Transplantation

Visual Abstracts (#VisualAbstract): A New Journal Initiative to Disseminate Research No abstract available

Eculizumab as Primary Therapy for Active Antibody-Mediated Rejection of Renal Allografts: A Matter of Timing, Severity, and Donor-Specific Antibodies No abstract available

Ultrasound Molecular Imaging of Lymphocyte-endothelium Adhesion Cascade in Acute Cellular Rejection of Cardiac Allografts Background: Acute cellular rejection is one of the main reasons for graft failure after heart transplantation. A precise diagnosis at the early-stage of acute cellular rejection is a big challenge for clinicians. Given the importance of the interaction between T cells and graft endothelia in initiating rejection, we developed T cell-microbubble complexes (cell-MBs) as ultrasound molecular imaging probes to monitor the lymphocyte-endothelium adhesion cascade in cardiac acute cellular rejection. Methods: Cell-MBs were fabricated by incubating lymphocytes with anti-CD4 antibody-conjugated microbubbles (MBCD4). The potential of cell-MBs as probes for detecting acute cardiac rejection was examined. Donor hearts from Brown Norway or Lewis rats were transplanted into Lewis recipients. Ultrasound molecular imaging was performed on allografts of untreated or cyclosporin A (CsA)-treated recipients, and isografts on post transplantation day 3. Histology was used to assess rejection grades. Results: We detected a significantly stronger ultrasound molecular imaging signal of cell-MBs than that of MBCD4 or plain MBs in allografts of untreated and CsA-treated recipients. No signal enhancement was observed in isografts with cell-MBs. The signal of cell-MBs in allografts of the untreated group was significantly higher than that in the CsA-treated group, and the signal in the CsA-treated group was higher than that in isografts. Histology confirmed grade 3R rejection in the untreated group, grade 2R rejection in CsA-treated group, and no rejection in isografts. Conclusions: Our study suggests that cell-MBs can function as a promising probe to image the dynamic lymphocyte-endothelium adhesion cascade for noninvasive diagnosis of cardiac acute cellular rejection. Disclosure: The authors declare no conflicts of interest. Funding: This work was supported by National Natural Science Foundation of China (Grant No. 81530056, 81727805, 81571701, 11325420, 11534013, 81527901), Natural Science Foundation of Guangdong Province (Grant No. 2014A030312006), and Shenzhen Science and Technology Innovation Committee (Grant No. JCYJ20170413100222613, JCYJ20170307165254568). Corresponding Authors: Mingxing Xie, PhD, 1277 Jeifang Avenue, Wuhan 430022, China. E-mail: xiemx@hust.edu.cn; Telephone: +86 27 85726386 Fei Yan, PhD, 1068 Xueyuan Avenue, Shenzhen University Town, Shenzhen 518055, China. E-mail: fei.yan@siat.ac.cn; Telephone: +86 755 86392284, Fax: +86 755 96382299. 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.

Aerosolization of second-generation triazoles: In vitro evaluation and application in therapy of invasive airway aspergillosis Background: A lung transplant patient with Invasive aspergillosis (IA) manifested symptoms of voriconazole induced transaminitis with systemic voriconazole and progression of IA after switching to oral posaconazole. With limited options for standard triazole therapy, aerosolized delivery with one of second generation triazoles was considered. Methods: Feasibility for aerosolized delivery was evaluated using cascade impactor and analysis of physicochemical characteristics of voriconazole (10 mg/mL) and posaconazole (6, 12 mg/mL) solutions. Results: Both triazoles showed favorable characteristics for aerosol delivery with mass median aerodynamic diameter, geometric standard deviation, respirable fraction (< 5.4 µm) of (2.8 µm, 2.0, 86%), (3.4 µm, 2.4, 78%) and (3.0 µm, 2.3, 79%) for voriconazole and 6, 12 mg/mL of posaconazole, respectively. The fumigatus isolate from patient was more susceptible to voriconazole, hence, aerosolized voriconazole was introduced around the 3rd month post transplant at 40 mg thrice daily for 1 week, 40 mg twice daily for 1 week, followed by 40 mg daily, thereafter, along with intravenous caspofungin (50 mg/day) and liposomal amphotericin B (300 mg/day). The aerosol regimen was well tolerated by patient with undetectable trough plasma levels of voriconazole. Bronchoscopy at 4th month, revealed improvement in anastomotic plaques with reduction in BAL galactomannan values (7.48 to 2.15 ng/mL). This consolidated aerosolized and intravenous regimen was maintained until 2.97 years post transplant. Conclusions: The intravenous solutions of both second generation triazoles showed characteristics that were suitable for aerosol delivery. Our report further adds to the therapeutic experience with use of aerosolized voriconazole for IA in a lung transplant patient. Disclosure:The authors declare no conflicts of interest. Funding:The authors declare no funding for this work. Corresponding author: Raman Venkataramanan, Professor of Pharmaceutical Sciences, Room 4103, University of Pittsburgh, 700 Technology drive, Pittsburgh Technology Center, Pittsburgh, PA 15219, Phone:412-648-8547, Fax:412-648-7671, Email: rv@pitt.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

