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Background: Lung transplantation (LTx) remains the only efficient treatment for selected patients with end-stage pulmonary disease. The age limit for the acceptance of donor organs in LTx is still a matter of debate. We here analyze the impact of donor organ age and the underlying pulmonary disease on short- and long-term outcome and survival after LTx., Methods: Donor and recipient characteristics of LTx recipients at our institution between 03/2003 and 12/2021 were analyzed. Statistical analysis was performed using SPSS and GraphPad software., Results: In 230 patients analyzed, donor age ≥ 55 years was associated with a higher incidence of severe primary graft dysfunction (PGD2/3) (46% vs. 31%, p = 0.03) and reduced long-term survival after LTx (1-, 5- and 10-year survival: 75%, 54%, 37% vs. 84%, 76%, 69%, p = 0.006). Notably, this was only significant in recipients with idiopathic pulmonary fibrosis (IPF) (PGD: 65%, vs. 37%, p = 0.016; 1-, 5-, and 10-year survival: 62%, 38%, 16% vs. 80%, 76%, 70%, p = 0.0002 respectively). In patients with chronic obstructive pulmonary disease (COPD), donor age had no impact on the incidence of PGD2/3 or survival (21% vs. 27%, p = 0.60 and 68% vs. 72%; p = 0.90 respectively). Moreover, we found higher Torque-teno virus (TTV)-DNA levels after LTx in patients with IPF compared to COPD (X 2  = 4.57, p = 0.033). Donor age ≥ 55 is an independent risk factor for reduced survival in the whole cohort and patients with IPF specifically., Conclusions: In recipients with IPF, donor organ age ≥ 55 years was associated with a higher incidence of PGD2/3 and reduced survival after LTx. The underlying pulmonary disease may thus be a relevant factor for postoperative graft function and survival., Trial Registration Number Dkrs: DRKS00033312., (© 2024. The Author(s).)

Objectives: To synthesize the clinical experience of patients with COVID-19-associated acute respiratory distress syndrome (ARDS) or pulmonary fibrosis (PF) receiving lung transplantation (LTx) and compare the characteristics and outcomes of COVID-19 and non-COVID-19 LTx patients., Methods: A literature search of online databases (PubMed, Web of Science, Embase, the Cochrane Library, China Science and Technology Journal Database, and Wan Fang databases) was performed regarding LTx for COVID-19-associated ARDS or PF. This study was registered on PROSPERO (CRD2024507647)., Results: Eight eligible studies were included with 478 COVID-19 LTx patients and 163 non-COVID-19 LTx patients. In COVID-19 LTx patients, the pooled hospital mortality and follow-up survival rate was 0.00% (95% CI 0.00-0.03) and 87.40% (95% CI 0.76-0.96). Compared to non-COVID-19 LTx patients, COVID-19 LTx patients were associated with significantly higher rate of primary graft dysfunction (odds ratio [OR] 8.72, 95% CI 3.54-21.47, P < 0.001) but significantly higher follow-up survival rate (OR 2.48, 95% CI 1.02-6.01, P = 0.04), within an overall similar follow-up period., Conclusions: For patients with COVID-19-associated ARDS or PF, LTx offers acceptable short-term outcomes and is suggested as a viable lifesaving treatment., Competing Interests: Declarations of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Primary non-function (PNF) and early allograft failure (EAF) after liver transplantation (LT) seriously affect patient outcomes. In clinical practice, effective prognostic tools for early identifying recipients at high risk of PNF and EAF were urgently needed. Recently, the Model for Early Allograft Function (MEAF), PNF score by King's College (King-PNF) and Balance-and-Risk-Lactate (BAR-Lac) score were developed to assess the risks of PNF and EAF. This study aimed to externally validate and compare the prognostic performance of these three scores for predicting PNF and EAF., Methods: A retrospective study included 720 patients with primary LT between January 2015 and December 2020. MEAF, King-PNF and BAR-Lac scores were compared using receiver operating characteristic (ROC) and the net reclassification improvement (NRI) and integrated discrimination improvement (IDI) analyses., Results: Of all 720 patients, 28 (3.9%) developed PNF and 67 (9.3%) developed EAF in 3 months. The overall early allograft dysfunction (EAD) rate was 39.0%. The 3-month patient mortality was 8.6% while 1-year graft-failure-free survival was 89.2%. The median MEAF, King-PNF and BAR-Lac scores were 5.0 (3.5-6.3), -2.1 (-2.6 to -1.2), and 5.0 (2.0-11.0), respectively. For predicting PNF, MEAF and King-PNF scores had excellent area under curves (AUCs) of 0.872 and 0.891, superior to BAR-Lac (AUC = 0.830). The NRI and IDI analyses confirmed that King-PNF score had the best performance in predicting PNF while MEAF served as a better predictor of EAD. The EAF risk curve and 1-year graft-failure-free survival curve showed that King-PNF was superior to MEAF and BAR-Lac scores for stratifying the risk of EAF., Conclusions: MEAF, King-PNF and BAR-Lac were validated as practical and effective risk assessment tools of PNF. King-PNF score outperformed MEAF and BAR-Lac in predicting PNF and EAF within 6 months. BAR-Lac score had a huge advantage in the prediction for PNF without post-transplant variables. Proper use of these scores will help early identify PNF, standardize grading of EAF and reasonably select clinical endpoints in relative studies., (Copyright © 2023 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)

Background: Due to development of chronic lung allograft dysfunction (CLAD), prognosis for patients undergoing lung transplantation (LTx) is still worse compared to other solid organ transplant recipients. Treatment options for slowing down CLAD progression are scarce with extracorporeal photopheresis (ECP) as an established rescue therapy. The aim of the study was to identify characteristics of responders and non-responders to ECP treatment, assess their survival, lung function development and by that define the subset of patients who should receive early ECP treatment., Methods: We performed a retrospective study of all LTx patients receiving ECP treatment at the University Hospital Zurich between January 2010 and March 2020. Patients were followed-up for a maximum period of 5 years. Mortality and lung function development were assessed by CLAD stage and by CLAD subtype before initiation of ECP treatment., Results: Overall, 105 patients received at least one ECP following LTx. A total of 57 patients (61.3%) died within the study period with a median survival of 15 months. Mortality was 57% for patients who started ECP at CLAD1, 39% for CLAD2, 93% for CLAD3, and 90% for CLAD4 (p < 0.001). Survival and lung function development was best in young patients at early CLAD stages 1 and 2. Response to ECP treatment was worst in patients with CLAD-RAS/mixed subtype (14.3%) and patients with ECP initiation in CLAD stages 3 (7.1%) and 4 (11.1%). Survival was significantly better in a subset of patients with recurrent acute allograft dysfunction and earlier start of ECP treatment (105 vs 15 months)., Conclusion: In this retrospective analysis of a large group of CLAD patients treated with ECP after LTx, early initiation of ECP was associated with better long-term survival. Besides a subset of patients suffering of recurrent allograft dysfunction, especially a subset of patients defined as responders showed an improved response rate and survival, suggesting that ECP should be initiated in early CLAD stages and young patients. ECP might therefore prevent long-term disease progression even in patients with CLAD refractory to other treatment options and thus prevent or delay re-transplantation., (© 2024 The Author(s). Journal of Clinical Apheresis published by Wiley Periodicals LLC.)

Background: Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) are acute, significant respiratory deteriorations in patients with IPF and can lead to increased morbidity and mortality. It remains unclear how AE-IPF impacts lung transplant (LTX) outcomes., Methods: All adult patients who were listed for LTX between July 2005 and October 2020 at the Loyola University Medical Center with a diagnosis of IPF were included. Pretransplant characteristics and posttransplant outcomes were gathered via retrospective chart review. The primary outcome was short- and long-term survival for patients transplanted during stable IPF versus those with AE-IPF., Results: One hundred fifty-nine patients were included in this study, 17.6% of whom were transplanted during AE-IPF. AE-IPF patients were more likely to have higher oxygen needs pretransplant, have higher lung allocation score, and were more likely to be intubated or be on extracorporeal membrane oxygenation as compared with stable IPF patients. Survival by AE status at transplant did not differ at 90 d or 1 y posttransplantation. There were also no significant differences in rates of severe primary graft dysfunction or acute rejection within 1 y., Conclusions: Patients with AE-IPF were more likely to have higher oxygenation requirements and higher lung allocation score at the time of LTX than those with stable IPF. Despite this, there were no differences in survival at 90 d, 1 y, or 3 y, or differences in incidence of severe primary graft dysfunction or acute cellular rejection. Transplantation of patients with AE-IPF has clinical outcomes comparable with transplantation of patients with stable IPF. This contrasts with previous studies examining LTX in patients with AE-IPF., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To investigate the association between driving pressure (ΔP) and 90-day mortality in patients following lung transplantation (LTx) in patients who developed primary graft dysfunction (PGD)., Methods: This prospective, observational study involved consecutive patients who, following LTx, were admitted to our intensive care unit (ICU) from January 2022 to January 2023. Patients were separated into two groups according to ΔP at time of admission (i.e., low, ≤15 cmH 2 O or high, >15 cmH 2 O). Postoperative outcomes were compared between groups., Results: In total, 104 patients were involved in the study, and of these, 69 were included in the low ΔP group and 35 in the high ΔP group. Kaplan-Meier analysis of 90-day mortality showed a statistically significant difference between groups with survival better in the low ΔP group compared with the high ΔP group. According to Cox proportional regression model, the variables independently associated with 90-day mortality were ΔP and pneumonia. Significantly more patients in the high ΔP group than the low ΔP group had PGD grade 3 (PGD3), pneumonia, required tracheostomy, and had prolonged postoperative extracorporeal membrane oxygenation (ECMO) time, postoperative ventilator time, and ICU stay., Conclusions: Driving pressure appears to have the ability to predict PGD3 and 90-day mortality of patients following LTx. Further studies are required to confirm our results., Competing Interests: Declaration of conflicting interestsThe authors declare that there are no conflicts of interest.

