Patients with Persistently Low MELD-Na Scores Continue to be at Risk of Liver Related Death Background: The vast majority of patients with cirrhosis have low Model for End Stage Liver Disease-Sodium (MELD-Na) scores, however the ability for the MELD-Na score to predict patient outcomes at low scores is unclear. Methods: Adult patients in a multicenter, Chicago-wide database of medical records with ICD-9 codes of cirrhosis and without a history of hepatocellular carcinoma were included. Records were linked with the state death registry and death certificates were manually reviewed. Deaths were classified as "liver related", "nonliver related", and "nondescript" as adjudicated by a panel comprised of a transplant surgeon, a hepatologist, and an internist. A sensitivity analysis was performed where patients with hepatocellular carcinoma were included. Results: Among 7922 identified patients, 3999 patients had MELD-Na scores that were never higher than 15. In total, 2137 (27%) patients died during the study period with higher mortality rates for the patients in the high MELD-Na group (19.4 (41.6%) vs 4.1 (12.6%) per 100 person years, p<0.001). . The high MELD-Na group died of a liver related cause in 1142/1632 (70%) as compared to 240/505 (47.5%) deaths in the low MELD-Na group. There was no difference in the distribution of subcategory of liver related death between low and high MELD-Na groups. Among subclassification of liver related deaths, the most common cause of death was ‘Infectious’ in both groups. Conclusions: Despite persistently low MELD-Na scores, patients with cirrhosis still experience high rates of liver related mortality. Funding: Drs. Atiemo and Mazumder were supported by NIH grant T32DK077662 PI MM Abecassis. Disclosures: The authors declare no conflicts of interest Corresponding author: Daniela P Ladner, MD, MPH, FACS, dladner@nm.org, Associate Professor of Surgery, Department of Surgery, Division of Organ Transplantation, Director Northwestern University Transplant Outcomes Research Collaborative (NUTORC), Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, 676 North Saint Clair St., Suite 1900, Chicago, Illinois 60611, Phone: 312-695-1703, Fax: 312-695-9194 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Incidence and Risk Factors of Obesity in Childhood Solid-Organ Transplant Recipients Background: Obesity is a significant public health concern; however, the incidence post solid-organ transplantation is not well reported. Methods: This study determined the incidence and risk factors of obesity among pediatric solid-organ transplant recipients (heart, lung, liver, kidney, multiorgan) at Hospital for Sick Children (2002-2011), excluding prevalent obesity. Follow-up occurred from transplantation until development of obesity, last follow-up or end of study. Incidence of obesity was determined overall, by baseline BMI and organ groups. Risk factors were assessed using Cox proportional-hazards regression. Results: Among 410 (55% male) children, median transplant age was 8.9 (interquartile range [IQR]:1.0-14.5) years. Median follow-up time was 3.6 (IQR:1.5-6.4) years. Incidence of obesity was 65.2 (95% confidence interval [CI]:52.7-80.4) per 1000 person-years. Overweight recipients had a higher incidence, 190.4 (95% CI:114.8-315.8) per 1000 person-years, than nonoverweight recipients, 56.1 (95% CI:44.3-71.1). Cumulative incidence 5-years posttransplant was 24.1%. Kidney relative to heart recipients had the highest risk (3.13 adjusted hazard ratio [aHR]; 95% CI:1.53-6.40) for obesity. Lung and liver recipients had similar rates to heart recipients. Those with higher baseline BMI (z-score; 1.72 aHR; 95% CI:1.39-2.14), overweight status (2.63 HR; 95% CI:1.71-4.04) and younger transplant age (years; 1.18 aHR; 95% CI:1.12-1.25) were at highest risk of obesity. Higher cumulative steroid dosage (per 10mg/kg) was associated with increased risk of obesity after adjustment. Conclusions: Among all transplanted children at Hospital for Sick Children, 25% developed obesity within 5-years posttransplant. Kidney recipients, younger children, those overweight at transplant, and those with higher cumulative steroid use (per 10mg/kg) were at greatest risk. Early screening and intervention for obesity are important preventative strategies. Funding: Dr. Rulan S. Parekh received funding from the Transplant & Regenerative Medicine Centre (TRMC) Catalyst Grant at The Hospital for Sick Children, Ashley's Angels Catwalk, and the Canadian Institutes of Health Research (CIHR) for the completion of this study. This research was undertaken, in part, thanks to funding from the Canada Research Chairs program. Disclosures: The authors declare no conflicts of interest. Authorship