The Importance of Prioritizing Pre and Post Transplant Immunizations in An Era of Vaccine Refusal and Epidemic Outbreaks Vaccine preventable infections are occurring at epidemic rates both nationally and internationally. At the same time, rates of vaccine hesitancy and refusal are increasing across the country leading to decreased herd immunity. For immunosuppressed transplant recipients, this situation poses great risk. Currently, one in six pediatric solid organ transplant recipients is hospitalized with a vaccine preventable infection in the first five-years post transplant. For many recipients, these infections result in significant morbidity, mortality and increased hospitalization costs. Surprisingly, despite this risk many transplant recipients are not up-to-date on age appropriate immunizations at the time of transplant and thereafter. As a transplant community, we must prioritize immunizations in both pre and post transplant care. Research is needed to understand how to monitor immune response to vaccines in immunosuppressed patients and when to optimally immunize patients post transplant. Finally, recommendations about administration of live vaccines post transplant may need to be re-evaluated in the setting of measles outbreaks and decreased herd immunity. Disclosures: The authors have no disclosures Funding: AF: Dr. Feldman was funded by a Children’s Hospital Colorado Research Institute Research Scholar Award, an NIH/NCATS Colorado CTSA KL2 TR002534, and an AHRQ K08 HS0265 10-01A1. Corresponding Author: Amy G. Feldman, MD MSCS, Assistant Professor of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition and the Digestive Health Institute, Adult and Child Consortium for Health Outcomes Research and Delivery Science, University of Colorado School of Medicine, Anschutz Medical Campus & Children’s Hospital Colorado, 13123 East 16th Avenue, B290, Aurora, CO 80045, Telephone: 720-777-6669 Fax: 720-777-7277 amy.feldman@childrenscolorado.org Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

High-Risk Corneal Transplantation: Recent Developments and Future Possibilities Human corneal transplantation (keratoplasty) is typically considered to have superior short- and long-term outcomes and lower requirement for immunosuppression compared to solid organ transplants because of the inherent immune privilege and tolerogenic mechanisms associated with the anterior segment of the eye. However, in a substantial proportion of corneal transplants, the rates of acute rejection and/or graft failure are comparable to or greater than those of the commonly transplanted solid organs. Critically, while registry data and observational studies have helped to identify factors that are associated with increased risk of corneal transplant failure, the extent to which these risk factors operate through enhancing immune-mediated rejection is less clear. In this overview, we summarize a range of important recent clinical and basic insights related to high-risk corneal transplantation, the factors associated with graft failure and the immunological basis of corneal allograft rejection. We highlight critical research areas from which continued progress is likely to drive improvements in the long-term survival of high-risk corneal transplants. These include further development and clinical testing of predictive risk scores and assays; greater use of multicenter clinical trials to optimize immunosuppressive therapy in high-risk recipients and robust clinical translation of novel, mechanistically-targeted immunomodulatory and regenerative therapies that are emerging from basic science laboratories. We also emphasize the relative lack of knowledge regarding transplant outcomes for infection-related corneal diseases that are common in the developing world and the potential for greater cross-pollination and synergy between corneal and solid organ transplant research communities. † Current Affiliation: Queensland Eye Institute, South Brisbane, Australia Disclosure: The authors of this manuscript have no conflicts of interest to disclose. Funding: The authors are supported by funding from the European Commission [EU FP7 Collaborative Health Project VISICORT (grant number 602470)] and by the European Regional Development Fund. MDG and TR are also supported by grants from Science Foundation Ireland [Principal Investigator Award to TR (grant number 12/IA/1624); REMEDI Strategic Research Cluster (grant number 09/SRC-B1794); CÚRAM Research Centre (grant number 13/RC/2073)]. Address for Correspondence: Prof. Matthew D Griffin, MB BCh, DMed; National University of Ireland, Galway; REMEDI, Biomedical Sciences; Corrib Village, Dangan; Galway; Ireland, H91 TK33. Email: matthew.griffin@nuigalway.ie 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.

