Transplantation

Induction therapy in elderly kidney transplant recipients with low immunological risk Background. In nonimmunized patients, similar rejection rates are observed for patients who have undergone Thymoglobulin (ATG) or Basiliximab (BSX) therapy. Whilst ATG may improve Delayed Graft Function (DGF), it may also be associated with higher infection rates and malignancy risk. We compared survival and clinical outcomes in elderly recipients with low immunological risk according to their induction therapy. Methods. We conducted a multicentric study on nonimmunized ≥ 65 years patients receiving a first kidney transplant between 2010 and 2017. The principal outcome was patient and graft survival. Secondary outcomes were cumulative probabilities of infection, first acute rejection episode, malignancy, de novo DSA, Post Transplant Diabetes (PTD), cardiac complications, eGFR, occurrence of DGF. Cox, logistic or linear statistical models were used depending on the outcome studied, and models were weighted on the propensity scores. Results. 204 patients were included in the BSX group and 179 in the ATG group, with the average age 71.0 and 70.5 years respectively. Patient and graft survival at 3 years posttransplantation were 74% (95%CI from 65% to 84%) and 68% (95%CI from 60% to 78%) in ATG and BSX group respectively, without significant difference. Occurrence of PTD was significatively higher in BSX group (23% vs 15%, p = 0.04) due to higher trough levels of Tacrolimus on month 3 (9.48 vs 7.30 ng/ml, p = 0.023). There was no difference in other evaluated outcomes. Conclusion. In elderly recipients, ATG does not lead to poorer outcomes compared to BSX and could permit lower trough levels of Tacrolimus, thus reducing occurrence of PTD. * Données Informatisées et VAlidées en Transplantation, DIVAT Cohort Collaborators listed at end of manuscript. Authorship: CM, JB, YF and JDcques Dantal participated in the research design and data analysis. All the authors participated in writing the paper. Disclosure: The authors declare no conflicts of interest. Funding: This work was partially supported by a public grant overseen by the French National Research Agency (ANR) to create the Common Laboratory RISCA (Research in Informatic and Statistic for Cohort Analyses, www.labcom-risca.com, reference: ANR-16-LCV1-0003-01) involving the development of Plug-Stat® software. Corresponding author: Christophe Masset - Centre de Recherche en Transplantation, Nantes, 30 boulevard Jean-Monnet, 44093 Nantes Cedex, France – Tel: +33 240087453 – christophe.masset@chu-nantes.fr Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Perceptions, Barriers, and Experiences with Successful Aging Before and After Kidney Transplantation: A Focus Group Study Background: End-stage kidney disease (ESKD) patients are living longer, often into older age, and commonly pursue kidney transplantation. Successful aging, a multidimensional construct of physical and social wellbeing, has been expanded and adapted for patients with chronic disease. However, perceptions of, barriers to, and experiences with successful aging among adults with ESKD are unclear and likely differ based on whether they have received a kidney transplant. Methods: Ten focus groups were held with 39 total ESKD patients aged≥50 (19 transplant candidates, 20 transplant recipients). Transcriptions were analyzed thematically by two independent coders using an inductive, constant comparative approach. Results: The mean age=64.8 (SD=7.5), 51% were African American, and 64% were male. Six themes were identified: familiarity with successful aging, perceptions of successful aging after ESKD diagnosis, barriers to successful aging, experiences with successful aging among transplant candidates, experiences with successful aging among transplant recipients, and suggested interventions. While all participants sought to achieve successful aging while living with ESKD, experiences with successful aging differed between candidates and recipients. Candidates struggled with the limitations of dialysis; some viewed transplantation as an opportunity to age successfully, while others were resigned to dialysis’ drawbacks. In contrast, transplant recipients were optimistic about their ability to age successfully, believing their transplant facilitated successful aging. Participants believed support groups for adults with ESKD and more thoughtful healthcare for aging adults would promote successful aging. Conclusions: Adults with ESKD may benefit from discussions with their clinicians and caregivers about goals, barriers, and strategies regarding successful aging. * These authors contributed equally to this work Funding: This study was supported by NIH grants R01AG042504 (PI: Dorry Segev), R01AG055781 (PI: McAdams-DeMarco), R01DK114074 (PI: McAdams-DeMarco), and K24DK101828 (PI: Dorry Segev). Mara McAdams-DeMarco was also supported by the Johns Hopkins University Claude D. Pepper Older Americans Independence Center (P30AG021334). Meera N. Harhay was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (K23DK105207). Nancy Schoenborn was supported by the National Institute on Aging (K76AG059984). Christine Haugen was supported by the National Institute on Aging (F32AG053025). Disclosure: The authors of this manuscript have no conflicts of interest to disclose as described Transplantation. Contact Information: Mara McAdams-DeMarco, Ph.D., Department of Epidemiology, 615 N. Wolfe St, W6033, Baltimore, MD 21205, (410) 502-1950 email: mara@jhu.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Oxygen supplementation supports energy production during hypothermic machine perfusion in a model of donation after circulatory death donors. No abstract available

