Ex vivo lung perfusion in donation after circulatory death: A post hoc analysis of the Normothermic Ex Vivo Lung Perfusion as an Assessment of Extended/Marginal Donors Lungs trial.

OBJECTIVE: Donation after circulatory death (DCD) donors offer the ability to expand the lung donor pool and ex vivo lung perfusion (EVLP) further contributes to this ability by allowing for additional evaluation and resuscitation of these extended criteria donors. We sought to determine the outcomes of recipients receiving organs from DCD EVLP donors in a multicenter setting. METHODS: This was an unplanned post hoc analysis of a multicenter, prospective, nonrandomized trial that took place during 2011 to 2017 with 3 years of follow-up. Patients were placed into 3 groups based off procurement strategy: brain-dead donor (control), brain-dead donor evaluated by EVLP, and DCD donors evaluated by EVLP. The primary outcomes were severe primary graft dysfunction at 72 hours and survival. Secondary outcomes included select perioperative outcomes, and 1-year and 3-years allograft function and quality of life measures. RESULTS: The DCD EVLP group had significantly higher incidence of severe primary graft dysfunction at 72 hours (P = .03), longer days on mechanical ventilation (P < .001) and in-hospital length of stay (P = .045). Survival at 3 years was 76.5% (95% CI, 69.2%-84.7%) for the control group, 68.3% (95% CI, 58.9%-79.1%) for the brain-dead donor group, and 60.7% (95% CI, 45.1%-81.8%) for the DCD group (P = .36). At 3-year follow-up, presence observed bronchiolitis obliterans syndrome or quality of life metrics did not differ among the groups. CONCLUSIONS: Although DCD EVLP allografts might not be appropriate to transplant in every candidate recipient, the expansion of their use might afford recipients stagnant on the waitlist a viable therapy.

Trainee experience on ischemic times and outcomes following orthotopic heart transplantation.

OBJECTIVE: This study was designed to evaluate the association of surgical training on outcomes following orthotopic heart transplantation in all levels of cardiothoracic surgery fellows. METHODS: A retrospective cohort analysis was performed on all heart transplants at a single institution from 2011 to 2020. Transplants performed using organ preservation systems (n = 10) or with significant missing data were excluded (n = 37), resulting in 154 transplants performed by faculty surgeons and 799 total transplants performed by first-year Accreditation Council for Graduate Medical Education fellows (n = 73), second-year Accreditation Council for Graduate Medical Education fellows (n = 124), or non-Accreditation Council for Graduate Medical Education fellows (n = 602) in a transplantation and mechanical circulatory support fellowship. Primary outcome was warm ischemic time analyzed by year of fellowship. Additional secondary outcomes included 30-day mortality, primary graft dysfunction, reoperation for bleeding, and 5-year survival. Median follow-up was 3 years (interquartile range [IQR], 1.0-5.5 years) and 100% complete. RESULTS: The median number of transplants performed was 30 (IQR, 19.5-51.8) during the study period performed by 22 trainees. Baseline transplant characteristics performed were similar amongst the trainee years, although the first-year Accreditation Council for Graduate Medical Education fellows approached significantly fewer re-do transplants (1.4% vs 8.1% and 4.3%; P = .07). Warm ischemic time was lower in the first-year fellows (49 minutes; IQR, 42-63 minutes) versus second-year fellows (56.5 minutes; IQR, 45.5-69 minutes) and mechanical circulatory support/transplant fellows (56 minutes; IQR, 46-67 minutes) (P = .028). Crossclamp time was also lower in the first-year fellows than in second-year and mechanical circulatory support/transplant fellows, respectively (79 minutes; IQR, 65-100 minutes vs 147 minutes; IQR, 125-176 minutes and 143 minutes; IQR, 119-175 minutes) (P = .008). Secondary outcomes, including 30-day mortality (4.1% [n = 3] vs 2.4% [n = 3] vs 2.7% [n = 16]; P = .76), primary graft dysfunction (5.5% [n = 4] vs 4.0% [n = 5] vs 4.3% [n = 26]; P = .88), reoperation for bleeding (2.7% [n = 2] vs 4.8% [n = 6] vs 4.2% [n = 25]; P = .78), and 5-year survival (82.2%; 95% CI, 66.7%-84.9% vs 77.3%; 95% CI, 66.7%-84.9% vs 79.3%; 95% CI, 74.9%-83.1%; P = .84) were comparable in all groups. CONCLUSIONS: This cohort of nearly 800 operations demonstrates that orthotopic heart transplantation may be performed by cardiac fellowship trainees all levels of training with acceptable short- and long-term outcomes.

