Transplantation

Clinical Profile and Outcome of COVID-19 in 250 Kidney Transplant Recipients: a Multicenter Cohort Study From India Background: There is scarcity of data on the consequences coronavirus 19 (COVID-19) infections in kidney transplant recipients (KTR) from emerging countries. Methods: Here, we present a cohort study of 13 transplant centers in India including 250 KTR (226 living and 24 deceased donor) with PCR confirmed COVID-19 positivity from March 23, 2020 until September 15, 2020. We detailed demographics, immunosuppression regimen, clinical profile, treatment and outcomes. Results: Median age of transplant recipients was 43 years and recipients presented at a median of 3.5 years after transplant. Most common comorbidities (94%) included arterial hypertension (84%), diabetes (32%); presenting symptoms at the time of COVID-19 included fever (88%), cough (72%) and sputum production (52%). Clinical severity ranged from asymptomatic (6%), mild (60%), moderate (20%) to severe (14%). Strategies to modify immunosuppressants included discontinuation of antimetabolites without changes in calcineurin inhibitors and steroids (60%). Risk factors for mortality included older age, dyspnoea, severe disease, obesity, allograft dysfunction prior to COVID-19 infection, acute kidney injury (AKI) , higher levels of inflammatory markers including C reactive protein, IL6 level, procalcitonin, chest XR abnormality, and ICU/ventilator requirements. Overall patient mortality was 11.6%(29/250), 14.5%(29/200) in hospitalized patients, 47%(25/53) in ICU patients and 96.7%(29/30) in patients requiring ventilation. KTR with mild COVID-19 symptoms(n=50) were managed as outpatients to optimize the utilization of scarce resources during the COVID-19 pandemic. Conclusions: Mortality rates in COVID-19 positive KTR appears to be higher than those in nonimmunosuppressed patients and high mortality was noted among those requiring intensive care and those on ventilator. Disclosure: The authors of this manuscript have no conflicts of interest to disclose Financial Disclosure: The authors declare no funding was received for this study. Correspondence: Vivek Kute, MD, FCPS, DM Nephrology, FASN, FISOT, FISN, FRCP (London) Professor Nephrology and Transplantation Institute of Kidney Diseases and Research Center and Dr. H L Trivedi Institute of Transplantation Sciences,(IKDRC-ITS) Ahmedabad India, Secretary, Indian society of Organ Transplantation (ISOT). Phone: +919099927543. Email: drvivekkute@rediffmail.com. Website: www.ikdrc-its.org. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Pathways to Clinical Cardiac Xenotransplantation Heart transplantation is the only long-lasting life-saving option for patients with terminal cardiac failure. The number of available human organs is however far below the actual need, resulting in substantial mortality of patients while waiting for a human heart. Mechanical assist devices are used to support cardiac function, but are associated with a high risk of severe complications and poor quality of life for the patients. Consistent success in orthotopic transplantation of genetically modified pig hearts into baboons indicates that cardiac xenotransplantation may become a clinically applicable option for heart failure patients who cannot get a human heart transplant. In this overview, we project potential paths to clinical cardiac xenotransplantation, including the choice of genetically modified source pigs, associated requirements of microbiological, including virological, safety, optimized matching of source pig and recipient, and specific treatments of the donor heart after explantation and of the recipients. Moreover, selection of patients and the regulatory framework will be discussed. Disclosure: The authors declare no conflicts of interest. Funding: Our studies are supported by the Deutsche Forschungsgemeinschaft (TRR127 Biology of xenogeneic cell tissue and organ transplantation – from bench to bedside; to B.R., M.L., J.D., R.S., and E.W.) and by the German Center for Diabetes Research (DZD; to E.W.). P.J.C. received a fellowship of the Center for Advanced Studies (CAS) of LMU Munich. Correspondence: Bruno Reichart, MD, Walter Brendel Center for Experimental Medicine, LMU Munich, Marchioninistr. 