Purpose: This meta-analysis aimed to compare the prognosis of lung transplantation recipients based on donor age., Methods: A detailed search was performed in PubMed, Embase, Web of Science, and the Cochrane Library for cohort studies on lung transplantation. The prognosis of lung transplant recipients was investigated based on the donor age, with the primary outcomes being 1-year overall survival (OS), 3-year OS, 5-year OS, and 5-year chronic lung allograft dysfunction (CLAD)-free survival., Results: This meta-analysis included 10 cohort studies. Among the short-term outcomes, the older donor group demonstrated no significant difference from the young donor group in primary graft dysfunction within 72 hours, use of extracorporeal membrane oxygenation, length of ventilator use, and intensive care unit hours. However, a longer hospital stay was associated with the older donor group. In terms of long-term outcomes, no difference was found between the two groups in 1-year OS, 3-year OS, and 5-year OS. Notably, patients with older donors exhibited a superior 5-year CLAD-free survival., Conclusions: The results of this meta-analysis indicate that older donors are not inferior to younger donors in terms of long-term and short-term recipient outcomes. Lung transplantation using older donors is a potential therapeutic option after rigorous evaluation.

Purpose: This meta-analysis aimed to examine the prognosis of patients with acute exacerbation of interstitial lung disease (AE-ILD) treated with lung transplantation compared to those with stable interstitial lung disease (ILD)., Methods: We conducted a detailed search in PubMed, Embase, Web of Science, and the Cochrane Library, with the primary outcomes being overall survival (OS), acute cellular rejection (ACR), primary graft dysfunction (PGD), and length of stay (LOS)., Results: Five cohort studies were included in this meta-analysis, with 183 patients enrolled in the AE-ILD group and 337 patients in the stable-ILD group. The results showed that in regard to perioperative outcomes, the AE-ILD group did not differ from the stable-ILD group in the incidence of ACR (relative risks [RR] = 0.34, p = 0.44) and the incidence of PGD Ⅲ (RR = 0.53, p = 0.43), but had a longer LOS (mean difference = 9.15, p = 0.02). Regarding prognosis, the two also did not differ in 90-day OS (RR = 0.97, p = 0.59), 1-year OS (RR = 1.05, p = 0.66), and 3-year OS (RR = 0.91, p = 0.76)., Conclusion: Our study concluded that the efficacy of lung transplantation in patients with AE-ILD is not inferior to that of patients with stable ILD. Lung transplantation is one of the potential treatments for patients with AE-ILD.

Objectives: To evaluate outcomes after heart retransplantation., Methods: From January 6, 1968, to June 2019, 123 patients (112 adult and 11 pediatric patients) underwent heart retransplantation, and 2092 received primary transplantation at our institution. Propensity-score matching was used to account for baseline differences between the retransplantation and the primary transplantation-only groups. Kaplan-Meier survival analyses were performed. The primary end point was all-cause mortality, and secondary end points were postoperative complications., Results: Retransplantation recipient age was 39.6 ± 16.4 years, and donor age was 26.4 ± 11.2 years. Ninety-two recipients (74.8%) were male. Compared with recipients who only underwent primary heart transplantation, retransplantation recipients were more likely to have hypertension (44/73.3% vs 774/53.3%, P = .0022), hyperlipidemia (40/66.7% vs 447/30.7%, P < .0001), and require dialysis (7/11.7% vs 42/2.9%, P = .0025). The indications for heart retransplantation were cardiac allograft vasculopathy (32/80%), primary graft dysfunction (6/15%), and refractory acute rejection (2/5%). After matching, postoperative outcomes such as hospital length of stay, severe primary graft dysfunction requiring intra-aortic balloon pump or extracorporeal membrane oxygenation, cerebral vascular accident, respiratory failure, renal failure requiring dialysis, and infection were similar between the 2 groups. Matched median survival after retransplantation was 4.6 years compared with 6.5 years after primary heart transplantation (log-rank P = .36, stratified log-rank P = .0063)., Conclusions: In this single-center cohort, the unadjusted long-term survival after heart retransplantation was inferior to that after primary heart transplantation, and short-term survival difference persisted after propensity-score matching. Heart retransplantation should be considered for select patients for optimal donor organ usage., (Copyright © 2020 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: Paediatric lung transplantation poses unique management challenges. Experience regarding indications and outcome is scarce, especially in younger children. The primary aim of this study was to investigate outcome after first lung transplantation in children <12 years of age in comparison to adolescents (12-17 years old)., Methods: Records of patients <18 years who underwent first lung transplantation between 01/2005 and 01/2021 were retrospectively reviewed, and compared between children <12 years old and adolescents. Median (IQR) follow-up was 51 (23-91) months., Results: Of the 117 patients underwent first lung transplantation at our institution, of whom 42 (35.8%) patients were <12 years and 75 (64.2%) ≥12 years old. Compared to adolescents, children were more often transplanted for interstitial lung disease (33.3% vs 12%, p = 0.005) and precapillary pulmonary hypertension (28.6% vs 12%, p = 0.025), and required more often intraoperative cardiopulmonary bypass (31% vs 14.7%, p = 0.036) and postoperative ECMO support (47.6% vs 13.3%, p < 0.001). Postoperatively, children required longer ventilation times (78 vs 18 hours, p = 0.009) and longer ICU stay (9.5 vs 3 days, p < 0.001) compared to their older counterparts. Primary graft dysfunction grade 3 at 72 hours (9.5% vs 9.3%, p = 0.999), in-hospital mortality (2.4% vs 6.7%, p = 0.418), graft survival (80% vs 62%, p = 0.479) and freedom from chronic lung allograft dysfunction (76% vs 59%, p = 0.41) at 8-year follow-up did not differ between groups., Conclusions: Lung transplantation in children under 12 years is challenging due to underlying medical conditions and operative complexity. Nevertheless, outcomes are comparable to those in older children., Competing Interests: Disclosure statement Fabio Ius declares a consulting contract with Biotest AG, outside the submitted work. Funding not to be declared., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Purpose: Anti-human leukocyte antigen (HLA) immunoglobulin (Ig) M production stimulated by an alloantigen is sensitive, making IgM a novel potential marker of allorejection after organ transplantation. This study examined the relationship between the serum levels of anti-HLA IgM early after clinical lung transplantation (LTx) and the post-transplant outcomes., Methods: Thirty-one consecutive patients who underwent deceased LTx were included. Immunoreactivity against HLA was retrospectively analyzed by measuring the anti-HLA IgM levels in the serum sampled for the first 14 days after LTx. The flow panel reactive antibody technique was used. The ratio of the anti-class I IgM level at each day to baseline was obtained, and the peak IgM level was determined for each case. The correlation between the peak IgM level and subsequent development of acute rejection (AR), chronic lung allograft dysfunction (CLAD), and survival outcomes were examined., Results: The peak IgM level was a significant risk factor for AR within 90 days in univariate and multivariate analyses. In the long term, the patients with positive IgM (peak level > 1.8) tended to have a poorer CLAD-free and overall survival than those with negative IgM., Conclusion: Elevation of anti-HLA IgM levels early after LTx may be correlated with a higher incidence of rejection and negative clinical outcomes., (© 2021. Springer Nature Singapore Pte Ltd.)

Background: Chronic Lung Allograft Dysfunction (CLAD) is a major obstacle for long term survival after lung transplantation (LTx). Besides Bronchiolitis Obliterans Syndrome, two other phenotypes of CLAD, restrictive allograft syndrome (RAS) and mixed phenotype, have been described. Trials to test in these conditions are desperately needed and analyzing natural outcome to plan such trials is essential., Methods: We performed a retrospective analysis of functional outcome in bilateral LTx recipients with RAS and mixed phenotype, transplanted between 2009 and 2018 in five large European centers with follow- up spirometry up to 12 months after diagnosis. Based on these data, sample size and power calculations for randomized therapeutic trial was estimated using two imputation methods for missing values., Results: Seventy patients were included (39 RAS and 31 mixed phenotype), median 3.1 years after LTx when CLAD was diagnosed. Eight, 13 and 25 patients died within 6, 9 and 12 months after diagnosis and a two patients underwent re-transplantation within 12 months leading to a graft survival of 89, 79 and 61% six, nine and 12 months after diagnosis, respectively. Observed FEV1 decline was 451 ml at 6 months and stabilized at 9 and 12 months, while FVC showed continuous decline. Using two methods of imputation, a progressive further decline after 6 months for FEV1 was noted., Conclusion: The poor outcome of these two specific CLAD phenotypes suggests the urgent need for future therapeutic randomized trials. The number of missing values in a potential trial seems to be high and most frequently attributed to death. Survival may be used as an endpoint in clinical trials in these distinct phenotypes and imputation techniques are relevant if graft function is used as a surrogate of disease progression in future trials., Competing Interests: The authors have declared that no competing interests exist.