Phenotyping CLAD after single lung transplant: Limits and prognostic assessment of the 2019 ISHLT classification system.

BACKGROUND: Phenotyping chronic lung allograft dysfunction (CLAD) in single lung transplant (SLTX) is challenging, due to the native lung contribution to pulmonary function test (PFT). We aimed to assess the applicability and prognostic performance of International Society for Heart and Lung Transplantation (ISHLT) classification in SLTX. METHODS: In this retrospective study of adult, first, SLTX performed 2009-2017, patients with persistent drop in FEV1≥20% were assessed by 2 independent adjudicators to determine CLAD status and phenotype. Interobserver agreement (IOA) was calculated (Cohen's Kappa) for CLAD, phenotype and presence of RAS (resttrictive allograft syndrome)-like opacities (RLO). Association of CLAD phenotypes with time to death or retransplant (ReTx), adjusted for age at SLTX, sex, CMV mismatch and native lung condition, were assessed using Cox proportional hazards models. RESULTS: Of 172 SLTX recipients, 92 experienced a persistent drop in FEV1>20%. Following adjudication, 67 were diagnosed with CLAD. We noted a moderate IOA for CLAD diagnosis (Kappa 0.69) and poor IOA for phenotype adjudication (Kappa 0.52). The final phenotype adjudication was 31 bronchiolitis obliterans syndrome (BOS) (46.3%), 13 RAS (19.4%), 2 mixed (3%), 2 Undefined (3%), and 19 remained Unclassified (28.3%). Using these adjudicated phenotypes, RAS was significantly associated with a higher risk of death/ReTx compared to other groups (HR 2.98, 95%CI [1.39-6.4]). The adjudication of RLO had the best IOA (Kappa 0.73). The presence of RLO was a strong predictor of death or ReTx (HR 2.37, 95%CI [1.2-4.5]), regardless of the final phenotype. CONCLUSIONS: PFT interpretation is challenging in SLTX. A classification essentially relying on imaging, which harbored good IOA, obtained better prognostic performance than a classification using published physiological cut-offs.

Early Allograft Dysfunction Increases Hospital Associated Costs After Liver Transplantation-A Propensity Score-Matched Analysis.

Concepts to ameliorate the continued mismatch between demand for liver allografts and supply include the acceptance of allografts that meet extended donor criteria (ECD). ECD grafts are generally associated with an increased rate of complications such as early allograft dysfunction (EAD). The costs of liver transplantation for the health care system with respect to specific risk factors remain unclear and are subject to change. We analyzed 317 liver transplant recipients from 2013 to 2018 for outcome after liver transplantation and hospital costs in a German transplant center. In our study period, 1-year survival after transplantation was 80.1% (95% confidence interval: 75.8%-84.6%) and median hospital stay was 33 days (interquartile rage: 24), with mean hospital costs of €115,924 (SD €113,347). There was a positive correlation between costs and laboratory Model for End-Stage Liver Disease score (rs = 0.48, P < 0.001), and the development of EAD increased hospital costs by €26,229. ECD grafts were not associated with a higher risk of EAD in our cohort. When adjusting for recipient-associated risk factors such as laboratory Model for End-Stage Liver Disease score, recipient age, and split liver transplantation with propensity score matching, only EAD and cold ischemia increased total costs. Conclusion: Our data show that EAD leads to significantly higher hospital costs for liver transplantation, which are primarily attributed to recipient health status. Strategies to reduce the incidence of EAD are needed to control costs in liver transplantation.

Multicenter validation of the liver graft assessment following transplantation (L-GrAFT) score for assessment of early allograft dysfunction.

