Use of donor-derived-cell-free DNA as a marker of early allograft injury in primary graft dysfunction (PGD) to predict the risk of chronic lung allograft dysfunction (CLAD)

J Heart Lung Transplant. 2021 Jun;40(6):488-493. doi: 10.1016/j.healun.2021.02.008. Epub 2021 Feb 20.

Abstract

Background: Primary graft dysfunction (PGD) is a risk factor for chronic lung allograft dysfunction (CLAD). However, the association between PGD and degree of allograft injury remains poorly defined. In this study, we leverage a novel biomarker for allograft injury, percentage donor-derived cell-free DNA (%ddcfDNA), to study the association between PGD, degree of allograft injury, and the development of CLAD.

Methods: This prospective cohort study recruited 99 lung transplant recipients and collected plasma samples on days 1, 3, and 7 for %ddcfDNA measurements. Clinical data on day 3 was used to adjudicate for PGD. %ddcfDNA levels were compared between PGD grades. In PGD patients, %ddcfDNA was compared between those who developed CLAD and those who did not.

Results: On posttransplant day 3, %ddcfDNA was higher in PGD than in non-PGD patients (median [IQR]: 12.2% [8.2, 22.0] vs 8.5% [5.6, 13.2] p = 0.01). %ddcfDNA correlated with the severity grade of PGD (r = 0.24, p = 0.02). Within the PGD group, higher levels of %ddcfDNA correlated with increased risk of developing CLAD (log OR(SE) 1.38 (0.53), p = 0.009). PGD patients who developed CLAD showed ∼2-times higher %ddcfDNA levels than patients who did not develop CLAD (median [IQR]: 22.4% [11.8, 27.6] vs 9.9% [6.7, 14.9], p = 0.007).

Conclusion: PGD patients demonstrated increased early posttransplant allograft injury, as measured by %ddcfDNA, in comparison to non-PGD patients, and these high %ddcfDNA levels were associated with subsequent development of CLAD. This study suggests that %ddcfDNA identifies PGD patients at greater risk of CLAD than PGD alone.

Trial registration: ClinicalTrials.gov NCT01985412 NCT02423070.

Keywords: Chronic lung allograft dysfunction (CLAD); Donorderived cell-free DNA (ddcfDNA); Primary graft dysfunction (PGD); Rejection.

Publication types

  • Comparative Study
  • Observational Study
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adult
  • Allografts
  • Biomarkers / blood
  • Cell-Free Nucleic Acids / blood*
  • Female
  • Follow-Up Studies
  • Graft Rejection / blood*
  • Graft Rejection / etiology
  • Humans
  • Lung Transplantation / adverse effects*
  • Male
  • Middle Aged
  • Primary Graft Dysfunction / blood*
  • Primary Graft Dysfunction / complications
  • Prospective Studies
  • Time Factors
  • Tissue Donors*
  • Transplant Recipients*

Substances

  • Biomarkers
  • Cell-Free Nucleic Acids

Associated data

  • ClinicalTrials.gov/NCT01985412
  • ClinicalTrials.gov/NCT02423070