Glycocalyx damage within human liver grafts correlates with graft injury and postoperative graft function after orthotopic liver transplantation Background. Destruction of the endothelial glycocalyx has been observed within lung and kidney grafts during ischemic organ preservation. We aimed to quantify glycocalyx damage within human liver grafts after organ preservation and correlate the results with graft injury and postoperative graft function in patients undergoing orthotopic liver transplantation (OLT). Methods. Syndecan-1 (Sdc-1) was measured as indicator of glycocalyx degradation in effluents of 38 liver grafts and in serum of patients undergoing OLT. Effluent Sdc-1 concentrations were correlated with hepatic injury markers from the effluent. Furthermore, we assessed the association of Sdc-1 with early allograft dysfunction (EAD), 1-year graft survival and 1-year patient survival. Results. Effluent Sdc-1 concentrations correlated with effluent concentrations of hepatocellular injury markers including alkaline phosphatase (R=0.543, P=0.003), aspartate aminotransferase (R=0.420, P=0.029) and lactate (R=0.574, P=0.002). Syndecan-1 effluent concentrations were greater in patients who developed EAD compared to those without EAD (4720 [4374-5133] versus 3838 [3202-4240] ng/ml, P=0.015). Furthermore, receiver operating characteristics analyses revealed that effluent Sdc-1 concentrations (AUC=0.82, P=0.017) and serum Sdc-1 concentrations (AUC=0.84, P=0.006) were associated with the development of EAD. These results were confirmed by regression analyses. No association was found between Sdc-1 and 1-year graft survival or 1-year patient survival. Conclusion. Our data suggest that the glycocalyx is damaged within human liver grafts during preservation, and that the extent of glycocalyx damage correlates with the severity of hepatocellular injury. Recipients of livers grafts with greater glycocalyx damage might be at higher risk for development of EAD after OLT. Acknowledgments; JS designed and conducted the study, collected and analyzed data, and drafted the manuscript. JB-S helped to design and conduct the study, performed data interpretation and data analysis, and reviewed the manuscript. SK performed data acquisition and reviewed the manuscript. PF, GB, DK and LK participated in the research design and reviewed the manuscript. DB helped to design the study and reviewed the manuscript. BT helped to conduct the study, provided help in data analysis and reviewed the manuscript. CK participated to design the study and edited the final version of the manuscript. All authors approved the final version of the manuscript. Grants and financial support: This study was supported by funds from the Department of Anesthesia, General Intensive Care and Pain Management of the Medical University of Vienna. This research was not supported by funding agencies in the public, commercial, or not-for-profit sectors. Conflict of interest: The authors declare no conflicts of interest. Results presented in this manuscript have not been published previously in whole or in part. Corresponding author: Peter Faybik, MD, Medical University of Vienna, Department of Anesthesia, Intensive Care Medicine and Pain Medicine, Waehringer Guertel 18-20, 1090 Vienna, Austria. T.: +43 1 40400 41500; F.: + 43 1 40400 40280, E.: peter.faybik@meduniwien.ac.at Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Safe use of right lobe live donor livers with up to 20% macrovesicular steatosis without compromising donor safety and recipient outcome Background: The principle in right lobe living donor liver transplantation (RLLDLT) is to use “near-perfect” grafts to maximise recipient benefit with minimal donor risk. Whether, and what degree of graft macrovesicular steatosis is safe for both recipient and donor, is debatable. Methods: We compared donor and recipient outcomes in 623 primary RLLDLT’s, using grafts with (Group A;10-20% steatosis, n=92), and without (Group B; <10%, n=531) significant macrovesicular steatosis, on pre or intra operative biopsy. Results: Group A donors had higher BMI, transaminases, fasting blood sugar, triglyceride, and low density lipoprotein level, and lower high density lipoprotein, and liver attenuation index (LAI) on CT scan, and similar future liver remnant (FLR). Mean post operative day [POD7] aspartate aminotransferase [AST] (61.13 + 24.77 vs. 73.17 + 53.71 IU/L;p=0.04), and prothrombin time-international normalized ratio [PT-INR] (1.16 + 0.36 vs. 1.28 + 0.24;p=0.0001) were lower in Group A donors. POD 3/7 total bilirubin [TB], and alanine aminotransferase [ALT], POD3 AST and PT-INR; postoperative morbidity (Dindo-Clavien >3b), hospital stay were similar in both groups. Recipients in both groups had similar age, MELD score. RL