Background: Acute cellular rejection (ACR) remains the most significant risk factor for chronic lung allograft dysfunction (CLAD). While clinically significant or higher-grade (≥A2) ACR is generally treated with augmented immunosuppression (IS), the management of clinically stable grade A1 ACR remains controversial. At our center, patients with clinically stable grade A1 ACR are routinely not treated with augmented IS. While the overall outcomes in this group of patients at our center are equivalent to patients with stable A0 pathology, CLAD and death rates remain overall high. We hypothesized that a distinct cytokine signature at the time of early minimal rejection state would be associated with worse outcomes. Specifically, we aimed to determine whether bronchoalveolar lavage (BAL) biomarkers at the time of first clinically stable grade A1 ACR (CSA1R) are predictive of subsequent CLAD or death., Methods: Among all adult, bilateral, first lung transplants, performed 2010-2016, transbronchial biopsies obtained within the first-year post-transplant were categorized as clinically stable or unstable based on the presence or absence of ≥10% concurrent drop in forced expiratory volume in 1 second (FEV 1 ). We assessed BAL samples obtained at the time of CSA1R episodes, which were not preceded by another ACR (i.e., first episodes). Twenty-one proteins previously associated with ACR or CLAD were measured in the BAL using a multiplex bead assay. Association between protein levels and subsequent CLAD or death was assessed using Cox Proportional Hazards models, adjusted for relevant peri-transplant clinical covariates., Results: We identified 75 patients with first CSA1R occurring at a median time of 98 days (range 48.5-197) post-transplant. Median time from transplant to CLAD or death was 1247 (756.5-1921.5) and 1641 days (1024.5-2326.5), respectively. In multivariable models, levels of MCP1/CCL2, S100A8, IL10, TNF-receptor 1, and pentraxin 3 (PTX3) were associated with both CLAD development and death (p < 0.05 for all). PTX3 remained significantly associated with both CLAD and death after adjusting for multiple comparisons., Conclusion: Our data indicate that a focused BAL protein signature, with PTX3 having the strongest association, may be useful in determining a subset of CSA1R patients at increased risk and may benefit from a more aggressive management strategy., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Purposes: Numerous indicators have been discussed as predictive markers for the incidence of chronic allograft dysfunction (CLAD) after lung transplantation (LTX). The aim of this study was to evaluate whether or not the preoperative prognostic nutrition index (PNI) correlated with the development of CLAD., Method: This study is a single-center and retrospective cohort study. Forty-six patients underwent cadaveric lung transplantation between 2000 and 2016 at our institution. The primary endpoint of this study was the CLAD-free survival of the patients., Result: CLAD was diagnosed in 11 patients (23%) during the follow-up period. Potential risk factors included recipient factors, donor factors, number of HLA mismatches, operation-related factors, and preoperative blood test results, including the preoperative PNI. The patients with a higher PNI showed a longer CLAD-free survival after LTX than those with lower values according to univariate and multivariate analyses (p = 0.01, 0.04, respectively). The 5-year CLAD-free survival rates in the higher-PNI patients and lower-PNI patients were 94% and 62%, respectively., Conclusion: We found that a lower preoperative PNI of the recipient was significantly associated with a higher incidence rate of CLAD. The preoperative PNI may, therefore, be useful as a predictor of the development of CLAD., (© 2021. Springer Nature Singapore Pte Ltd.)

Background: Six hours was historically regarded as the limit of acceptable ischemic time for lung allografts. However, broader sharing of donor lungs often necessitates use of allografts with ischemic time >6 hours. We characterized the association between ischemic time ≥8 hours and outcomes after lung transplantation using a contemporary cohort from a high-volume institution., Methods: Patients who underwent primary isolated bilateral lung transplantation between 1/2016 and 5/2020 were included. Patients bridged to transplant with extracorporeal membrane oxygenation or mechanical ventilation, and ex-vivo perfusion cases were excluded. Recipients were stratified by total allograft ischemic time <8 hours (standard) vs ≥8 hours (long). Perioperative outcomes and post-transplant survival were compared between groups., Results: Of 358 patients, 95 (26.5%) received long ischemic time (≥8 hours) lungs. Long ischemic time recipients were more likely to be male and have donation after circulatory death donors than standard ischemic time recipients. On unadjusted analysis, long and standard ischemic time recipients had similar survival, and similar rates of grade 3 primary graft dysfunction at 72 hours, extracorporeal membrane oxygenation post-transplant, acute rejection within 30 days, reintubation, and post-transplant length of stay. After adjustment, long and standard ischemic time recipients had comparable risks of mortality or graft failure., Conclusions: In a modern cohort, use of lung allografts with "long" ischemic time ≥8 hours were associated with acceptable perioperative outcomes and post-transplant survival. Further investigation is required to better understand how broader use impacts post-lung transplant outcomes and the implications for smarter sharing under an evolving national allocation policy., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Advanced donor age is a risk factor for poor survival following lung transplantation. However, recent work identifying epigenetic determinants of aging has shown that biologic age may not always reflect chronologic age and that stressors can accelerate biologic aging. We hypothesized that lung allografts that experienced primary graft dysfunction (PGD), characterized by poor oxygenation in the first three post-transplant days, would have increased biologic age. We cultured airway epithelial cells isolated by transbronchial brush at 1-year bronchoscopies from 13 subjects with severe PGD and 15 controls matched on age and transplant indication. We measured epigenetic age using the Horvath epigenetic clock. Linear models were used to determine the association of airway epigenetic age with chronologic ages and PGD status, adjusted for recipient PGD risk factors. Survival models assessed the association with chronic lung allograft dysfunction (CLAD) or death. Distributions of promoter methylation within pathways were compared between groups. DNA methyltransferase (DNMT) activity was quantified in airway epithelial cells under hypoxic or normoxic conditions. Airway epigenetic age appeared younger but was strongly associated with the age of the allograft (slope 0.38 per year, 95% CI 0.27-0.48). There was no correlation between epigenetic age and recipient age (P = 0.96). Epigenetic age was 6.5 years greater (95% CI 1.7-11.2) in subjects who had experienced PGD, and this effect remained significant after adjusting for donor and recipient characteristics (P = 0.03). Epigenetic age was not associated with CLAD-free survival risk (P = 0.11). Analysis of differential methylation of promoters of key biologic pathways revealed hypomethylation in regions related to hypoxia, inflammation, and metabolism-associated pathways. Accordingly, airway epithelial cells cultured in hypoxic conditions showed suppressed DNMT activity. While airway methylation age was primarily determined by donor chronologic age, early injury in the form of PGD was associated with increased allograft epigenetic age. These data show how PGD might suppress key promoter methylation resulting in long-term impacts on the allograft., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dugger, Calabrese, Gao, Deiter, Tsao, Maheshwari, Hays, Leard, Kleinhenz, Shah, Golden, Kukreja, Gordon, Singer and Greenland.)

Importance: Rates of cesarean delivery (CD) are increased among transplant recipients. There is a need to define the indications for CD and associated outcomes among transplant recipients to determine the safest mode of obstetric delivery., Objective: To evaluate the association of mode of obstetrical delivery with maternal and neonatal morbidity among pregnant women who have received a kidney or liver transplant., Design, Setting, and Participants: This registry-based retrospective cohort study used data from the Transplant Pregnancy Registry International, which has recruited participants since 1991 from 289 diverse academic and community settings, mainly in North America. Eligible participants were recipients of a kidney or liver transplant who were aged 18 years or older at the time of a live birth at or later than 20 weeks' gestational age and who delivered between 1968 and 2019. The data were analyzed from April 30, 2020, to April 16, 2021., Exposures: Scheduled CD, a trial of labor resulting in CD (TOL-CD), or a TOL resulting in vaginal delivery (TOL-VD)., Main Outcomes and Measures: The primary outcomes were severe maternal morbidity and neonatal composite morbidity. Multivariate regression was conducted to calculate odds ratios (ORs) or β values and 95% CIs with adjustment for differences in maternal comorbidities and gestational age at delivery. Nonmedical indications for CD are those not associated with decreased morbidity or mortality in the obstetric literature., Results: This study included 1865 women, of whom 1435 were kidney transplant recipients and 430 were liver transplant recipients. The age range of the participants was 18 to 48 years; the median body mass index among the participants was in the normal range, and the median transplant-to-conception interval was more than 2 years. Compared with a scheduled CD, a TOL was not associated with increased severe maternal morbidity among kidney transplant recipients (TOL-CD: adjusted odds ratio [aOR], 1.80 [95% CI, 0.77-4.22]; TOL-VD: aOR, 1.22 [95% CI, 0.57-2.62]) (for liver transplant recipients, the numbers were too small for multivariate modeling). In the adjusted model, a TOL was associated with a decrease in neonatal composite morbidity among kidney transplant recipients who underwent TOL-CD (aOR, 0.52; 95% CI, 0.32-0.82) and TOL-VD (aOR, 0.36; 95% CI, 0.24-0.53) and liver transplant recipients who underwent TOL-VD (aOR, 0.41; 95% CI, 0.19-0.87) but not for TOL-CD (aOR, 0.58; 95% CI, 0.21-1.61). The main factors associated with CD after labor were placental abruption (aOR, 12.96; 95% CI, 2.85-59.07) and pregestational diabetes (aOR 5.44; 95% CI, 2.54-11.68). The rate of CD was 51.6% (741 of 1435) among kidney transplant recipients and 41.4% (178 of 430) among liver transplant recipients. In total, 229 of 459 kidney transplant recipients (49.9%) and 50 of 105 liver transplant recipients (47.6%) had scheduled CDs performed for either a nonmedical indication or a repeated indication, although women with these indications are candidates for a TOL., Conclusions and Relevance: In this cohort study, TOL vs a scheduled CD was associated with improved neonatal outcomes among kidney and transplant recipients and not with increased severe maternal morbidity among kidney transplant recipients. These findings may be used to facilitate multidisciplinary decisions regarding the mode of obstetrical delivery.