27, 81377 Munich, Germany Phone: +49-89-4400-73727 Email: bruno.reichart@med.uni-muenchen.de Eckhard Wolf, DVM, Gene Center, LMU Munich, Feodor-Lynen-Str. 25, 81377Munich,Germany Phone: +49-89-2180-76800 Email: ewolf@genzentrum.lmu.de Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Sex-Based Disparities in Hepatocellular Carcinoma Recurrence After Liver Transplantation Background: Women with chronic liver disease have lower rates of hepatocellular carcinoma (HCC) as compared to men; it is unknown if there are sex-based differences in HCC recurrence post-liver transplant. Methods: We conducted an analysis of patients who underwent liver transplant for HCC in the United Network for Organ Sharing/Organ Procurement and Transplantation Network from January 1, 2012 through December 31, 2017. Results: A total of 12,711 patients underwent liver transplant for HCC: 2,909 (23%) women and 9,802 (73%) men. Women had significantly lower rates of post-liver transplant HCC recurrence than men (4.0 v. 5.4%, p=0.002). A cox-regression analysis for post-liver transplant HCC recurrence highlighted that even after accounting for etiology of cirrhosis, alpha-fetoprotein (AFP) at liver transplant, tumor diameter, tumor pathology, and vascular invasion, female sex was associated with a 25% lower risk of post-liver transplant HCC recurrence (95CI 0.57–0.99). There were no interactions between female sex and the following variables: age, type of locoregional therapy, AFP, donor sex, body mass index, or nonalcoholic steatohepatitis etiology (p>0.05 for each). Conclusions: This study demonstrates an independent effect of sex on risk for HCC recurrence post-liver transplant. Our data highlight an opportunity to better understand HCC tumor biology by investigating the drivers of this sex-based difference in HCC recurrence. Financial Support: This study was funded by NIA Research Project Grant (R01AG059183; Lai), K23AG048337 (Paul B. Beeson Career Development Award in Aging Research; Lai) and by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (T32 DK060414; Cullaro), all of which played no role in the analysis of the data or the preparation of this manuscript Disclosures: The authors have no conflicts of interest to disclose. Correspondence: Jennifer C. Lai, MD, MBA 513 Parnassus Avenue, UCSF Box 0538 San Francisco, CA 94143 Telephone: 415-476-2777 Fax: 415-476-0659 E-mail: Jennifer.Lai@ucsf.edu Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Fluid Management During Kidney Transplantation: A Consensus Statement of the Committee on Transplant Anesthesia of the American Society of Anesthesiologists Background: Intraoperative fluid management may affect outcome after kidney transplantation. However, the amount and type of fluid administered, and monitoring techniques vary greatly between institutions and there are limited prospective randomized trials and meta-analyses to guide fluid management in kidney transplant recipients. Methods: Members of the American Society of Anesthesiologists (ASA) committee on transplantation reviewed the current literature on the amount and type of fluids (albumin, starches, 0.9% saline and balanced crystalloid solutions) administered and the different monitors used to assess fluid status, resulting in this consensus statement with recommendations based on the best available evidence. Results: Review of the current literature suggests that starch solutions are associated with increased risk of renal injury in randomized trials and should be avoided in kidney donors and recipients. There is no evidence supporting the routine use of albumin solutions in kidney transplants. Balanced crystalloid solutions such as Lactated Ringer are associated with less acidosis and may lead to less hyperkalemia than 0.9% saline solutions. Central venous pressure is only weakly supported as tool to assess fluid status. Conclusion: These recommendations may be useful to anesthesiologists making fluid management decisions during kidney transplantation and facilitate future research on this topic. Financial Disclosure: Support was provided solely from institutional and/or departmental sources Disclaimer: NONE. Correspondence:Gebhard Wagener, MD Professor of Anesthesiology at CUMC Department of Anesthesiology, Columbia University P&S Box 46 (PH-5)630 West 168th Street New York, NY 10032-3784 Tel: (212) 305-6494 (Office) Fax: (212) 305-2182 Email: gw72@cumc.columbia.edu Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

