Arne Neyrinck

Ex-vivo lung perfusion.

This review outlines the new and promising technique of ex vivo lung perfusion and its clinical potential to increase the number of transplantable lungs and to improve the early and late outcome after transplantation. The rationale, the experimental background, the technique and protocols, and available devices for ex vivo lung perfusion are discussed. The current clinical experience worldwide and ongoing clinical trials are reviewed.

Machine perfusion in organ transplantation: a tool for ex-vivo graft conditioning with mesenchymal stem cells?

Purpose of reviewMachine perfusion has emerged as a tool to evaluate pretransplant graft function more objectively during preservation. Machine perfusion also offers the possibility to recondition questionable organs and to ‘immunomodulate’ allografts ex vivo. This article aims to review the current knowledge on machine perfusion of the various solid thoracic and abdominal organs, and to discuss the new possibility of conditioning and treating grafts with mesenchymal stem cells (MSCs) during machine perfusion. Recent findingsDifferent methods of machine perfusion have been described varying among organs in temperature and composition of perfusate. Commercial devices have recently become available for machine perfusion of all organs, with the largest clinical experience acquired in kidney and lung transplantation. Clinical studies are ongoing for liver, heart, and pancreas. MSC therapy in organ transplantation is now emerging with clinical studies set up to investigate its potential to attenuate ischemia/reperfusion injury (innate immunity) and to downregulate the alloimmune response (adaptive immunity) and promote engraftment after transplantation. We hypothesize that delivery of MSCs directly into the machine perfusion circuit may provide a unique opportunity to treat and immunomodulate organs prior to transplantation. To our knowledge, no study on ex-vivo delivery of MSCs during machine perfusion has been reported. SummaryMachine perfusion of solid organs has regained much attention during the last decade. It provides a new promising tool that may allow pretransplant ex-vivo assessment, preservation, repair, and conditioning of grafts. Experimental research and clinical trials testing the administration of MSCs during machine perfusion are warranted to explore the potential benefit and mechanisms of this approach.

Impact of CLAD Phenotype on Survival After Lung Retransplantation: A Multicenter Study

Chronic lung allograft dysfunction (CLAD) remains a major problem after lung transplantation with no definitive treatment except redo lung transplantation (re‐LTx) in selected candidates. However, CLAD is not a homogeneous entity and different phenotypes exist. Therefore, we aimed to evaluate the effect of CLAD phenotypes on survival after re‐LTx for CLAD. Patients who underwent re‐LTx for respiratory failure secondary to CLAD in four LTx centers between 2003 and 2013 were included in this retrospective analysis. Bronchiolitis obliterans syndrome (BOS) and restrictive CLAD (rCLAD) were distinguished using pulmonary function, radiology and explant lung histopathology. Patient variables pre‐ and post‐re‐LTx were collected and analyzed. A total of 143 patients underwent re‐LTx for CLAD resulting in 94 BOS (66%) and 49 rCLAD (34%) patients. Unadjusted and adjusted survival after re‐LTx for rCLAD was worse compared to BOS (HR = 2.60, 1.59–4.24; p < 0.0001 and HR = 2.61, 1.51–4.51; p = 0.0006, respectively). Patients waiting at home prior to re‐LTx experienced better survival compared to hospitalized patients (HR 0.40; 0.23–0.72; p = 0.0022). Patients with rCLAD redeveloped CLAD earlier and were more likely to redevelop rCLAD. Survival after re‐LTx for rCLAD is worse compared to BOS. Consequently, re‐LTx for rCLAD should be critically discussed, particularly when additional peri‐operative risk factors are present.

Donation after circulatory death: current status.

Purpose of review Donor shortage has forced transplant teams to explore new methods to increase the potential donor pool. Donation after circulatory death (DCD) has opened new perspectives and could be a valuable option to expand the brain-dead donors. The purpose of this review is to provide an overview of current practice and to identify remaining questions related to ethical and medical issues that should be further addressed in the future. Recent findings Recent findings demonstrate acceptable outcomes after DCD kidney and lung transplantation but inferior graft survival for liver transplantation. The impact and importance of the agonal phase following withdrawal of treatment in controlled DCD is increasingly recognized. Premortem interventions are currently under debate related to preservation strategies or comfort therapy. New preservation strategies using in-situ/in-vivo extracorporeal membrane oxygenation or ex-vivo machine perfusion have large potential in the future. Finally, organizations and institutions are reporting more uniform guidelines related to declaration of death and DCD organ procurement. Summary DCD donation has regained much attention during the last decade and is now part of standard clinical practice albeit this type of donation should not be regarded as an equally acceptable alternative for donation after brain death. It will be important to further explore the potential of DCD, to monitor the long-term outcomes and to further optimize the quality of these grafts. Development and implementation of uniform guidelines will be necessary to guarantee the clinical use of these donor pools.

