Background: Controlled donation after circulatory determination of death (cDCD) has become a widely used strategy to expand the lung donor pool. Despite favorable outcomes, concerns exist about the effects of warm ischemia time (WIT) on the lungs, that may experience hypoxia, metabolic stress, and mitochondrial dysfunction, potentially leading to ischemia-reperfusion injury (IRI) and systemic release of damage-associated molecular patterns (DAMPs), particularly cell-free mitochondrial DNA (cf-mtDNA). These molecules have been linked to innate immune activation and complications such as primary graft dysfunction (PGD). While molecular injury patterns in cDCD lungs are known, it remains unclear whether these changes are reflected systemically and how they relate to clinical outcomes.
Methods: We conducted a prospective, multicenter, observational study in four Spanish transplant centers. Adult recipients of single or bilateral lung transplantation (LTx) from cDCD and brain-dead donors (DBD) were matched 1:1 by age, sex, and indication. Blood samples were collected from donors (before skin incision and before perfusion) and from recipients (before implantation, immediately after reperfusion, and 72 hours post-transplant). Plasma  cf-mtDNA levels were measured and analyzed by donor type, PGD, and early mortality (≤3 months).
Results: We included 80 LTx recipients (40 cDCD, 40 DBD). Baseline demographic and clinical characteristics were similar, except for more corticosteroid and vasoactive use in DBD donors. Donor cf-mtDNA levels were comparable between cDCD and DBD at both sampling points, suggesting WIT does not lead to greater systemic mitochondrial injury before organ retrieval. In recipients, a delayed increase in cf-mtDNA  was observed at 72 hours post-transplant in the cDCD group, but not immediately after reperfusion, indicating a delayed systemic response (Figure1). Higher cf-mtDNA levels in donor plasma were associated with PGD in recipients, though this was not reflected in recipient plasma at any time. PGD incidence and early mortality were similar between groups.

Conclusions: cDCD lung donors do not show increased systemic mitochondrial damage markers cf-mtDNA at procurement, but their recipients develop a delayed rise in  cf-mtDNA post-transplantation. This suggests WIT-related injury may present subacutely. Donor cf-mtDNA may serve as a pre-implantation biomarker of PGD risk. Overall, cDCD is a safe, effective donor source, and these molecular insights may help refine graft evaluation.