BACKGROUND & AIMS: Early allograft dysfunction (EAD) following liver transplantation (LT) negatively impacts graft and patient outcomes. Previously we reported that the liver graft assessment following transplantation (L-GrAFT7) risk score was superior to binary EAD or the model for early allograft function (MEAF) score for estimating 3-month graft failure-free survival in a single-center derivation cohort. Herein, we sought to externally validate L-GrAFT7, and compare its prognostic performance to EAD and MEAF. METHODS: Accuracies of L-GrAFT7, EAD, and MEAF were compared in a 3-center US validation cohort (n = 3,201), and a Consortium for Organ Preservation in Europe (COPE) normothermic machine perfusion (NMP) trial cohort (n = 222); characteristics were compared to assess generalizability. RESULTS: Compared to the derivation cohort, patients in the validation and NMP trial cohort had lower recipient median MELD scores; were less likely to require pretransplant hospitalization, renal replacement therapy or mechanical ventilation; and had superior 1-year overall (90% and 95% vs. 84%) and graft failure-free (88% and 93% vs. 81%) survival, with a lower incidence of 3-month graft failure (7.4% and 4.0% vs. 11.1%; p <0.001 for all comparisons). Despite significant differences in cohort characteristics, L-GrAFT7 maintained an excellent validation AUROC of 0.78, significantly superior to binary EAD (AUROC 0.68, p = 0.001) and MEAF scores (AUROC 0.72, p <0.001). In post hoc analysis of the COPE NMP trial, the highest tertile of L-GrAFT7 was significantly associated with time to liver allograft (hazard ratio [HR] 2.17, p = 0.016), Clavien ≥IIIB (HR 2.60, p = 0.034) and ≥IVa (HR 4.99, p = 0.011) complications; post-LT length of hospitalization (p = 0.002); and renal replacement therapy (odds ratio 3.62, p = 0.016). CONCLUSIONS: We have validated the L-GrAFT7 risk score as a generalizable, highly accurate, individualized risk assessment of 3-month liver allograft failure that is superior to existing scores. L-GrAFT7 may standardize grading of early hepatic allograft function and serve as a clinical endpoint in translational studies (www.lgraft.com). LAY SUMMARY: Early allograft dysfunction negatively affects outcomes following liver transplantation. In independent multicenter US and European cohorts totaling 3,423 patients undergoing liver transplantation, the liver graft assessment following transplantation (L-GrAFT) risk score is validated as a superior measure of early allograft function that accurately discriminates 3-month graft failure-free survival and post-liver transplantation complications.

Financial implications of using extracorporeal membrane oxygenation following heart transplantation.

OBJECTIVES: Primary graft dysfunction after heart transplant is associated with high morbidity and mortality. Extracorporeal membrane oxygenation (ECMO) can be used to wean patients from cardiopulmonary bypass. This study retrospectively reviews a single-centre experience of post-transplant ECMO in regard to outcomes and associated costs. METHODS: Between May 2006 and May 2019, a total of 267 adult heart transplants were performed. We compared donor and recipient variables, ECMO duration and the incidence of renal failure, bleeding, infection and cost analysis between ECMO and non-ECMO groups. RESULTS: ECMO support was required postoperatively to manage primary graft dysfunction in 72 (27%) patients. The mean duration of ECMO support was 6 ± 3.2 days. Mean ischaemic times were similar between the groups. There was a significantly higher proportion of ventricular assist device explant to transplant in the ECMO group versus non-ECMO (38.2% vs 14.1%; P < 0.0001). ECMO patients had a longer duration of stay in the intensive care unit (P < 0.0001) and total hospital stay (P < 0.0001). Greater mortality was observed in the ECMO group (P < 0.0001). The median cost of providing ECMO was £18 000 [interquartile range (IQR): £12 750-£24 000] per patient with an additional median £35 225 (IQR: £21 487.25-£51 780.75) for ITU stay whilst on ECMO. The total median cost per patient inclusive of hospital stay, ECMO and dialysis costs was £65 737.50 (IQR: £52 566.50-£95 221.75) in the non-ECMO group compared to £145 415.71 (IQR: £102 523.21-£200 618.96) per patient in the ECMO group (P < 0.0001). CONCLUSIONS: Patients with primary graft dysfunction following heart transplantation who require ECMO are frequently bridged to a recovery; however, the medium and longer-term survival for these patients is poorer than for patients who do not require ECMO.

Ex vivo lung perfusion for donor lung assessment and repair: a review of translational interspecies models.

For patients with end-stage lung disease, lung transplantation is a lifesaving therapy. Currently however, the number of patients who require a transplant exceeds the number of donor lungs available. One of the contributing factors to this is the conservative mindset of physicians who are concerned about transplanting marginal lungs due to the potential risk of primary graft dysfunction. Ex vivo lung perfusion (EVLP) technology has allowed for the expansion of donor pool of organs by enabling assessment and reconditioning of these marginal grafts before transplant. Ongoing efforts to optimize the therapeutic potential of EVLP are underway. Researchers have adopted the use of different large and small animal models to generate translational preclinical data. This includes the use of rejected human lungs, pig lungs, and rat lungs. In this review, we summarize some of the key current literature studies relevant to each of the major EVLP model platforms and identify the advantages and disadvantages of each platform. The review aims to guide investigators in choosing an appropriate species model to suit their specific goals of study, and ultimately aid in translation of therapy to meet the growing needs of the patient population.