The mode of death in the non-heart-beating donor has an impact on lung graft quality

OBJECTIVE We hypothesised that the agonal phase prior to cardiac death may negatively influence the quality of the pulmonary graft recovered from non-heart-beating donors (NHBDs). Different modes of death were compared in an experimental model. METHODS Non-heparinised pigs were divided into three groups (n=6 per group). Animals in group I [FIB] were sacrificed by ventricular fibrillation resulting in immediate circulatory arrest. In group II [EXS], animals were exsanguinated (45+/-11 min). In group III [HYP], hypoxic cardiac arrest (13+/-3 min) was induced by disconnecting the animal from the ventilator. Blood samples were taken pre-mortem in HYP and EXS for measurement of catecholamine levels. After 1 h of in situ warm ischaemia, unflushed lungs were explanted and stored for 3 h (4 degrees C). Left lung performance was then tested during 60 min in our ex vivo reperfusion model. Total protein concentration in bronchial lavage fluid was measured at the end of reperfusion. RESULTS Pre-mortem noradrenalin (mcg l(-1)) concentration (baseline: 0.03+/-0) increased to a higher level in HYP (50+/-8) vs EXS (15+/-3); p=0.0074. PO(2) (mmHg) at 60 min of reperfusion was significantly worse in HYP compared to FIB (445+/-64 vs 621+/-25; p<0.05), but not to EXS (563+/-51). Pulmonary vascular resistance (dynes s cm(-5)) was initially higher in EXS (p<0.001) and HYP (NS) vs FIB (15824+/-5052 and 8557+/-4933 vs 1482+/-61, respectively) but normalised thereafter. Wet-to-dry weight ratio was higher in HYP compared to FIB (5.2+/-0.3 vs 4.7+/-0.2, p=0.041), but not to EXS (4.9+/-0.2). Total protein (g l(-1)) concentration was higher, although not significant in HYP and EXS vs FIB (18+/-6 and 13+/-4 vs 4.5+/-1.3, respectively). CONCLUSION Pre-mortem agonal phase in the NHBD induces a sympathetic storm leading to capillary leak with pulmonary oedema and reduced oxygenation upon reperfusion. Graft quality appears inferior in NHBD lungs when recovered in controlled (HYP) vs uncontrolled (EXS and FIB) setting.

Prophylactic Azithromycin Therapy After Lung Transplantation: Post hoc Analysis of a Randomized Controlled Trial.

Prophylactic azithromycin treatment has been demonstrated to improve freedom from bronchiolitis obliterans syndrome (BOS) 2 years after lung transplantation (LTx). In the current study, we re‐evaluated the long‐term effects of this prophylactic approach in view of the updated classification system for chronic lung allograft dysfunction (CLAD). A retrospective, intention‐to‐treat analysis of a randomized controlled trial comparing prophylactic treatment with placebo (n = 43) versus azithromycin (n = 40) after LTx was performed. Graft dysfunction (CLAD), graft loss (retransplantation, mortality), evolution of pulmonary function and functional exercise capacity were analyzed 7 years after inclusion of the last study subject. Following LTx, 22/43 (51%) patients of the placebo group and 11/40 (28%) patients of the azithromycin group ever developed CLAD (p = 0.043). CLAD‐free survival was significantly longer in the azithromycin group (p = 0.024). No difference was present in proportion of obstructive versus restrictive CLAD between both groups. Graft loss was similar in both groups: 23/43 (53%) versus 16/40 (40%) patients (p = 0.27). Long‐term pulmonary function and functional exercise capacity were significantly better in the azithromycin group (p < 0.05). Prophylactic azithromycin therapy reduces long‐term CLAD prevalence and improves CLAD‐free survival, pulmonary function, and functional exercise capacity after LTx.