Statement: B.C.B., T.M.B., J.V-R., and R.S.P. participated in the study design. B.C.B., A.S., J.V-R., and R.C. participated in the data abstraction. B.C.B., T.M.B., and R.S.P participated in the data analysis. B.C.B. and R.S.P. drafted the manuscript. All authors read and approved the final manuscript. Corresponding Author: Dr. Rulan S. Parekh, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, rulan.parekh@sickkids.ca. (416) 813-7654 x 328042 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Effects of intraoperative fluid balance during liver transplantation on postoperative acute kidney injury: an observational cohort study. Background: Liver transplant recipients suffer many postoperative complications. Few studies evaluated the effects of fluid management on these complications. We conducted a retrospective cohort study to evaluate the association between intraoperative fluid balance and postoperative acute kidney injury (AKI) and other postoperative complications. Methods: We included consecutive adult liver transplant recipients who had their surgery between July 2008 and December 2017. Our exposure was intraoperative fluid balance and our primary outcome was the grade of acute kidney injury (AKI) at 48 hours after surgery. Our secondary outcomes were the grade of AKI at 7 days, the need for postoperative renal replacement therapy (RRT), postoperative red blood cells transfusions, time to extubation, time to discharge from the intensive care unit (ICU) and one-year survival. Every analysis was adjusted for potential confounders. Results: We included 532 transplantations in 492 patients. We observed no effect of fluid balance on either 48-hour AKI, 7-day AKI or on the need for postoperative RRT after adjustments for confounders. A higher fluid balance increased the time to extubation, to ICU discharge and increased the risk of dying (hazard ratio = 1.19 [1.06, 1.33]). Conclusions: We observed no association between intraoperative fluid balance and postoperative AKI. Fluid balance was associated with a longer time to first extubation, longer time to ICU discharge and lower survival. This study provides insight that might inform the design of a clinical trial on fluid management strategies in this population. DISCLOSURES: The authors declare that they have no competing interests. FUNDING: This work was funded by the Fondation du CHUM (“Don d’organes et transplantation” program). Dr Chassé is a recipient of a Career Award Junior 1 from the Fonds de la Recherche du Québec – Santé. Corresponding author:François Martin Carrier, MD MSc , Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), 900, rue St-Denis, porte S03-434, Montréal (Québec) H2X 0A9, Email: francois.martin.carrier@umontreal.ca Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Wide variation in the percentage of donation after circulatory death donors across donor service areas – a potential target for improvement Background: Substantial differences exist in the clinical characteristics of donors across the 58 donor services areas (DSAs). Organ procurement organization (OPO) performance metrics incorporate organs donated after circulatory determination of death (DCDD) donors, but do not measure potential DCDD donors. Methods: Using 2011-2016 UNOS data, we examined the variability in DCDD donors/all deceased donors (%DCDD) across DSAs. We supplemented UNOS data with CDC death records and OPO statistics to characterize underlying process and system factors that may correlate with donors and utilization. Results: Among 52,184 deceased donors, the %DCDD varied widely across DSAs, with a median of 15.1% (IQR [9.3%, 20.9%]; range 0.0-32.0%). The %DCDD had a modest positive correlation with 4 DSA factors: median match MELD, proportion of white deaths out of total deaths, kidney center competition, and %DCDD livers by a local transplant center (all Spearman coefficients 0.289-0.464), and negative correlation with 1 factor: mean kidney waiting time (Spearman coefficient -0.388). Adjusting for correlated variables in linear regression explained 46.3% of the variability in %DCDD. Conclusions: Donor pool demographics, waitlist metrics, center competition and DCDD utilization explain only a portion of the variability of DCDD donors. This requires further studies and policy changes to encourage consideration of all possible organ donors. Author Disclosure Statement: The authors of this manuscript have no conflicts of interest to disclose as described by Transplantation. Funding: ES is supported by NIH grant (T32-DK07006-44). Name and Address of Corresponding Author: Elizabeth M. Sonnenberg, Hospital of the University of Pennsylvania, 5 Silverstein, Philadelphia, PA 19104, Email: elizabeth.sonnenberg@uphs.upenn.edu, Cell: 215-796-8026 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Long term graft survival and graft function following pregnancy in kidney transplant recipients: a systematic review and meta-analysis Background: The incidence of pregnancy in kidney transplant (KT) recipients is increasing. Studies report that the incidence of graft loss (GL) during pregnancy is low, but less data is available on long-term effects of pregnancy on the graft. Methods: Therefore, we performed a meta-analysis and systematic review on GL and graft function, measured by serum creatinine (SCr), after pregnancy in KT recipients, stratified in years postpartum. Furthermore, we included studies of nulliparous KT recipients Results: Our search yielded 38 studies on GL and 18 studies on SCr. The pooled incidence of GL was 9.4 % within 2 years post pregnancy, 9.2% within 2 to 5 years, 22.3% within 5 to 10 years and 38,5% more than ten years postpartum. In addition, our data show that, in case of graft survival, SCr remains stable over the years. Only within 2 years postpartum Δ SCr was marginally higher (0.18 mg/dL, 95%CI [0.05-0.32], p = 0.01). Furthermore, no differences in GL was observed in 10 studies comparing GL post pregnancy with nulliparous controls. Systematic review of the literature showed that mainly pre pregnancy proteinuria, hypertension and high SCr are risk factors for GL. Conclusions: Overall, these data show that pregnancy after KT has no effect on long-term graft survival and only a possible effect on graft function within 2 years postpartum. This might be due to publication bias. No significant differences were observed between pre and postpartum SCr at longer follow-up intervals. * Authors contributed equally The authors declare no conflicts of interest. There are no financial disclosures. Corresponding author: Marleen van Buren, Erasmus Medical Center, RG-5, Department of Internal Medicine, Section Nephrology & Transplantation, P/O Box 2040, 3000 CA Rotterdam, The Netherlands. m.c.vanburen@erasmusmc.nl 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.

USE OF DE-NOVO mTOR INHIBITORS IN HYPERSENSITZED KIDNEY TRASPLANT RECIPIENTS: EXPERIENCE FROM CLINICAL PRACTICE BACKGROUND: It is commonly believed that mTOR inhibitors (mTORi) should not be used in high-immunological risk kidney transplant recipients, due to a perceived increased risk of rejection. However, almost all trials that examined the association of optimal-dose mTORi with Calcineurin Inhibitor (CNI) have excluded hypersensitized recipients from enrollment. METHODS: To shed light on this issue, we examined 71 consecutive patients with a baseline cPRA ≥ 50% that underwent kidney transplantation from June 2013 to December 2016 in our Unit. Immunosuppression was based on CNI (tacrolimus), steroids and alternatively Mycophenolic Acid (MPA, n=38) or mTORi (either everolimus or sirolimus, n=33, target trough levels 3-8 ng/ml). RESULTS: Demographic and immunological risk profiles were similar and almost 90% of patients in both groups received induction with lymphocyte-depleting agents. Cox-regression analysis of rejection-free survival revealed better results for mTORi versus MPA in terms of biopsy-proven acute rejection [Hazard Ratio (HR)(Confidence Interval) 0.32 (0.11-0.90), P=0.031 at univariable analysis, and 0.34 (0.11-0.95), P=0.040 at multivariable analysis]. There were no differences in 1-year renal function, Banff chronicity score at 3- and 12-month protocol biopsy and development of de-novo DSAs. Tacrolimus trough levels along the first year were not different between groups (12-month levels were 8.72 ± 2.93 and 7.85 ± 3.07 ng/ml for MPA and mTORi group respectively, P=0.277). CONCLUSIONS: This single-center retrospective cohort analysis suggests that in hypersensitized kidney transplant recipients receiving tacrolimus-based immunosuppressive therapy similar clinical outcomes may be obtained using mTOR inhibitors compared to mycophenolate. CONFLICT OF INTEREST STATEMENT: DC has received speaker fees from Novartis and travel support from Astellas and Novartis. PVA has received travel support from Astellas, Novartis, Chiesi, Sandoz and speaker fees from Alexion and Mallinkrodt. GJP has received travel support from Sandoz. NE has received travel support from Novartis, Astellas and Chiesi. IR received speaker fees from Novartis and travel support from Sandoz, Pfizer y Astellas. JMC has had consultancy agreements with Pfizer, Wyeth, Novartis and Roche; has received research funding from Pfizer and Novartis; and has been a scientific advisor or board member for Novartis and Pfizer and has received lecture fees from Alexion. FD has received research grants and speaker fees from Astellas, Neovii, Novartis, Pfizer, Teva, Transplant Biomedicals. FO has received speaker fees from Novartis, Sanofi and Neovii and travel support from Novartis. AMJ, ENM, EDSA, FC, MS, JVT, JM and MJR reported no conflict of interest. FUNDING: none CORRESPONDING AUTHOR: Fritz Diekmann, fdiekman@clinic.cat - Carrer Villaroel 170, Barcelona, 08023, Spain. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Balancing efficiency and fairness in liver transplant access: tradeoff curves for the assessment of organ distribution policies. Background: Current distribution policies have resulted in persistent geographic disparity in access to donated livers across the country for waitlisted candidates. Methods: Using mathematical optimization, and subsequently the Liver Simulation Allocation Model, the following organ distribution concepts were assessed 1.) current policy, 2.) proposed alternative models, and 3.) a novel continuous distribution model. A number of different scenarios for each policy distribution concept were generated and analyzed through efficiency-fairness tradeoff curves. Results: The continuous distribution concept allowed both for the greatest reduction in patient deaths and for the most equitable geographic distribution across comparable organ transportation burden. When applied with an Optimized Prediction of Mortality allocation scheme, continuous distribution allowed for a significant reduction in number of deaths—on the order of 500 lives saved annually. (https://livervis.github.io/) Conclusions: Tradeoff curves allow for a visualized understanding on the efficiency/fairness balance, and have demonstrated that liver candidates awaiting transplant would benefit from a model employing continuous distribution as this holds the greatest advantage for mortality reduction. Development and implementation of continuous distribution models for all solid organ transplants may allow for minimization of the geographic disparity in organ distribution, and allow for efficient and fair access to a limited national resource for all candidates. Disclosure: The authors declare no conflicts of interest. Funding: None Corresponding Author: Dimitris Bertsimas, Ph.D., Operations Research Center, E40-111, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Phone: 617-253-4223, Email: dbertsim@mit.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Imlifidase Inhibits HLA Antibody-Mediated NK Cell Activation and Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) In Vitro Background: Antibody-dependent cell-mediated cytotoxicity (ADCC) is an important pathway responsible for antibody-mediated rejection (AMR). Imlifidase (IdeS) cleaves human IgG into F(ab’)2 and Fc fragments, potentially inhibiting ADCC. Here we examined the effect of imlifidase on allo-antibody-mediated NK cell activation (Allo-CFC) and ADCC in vitro. Methods: For Allo-CFC, normal whole blood was incubated with third-party peripheral blood mononuclear cells (PBMCs) pretreated with anti-HLA antibody positive (HS) or negative (NC) sera to measure IFNγ+ NK cell%. For ADCC, normal PBMCs were incubated with Farage B cells (FB) with HS or NC sera to measure 7-AAD+ lysed FB cell%. To assess the effect of imlifidase on these assays, serum-treated PBMCs (Allo-CFC-1) and serum used for PBMC pretreatment (Allo-CFC-2) in Allo-CFC, and serum used for ADCC were preincubated with imlifidase. Sera from imlifidase-treated patients were also tested for Allo-CFC (Allo-CFC-3). Results: IFNγ+ NK cell% were significantly elevated in HS vs. NC sera in Allo-CFC-1 (10 ± 3% vs. 2 ± 1%, p=0.001), Allo-CFC-2 (20 ± 10% vs. 4 ± 2%, p=0.01) and 7AAD+ FB cell% (11 ± 3% vs. 4 ± 2%, p=0.02) in ADCC. These were significantly reduced by imlifidase treatment. Patient sera with significantly reduced anti-HLA antibody levels at 1 day postimlifidase lost the capacity to activate NK cells in Allo-CFC-3, but those at 1-3 months postimlifidase regained the capacity. Conclusions: Imlifidase inhibited NK cell activation and ADCC in vitro and in treated patients. These results and reported inhibition of complement activating anti-HLA antibodies by imlifidase suggest its possible role in treatment of AMR. Funding: No funding was received for this study. Correspondence: Shili Ge, PhD, MD, Transplant Immunology Laboratory , Comprehensive Transplant Center, Cedars-Sinai Medical Center, 8700 Beverly Blvd., SSB#336, Los Angeles, CA 90048, United States, Tel: 310-423-4975, FAX: 310-423-0268, E-mail: shili.ge@cshs.org Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

