Transplantation

Defining a willingness-to-transplant threshold in an era of organ scarcity: Simultaneous liver-kidney transplant as a case example Background: Organ scarcity continues in solid organ transplantation, such that the availability of organs limits the number of people able to benefit from transplantation. Medical advancements in managing end-stage organ disease have led to an increasing demand for multi-organ transplant, wherein a patient with multi-organ disease receives more than one organ from the same donor. Current allocation schemes give priority to multi-organ recipients over single-organ transplant recipients, which raises ethical questions regarding equity and utility. Methods: We use simultaneous liver-kidney (SLK) transplant, a type of multi-organ transplant, as a case study to examine the tension between equity and utility in multi-organ allocation. We adapt the health economics willingness-to-pay threshold to a solid organ transplant setting by coining a new metric: the willingness-to-transplant (WTT) threshold. Results: We demonstrate how the WTT threshold can be used to evaluate different SLK allocation strategies by synthesizing utility and equity perspectives. Conclusions: We submit that this new framework enables us to distill the question of SLK allocation down to: what is the minimum amount of benefit we require from a deceased donor kidney to allocate it for a particular indication? Addressing the above question will prove helpful to devising a rational system of SLK allocation and is applicable to other transplant settings. Disclosure: The authors declare no conflict of interest. Findings in this manuscript were partly reported in abstract form at the National Kidney Foundation Young Investigator Forum in April, 2017 and American Transplant Congress in May, 2017. Funding: Research reported here was supported by the John M. Sobrato Gift Fund (J.C.T.) and National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under award number K24DK092336 (W.R.K.) and K24 DK085446 (G.M.C.). Corresponding Author: Xingxing S. Cheng xscheng@stanford.edu, 777 Welch Road, Suite DE Palo Alto, CA, USA 94304 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Letermovir as Salvage Therapy for CMV Infection in Transplant Recipients BACKGROUND: Letermovir, a new viral terminase complex inhibitor, has been approved for the prevention of cytomegalovirus (CMV) infection in hematopoietic stem cell transplant patients. However, data on the efficacy and safety of letermovir for the treatment of CMV infection in transplant recipients remain scarce. METHODS: We performed a single-center retrospective study of stem cell and organ transplant recipients who received letermovir for the treatment of CMV infection from November 2017 to October 2018. RESULTS: Six patients were included and five were evaluable. All received letermovir in the context of a refractory or resistant CMV infection including asymptomatic CMV viremia (n=3), CMV syndrome (n=1) and CMV pneumonitis and colitis (n=1). The three asymptomatic patients experienced a decrease of the viral load to less than 200 IU/mL after letermovir therapy. One patient displayed a partial viral load response (2 log of viral load reduction) but a good clinical response, and one who received a suboptimal dose of letermovir experienced an increase of viremia. There were no treatment-related adverse effects. CONCLUSION: We demonstrate mixed efficacy in patients with refractory CMV infection suggesting that letermovir may be a useful therapeutic adjunct, potentially in combination with other antivirals. * denotes joint senior authorship DISCLOSURES: AH has received clinical trials grants from Merck, Shire, Roche, Qiagen, and Astellas. DK has received clinical trials grant from Roche, Shire, Qiagen, Oxford Immunotec and honoraria from Merck, Shire. PP, JT, AV, SH, VHF have no relevant disclosures. FUNDING: None Corresponding Author: Atul Humar MD MSc FRCPC, University Health Network, Toronto, Ontario, Canada M5G 2N2, Atul.humar@uhn.ca Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Changes of T-cell immunity over a lifetime T cell immunity undergoes a complex and continuous remodeling with aging. Understanding those dynamics is essential in refining immunosuppression. Aging is linked to phenotypic and metabolic changes in T-cell immunity, many resulting into impaired function and compromised effectiveness. Those changes may impact clinical immunosuppression with evidences suggesting age-specific efficacies of some (CNI and mTORi) but not necessarily all immunosuppressants. Metabolic changes of T cells with aging have only recently been appreciated and may provide novel ways of immunosuppression. Here, we provide an update on changes of T-cell immunity in aging. Disclosure: The authors declare no conflicts of interest. Funding: This work was supported by National Institutes of Health grants R56/R01AG039449. Y.N. was supported by the Chinese Scholarship Council (201606370196) and Central South University. K.M and R.M. were supported by the Osaka Medical Foundation. J.I was supported by the Biomedical Education Program and The German Academic Exchange Service. Address correspondence to: Stefan G. Tullius MD, PhD, 75 Francis St, 02115, Boston, MA. Stullius@bwh.harvard.