collected serially during the first 3 months following transplantation and assayed for %ddcfDNA using shotgun sequencing.
The researchers computed the average levels of %ddcfDNA over 3 months for each patient (avddDNA) and determined its relationship to allograft failure using Cox-regression analysis.
A total of 1,145 plasma samples were analyzed (median, 9.7 samples per patient), and 505 of these were within 3 months post-transplant.
Among the main findings were the following:
- AvddDNA 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 with 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% CI, 1.6–19.9, P=0.007)
- Patients with avddDNA in the upper tertile also had lower peak FEV1 values, and more frequent %ddcfDNA elevations that were not clinically detectable
"At the molecular level, (lung recipients with high avddDNA levels) show more frequent elevated %ddcfDNA levels beyond the early post-transplantation period, suggesting that early unresolved allograft injury sets the stage for further allograft injury and dysfunction," the researchers wrote.
Only a third of these elevated %ddcfDNA episodes were associated with acute rejection or clinical infection.
"The remainder were not coincident to any signs detectable by histopathology, spirometry, clinical examination, or by any other clinical test. These episodes of clinically silent elevations in %ddcfDNA episodes could represent early detection of injury that progresses to pathologically overt changes," the team said.
Study limitations cited by the researchers included the lower than anticipated survival in the cohort, the inability to assess CLAD in study participants who were too sick to undergo spirometry assessment, and variability in the number of samples analyzed per patient.
"Future studies should address these limitations, validate our findings, and concurrently employ machine learning algorithm to compute avddDNA measurement with less time lag than the 3 months used in this study," Valantine and co-authors wrote. "Such future studies would require a larger cohort size and more frequent %ddcfDNA measurements. The earlier measures may enable assessments of the risk of allograft failure in the initial 3 months after transplantation."
Disclosures
Funding for the research was provided by grants from the National Institutes of Health and the National Heart, Lung, and Blood Institute.
Primary Source
EBioMedicine
Agbor-Enoh S, et al "Donor-derived cell-free DNA predicts allograft failure and mortality after lung transplantation" EbioMed 2019; DOI: 10.1016/j.ebiom.2018.12.0292352-3969.