Background: N-acetylcysteine infusions have been widely used to reduce ischemia/reperfusion damage to the liver; however, convincing evidence of their benefits is lacking., Objective: To perform the largest randomized controlled trial to compare the impact of N-acetylcysteine infusion during liver procurement on liver transplant outcomes., Methods: Single center, randomized trial with patients recruited from La Fe University Hospital, Spain, from February 2012 to January 2016. A total of 214 grafts were transplanted and randomized to the N-acetylcysteine group (n = 113) or to the standard protocol without N-acetylcysteine (n = 101). The primary endpoint was allograft dysfunction (Olthoff criteria). Secondary outcomes included metabolomic biomarkers of oxidative stress levels, interactions between cold ischemia time and alanine aminotransferase level and graft and patient survival (ID no. NCT01866644)., Results: The incidence of primary dysfunction was 34% (31% in the N-acetylcysteine group and 37.4% in the control group [P = 0.38]). N-acetylcysteine administration reduced the alanine aminotransferase level when cold ischemia time was longer than 6 h (P = 0.0125). Oxidative metabolites (glutathione/oxidized glutathione and ophthalmic acid) were similar in both groups (P > 0.05). Graft and patient survival rates at 12 mo and 3 y were similar between groups (P = 0.54 and P = 0.69, respectively)., Conclusions: N-acetylcysteine administration during liver procurement does not improve early allograft dysfunction according to the Olthoff classification. However, when cold ischemia time is longer than 6 h, N-acetylcysteine improves postoperative ALT levels., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background Previous studies suggest that infant heart transplant (HT) recipients are at higher risk of developing severe primary graft dysfunction (PGD) than older children. We sought to identify risk factors for developing severe PGD in infant HT recipients. Methods and Results We identified all HT recipients aged <1 year in the United States during 1996 to 2015 using the Organ Procurement and Transplant Network database. We linked their data to ELSO (Extracorporeal Life Support Organization) registry data to identify those with severe PGD, defined by initiation of extracorporeal membrane oxygenation support for PGD within 2 days following HT. We used multivariable logistic regression to assess risk factors for developing severe PGD. Of 1718 infants analyzed, 600 (35%) were <90 days old and 1079 (63%) had congenital heart disease. Overall, 134 (7.8%) developed severe PGD; 95 (71%) were initiated on extracorporeal membrane oxygenation support on the day of HT, 34 (25%) the next day, and 5 (4%) the following day. In adjusted analysis, recipient congenital heart disease, extracorporeal membrane oxygenation, or biventricular assist device support at transplant, recipient blood type AB, donor-recipient weight ratio <0.9, and graft ischemic time ≥4 hours were independently associated with developing severe PGD whereas left ventricular assist device support at HT was not. One-year graft survival was 48% in infants with severe PGD versus 87% without severe PGD. Conclusions Infant HT recipients with severe PGD have poor graft survival. Although some recipient-level risk factors are nonmodifiable, avoiding modifiable risk factors may mitigate further risk in infants at high risk of developing severe PGD.

Background: Primary graft dysfunction (PGD) is a common cause of early death after heart transplantation (htx). The use of extracorporeal life support (ECLS) after htx has increased during the last years. It is still discussed controversially whether peripheral cannulation is favorable compared to central cannulation. We aimed to compare both cannulation techniques., Methods: Ninety patients underwent htx in our department between 2010 and 2017. Twenty-five patients were treated with ECLS due to PGD (10 central extracorporeal membrane oxygenator [cECMO] and 15 peripheral extracorporeal membrane oxygenator [pECMO] cannulation). Pre- and intraoperative parameters were comparable between both groups., Results: Thirty-day mortality was comparable between the ECLS-groups (cECMO: 30%; pECMO: 40%, p  = 0.691). Survival at 1 year ( n  = 18) was 40 and 30.8% for cECMO and pECMO, respectively. The incidence of postoperative renal failure, stroke, limb ischemia, and infection was comparable between both groups. We also did not find significant differences in duration of mechanical ventilation, intensive care unit stay, or in-hospital stay. The incidence of bleeding complications was also similar (cECMO: 60%; pECMO: 67%). Potential differences in support duration in pECMO group (10.4 ± 9.3 vs. 5.7 ± 4.7 days, p  = 0.110) did not reach statistical significance., Conclusions: In patients supported for PGD, peripheral and central cannulation strategies are safe and feasible for prolonged venoarterial ECMO support. There was no increase in bleeding after central implantation. With regard to the potential complications of a pECMO, we think that aortic cannulation with tunneling of the cannula and closure of the chest could be a good option in patients with PGD after htx., Competing Interests: None declared., (Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany.)

Introduction: Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are low-cost and readily available inflammation markers. Previously, we revealed that the high preoperative neutrophil level is a recipient-related risk factor for the primary liver graft dysfunction (PGD), associated with a higher risk of early retransplantation or death. Here we aimed to evaluate the prognostic significance of preoperative neutrophil level, as well as the NLR and PLR in predicting a 1-year outcome of the orthotopic liver transplantation (OLTx)., Materials and Methods: One hundred and thirty-four patients who underwent the OLTx between 2012 and 2017 were enrolled. Analysis included, inter alia, etiology of liver failure and preoperative blood morphology. In the statistical analysis, the logistic regression model and receiver operator characteristic analysis were applied., Results: In 1-year follow-up, 11% of patients died and 5% were retransplanted. Acute liver failure (ALF; odds ratio [OR] = 8.62, P = .007), autoimmune hepatitis (AIH; R = 5.25, P = .006), neutrophil level (OR = 1.23, P = .0003), MELD (OR = 1.05, P = .038), and the NLR (OR = 1.16, P = .001) were significant predictors of these detrimental outcomes. The multivariate analysis revealed etiology (AIH, P < .001 or ALF, P = .006) and NLR (P = .008) as the only independent predictors of 1-year graft loss or patient's death. Receiver operator characteristic analysis pointed at the NLR above 5.48 as their highly sensitive and specific risk factor. The PLR was not a prognostic biomarker., Conclusion: Achieved results call for further studies on the influence of the preoperative balance between systemic inflammation and immunity, expressed with the NLR on the long-term liver graft function., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Severe primary graft dysfunction (PGD) is the leading cause of early death following cardiac transplantation. The early use of venoarterial extracorporeal membrane oxygenation (VA-ECMO) may facilitate graft rescue. However, the additional risks of its use are unknown., Methods: We retrospectively reviewed the medical records of all adult patients who underwent cardiac transplantation from January 2009 to February 2016 at St Vincent's Hospital, Sydney, to evaluate risk factors for the use of VA-ECMO and related morbidity and long-term survival., Results: One hundred ninety-two transplanted patients were identified, 49 (25%) of whom developed left or biventricular PGD requiring VA-ECMO. The total operation time (median 495 [interquartile range 139.8] versus 412.8 [132] min, P < 0.001), cardiopulmonary bypass time (220 [63] versus 176 [73] min, P < 0.001) and the presence of a previous sternotomy (29 [59%] versus 51 [36%], P = 0.019) were associated with the use of VA-ECMO. One-year survival in the VA-ECMO cohort was 71%. After a median follow-up time of 696 days (interquartile range 1201 d), survival was significantly higher in the non-ECMO group (P = 0.004) but not when conditioned on hospital survival (P = 0.34). Patients with shorter than median ECMO runtime (<108 h) had a similar long-term survival to patients who did not require ECMO (P = 0.559). In the ECMO cohort, multivariable logistic regression revealed baseline creatinine in µmol/L (odds ratio 0.99 [95% confidence interval 0.99-1.00], P = 0.019) and duration of ECMO support in days (odds ratio 0.65 [95% confidence interval 0.44-0.97], P = 0.034) were inversely and independently associated with 1-year survival., Conclusions: Short- and long-term survival of PGD supported with VA-ECMO was better than previously described. Early recovery of PGD on VA-ECMO support negates its negative impact on short- and long-term survival.

