PCSK9 Inhibitor Use in Heart Transplant Recipients: A Case Series and Review of the Literature No abstract available

Constrictive Pericarditis after Lung Transplantation Background: Constrictive pericarditis is a rare, but increasingly recognized long-term post-operative complication of lung transplantation. Heightened clinical suspicion, improved diagnostic imaging and effective surgical treatment of the disease have led to progressive awareness of the pathology. We present our institutional experience with constrictive pericarditis after lung transplant in an effort to investigate the etiology and natural history of the disease. Methods: From October 2005 to October 2018, 1,234 patients underwent orthotopic lung transplantation at Duke University Hospital. An institutional database was queried to identify incident patients and determine baseline clinical data. At a median of 11.2 months (IQR 4.6-28.6 months), 10 patients (0.8%) developed constrictive pericarditis. Simple descriptive statistics were used to describe cohort characteristics and identify variables associated with constrictive pericarditis after lung transplantation. Results: The indication for transplantation at index operation was idiopathic pulmonary fibrosis in 8 of 10 patients (1.2% of the 760 restrictive lung disease patients transplanted in the same time period). All ten patients presented with worsening dyspnea and pleural effusions. Right heart catheterization confirmed constrictive physiology in all cases. Eight patients underwent pericardiectomy with improvement in cardiovascular hemodynamics and resolution of symptoms with no 30-day mortality. Conclusions: Diagnosis of constrictive pericarditis should be considered in patients with new onset heart failure symptoms and/or recurrent pleural effusions within 2 years of lung transplantation. Idiopathic pulmonary fibrosis may be associated with increased risk for constrictive pericarditis. Pericardiectomy is a safe and effective treatment for post-transplant constrictive pericarditis. Financial Disclosure: The authors declare no funding sources for this project. Conflict of Interest: The authors declare no conflicts of interest Corresponding Author: Charles M. Wojnarski, MD, Department of Surgery, Duke University Medical Center, Durham, NC 27705, USA. Email: charles.wojnarski@duke.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Alterations In NKG2A and NKG2C Subsets Of Natural Killer Cells following Epstein Barr Virus Reactivation In CTLA4Ig Based Haploidentical Transplantation Is Associated With Increased Chronic Graft-Versus-Host Disease Background: The impact of newer approaches to haploidentical transplantation on Epstein Barr virus (EBV) is largely unknown. Methods: We prospectively evaluated the incidence of EBV reactivation and its impact on transplantation outcomes in 71 patients undergoing haploidentical transplantation with post-transplantation cyclophosphamide (PTCy) in combination with CTLA4Ig based T-costimulation blockade (COSBL). Results: Eight patients developed EBV reactivation at a median of 96 days with no incidence of lymphoproliferative disorder (LPD). There was no impact of EBV reactivation on acute GVHD, non-relapse mortality, progression-free or overall survival. Despite an overall incidence of 19%, there was a significant increase in chronic GVHD following EBV reactivation (62.5% vs 8%, p=0.01). NKG2Apos subset of CD56dim NK cells increased substantially and persisted following EBV reactivation and chronic GVHD, with a reciprocal decrease in NKG2Cpos subset, whereas the reverse was witnessed in those without chronic GVHD (p< 0.01). Increase in NKG2Cpos subset and a decrease in the NKG2Apos subset was witnessed within 3 months of subsidence of chronic GVHD. Conclusion: Thus, CTLA4Ig based haploidentical transplantation was associated with a low incidence of EBV reactivation without EBV-LPD. However, EBV reactivation was associated with a sustained alteration in NKG2A and NKG2C subsets of CD56dim NK cells which might have a pathogenic role in chronic GVHD. Financial Disclosure: None Authorship Contribution: SRJ, and SC designed and performed the study. SRJ and PB performed the experiments. GB, HMA and PB collected the data and SRJ and SC analysed the data; SRJ, AC and SC wrote the manuscript. All the co-authors reviewed and approved the manuscript. Acknowledgments: We thank all the patients and family members who participated in this study. We also thank each and every member of our department for their help in patient care and execution of the study. Financial disclosure: The authors have no conflicts of interest to disclose. Funding: None to declare ADDRESS FOR CORRESPONDENCE: Sarita Rani Jaiswal, Program Director, Department of Blood and Marrow Transplantation & Hematology, Dharamshila Narayana Superspeciality Hospital and Research Centre, Vasundhara Enclave, New Delhi-110096, India. Email: drsaritaranij@gmail.com; Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Implications of NKG2A in EBV reactivation and chronic graft-versus-host disease following allogeneic hematopoietic stem cell transplantation No abstract available

Immunosuppression and Graft Rejection in Living-Related HLA-Identical Renal Transplantation: The RADOVFULL Study Purpose We aimed to describe the immunosuppressive regimens and graft rejection rates in living-related HLA-identical (LR HLAid) renal transplantation. Methods We performed a retrospective multicenter analysis of the French national database for LR HLAid renal transplantations performed between 2002 and 2012. Univariate and multivariate analysis were performed to determine risk factors for graft rejection in LR HLAid recipients. Results 27.218 renal transplantations were performed of whom 163 had a LR HLAid donor. Concerning immunosuppressive treatment, less than 60% of the cohort had induction therapy with polyclonal or monoclonal antibodies, 28% did not receive calcineurin inhibitors and 36% did not receive steroids in maintenance. Biopsy-proven acute rejection was diagnosed in 21 patients (12.9%). Rejection occurred on an average of 24 months after transplantation, in 28.5% of the cases after minimization of immunosuppression. Factors associated with rejection were age of recipient (OR = 0.91[0.84-0.96], p=0.003), the body mass index of donors (OR = 1.22[1.04-1.46], p=0.01) and minimization of immunosuppression (OR = 26.2[5.48-166.6], p < 0.001). Overall and graft survival rates were not statistically different according to rejection at 1, 5 and 10 years post transplantation. Conclusion Minimization of immunosuppression should be done with caution in LR HLAid renal transplantations. Disclosures The authors have no conflicts of interest to disclose relevant to the contents of this paper. Funding: The authors have received no financial support for the publication of this article. Corresponding author: Dr Rim OSSMAN, Urgences Néphrologiques et Transplantation Rénale – Hôpital Tenon – APHP, 4 rue de Chine, 75020 Paris, France. Phone: 33 6 73 32 99 91, Fax: 33 1 56 01 79 68, E-mail: rimossman@hotmail.com Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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.