A Comprehensive Evaluation of Risk Factors for Pneumocystis Jirovecii Pneumonia in Adult Solid Organ Transplant Recipients: a Systematic Review and Meta-Analysis Background: There is no consensus guidance on when to reinitiate Pneumocystis jirovecii pneumonia (PJP) prophylaxis in solid organ transplant (SOT) recipients at increased risk. The 2019 American Society of Transplantation Infectious Diseases Community of Practice (AST IDCOP) guidelines suggested to continue or reinstitute PJP prophylaxis in those receiving intensified immunosuppression for graft rejection, CMV infection, higher dose of corticosteroids, or prolonged neutropenia. Methods: A literature search was conducted evaluating all literature from existence through April 22, 2020 using MEDLINE and EMBASE. (PROSPERO: CRD42019134204) Results: A total of 30 studies with 413 276 SOT recipients were included. The following factors were associated with PJP development: acute rejection (pooled odds ratio (pOR) = 2.35 (1.69, 3.26), study heterogeneity index (I2)= 23.4%), cytomegalovirus (CMV)-related illnesses (pOR = 3.14 (2.30, 4.29), I2=48%), absolute lymphocyte count < 500 cells/mm3 (pOR = 6.29[3.56, 11.13], I2 0%), BK-related diseases (pOR = 2.59[1.22, 5.49], I2 0%), HLA mismatch ≥ 3 (pOR = 1.83 [1.06, 3.17], I2= 0%), rituximab use (pOR =3.03 (1.82, 5.04); I2 =0%) and polyclonal antibodies use for rejection (pOR = 3.92 [1.87, 8.19], I2= 0%). On the other hand, sex, CMV mismatch, interleukin-2 inhibitors, corticosteroids for rejection, and plasmapheresis were not associated with developing PJP. Conclusion: PJP prophylaxis should be considered in SOT recipients with lymphopenia, BK-related infections and rituximab exposure in addition to the previously mentioned risk factors in the AST IDCOP guidelines. Correspondence: Nitipong Permpalung, MD, MPH E-mail: npermpa1@jhmi.edu Address: 601 N Wolfe Street, Carnegie Building #340, Baltimore, MD 21287; Tel: 443-287-6217; Fax: 410-955-0788 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Early Signs of Sinoatrial Reinnervation in the Transplanted Heart Background: Heart transplantation (HTx) surgically transects all connections to the heart, including the autonomic nerves. We prospectively examined signs, timing and consequences of early sympathetic and parasympathetic sinoatrial reinnervation, as well as explored indirect evidence of afferent cardiopulmonary reinnervation. Methods: Fifty HTx recipients were assessed at 2.5, 6 and 12 months after HTx. For comparison, 50 healthy controls were examined once. Continuous, noninvasive recordings of hemodynamic variables and heart rate variability indices were carried out at supine rest, 0.2 Hz controlled breathing, 60 degrees head-up-tilt, during the Valsalva maneuver and during handgrip isometric exercise. Results: In HTx recipients, supine low-frequency heart rate variability gradually increased; supine high-frequency variability did not change; heart rate variability indices during controlled breathing remained unaltered; heart rate responses during tilt and isometric exercise gradually increased; the tachycardia response during Valsalva maneuver increased while the bradycardia response remained unchanged; and indices of baroreflex sensitivity improved. Responses remained low compared to healthy controls. A negative correlation between indices of preload and heart rate response during head-up tilt emerged at 12 months. Conclusions: Results suggest that sympathetic reinnervation of the sinoatrial node starts within 6 months after HTx and strengthens during the first year. No evidence of early parasympathetic reinnervation was found. Indirect signs of afferent reinnervation of cardiopulmonary low-pressure baroreceptors emerged at 12 months. Better sympathetic sinoatrial control improved heart rate responsiveness to orthostatic challenge and isometric exercise, as well as heart rate buffering of blood pressure fluctuations. Financial Disclosure This study was founded by the Health South–East Hospital Trust, Norway. Data availability The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Clinical trial notation: Autonomic Cardiovascular Control after Heart Transplantation (AccHEART), Clinical Trials ID: NCT01759966. Correspondence Anders Haugom Christensen, Dept. of Pediatric Cardiology, Oslo University Hospital, Rikshospitalet, N-0372, Oslo, Norway. Cell phone + 47 99 61 99 06. E-mail: a.h.christens1@gmail.com. Twitter: @AndersHaugom. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Pneumocystis jirovecii: the Changing Landscape for Prophylaxis No abstract available