Practical considerations for APOL1 genotyping in the living kidney donor evaluation Background: Association between the apolipoprotein L1 gene (APOL1) and nephropathy has altered the epidemiology of chronic kidney disease (CKD). In addition, donor APOL1 genotypes play important roles in the time to allograft failure in kidneys transplanted from deceased donors and the safety of living kidney donation. Methods: This manuscript reviews genetic testing for inherited kidney disease in living kidney donors to improve donor safety. APOL1 genotyping in donors with recent African ancestry is considered. Results: Based on current data, transplant physicians should discuss APOL1 genotyping with potential living kidney donors self-reporting recent African ancestry. Until results from APOL1 Long-term Kidney Transplant Outcomes Network (APOLLO) ancillary studies are available, we present practical approaches from our experience for considering APOL1 genotyping in the living donor evaluation. Conclusions: Transplant physicians should inform potential living kidney donors at-risk for APOL1-associated nephropathy about the gene and possibility of genetic testing early in the donor evaluation, well before scheduling the donor nephrectomy. Transplant programs must weigh risks of performing a donor nephrectomy in those with two APOL1 renal-risk variants (high-risk genotypes), particularly younger individuals. Our program counsels kidney donors with APOL1 high-risk genotypes in the same fashion as with risk genotypes in other nephropathy genes. Because most African American kidney donor candidates lacking hypertension, proteinuria and reduced kidney function after workup will not possess APOL1 high-risk genotypes, genetic testing is unlikely to markedly increase donor declines and may reassure donors with regard to their long-term kidney outcomes, potentially increasing the number of African American donors. * equal contributors Support: NIH grants R01 DK084149 (BIF), R01 DK070941 (BIF), R01 MD009055 (BIF), U01 DK116041 (BIF), U01 DK116040 (AMR) Financial Disclosures: Wake Forest University Health Sciences and Barry Freedman have rights to an issued US patent related to APOL1 genetic testing (www.apol1genetest.com). Dr. Freedman is a consultant for AstraZeneca and Renalytix AI. Other authors have no disclosures. Conflict of interest: The authors report no relevant conflicts of interest related to the preparation of this invited manuscript. Correspondence: Barry I. Freedman, MD, Section on Nephrology, Wake Forest School of Medicine, 1 Medical Center Boulevard, Winston-Salem, North Carolina, USA 27157-1053, Phone: 336-716-6461, Fax: 336-716-4318, Email: bfreedma@wakehealth.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Response to Bui et al, “Patient functional status at transplant and its impact on posttransplant survival of adult deceased-donor kidney recipients” No abstract available

Further Evidence that the Soluble Urokinase Plasminogen Activator Receptor Does Not Directly Injure Mice or Human Podocytes Background: The role of the soluble urokinase receptor (suPAR) in focal segmental glomerulosclerosis (FSGS) as the circulating factor or as a predictor of recurrence after transplantation remains controversial. Previously published studies in mice and isolated podocytes produced conflicting results on the effect of suPAR on podocyte injury, effacement of foot processes and proteinuria. These discordant results were in part due to diverse experimental designs and different strains of mice. The aim of our study was to determine the reasons for the inconsistencies of the previous studies results with suPAR by using uniform methods and studies in different strains of mice. Methods: We utilized a primary culture of human podocytes and two mouse models, the wild type (WT) and the uPAR KO (uPAR-/-), in an attempt to resolve the reported conflicting results. Results: In both wild-type and uPAR-/- mouse models, injection of recombinant uPAR, even at a high dose (100 μ g), did not induce proteinuria, effacement of podocytes or disruption of the cytoskeleton. Injection of suPAR resulted in its deposition exclusively in the glomerular endothelial cells and not in the podocytes of WT mice, and was not detected at the uPAR KO mice. Kidneys from patients with recurrent FSGS had negative immunostaining for uPAR. We also evaluated the effect of recombinant uPAR on primary culture of human podocytes. uPAR did not result in podocytes damage. Conclusions: suPAR by itself is not the cause for direct podocyte injury, in vitro or in vivo These findings suggest a more complex and still poorly understood role of suPAR in FSGS. Disclosure:Co-authors Vivek Abraham, Loan Miller, Andrew King are (or were) employees of AbbVie. We have no other conflicts of interest to disclose. Funding:This work was supported in part by AbbVie’s contribution of funding to the Study; NCI P41 CA196276 and a fellowship award to (EH) from Susan G. Komen (PDF15330246) made possible through funding from American Airlines.; National Cancer Institute Cancer Center Support Grant (5P30CA082103). In addition, the early stages of the study were supported by the UCSF-Pfizer Center for Therapeutic Innovation (CTI). Address correspondence to:. Dr. Flavio Vincenti: address: 505 Parnassus Ave San Francisco, CA 94131; phone: 415-353-8390; Fax: 415-353-8974; email: Flavio.Vincenti@ucsf.edu Dr. Charles Craik: address: 600 16th Street San Francisco CA 94158; phone: 415-476-8146; Fax: 415-502-8298; email: charles.craik@ucsf.