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Living Donor Liver Transplant for Alcoholic Liver Disease: Data from the Adult to Adult Living Donor Liver Transplantation Study (A2ALL) Background: Alcoholic liver disease (ALD) accounts for 15-30% of transplants performed in the United States and Europe, however the data on living donor liver transplantation (LDLT) for ALD remains sparse. The purpose of this study was to examine the outcomes following LDLT for ALD using data from the Adult to Adult Living Donor Liver Transplantation Study (A2ALL), which represents the largest Western experience with adult to adult LDLT. Methods: A retrospective review of A2ALL data collected between 1998-2014 was performed. Patients were excluded if they received a deceased donor liver transplant. Demographic data, post-operative outcomes and complications, graft and patient survival, and predictors of graft and patient survival were assessed. Results: Of the 1065 patients who underwent LDLT during the study time period, 168 (15.8%) were transplanted for a diagnosis of ALD. Comparing patients who underwent transplant for ALD with those who were transplanted for other etiologies of liver disease, there was no significant difference in graft survival at one (88% vs. 84%), five (76% vs. 74%), or ten years following transplant (55% vs. 61%, p=0.29). Similarly, there was no difference in patient survival at one (94% vs. 91%), five (83% vs. 79%), or ten years following transplant (61% vs. 66%, p=0.32). Conclusions: LDLT for ALD results in excellent one, five, and ten-year graft and patient survival. Patients with ALD and impaired renal function have a higher risk of graft loss and death. These findings support the notion that early LDLT for patients with ALD may help optimize outcomes. Disclosures: the authors declare no conflicts of interest Funding: Supported in part by the UCSF Liver Center (P30 DK026743). Corresponding Author: Dr. Nancy L. Ascher, MD, PhD, Professor of Surgery , Division of Transplant, University of California, San Francisco, Box 0780, 505 Parnassus Avenue, M884, San Francisco, CA 94117, Phone: (415) 353- 8615, Fax: (415) 353-8974, Email: nancy.ascher@ucsf.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Living Donor Liver Transplant in Alcohol-related Liver Disease: An Option Whose Time has Come No abstract available

Restoring activity of pig brain cells after death does not invalidate the determination ofdeath by neurologic criteria or undermine the propriety of organ donation after death No abstract available

DEVELOPMENT AND PRELIMINARY EVALUATION OF IRD-1-2-3: AN ANIMATED VIDEO TO INFORM TRANSPLANT CANDIDATES ABOUT INCREASED RISK DONOR KIDNEYS Background: Current educational interventions about increased risk donors (IRDs) are less effective in improving knowledge among African American (AA) kidney transplant candidates compared to other races. We aimed to develop an IRD educational animated video culturally responsive to AAs and conduct feasibility testing. Methods: Between 5/1/18-6/25/18 we iteratively refined a culturally targeted video for AAs with input from multiple stakeholders. We then conducted a one group pre post study between 6/28/18-10/29/18 with 40 kidney transplant candidates to assess the feasibility and acceptability of the video to improve participant knowledge and obtain feedback about IRD understanding, self-efficacy, and willingness. A mixed population was chosen to obtain race-specific acceptability data and efficacy estimates to inform a larger study. Results: Three themes emerged and informed video development; misattribution of IRD to kidney quality, IRD terminology as a barrier to meaningful understanding, and variable reactions to a 1:1000 risk estimate. The study cohort was 50% AA. Median IRD knowledge increased from 5 to 7.5 (p=0.001) overall and from 5 to 7 (p<0.001) among AAs. The frequency of positive responses increased pre