A CLUE for better assessment of donor lungs: Novel technique in clinical ex vivo lung perfusion.

BACKGROUND: The direCt Lung Ultrasound Evaluation (CLUE) technique was proven to be an accurate method for monitoring extravascular lung water in donor lungs during ex vivo lung perfusion (EVLP) in an experimental model. The aim of this study was to examine the application of CLUE in the clinical setting. METHODS: Lungs were evaluated using acellular EVLP protocol. Ultrasound images were obtained directly from the lung surface. Images were graded according to the percentage of B-lines seen on ultrasound. CLUE scores were calculated at the beginning and end of EVLP for the whole lung, each side, and lobe based on the number (No.) of images in each grade and the total No. of images taken and evaluated retrospectively. RESULTS: A total of 23 EVLP cases were performed resulting in 13 lung transplants (LTxs) with no hospital mortality. Primary graft dysfunction (PGD) occurred in only 1 recipient (PGD3, no PGD2). Significant differences were found between suitable and non-suitable lungs in CLUE scores (1.03 vs 1.85, p < 0.001), unlike the partial pressure of oxygen/fraction of inspired oxygen ratio. CLUE had the highest area under the receiver operating characteristic curve (0.98) compared with other evaluation parameters. The initial CLUE score of standard donor lungs was significantly better than marginal lungs. The final CLUE score in proned lungs showed improvement when compared with initial CLUE score, especially in the upper lobes. CONCLUSIONS: The CLUE technique shows the highest accuracy in evaluating donor lungs for LTx suitability compared with other parameters used in EVLP. CLUE can optimize the outcomes of LTx by guiding the decision making through the whole process of clinical EVLP.

Risk assessment of chronic lung allograft dysfunction phenotypes: Validation and proposed refinement of the 2019 International Society for Heart and Lung Transplantation classification system.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) is a heterogeneous condition. Characterization of CLAD phenotypes is essential to enhance the understanding of pathogenesis and guide new therapies. The study objective was to validate the new International Society for Heart and Lung Transplantation (ISHLT) CLAD classification system and further explore patients who do not fall into the defined CLAD sub-categories. METHODS: We performed a single-center, retrospective cohort study of adult, first, bilateral lung transplants performed from 2010 to 2015. Patients with CLAD were classified on the basis of the 2019 ISHLT consensus document. CLAD phenotypes and other potential predictors of survival after CLAD onset were assessed using Kaplan-Meier and Cox proportional hazards models. RESULTS: Among the 174 subjects with CLAD, 104 (59.8%) had bronchiolitis obliterans syndrome (BOS), 16 (9.2%) restrictive allograft syndrome (RAS), 9 (5.2%) mixed, and 19 (10.9%) undefined phenotype. A total of 26 patients (14.9%) did not match any of these 4 categories and remained unclassified. Allograft survival post-CLAD onset was longer for patients with BOS (median, 500 days) than patients with RAS (median, 372 days) or mixed (median, 328 days). The 45 patients (26.8%) with undefined/unclassified phenotype were combined and recategorized on the basis of the presence or absence of characteristic RAS-like opacities on chest imaging; those with RAS-like opacities had significantly worse allograft survival than patients with BOS (hazard ratio, 2.14; 95% confidence interval, 1.17-3.93; p = 0.014) and similar survival to RAS or mixed phenotype. CONCLUSIONS: The new ISHLT CLAD phenotype classification is informative with regards to post-CLAD outcomes. Chest imaging demonstrating persistent parenchymal or pleural fibrosis may be used for risk-stratification of patients who do not match the major CLAD phenotypes.

Can texture analysis in ultrashort echo-time MRI distinguish primary graft dysfunction from acute rejection in lung transplants? A multidimensional assessment in a mouse model.

