| Volume: 18 | Issue: 7 | December 2020 EXPERIMENTAL AND CLINICAL TRANSPLANTATION Experimental and Clinical Transplantation | Volume: 18
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Issue: 7 Issue:
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December 2020
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Pages 751-852
OFFICIAL JOURNAL OF THE MIDDLE EAST SOCIETY FOR ORGAN TRANSPLANTATION
| www.ectrx.org | Print ISSN 1304-0855 | Online ISSN 2146-8427 Experimental and Clinical Transplantation Official Journal of the Middle East Society for Organ Transplantation
Editor-in-Chief
Mehmet HABERAL, Ankara, TURKEY
Honorary Board Members
*Thomas E STARZL, Pittsburgh, PA, USA *John S NAJARIAN, Minneapolis, MN, USA *J Wesley ALEXANDER, Cincinnati, OH, USA *George M ABOUNA, Radnor, PA, USA *Nevzat BİLGİN, Ankara, TURKEY *Nebil BÜYÜKPAMUKÇU, Ankara, TURKEY
Associate Editors Senior Editorial Board Members
Mustafa AL-MOUSAWI, Kuwait, KUWAIT Roy CALNE, Cambridge, UK Hassan ARGANI, Tehran, IRAN Jeremy CHAPMAN, Westmead, NSW, AUSTRALIA Antoine BARBARI, Beirut, LEBANON Iradj FAZEL, Tehran, IRAN Nadey S HAKIM, London, UK Ahad J GHODS, Tehran, IRAN Refaat R KAMEL, Cairo, EGYPT *Pekka HAYRY, Helsinki, FINLAND S Ali MALEK HOSSEINI, Shiraz, IRAN Josep LLOVERAS, Barcelona, SPAIN Marwan MASRI, Beirut, LEBANON Ignazio R MARINO, Philadelphia, PA, USA S A Anwar NAQVI, Karachi, PAKISTAN Anthony P MONACO, Boston, MA, USA Bassam SAEED, Damascus, SYRIA S Adibul Hasan RIZVI, Karachi, PAKISTAN Faissal A M SHAHEEN, Riyadh, SAUDI ARABIA
Editorial Board Members
Abdulla A AL-SAYYARI, Riyadh, SAUDI ARABIA Elmi MULLER, Cape Town, SOUTH AFRICA Gülnaz ARSLAN, Ankara, TURKEY Shahrzad OSSAREH, Tehran, IRAN Hande ARSLAN, Ankara, TURKEY Rutger J PLOEG, Oxford, UK Mohamed Adel BAKR, Mansoura, EGYPT Nasser SIMFOROOSH, Tehran, IRAN Behrooz BROUMAND, Tehran, IRAN Hans W. SOLLINGER, Madison, WI, USA Marcelo CANTAROVICH, Montreal, CANADA Jean-Paul SQUIFFLET, Brussels, BELGIUM J Michael CECKA, Los Angeles, CA, USA David E R SUTHERLAND, Minneapolis, MN, USA Cataldo DORIA, Pennington, NJ, USA Alexander H TOLEDO, Chapel Hill, NC, USA Gabriel E. GONDOLESI, Buenos Aires, ARGENTINA Andreas G TZAKIS, Miami, FL, USA Nabil MOHSIN, Muscat, OMAN Magdi YAQOOB, London, UK Gökhan MORAY, Ankara, TURKEY Hasan YERSIZ, Los Angeles, CA, USA
*Deceased BAŞKENT UNIVERSITY Printed by Elma Teknik Basım Matbacılık Tic. Ltd. Şti. Print ISSN 1304-0855 İvedik OSB Matbaacılar Sitesi 1516 / 1 Sokak No: 35 publisher Online ISSN 2146-8427 Yenimahalle 06378, Ankara-Türkiye (+90.312) 229 92 65 www.ectrx.org Date Printed 5 December 2020 EDITORIAL POLICY MISSION SCOPE Experimental and Clinical Transplantation (ECT) is the official The scope of the journal includes the following: journal of the Middle East Society for Organ Transplantation Surgical techniques, innovations, and novelties (MESOT). The Society was originally founded in Turkey in 1987, Immunobiology and immunosuppression and was subsequently incorporated at Bern, Switzerland, in 1988 Clinical results as a non-profit, international, scientific organization comprising Complications 20 countries of the Middle East, North Africa, Mid-Asia, and Infection neighboring nations. Malignancies Organ donation The aim of the journal is to provide a medium forum for where Organ and tissue procurement and preservation clinical scientists, basic scientists, ethicists, and public health Sociological and ethical issues professionals to communicate ideas and advances in the field of Xenotransplantation experimental and clinical organ and tissue transplantation, and to discuss related social and ethical issues. The topics will be of interest to transplant surgeons, clinicians in all major disciplines ETHICS and subspecialties, basic science researchers, and other The Journal expects that all procedures and studies involving professionals involved with sociological aspects of experimental human subjects have been reviewed by the appropriate ethics and clinical transplantation. committee and have therefore been performed in accordance with the ethical standards laid down in The Helsinki Declaration Experimental and Clinical Transplantation is a peer-reviewed as well as The Declaration of Istanbul on Organ Trafficking international publication that accepts manuscripts of full-length and Transplant Tourism. Manuscripts must contain a statement original articles, case reports, letters to the editor, and invited to this effect. reviews. It is published in English bimonthly (February, April, June, August, October, and December). All authors are required to sign an ethical disclosure form stating that they have not been involved in commercial Our editorial team is committed to producing a journal of transactions or other unethical practices in obtaining donor extremely high standards. The journal is fully indexed in EBSCO, organs, and that no organs or tissues from executed prisoners Excerpta Medica, Index Medicus, Journal Citation Reports/ have been used in this research. Science Edition, MEDLINE, Science Citation Index Expanded™, and Turkey Citation Index. Full-text articles are available on the Experimental and Clinical Transplantation adheres to the Internet via PubMed or at the Journal’s Web site, at http://www. ethical principles outlined by COPE (Committee on Publication ectrx.org. ECT is also available as hard-copy bound volumes by Ethics). subscription, printed on acid-free paper.
SUBSCRIPTION RATES * These rates and terms are not applicable, if membership dues not paid for two consecutive years. MESOT Members* Single Issue: $20.00 Twelve issues per year, appearing in January, February, Annual Subscription: $100.00 March, April, May, June, July, August, September, October, Non- MESOT Members November and December Single Issue: $50.00 Annual Subscription: $250.00 Shipping Outside Turkey Surface Delivery: No additional charge Institutions Air Mail Delivery: Add $8.00 extra Annual Subscription: $1000.00
Yayın Adı: Experimental and Clinical Transplantation Name of the Journal: Experimental and Clinical Transplantation Yayın Türü: Yerel süreli yayın Type of Publication: Academic Journal Yayın Şekli: Aylık-İngilizce Type of Release: Bimonthly - English Yayın Sahibi: Başkent Üniversitesi adına Mehmet Haberal Publisher: Mehmet Haberal on behalf of Baskent University Sorumlu Yazı İşleri Müdürü: Mehmet Haberal Editor in Chief: Mehmet Haberal Yayının İdare Adresi: Taşkent Cad. No:77 Address: Taskent Cad. No:77 06490 Bahçelievler, Çankaya, Ankara 06490 Bahcelievler, Cankaya, Ankara
For all editorial and business matters, please send correspondence to or contact: Editorial Office Taskent Caddesi, No:77, Kat 4, Bahcelievler, Ankara, 06490 Turkey Telephone: +90 (312) 212 73 93 Fax: +90 (312) 215 08 35 E-mail: [email protected] EDITORIAL POLICY FOR LIVING DONOR TRANSPLANTATION
Dear Colleagues,
Kindly be reminded of our Editorial Policy regarding Living Donation in transplantation.
As per our acceptance criteria, donor must be a relative (up to the 4th degree) or spouse of the recipient and over 18 years old. We would like to remind all of you that as per our Journal policy, we do not accept any papers that involve transplantation from living unrelated donors.
In the recent period (from January 2019 to present), 662 manuscripts have been submitted to our Journal from various countries throughout the world. Out of these 662 manuscripts, a decision has been made for 554 manuscripts and 377 (68%) of them were rejected. Of these 377 rejected manuscripts, 55 (14.6%) of them have been rejected as they involved transplantation from unrelated living donors.
We hope that an increase in such policies will help to underline the importance of the legal and ethical aspects of transplantation. Please feel free to contact us regarding any comments as our aim is to contribute to the transplantation field in the world.
Please keep safe and healthy during these times of Covid-19 pandemic.
Sincerely,
Mehmet Haberal, MD, FACS (Hon), FICS (Hon), FASA (Hon), FIMSA (Hon), Hon FRCS (Glasg) Editor-in-Chief Experimental and Clinical Transplantation Stay at Home Stay Healthy and Safe TTS 2024 TH INTERNATIONAL CONGRESS 30 OF THE TRANSPLANTATION SOCIETY ISTANBUL, TURKEY www.tts.org MESOT Options.pdf 5 11/22/20 10:19 PM
th Congress of the Middle East Society 17For Organ Transplantation
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M
Y
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MY
CY
CMY
K SAVE THE DATE SAVE THE DATE SAVE THE DATE MESOT 03-05 September 2021 AMMAN-JORDAN
JORDAN 2021 MESOT Options.pdf 5 11/22/20 10:19 PM
The Middle East Society for Organ Transplantation
MESOT welcomes professionals actively involved in all fields of transplantation. th Congress of the Middle East Society The benefits of membership: For Organ Transplantation ■ The opportunity to be part of a regional network of physicians, surgeons and 17 scientists involved in transplantation ■ Free online access to the journal “Experimental and Clinical Transplantation”,
C the official journal of The Middle East Society for Organ Transplantation
M ■ Substantially reduced rates for subscription to print copies of “Experimental and Y Clinical Transplantation” CM
MY ■ Entitlement to apply to take part in a fellowship program in one of several leading CY transplantation centers in the Middle East
CMY ■ Reduced registration fee at the biennial international congresses which provide K an innovative and comprehensive overview of the latest research developments SAVE THE DATE in the field transplantation SAVE THE DATE ■ Free online access to the “Transplant Library” ■ MESOT newsletter updating members about the latest activities in the transplant SAVE THE DATE community MESOT ■ Access to the online MESOT Member Directory 03-05 September 2021 AMMAN-JORDAN Apply online today at http://www.mesot-tx.org
Experimental and JORDAN Clinical Transplantation Official Journal of the Middle East Society for Organ Transplantation 2021 www.ectrx.org MESOT Fellowship Program in Organ Transplantation
The Middle East Society for Organ Transplantation is pleased to announce the establishment of the MESOT Fellowship Program. The program, which will be 1-2 years in duration, has been created for physicians and surgeons from the Middle East region willing to acquire particular skills related to clinical and medical aspects of organ transplantation.
The objective of this program is to promote and advance organ transplantation in underserved areas of the region by helping physicians to establish new programs or improve already existing ones. In addition to liver, kidney, pancreas, heart and cornea transplant fellowships, training will be offered in various other departments to support the multidisciplinary nature of transplantation, including gastroenterology, nephrology, cardiology, immunology, radiology, pathology, infectious diseases and intensive care.
A limited number of grants will also be available, with recipients being determined by the Fellowship Program Committee.
Further information can be found online at http://www.mesot-tx.org/home/ fellowship.php, where candidates may also apply online. The application deadline is the 30th of June of each year.
Inquiries may be directed to the Chairman of the MESOT Fellowship Program Committee:
Mustafa Al-Mousawi, MD, FRCS Chairman, MESOT Fellowship Program Committee P.O. Box 288, Safat 13003 Kuwait
Fax: +965 24848615 Email: [email protected]
International Symposium on Benign and Malignant Tumors in Liver With or Without Cirrhosis
24-25 June 2021 Kızılcahamam-Turkey
Basken t U n i v e Congress Secretariat r s
i
Şehit Temel Kuğuoğlu Cad. Yonca Apt. No: 28 / 4 t y Bahçelievler-Ankara-Turkey Phone: +90 312 215 51 60 • Fax: +90 312 215 14 85 [email protected] • http://www.buto-org.com liverbmt2021.com• [email protected] Turkish Transplantation Society Turkic World (TOND) Transplantation Society (TDTD)
Founder Professor Mehmet Haberal, Founder Professor Mehmet Haberal, Founded in 1990. Founded in December 2014.