THE ASSOCIATION BETWEEN CYTOMEGALOVIRUS INFECTION AND CARDIAC ALLOGRAFT VASCULOPATHY IN THE ERA OF ANTIVIRAL VALGANCICLOVIR PROPHYLAXIS Background: Previous studies on the association between cytomegalovirus (CMV) infection and cardiac allograft vasculopathy (CAV) were conducted on patients transplanted in the pre valganciclovir (VGCV) prophylaxis era. The aim of our study is to evaluate this relation in heart transplantation (HTx) recipients treated according to current prophylactic and immunosuppressive regimens. Methods: This single-center retrospective study included all consecutive adult patients that underwent HTx between 1st Jan 2000 – 31st May 2018. Clinically relevant CMV infection was defined as either plasma CMV DNAemia≥1000 IU/ml with/without clinical symptoms or <1000 IU/ml with symptoms. The primary endpoint was first manifestation of CAV diagnosed by coronary angiography. For statistical analysis the cause-specific hazard regression model was applied, with clinically relevant CMV infection and any CMV infection as time-dependent variables. Results: In total, 260 patients were included in the analysis. The median (IQR) follow-up was 7.88 (4.21-12.04) years. During the follow-up, clinically relevant CMV infection was diagnosed in 96 (37%) patients and CAV in 149 (57%) patients. In the multivariate regression analysis, independent predictors of CAV were: number of rejection episodes (CSHR (95% CI): 1.18 [1.04-1.34], p=0.01), hypertension (1.61 [1.11-2.34], p=0.01), treatment with mycophenolate mofetil (0.68 [0.47-0.97], p= 0.03). No significant association was observed between CMV infection and CAV, except for patients who experienced a breakthrough CMV infection (n=24) during prophylaxis (1.94 [1.11- 3.40], p=0.02). Conclusion: In the era of contemporary immunosuppression and VGCV prophylaxis, a significant effect of CMV infection on the risk of CAV was seen only among HTx recipients with CMV breakthrough infection. Funding: No funding was received for this study. Conflict of interest: The authors declare no conflicts of interest Corresponding author: Olivier Manintveld, MD PhDa, Thorax Center, Room Rg-431, Erasmus MC, University Medical Center Rotterdam, Doctor Molewaterplein 40, 3015 GD Rotterdam, the Netherlands. Phone number: 0031-107035078, Email: o.manintveld@erasmusmc.nl 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.

Inducing transient mixed chimerism for allograft survival without maintenance immunosuppression with combined kidney and bone marrow transplantation: Protocol Optimization Background. Tolerance induction is an important goal in the field of organ transplantation. We have sequentially modified our conditioning regimen for induction of donor-specific tolerance in recipients of major histocompatibility complex (MHC)-mismatched combined kidney and bone marrow transplantation (CKBMT). Methods. From December 2011 to May 2017, eight MHC-mismatched patients received CKBMT. The initial conditioning regimen (Protocol 1) consisted of cyclophosphamide (CP), rituximab, antithymocyte globulin (rATG), and thymic irradiation. Tacrolimus and steroids were used for the maintenance of immunosuppression (IS). Results. This regimen was complicated by transient acute kidney injury which has been the major clinical feature of engraftment syndrome and side effects of CP, although one of two subjects successfully discontinued his IS for 14 months. The conditioning regimen was modified by reducing the CP dose and adding fludarabine (Protocol 2). The final modification was reducing the fludarabine and rATG doses (Protocol 3). Mixed chimerism, detected by the short-tandem repeat method, was achieved transiently in all subjects for 3-20 weeks. Among the three subjects treated with Protocol 2, IS was successfully discontinued for >35 months in one subject, but the other two subjects suffered from severe BK virus associated nephritis (BKVAN). All three subjects treated with Protocol 3 tolerated the protocol well and have successfully discontinued IS for >4-41 months. Interestingly, de novo DSA was not detected in any subject during all the follow-up periods. Conclusions. Our clinical trial has shown that long-term renal allograft survival without maintenance IS can be achieved by induction of mixed chimerism following CKBMT. Disclosure of potential Conflict of interest: The authors indicated no potential conflicts of interest. Funding: This work was supported by a grant from the Korean Health Technology R&D project, Ministry of Health and Welfare, Republic of Korea (HI13C1263). This work also supported by Samsung Medical Center grant (GFO0170041). Correspondence: Jae Berm Park, MD, PhD Professor Department of Surgery, Samsung Medical Center, Sunkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Korea Tel: +82-2-3410-3647; Fax: +82-2-3410-0400; E-mail: jbparkmd@gmail.com Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.