Background: Ex vivo lung perfusion (EVLP) allows for a reassessment of lung grafts initially deemed unsuitable for transplantation, increasing the available donor pool; however, this requires a pre- and post-EVLP period of cold ischemic time (CIT). Paucity of data exists on how the sequence of cold normothermic-cold preservations affect outcomes., Methods: A total of 110 patients were retrospectively analyzed. Duration of 3 preservation phases was measured: cold pre-EVLP, EVLP, and cold post-EVLP. The donor and recipient clinical data were collected. Primary graft dysfunction (PGD) and survival were monitored. Risk of mortality or PGD was calculated using Cox proportional hazards and logistic regression models to adjust for baseline characteristics., Results: Using the highest quartile, patients were stratified into extended vs non-extended pre-EVLP (<264 vs ≥264 minutes) and post-EVLP (<287 vs ≥287 minutes) CIT. The rates of 1-year mortality (8.4% vs 29.6%, p = 0.013), PGD 2-3 (20.5% vs 52%, p = 0.002), and PGD 3 (8.4% vs 29.6%, p = 0.005) at 72 hours were increased in the extended post-EVLP CIT group. After adjusting for baseline risk factors, the extended group remained an independent predictor of PGD ≥2 (odd ratio: 6.18, 95% CI: 1.88-20.3, p = 0.003) and PGD 3 (odd ratio: 20.4, 95% CI: 2.56-161.9, p = 0.004) at 72 hours and 1-year mortality (hazard ratio: 17.9, 95% CI: 3.36-95.3, p = 0.001). Cold pre-EVLP was not a significant predictor of primary outcomes., Conclusions: Extended cold post-EVLP preservation is associated with a risk for PGD and 1-year mortality. Pre-EVLP CIT does not increase mortality or high-grade PGD. These findings from a multicenter trial should caution on the implementation of extended cold preservation after EVLP., (Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Chronic lung allograft dysfunction (CLAD), the primary cause of poor outcome after lung transplantation, arises from fibrotic remodeling of the allograft and presents as diverse clinical phenotypes with variable courses. Here, we investigate whether bronchoalveolar lavage (BAL) mesenchymal cell activity at CLAD onset can inform regarding disease phenotype, progression, and survival., Methods: Mesenchymal cell colony-forming units (CFUs) were measured in BAL obtained at CLAD onset (n = 77) and CLAD-free time post-transplant matched controls (n = 77). CFU counts were compared using Wilcoxon's rank-sum test. Cox proportional hazards and restricted means models were utilized to investigate post-CLAD survival., Results: Higher mesenchymal CFU counts were noted in BAL at the time of CLAD onset than in CLAD-free controls. Patients with restrictive allograft syndrome had higher BAL mesenchymal CFU count at CLAD onset than patients with bronchiolitis obliterans syndrome (p = 0.011). Patients with high mesenchymal CFU counts (≥10) at CLAD onset had worse outcomes than those with low (<10) CFU counts, with shorter average survival (2.64 years vs 4.25 years; p = 0.027) and shorter progression-free survival, defined as time to developing either CLAD Stage 3 or death (0.97 years vs 2.70 years; p < 0.001). High CFU count remained predictive of decreased overall survival and progression-free survival after accounting for the CLAD phenotype and other clinical factors in multivariable analysis., Conclusions: Fulminant fibroproliferation with higher mesenchymal CFU counts in BAL is noted in restrictive allograft syndrome and is independently associated with poor survival after CLAD onset., (Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Primary graft dysfunction (PGD) is a rare complication associated with high mortality after heart transplantation, which may require veno-arterial extra-corporeal membrane oxygenation (VA-ECMO) support. A standardized definition for PGD was developed by the International Society of Heart and Lung Transplantation in 2014. Due to limited reports using this definition, the detailed outcomes after VA-ECMO support remain unclear. Therefore, we retrospectively analyzed our single-center outcomes of PGD following VA-ECMO support. Between September 2014 and August 2018, 160 patients underwent heart transplantation in our single center. Nine PGD patients required VA-ECMO support, with an incidence of 5.6%. Pre-operative recipient/donor demographics, intra-operative variables, timing of VA-ECMO initiation and support duration, graft function recovery during 30 days after heart transplant, VA-ECMO complications, and survival were analyzed. The indication for VA-ECMO support was biventricular failure for all nine patients. Six patients had severe PGD requiring intra-operative VA-ECMO, while two patients had moderate PGD and one patient had mild PGD requiring post-operative VA-ECMO. All cohorts were successfully decannulated in a median of 10 days. Survival to discharge rate was 88.9%. One-year survival rate was 85.7%. Left ventricular ejection fraction recovered to normal within 30 days in all PGD patients. Our study showed VA-ECMO support led to high survival and timely graft function recovery in all cohorts. Further larger research can clarify the detailed effects of VA-ECMO support which may lead to standardized indication of VA-ECMO support for PGD patients.

Background: Primary graft Dysfunction (PGD) results in significant mortality and morbidity after lung transplantation (LT). The objective of this study was to evaluate if pre-existing antibodies to self-antigens in sera of LT recipients are associated with PGD., Methods: The serum profiles of IgG and IgA autoantibodies were analyzed using a customized proteomic microarray bearing 124 autoantigens. Autoantibodies were analyzed using Mann-Whitney U test or Fisher exact test. The association of the autoantibodies with clinical phenotypes and survival was analyzed by Kaplan-Meier Survival Analysis. Receiver operating curve characteristics (ROC) were calculated to evaluate the predictive value of the autoantibodies for PGD., Results: 51 patients were included in this study. Autoantigen microarray analysis on the pre-transplantation samples identified 17 IgA and 3 IgG autoantibodies which were significantly higher in recipients who developed PGD compared to those who did not (adjusted p < .05 and fold change>1.5). 6 IgA Abs were significantly associated with survival. Taken as a panel, an elevation of 6 IgA Abs had significant predictive value for PGD. Area under the curve value for the panel was 0.9413 for PGD with ROC analysis. Notably, 6 of the 17 IgA autoantigen targets are belong to proteoglycan family of extracellular matrix proteins., Conclusion: Pre-existing IgG and IgA autoantibodies in LT patients correlate with PGD and with survival in a single center, small cohort of lung transplant recipients. Further validation is needed to confirm the findings in the study., Competing Interests: Declaration of Competing Interest All authors report no conflict of interest., (Published by Elsevier B.V.)

Objective: Comparison of different diagnostic criteria for early liver allograft dysfunction (EAD) and their capability to predict mortality., Design: Single-center, prospective, cohort study., Settings: ICU in a Regional Hospital with a liver transplant program since 1997., Patients: 253 consecutive patients admitted to our ICU immediately after liver transplantation between 2009 and 2015., Variables of Interest: Differences in the incidence of EAD and its relation with ICU, Hospital and 2-year mortality depending on the definition applied using as comparator the UNOS (United Network for Organ Sharing) primary non-function criterion., Results: The incidence of early liver allograft dysfunction according to UNOS was 13.8%, to Makowka 6.3%, to Ardite 10.7%, to Nanashima 20.6%, to Dhillon 30.8% and to MEAF 13.4%. Kappa test did not show a good correlation among these criteria. EAD was related with ICU mortality for all diagnostic criteria except Dhillon but only UNOS, Makowka and MEAF were associated with 2-year mortality. Hospital mortality was poorly predicted by all criteria except for the MEAF score., Conclusion: We found a poor agreement between different criteria analyzed for the diagnosis of EAD. In our population, the MEAF score showed the best relationship with short- and long-term mortality., (Copyright © 2018 Elsevier España, S.L.U. y SEMICYUC. All rights reserved.)

Background: The interest in donation after cardiocirculatory death (DCD) donors for lung transplantation (LT) has been recently rekindled due to lung allograft shortage. Clinical outcomes following DCD have proved satisfactory. The aim of this systematic review is to provide a thorough analysis of published experience regarding outcomes of LT after controlled DCD compared with donation after brain death (DBD) donors., Methods: We performed a literature search in Cochrane Database of Systematic Reviews, PubMed and Web of Science using the items "lung transplantation" AND "donation after circulatory death" on November 1, 2018. The full text of relevant articles was evaluated by two authors independently. Quality assessment was performed using the NIH protocol for case-control and case series studies. A pooled Odds ratio (OR) and mean differences with inverse variance weighting using DerSimonian-Laird random effect models were computed to account for between-trial variance (τ2)., Results: Of the 508 articles identified with our search, 9 regarding controlled donation after cardiac death (cDCD) were included in the systematic review, including 2973 patients (403 who received graft from DCD and 2570 who had DBD). Both 1-year survival and 2 and 3-grade primary graft dysfunction (PGD) were balanced between the two cohorts (OR = 1.00 and 1.03 respectively); OR for airway complications was 2.07 against cDCD. We also report an OR = 0.57 for chronic lung allograft dysfunction (CLAD) and an OR = 0.57 for 5-year survival against cDCD., Conclusions: Our meta-analysis shows no significant difference between recipients after cDCD or DBD regarding 1-year survival, PGD and 1-year freedom from CLAD. Airway complications and long-term survival were both related with transplantation after cDCD, but these statistical associations need further research., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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., (© 2019 Wiley Periodicals, Inc.)

Objective: Venoarterial extracorporeal membrane oxygenation is a useful treatment for severe primary graft dysfunction after heart transplant. The ideal timing of initiation is unknown., Methods: We retrospectively reviewed 362 adult heart transplant recipients at our center between January 2011 and December 2017. Thirty-eight patients (10.5%) experienced severe primary graft dysfunction treated with venoarterial extracorporeal membrane oxygenation. As our institution adopted a prompt venoarterial extracorporeal membrane oxygenation policy in 2015, patients were stratified into pre-2015 (conservative extracorporeal membrane oxygenation: n = 18) and post-2015 (prompt extracorporeal membrane oxygenation: n = 20) cohorts. Clinical outcomes were compared., Results: Baseline characteristics were similar (conservative vs prompt) except for age (51.82 vs 59.96 years, P = .036), aspartate transaminase (32 vs 21.5 U/L, P = .038), male donor (44.4 vs 80%, P = .042), and donor ejection fraction (60 vs 65%, P = .047). Median ischemic time was significantly longer in the conservative extracorporeal membrane oxygenation cohort (210 vs 148 minutes, P = .005). Median time to initiation of extracorporeal membrane oxygenation was significantly shorter in the prompt extracorporeal membrane oxygenation cohort (7.26 vs 1.95 hours, P < .0001). There was no difference in intensive care unit stay or major complications. In-hospital mortality improved from 28% (conservative) to 5% (prompt, P = .083). Post-transplant survival at 1 year was 67% in the conservative extracorporeal membrane oxygenation cohort and 90% in the prompt extracorporeal membrane oxygenation cohort (P = .117). There was no difference in the Kaplan-Meier survival curves (P = .071), although Cox regression suggested, but certainly did not prove, a 74.6% lower risk of mortality in the prompt extracorporeal membrane oxygenation group (P = .094)., Conclusions: Prompt venoarterial extracorporeal membrane oxygenation use for primary graft dysfunction after heart transplant results in excellent myocardial recovery and a possible decrease in mortality without increased risk of complications., (Copyright © 2019 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