Aims to promote and encourage research and education Aims to create an arena of communication and collaboration in the field of organ transplantation, to partake in national in the field of organ transplantation among the Turkic States and international scientific activities and to ensure of the world. Inclusive of Turkey, Azerbaijan, Kazakhstan, communication between organizations alike. Kyrgyzstan, Tajikistan, Turkmenistan, and Uzbekistan, the society already has a total of 485 members from all member The primary goals of TOND are: countries. • To collaborate with other organizations alike in Turkey The primary goals of TDTD are: and to organize meetings, symposiums and conferences • To promote and encourage education, research and • To inform and educate the public at large on organ cooperation in the field of organ transplantation transplantation by means of publications and conferences for the purpose of advancing the art and science of • To organize programs which will promote organ donation transplantation, and to serve the patients of these states and its importance in saving lives through the application of new knowledge and technical advances • To ensure the training of qualified personnel in the field of organ transplantation and encourage research by means • To create a scientific forum for the discussion of all of funds problems related to the field of transplantation, including medical, social and legal aspects • To collaborate with existing international organizations alike to promote and encourage scientific research • To collaborate with existing public and private organizations to promote and encourage research and • To work on ethical and legal aspects of organ clinical applications related to transplantation, and transplantation and related fields and to encourage social to participate and assist in the promotion of organ and medical collaboration of organizations alike. procurement and donation • To encourage meetings, symposia and congresses to fulfill the above objectives NGO in official relations with the World Health Organization (WHO)
Join TTS TODAY!
BENEFITS INCLUDE:
• The opportunity to be part of the leading global network of physicians, surgeons and basic scientists involved in transplantation, representing more than 105 countries around the world
• Free online access to the Transplantation journal and free educational material on the Society’s website
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Cell Transplant and Regenerative Medicine Society Official Sections of TTS
INTERNATIONAL SOCIETY OF VASCULARIZED International COMPOSITE ALLOTRANSPLANTATION I AXenotransplantation Association Intestinal Rehabilitation & Transplant ASSOCIATION
By joining TTS way to there is no BETTER invest in YOUR CAREER and in one of the most dynamic professions in medical science TODAY
BAŞKENT
1993 UNIVERSITY
International Center for Transplant Ethics
We are proud to announce the establishment of the International Center for Transplant Ethics under the aegis of the World Academy of Medical, Biomedical and Ethical Sciences at Başkent University
The center’s mission is: · to provide leadership in ethical activities and policy
· to promote ethical activities in transplantation
· to introduce ethically sound procurement policies and practice in order to prevent exploitation of individuals as organ providers based on human dignity and human rights. Diagnostic and Interventional Radiology in Liver & Kidney Transplantation Fatih BOYVAT, MD, FICS Mehmet HABERAL, MD, FACS (HON), FICS (HON), FASA (HON), FIMSA (HON), HON FRCS (GLASG)
Transplant medicine remains one of the most challenging and complex areas of modern medicine. Although important medical breakthroughs such as immunosuppressive drugs have allowed for more organ transplants and a longer survival rate, transplant professionals still face serious problems, especially with regard to achieving correct diagnosis and treating postoperative complications.
Advances in imaging techniques, including in computed tomography, magnetic resonance imaging, and ultrasonography, and the use of interventional radiology have allowed transplant professionals to provide more accurate results both for diagnosis and for treatment of complications that occur after liver and kidney transplant. Moreover, with the use of interventional radiology, transplant professionals can now reach deep structures of the body, enabling correct diagnoses and treatment without performing surgery.
BAŞKENT Editorial Office Publisher BAŞKENT Taskent Caddesi, No:77, Kat 4, Bahcelievler 1993 UNIVERSITY 1993 UNIVERSITY Ankara, 06490 Turkey Telephone: +90 (312) 212 73 93 Fax: +90 (312) 215 08 35 [email protected] Experimental and Clinical Transplantation Official Journal of the Middle East Society for Organ Transplantation Volume: 18 Issue: 7 December 2020
Contents
Artıcle
751-756 Alemtuzumab Induction and Steroid 791-795 Comparison of Standard and Modified Minimization in IgA Nephropathy: A Matched- Standard Organ Procurement Techniques for Cohort Analysis Deceased Donors Kevin Becker, Joseph Brooks, Graham Mitro, Cemalettin Koc, Sami Akbulut, Sezai Yilmaz Michael Rees, Jorge Ortiz 796-802 Living Donor Liver Transplant in Patients 757-762 Gene Expression of Toll-Like Receptors 2 and 4 With Budd-Chiari Syndrome: A Single-Center in Renal Transplant Rejection Experience at Our University Hospital Mozhdeh Heidari, Padideh Ebadi, Sanaz Abbasi, Mikal Obed, Mohammad Ibrahim Othman, Afsoon Afshari, Ramin Yaghobi, Mehdi Salehipour, Saeb Hammoudi, Mahmoud Abdelkader Chattab, Mohammad Hossein Karimi Anwar Jarrad, Abdalla Bashir, Aiman Obed
763-770 Management of Multiple Renal Arteries and 803-807 Evaluation of Underlying Liver Disease and Unusual Venous Anatomy During Kidney Its Severity in Children Referred for Liver Transplant: From a Simple Technical Problem Transplant: a Single-Center Report From to a Graft-Saving Procedure Nemazee Hospital of Shiraz Zivko Popov, Oliver Stankov, Sotir Stavridis, Seyed Mohsen Dehghani, Iraj Shahramian, Skender Saidi, Ognen Ivanovski, Goce Spasovski, Ali Bazi, Maryam Mohammadi Mofrad, Koco Cakalaroski, Ninoslav Ivanovski Samira Mardani
771-777 Prophylactic Wound Drainage in Renal 808-813 Utility of Transjugular Intrahepatic Transplant: A Survey of Practice Patterns in Portosystemic Shunt Placement for Maintaining Australia and New Zealand Portal Vein Patency in Candidates on Wait Lists Miho Mugino, Taina Lee, Susanna Lam, Who Develop Thrombus Ahmer Hameed, Charbel Sandroussi, Mustafa Alani, Michael Rowley, Paul Kang, Steven Chadban, Henry Pleass, Steve Chen, Kevin Hirsch, Anil Seetharam Jerome Martin Laurence 814-822 Evaluation of Neuroimaging Findings of 778-784 Hidden Granzyme B-Mediated Injury in Central Nervous System Complications in Chronic Active Antibody-Mediated Rejection Heart Transplant Recipients Brijesh Yadav, Narayan Prasad, Vikas Agarwal, Hale Turnaoglu, Ahmet Muhtesem Agildere, Vinita Agarwal, Manoj Jain Feride Kural Rahatli, FuldemYildirim Donmez, Ruhsen Ocal, Taner Sezer, Ufuk Can, Atilla Sezgin, 785-790 Liver Allografts From Older Donors With or Sait Aslamaci Without Recovery of Thoracic Organs and Their Impact on Hepatic Graft and Patient Survival Ricci Kalayanamitra, Ashton Brooks, Sushrut Trakroo, Zakiyah Kadry, Ashokkumar Jain BAŞKENT UNIVERSITY FACULTY OF MEDICINE DIVISION OF DEPARTMENT OF GENERAL SURGERY TRANSPLANTATION Kidney & Liver Transplantation Observer & Fellowship Programs
www.baskent.edu.tr 823-831 Therapeutic Potential of Bama Pig Adipose- 842-846 Liver Transplant for Nonresectable Colorectal Derived Mesenchymal Stem Cells for the Cancer Liver Metastases in South Africa: A Treatment of Carbon Tetrachloride-Induced Single-Center Case Series Liver Fibrosis Jean Botha, Georgia Demetriou, June Fabian, Xinran Wu, Shuang Zhang, Junhui Lai, Huidi Lu, Harriet Etheredge Yuchen Sun, Weijun Guan 847-850 Role of Fluorodeoxyglucose Positron Emission Case Report Tomogram Scan in Sirolimus-Induced Lung Toxicity: A Rare Case Report 832-833 Successful Kidney Transplant From a Brain Sarfraz Saleemi, Bader Alothman, Stem-Dead Donor Due To Lethal Methanol Faisal Albaiz, Sami Alrasheedi, Yaser Z. Shah, Poisoning Aman Saleemi Afshar Zomorrodi, Farzad Kakaei Letter to Edıtor 834-837 En Bloc Kidney Transplant From a Pediatric Donor to a Pediatric Recipient Through a 851-852 Ex Vivo Lung Perfusion Using Whole Blood: Total Extraperitoneal Approach: A Case How? Report Mohamed S. A. Mohamed Kwangho Yang, Dongil Kim, Soohong Kim, Hyojung Ko, Jaeryong Shim, Taebeom Lee, Jeho Ryu, Seongheon Kim, Byunghyun Choi
838-841 Pediatric Pure Red Cell Aplasia Caused by Tacrolimus After Living-Donor Liver Transplant Suguru Watanabe, Rieko Sakamoto, Hidekazu Yamamoto, Masayuki Imaya, Takahiro Yamashita, Tadashi Anann, Kimitoshi Nakamura
Artıcle
Alemtuzumab Induction and Steroid Minimization in IgA Nephropathy: A Matched-Cohort Analysis
Kevin Becker,1 Joseph Brooks,1 Graham Mitro,1 Michael Rees,2 Jorge Ortiz3
Abstract pair analyses did not yield significant differences in outcomes. Objectives: Immunoglobulin A nephropathy is the Conclusions: Recurrence rate of immunoglobulin A most common primary glomerulonephritis in adults. nephropathy in those induced with alemtuzumab in Transplant can be complicated by immunoglobulin A the setting of steroid minimization is similar to nephropathy recurrence in up to 60% of allografts, previously reported rates. Although recipients with sometimes causing graft loss. The use of alemtuzumab immunoglobulin A nephropathy had significantly for induction therapy in the setting of steroid higher 1-year rejection rate, no other differences in minimization for recipients with immunoglobulin A graft or patient survival were shown versus recipients nephropathy is unclear. Here, we investigated patient without this condition. and graft outcomes in patients with this condition who were induced with alemtuzumab and a steroid Key words: Allograft loss, End-stage renal disease, minimization protocol. Glomerulonephritis, Kidney transplant Materials and Methods: We performed a retrospective analysis of a database containing 29 patients with Introduction immunoglobulin A nephropathy and 646 other recipients who underwent transplant and were Immunoglobulin A nephropathy (IgAN) is the most induced with alemtuzumab and steroid minimization common primary glomerulonephritis in adults.1 treatment between March 2006 and May 2015. A End-stage renal disease occurs in 50% of IgAN matched cohort generated using propensity scoring patients after 20 to 30 years.2 Kidney transplant is the was also analyzed. treatment of choice and is associated with improved Results: Recipients with immunoglobulin A nephro - quality of life, better patient survival, and lower pathy were significantly younger at transplant (37.3 ± health care costs.3-5 Unfortunately, IgAN recurrence 11.9 vs 55.6 ± 13.4 years; P < .001), less likely to be African American (6.9% vs 23.2%; P = .04), less likely to may result in chronic graft dysfunction and the have diabetes mellitus (10.3% vs 39.8%; P < .001), and subsequent need for retransplant. The recurrence rate more likely to have private insurance (72.4% vs 45.9%; of IgAN ranges from 13% to 50%, and graft loss P = .007). There were no significant differences in graft occurs in up to 16%.6 The risk of recurrence is and patient survival. Recipients with immunoglobulin increased with living-related donation7 and is A nephropathy experienced a higher rate of 1-year associated with younger recipient age.8 rejection (24.1% vs 21.4%; P = .043). Of the 29 patients Recurrence risk is reduced in the presence of long- with immunoglobulin A nephropathy, 8 experienced term steroid therapy.9 However, steroid withdrawal recurrence (27.6%; average time of 1120.5 ± 982.9 and steroid minimization, especially in the setting days), with all 8 patients having allograft loss. Matched of induction immunosuppression, have recently
