Calcineurin Inhibitors in Lung Donors to Attenuate Ischemia–Reperfusion Injury in Recipients: Next Steps?

Lung transplantation is a life-saving procedure for patients with advanced lung disease. However, a major challenge in lung transplantation has been the low use of donor lungs, with rates estimated at 20%, internationally (1). The early post-transplant period can be complex, and ischemia-reperfusion (IR) injury of the lung graft is one of the most common risk factors for primary graft dysfunction (2), observed in approximately 30% of lung transplants (3). Primary graft dysfunction can lead to significant early morbidity (prolonged length of mechanical ventilation and hospital stay) (4) and also increase the risk of premature graft loss, chronic allograft dysfunction, and mortality (5).

Donor shortage is more common in lung transplantation than in other solid-organ transplants (6). Organ donation after circulatory death can expand lung donor availability to some extent; however, most donations (>98%) continue to originate from neurologically deceased donors (6). Unfortunately, brain death itself can induce a systemic inflammatory response that causes direct injury to the lungs. The associated acute lung injury compromises lung suitability for transplantation and, more importantly, predisposes the donor lungs to more severe IR injury after transplantation. Specifically, inflammation and reactive oxygen radicals can induce further injury within the lung endothelium, resulting in pulmonary edema, increased vascular resistance, and decreased pulmonary compliance (7).

For good reason, investigators have tested a number of strategies to attenuate IR injury, including efforts to reduce ischemic time, various reperfusion strategies, protective mechanical lung ventilation, ex vivo lung perfusion, and modulatory medications (8, 9). Interventions aimed toward the deceased donor provide an upstream opportunity to prevent IR injury among lung recipients. This is theoretically ideal, and now there is consistent evidence emerging from small animal models, primarily in renal and liver allotransplantation, that donor preconditioning with calcineurin inhibitors (CNIs) can reduce the risk of IR injury and improve early graft function through antiinflammatory and antiischemic mechanisms (10, 11).

In this issue of the Journal, Belhaj and colleagues (pp. 584–595) evaluated the effects of CNI (tacrolimus) preconditioning in a randomized experimental pig model of brain death–induced lung injury (12). The investigators administered intravenous tacrolimus (n = 8) or placebo (n = 9) before inducing brain death through the infusion of autologous blood. They measured hemodynamic changes for up to 7 hours after brain death and analyzed the histological features of lung tissue after euthanasia. The authors observed that tacrolimus pretreatment was associated with favorable hemodynamic effects, and it offset many other deleterious effects of brain death. Specifically, tacrolimus improved lung physiology (i.e., prevented a decline in the ratio of Pa_O2 to Fi_O2), reduced circulating inflammatory markers (i.e., IL-6 to IL-10 ratio, IL-1β), and improved pulmonary vascular endothelial integrity (i.e., vascular cell adhesion molecule-1, glycocalyx-derived molecules) and also lung histology (i.e., reduced inflammatory and apoptotic cells). Despite these promising findings, there was no difference in the lung injury score (i.e., a composite marker of cellular infiltration, edema, hemorrhage, and airway epithelial damage) (13). The authors speculate that tacrolimus therapy did not entirely eliminate the effects of systemic inflammation on donor lungs, highlighting the potential for combined therapies.

Strengths of the present study include randomized assessment of the effects of tacrolimus on both pulmonary and systemic markers of inflammation, hemodynamic measures, and histopathological correlates, thus providing a greater understanding of systemic circulatory implications of brain death on IR injury in the donor lungs. Furthermore, various clinical and research steps, from the induction of neurological death, the provision of hemodynamic and ventilator care, and all subsequent measurements, were well standardized. In addition, technicians were blinded to group assignment, and all outcomes and analyses were performed in a blinded fashion. The histological analyses, such as acute lung injury scoring and inflammatory assessments, were performed in duplicate by at least two investigators.

There are also some noteworthy limitations. First, the experimental approach administered tacrolimus to the donor before brain death. This would not translate to the usual clinical scenario of organ donation, where the timing of this neurologic event is unpredictable, and, more importantly, clinicians in most jurisdictions wait until after brain death to initiate specific organ donor management. As Belhaj and colleagues (12) highlight in their conclusions, however, CNIs should be tested shortly after brain death (alone or in combination with other pharmacological strategies) to further elucidate the pathophysiological effects on the donor lungs. The present study focused on pathogenic effects within 7 hours of brain death, and longer follow-up of the pulmonary and systemic effects are now of interest, including future study designs to monitor effects after graft implementation.

The present work by Belhaj and colleagues (12) found that tacrolimus pretreatment attenuated adverse physiologic, inflammatory, and histologic effects of brain death on the lung. This study builds on earlier evidence from animal models that CNIs may reduce the risk of IR injury in neurologically deceased donors and improve graft function (10, 11, 14). The translation of these findings to humans will need to proceed cautiously, however, to elucidate the potential modifying effects of organ donor comorbidities and implications for transplant recipient outcomes. For these reasons, clinical studies are currently underway, mainly in deceased renal transplant donors. The ongoing Cis-A-Rein study in France is studying the effects of treating deceased brain-dead donors with cyclosporine A versus no pretreatment among approximately 650 renal transplant recipients (15). Similarly, a Canadian pilot trial of deceased donors (Calcineurin Inhibitor in NEuRoloGically deceased donors to decrease kidney delaYed graft function; NCT05148715), including multiorgan donors, aims to study the feasibility of administering tacrolimus before organ procurement, with a view to measuring the effects on 7-day and 1-year transplant outcomes for all organ recipients.

Another direction for future clinical randomized controlled trials will be the evaluation of combined strategies for IR injury prevention, such as the use of ex vivo organ perfusion technology to assist with evaluation and repair, and tracking the longevity of lung and other solid organ grafts. Ultimately, interventions such as CNI administration for the organ donor may have tremendous societal implications because of the dual possibilities of increasing the donor pool and enhancing transplant outcomes.