Retrograde Flush Following Warm Ischemia in the Non-Heart-Beating Donor Results in Superior Graft Performance at Reperfusion

BACKGROUND The use of non-heart-beating donors (NHBD) has been propagated as an alternative to overcome the scarcity of pulmonary grafts. The presence of postmortem thrombi, however, is a concern for the development of primary graft dysfunction. In this isolated lung reperfusion study, we looked at the need and the best route of preharvest pulmonary flush. METHODS Domestic pigs were sacrificed by ventricular fibrillation and divided in 3 groups (n = 6 per group). After 1 h of in situ warm ischemia, lungs in group I were retrieved unflushed (NF). In group II, lungs were explanted after an anterograde flush (AF) through the pulmonary artery. Finally, in group III, lungs were explanted after a retrograde flush (RF) via the left atrium. After 3 h of cold storage, the left lung was assessed for 60 min in our ex vivo reperfusion model. Wet-to-dry weight ratio (W/D) was calculated after reperfusion. RESULTS Pulmonary vascular resistance (dynes x sec x cm(-5)) was 1145 +/- 56 (RF) versus 1560 +/- 123 (AF) and 1435 +/- 95 (NF) at 60 min of reperfusion (P < 0.05). Oxygenation and compliance were higher and plateau airway pressure was lower in RF versus AF and NF, although the difference did not reach statistical significance. No differences in W/D were observed between groups after reperfusion. Histological examination revealed fewer microthrombi in the left lung in RF compared with AF and NF. CONCLUSION RF of lungs from NHBD improves graft function by elimination of microthrombi from the pulmonary vasculature, resulting in lower pulmonary vascular resistance upon reperfusion.

Combined liver and lung transplantation with extended normothermic lung preservation in a patient with end-stage emphysema complicated by drug-induced acute liver failure.

Isolated lung transplantation (LuTx) and liver transplantation are established treatments for irreversible lung and liver failure. Combined liver and lung transplantation (cLiLuTx) is a less common, but approved therapy of combined organ failure, mostly applied in patients suffering from progressive cystic fibrosis and advanced liver disease. We report a patient who was listed for LuTx due to end‐stage chronic obstructive pulmonary disease and who developed drug‐induced acute hepatic failure. The only therapeutic option was hyper‐urgent cLiLuTx. To correct the poor coagulation in order to reduce the per‐operative risk of bleeding, the liver was transplanted first. In anticipation of the longer lung preservation time, cold flushed lungs were preserved on a portable lung perfusion device for ex vivo normothermic perfusion for 11 h 15 min, transplanted sequentially off‐pump, and reperfused after a total ex vivo time of 13 h 32 min and 16 h for the first and second lung, respectively. Ten months later, the patient is doing well and no rejection occurred. Normothermic ex vivo lung perfusion may help to prolong preservation time, facilitating long‐distance transport and combined organ transplantation.

Azithromycin and the Treatment of Lymphocytic Airway Inflammation After Lung Transplantation

Lymphocytic airway inflammation is a major risk factor for chronic lung allograft dysfunction, for which there is no established treatment. We investigated whether azithromycin could control lymphocytic airway inflammation and improve allograft function. Fifteen lung transplant recipients demonstrating acute allograft dysfunction due to isolated lymphocytic airway inflammation were prospectively treated with azithromycin for at least 6 months (NCT01109160). Spirometry (FVC, FEV1, FEF25–75, Tiffeneau index) and FeNO were assessed before and up to 12 months after initiation of azithromycin. Radiologic features, local inflammation assessed on airway biopsy (rejection score, IL‐17+ cells/mm2 lamina propria) and broncho‐alveolar lavage fluid (total and differential cell counts, chemokine and cytokine levels); as well as systemic C‐reactive protein levels were compared between baseline and after 3 months of treatment. Airflow improved and FeNO decreased to baseline levels after 1 month of azithromycin and were sustained thereafter. After 3 months of treatment, radiologic abnormalities, submucosal cellular inflammation, lavage protein levels of IL‐1β, IL‐8/CXCL‐8, IP‐10/CXCL‐10, RANTES/CCL5, MIP1‐α/CCL3, MIP‐1β/CCL4, Eotaxin, PDGF‐BB, total cell count, neutrophils and eosinophils, as well as plasma C‐reactive protein levels all significantly decreased compared to baseline (p < 0.05). Administration of azithromycin was associated with suppression of posttransplant lymphocytic airway inflammation and clinical improvement in lung allograft function.

DCD lung donation: donor criteria, procedural criteria, pulmonary graft function validation, and preservation

In an era where there is a shortage of lungs for transplantation is increased utilization of lungs from donation after circulatory death (DCD) donors. We review the reports of 11 controlled and 1 uncontrolled DCD programs focusing on donor criteria, procedural criteria, graft assessment, and preservation techniques including the use of ex vivo lung perfusion. We have formulated conclusions and recommendations for each of these areas, which were presented at the 6th International Conference on Organ Donation. A table of recommendations, the grade of recommendations, and references are provided.