From the 1College of Medicine and Life Sciences, University of Toledo, the 2Department of become more popular among transplant practi - Urology and Pathology, University of Toledo College of Medicine and Life Sciences, and the tioners given the adverse effects of steroid therapy. 3Department of Surgery, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA Alemtuzumab is an induction agent utilized in Acknowledgements: The authors have no sources of funding for this study and have no conflicts the setting of steroid minimization. It is a humanized of interest to declare. Corresponding author: Kevin Becker, College of Medicine and Life Sciences, University of monoclonal antibody that targets the CD52 glyco - Toledo, Toledo, OH, USA protein and results in lymphocyte depletion.10 The E-mail: [email protected] use of alemtuzumab induction in the setting of Experimental and Clinical Transplantation (2020) 7: 751-756 steroid minimization for kidney transplant recipients
Copyright © Başkent University 2020 DOı: 10.6002/ect.2018.0310 Printed in Turkey. All Rights Reserved. 752 Kevin Becker et al/Experimental and Clinical Transplantation (2020) 7: 751-756 Exp Clin Transplant
with IgAN has not been well demonstrated. at 2/3 dose until the white blood cell counts returned Therefore, we evaluated the long-term patient and to normal. graft outcomes of these individuals. Antimicrobial prophylaxis was started post - operatively with 1 oral tablet of sulfamethoxazole Materials and Methods (800 mg)-trimethoprim (160 mg) (Bactrim DS, AR Scientific, Philadelphia, PA, USA) 3 times per week We performed an institutional review board-approved and clotrimazole troche 10 mg dissolved in the retrospective analysis of a database of 464 kidney mouth 4 times per day following oral care. Daily transplant recipients who were induced with valganciclovir (Valcyte, Hoffman-La Roche, Basel, alemtuzumab at the University of Toledo Medical Switzerland) was prescribed for cytomegalovirus Center (Toledo, OH, USA) between March 2006 and prophylaxis. May 2015. We only included recipients of deceased- donor allografts to make outcomes more comparable. Statistical analyses Data were reviewed using TransChart (TransChart Continuous variables such as age, length of dialysis, LLC, Dublin, OH, USA) electronic medical record cold ischemia time, and kidney donor profile index software. Donor information included age, ethnicity, were presented in medians and were compared presence of hypertension, presence of diabetes using t tests or the Mann-Whitney U test when mellitus, and type of donor. Recipient information appropriate. Categorical variables, including sex, included sex, age, ethnicity, type of graft received, ethnicity, education level, delayed graft function, and panel reactive antibody, and number of transplants. early rejection, were presented in terms of percentage All recipients were negative cross-matches for both of the total numbers within the group. These results T and B cells. All cases of acute rejection and IgAN were compared with the Pearson chi-square or Fisher recurrence were biopsy-proven. Biopsies were only exact test. Survival curves were generated using the life performed in the presence of allograft dysfunction. table method, with statistical comparisons computed Patients were pretreated with 25 mg of diphen - with the log-rank method. Multivariate survival hydramine intravenously. At the time of the analysis was done using Cox regression analysis with procedure, induction immunosuppression with multivariate factors selected from univariate results intravenous methylprednisolone 500 mg (Solu- and with patient ethnicity included for comparison. Medrol, Pfizer, New York, NY, USA), oral myco - Type I error level was set at .05. All statistical analyses phenolate sodium 540 mg (Myfortic, Novartis were conducted using IBM SPSS version 23 (IBM Pharmaceuticals, Basel, Switzerland or CellCept, Corp., Armonk, NY, USA). Additionally, a matched Genentech, San Francisco, CA, USA), and intravenous cohort analysis was generated using propensity alemtuzumab 30 mg was administered. Before 2011, scoring for the major statistically significant we used alemtuzumab induction alone. After 2011, a demographic differences using regression. steroid bolus and taper were added to the protocol. The postoperative steroid taper consisted of Results intravenous methylprednisolone 250 mg on post - operative day 1, intravenous methylprednisolone Recipient and donor characteristics are shown in 125 mg on postoperative day 2, oral prednisone 60 mg Table 1. Of the 675 total recipients, 29 (4.3%) received on postoperative day 3, oral prednisone 40 mg on a transplant due to IgAN. These recipients were postoperative day 4, and oral prednisone 20 mg on significantly younger at time of transplant (37.3 ± 11.9 postoperative day 5. Starting in 2015, patients at vs 55.6 ± 13.4 y; P < .001) and more likely to have high-risk for rejection were continued indefinitely on private health insurance (72.4% vs 45.9%; P = .007). oral prednisone (5-10 mg). The IgAN group was less likely to be African On postoperative day 1, oral tacrolimus 1.5 mg American (6.9% vs 23.2%; P = .001) or to have (Prograf, Astellas Pharma, Tokyo, Japan) and oral diabetes mellitus (10.3% vs 39.8%; P = .001). mycophenolate sodium 540 mg twice per day were Donors to IgAN recipients were significantly administered. Tacrolimus levels were measured and younger (29 ± 13.6 vs 41 ± 14.9 y; P = .025) and had titrated to the correct dose. When side effects lower terminal creatinine (0.8 ± 0.3 vs 1 ± 0.9 mg/dL; permitted, mycophenolate sodium was administered P = .049). These donors were less likely to be deceased Kevin Becker et al/Experimental and Clinical Transplantation (2020) 7: 751-756 753
(44.8% vs 75.4%; P = .001), although living donors were Outcomes excluded from our analysis. Matched pair analysis was Transplant recipients with IgAN were more likely completed but did not yield statistically significant to experience rejection at 1 year (24.1% vs 21.4%; differences in recipient or donor factors. Recipient and P = .043). No significant differences were noted for donor factors are listed in Table 2. rejection at 3 years (28.4% vs 26.4%; P = .898) or at 5 years (35.5% vs 29.1%; P = .734), for delayed graft table 1. Recipient and Donor Demographics function (6.9% vs 9.8%), or for death-censored graft IgAN Control P Value survival at 1 year (100% vs 94.8%; P = .215), 3 years Recipient factors (91.1% vs 89.3%; P = .588), or 5 years (85.7% vs 84.8%; Total number 29 (4.3%) 646 (95.7%) Elderly 6.9% 18.6% .139 P = .778). One recipient with IgAN died at 104 Age at transplant, y 37.3 ± 11.9 55.6 ± 13.4 < .001 months posttransplant due to metastatic lung cancer Male recipient 65.5% 65.3% .822 African American 6.9% 23.2% .04 at age 74.6 years. Cox proportional hazards model Recipient diabetes mellitus 10.3% 39.8% .001 determined that IgAN status was not an independent Retransplant 20.7% 27.1% .526 PRA > 20% 14.3% 18.9% .804 predictor of rejection within 1 year (hazards ratio of Private health insurance 72.4% 45.9% .007 1.26; 95% confidence interval, 0.571-2.777; P = .567). BMI, kg/m2 30.7 ± 5.3 28.3 ± 5.1 .206 Donor factors General outcomes are listed in Table 3. Matched pair Donor age, y 29 ± 13.6 41 ± 14.9 .025 analysis did not yield significant differences in Donor BMI, kg/m2 25.0 ± 5.2 26.9 ± 5.1 .645 outcomes. Matched pair outcomes are listed in African American donor 6.9% 11.1% .76 Donor-recipient Table 4. race/ethnicity mismatch 17.2% 33.6% .071 Deceased donor 44.8% 75.4% .001 Extended criteria donor 0 12.1% .376 table 3. Outcomes Donor deceased after IgAN Control P Value cardiac death 7.7% 9.9% .796 DGF 6.9% 9.8% .606 Donor hypertension 13.8% 20.6% .483 1-Year rejection 24.1% 21.4% .043 Donor diabetes mellitus 0 6.1% .404 3-Year rejection 28.4% 26.4% .898 Cold ischemia time, h 12 ± 4.3 12 ± 7.5 .437 5-Year rejection 35.5% 29.1% .734 KDPI 15 ± 12.7 38 ± 27.9 .051 1-Year DCGS 100.0% 94.8% .215 Terminal creatinine, mg/dL 0.8 ± 0.3 1 ± 0.9 .049 3-Year DCGS 91.1% 89.3% .588 Abbreviations: BMI, body mass index; IgAN, immunoglobulin A nephro - 5-Year DCGS 85.7% 84.8% .778 pathy; KDPI, kidney donor profile index; PRA, panel reactive antibody Abbreviations: DCGS, death-censored graft survival; DGF, delayed graft function; IgAN, immunoglobulin A nephropathy table 2. Matched Pair Recipient and Donor Factors table 4. Matched Pair Outcomes IgAN Control P Value Recipient factors IgAN Control P Value Total number 29 (9.6%) 272 (90.4%) DGF 6.9% 6.4% .912 Age at transplant, y 37.3 ± 11.9 44.5 ± 11.1 .468 1-Year Rejection 24.1% 21.4% .815 Male recipient 65.5% 60.7% .691 3-Year Rejection 28.4% 27.6% .97 African American 6.9% 15.1% .399 5-Year Rejection 35.5% 30.6% .813 Recipient diabetes mellitus 10.3% 20.7% .226 1-Year DCGS 100.0% 96.3% .296 Retransplant 20.7% 29.0% .394 3-Year DCGS 91.1% 90.8% .77 PRA > 20% 14.3% 20.2% .619 5-Year DCGS 85.7% 87.1% .984 Private health insurance 72.4% 53.4% .075 Abbreviations: DCGS, death-censored graft survival; DGF, delayed graft BMI, kg/m2 30.7 ± 5.3 27.5 ± 5.4 .091 function; IgAN, immunoglobulin A nephropathy Donor factors Donor age, y 29 ± 13.6 33.0 ± 13.7 .416 Donor BMI, kg/m2 25.0 ± 5.2 26.2 ± 5.0 .956 recurrence results African American donor 6.9% 13.6% .396 Of the 29 recipients with IgAN, 8 (27.5%) experienced Donor-recipient race/ethnicity mismatch 28.3% 27.6% .374 IgAN recurrence. These 8 individuals eventually lost Deceased donor 44.8% 61.0% .112 their allografts after diagnosis of IgAN recurrence. Extended criteria donor 0.0% 3.6% .503 Donor deceased after The average time to recurrence was 1120.5 ± 982.9 cardiac death 7.7% 7.8% .986 days. Recipient factors for those who experienced Donor hypertension 13.8% 9.3% .505 recurrence did not vary with any significance. Those Donor diabetes mellitus 0.0% 2.2% .416 Cold ischemia time, h 12 ± 4.3 10.9 ± 7.3 .239 who experienced recurrence were more likely to have KDPI 15 ± 12.7 26.0 ± 21.6 .345 female donors (87.5% vs 42.9%; P = .044), but donor- Terminal creatinine, mg/dL 0.8 ± 0.3 0.9 ± 0.4 .161 recipient male-female mismatch was not significant Abbreviations: BMI, body mass index; IgAN, immunoglobulin A nephro - pathy; KDPI, kidney donor profile index; PRA, panel reactive antibody (37.5% vs 23.8%; P = .646). Recurrence was associated 754 Kevin Becker et al/Experimental and Clinical Transplantation (2020) 7: 751-756 Exp Clin Transplant
with significantly lower donor terminal creatinine table 6. Rejection Results (0.65 ± 0.13 vs 0.93 ± 0.30 mg/dL; P = .01). Three Cell Type Control IgAN P Value patients experienced both graft rejection and IgAN Neutrophils 11% 0% > .05 Eosinophils 5.6% 22.2% < .05 recurrence. These incidences recurred at a signi - Plasma cells 13.6% 10% > .05 ficantly earlier time versus recipients with IgAN Monocytes 25.9% 56% > .05 Lymphocytes 31.5% 11% > .05 (775 ± 532.5 vs 1774 ± 1033.6 days; P = .017). Abbreviations: IgAN, immunoglobulin A nephropathy Recurrence demographics are listed in Table 5. Discussion table 5. Recurrence Demographics Patients With Control P Value Immunoglobulin A nephropathy is the most IgAN Recurrence Recipient factors common cause of glomerulonephritis worldwide. Total number 8 21 Kidney transplant is associated with superior Days to recurrence 1120.5 ± 982.9 2117 ± 948.9 .024 Elderly 50% 50% .462 outcomes compared with chronic dialysis. However, Age at transplant, y 37.3 ± 13.4 37.1 ± 11.4 .905 the recurrence of IgAN in renal allograft recipients Male recipient 50% 71.4% .39 remains a substantial complication, frequently African American 0 9.5% .366 Recipient diabetes mellitus 12.5% 9.5% .814 leading to graft failure and return to wait list. Retransplant 25% 19% .724 In the setting of alemtuzumab induction and PRA > 20% 0 20% .295 Private health insurance 50% 81% .164 steroid minimization, we demonstrated no significant BMI, kg/m2 29.2 ± 7.0 28.3 ± 5.4 .615 differences in death-censored graft survival between Donor factors Donor age, y 32 ± 11.9 33 ± 14.8 .457 recipients with IgAN and the control group at 1, 3, Donor BMI, kg/m2 28.0 ± 3.5 25.7 ± 6.9 .64 and 5 years. Our initial analysis demonstrated an Female donor 87.5% 42.9% .044 Female donor + male recipient 37.5% 23.8% .646 elevated rate of rejection at 1 year in the IgAN group. Black donor 0 9.5% .366 However, our matched cohort analysis did not yield Donor-recipient statistically significant differences in either death- race/ethnicity mismatch 0 23.8% .283 Deceased donor 25% 52.4% .238 censored graft survival or rejection between patients Extended criteria donor 0 0 with a kidney transplant due to IgAN matched Donor deceased after cardiac death 50% 0 .154 against patients who underwent kidney transplant Donor hypertension 0 19% .552 for other reasons. Donor diabetes mellitus 0 0 Cold ischemia time, h 5 ± 0.6 