Systemic mitochondrial DNA kinetics after controlled donation after circulatory determination of death lung transplantation do not reflect donor warm ischemic injury: DACMEDAMPs, a prospective multicenter translational study.

Controlled donation after circulatory determination of death has markedly expanded the lung donor pool; however, the biological consequences of donor warm ischemia on mitochondrial injury and systemic danger signaling remain uncertain. Cell-free mitochondrial DNA (cf-mtDNA) has been implicated in ischemia-reperfusion injury, yet its systemic behavior in ventilated human lungs is incompletely characterized. We conducted a prospective, multicenter observational study in matched adult lung transplant recipients from controlled donation after circulatory determination of death and donation after brain death to characterize donor and recipient plasma cf-mtDNA kinetics and evaluate their relationship with warm ischemic exposure. Serial plasma samples were obtained from donors and from recipients. Donor plasma cf-mtDNA levels were comparable between groups. A divergence emerged at 72 hours after transplantation, reflected by a significant donor type-by-time interaction in adjusted longitudinal analysis. Neither total nor functional warm ischemia time was associated with cf-mtDNA concentrations. In multivariable analysis restricted to 72 hours, donor type was not independently associated with absolute systemic cf-mtDNA levels. Exploratory analysis of donor-derived cf-mtDNA demonstrated a decline in graft-derived mitochondrial DNA between reperfusion and 72 hours despite a concurrent increase in total cf-mtDNA. These findings suggest that posttransplant systemic cf-mtDNA dynamics reflect recipient-driven inflammatory processes rather than a direct surrogate of donor warm ischemic injury.