BACKGROUND: Differentiation of early postoperative complications affects treatment options after lung transplantation. PURPOSE: To assess if texture analysis in ultrashort echo-time (UTE) MRI allows distinction of primary graft dysfunction (PGD) from acute transplant rejection (ATR) in a mouse lung transplant model. STUDY TYPE: Longitudinal. ANIMAL MODEL: Single left lung transplantation was performed in two cohorts of six mice (strain C57BL/6) receiving six syngeneic (strain C57BL/6) and six allogeneic lung transplants (strain BALB/c (H-2Kd )). FIELD STRENGTH/SEQUENCE: 4.7T small-animal MRI/eight different UTE sequences (echo times: 50-5000 µs) at three different postoperative timepoints (1, 3, and 7 days after transplantation). ASSESSMENT: Nineteen different first- and higher-order texture features were computed on multiple axial slices for each combination of UTE and timepoint (24 setups) in each mouse. Texture features were compared for transplanted (graft) and contralateral native lungs between and within syngeneic and allogeneic cohorts. Histopathology served as a reference. STATISTICAL TESTS: Nonparametric tests and correlation matrix analysis were used. RESULTS: Pathology revealed PGD in the syngeneic and ATR in the allogeneic cohort. Skewness and low-gray-level run-length features were significantly different between PGD and ATR for all investigated setups (P < 0.03). These features were significantly different between graft and native lung in ATR for most setups (minimum of 20/24 setups; all P < 0.05). The number of significantly different features between PGD and ATR increased with elapsing postoperative time. Differences in significant features were highest for an echo-time of 1500 µs. DATA CONCLUSION: Our findings suggest that texture analysis in UTE-MRI might be a tool for the differentiation of PGD and ATR in the early postoperative phase after lung transplantation. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2020;51:108-116.

Inhaled Pulmonary Vasodilators and Thoracic Organ Transplantation: Does Evidence Support Its Use and Cost Benefit?

In heart transplantation, pulmonary hypertension and increased pulmonary vascular resistance followed by donor right ventricular dysfunction remain a major cause of perioperative morbidity and mortality. In lung transplantation, primary graft dysfunction remains a major obstacle because it can cause bronchiolitis obliterans and mortality. Pulmonary vasodilators have been used as an adjunct therapy for heart or lung transplantation, mainly to treat pulmonary hypertension, right ventricular failure, and associated refractory hypoxemia. Among pulmonary vasodilators, inhaled nitric oxide is unique in that it is selective in pulmonary circulation and causes fewer systemic complications such as hypotension, flushing, or coagulopathy. Nitric oxide is expected to prevent or attenuate primary graft dysfunction by decreasing ischemia-reperfusion injury in lung transplantation. However, when considering the long-term benefit of these medications, little evidence supports their use in heart or lung transplantation. Current guidelines endorse inhaled vasodilators for managing immediate postoperative right ventricular failure in lung or heart transplantation, but no guidance is offered regarding agent selection, dosing, or administration. This review presents the current evidence of inhaled nitric oxide in lung or heart transplantation as well as comparisons with other pulmonary vasodilators including cost differences in consideration of economic pressures to contain rising pharmacy costs.

Primary graft dysfunction after heart transplantation: Outcomes and resource utilization.

BACKGROUND: A unified definition of primary graft dysfunction (PGD) after heart transplantation was adopted in 2014, with moderate and severe PGD defined as a need for mechanical circulatory support. While risk factors for PGD are well identified, outcomes and resource utilization have not been well-studied. We examined the resource utilization and associated costs with PGD. METHODS: All adult heart transplantations (2001-2016) from a statewide Society of Thoracic Surgery database were analyzed by dividing them into two groups-with PGD (requiring mechanical circulatory support) and without PGD. RESULTS: Of the 718 heart transplants, 110 (15.3%) patients developed PGD. Prevalence of PGD for the study duration ranged from 3.7% to 22.7% with no significant trend. The most frequently used mechanical circulatory support device was intra-aortic balloon pump (88%), followed by extracorporeal membrane oxygenation (17%), and catheter-based circulatory support devices (3%). There were no significant differences in demographics or preoperative variables between the two groups. Resource utilization such as total intensive care unit hours, ventilation hours, reoperation for bleeding, blood product transfusions, and length of stay were significantly higher in the PGD group. Postoperative complications were also higher in PGD group including operative mortality (31.8% vs 3.8%, P < .0001). The median cost of heart transplantation was significantly higher in the PGD group $229 482 ($126 044-$388 889) vs $101 788 ($72 638-$181 180) P < .0001. CONCLUSION: Primary graft dysfunction following heart transplantation developed in 15% of patients. Patients with PGD had significantly higher complications, resource utilization, and mortality. Preventive measures to address the development of PGD would reduce resource utilization and improve outcomes.

Assessment of lung edema during ex-vivo lung perfusion by single transpulmonary thermodilution: A preliminary study in humans.

