A study led by the Organ, Tissue and Cell Donation and Transplantation Research Group at the Vall d’Hebron Research Institute (VHIR), comprising professionals from the Thoracic Surgery Department and the Transplant Coordination Unit of Vall d’Hebron University Hospital, has provided new insights into the biological mechanisms that occur after lung transplantation.

The study, led by Dr Alberto Sandiumenge, with Dr Irene Bello as first author, has been published in the American Journal of Transplantation, one of the leading international publications specialising in transplant medicine.

The research is part of the DACMEDAMPs study, a prospective, multicentre project analysing mitochondrial damage associated with different types of lung donation. The project compares organs from controlled donation after circulatory death (cDCD) donors with those from donors after brain death (DBD). Controlled donation after circulatory death has contributed significantly to increasing the number of lungs available for transplantation, but questions remain about the biological consequences of the warm ischemia experienced by the organ before it is removed.

In this context, the research team studied the behaviour of cell-free mitochondrial DNA (cf-mtDNA) in the blood. This genetic material, which is released when cellular damage occurs, had been proposed as a potential marker of the injury caused by ischemia and subsequent reperfusion of the organ.

Mitochondrial DNA does not directly reflect warm ischemia in the donor lung

To analyse this issue, the study prospectively and multicentrically followed adult lung transplant recipients, comparing cases involving controlled donation after circulatory death donors and donors after brain death. Plasma samples were obtained from donors and recipients at different time points to analyse changes in cell-free mitochondrial DNA levels.

The results show that cell-free mitochondrial DNA levels in donor plasma were similar between the two types of donation. Furthermore, neither total warm ischemia time nor functional warm ischemia time was associated with the levels of this marker, questioning whether systemic cf-mtDNA can be used as a direct indicator of the damage caused by warm ischemia in the donor lung.

Differences in systemic levels of the marker became particularly evident 72 hours after transplantation. At this point, while total cell-free mitochondrial DNA levels increased, analysis of mitochondrial DNA originating specifically from the graft showed a decrease. This behaviour suggests that the overall increase detected after transplantation does not mainly originate from the donor lung.

A response associated with recipient inflammation

The data indicate that the dynamics of cell-free mitochondrial DNA after transplantation are mainly associated with inflammatory processes triggered by the recipient themselves, rather than with a direct measure of the injury caused by warm ischemia in the donor lung.

This finding is relevant because cell-free mitochondrial DNA had been proposed as a potential biomarker for estimating the damage caused by the organ donation and preservation process. The study’s results indicate that, at least in this context, systemic cf-mtDNA levels do not allow the degree of warm ischemic injury in the donor lung to be assessed directly.

“These results help us better define what we can and cannot interpret from cell-free mitochondrial DNA levels. The next challenge is to identify biomarkers that allow us to characterise the condition of the graft and the patient’s response after transplantation more precisely,” says Dr Albert Sandiumenge, coordinator of Donation and Transplantation at Vall d’Hebron University Hospital and head of the Organ, Tissue and Cell Donation and Transplantation Research Group at VHIR.