BACKGROUNDInnate immune activation impacts lung transplant outcomes. Dectin-1 is an innate receptor important for pathogen recognition. We hypothesized that genotypes reducing dectin-1 activity would be associated with infection, graft dysfunction, and death in lung transplant recipients.METHODSWe assessed the rs16910526 CLEC7A gene polymorphism Y238X, which results in dectin-1 truncation, in 321 lung allograft recipients at a single institution and in 1,129 lung allograft recipients in the multicenter Lung Transplant Outcomes Group (LTOG) cohort. Differences in dectin-1 mRNA, cytokines, protein levels, immunophenotypes, and clinical factors were assessed.RESULTSY238X carriers had decreased dectin-1 mRNA expression (P = 0.0001), decreased soluble dectin-1 protein concentrations in bronchoalveolar lavage (P = 0.008) and plasma (P = 0.04), and decreased monocyte surface dectin-1 (P = 0.01) compared with wild-type subjects. Y238X carriers had an increased risk of fungal pathogens (HR 1.17, CI 1.0-1.4), an increased risk of graft dysfunction or death (HR 1.6, CI 1.0-2.6), as well increased mortality in the UCSF cohort (HR 1.8, CI 1.1-3.8) and in the LTOG cohort (HR 1.3, CI 1.1-1.6), compared with wild-type CLEC7A subjects.CONCLUSIONIncreased rates of graft dysfunction and death associated with this dectin-1 polymorphism may be amplified by immunosuppression that drives higher fungal burden from compromised pathogen recognition.FUNDINGThe UCSF Nina Ireland Program for Lung Health Innovative Grant program, the Clinical Sciences Research & Development Service of the VA Office of Research and Development, and the Joel D. Cooper Career Development Award from the International Society for Heart and Lung Transplantation.

Background: Prior studies of post-lung transplant acute kidney injury (AKI) have not accounted for confounding effects of primary graft dysfunction (PGD). We sought to test the impact of PGD on AKI risk factors and on the association of AKI with mortality., Methods: We included patients transplanted at the University of Pennsylvania from 2005-12, defined AKI using consensus criteria during transplant hospitalization, and defined PGD as grade 3 at 48-72 hours. We used multivariable logistic regression to test the impact of PGD on AKI risk factors and Cox models to test association of AKI with one-year mortality adjusting for PGD and other confounders., Results: Of 299 patients, 188 (62.9%) developed AKI with 142 (75%) cases occurring by postoperative day 4. In multivariable models, PGD was strongly associated with AKI (OR 3.76, 95% CI 1.72-8.19, P = .001) but minimally changed associations of other risk factors with AKI. Both AKI (HR 3.64, 95% CI 1.68-7.88, P = .001) and PGD (HR 2.55, 95% CI 1.40-4.64, P = .002) were independently associated with one-year mortality., Conclusions: Post-lung transplant AKI risk factors and association of AKI with mortality were independent of PGD. AKI may therefore be a target for improving lung transplant mortality rather than simply an epiphenomenon of PGD., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: The differences in chronic lung allograft dysfunction (CLAD) between living-donor lobar lung transplantation (LDLLT) and cadaveric lung transplantation (CLT) remain unclear. We conducted this study to compare the impact of CLAD on the outcomes after LDLLT vs. CLT., Methods: We conducted a retrospective review of the data of 97 recipients of bilateral lung transplantation, including 51 recipients of LDLLT and 46 recipients of CLT., Results: The CLAD-free survival and overall survival after LDLLT were similar to those after CLT. CLAD and restrictive allograft syndrome (RAS), but not bronchiolitis obliterans syndrome (BOS), developed significantly later after LDLLT than after CLT (p = 0.015 and p = 0.035). Consequently, patients with CLAD and RAS, but not those with BOS, after LDLLT had a significantly better overall survival than those after CLT (p = 0.037 and p = 0.0006). Furthermore, after the diagnosis of CLAD, the survival of patients with RAS after LDLLT tended to be better than that after CLT (p = 0.083)., Conclusion: CLAD, especially RAS, appears to develop later after LDLLT than after CLT and seems to have a lower impact on the overall survival after LDLLT than that after CLT.

Objective: Potential interactions between donor-recipient age difference and outcomes after heart transplantation are not well known. We thus aimed to study the impact of donor-recipient age difference on heart transplantation outcomes., Methods: Between 1995 and 2017, we assessed 234 heart transplantation patients. Based on donor-recipient age difference histogram, we stratified these patients into three groups: older donors (donor-recipient difference > 0; n = 48), younger donors (donor-recipient difference 0 to -20 years; n = 82), and much younger donors (donor-recipient difference <-20 years; n = 104)., Results: The baseline metabolic risk profile of the recipients was significantly higher for the much younger donor group compared with the younger and older groups, including hypertension (52% vs 33% vs 25%, P = 0.002), dyslipidemia (51% vs 51% vs 29%, P = 0.027), diabetes (30% vs 16% vs 17%, P = 0.044), and smoking history (53% vs 46% vs 29%, P = 0.024), respectively. There were no significant differences between the groups in long-term survival, cardiac allograft vasculopathy, or rejection-free survival in unadjusted and adjusted analyses. In the much younger donor group, gender matching was associated with a lower incidence of primary graft dysfunction (37% vs 58% P = 0.05)., Conclusions: Donor-recipient age difference does not significantly impact long-term heart transplantation outcomes., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Uncontrolled donation after cardiac death is an appealing source of organs for lung transplantation. We compare early and long-term outcomes of lung transplantation with these donors with a cohort of transplants from brain death donors at our institution. Retrospective analysis of all lung transplantations was performed from 2002 to 2012. We collected variables regarding recipients, donors, recover and transplant procedures, early and late complications, and survival. We included 292 lung transplants from brain death donors and 38 from uncontrolled donors after cardiac death. Both groups were comparable except for sex mismatch (male recipient-female donor was more frequent in the brain death cohort, 17.8% vs 0%, P 0.002), total ischemic time (longer for donors after cardiac death, 657 minutes for the first lung and 822 minutes for the second vs 309 and 425 minutes, P < 0.001), and ex vivo evaluation (more frequent in cardiac death donors, 21.1% vs 1.4%, P < 0.001). Early and late outcomes were not different (ICU stay [9 vs 10.5 days], hospital stay [33.5 vs 35 days], primary graft dysfunction G3 [24 vs 34.2%], and chronic graft dysfunction HR 1.19 [0.61-2.32]), but overall survival was significantly lower for patients transplanted from cardiac death donors [HR 1.67 (1.06-2.64)]. Lung transplantation after uncontrolled cardiac death offers poorer results in terms of survival compared to brain death donation. Refinement of current strategies for graft preservation and evaluation is essential to improve outcomes with this source of grafts., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and Aims: Liver transplantation is one of the most effective treatments for end-stage liver disease as well as for cases of acute liver failure. Facing organ donor shortage, liver transplant teams had to use marginal organs. Thus, increasing availability is a key concern of donor liver grafts including steatotic livers. However, the use of steatotic liver is still controversial. The aim of this systematic review and meta-analysis was to analyze the impact of steatosis on the outcome of liver transplantation., Methods: We searched PubMed, Cochrane Library, Embase, Web of knowledge, and so on for studies published through May 31, 2018, in which patients experienced liver transplantation using fatty liver. All studies extracted outcome indicators, and we draw conclusions by contrasting outcome indicators in different groups of steatosis. Odds ratios and 95% confidence intervals were calculated. P<0.05 was considered as statistically significant difference., Results: 19 publications were included. There was no significant difference between the group of no steatosis and mild group in primary nonfunction rate (P=0.605) or early graft dysfunction rate (P=0.44). The PNF rate was significantly higher in moderate group (P=0.003) and severe group (P <0.001) compared with that in no steatosis group. The same results were seen in early graft dysfunction rate. However, graft survival rate and patient survival rate did not differ between groups., Conclusions: Livers with mild steatosis, even with moderate or severe steatosis, could be suitable donor under strict control of transplant conditions.

Background: PGD is a complication after heart transplantation (OHT) and a significant cause of mortality, particularly in infant recipients. Lack of standardized definition of PGD in the pediatric population makes the prevalence and magnitude of impact unclear., Methods: ISHLT PGD consensus guidelines, which include inotrope scores and need for MCS, were applied retrospectively to 208 pediatric OHT recipients from a single institution from 1/2005-5/2016. PGD was defined as: moderate PGD-inotrope score >10 on postoperative day 1 (24-48 hours), and severe PGD-MCS within 24 hours (in the absence of detectable rejection)., Results: PGD occurred in 34 patients (16.3%); 14 of which had severe PGD (6.7%). Multivariate risk factors for PGD included CPB time (OR 10.3/10 min, 95% 10.05, 10.2, P = 0.03), Fontan palliation (OR 1.9, 95% 1.2, 3.97), and PCM (OR 5.65, 95% 1.52, 22.4); but not age, weight, ischemic time, or donor characteristics. Upon sub-analysis excluding patients with PCM, increased CPB was a significant multivariate risk factor (OR 10.09, 95% 9.89, 10.12, P = 0.003). Patients with PGD had decreased discharge survival compared to those without PGD (85% vs 96%, P < 0.01). Severe PGD was associated with the poorest 1-year survival (57% vs 91% without PGD, P = 0.04)., Conclusion: Patients with prolonged CPB are potentially at risk for developing PGD. Neither infant recipients nor donor characteristics were associated with an increased risk of PGD in the current era., (© 2019 Wiley Periodicals, Inc.)