8.5 ± 6.5 .442 Similarly, Choy and associates and Kim and KDPI 12.5 ± 2.1 21 ± 22.8 .41 associates both reported that long-term graft survival Terminal creatinine, mg/dL 0.65 ± 0.13 0.93 ± 30 .01 Abbreviations: BMI, body mass index; IgAN, immunoglobulin A rates in IgAN patients do not differ significantly from nephropathy; KDPI, kidney donor profile index; PRA, panel reactive antibody graft survival in recipients with renal diseases from other causes.7,11 However, it has been postulated that rejection results IgAN graft survival diminishes beyond 10 years The rate of graft loss due to rejection did not differ compared with other patients, although long-term significantly between IgAN and controls. However, studies are needed.8 IgAN recipients were more likely to experience all- Regarding recurrence, our rate was 27.5%. In a cause graft loss (P = .043). Rejection outcomes are recent review, Wyld and associates reported rates listed in Table 6. The IgAN group had significantly ranging from 8% to 53%.12 Others have suggested more eosinophils on biopsy than the control group that younger age, rapid progression of the innate (22.2% vs 5.6%; P < .05). Other cell types did not vary disease, degree of proteinuria, and various donor with any significance. There were no significant factors are associated with increased recurrence differences in the type of rejection (acute cellular vs rates.13-15 Demographically, there were no clinically antibody-mediated) or in Banff score between the significant differences between recipients with IgAN IgAN and control groups (P = .298 and P = .285, who experienced recurrence and those who did not. respectively). Regarding those who experienced Recipients who experienced recurrence were more recurrence, there were no significant differences in likely to have a female donor. This finding is cell type (P = .308), type of rejection (P = .464), or somewhat surprising given that it has been Banff score (P = .624) compared with those who did demonstrated that having a female donor is associated not experience recurrence. with improved graft survival.16 However, given the Kevin Becker et al/Experimental and Clinical Transplantation (2020) 7: 751-756 755
small number of recipients who experienced a signi ficantly higher risk of recurrence with recurrence, the statistical power of this finding was steroid withdrawal protocols (hazards ratio of 8.59; likely low. 95% confidence interval, 3.03-24.38; P < .001).22 In a It is important to note that our recurrence rate large, retrospective review of the UNOS/OPTN could be falsely low given that we performed no database, Leeaphorn and associates showed screening biopsies for recurrence. We performed that steroid continuation was associated with a biopsies only in the presence of graft dysfunction, significantly lower rate of graft loss due to which was defined as elevated creatinine and recurrence.23 proteinuria. However, Odum and associates Given that our center only utilized a steroid demonstrated that more than one-half of their minimization protocol, we were unable to compare patients who experienced biopsy-proven recurrence our recurrence rate to that of a steroid continuation had stable renal function and almost 20% had group within the same patient population. However, negative urinalysis results.17 Furthermore, Ortiz and the recurrence rate in our steroid minimization associates found clinical signs such as hematuria population is similar to that demonstrated by Kukla were absent in 64% of patients with biopsy-proven and associates.21 Thus, our data suggest that disease recurrence.18 Given that all of our alemtuzumab induction in the setting of steroid patients who experienced recurrence ultimately lost minimization has little effect on recurrence rates their graft, it is reasonable to conclude that our compared with other induction immunosuppression current biopsy protocol needs to be adjusted to agents. identify recurrence at an earlier stage and to better It is important to mention that, in 2016, after manage it. analyzing our outcome data and noting a greater Although our recurrence rate was relatively than 20% rejection rate, we have since altered our similar to previously reported rates in the literature, protocol to include maintenance steroids for our few studies have reported on outcomes in individuals IgAN patients, African American patients, and other with IgAN who undergo kidney transplant with high-risk groups. alemtuzumab induction therapy. Pascual and The strengths of our present analysis include a associates demonstrated that alemtuzumab was not relatively long follow-up period and a consistent associated with an increased rate of recurrence of immunosuppressive protocol. Weaknesses include a glomerular disease compared with interleukin 2 small sample size of patients with IgAN, a lack of receptor antagonists or antithymocyte globulin.19 comparison to other induction immunosuppression Furthermore, immunodepletion is potentially drugs, and a lack of comparison between a steroid protective and associated with reduced recurrence in minimization and a steroid continuation group. IgAN patients, although the mechanism is still However, the literature on IgAN is partly based on unknown.20 single-center studies. There has been controversy regarding the role of steroid minimization protocols in the treatment of Conclusions kidney transplant recipients with IgAN. Traditionally, steroids have been the preferred treatment for patients Steroid minimization in kidney transplant recipients with IgAN and an important part of the immuno - with IgAN remains controversial. We have demon - suppressive protocol after kidney transplant. strated that, in the setting of steroid minimization Recently, steroid-free and steroid minimization and alemtuzumab induction, graft outcomes in IgAN protocols were developed to avoid many of the recipients are similar to those in recipients without adverse effects of long-term steroid use. However, IgAN. Furthermore, our recurrence rate was steroid minimization protocols are associated comparable to previous rates reported in the with increased rates of recurrence in IgAN transplant literature for steroid minimization protocols. recipients.8,21 For example, Kukla and associates21 However, our recurrence rate was elevated observed a recurrence rate of 22% in their compared with other studies that utilized steroid early steroid withdrawal group compared with continuation protocols. At this time, we recommend 5.2% in their steroid continuation group (P = .02). maintenance steroid therapy with the use of Similarly, Von Visger and associates demonstrated alemtuzumab for patients with IgAN. 756 Kevin Becker et al/Experimental and Clinical Transplantation (2020) 7: 751-756 Exp Clin Transplant
References 14. Ponticelli C, Traversi L, Feliciani A, et al. Kidney transplantation in patients with IgA mesangial glomerulonephritis. Kidney Int. 1. Levy M, Berger J. Worldwide perspective of IgA nephropathy. Am 2001;60(5):1948-1954. J Kidney Dis. 1988;12(5):340-347. 15. Ponticelli C, Glassock RJ. Posttransplant recurrence of primary 2. Galla JH. IgA nephropathy. Kidney Int. 1995;47(2):377-387. glomerulonephritis. Clin J Am Soc Nephrol. 2010;5(12):2363-2372. 3. Simmons RG, Abress L. Quality-of-life issues for end-stage renal 16. Oien CM, Reisaeter AV, Leivestad T, et al. Living donor kidney disease patients. Am J Kidney Dis. 1990;15(3):201-208. transplantation: the effects of donor age and gender on short- 4. Wolfe RA, Ashby VB, Milford EL, et al. Comparison of mortality in and long-term outcomes. Transplantation. 2007;83(5):600-606. all patients on dialysis, patients on dialysis awaiting 17. Odum J, Peh CA, Clarkson AR, et al. Recurrent mesangial IgA transplantation, and recipients of a first cadaveric transplant. N nephritis following renal transplantation. Nephrol Dial Transplant. Engl J Med. 1999;341(23):1725-1730. 1994;9(3):309-312. 5. Eggers P. Comparison of treatment costs between dialysis and 18. Ortiz F, Gelpi R, Koskinen P, et al. IgA nephropathy recurs early in transplantation. Semin Nephrol. 1992;12(3):284-289. the graft when assessed by protocol biopsy. Nephrol Dial 6. Lionaki S, Panagiotellis K, Melexopoulou C, Boletis JN. The clinical Transplant. 2012;27(6):2553-2558. course of IgA nephropathy after kidney transplantation and its 19. Pascual J, Mezrich JD, Djamali A, et al. Alemtuzumab induction management. Transplant Rev (Orlando). 2017;31(2):106-114. and recurrence of glomerular disease after kidney transplantation. 7. Choy BY, Chan TM, Lai KN. Recurrent glomerulonephritis after Transplantation. 2007;83(11):1429-1434. kidney transplantation. Am J Transplant. 2006;6(11):2535-2542. 20. Berthoux F, El Deeb S, Mariat C, et al. Antithymocyte globulin (ATG) 8 .Moroni G, Longhi S, Quaglini S, et al. The long-term outcome of induction therapy and disease recurrence in renal transplant renal transplantation of IgA nephropathy and the impact of recipients with primary IgA nephropathy. Transplantation. 2008; recurrence on graft survival. Nephrol Dial Transplant. 2013;28(5): 85(10):1505-1507. 1305-1314. 21. Kukla A, Chen E, Spong R, et al. Recurrent glomerulonephritis 9. Clayton P, McDonald S, Chadban S. Steroids and recurrent IgA under rapid discontinuation of steroids. Transplantation. 2011; nephropathy after kidney transplantation. Am J Transplant. 91(12):1386-1391. 2011;11(8):1645-1649. 22. Von Visger JR, Gunay Y, Andreoni KA, et al. The risk of recurrent IgA 10. Watson CJ, Bradley JA, Friend PJ, et al. Alemtuzumab (CAMPATH nephropathy in a steroid-free protocol and other modifying 1H) induction therapy in cadaveric kidney transplantation-- immunosuppression. Clin Transplant. 2014;28(8):845-854. efficacy and safety at five years. Am J Transplant. 2005;5(6):1347- 23. Leeaphorn N, Garg N, Khankin EV, Cardarelli F, Pavlakis M. 1353. Recurrence of IgA nephropathy after kidney transplantation in 11. Kim JK, Kim JH, Lee SC, et al. Clinical features and outcomes of IgA steroid continuation versus early steroid-withdrawal regimens: a nephropathy with nephrotic syndrome. Clin J Am Soc Nephrol. retrospective analysis of the UNOS/OPTN database. Transpl Int. 2012;7(3):427-436. 2018;31(2):175-186. 12. Wyld ML, Chadban SJ. Recurrent IgA nephropathy after kidney transplantation. Transplantation. 2016;100(9):1827-1832. 13. Han SS, Huh W, Park SK, et al. Impact of recurrent disease and chronic allograft nephropathy on the long-term allograft outcome in patients with IgA nephropathy. Transpl Int. 2010;23(2): 169-175. Artıcle
Gene Expression of Toll-Like Receptors 2 and 4 in Renal Transplant Rejection
Mozhdeh Heidari,1 Padideh Ebadi,2 Sanaz Abbasi,1 Afsoon Afshari,1 Ramin Yaghobi,1 Mehdi Salehipour1, Mohammad Hossein Karimi1