BACKGROUND: Single transpulmonary thermodilution (SD) with extravascular lung water index (EVLWI) could become a new tool to better assess lung graft edema during ex-vivo lung perfusion (EVLP). In this study we compare EVLWI with conventional methods to better select lungs during EVLP and to predict post-transplant primary graft dysfunction (PGD). METHODS: We measured EVLWI, arterial oxygen/fraction of inspired oxygen (P/F) ratio, and static lung compliance (SLC) during EVLP in an observational study. At the end of EVLP, grafts were accepted or rejected according to a standardized protocol blinded to EVLWI results. We compared the respective ability of EVLWI, P/F, and SLC to predict PGD. Mann-Whitney U-test, Fisher's exact test, and receiver-operating characteristic (ROC) curve data were used for analysis. p < 0.05 was considered statistically significant. RESULTS: Thirty-five lungs were evaluated by SD during EVLP. Three lungs were rejected for pulmonary edema. Thirty-two patients were transplanted, 8 patients developed Grade 2 or 3 PGD, and 24 patients developed Grade 0 or 1 PGD. In contrast to P/F ratio, SLC, and pulmonary artery pressure, EVLWI differed between these 2 populations (p < 0.001). The area under the ROC for EVLWI assessing Grade 2 or 3 PGD at the end of EVLP was 0.93. Donor lungs with EVLWI >7.5 ml/kg were more likely associated with a higher incidence of Grade 2 or 3 PGD at Day 3. CONCLUSIONS: Increased EVLWI during EVLP was associated with PGD in recipients.

Evaluation of Early Allograft Function Using the Liver Graft Assessment Following Transplantation Risk Score Model.

Importance: Early allograft dysfunction (EAD) following a liver transplant (LT) unequivocally portends adverse graft and patient outcomes, but a widely accepted classification or grading system is lacking. Objective: To develop a model for individualized risk estimation of graft failure after LT and then compare the model's prognostic performance with the existing binary EAD definition (bilirubin level of ≥10 mg/dL on postoperative day 7, international normalized ratio of ≥1.6 on postoperative day 7, or aspartate aminotransferase or alanine aminotransferase level of >2000 U/L within the first 7 days) and the Model for Early Allograft Function (MEAF) score. Design, Setting, and Participants: This retrospective single-center analysis used a transplant database to identify all adult patients who underwent a primary LT and had data on 10 days of post-LT laboratory variables at the Dumont-UCLA Transplant Center of the David Geffen School of Medicine at UCLA between February 1, 2002, and June 30, 2015. Data collection took place from January 4, 2016, to June 30, 2016. Data analysis was conducted from July 1, 2016, to August 30, 2017. Main Outcomes and Measures: Three-month graft failure-free survival. Results: Of 2021 patients who underwent primary LT over the study period, 2008 (99.4%) had available perioperative data and were included in the analysis. The median (interquartile range [IQR]) age of recipients was 56 (49-62) years, and 1294 recipients (64.4%) were men. Overall survival and graft-failure-free survival rates were 83% and 81% at year 1, 74% and 71% at year 3, and 69% and 65% at year 5, with an 11.1% (222 recipients) incidence of 3-month graft failure or death. Multivariate factors associated with 3-month graft failure-free survival included post-LT aspartate aminotransferase level, international normalized ratio, bilirubin level, and platelet count, measures of which were used to calculate the Liver Graft Assessment Following Transplantation (L-GrAFT) risk score. The L-GrAFT model had an excellent C statistic of 0.85, with a significantly superior discrimination of 3-month graft failure-free survival compared with the existing EAD definition (C statistic, 0.68; P < .001) and the MEAF score (C statistic, 0.70; P < .001). Compared with patients with lower L-GrAFT risk, LT recipients in the highest 10th percentile of L-GrAFT scores had higher Model for End-Stage Liver Disease scores (median [IQR], 34 [26-40] vs 31 [25-38]; P = .005); greater need for pretransplant hospitalization (56.8% vs 44.8%; P = .003), renal replacement therapy (42.9% vs 30.5%; P < .001), mechanical ventilation (35.8% vs 18.1%; P < .001), and vasopressors (22.9% vs 11.0%; P < .001); longer cold ischemia times (median [IQR], 436 [311-539] vs 401 [302-506] minutes; P = .04); greater intraoperative blood transfusions (median [IQR], 17 [10-26] vs 10 [6-17] units of packed red blood cells; P < .001); and older donors (median [IQR] age, 47 [28-56] vs 41 [25-52] years; P < .001). Conclusions and Relevance: The L-GrAFT risk score allows a highly accurate, individualized risk estimation of 3-month graft failure following LT that is more accurate than existing EAD and MEAF scores. Multicenter validation may allow for the adoption of the L-GrAFT as a tool for evaluating the need for a retransplant, for establishing standardized grading of early allograft function across transplant centers, and as a highly accurate clinical end point in translational studies aiming to mitigate ischemia or reperfusion injury by modulating donor quality and recipient factors.