Urine the Right Direction: The Consensus Statement from the Committee on Transplant Anesthesia of the American Society of Anesthesiologists on Fluid Management During Kidney Transplantation No abstract available

Uterine Transplantation; Review of Livebirths and Reproductive Implications Uterine transplantation (UTx) is a fertility restoring treatment for women with absolute uterine factor infertility. At a time when there is no question of the procedure's feasibility, and as the number of livebirths begins to increase exponentially, various important reproductive, fetal and maternal medicine implications have emerged. Detailed outcomes from 17 livebirths following UTx are now available, which are reviewed herein, along with contextualized extrapolation from pregnancy outcomes in other solid organ transplants. Differences in recipient demographics and reproductive aspirations between UTx and other transplant recipients make extrapolating management strategies and outcomes in other solid organ transplants inappropriate. Whereas preterm delivery remains prominent, small for gestational age or hypertensive disorders do not appear to be as prevalent following UTx when compared to other solid organ transplants. Given the primary objective of undertaking UTx is to achieve a livebirth, publication of reproductive outcomes is essential at this early stage, to reflect upon and optimize the management of future cases. Financial Disclosure: None Disclaimer: The authors report no conflict of interest Correspondence: Mr Benjamin P Jones MBChB BSc (Hons) MRCOG epartment of Surgery and Cancer, Imperial College London, London W12 0NN, United Kingdom. Telephone: 07740358900. E-mail: Benjamin.jones@nhs.net Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Chronic Histologic Changes Are Present Regardless of HLA Mismatches: Evidence from HLA Identical Living Donor Kidney Transplants Background: At 5 and 10 years after kidney transplantation, chronic histologic changes such as arteriolar hyalinosis and mesangial expansion are common, however, determining etiology is difficult. We compared surveillance biopsies in living donor kidney transplants (LDKTx) from HLA matched siblings (termed HLA-identical (HLA-ID)) to HLA non-ID to investigate which histologic changes were likely due to alloimmune injury and which were due to non-alloimmune injury. Methods: We performed a retrospective, cohort study comparing HLA-ID sibling LDKTx (n=175) to HLA non-ID LDKTx (n=175; matched for age, sex and year of transplant +/- 2 years) performed at a single institution from 03/1999 to 11/2018. Results: Baseline characteristics and maintenance immunosuppression were similar. Mortality rates were similar, but in the HLA-ID group, 10-year death-censored graft survival was higher (93.8% vs 80.9% HLA non-ID LDKTx, p<0.001), rejection rates were lower (after 1 year 9.6% vs 27.1%; p<0.001) and Banff inflammation scores including glomerulitis and peritubular capillaritis were lower on surveillance biopsies at 1, 5 and 10 years. In contrast, chronic Banff scores (interstitial fibrosis, arteriolar hyalinosis, mesangial expansion, etc.) were similar in prevalence and severity on surveillance biopsies at 1, 5 and 10 years. Conclusions: HLA-ID LDKTx have less inflammation and less transplant glomerulopathy, but most chronic histologic changes were similar to less-well matched LDKTx. We conclude that these types of chronic changes are not associated with HLA mismatches and may be due to non-immunologic causes (hypertension, obesity, etc.) suggesting that new management approaches to prevent these lesions may be needed. Funding Andrew Bentall would like to acknowledge internal funding awards including the 'Transplant Scholar Award' and the 'Career Development Award in Transplantation' although these funds were not directly used in this study. All other authors have no acknowledgements. Disclosure: The authors declare no conflicts of interest. Address correspondence to: Dr. Mark D. Stegall, Department of Surgery and Immunology, Division of Transplant Surgery; von Liebig Transplant Center, Mayo Clinic, Rochester, MN E-mail: stegall.mark@mayo.edu Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,

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