Abstract Key words: Acquired immunity system, Acute allograft rejection, Innate immune system Objectives: Toll-like receptors are a crucial part of the Introduction innate immune system and have a pivotal role in the acquired immunity system. Studies have shown that Toll-like receptors 2 and 4 are important during the Kidney transplant is the current standard treatment transplant process. Therefore, we analyzed the gene for most patients with end-stage renal disease; expression of Toll-like receptors 2 and 4 in cases unfortunately, adaptive and innate immune responses of renal transplant rejection. We measured the to graft alloantigens are the highest threats to graft messenger RNA expression levels of Toll-like receptors survival.1,2 Acute graft rejection is a phenomenon once 2 and 4 in renal transplant rejection recipients thought to be initiated by the adaptive immune compared with nonrejection recipients. system, but further studies revealed that the innate Materials and Methods: We enrolled 151 deceased- immune system is critical in initiating acute donor kidney transplant recipients, whom we divided inflammatory responses during organ transplant.3 into 2 groups: 101 nonrejection recipients and 50 Acute rejection of kidney allograft is still the cause recipients with acute allograft rejection. We collected 3 mL of blood (treated with ethylenediaminetetraacetic of 10% to 20% of renal transplant rejections in acid) from each patient. Ribonucleic acid extraction and patients with kidney grafts, which can be a threat complementary DNA synthesis were conducted for all for graft survival. The innate immune system samples, and the constructed complementary DNAs could initiate the rejection after transplant, were used for real-time polymerase chain reaction and Toll-like receptors (TLRs), as members of innate analysis. immune system, may have a major role in the Results: We measured gene expression levels of Toll- rejection.4,5 like receptors 2 and 4 in renal transplant recipients Toll-like receptors are expressed in several types with acute allograft rejection and in recipients who did of immune cells, at various levels.6,7 Toll-like not experience acute renal allograft rejection, and the receptors are conserved molecules that can cause results showed that messenger RNA expression levels for both Toll-like receptors 2 and 4 were significantly induction of innate immune responses, which may 8 increased in the acute rejection group compared with lead to antigen-specific adaptive immunity. At the nonrejection group. present, 13 types of human TLRs have been detected; Conclusions: Toll-like receptors 4 and 2 could increase among them, TLR2 and TLR4 are well known for the risk of acute rejection after renal transplant and being activated during several events, including the could be defined as a risk factor for rejection. Further transplant process.9 studies are recommended. Toll-like receptor-mediated signals are known to play a crucial role in various organs with regard to From the 1Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; and the many facets of transplantation biology, including the 2Department of Basic Science, School of Medicine, Islamic Azad Shiraz, Iran Acknowledgements: This article was supported by the Transplant Research Center, Shiraz rejection and tolerance, ischemia-reperfusion injury, University of Medical Sciences, Shiraz, Iran. The study team would like to gratefully and infections after transplant.10 Toll-like receptors acknowledge the staff of this center. are expressed in a wide range of kidney cells (14 types) Corresponding author: Mohammad Hossein Karimi, Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran and can induce innate immune function by detecting E-mail: [email protected] motifs of endogenous and exogenous molecules
Experimental and Clinical Transplantation (2020) 7: 757-762 during cellular injuries.11 The TLR stimulation by
Copyright © Başkent University 2020 DOı: 10.6002/ect.2019.0242 Printed in Turkey. All Rights Reserved. 758 Mozhdeh Heidari et al/Experimental and Clinical Transplantation (2020) 7: 757-762 Exp Clin Transplant
exogenous and endogenous ligands induces the excluded. Moreover, transplant recipients with viral release of inflammatory cytokines and chemokines, infections such as cytomegalovirus and polyoma BK which is a phenomenon associated with allograft virus were excluded from the project. rejection.3 The remaining transplant recipients (151) were The messenger RNA (mRNA) of TLR2 in the divided into 2 groups. The first group, without acute murine kidney is often expressed in the renal tubular rejection (non-AR), consisted of 101 patients who had and Bowman capsule epithelial cells.8 Toll-like not experienced any episodes of AR during the receptor 2 is a transmembrane protein, the activation study period; the second group was composed of of which starts a signaling pathway composed of 50 patients who had experienced AR during the adaptor proteins such as myeloid differentiation first week after transplant. Expert pathologists, primary response gene 88 (MyD88) and MyD88 according to Banff criteria, certified the AR state adapter-like (Mal; also known as TIRAP) and finally of the second group after analysis of the patients’ culminates in the induction of proinflammatory kidney biopsies.21 The present study was conducted cytokines.12 according to the Declaration of Helsinki and was Toll-like receptor 4 is one of the first molecules approved by the Ethics Committee of Shiraz that, once activated, leads to quick production of University of Medical Sciences, and the patients were cytokines and interferes in inflammation during informed and signed the consent form before cellular damage.13,14 This molecule is strongly participating in this study. According to the rules of expressed in leukocytes and also in organs such as the transplantation ward of Namazi Hospital, all the kidney.15,16 Furthermore, the role of TLR4 has transplant recipients received organs from deceased previously been recognized in ischemia-reperfusion donors. Human leukocyte antigen typing and ABO injury, kidney repair, renal injury progression, and blood compatibility were performed for all kidney renal fibrosis.17,18 Toll-like receptors such as TLR2 transplant patients. and TLR4 are critical factors of innate immunity, which start rejection processes and could be Sample collection important to increase long-term survival after Blood samples (3 mL, treated with EDTA) were transplant.19,20 In this study, we evaluated the mRNA collected from each patient. Serum and buffy coat expression levels of TLR2 and TLR4 in recipients from each sample were separated using Ficoll with acute renal allograft rejection versus gradient (Nycomed, Zurich, Switzerland). nonrejection recipients. ribonucleic acid isolation and quantitative real- Materials and Methods time polymerase chain reaction To evaluate gene expression of TLR2 and TLR4 in Patients cases of renal transplant rejection, quantitative real- The present study was performed from 2012 to 2014 time polymerase chain reaction (qRT-PCR) was for patients admitted to the kidney transplant ward performed. For this purpose, the total RNA was of Namazi Hospital, Shiraz, Iran. We collected 3 mL extracted using the RNX-Plus solution (CinnaGen, of blood (treated with ethylenediaminetetraacetic Tehran, Iran) according to the manufacturer’s acid [EDTA]) from 151 kidney transplant recipients. protocol, and the concentration of extracted RNA The patients were enrolled in the study according to was then quantified using a NanoDrop Lite the following inclusion criteria: the recipients had Spectrophotometer (Thermo Fisher Scientific). The received a kidney transplant just 1 time from a quality of extracted RNA was considered by 1% deceased donor, and the recipients were treated with agarose gel electrophoresis, as well. Subsequently, the specific immunosuppressive drug regimens. These complementary DNA (cDNA) was synthesized. We specific immunosuppressive drugs were calcineurin used 1 μg of extracted RNA for cDNA synthesis, inhibitors and were administered to all patients by adding random hexamer (1 μL, 0.2 μg) and in each study group. The exclusion criteria were deoxynucleoside triphosphates (1 μL, 10 mM); the mix retransplant or combined transplant. Also, the was incubated at 65°C for 7 minutes and then put on samples of transplant recipients who were deceased ice for 2 minutes. In the next step, Moloney murine before completing the sample collection were leukemia virus reverse transcriptase (RT) enzyme Mozhdeh Heidari et al/Experimental and Clinical Transplantation (2020) 7: 757-762 759
(1 μL, 200 U; Vivantis, Selangor, Malaysia), RT buffer Statistical analyses (2 μL, 10×), and ribonuclease inhibitor (1.3 μL, 60 U) The statistical differences in the expression levels of were mixed and added to the first mix. The new genes and the fold changes in patients and controls whole mix was incubated for 90 minutes at 45°C and were compared via the Livak methods (2-∆∆CT). then 5 minutes at 85°C. All RNA samples were treated Statistical analyses were performed through SPSS with deoxyribonuclease (DNase; Thermo Fisher software (version 22.0; IBM Corporation, Armonk, Scientific) before changing to cDNA. For this reason, NY, USA), using parametric and nonparametric 1 μL for each μg of RNA was treated with DNase. analyses. P < .05 was considered significant. The AlleleID 6 software (Premier Biosoft International) was used to design the primers for Results amplification of the genes of interest (TLR2 and 4 genes). Subsequently, the primer specificity was Descriptive characteristics confirmed by Primer-BLAST (https://www.ncbi. The non-AR group consisted of 101 kidney trans - nlm.nih.gov/tools/primer-blast) and In-Silico PCR plant recipients: 62 were male (61.4%; age range, (https://genome.ucsc.edu/cgi-bin/hgPcr). The beta- 14-69 years), and 39 were female (38.6%; age range, actin gene was used as the housekeeping gene, as it 15-61 years). The AR group consisted of 50 kidney is known to have only minor fluctuations versus the transplant recipients: 33 were male (66%; age range, comparatively higher fluctuations of other genes. 6-68 years), and 17 were female (39%; age range, The amplification mixes and primer sequences are 13-58 years). The mean ages in the non-AR group summarized in Tables 1 and 2. and AR group were 42 ± 14.6 years and 42 ± 14.9 To check the specificity of an amplification years, respectively. The ABO blood groups and reaction, the melting-curve analysis was evaluated. underlying diseases in both study groups are The results for the target genes were measured as summarized in Tables 3 and 4. fluorescence signal intensity and normalized to the internal standard gene, beta-actin. The program for table 3. Blood Group Distribution in the Study Groups Blood Group Patient Group, No. of patients (%) thermocycling as follows: 1 cycle at 95°C for 2 min, AR Non-AR followed by 40 cycles at 95°C for 30 seconds, and O Rh+ 25 (50%) 33 (33%) then 1 cycle at 65°C for 20 seconds following melting- A Rh+ 16 (32%) 24 (24%) B Rh+ 4 (8%) 24 (24%) curve analysis to confirm the specificity of the AB Rh+ 2 (4%) 11 (11%) reaction. O Rh- 1 (2%) 3 (3%) A Rh- 1 (2%) 4 (4%) B Rh- 0 0 table 1. Amplification Program of Real-Time Polymerase Chain Reaction AB Rh- 1 (2%) 0 Master Mix Volume, μL Abbreviations: AR, acute rejection SYBR Premix EX Taq II 5 PCR forward primer (3 pM) 0.2 PCR reverse primer (3 pM) 0.2 table 4. Underlying Diseases in Recipients with Acute Allograft Rejection ROX reference dye (50×) 0.2 and Nonrejection Recipients Template (< 100 ng) 1 Underlying Disease Patient Group, No. of patients (%) Distilled H O 3.4 2 AR Non-AR Abbreviations: PCR, polymerase chain reaction; ROX, carboxy-X-rhodamine Hypertension 2 (4%) 9 (18%) 7 (6.8%) 7 (6.8%) (passive reference dye); SYBR Premix EX Taq II, a reagent specifically Renal stone 1 (2%) 1 (2%) 2 (2%) 10 (10%) designed for real-time PCR Diabetes 1 (2%) 4 (8%) 2 (2%) 0 Chronic renal failure 5 (10%) 7 (14%) 12 (12%) 10 (10%) Insulin-dependent table 2. Primer Sequence for Amplification of Genes of Interest diabetes mellitus 0 1 (2%) 1 (2%) 5 (4.9%) Gene Primer Sequence Product Renal stone and hypertension 0 0 1 (1%) 2 (2%) Length, Insulin-dependent diabetes base mellitus and hypertension 0 4 (8%) 3 (2.9%) 6 (5.9%) pairs Autosomal dominant polycystic kidney disease 0 0 3 (2.9%) 3 (2.9%) TLR2 Forward 5′-TCCGCCTCTCGGTGTCGGA-3′ 102 Focal segmental Reverse 5′-AAACGGTGGCACAGGACCCC-3′ glomerulosclerosis 0 2 (4%) 2 (2%) 1 (1%) TLR4 Forward 5′-TCAAGCCCAGGATGAGGACTGGGT-3′ 117 Rapidly progressive Reverse 5′-CAGCAATGGCCACACCGGGA-3′ glomerulonephritis 0 1 (2%) 1 (1%) 5 (4.9%) Beta-actin Forward 5′-GGGCGGCACCATGTACC-3′ 203 Nephropathy 2 (4%) 4 (8%) 2 (2%) 2 (2%) Reverse 5′-GATGGAGGGGCCCGACT-3′ Other diseases 2 (4%) 4 (8%) 2 (2%) 3 (3%) Abbreviations: TLR, Toll-like receptor Abbreviations: AR, acute rejection 760 Mozhdeh Heidari et al/Experimental and Clinical Transplantation (2020) 7: 757-762 Exp Clin Transplant