Background: Patients with diffuse parenchymal lung disease (DPLD) have the poorest survival rates both before and after lung transplantation (LT). Early mortality among LT patients as a result of DLPD is estimated at 10% to 20%. The aim of the study was to assess intrahospital mortality after LT procedures for DLPD and to identify factors in the recipient, donor, intra- and postoperative periods that might improve early outcomes., Methods: A retrospective, observational, cohort, single-hospital study was conducted. Data from 67 patients with LT patients owing to DPLD were recorded between October 2008 to June 2017 in Madrid, Spain., Results: Out of 67 LT recipients with DPLD, 51 had idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP), 6 nonspecific interstitial pneumonia (NSIP), and 10 other DPLD. Intrahospital mortality took place in 13.4% of patients, with a median survival time of 34 days (interquartile range [IQR], 27.50-66). In the preoperative period, there were no differences in the recipients' demographic and hemodynamic characteristics, respiratory function, or time spent in the waiting list, except higher doses of systemic steroids in nonsurvivors (prednisone 15 vs 10 mg, P = .046). No differences were reported in the donors' characteristics (age, mechanical ventilation hours, PaO 2 /FiO 2 ). In the intraoperative and postoperative periods, we found differences statistically significant in longer cold ischemia time and development of primary graft dysfunction (PGD) grade 3 in the nonsurvivor group., Conclusions: The mortality rate in our series was 13.4%, and the main risk factors for intrahospital mortality were longer cold ischemia time and greater incidence of PGD grade 3., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Heart transplantation (HTx) remains the most effective long-term treatment for advanced heart failure. Primary graft dysfunction (PGD) continues to be a potentially life-threatening early complication. In 2014, a consensus statement released by International Society for Heart and Lung Transplantation (ISHLT) established diagnostic criteria for PGD. We studied the incidence of PGD across the United Kingdom., Methods: We analyzed the medical records of all adult patients who underwent HTx between October 2012 and October 2015 in the 6 UK heart transplant centers Preoperative donor and recipient characteristics, intraoperative details, and posttransplant complications were compared between the PGD and non-PGD groups using the ISHLT definition. Multivariable analysis was performed using logistic regression., Results: The incidence of ISHLT PGD was 36%. Thirty-day all-cause mortality in those with and without PGD was 31 (19%) versus 13 (4.5%) (P = 0.0001). Donor, recipient, and operative factors associated with PGD were recipient diabetes mellitus (P = 0.031), recipient preoperative bilateral ventricular assist device (P < 0.001), and preoperative extracorporeal membranous oxygenation (P = 0.023), female donor to male recipient sex mismatch (P = 0.007), older donor age (P = 0.010), and intracerebral haemorrhage/thrombosis in donor (P = 0.023). Intraoperatively, implant time (P = 0.017) and bypass time (P < 0.001) were significantly longer in the PGD cohort. Perioperatively, patients with PGD received more blood products (P < 0.001). Risk factors identified by multivariable logistic regression were donor age (P = 0.014), implant time (P = 0.038), female: male mismatch (P = 0.033), recipient diabetes (P = 0.051) and preoperative ventricular assist device/extracorporeal membranous oxygenation support (P = 0.012)., Conclusions: This is the first national study to examine the incidence and significance of PGD after HTx using the ISHLT definition. PGD remains a frequent early complication of HTx and is associated with increased mortality.

Objectives: An optimal initial graft function after living-donor liver transplant depends on optimal graft hemodynamics. Nonmechanical impediments to free hepatic venous outflow, due to elevated central venous pressure, may obstruct the "functional" hepatic venous outflow. Here, we evaluated whether central venous pressure affected early graft function and outcomes in adult living-donor liver transplant recipients., Materials and Methods: This prospective observational study included 61 living-donor liver transplant recipients without technical complications who received transplants from August 2013 to November 2014. Hemodynamic variables were measured preoperatively, at anhepatic phase, 30 minutes postreperfusion, at end of surgery, and during postoperative days 1-5., Results: Patients with high central venous pressure showed functional hepatic venous outflow obstruction, which caused delayed recovery of graft function. Although postoperative central venous pressure was the only identified independent risk factor for mortality, all 5 deaths in our study group occurred in those who had high central venous pressure at the anhepatic, postreperfusion, end of surgery, and postoperative phases. A postoperative central venous pressure value of ~11 mm Hg was determined to be the cutoff for high-risk mortality, with area under the curve of 0.859 (sensitivity of 80%, specificity of 68%). Increased central venous pressure was associated with increased portal venous pressure (increase of 45%, range, 28%-89%; P = .001). Central venous pressure at end of surgery (r = 0.45, P ≤ .001) and at posttransplant time points (r = 0.29, P = .02) correlated well with portal venous pressure at end of surgery. Other risk factors for early allograft dysfunction were Model for End-Stage Liver Disease and cardiac output posttransplant., Conclusions: High central venous pressure, modulating portal venous pressure, can result in functional hepatic venous outflow obstruction, causing delayed graft function recovery and increased risk of mortality. Maintaining a central venous pressure below 11 mm Hg is beneficial.

Background: Liver transplantation (LT) is an established treatment for patients with end-stage liver disease. The significant advances in surgical technique, immunosuppression therapy, and anesthesiological management have dramatically improved short- and long-term outcomes. The aim of this study is to correlate specific surgical and anesthesiological variables with causes of early death in LT recipients., Methods: A retrospective observational analysis of adult patients who underwent LT in the period 2012 to 2016 and died within 90 days following LT was conducted. Exclusion criteria were intraoperative death, split liver, and domino transplant. Death was considered a dependent variable and classified into 3 different groups: death by sepsis, vascular events not related to the graft, and primary non-function. Donor and recipient variables were considered and analyzed using Fisher's exact test., Results: Statistically significative associations (P value < .05) were found between renal function support, retransplantation, and the number of fresh frozen plasma units transfused in one group and early death due to sepsis in the other., Conclusions: This study identified some risk factors associated with the specific cause of early death in liver transplantation. The clinical implications of these findings are the ability to stratify patients at high risk of early death by planning more intensive and accurate management for them., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The clinical significance of apoptosis in assessing the quality of donor liver grafts remains unknown., Aims: This study aimed to determine whether apoptosis in a donor liver is predictive of early allograft dysfunction (EAD) and graft survival after liver transplantation (LT)., Methods: Donor liver specimens were analyzed for apoptosis using TUNEL assays. The prognostic factors for EAD were identified through logistic regression analyses, and a nomogram was developed., Results: The apoptosis index of donor livers in EAD patients was significantly higher than that of donors livers in non-EAD patients (median 5.3; interquartile range [IQR] 3.4 vs 3.5; 3.6, P < 0.001). Multivariate analyses identified the apoptosis index of the donor liver (HR = 6.927, P < 0.001) and five other characteristics as independent predictors of EAD. A nomogram built on these predictive variables showed good calibration and discriminatory abilities, with a c-index value of 0.847. The 30-day graft survival rates in the high apoptosis index (apoptosis index >4.4%) group were significantly lower than those in the low apoptosis index (apoptosis index ≤4.4%) group (84.4% vs 97.6%, P = 0.004)., Conclusions: Donor liver apoptosis plays a significant role in predicting EAD after LT. Furthermore, a high apoptosis index in the donor liver was associated with inferior graft survival in the short-term., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Lung transplants from donation after circulatory death (DCD) have been scarcely used in the United States. Concerns about the warm ischemic injury, resource mal-utilization due to the uncertain timing of death, and public scrutiny may be some factors involved., Methods: Survival for recipients of a donation after brain death (DBD) versus DCD was analyzed by using the United Network for Organ Sharing and our institutional database. A propensity-matching and Cox regression analysis was performed for 25 characteristics. Primary graft dysfunction metrics were compared., Results: A total of 389 of 20,905 lung transplantations (2%) were performed by using DCDs in the United States, and 15 of 128 (12%) at our institution. Five and 10-year survival for DBDs was 55% and 30% and 59% and 33% for DCDs, respectively. Propensity-matched analysis of 311 DBD/DCD pairs did not demonstrate any difference in survival. On Cox regression, DCD was not associated with impaired survival. Male sex, Karnofsky class greater than 50, double lung transplantation, and transplantation year were predictors of improved survival. Age, creatinine, pulmonary fibrosis, retransplantation, extracorporeal membrane oxygenation, allocation score, and donor age were predictors of worse survival. Primary graft dysfunction at time 0 was worse for recipients of DCDs (p = 0.005) but equivalent at 24, 48, and 72 hours., Conclusions: DCD lung transplants remain underused in the United States. Nevertheless, survival is similar to DBD. Primary graft dysfunction metrics for DCDs are worse than DBDs on intensive care arrival but improved subsequently., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Primary graft dysfunction (PGD) remains a significant cause of post-transplant morbidity and mortality. The exact mechanism and risk factors for this phenomenon remain unknown in the contemporary era., Methods: In this study we reviewed adult patients undergoing heart transplantation (HT) at our institution between 2009 and 2017. Severe PGD was defined as the need for mechanical circulatory support (MCS) within the first 24 hours after HT. Multivariate logistic regression analysis was used to identify risk factors for severe PGD, focusing on those bridged to transplant (BTT) with a continuous-flow left ventricular assist device (CF-LVAD)., Results: Fifty-six of 480 (11.7%) HT patients experienced severe PGD. Eighty percent of the severe PGD patients were BTT with a CF-LVAD (odds ratio [OR] 3.86, 95% confidence interval [CI] 1.94 to 7.68, p < 0.001). Among the BTT patients, significant associations between >1 year of CF-LVAD support (OR 2.48, 95% CI 1.14 to 5.40, p = 0.022), pre-HT creatinine (OR 3.35, 95% CI 1.42 to 7.92, p = 0.006), elevated central venous pressure/pulmonary capillary wedge pressure (CVP/PCWP) ratio (OR 3.32, 95% CI 1.04 to 10.60, p = 0.043), use of amiodarone before HT (OR 2.69, 95% CI 1.20 to 6.20, p = 0.022), and severe PGD were identified. RADIAL score did not accurately predict severe PGD in this contemporary cohort. Those patients who developed severe PGD had decreased 1-year post-transplant survival (78.3% vs 91.8%, p = 0.007)., Conclusions: Use of CF-LVAD as BTT is associated with an increased risk of severe PGD. Increased time on device support, renal dysfunction, right ventricular dysfunction as assessed by CVP/PCWP ratio, and pre-transplant amiodarone may identify those patients at high risk. Further research is warranted focusing on optimal timing of device implantation and transplantation, as well as the underlying mechanisms of PGD., (Copyright © 2018 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Patients with greater adiposity before lung transplantation are at an increased risk for worse post-transplant outcomes. Few studies have addressed whether pre-transplant weight loss mitigates this risk. In this study we examined the association between pre-transplant weight loss and post-transplant clinical outcomes., Methods: We conducted a retrospective cohort study of patients who received a lung transplant at the Duke University Hospital from May 1, 2005 to April 30, 2015. The sample included adult transplant recipients with restrictive, obstructive, and vascular diseases. Cox proportional hazards models were used to examine mortality and chronic lung allograft dysfunction (CLAD)-free survival, and negative binomial regression analyses were used to examine length of stay (LOS). Weight loss was assessed from change in body mass index (BMI)., Results: The cohort consisted of 810 patients. Initially, 403 (50%) were overweight and 109 (13%) were obese by BMI criteria. Greater pre-transplant weight loss was associated with dose-response improvements in survival (hazard ratio [HR] 0.83 [0.72 to 0.97], p = 0.018), with modest (0% to 3%, HR 0.91), moderate (7% to 10%, HR 0.83), and high (>15%, HR 0.71) levels of weight loss conferring longer survival, independent of initial weight (p = 0.533 for interaction). Weight loss was also associated with improved CLAD-free survival (HR 0.84 [0.71 to 0.99], p = 0.034) and shorter LOS (b = ‒0.17, p < 0.001)., Conclusions: Weight loss before transplantation was associated with improved short- and long-term clinical outcomes, independent of initial weight. Survival improved proportionally to percentage of weight lost. The mechanisms by which weight loss improve clinical outcomes warrant further exploration., (Copyright © 2018 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Donor-derived cell-free DNA (dd-cf-DNA) has been shown to be an informative biomarker of rejection after lung transplantation (LT) from deceased donors. However, in living-donor lobar LT, because small grafts from blood relatives are implanted with short ischemic times, the detection of dd-cf-DNA might be challenging. Our study was aimed at examining the role of dd-cf-DNA measurement in the diagnosis of primary graft dysfunction and acute rejection early after living-donor lobar LT. Immediately after LT, marked increase of the plasma dd-cf-DNA levels was noted, with the levels subsequently reaching a plateau with the resolution of primary graft dysfunction. Increased plasma levels of dd-cf-DNA were significantly correlated with decreased oxygenation immediately (p = 0.022) and at 72 hours (p = 0.046) after LT. Significantly higher plasma dd-cf-DNA levels were observed in patients with acute rejection (median, 12.0%) than in those with infection (median, 4.2%) (p = 0.028) or in a stable condition (median, 1.1%) (p = 0.001). Thus, measurement of the plasma levels of dd-cf-DNA might be useful to monitor the severity of primary graft dysfunction, and plasma dd-cf-DNA could be a potential biomarker for the diagnosis of acute rejection after LT.