Cessation of extracorporeal photopheresis in chronic lung allograft dysfunction: effects on clinical outcome in adults.

BACKGROUND: Extracorporeal photopheresis (ECP) has been reported to be safe and the ultimate treatment option in lung transplant recipients with chronic lung allograft dysfunction (CLAD), the main overall cause of mortality in lung transplant recipients. However, ECP is not reimbursed in selected health jurisdictions, and reimbursement by health insurance providers is a major issue. In Switzerland, ECP is not recognised by the health authorities as a therapy option for CLAD; thus by the end of 2014, ECP had to be stopped in the majority of adult lung transplant recipients cared for at the University Hospital Zurich because of lack of continuous funding. OBJECTIVE: To describe the outcome of lung transplant recipients after forced cessation of ECP treatment. METHOD: We retrospectively analysed outcome of 12 lung transplant recipients undergoing ECP for different phenotypes of CLAD (bronchiolitis obliterans syndrome, restrictive allograft syndrome) at our centre followed-up for 12 months after forced cessation of ECP. RESULTS: Within the 12 months after treatment cessation, seven patients (58%) died with a median survival of 207 days (range 6-365 days). Lung function (FEV1, forced expiratory volume in 1 second) declined significantly 6 months after ECP cessation (p = 0.003). CONCLUSION: Our data support the role of ECP as valuable treatment option in lung transplant recipients with CLAD.

An observational study of Donor Ex Vivo Lung Perfusion in UK lung transplantation: DEVELOP-UK.

BACKGROUND: Many patients awaiting lung transplantation die before a donor organ becomes available. Ex vivo lung perfusion (EVLP) allows initially unusable donor lungs to be assessed and reconditioned for clinical use. OBJECTIVE: The objective of the Donor Ex Vivo Lung Perfusion in UK lung transplantation study was to evaluate the clinical effectiveness and cost-effectiveness of EVLP in increasing UK lung transplant activity. DESIGN: A multicentre, unblinded, non-randomised, non-inferiority observational study to compare transplant outcomes between EVLP-assessed and standard donor lungs. SETTING: Multicentre study involving all five UK officially designated NHS adult lung transplant centres. PARTICIPANTS: Patients aged ≥ 18 years with advanced lung disease accepted onto the lung transplant waiting list. INTERVENTION: The study intervention was EVLP assessment of donor lungs before determining suitability for transplantation. MAIN OUTCOME MEASURES: The primary outcome measure was survival during the first 12 months following lung transplantation. Secondary outcome measures were patient-centred outcomes that are influenced by the effectiveness of lung transplantation and that contribute to the health-care costs. RESULTS: Lungs from 53 donors unsuitable for standard transplant were assessed with EVLP, of which 18 (34%) were subsequently transplanted. A total of 184 participants received standard donor lungs. Owing to the early closure of the study, a non-inferiority analysis was not conducted. The Kaplan-Meier estimate of survival at 12 months was 0.67 [95% confidence interval (CI) 0.40 to 0.83] for the EVLP arm and 0.80 (95% CI 0.74 to 0.85) for the standard arm. The hazard ratio for overall 12-month survival in the EVLP arm relative to the standard arm was 1.96 (95% CI 0.83 to 4.67). Patients in the EVLP arm required ventilation for a longer period and stayed longer in an intensive therapy unit (ITU) than patients in the standard arm, but duration of overall hospital stay was similar in both groups. There was a higher rate of very early grade 3 primary graft dysfunction (PGD) in the EVLP arm, but rates of PGD did not differ between groups after 72 hours. The requirement for extracorporeal membrane oxygenation (ECMO) support was higher in the EVLP arm (7/18, 38.8%) than in the standard arm (6/184, 3.2%). There were no major differences in rates of chest radiograph abnormalities, infection, lung function or rejection by 12 months. The cost of EVLP transplants is approximately £35,000 higher than the cost of standard transplants, as a result of the cost of the EVLP procedure, and the increased ECMO use and ITU stay. Predictors of cost were quality of life on joining the waiting list, type of transplant and number of lungs transplanted. An exploratory model comparing a NHS lung transplant service that includes EVLP and standard lung transplants with one including only standard lung transplants resulted in an incremental cost-effectiveness ratio of £73,000. Interviews showed that patients had a good understanding of the need for, and the processes of, EVLP. If EVLP can increase the number of usable donor lungs and reduce waiting, it is likely to be acceptable to those waiting for lung transplantation. Study limitations include small numbers in the EVLP arm, limiting analysis to descriptive statistics and the EVLP protocol change during the study. CONCLUSIONS: Overall, one-third of donor lungs subjected to EVLP were deemed suitable for transplant. Estimated survival over 12 months was lower than in the standard group, but the data were also consistent with no difference in survival between groups. Patients receiving these additional transplants experience a higher rate of early graft injury and need for unplanned ECMO support, at increased cost. The small number of participants in the EVLP arm because of early study termination limits the robustness of these conclusions. The reason for the increased PGD rates, high ECMO requirement and possible differences in lung injury between EVLP protocols needs evaluation. TRIAL REGISTRATION: Current Controlled Trials ISRCTN44922411. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 85. See the NIHR Journals Library website for further project information.