toll-like receptors 2 and 4 gene expression levels: regulatory T cells, enabling pathogen-specific immune comparison between nonrejection and acute responses.25 rejection groups In the present study, we evaluated the expression The gene expression levels of TLR2 and TLR4 were levels of TLR2 and TLR4 in AR and non-AR renal compared between AR and non-AR groups (Figure transplant recipients. Our results showed that the 1). The expression level of TLR2 was significantly expression levels of TLR2 and TLR4 in the AR group increased in the AR group compared with the non- were statistically significant versus the non-AR AR group (P = .046). Furthermore, the increase in the group. It is known that TLR2 protein is constitutively level of TLR4 gene expression was significant in expressed in the kidney. However, the distribution of the AR group compared with the non-AR group TLR2 was not uniform throughout the nephron.26 (P = .034). Previous studies have shown the importance of TLR2 in renal function after transplant.12 Discussion Hoffmann and colleagues completed the first study to show the time course of TLR2 expression Recent studies have emphasized the importance of after kidney transplant in an experimental rat model. the immune system in transplant rejection.19 Toll-like The results of that study were then compared with receptors express a strong affinity for infection and TLR2 expression in human renal allograft biopsies.3 tissue injury-associated molecules. Toll-like receptors The new findings of Hoffmann and colleagues suggest are expressed throughout the animal and plant a role for TLR2 in the early time course of AR. The kingdoms, which has generated a powerful interest cellular localization of TLR2 was analyzed by in defining the characteristics of TLRs in health and immunohistochemistry, and positive staining data in disease.22,23 uninjured renal tissue were detected.16,26 Supplemental The stimulation TLRs with ligands, except for investigation of TLR2 induction with renal function TLR3, can activate the interferon regulatory factor 3 confirmed that higher TLR2 mRNA levels were related and MyD88 pathways. Activation MyD88-dependent to higher serum creatinine levels under standardized TLRs signaling pathways may cause the activation experimental conditions. Also, TLR2 was induced in of the transcription factors nuclear factor-kappaB and both the kidney and urine of rats that had received activator protein 1. Finally, these proteins lead to the renal transplants. Moreover, this excretion was related induction of innate immune responses by producing to the severity of allograft rejection and renal function. inflammatory cytokines, including interleukin-6, Toll-like receptor 2 could initiate mechanisms related tumor necrosis factor, and interleukin-12. MyD88 is to the induction and severity of AR episodes. an adapter protein that facilitates signal transduction Furthermore, TLR2 activation of innate immunity in by TLRs.24 Furthermore, a recent study by Pasare kidney transplants may contribute to acute allograft and Medzhitov confirmed the manner in which rejection.3 Another study showed that TLR2 antisense TLR activation blocked the suppressive effects of oligonucleotide treatment in an experimental
Figure 1. Messenger Ribonucleic Acid Expression Levels of Toll-like Receptors 2 and 4 in Kidney Transplant Patients
Abbreviations: AR, acute rejection; Med, median; TLR, Toll-like receptor (A) TLR2 in non-AR kidney transplant recipients. (B) TLR4 in AR kidney transplant recipients. Mozhdeh Heidari et al/Experimental and Clinical Transplantation (2020) 7: 757-762 761
ischemia-reperfusion model in mice reduced renal TLR2 and TLR4 have prominent constitutive protein dysfunction after ischemia-reperfusion injury expression through the kidney tissue, and the compared with nonsense oligonucleotide treatment.8 profound protection gained by blockade of this TLR2 targeting in order to abrogate inflammation protein expression not only shows these receptors to in diabetes resulted in reduced complications, be a chief regulator of renal injury but also suggests including nephropathy.27 Furthermore, it seems that a significant role in normal renal physiology. Toll-like TLR2 is capable of monitoring cellular injury that is receptors 2 and 4 were expressed more in the AR the result of ischemic stress and that TLR2 is crucial group compared with the non-AR group. Therefore, for the initiation of a proinflammatory immune TLR2 and TLR4 could be defined as risk markers for response.8 the induction of the innate immune system to The importance of TLR4 activation in allograft promote allograft rejection. damage in human kidney transplants has not been identified, but animal model studies have shown that References TLR4 signaling is connected to kidney injury induced 1. Kalble T, Lucan M, Nicita G, et al. EAU guidelines on renal by ischemia and reperfusion; also, in vitro studies transplantation. Eur Urol. 2005;47(2):156-166. doi:10.1016/j.eururo. revealed that renal tubular epithelial cells can 2004.02.009 2. Grassmann A, Gioberge S, Moeller S, Brown G. ESRD patients in synchronize an immune response to injuries in a 2004: global overview of patient numbers, treatment modalities TLR4-dependent manner. Studies suggest that and associated trends. Nephrol Dial Transplant. 2005;20(12):2587- 2593. doi:10.1093/ndt/gfi159 TLR4-selective targeting may be useful for the 3. Hoffmann U, Bergler T, Rihm M, et al. Impact of Toll-like receptor development of therapeutic tools to avoid injury, ie, 2 expression in renal allograft rejection. Nephrol Dial Transplant. more so than targeting the intracellular pathways 2011;26(3):1080-1087. doi:10.1093/ndt/gfq420 4. Dessing MC, Bemelman FJ, Claessen N, Ten Berge IJ, Florquin S, used by TLR4. Toll-like receptor 4 is recognized as a Leemans JC. Intragraft Toll-like receptor profiling in acute renal cellular sentinel for acute renal damage that later allograft rejection. Nephrol Dial Transplant. 2010;25(12):4087-4092. doi:10.1093/ndt/gfq589 controls the orientation of an innate immune 5. Magee CC, Pascual M. Update in renal transplantation. Arch Intern response.17,18 For instance, a study in 2007 suggested Med. 2004;164(13):1373-1388. doi:10.1001/archinte.164.13.1373 that TLR4 induction in cells is involved in cell death 6. Goldstein DR. Toll like receptors and acute allograft rejection. Transpl Immunol. 2006;17(1):11-15. doi:10.1016/j.trim.2006.09.012 and graft rejection after transplant.4 Kruger and 7. Goldstein DR, Tesar BM, Akira S, Lakkis FG. Critical role of the Toll-like colleagues showed that TLR4 was permanently receptor signal adaptor protein MyD88 in acute allograft rejection. J Clin Invest. 2003;111(10):1571-1578. doi:10.1172/ JCI17573 expressed within all kidney donors; nonetheless, it was 8. Leemans JC, Stokman G, Claessen N, et al. Renal-associated TLR2 significantly higher in deceased donor organs mediates ischemia/reperfusion injury in the kidney. J Clin Invest. 2005;115(10):2894-2903. doi:10.1172/JCI22832 compared with living donor organs. They proposed 9. Goldberg A, Parolini M, Chin BY, et al. Toll-like receptor 4 that targeting TLR4 signaling may have value in suppression leads to islet allograft survival. FASEB J. preventing or treating acute kidney injury after 2007;21(11):2840-2848. doi:10.1096/fj.06-7910com 10. Alegre ML, Goldstein DR, Chong AS. Toll-like receptor signaling in 28 transplant. Also, TLR4 attenuates tubular damage transplantation. Curr Opin Organ Transplant. 2008;13(4):358-365. but promotes renal fibrosis by controlling the doi:10.1097/MOT.0b013e3283061149 11. Johnson GB, Brunn GJ, Platt JL. Activation of mammalian Toll-like vulnerability of the renal cells to transforming growth receptors by endogenous agonists. Crit Rev Immunol. 2003;23(1- factor beta. Together, the results of the present study 2):15-44. doi:10.1615/critrevimmunol.v23.i12.20 suggest that TLR4 signaling may be a therapeutic 12. Farrar CA, Keogh B, McCormack W, et al. Inhibition of TLR2 promotes graft function in a murine model of renal transplant target for the inhibition of renal fibrosis.18 Other studies ischemia-reperfusion injury. FASEB J. 2012;26(2):799-807. doi:10. also proposed that inhibition of TLR2 and TLR4 might 1096/fj.11-195396 13. Cunningham PN, Wang Y, Guo R, He G, Quigg RJ. Role of Toll-like be potential therapeutic targets to control tumor receptor 4 in endotoxin-induced acute renal failure. J Immunol. progression and ischemia-reperfusion results.29,30 2004;172(4):2629-2635. doi:10.4049/jimmunol.172.4.2629 14. Ohashi K, Burkart V, Flohe S, Kolb H. Cutting edge: heat shock protein 60 is a putative endogenous ligand of the toll-like Conclusions receptor-4 complex. J Immunol. 2000;164(2):558-561. doi:10.4049/ jimmunol.164.2.558 15. Medzhitov R, Preston-Hurlburt P, Janeway CA, Jr. A human It is likely that renal injuries initiate multiple homologue of the Drosophila Toll protein signals activation of pathophysiological mechanisms that culminate in adaptive immunity. Nature. 1997;388(6640):394-397. doi:10.1038/ 41131 the expression of survival genes, proinflammatory 16. Wolfs TG, Buurman WA, van Schadewijk A, et al. In vivo expression cytokines, and chemokines, which ultimately lead to of Toll-like receptor 2 and 4 by renal epithelial cells: IFN-gamma and TNF-alpha mediated up-regulation during inflammation. J Immunol. activation of inflammatory cells. It is known that 2002;168(3):1286-1293. doi:10.4049/jimmunol.168.3. 1286 762 Mozhdeh Heidari et al/Experimental and Clinical Transplantation (2020) 7: 757-762 Exp Clin Transplant
17. Pulskens WP, Teske GJ, Butter LM, et al. Toll-like receptor-4 25. Pasare C, Medzhitov R. Toll pathway-dependent blockade of coordinates the innate immune response of the kidney to renal CD4+CD25+ T cell-mediated suppression by dendritic cells. ischemia/reperfusion injury. PLoS One. 2008;3(10):e3596. Science. 2003;299(5609):1033-1036. doi:10.1126/science.1078231 doi:10.1371/journal.pone.0003596 26. Shigeoka AA, Holscher TD, King AJ, et al. TLR2 is constitutively 18. Pulskens WP, Rampanelli E, Teske GJ, et al. TLR4 promotes fibrosis expressed within the kidney and participates in ischemic renal but attenuates tubular damage in progressive renal injury. J Am injury through both MyD88-dependent and -independent Soc Nephrol. 2010;21(8):1299-1308. doi:10.1681/ASN.2009070722 pathways. J Immunol. 2007;178(10):6252-6258. doi:10.4049/ 19. Brennan TV, Lunsford KE, Kuo PC. Innate pathways of immune jimmunol.178.10.6252 activation in transplantation. J Transplant. 2010;2010. doi:10.1155/ 27. Devaraj S, Tobias P, Kasinath BS, Ramsamooj R, Afify A, Jialal I. 2010/826240 Knockout of toll-like receptor-2 attenuates both the 20. Andrade CF, Waddell TK, Keshavjee S, Liu M. Innate immunity and proinflammatory state of diabetes and incipient diabetic organ transplantation: the potential role of toll-like receptors. Am nephropathy. Arterioscler Thromb Vasc Biol. 2011;31(8):1796-1804. J Transplant. 2005;5(5):969-975. doi:10.1111/j.1600-6143.2005. doi:10.1161/ATVBAHA.111.228924 00829.x 28. Kruger B, Krick S, Dhillon N, et al. Donor Toll-like receptor 4 21. Haas M, Loupy A, Lefaucheur C, et al. The Banff 2017 Kidney contributes to ischemia and reperfusion injury following human Meeting Report: Revised diagnostic criteria for chronic active T kidney transplantation. Proc Natl Acad Sci U S A. 2009;106(9):3390- cell-mediated rejection, antibody-mediated rejection, and 3395. doi:10.1073/pnas.0810169106 prospects for integrative endpoints for next-generation clinical 29. Goto Y, Arigami T, Kitago M, et al. Activation of Toll-like receptors trials. Am J Transplant. 2018;18(2):293-307. doi:10.1111/ajt.14625 2, 3, and 4 on human melanoma cells induces inflammatory 22. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate factors. Mol Cancer Ther. 2008;7(11):3642-3653. doi:10.1158/1535- immunity. Cell. 2006;124(4):783-801. doi:10.1016/j.cell.2006.02.015 7163.MCT-08-0582 23. Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol. 30. Arslan F, Keogh B, McGuirk P, Parker AE. TLR2 and TLR4 in ischemia 2004;4(7):499-511. doi:10.1038/nri1391 reperfusion injury. Mediators Inflamm. 2010;2010:704202. 24. Kim IK, Bedi DS, Denecke C, Ge X, Tullius SG. Impact of innate and doi:10.1155/2010/704202 adaptive immunity on rejection and tolerance. Transplantation. 2008;86(7):889-894. doi:10.1097/TP.0b013e318186ac4a Artıcle
Management of Multiple Renal Arteries and Unusual Venous Anatomy During Kidney Transplant: From a Simple Technical Problem to a Graft-Saving Procedure
Zivko Popov,3-5 Oliver Stankov,1,3 Sotir Stavridis,1,3 Skender Saidi,1,3 Ognen Ivanovski,1,3 Goce Spasovski,2,3 Koco Cakalaroski,2 Ninoslav Ivanovski3,4