TUBULAR ECTASIA IN RENAL ALLOGRAFT BIOPSY- ASSOCIATIONS WITH OCCULT OBSTRUCTIVE UROLOGICAL COMPLICATIONS Background: Urological obstructive complications (UOC) affect up to 15% of kidney transplants (KTX). Most cases are excluded by ultrasound (US), however accuracy may be limited in the early transplant phase. Features of acute tubular injury (ATI) in KTX biopsy may be informative, but histological features indicating UOC are ill defined. Tubular ectasia (TE) was shown to be associated with UOC in experimental data. We evaluated the association of histomorphological features, particularly TE, with occult (=without relevant hydronephrosis in US) UOC and renal outcomes. Methods: We included all recipients with early indication biopsy (976 of 1537 consecutive KTX). The biopsy finding of TE classified “suspicious of UOC” was compared to following endpoints: delayed graft function (DGF), eGFR and occult UOC. Additionally histopathological features of ATI were reevaluated by a single pathologist to increase diagnostic accuracy. Results: Fifty eight (5.9%) patients presented with TE, which was not related to DGF or eGFR. Forty % had a UOC, (most frequently ureteral stenosis) close to biopsy. Comparing these biopsies to matched controls, TE was significantly associated with UOC, [OR 2.69, p = 0.018]. After histopathological reevaluation of these biopsies including additional features of ATI we developed a final multivariate model with a highly significant relationship to UOC (ROC–AUC: 0.77, p=0.001). The model provides a specificity 78% and NPV: 73%. Conclusions: TE together with additional signs of ATI indicates occult UOC. This histological phenotype should trigger more detailed evaluation for UOC when there is no evidence of relevant hydronephrosis in the ultrasound. Author responsibilities: ZK, MB, HR, CS and HH participated in research design, data acquisition and analysis and writing of the paper. GB, CB, JK participated in data acquisition and analysis and writing of the paper Disclosure declaration: The authors declare no funding or conflicts of interest. DISCLOSURE: The authors have nothing to disclose Address correspondence to: Željko Kikić, M.D., Division of Nephrology and Dialysis, Department of Medicine III , Medical University Vienna. Währinger Gürtel 18-20, A-1090 Vienna, Austria. Phone: +43-1-40400-43910; Fax: +43-1-40400-43920, E-mail: zeljko.kikic@meduniwien.ac.at Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Favorable Outcome of Lung Transplantation for Severe Pulmonary Graft-Versus-Host-Disease: An Australian Multicenter Case Series Background: Severe pulmonary chronic graft-versus-host disease (cGVHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplant (alloSCT). Few treatments influence outcome, with 5-year overall survival (OS) as low as 13%. Lung transplantation (LTx) has been reported in small numbers of patients worldwide. Methods: We investigated the outcomes of LTx performed for this indication at two large Australian LTx centres. Results Eighteen patients (ages 10-64, median 29.6 years) received bilateral deceased lung transplants for pulmonary cGVHD between 2002-2017. LTx were performed at a median of 8.6 years post alloSCT (range 2-23) with a median interval of 16 months from time of transplant unit review to LTx. There were two early infective deaths and three further deaths from pulmonary infection and lung allograft rejection. There were no primary disease relapses. At a median follow up of 5 years the five-year OS post LTX is 80% and comparable to the Australia and New Zealand registry data of 64% for LTx performed for all indications. Conclusions: From one of the largest series of deceased LTx for this indication, we conclude that it is a feasible option for selected patients with severe pulmonary GVHD. The outcomes appear superior to that of non-LTx based therapies and similar to the survival of the general LTx population. Establishing guidance on referral triggers, patient eligibility, organ selection, prophylaxis of allograft rejection and supportive care would assist hematopoietic and lung transplant units in optimizing resource allocation and patient outcomes. * Current address: Department of Haematology, The Alfred Hospital, Melbourne, Australia Disclosure: The authors declare no conflicts of interest Funding: None to declare Correspondence: David D.F. Ma, Department of Haematology and BMT, St Vincent’s Hospital Sydney, 370 Victoria Street, Darlinghurst, NSW 2010, Australia. Email: a.lafferty@amr.org.au Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Improved survival in liver transplant patients receiving prolonged-release tacrolimus-based immunosuppression in the European Liver Transplant Registry (ELTR): an extension study. Background: We compare, through the European Liver Transplant Registry, long-term liver transplantation outcomes with