BACKGROUND Donor hypernatremia has been associated with reduced graft and recipient survival after heart, liver, kidney, and pancreas transplantation. However, it is unknown what effect donor hypernatremia has on graft and recipient outcomes after lung transplantation. The aim of this study was to investigate the relation of donor hypernatremia with the duration of postoperative mechanical ventilation, the incidence of severe primary graft dysfunction, and survival following lung transplantation. MATERIAL AND METHODS We analyzed all consecutive lung transplantations performed in adult patients at our center between 1995 and 2016. During the study period, donor hypernatremia was not considered a reason to reject lungs for transplantation. Donors were classified into 3 groups: normonatremia (sodium <145 mmol/L), moderate hypernatremia (sodium 145-154 mmol/L), or severe hypernatremia (sodium ≥155 mmol/L). Short-term outcome was defined by the duration of mechanical ventilation and incidence of primary graft dysfunction; long-term outcome was defined by 10-year mortality. RESULTS Donor hypernatremia was recorded in 275 (58%) of the 474 donors. There were no differences in baseline characteristics between the 3 study groups. The duration of mechanical ventilation was similar for all groups (8±25, 7±17, and 9±15 days respectively, P=0.204). Severe primary graft dysfunction was not different between the 3 groups (29%, 26%, 28%, P=0.724). Donor hypernatremia was not associated with (graft) survival, or after correction for potential confounders. CONCLUSIONS Donor hypernatremia was not associated with a worse outcome in lung transplant recipients. Thus, in contrast to solid organ transplantation, donor hypernatremia is not a contraindication for lung transplantation.

Background: The prognostic value of defining normal vs abnormal baseline post-transplant lung function (or baseline lung allograft dysfunction [BLAD]) has not been studied using standardized reference values of percent predicted of the population. Our aim was to assess the association between BLAD and survival in double-lung transplant recipients and assess for potential pre-transplant donor and recipient risk factors for BLAD., Methods: We conducted a retrospective cohort study of double-lung transplant recipients in our program during the period 2004 to 2009. We defined normal baseline function as both forced expiratory volume in 1 second (FEV 1 ) and forced vital capacity (FVC) ≥80% predicted on at least 2 consecutive tests ≥3 weeks apart; we defined BLAD as failure to meet these criteria. We used a Cox regression model to assess the association between BLAD and survival. We used logistic regression to assess potential pre-transplant donor and recipient factors associated with BLAD., Results: Of 178 patients double-lung transplant recipients eligible for study, 75 (42%) met the criteria for BLAD. BLAD was associated with impaired survival (hazard ratio [HR] 2.23, 95% confidence interval [CI] 1.41 to 3.54]) via Cox regression compared to patients with normal baseline, and lower baseline was associated with greater risk of death in a dose-dependent fashion. Pre-transplant factors associated with BLAD included interstitial lung disease (ILD) as an indication for transplant (odds ratio [OR] 2.66, 95% CI 1.17 to 6.15) and heavy donor smoking history (OR 3.07, 95% CI 1.17 to 8.43)., Conclusions: BLAD is dynamic risk state associated with impaired survival after double-lung transplantation, and should be considered when physiologically phenotyping patients., (Copyright © 2018 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Chronic lung allograft dysfunction (CLAD) is a major cause of mortality in lung transplant recipients. CLAD can be sub-divided into at least 2 subtypes with distinct mortality risk characteristics: restrictive allograft syndrome (RAS), which demonstrates increased overall computed tomography (CT) lung density in contrast with bronchiolitis obliterans syndrome (BOS), which demonstrates reduced overall CT lung density. This study aimed to evaluate a reader-independent quantitative density metric (QDM) derived from CT histograms to associate with CLAD survival. A retrospective study evaluated CT scans corresponding to CLAD onset using pulmonary function tests in 74 patients (23 RAS, 51 BOS). Two different QDM values (QDM1 and QDM2) were calculated using CT lung density histograms. Calculation of QDM1 includes the extreme edges of the histogram. Calculation of QDM2 includes the central region of the histogram. Kaplan-Meier analysis and Cox regression analysis were used for CLAD prognosis. Higher QDM values were significantly associated with decreased survival. The hazard ratio for death was 3.2 times higher at the 75th percentile compared to the 25th percentile using QDM1 in a univariate model. QDM may associate with CLAD patient prognosis., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Prolonged cold ischemia storage (CIS) is a leading risk factor for poor transplant outcome. Existing strategies strive to minimize ischemia-reperfusion injury in transplanted organs, yet there is a need for novel approaches to improve outcomes of marginal allografts and expand the pool of donor organs suitable for transplantation. Aquaporins (AQPs) are a family of water channels that facilitate homeostasis, tissue injury, and inflammation. We tested whether inhibition of AQP4 improves the survival of fully MHC-mismatched murine cardiac allografts subjected to 8 hours of CIS. Administration of a small molecule AQP4 inhibitor during donor heart collection and storage and for a short-time posttransplantation improves the viability of donor graft cells, diminishes donor-reactive T cell responses, and extends allograft survival in the absence of other immunosuppression. Furthermore, AQP4 inhibition is synergistic with cytotoxic T lymphocyte-associated antigen 4-Ig in prolonging survival of 8-hour CIS heart allografts. AQP4 blockade markedly reduced T cell proliferation and cytokine production in vitro, suggesting that the improved graft survival is at least in part mediated through direct effects on donor-reactive T cells. These results identify AQPs as a promising target for diminishing donor-specific alloreactivity and improving the survival of high-risk organ transplants., (© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.)