Abstract survival rates between the groups with or without vascular anomalies. Objectives: Incidence of vascular anomalies in donor Conclusions: Vascular anomalies should no longer be kidneys varies from 18% to 30% and presents a considered a contraindication for transplant, if careful challenge for a transplant surgeon in kidney transplant. anastomosis is performed in every case to avoid Here we present our personal experience for man- ischemia and further complications. Therefore, agement of the complicated and unexpected cases. management of vascular anomalies could be a graft- Materials and Methods: A total of 250 kidney saving procedure. transplants (226 living, 24 deceased) were performed in a period of 24 years; mean donor age was 55 years Key words: Graft survival, Organ donation, Surgical (range, 25-86 years), and mean recipient age was 38.6 techniques, Vascular anomalies years (range, 14-66 years). We analyzed the surgical techniques, complications and outcomes, rejection Introduction episodes, kidney function, and graft and patient survival rates. The surgical reconstruction of the blood circulation Results: Of 250 nephrectomies, 209 had a single artery is one of the most important parts of transplant (83.6%), 34 had 2 arteries (13.6%), and 7 had 3 arteries surgery, including living donor (LD) and deceased (2.8%). Of 34 double arteries, 14 had 2 main arteries, donor (DD) organs. The anatomic region of the 15 had a main and a polar artery, and 5 had an aortic kidneys and blood supply system is prone to common Carrel patch after deceased donation. According to the congenital malformations, as well as uncommon size, type, and position, the anastomoses were malformations, any of which may present a challenge performed with branches of hypogastric, epigastric inferior, iliac external, and main renal artery, for transplant surgeons. The efficacy of the surgical intracorporeally or in bench surgery. Regarding veins, correction and adaptation of the local arterial and 1 double inferior vena cava, 1 left-side inferior vena venous blood supply are crucial to achieving short- cava, 4 retroaortic, 2 circumaortic, 10 large lumbar veins and long-term graft survival. In the past, most cases draining into the left renal veins, and 8 cases with 2 or with arterial anomalies (multiple) were a genuine more different size renal veins were managed. In 9 cases contraindication for kidney transplant, especially in with short right renal vein, an extension with vena cava living donor transplant.1 The problem of multiple (a “Barry cavoplasty”) was performed in deceased donor renal arteries (MRA) is associated with other surgical organs. No serious surgical complications related to problems in kidney transplant recipients, such as vascular anomalies were observed. There were no delayed graft function, acute rejection, and increased statistical differences in 1-, 6-, and 12-month graft urological and vascular complications. Some of From the 1University Clinic of Urology; the 2University Clinic of Nephrology; the 3Medical Faculty, University Saints Cyril and Methodius; the 4Zan Mitrev Clinic; and the 5Macedonian these problems are discussed in the literature, Academy of Sciences and Arts, Skopje, North Macedonia such as renal infarcts, ureteral necrosis and ureteral Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no further declarations of potential fistula, hemorrhage, and hematoma, as well as interest. thrombosis. Corresponding author: Zivko Popov, MASA-Bulevar Krste Misirkov br 2, 1000 Skopje, North Macedonia The presence of MRA is the most frequently E-mail: [email protected] encountered anatomic variation in kidneys.2-4
Experimental and Clinical Transplantation (2020) 7: 763-770 Incidence of unilateral and bilateral MRA during
Copyright © Başkent University 2020 DOı: 10.6002/ect.2019.0314 Printed in Turkey. All Rights Reserved. 764 Zivko Popov et al/Experimental and Clinical Transplantation (2020) 7: 763-770 Exp Clin Transplant
kidney transplant is 23% and 10%, respectively.2 at our center, the suitable donors (living and Autopsy studies have suggested that the prevalence deceased) were accepted with a minimum of 50% of rate of MRA is 18% to 30%, with 15% being bilateral.5 human leukocyte antigen compatibility and A variety of methods have been described to complement-dependent cytotoxicity cross-match transplant these MRA kidneys, including micro - negativity. For imaging a vascular structure of vascular surgery. Here we review the available the kidneys (arterial and venous), a standard operative techniques, the relative merits and angiography, computed tomography angiography, or indications, and the reasons for our preferences. magnetic resonance imaging angiography was The venous anomalies, such as double veins with performed. different size, retroaortic veins, and circumaortic The final decision regarding which kidney should veins, as well as anomalies in venous and vena be removed was based on the established criteria that cava position, are important considerations in the donor should retain the better kidney and that kidney transplant surgery and can cause difficulties the donor nephrectomy should be performed on the in open surgery and laparoscopic surgery. Although side that is the least complicated, to reduce risk to the venous anomalies are not common in kidney donor.18 The standard transplant procedure was transplant surgery, these present a real clinical performed for all kidney transplant recipients, ie, dilemma if discovered during the surgical end-to-end or end-to-side arterial anastomosis with procedure.6-10 hypogastric or iliac external artery and end-to-side Today, MRA are no longer considered a venous anastomosis with external iliac vein. contraindication for transplant, even in living donor Ureterovesicular anastomosis was performed using nephrectomies.11-13 With current advances in the Lich-Gregoire procedure in all kidney transplant vascular surgical techniques, kidneys with MRA are recipients. All vascular anastomoses were performed engrafted without hesitation in cases when the blood by a well-skilled transplant surgeon who used vessels supply more than 5% to 10% of renal optical loupes with the standard ×2.5 magnification parenchyma.14 and standard surgical instruments and materials, With the inclusion of all possible kidneys for including monofilament nonabsorbable suture (5-0, transplant with MRA and other vascular anomalies, 6-0, 7-0, or 8-0). All grafts were transplanted into including those with arteries and veins inadvertently iliac fosse via extraperitoneal access. Most damaged during donor kidney removal, the potential of the cases with vascular anomalies (arterial and donor pool is expanded, and more organs are venous) were successfully managed during the available for the increasing number of patients on surgery procedure by performing microvascular wait lists.15,16 anastomoses. In a few complicated cases, bench The worldwide popularity of laparoscopic donor surgery was needed.2 nephrectomy, with the accumulation of surgical and A quadruple sequential immunosuppression technical experience, is now extended to donor (antithymocyte globulin, basiliximab, and daclizumab organs with MRA, but MRA remain a technically as an induction and triple-drug maintenance therapy challenging condition, especially for right-side with calcineurin inhibitors, mycophenolate mofetil, kidney procedures.17 and steroids) was introduced in all patients regardless of the immunological risk of the kidney transplant Materials and Methods recipient.19 The demographic and clinical charac - teristics of the donors and recipients are presented in We retrospectively analyzed 250 kidney transplant Table 1. recipients (226 LD and 24 DD) during the period of Survival rates of patients and grafts, delayed graft 1987 to 2011 at the University Clinics of Urology, function, rejection rate, bleeding episodes and Nephrology and Transfusiology at the Clinical hematomas, vascular and urological complications, Centre in Skopje, North Macedonia. Among and cold and warm ischemia times were analyzed 226 living donors, 202 were parents of recipients, during the study. The results were compared while 24 were unrelated donors who were with patients who had single renal arteries and spouses (17), mothers-in-law (4), fathers-in-law veins, which was considered as the control (2), and a brother-in-law (1). According to the policy group. Zivko Popov et al/Experimental and Clinical Transplantation (2020) 7: 763-770 765
table 1. Clinical and Demographic Characteristics in Our Series (1987-2011) end-to-end anastomosis to the branches of the Characteristic Result internal iliac artery was used. In 2 cases, a double- Total number of transplants, No. (%) 250 (100%) barrel technique (side-to-side conjoined artery to Living donors 226 (90.4%) Deceased donors 24 (9.6%) artery anastomosis) was performed. Fifteen LD had Living-unrelated donors, No. (%) 31 (12.4%) main and polar arteries (7 upper polar and 8 lower Recipient mean age, years (range) 38.6 (14-66) Male recipients, No. (%) 140 (56%) polar), and among these were 3 that were Donor mean age, years (range) 55 (25-86) anastomosed into the main artery. Four smaller Male donors, No. (%) 105 (42%) Human leukocyte antigen mismatch ~2.6 upper polar arteries, which supply less than 10% of Mean warm ischemia time, min ~2.7 the kidney surface area, were ligated. Five lower Mean cold ischemia time, h 5.82 Living donors 3.10 polar arteries were anastomosed end-to-end with the Deceased donors 15.60 epigastric inferior artery, 1 end-to-side with external Delayed graft function, No. (%) 45 (18%) Living donors 36 (14.4%) iliac artery, 1 end-to-side to main renal artery, and 1 Deceased donors 9 (37.5%) was ligated. Despite the ligation of the lower polar Rejections, No. (%) 44 (17.6%) Living donors 35 artery, we did not observe any ureteral consequences. Deceased donors 9 In 5 DD, an aortic Carrel patch was used for end-to- side to external/common iliac artery anastomosis. In Results a single patient, an aortic patch between 2 widely separated arteries was created to approach these and Of 250 donor nephrectomies (84% left side and 16% revascularize with a single suitable Carrel aortic right side), 209 donor organs had a single renal artery patch. and 41 had MRA (34 donor organs had 2 arteries, and In 7 donors (5 LD and 2 DD), 3 arteries were 7 donor organs had 3 arteries). With regard to the found. Of 5 LD, 3 kidneys had 3 hilar arteries. Two venous system, 242 kidneys had a single vein arteries were anastomosed end-to-end with the (96.8%), and 8 donor kidneys had 2 or more different branches of hypogastric artery, and the third artery size renal veins. Among the donors with a single was anastomosed end-to-side with the external iliac vein, the specific different venous anatomic position artery. For 2 LD with 2 main arteries and 1 lower pole had been determined, ie, retroaortic left vein in 4 artery, the arteries were anastomosed end-to-end cases (3 with type 1, and 1 with type 4) and with the branches of the hypogastric artery and circumaortic (collar) left renal veins in 2 cases. In 10 lower polar artery end-to-end with the epigastric LDs a large lumbar vein was drained into renal vein, inferior artery. For 2 DD with 3 renal arteries, the and in 9 DDs a short right renal vein was discovered arteries were anastomosed with an aortic Carrel and resolved. patch end-to-side to the external/common iliac Surgical and microsurgical techniques of intra - artery (Table 2, Figure 1). corporeal in situ and ex vivo bench surgery anastomotic techniques were applied.2 Venous reconstruction Before and during the preparation of the LD and Similar to arterial anatomy variations, venous recipient pair, arterial anatomy was carefully evaluated variations have been observed with as many as 8 for both, usually by computed tomography accessory veins. In this case, 7 veins were ligated; angiography.20 With regard to our center’s policy to however, for 1 vein, an end-to-side anastomosis into accept expanded criteria donors (eg, elderly, marginal), the main renal vein was necessary. An extension of a the renal vascular anatomy of the donor was an short right renal vein was created with an adherent important consideration for the final decision to caval patch in 9 DD cases. transplant, and a plan was established to manage Regarding anatomy position variations in LD potential MRA or atherosclerotic plaques on the cases, 4 retroaortic left renal veins were detected donor renal arteries and recipient pelvic arteries. (type 1 joining IVC in the orthotopic position in 3 cases, and type 4 joining IVC close to the union of the Arterial reconstruction common iliac vein in 1 case). Two circumaortic left Ex vivo bench surgery anastomotic technique was collar veins were observed for which the main and used in 13 cases and in 28 intracorporeal in situ dominate vessel was the preaortic branch. After reconstructions. In the case of 2 main arteries (12 LD), careful surgical assessment and investigation, the 766 Zivko Popov et al/Experimental and Clinical Transplantation (2020) 7: 763-770 Exp Clin Transplant