prolonged-release tacrolimus (PR-T) versus immediate-release-tacrolimus (IR-T)-based immunosuppression. This retrospective analysis comprises up to 8-year data collected 2008–2016, in an extension of our previously-published study. Methods: Patients with <1 month follow-up were excluded; patients were propensity score-matched for baseline characteristics. Efficacy measures included: univariate/multivariate analyses of risk factors influencing graft/patient survival up to 8-years post transplantation; graft/patient survival up to 4 years with PR-T versus IR-T. Overall, 13,088 patients were included from 44 European centers; propensity-score-matched analyses comprised 3006 patients (PR-T: n=1002; IR-T: n=2004). Results: In multivariate analyses, IR-T-based immunosuppression was associated with reduced graft survival (risk-ratio: 1.49; p=0.0038) and patient survival (risk-ratio: 1.40; p=0.0215). There was improvement with PR-T versus IR-T in graft survival (83% vs 77% at 4 years, respectively; p=0.005) and patient survival (85% vs 80%; p=0.017). Patients converted from IR-T to PR-T after 1 month had a higher graft survival rate versus patients receiving IR-T at last follow-up (p<0.001), or started and maintained on PR-T (p=0.019). One graft loss in 4 years was avoided for every 14.3 patients treated with PR-T versus IR-T. Conclusion: PR-T-based immunosuppression might improve long-term outcomes in liver transplant recipients versus IR-T. Disclosure: R. Adam, V. Karam, V. Cailliez, G. Tisone, O. Soubrane, B. Gridelli, P. D. Line, M. Rossi, J. Pirenne, O. O. Rummo, F. Di Benedetto, K. Zieniewicz, R. Troisi, A. Paul, T. Vali, O. Kollmar, K. Boudjema, J. Pratschke, J. Gugenheim, A. D. Pinna, W. Bennet, P. Bachellier, S. J. Wigmore, A. Rasmussen, P. A. Clavien, E. Hidalgo, and F. Zamboni declare no conflict of interests with respect to this manuscript. P. Trunečka has received speaker honorarium from Pfizer and has been involved in advisory boards and received consultancy agreements from Astellas. D. Samuel has received consultant fees from Astellas, Novartis and Roche. P. Němec has received speaker honoraria from Astellas and Novartis. W. O. Bechstein has received honoraria and served on advisory boards for Astellas. M. Vivarelli has received honorarium for an advisory board for Novartis. J. Klempnauer has received support from Astellas, Novartis, Roche, BMS and Genzyme. M. Colledan has received honorarium for an advisory board for Novartis. B. G. Ericzon has received speaker honorarium from Pfizer, Astellas and Novartis. P. De Simone has received speaker fees and served as an advisory board member for Astellas. C. Duvoux has received grants from Astellas, grants from Novartis, grants and other from Chiesi, personal fees from Sandoz, and non financial support from Biotest. Fundings: The ELTR is supported by a grant from Astellas, Novartis, and Institut Georges Lopez, and logistic support from the Paul Brousse Hospital (Assistance Publique – Hôpitaux de Paris). Correspondence information: Prof. René Adam, Centre Hépatobiliaire, Hôpital Paul Brousse, Avenue Paul Vaillant Couturier, 94804 Villejuif, France. rene.adam@aphp.fr Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Impact of Rural Residence on Kidney Transplant Rates Among Waitlisted Candidates in the VA Transplant Programs Background: Although proportionally more veterans live in rural areas compared to non-veterans, the impact of rurality status on kidney transplantation (KTP) access among veterans is unknown. Our objective was to study KTP rates among veterans listed for KTP, and to compare the impact of rurality status on KTP rates among veterans and non-veterans. Methods: Retrospective cohort study of adult patients waitlisted per the United Network for Organ Sharing (UNOS) from January 2000 to December 2014. Patient characteristics were compared using chi-square or t-tests, as appropriate, by veteran status and patient rurality. Multivariable competing risks Cox regression was performed. Results: The study sample included 3,281 veterans receiving care in Veteran Health Administration (VHA) transplant programs and 445,177 non-veterans. Veterans, compared to non-veterans, were older (57 vs 50 years; p<0.001), more likely to be male (96% vs 60%; p<0.001) or diabetic at waitlisting (51% vs. 41%; p<0.001), and less likely be an urban resident (79% vs. 84%; p<0.001). Among veterans, dialysis duration prior to registration was longer among urban compared to all other rurality types (810 ± 22.1 days vs. 632-702 ± 41.6-77.6 days; p=0.02). In multivariate competing risks models, there was no evidence that the hazard of transplant among veterans differs by residential rurality. Conclusions: Among waitlisted veterans served by VHA transplant programs, residential rurality status does not portend longer waiting time for KTP. Disclosure: The authors declare no conflicts of interest Funding: Veterans Administration Rural Health Center-Central Region Corresponding author: Roberto S. Kalil, MD, e-mail: rkalil@som.umaryland.