Ten year follow-up of lung transplantations using initially rejected donor lungs after reconditioning using ex vivo lung perfusion

Lung transplantation (LTx) is the golden standard for treating patients with irreversible end-stage pulmonary disease. A major challenge to LTx is the scarcity of donor organs resulting in deaths on the waiting list [1, 2]. Contrary to transplantation of other organs, only between 30% of potential donor organs are being utilized for LTx. This low proportion for acceptance of donor grafts is due to fact that the vast majority of grafts do not meet the criteria for transplantation [3, 4]. In 2006 we transplanted the first six patients with double LTX (DLTx) performed with donor lungs reconditioned ex vivo. The lungs were rejected for transplantation by the Scandia-transplant, Euro-transplant, and UK- transplant organizations due to arterial oxygen pressure less than 40 kPa. The donor lungs were reconditioned ex vivo in an extracorporeal membrane oxygenation circuit with STEEN solution mixed with erythrocytes. Ex vivo lung perfusion (EVLP) is today used at many lung transplant centers all over the world and is considered to be the golden standard in assessing and reconditioning marginal donor lungs for transplantation [5‐9]. We have earlier reported the promising early outcome of these first six patients with a three-month survival at 100% while four of these patients showed no signs of Chronic Lung Allograft Dysfunction (CLAD) two years post-transplant [6] .

Long-term outcome including survival, pulmonary function, and occurrence of CLAD is to some extent unknown regarding EVLP as is whether there is any disadvantage compared to conventional LTx. This retrospective cohort study reviews the 10-year follow-up of the first six transplanted recipients. The study also compares EVLP DLTx to conventional DLTx performed at our center during the same time period.

A new era is at hand in the field of LTx due to the immense potential of EVLP. The number of patients who are in need of a LTx surpasses the amount of available grafts. Using cellular and normothermic perfusion in combination with ventilation, EVLP improves marginal lungs and allows for an objective assessment of their viability. By increasing the availability of donor organs for transplantation, EVLP is being established as the new cornerstone in LTx. The very first LTx evaluated ex vivo was performed in 2001 by Steen et al. at our center in Lund, Sweden, from a non-heart beating donor [14]. A few years later we were again the first team to successfully perform a series of LTx by using grafts that did not meet standard transplantation criteria (i.e. marginal donor lungs) [7], with significant lower PaO₂ levels. In the present study, we present our 10-year experience regarding the short- and long-term outcome of the first six patients that underwent LTx using marginal donor lungs evaluated using EVLP at our center. We also compare the outcome with conventional LTx performed at our clinic during the same time period. None of the marginal donor lungs would have normally been used for LTx if not for EVLP at our center. The marginal donor lungs used had been rejected by national and international transplantation centers due to low PaO₂. The Lund EVLP protocol include priming the system with Steen solution and red blood cells with a target hematocrit at 14%, the pressure in the left atrium is kept at 0 mmHg by leaving the atrium open. The pulmonary artery pressure is kept under 20 mmHg to avoid pulmonary edema. During the evaluation the cardiac output target flow is 100%. Our EVLP protocols have been described in detail in our previous publications [7, 10].

Long term follow-up after EVLP has been limited by the recent introduction of the technique in clinical LTx. We have previously reported our short-term EVLP experience with a 100% survival rate at 30 days, with no significant differences shown between EVLP and standard LTx regarding time on mechanical ventilation, ICU stay, and overall hospital stay [6].

Up to 12 months after transplantation, Fildes et al. [15] reported no difference in mortality or number of infections between EVLP-LTx and conventional LTx. Wallinder et al. having one of the longest follow-ups with their 4-year experience, were able to demonstrate that conventional LTx lungs showed no superiority over EVLP-LTx in terms of survival and post-operative complications [16]. Our 10-year experience, the longest clinical EVLP follow-up to date, detected no significant difference between EVLP-LTx vs. conventional-LTx. The same pattern emerged in our sub analyses concerning patients with a limited survival up to 1 and 5 years. These findings, along with the fact that all EVLP donor lungs were initially rejected for LTx, are highly encouraging as it may allow for the expansion of the donor pool with grafts from marginal donor lungs. An important report that has studied EVLP for marginal donors is the NOVEL Lung trial, an FDA-mandated multicenter clinical trial that included 31 patients who received EVLP lungs [17]. Early outcomes in this trial regarding ICU/hospital stay, time on mechanical ventilation, primary graft dysfunction, and 30-day mortality showed great promise as they were similar to the control group consisting of 31 conventional LTx. It has been hypothesized in previous studies that EVLP provides its protective effect on the graft by interrupting possible cold storage injury and resuming the lungs to its proper physiological metabolic state. In addition, it decreases the microbial load from the donor, thereby protecting the immunosuppressed LTx-recipient from infection [18, 19].

In the present study no significant difference was found in freedom from CLAD between EVLP-LTx and conventional-LTx. This finding is in accordance with previous studies showing similar outcomes between the two groups concerning freedom from CLAD up to five years after LTx [16, 20]. Pulmonary function was followed up in our clinical program by FEV1 and 6MWT at 3, 6, and 12 months and annually thereafter for a period of ten years. Interestingly, no superiority was recognized regarding conventional-LTx over EVLP-LTx. FEV1 and 6MWT are well-known clinical tools that are non-invasive and provide excellent data on the clinical status of the recipient after transplantation [21]. To the authors knowledge, this is the first time that long-term outcome regarding pulmonary function has been investigated between the two groups. This finding is highly encouraging as it provides further evidence that EVLP is a reliable instrument in LTx for increasing the donor pool. EVLP has been suggested as a platform for administering medical agents and thus improving patient outcome. It has been shown that inhalation of CO prevents ischemia-reperfusion injury in animal models. It has also been shown that administration of nitroglycerin, selective adenosine 2A agonists, and dibutyryl cyclic adeonosine monophosphate in Steen solution lowers the rate of histological graft injury, lowers the levels of inflammatory cytokines, and keeps the microvascular structure of the graft unharmed compared to conventional LTx [22, 23]. It has also been reported that decreasing levels of thyroid stimulating hormone and desmopressin in brain-dead donors might have a role to play in LTx, where administration of such hormone replacements are made possible through EVLP and could improve graft function [24]. EVLP may also play a role in donation after circulatory death (DCD) especially in uncontrolled DCD donors when lung function is often unknown. Interestingly it has been reported that DCD-lungs that underwent EVLP showed better outcome regarding length of hospital stay and time on mechanical ventilation [25].

As EVLP allows for the extension of preservation time, it has the potential to open up possibilities for safer procedures by enabling more daytime surgery [26]. Extra preservation time could also reduce geographical limitations for recipients and donors, thus increasing both the safety and number of LTx [8].

EVLP might also serve as an important bridge in the future taking ex vivo lung bioengineering approaches to create functional, transplantable grafts into the clinic. Ex vivo lung bioengineering has the potential to overcome the challenges of organ donor shortages and prevent allograft immune rejection [27].

On average 40% of brain dead donor lungs do not meet the criteria for LTx and are therefore not accepted for LTx. A considerable number of these organs may have been utilized in LTx through EVLP, which provides a method to evaluate and improve marginal donor lungs. According to the findings of our 10-year follow-up, the longest clinical follow-up to date, no differences were found between conventional LTx and EVLP regarding survival, pulmonary function, or incidence of CLAD.