graft weight (764.8 + 145.46 vs. 703.24 + 125.53 grams;p<0.0001), and GRWR (1.09 + 0.29 vs. 1.00 + 0.21;p=0.0004) were higher in Group A. All biochemical parameters at POD3/7, as well as hospital stay, 30-day mortality were similar in recipients of both groups, even after matching both groups for age, MELD and GRWR. Conclusion: Use of well selected RL grafts (adequate FLR in donor, GRWR in recipient) with up to 20% macrovesicular steatosis, does not compromise graft function and outcomes, and is safe for the donor. Conflicts Of Interest: The authors declare no conflicts of interest. Funding: None Disclosure: The authors of this manuscript have no conflicts of interest to disclose as described by the Transplantation. Corresponding Author and Reprint Requests: Prashant Bhangui, Senior Consultant Liver Transplant and Hepatobiliary Surgeon, Medanta Institute Of Liver Transplantation and Regenerative Medicine, Medanta-The Medicity, Gurugram, Delhi NCR, INDIA 122001, Email: pbhangui@gmail.com, prashant.bhangui@medanta.org, Telephone: +(91) 9871299733 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Immunity to vaccine-preventable viral infections in Australians being evaluated for liver transplantation Background: Vaccine-preventable viral infections are associated with increased risk of morbidity and mortality in immunocompromised patients. Current guidelines recommend routine screening and vaccination of all patients prior to solid organ transplantation. We studied rates of immunity against vaccine-preventable viruses in liver transplantation (LT) recipients. Methods: We retrospectively studied consecutive adult patients who underwent first deceased donor LT at a single center between August 2008 to October 2017. Viruses studied were: hepatitis A (HAV), hepatitis B (HBV), varicella zoster virus (VZV), measles, and mumps. Hepatitis B surface antibody (anti-HBs) <10 IU/mL in HBV surface antigen negative patients and negative IgG to other viruses was regarded as absent immunity. Results: 555 patients underwent LT (72.4% male, median age 55.0 years). Percentages of patients who lacked immunity to vaccine preventable infections were: HAV (31.8%), HBV (63.8%), measles (1.4%), mumps (6.6%) and VZV (3.8%). Age was positively associated with immunity (from either past exposure or vaccination) against most viruses including: HAV, measles, mumps, and VZV (P<0.05 for all). In contrast, older age was marginally associated with anti-HBs <10 IU/mL (P=0.046). No significant changes in immunity rates were observed over the duration of the study. Conclusions: A substantial number of patients undergoing LT are not immune to vaccine-preventable viruses at time of assessment. This presents an opportunity for pre-LT vaccination and in particular younger patients may need to be targeted. Astrid Gardiner and Ken Liu contributed to the manuscript equally. Financial support: None Authors’ declaration of personal interests: All authors have nothing to disclose in relation to this manuscript. Corresponding Author: A/Prof Simone I. Strasser, AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW, 2050, Australia, Telephone: +612 9515 7606, Fax: +612 9515 5182, Email: simone.strasser@health.nsw.gov.au Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

The role of miR-200b-3p in modulating TGF-β1 induced injury in human bronchial epithelial cells Background: Dysregulation of miRNAs has been implicated in airway diseases where TGF-β induced Epithelial-Mesenchymal Transition (EMT) may contribute to pathophysiology. Our study investigated the role of miRNA-200b in TGF-β1 induced EMT in human bronchial epithelial cells. Methods: NanoString® nCounter miRNA assay was used to profile miRNA in control versus TGF- β1 (1, 4 and 24 hrs) stimulated BEAS-2B cells. Immortalized primary bronchial epithelial cell line (BEAS-2B cells), human primary bronchial epithelial cells (PBECs) and PBECs derived post lung transplant were transfected with miR-200b-3p mimics and EMT marker expression was examined at RNA and protein level. MiRNA target studies was performed and validated using computational tools and luciferase assay. In situ hybridization was done on normal lung tissue to localize miR-200b-3p in airway epithelium. Results: MiR-200b-3p was downregulated post TGF- β1 treatment compared to control in BEAS-2B. MiR-200b-3p mimic transfection prior to TGF-β1 stimulation maintained epithelial marker expression and downregulated mesenchymal cell markers at RNA and protein level in BEAS-2B cells and PBECs. Furthermore, miR-200b-3p mimics reversed established TGF-β1 induced EMT in BEAS-2B cells. MiR-200b-3p targets, ZNF532 and ZEB2 were validated as direct targets using luciferase assay. miR-200b-3p mimics suppress TGF-β1 induced EMT via inhibition of ZNF532 and ZEB2. In situ hybridization showed that miR-200b-3p is expressed in the normal lung epithelium. Additionally, miR-200b-3p mimics inhibit EMT in the presence of TGF-β1 in PBECs derived from lung allograft. Conclusion: We provide proof of concept that miR-200b-3p protects airway epithelial cells from EMT. Manipulating miR-200b-3p expression may represent a novel therapeutic modulator in airway pathophysiology. + Joint senior authors Authors have no conflicts of interest to disclose Funding: This work was supported by a Newcastle University Overseas Research Scholarship and grant from FP7-MCITN (POSAT, 606979). This work was also supported by the NIHR Blood and Transplant Research Unit in Organ Transplantation at the University of Cambridge in partnership with Newcastle University and the Newcastle NIHR Biomedical Research Centre in Ageing and Long-Term Conditions. Simi.ali@newcastle.ac.uk (corresponding author), Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH. UK, Tel:+441912087158. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Existing and Evolving Bioethical Dilemmas, Challenges and Controversies in Vascularized Composite Allotransplantation - An International Perspective from the Brocher Bioethics Working Group Early results of hand and face transplants and other grafts such as those of uterus, penis, trachea, larynx or abdominal wall have confirmed the potential for vascularized composite allotransplantation (VCA) to restore appearance, anatomy, function, independence, and social integration in patients suffering from devastating tissues deficits untreatable by conventional treatment options. Despite such promise, these novel and complex procedures face challenges and controversies that remain open to discussion and debate. Indeed, many barriers to clinical advancement and negative stakeholder perceptions still exist. The bioethical challenges surrounding VCA include but are not limited to justice and vulnerability of subjects, and their experiences with risks, benefits and outcomes, provider economy of fame, public awareness and attitudes towards transplantation, and policy and regulatory issues shaping progress of the field. The First International Workshop on Bioethical Challenges in Reconstructive Transplantation was organized by the Brocher Foundation in Hermance, Switzerland. VCA professionals representing teams from across the world examined bioethical issues in VCA related to standards for safety, efficacy, feasibility, privacy, confidentiality, and equitability. Key discussion topics from the workshop were included in a survey questionnaire implemented across VCA professionals attending the 13th Congress of International Society of VCA (ISVCA) held in Salzburg, Austria. The insights from the Brocher workshop and the ISVCA survey as presented here could help inform the future development of clinical practice and policy strategies in VCA to ensure value, accessibility, and acceptance of these procedures by potential donors, potential or actual recipients and their families as well as providers and payers. * Equal Contribution Corresponding Author Contact Information: Vijay S. Gorantla, MD, PhD, MMM, FRCS, Associate Professor of Surgery | Ophthalmology | Bioengineering, Director | Vascularized Composite Allotransplantation Program, Expert Consultant for Military Medicine | Wake Forest Institute for Regenerative Medicine, Suite 260, Richard H. Dean Biomedical Building, 391 Technology Way, Winston-Salem, NC 27101, Office: 336-713-1494 | Cell: 724-624-5915 | Email: vgorantl@wakehealth.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Prediction of Perioperative Mortality of Cadaveric Liver Transplant Recipients during their evaluations Background: There are no instruments that can identify patients at increased risk of poor outcomes after liver transplantation (LT) based only on their preoperative characteristics. The primary aim of this study was to develop such a scoring system. Secondary outcomes were to assess the discriminative performance of the predictive model for 90-day mortality, 1-year mortality and 5-year patient survival. Methods: The study population was represented by 30,458 adults who underwent LT in the United States between January 2002 and June 2013. Machine learning techniques identified recipient age, MELD score, BMI, diabetes, and dialysis before LT as the strongest predictors for 90-day postoperative mortality. A weighted scoring system, (minimum of 0 to a maximum of 6 points) was subsequently developed. Results: Recipients with 0, 1, 2, 3, 4, 5, and 6 points had an observed 90-day mortality of 6.0%, 8.7%, 10.4%, 11.9%, 15.7%, 16.0%, and 19.7% respectively (P≤0.001). One-year mortality was 9.8%, 13.4%, 15.8%, 17.2%, 23.0%, 25.2% and 35.8% (P≤0.001) and five-year survival was 78%, 73%, 72%, 71%, 65%, 59% and 48% respectively (P=0.001). The mean 90-day mortality for the cohort was 9%. The area under the curve (AUC) of the model was 0.952 for the discrimination of patients with 90-day mortality risk ≥10%. Conclusions: Short and long-term outcomes of patients undergoing cadaveric LT can be predicted using a scoring system based on recipients’ preoperative characteristics. This tool could assist clinicians and researchers in identifying patients at increased risks of postoperative death. Disclosure: The authors declare no conflict of interest Funding: This study did not receive any funding Corresponding author: Michele Molinari, MD, MSc, UPMC Montefiore, 3459 Fifth Avenue, N758, Pittsburgh, PA 15213, Fax 412 647-5736, Telephone: 412 647-5734, Email: molinarim@upmc.edu This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Commentary on Long-Term Growth following Renal Transplantation in Children No abstract available