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Long-term outcome of allogeneic hematopoietic stem cell transplantation from unrelated donor using tacrolimus/sirolimus-based GVHD prophylaxis: impact of HLA mismatch Background: While Tacrolimus/Sirolimus (T/S)-based graft-versus-host disease (GvHD) prophylaxis has been effective in preventing acute GvHD post hematopoietic cell transplantation (HCT), its efficacy and long-term outcome in matched (MUD) and mismatched unrelated donor (mMUD) setting is not well defined. Methods: Herein, we evaluated a consecutive case-series of 482 patients who underwent unrelated donor (URD) HCT (2005 – 2013) with T/S-based GvHD prophylaxis. Results: With a median follow-up of 6.2 years (range=2.4-11.3), the 5-year overall survival (OS) and relapse/progression-free survival were 47.5% (95%CI: 43.0-52.0) and 43.6% (95%CI: 39.1-48.1), respectively; and the 5-year cumulative incidence of non relapse mortality (NRM) and relapse were 24.9%, and 31.5%, respectively. In this cohort, mMUD was associated with worse OS (39.0% vs. 50.7% at 5 years, p=0.034), primarily due to greater risk of NRM (33.5% vs. 21.7%, p=0.038). While rates of relapse, acute (II-IV or III-IV) or chronic GvHD (limited or extensive) were not different, death caused by chronic GvHD (20.8% vs. 12.8%, p=0.022) and infection (33.0% vs. 18.1%, p<0.01) were significantly greater in mMUD. In multivariable analysis, high-risk disease (HR= 2.21, 95%CI: 1.16-4.23; p<0.01) and mMUD (HR=1.55, 95%CI:.1.15-2.08; p=0.004) were independent predictive factors for OS. Conclusions: T/S-based GvHD prophylaxis is an effective and acceptable GvHD prophylactic regimen. However, survival after mMUD remained poor, possibly related to the severity of chronic GvHD. Funding: This study was partially supported by NIH P30 CA033572 (Biostatistics Core). Conflict of Interest: Authors declare no conflict of interest. Corresponding author: Monzr M Al Malki, M.D. Assistant Clinical Professor, Department of Hematology/HCT, City of Hope, 1500 E. Duarte Road, Duarte, CA 91101, phone: 626-218-2405; fax: 626-218-6116, email: Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

AntagomiR-199a enhances the liver protective effect of hypoxia-preconditioned BM-MSCs in a rat model of reduced-size liver transplantation Background: Reduced-size liver transplantation was invented to overcome the shortage of donor livers; however, it has proven to be more susceptible to ischemia-reperfusion injury. Bone marrow derived mesenchymal stem cells (BM-MSCs) infusion has been shown to be protective following liver transplantation. Optimization of MSC infusion has been performed, among which hypoxia preconditioning and miRNA modulation have shown promise. MiR-199a inhibition was reported to induce angioneogenesis; however, whether mir-199a inhibition enhances the protective effect of BM-MSCs in liver transplantation remains unknown. In this study, we combined antagomiR-199a with hypoxia-preconditioned MSC infusion to discuss their effect and mechanism in a rat model of reduced-size liver transplantation. Methods: A reduced-size liver transplantation model was constructed and hypoxia-preconditioned MSCs (H-MSC) were intra-portally injected during operation. AgomiR-199a and antagomir-199a were injected through the caudal vein once a day after liver transplantation. The level of apoptosis and pro-inflammatory cytokines were measured An anti-VEGF antibody was injected to further explore the underlying mechanism. Results: AntagomiR-199a plus H-MSC not only significantly decreased ALT and AST 72 h after LT, but also ameliorated the level of apoptosis and inhibited inflammatory reactions. On the contrary, agomir-199a reduced the protective effect of the H-MSC infusion. In terms of mechanism, the liver protective effect of miR-199a inhibition was abolished by treatment with a VEGF neutralizing antibody. Conclusion: AntagomiR-199a enhanced the protective effect of H-MSCs infusion via activation of the Hif-1α/VEGF axis. Wichen Zhang and Qi Chen contributed equally to this work. Conflicts of interest: The authors declare no conflicts of interest. Correspondence: Zheng Shusen, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. (shusenzheng@zju.edu.cn); Yu Jun, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. (dryujun@zju.edu.cn). Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Graft Portal Vein Thrombosis Before Liver Transplant No abstract available