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Efficacy and Safety of a Weight-Based Dosing Regimen of Valganciclovir for Cytomegalovirus Prophylaxis in Pediatric Solid Organ Transplant Recipients Background: Valganciclovir has been widely used for cytomegalovirus (CMV) prophylaxis in solid-organ transplant recipients. However, the optimal dosing protocol and target exposure in children is still unclear. Specific data as to the efficacy and safety of low dose/low exposure regimens are lacking and urgently needed. Methods: During 2010-2015, the clinical efficacy and safety of a weight-based regimen of valganciclovir 17mg/kg/day, with a stratified dose reduction for impaired creatinine clearance, given as a CMV prophylaxis for 3-6 months, was retrospectively evaluated amongst pediatric kidney and liver transplant recipients, 12 months post-transplantation. Incidence of CMV infection was assessed by periodic measurements of viral load; adverse events were evaluated. Results: Eighty-three children who had undergone 86 transplantations and were treated with 17 mg/mg valganciclovir, were included. Median age was 9.77 years (range 0.6-18.9). Twelve (14%) developed CMV infection; one during prophylaxis and 11 during follow-up. These events comprised six cases of asymptomatic viremia and six cases of a clinically significant disease, without occurrences of tissue-invasive disease. Treatment-related adverse effects occurred in 7 patients (8%), mostly hematological, resulting in premature drug cessation. Conclusions: Our results support the use of 17mg/kg valganciclovir for CMV prophylaxis in liver and kidney transplanted children as it showed satisfactory long-term efficacy and a good safety profile. Financial disclosure: None. Conflicts of interest: The authors declare no conflicts of interest. Corresponding Author: Liat Ashkenazi-Hoffnung, MD, Infectious Diseases Unit, Schneider Children’s Medical Center of Israel, 14 Kaplan Street, Petah Tiqva 49202, Israel. Phone: +972-3-925 3681; Fax: +972-3-925-3257. Email: ashkenazi.liat@gmail.com Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Lung Density Analysis Using Quantitative Chest CT for Early Prediction of Chronic Lung Allograft Dysfunction Background: Chronic lung allograft dysfunction (CLAD) limits long-term survival following lung transplantation (LTx). Early detection or prediction of CLAD can lead to changes in patient management that, in turn, may improve prognosis. The purpose of this study was to investigate the utility of quantitative computed tomography (CT) lung density analysis in early prediction of CLAD. Methods: This retrospective cohort was drawn from all consecutive adult, first, LTxs performed between 2006 and 2011. Post-transplant monitoring included scheduled surveillance bronchoscopies with concurrent pulmonary-functions tests and low-dose chest CT. Quantitative density metrics (QDM) derived from CT scans obtained at the time of 10-19% decline in Forced Expiratory Volume in 1 second (FEV1) were evaluated. 14 bilateral LTx recipients (66 with CLAD and 48 Stable) and 23 single LTx recipients (11 with CLAD, 12 Stable) were included in the analysis. Results: In both single and double LTx, at the time of 10-19% drop in FEV1 from baseline, the QDM was higher in patients who developed CLAD within 3 years compared to those patients who remained stable for at least 3.5 years. The area under the receiver operating characteristic curve (AUC) was 0.89 for predicting CLAD in single LTx and 0.63 in bilateral LTx. A multi predictor AUC accounting for FEV1, QDM, presence of consolidation, and ground glass opacities, increased the AUC to 0.74 in double LTx. Conclusions: QDM derived from a CT histogram at the time of early drop in FEV1 may allow prediction of CLAD in patients after single or double LTx. M.H. designed the study, analyzed the data, and wrote the manuscript. L.L. collected clinical data and edited the manuscript. C.H., C.B., S.S. performed analysis of CT scan data. P.S. performed statistical analysis. T.S., S.K., N.P., K.Y., K.B., M.P. contributed to supervision, experimental design and interpretation of results. T.M. designed and supervised the study, collected and analyzed data, and wrote the manuscript. The authors have no conflicts of interest to disclose. T.S. was supported by research fellowships from the Japan Society for Promotion of Science for Young Scientists. N.P. and M.H. were supported by educational grants from Canon Medical Systems. P.S. is an employee of Vital Images. Canon Medical Systems and Vital Images did not participate in study design, result interpretation, or manuscript preparation. Parts of this article were presented at the annual meeting of the Radiological Society of North America in December 2017. Disclosure statement: The authors have no conflicts of interest to disclose. N.P. has received research grants from Canon Medical Systems. T.S. is supported by research fellowships from the Japan Society for Promotion of Science for Young Scientists. P.S. is an employee at Vital Images. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.