Nephrologists' management of patient medications in kidney transplantation: results of an online survey.

RATIONALE, AIMS AND OBJECTIVES: Medication adherence is essential in kidney transplant recipients to reduce the risk of rejection and subsequent allograft loss. The aim of this study was to delineate what 'usual care' entails, in relation to medication management, for adult kidney transplant recipients. METHODS: An online survey was developed to explore how nephrologists promote and assess medication adherence, the management of prescriptions, the frequency of clinic appointments and the frequency of clinical screening tests. Nephrologists from all acute kidney transplant units in Victoria, Australia, were invited to participate. Data were collected between May and June 2014. RESULTS: Of 60 nephrologists invited to participate, 22 completed the survey (response rate of 36.6%). Respondents had a mean age of 49.1 ± 10.1 years, with a mean of 20.1 ± 9.9 years working in nephrology and 14 were men. Descriptive analysis of responses showed that nephrologists performed frequent screening for kidney graft dysfunction that may indicate medication non-adherence, maintained regular transplant clinic visits with patients and emphasized the importance of medication education. However, time constraints during consultations impacted on extensive patient education and the long-term medication follow-up support was often delivered by the renal transplant nurse coordinator or pharmacist. CONCLUSIONS: This study highlighted that nephrologists took an active approach in the medication management of kidney transplant recipients, which may assist with facilitating long-term graft survival. Ultimately, promoting medication adherence needs to be patient centred, involving an interdisciplinary team of nephrologists, pharmacists and renal transplant nurse coordinators, working together with the patient to establish optimal adherence.

PREventing Delayed Graft Function by Driving Immunosuppressive InduCtion Treatment (PREDICT-DGF): study protocol for a randomized controlled trial.

BACKGROUND: In kidney transplantation, the use of Anti-Thymocyte Globulins (ATG) as induction therapy has been described as a possible treatment for reducing the prevalence of Delayed Graft Function (DGF). ATG possesses pharmaceutical proprieties that could help control the lesions caused by ischemia reperfusion injury. However, other studies have questioned this potential protective effect. We hypothesized that the benefits related to ATG for reducing DGF prevalence may be higher and more consistently recognized if only patients with high DGF risk are considered. We recently proposed a scoring system entitled DGFS (Delayed Graft Function Score) for such stratification of kidney transplant recipients according to their risk of DGF. Using the DGFS calculation, we aim to determine whether a short course of ATG can decrease the incidence of DGF in comparison with Basiliximab in kidney transplant recipients with low immunological risk but high DGF risk. METHODS: We conduct a phase IV, open label, randomized, multicentric and prospective study, to compare ATG in parallel with a control group treated by Basiliximab. The 1:1 randomized allocation of patients between groups is stratified on the clinical center, and on the hypothermic machine-perfusion device. We aimed to include a total of 384 patients to achieve a statistical power at 0.80. The study was initiated at the Nantes University hospital in July 2014, with data collection continuing until April 2018, and publication of the results proposed for 2019. DISCUSSION: The main expected benefits of this study are i) the reduction of unjustified ATG over-prescriptions associated with serious adverse events, ii) the reduction of chance losses related to ATG under-prescription, iii) the decrease in the incidence of DGF which was described as a risk factor of graft failure and patient death, and iv) the reduction in hospitalization duration and number of post transplantation dialysis sessions, both being associated with reduced medical costs. In conclusion, the current study is innovative by proposing a more efficient and personalized induction therapy. TRIAL REGISTRATION: The study was registered in the Clinical Trials Registry (# NCT02056938, February 5, 2014), and in the European Clinical Trials Database (EudraCT #2014-000332-42, January 30, 2014).