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Preventing Primary Graft Dysfunction Before Transplantation

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Andrea Mariscal de Alba, MD
Toronto General Hospital
Toronto, ON, Canada

Primary graft dysfunction (PGD) is an acute lung injury syndrome that occurs within the first 3 days of the post- transplant period, and is the most serious early complication after lung transplantation (1-3). It is characterized by lung edema, radiographic pulmonary infiltrates and hypoxemia. Clinically and pathologically, the syndrome behaves in many ways similar to the Acute Respiratory Distress Syndrome (ARDS) (4). The incidence of severe PGD is 11-25% (1,5) and it is associated with a 20-30% mortality rate in the first month after lung transplant and it is also associated with worse long-term survival (2,5,6). The specific pathophysiologic mechanisms resulting in PGD remain unknown and represent a very active area of investigation. Ischemia-reperfusion (IR)- related processes are the most common contributing factors for PGD. Currently, there is no effective therapy for the prevention or treatment of PGD.

Donor lung quality has been shown to have a direct relation with post transplantation outcomes. Donor lungs can be injured by a variety of mechanisms including brain death, contusion, aspiration, infection, edema, and atelectasis (7). Targeted therapies for each of these injuries can be delivered in vivo and ex vivo for repair. Here, I describe potential ways to treat the donor lung prior to transplant to prevent PGD.

Ex vivo lung perfusion (EVLP) was initially described by Steen et al to assess organs from donors after cardiac death (8). This normothermic preservation method has been further developed and has demonstrated great promise for resuscitating injured donor lungs (9-11). More than 150 clinical EVLP procedures leading to lung transplantation have been performed in our center, demonstrating the safety and efficacy of this technique (9,10,12).

EVLP is a very promising tool to improve lung quality and treat lung injury before transplantation in an attempt to reduce the development of PGD after transplantation (13).

During EVLP lungs can be recruited, secretions can be suctioned and clots can be removed from the pulmonary circulation. There are other benefits of treating donor lungs using the ex vivo technique, EVLP allows treatment of lungs without collateral drug toxicity from the treatment to other organs (7). Different drugs for different possible target can be administered at high doses and repeated intervals during EVLP. These include antibacterial, antiviral, and antifungal agents to treat infection, cytokine inhibitors to block pro-inflammatory responses, bronchodilating and vasodilating agents to improve ventilation-perfusion matching, fibrinolytic agents to dissolve microthrombi, high osmotic agents to remove interstitial edema etc. (7)

The easiest way to deliver drugs in ex vivo is by adding drugs to the perfusate or by injecting them into the afferent tubing running to the vasculature of the graft. Pharmacological interventions to the lungs in the ex vivo circuit can also be done endotracheally.

Perfusates with a high oncotic pressure gradient or ß- adrenergic drugs have been used to reduce lung edema (14). Lungs damaged by gastric aspiration could potentially be repaired during EVLP administrating surfactant (15).

Fibrinolytic agents as urokinase had been used to improve graft function (16). A successful use of tPA during EVLP has been published as a case report of a donor lung affected with massive pulmonary emboli (17).

Mesenchymal stem cells (MSC's) are being studied for their potential anti-inflammatory and antibacterial properties (18). The possible MSC's-based therapies for acute lung injury include both targeted intrapulmonary and intravascular administration during EVLP (7).

Recent studies have shown Alpha 1 antitrypsin (A1AT) may have the potential to reduce IR-induced lung injury through its anti-inflammatory and anti-apoptotic effects. A1AT modifies dendritic cell maturation and promotes T regulatory cell differentiation, induces interleukin (IL)-1 receptor antagonist and IL-10 release, protects various cell types from cell death, inhibits caspases-1 and -3 activity and inhibits IL-1 production and activity (19). Beneficial effects of A1AT have been demonstrated in cell culture and also in large animals. In a recently published study A1AT showed improved significantly graft function after transplantation (20,21). A1AT has also been shown to have beneficial effects for ischemia reperfusion-induced injury of other organs such as the kidney, heart, and liver. This drug appears to be unique in the setting of lung transplantation in that it interacts with multiple pathways that are known to play a role in ischemia reperfusion related lung injury. Therefore A1AT appears to be a promising potential clinical therapy to prevent PGD after lung transplantation (21).

Damage to donor lungs is manifested, by clinical findings of PGD and also by release of the pro-inflammatory cytokines including, interleukin-6 (IL-6), IL-8, and IL-1b (22). This evidence suggests that injury mediated by endogenous inflammatory mediators may play an important role. One potential therapeutic approach is to use IL-10 gene therapy. In pre-clinical studies, EVLP proved to be the ideal platform for gene therapy delivery to the donor lung: intrabronchial AdhIL-10 delivered during EVLP achieved clinically relevant tissue levels and attenuated post-transplant injury. Significant expression of the IL-10 transgene was consistently observed in the perfusate during the 12h EVLP procedure and excellent post-transplant lung function was documented (23-30).

Despite new advances in donor management, surgical technic and post-transplant care, PGD remains a major cause of morbidity and mortality after lung transplantation. The lung transplant community is striving to find a way to decrease its incidence and to repair damaged lung donors. There are many very promising strategies that may be the key to finally understand the physiopathology of PGD and translate them to a clinical setting. ■

Disclosure Statement: The author has no conflicts of interest to disclose.


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