A virtual crossmatch based strategy facilitates sharing of deceased donor kidneys for highly sensitized recipients Background: It is estimated that 19.2% of kidneys exported for candidates with >98% Calculated Panel Reactive Antibodies (CPRA) are transplanted into unintended recipients, most commonly due to positive physical crossmatch (PXM). We describe the application of a virtual crossmatch (VXM) that has resulted in a very low rate of transplantation into unintended recipients. Methods: We performed a retrospective review of kidneys imported to our center to assess the reasons driving late reallocation based on the type of pretransplant crossmatch used for the intended recipient. Results: From December-2014 to October-2017, 254 kidneys were imported based on our assessment of a VXM. Of these, 215(84.6%) were transplanted without a pretransplant PXM. The remaining 39(15.4%) recipients required a PXM on admission using a new sample because they did not have an HLA antibody test within the preceding 3-months or because they had a recent blood-transfusion. 93% of the imported kidneys were transplanted into intended recipients. There were 18 late reallocations: 9(3.5%) due to identification of a new recipient medical problem upon admission, 5(2%) due to suboptimal organ quality on arrival, and only 4 (1.6%) due to a positive PXM or HLA antibody concern. 42% of the recipients of imported kidneys had a 100% CPRA. There were no hyperacute rejections, and very infrequent acute rejection in the first year suggesting immunologic memory. Conclusions: Seamless sharing is within reach, even when kidneys are shipped long distances for highly sensitized recipients. Late reallocations can be almost entirely avoided with a strategy that relies heavily on VXM. CONFLICT OF INTEREST. The authors declare no conflicts of interest. FINANCIAL DISCLOSURE. The authors declare that no financial support received to perform this study. DISCLOSURE: The authors of this manuscript have no conflicts of interest to disclose as described by Transplantation Corresponding author: Raja Rajalingam, PhD, UCSF Immunogenetics and Transplantation Laboratory, 3333 California Street, Suite 150, San Francisco, CA 94118, Rajalingam.Raja@ucsf.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Recipient Comorbidity and Survival Outcomes after Kidney Transplantation: a UK-wide Prospective Cohort Study Background: Comorbidity is increasingly common in kidney transplant recipients, yet the implications for transplant outcomes are not fully understood. We analysed the relationship between recipient comorbidity and survival outcomes in a UK-wide prospective cohort study – ATTOM. Methods: 2100 adult kidney transplant recipients were recruited from all 23 UK transplant centers between 2011-2013. Data on 15 comorbidities were collected at the time of transplantation. Multivariable Cox regression models were used to analyse the relationship between comorbidity and 2-year graft survival, patient survival and transplant survival (earliest of graft failure or patient death) for deceased-donor kidney transplant (DDKT) recipients (n=1288) and living-donor kidney transplant (LDKT) recipients (n=812). Results: For DDKT recipients, peripheral vascular disease (HR 3.04, 95%CI 1.37, 6.74, p=0.006) and obesity (HR 2.27, 95%CI 1.27, 4.06, p=0.006) were independent risk factors for graft loss, while heart failure (HR 3.77, 95%CI 1.79, 7.95, p=0.0005), cerebrovascular disease (HR 3.45, 95%CI 1.72, 6.92, p=0.0005) and chronic liver disease (HR 4.36, 95%CI 1.29, 14.71, p=0.018) were associated with an increased risk of mortality. For LDKT recipients, heart failure (HR 3.83, 95%CI 1.15, 12.81, p=0.029) and diabetes (HR 2.23, 95%CI 1.03, 4.81, p=0.042) were associated with poorer transplant survival. Conclusion: The key comorbidities that predict poorer 2-year survival outcomes after kidney transplantation have been identified in this large prospective cohort study. The findings will facilitate assessment of individual patient risks and evidence-based decision making. * Joint first authors Disclosure: All authors declared no conflicts of interests. Funding: This work is part of the Access to Transplantation and Transplant Outcome Measures (ATTOM) research programme funded by the National Institute for Health Research (grant number RP-PG-0109-10116). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The funding body had no role in study design, data collection, data analysis, data interpretation, writing of the manuscript or decision to submit for publication. Correspondence to: Gabriel C. Oniscu, Consultant Transplant Surgeon and Honorary Reader, Transplant Unit, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh, EH16 4SA, UK. Tel: 0044-1312421715, gabriel.oniscu@ed.ac.uk This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.