post video for understanding of (23% vs. 83%, p<0.001), self-efficacy to decide about (38% vs. 70%, p<0.001) and willingness to accept IRD kidneys (25% vs 72%, p<0.001). Over 90% of participants provided positive ratings on each of 6 acceptability items. Conclusion: A culturally responsive IRD educational video was developed in collaboration with key stakeholders. Quantitative results indicate the video was acceptable and promising to impact IRD knowledge among AA and non-AA kidney transplant candidates. Authorship: LK and MCL participated in research design, data collection and analysis, manuscript preparation and editing. MM and TF participated in analysis and editing. RC and BD participated in editing. Disclosure: The authors declare no conflict of interest. Funding: The work reported in this paper was supported by Research for Health in Erie County, Inc. Corresponding Author: Michael D Cobler-Lichter BS1, M.D. Candidate, Class of 2021, Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo, 955 Main Street, Buffalo, NY 14203, Tel: 716-481-7805 EMAIL: mcoblerl@buffalo.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Area under trough concentrations of tacrolimus as a predictor of progressive renal impairment after liver transplantation. Background: Tacrolimus minimization is usually restricted to patients with pre-transplant renal impairment and this strategy could result into worse renal outcomes after liver transplantation (LT). Methods: A consecutive cohort of 455 LT patients receiving tacrolimus-based immunosuppression was studied (2008-2013). Cumulative exposure to tacrolimus was calculated as the area under curve of trough concentrations (AUCtc). Patients were stratified as tacrolimus minimization, conventional or high exposure according to thresholds based in the COMMIT consensus. Estimated glomerular filtration rates (eGFR) were assessed by the MDRD-4 formula up to 5 years post-LT. Results: Seventy patients (15.4%) had pre-transplant eGFR<60 ml/min, which was associated with increased mortality rates, particularly within the first 5 years post-LT (31.4% vs 17.5%; Breslow p= 0.010). After LT, there was an abrupt eGFR decline within the first 3 months (median 18.6 ml/min; p<0.001), further decreasing up to 12 months (additional 3 ml/min), without any improvement thereafter. According to AUCtc, 33.7% of patients received tacrolimus minimization, 44.8% conventional exposure and 21.5% high exposure. Conventional/high exposure to tacrolimus resulted in a more pronounced eGFR decline within the first 3 months as compared with minimization (23.3ml/min vs 9.5ml/min; p<0.001). This gap was even higher in patients with initially preserved renal function. Tacrolimus AUCtc was an independent predictor of eGFR decline within the first 3 months after controlling for potential confounders. Conclusions: AUCtc is a surrogate of cumulative exposure to tacrolimus and may be helpful for routine dose adjustments. Tacrolimus minimization should be universally attempted after LT in order to preserve renal function. Disclosure: The authors of the present manuscript have no conflict of interest to disclose as described by the Transplantation Journal. Funding: The present study was investigator-driven and it is free from any industry sponsorship. Marta Guerrero is a recipient of a research grant awarded by the Asociación Española para el Estudio del Hígado (AEEH). * Corresponding author. ** These authors had equal contribution to the manuscript and are joint senior authors. Correspondence information: Manuel Rodríguez-Perálvarez, MD, PhD. Hospital Universitario Reina Sofía. Avda/ Menéndez Pidal s/n; Postal Code 14004; Córdoba, Spain. E-mail: ropeml@hotmail.com Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

MHC-mismatched Allotransplantation of Induced Pluripotent Stem Cell-Derived Cardiomyocyte Sheets to Improve Cardiac Function in A Primate Ischemic Cardiomyopathy Model Background: Although allogeneic induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) exhibit potential in cardiomyogenesis for heart failure, whether major histocompatibility complex (MHC) -matched allogenic iPSC implantation (MMAI) minimizes immune rejection for cell survival or functional recovery remains unknown. We herein explored whether MMAI with an iPSC-CM sheet is stable for a longer period and therapeutically more effective than MHC-mismatched AI in a primate ischemic cardiomyopathy model. Methods: Green fluorescent protein (GFP)-transfected iPSC-CM sheets, derived from cynomolgus macaques with homozygous MHC haplotypes ''HT1'', were transplanted on the left ventricle (LV), generated by ligating the left anterior descending (LAD) artery for 2 weeks in an ischemic model with or without heterozygous HT1 as MMAI and MHC-mismatched AI. Sham models were made by opening chest at 14 days after LAD ligation without any treatment. Results: Stereomicroscopy revealed that at 4 months post transplantation, GFP intensity was higher in the MMAI group than in the MHC-mismatched AI group and the sham group. Immunohistochemistry staining revealed that host immune reaction with CD3-positive cells was stronger in MHC-mismatched AI than in MMAI at 3 months. Cardiac function improved both in MMAI and MHC-mismatched AI at 1 month after transplantation and was preserved until 6 months, whereas in the sham group, functional deterioration progressed over time. Conclusion: Although MHC-homo-iPSCs are preferred to avoid immune rejection, MHC-mismatched iPSC-CMs can also induce comparable cardiac functional recovery at late follow-up, suggesting that MHC-mismatched iPSC-based cardiac regenerative therapy with immunosuppressants is a feasible option for treating heart failure in clinical settings. Authorship: NK performed all the experiments, collected and/or assembled all the data, wrote the manuscript, and prepared the figures. SM provided financial support and helped to set up all the experiments and contributed to data analysis and interpretation. SF, TK, AK, SY, AH and KT helped data analysis and interpretation. SE provided study materials. KM, TW and JH contributed to the analysis of cardiac perfusion in experimental animals by positron emission tomography scanning. YS is the corresponding author and conceived and designed the study and provided financial support. Disclosure: The authors declare no conflicts of interest. Funding: This work was supported by the Japan Science and Technology Agency as a part of the project, Center for the Development of Myocardial Regenerative Treatments Using iPS Cells. Corresponding Author: Yoshiki Sawa, MD, PhD, Yamadaoka, 2-2, Suita-city, Osaka 565-0087, Japan. Tel: +81-6-6879-3154, Fax: +81-6-6879-3159, E-mail: sawa-p@surg1.med.osaka-u.ac.jp6 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Liver Transplantation Using Uncontrolled Donors After Circulatory Death: A 10-Year Single-Center Experience Background. One method for increasing the donor pool for orthotopic liver transplantations (OLTs) is to use uncontrolled donations after circulatory death (uDCDs). Methods. From January 2006 to December 2016, we performed 75 OLTs using uDCD livers. The control group comprised a sample of 265 OLTs using livers of donations after brain death (DBDs). A comparative study was performed. Results. Of 256 potential uDCD donors cannulated, 75 (29.3%) livers were accepted for OLT. The amount of hemoderivatives transfused was significantly higher in the uDCD group. The rate of primary nonfunction was also significantly higher (p = 0.031) in uDCD recipients (8%) than in DBD recipients (1.5%). The overall rate of biliary complications was significantly higher (p = 0.001) in uDCD recipients (23 cases, 30.6%) than DBD recipients (28 cases, 10.6%). In the uDCD group, 1-, 3-, and 5-year patient survival rates were 82.7%, 73%, and 71.5%, respectively; in the DBD group, they were 89%, 83.7%, and 78.8%, respectively (p = 0.180). In the uDCD group, 1-, 3- and 5-year graft survival rates were 73.3%, 65.1%, and 63.6%, respectively; in the DBD group, they were 87.1%, 81.9%, and 76.5%, respectively (p = 0.013). Multivariate analysis showed that independent risk factors for patient and graft survival were intraoperative transfusion of more than six units of packed red blood cell concentrates and recipients who were older than 60 years. Conclusions. Although graft survival is significantly lower using uDCD livers, 5-year patient survival in recipients of DBD and uDCD livers is similar. After careful selection, the livers of uDCD can be selectively used for OLT. Disclosure: The authors declare no conflicts of interest. The authors declare no applicable funding. 3Presented this research as oral communication at the 27th International Congress of The Transplantation Society (2018) held in Madrid, Spain. *Corresponding Author: Carlos Jiménez-Romero PhD, FACS. Prof. of Surgery. Unit of HPB Surgery and Abdominal Organ Transplantation, Doce de Octubre University Hospital, 4ª Planta, Ctra. Andalucía Km 5.4, 28041, Madrid, Spain. Phone: +34 91 3908294. Fax: +34 91 519271. E-mail: carlos.jimenez@inforboe.es Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Alexandros Sfakianakis
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