Figure 1. Schematic Examples of Our Surgical and Microsurgical Techniques of Intracorporeal and Ex Vivo Anastomosis for Grafts With Multiple Renal Arteries
Schematic examples of surgical and microsurgical techniques of (a-c) intracorporeal and (d-f) ex vivo anastomoses for grafts with multiple renal arteries (Popov Z, Personal data) smaller retroaortic branch was ligated without that for arterial reconstruction; there are surprisingly complications. The other anatomic variations high numbers of congenital variations (Figures 4 and included large lumbar veins draining to the left renal 5). In many cases, the venous reconstruction presents veins, which were carefully ligated. Curiously, a real surgical dilemma, and yet it may be the best among the cases presented in our study, the solution. congenital anomalies of affected IVC were observed in 2 LD left nephrectomy, ie, the left side in one table 3. Venous Anomalies and Type of Anastomosis and a double IVC in the other (Table 3, Figures 2 Malformation and Technique Number (%) Single renal vein, end-to-side to external iliac vein 242 (96.8%) and 3). Two or more different size renal veins 8 (3.2%) The surgical approach to the venous system Ligation of the smaller vessel 7 anomalies should be performed with care equal to Anastomosis, end-to-side with main renal vein 1 Retroaortic veins 4 (1.6%) Circumaortic veins 2 (0.8%) table 2. Arterial Malformations and Technique of Reconstruction Large lumbar vein draining into the left renal vein 10 (4%) “Barry cavoplasty” of the short right renal vein, deceased donor 9 (37.5%) Malformation and Technique Number (%) Double vena cava, left kidney 1 (0.4%) Single renal artery, No. (%) 209 (83.6%) Left-side vena cava 1 (0.4%) End-to-end with hypogastric artery 198 (79.2%) Absence of the infrarenal vena cava 0 End-to-side with iliac external artery 11 (4.4%) Two arteries, No. (%) 34 (13.6%) Two main renal arteries anastomosed end-to-end to Figure 2. Left-Side Inferior Vena Cava (Living Donor Nephrectomy) the branches of internal iliac artery 12 (4.8%) Side-to-side conjoined artery-to-artery anastomosis (double-barrel technique) 2 (0.8%) Main and polar arteries, No. (%) 15 (6%) Seven upper polar arteries (3 into the main renal artery, 4 smaller ligated), 8 lower polar arteries (5 to epigastric inferior, 1 end-to-side with external iliac, 1 end-to-side lower polar artery to main renal artery, 1 ligated), Carrel patch from the aorta with end-to-side with common/external iliac artery 5 (2%) Three arteries, No. (%) 7 (2.8%) Three 3-hilar arteries (internal plus external artery), 2 main with lower pole arteries (epigastric artery) 5 (2%) Carrel patch from the aorta with end-to-side with common/external iliac artery 2 (0.8%) Zivko Popov et al/Experimental and Clinical Transplantation (2020) 7: 763-770 767
Figure 3. Duplication of Inferior Vena Cava (Living Donor Nephrectomy) Discussion
The present worldwide organ shortage causes 20 deaths every day, and every 10 minutes someone new is added to the wait lists; therefore, every available organ is important and has the potential to save a human life. No available kidneys should be considered unsuitable for transplant if there is a possibility for their successful use. Organ shortage remains a major problem, especially in developing countries, where the rate of transplant is significantly 21 lower than in the developed world. Our task as surgeons is to perform any possible surgical procedure Figure 4. Two Different Sizes of Renal Veins Found Incidentally With 2 Renal Arteries (Living Donor Nephrectomy) to best facilitate a successful kidney transplant. With this practice, the percentage of marginal donors (eg, donors with vascular anomalies, controlled hypertension, and urological problems, as well as elderly donors) can be increased.15,16 Vascular anomalies in donors and recipients, which were long considered to be a contraindication for transplant, are now increasingly accepted because of improvements in surgical techniques and imaging procedures.11 Usually, MRA are identified from the results of the donor angiography. Our center’s policy is to use a donor kidney with MRA only if the presentation is bilateral or if the kidney has a single artery that cannot be used for medical and ethical reasons.19,22 The introduction of bench ex vivo surgery or intracorporeal microsurgery enables Figure 5. Retroaortic Renal Vein Draining Into Inferior Vena Cava Close to the Union of the Common Iliac Veins (Living Donor Nephrectomy) most arterial anomalies to be reconstructed and reanastomosed with good short- and long-term outcomes that are equal to those with single artery.2 Arterial reconstruction is performed according to known experiences in transplant surgery using techniques that best fit the situation and with which the surgeon feels most comfortable. The reconstruction of the arterial supply of the graft is a difficult surgical procedure that may require the introduction of an ex vivo microsurgery procedure (bench) in some cases; hence, this approach may represent a clinical dilemma. When a donor kidney has 2 arteries of unequal size, it is preferable to anastomose these arteries separately rather than perform an end-to-side bench surgery, which carries the potential risk of compromising the lumen of the larger renal artery. Care must be taken with intrahilar dissection and vascular anastomosis, which may jeopardize ureteral blood supply. Lower polar arteries must be anastomosed with attention to the risk that occlusion of lower polar arteries may cause 768 Zivko Popov et al/Experimental and Clinical Transplantation (2020) 7: 763-770 Exp Clin Transplant
ischemia, infarction, and urology complications such en bloc binephrectomy in DDs, the problem of short as caliceal or ureteral necrosis and fistulae. Regarding right renal veins could be solved by so-called “Barry the use of inferior epigastric artery, it is especially cavoplasty,” which we have used successfully in 9 suitable for anastomosis with an injured length cases of our DD transplant program.26 of lower polar artery to avoid further ureteral The venous variations and anomalies are a complications on the same side. Therefore, the specific challenge for the transplant surgeon and inferior epigastric artery should be carefully represent a real clinical dilemma. The total number prepared from the start of surgical incision to secure of more than 60 cases with vascular anomalies in our sufficient length. On the other hand, the inferior experience confirms that these cases could represent epigastric artery is rarely involved with a serious problem for transplant surgeons, especially atherosclerosis, and wall thickness and diameter are in laparoscopic LD27,28 and DD nephrectomy. almost the same with the polar arteries. Any eventual Theoretically, the transplant team could expect more anastomosis with epigastric arteries should be complications such as prolonged cold ischemia time, performed only after removal of the vascular clamps second warm ischemia time, time of reanastomosis, on the main vessels to avoid the prolongation of higher rate of vascular and urology complications, warm ischemia time. In the present study, no ureteral readmissions, long-term hospitalization, and addi - fistula was observed.2,21,23-25 With DD cases, the tional surgery. In analyses of surgical complications reimplantation of MRA on a common Carrel patch is (Table 4), we observed no differences between the the preferable technique. The arterial reconstructive group with vascular anomalies and the group with procedure is presented in Figure 1. single artery and vein. In our study, the incidence of MRA (16.4%) was Most of the complications presented in our study low compared with other studies.2,5 The reason for are typical, ie, common in routine transplant surgery. this may be the large number of living-related and The percentage of 2% renal artery thrombosis in the living-unrelated donors in our program.22 whole group of patients corresponds with previous The percentage of venous anomalies was much results.29 Of note, we did not observe any episode of lower (3.2%) than arterial anomalies. Most venous thrombosis after reconstruction surgery in the group anomalies were multiple renal veins or retroaortic with MRA. Regarding late artery stenosis, our rate is and circumaortic collar veins. In our experience, the 6%, which is in accordance with published data.30 2 components of the circumaortic veins must be Similar to the case of artery thrombosis, we did not identified, and this is not always an easy task. In find any differences between group 1 and group 2. every case of circumaortic veins, we decided to However, we observed these complications at the ligate a slightly smaller vein, usually a retroaortic beginning of our transplant program. The routine component. We did not observe any complication of method of treatment of late artery stenosis was importance after the ligation.7,8,10 A special challenge percutaneous balloon dilatation or stenting. The was presented by the position and structure of urinary fistulas arose mostly as a complication of venous system anomalies discovered incidentally vascular irrigation of ureter in 5.6% of our cohort, but (drainage of large lumbar veins into the left renal this complication was not associated with the cases of vein, double IVC, and left-side IVC) (Figure 2). MRA. The routine treatment was terminoterminal Therefore, modern imaging techniques, including table 4. Number of Surgical Complications (N = 250) multidetector computed tomography angiography, Malformation and Technique Number (%) could reveal not only arterial anomalies but also Graft rupture 9 (3.6%) different complicated venous system variations.9,10 Renal vascular thrombosis 7 (2.8%) Arterial 5 (2%) The presentation of the venous variations before Venous 2 (0.8%) surgery to an experienced radiologist and transplant Urinary fistula 14 (5.6%) Intestinal perforation 2 (0.8%) surgeon could be especially important in the final Renal artery stenosis 15 (6%) decision regarding kidney choice (ie, left or right). In Hematoma 11 (4. 4%) Arterial or venous bleeding 4 (1.6%) our series of venous anomalies, of particular interest Wound infection 9 (3.6%) were the cases of double IVC and left-side IVC Lymphocele 14 (5.6%) because of the short renal veins from both sides that Hemopneumothorax 1 (0.4%) Subdural hematoma 1 (0.4%) could be represent a surgical problem.9,10 In case of Intracerebral hematoma 1 (0.4%) Zivko Popov et al/Experimental and Clinical Transplantation (2020) 7: 763-770 769
table 5. Graft Function at 1, 6, and 12 Months 4. Eibl N, Rudolph B, Roser M, Kahl A, Mihatsch MJ, Gollasch M. Arteriovenous malformation in a kidney allograft. NDT Plus. Parameter Group 1: Group 2: P 2009;2(4):320-322. doi:10.1093/ndtplus/sfp036 Patients With Patients With MRA and VA Single Artery 5. Roza AM, Perloff LJ, Naji A, Grossman RA, Barker CF. Living-related and Vein donors with bilateral multiple renal arteries. A twenty-year experience. Transplantation. 1989;47(2):397-399. Serum creatinine, μmol/L 6. Haladaj R, Polguj M, Wysiadecki G, Zytkowski A, Topol M. 1 mo 147 ± 0.6 125 ± 0.7 <.07 Circumaortic left renal vein (circumaortic renal collar) associated 6 mo 131 ± 0.4 110 ± 0.5 <.9 with the presence of vascular anomalies: a case series and review 12 mo 115 ± 0.5 98 ± 0.6 <.4 Graft survival rate, % of literature. Folia Morphol (Warsz). 2019;78(2):437-443. doi:10. 6 mo 96 93 NS 5603/FM.a2018.0090 12 mo 93.7 94 NS 7. Lin CH, Steinberg AP, Ramani AP, et al. Laparoscopic live donor nephrectomy in the presence of circumaortic or retroaortic left Abbreviations: MRA, multiple renal arteries; NS, not significant; VA, venous renal vein. J Urol. 2004;171(1):44-46. doi:10.1097/01.ju.0000 anomalies 099895.62724.04 8. Modi P. Retroperitoneoscopic donor nephrectomy for retroaortic renal vein draining into left common iliac vein. Urology. anastomosis with ipsilateral or contralateral ureter 2008;71(5):964-966. doi:10.1016/j.urology.2007.11.104 of the same side. According to our experience, 9. Fronek JP, Morsy MA, Singh U, Chemla E, Chang RW. Retroperitoneoscopic live donor nephrectomy in a patient with a reconstructive surgery of the accessory lower polar double inferior vena cava. J Laparoendosc Adv Surg Tech A. artery is mandatory. 2006;16(4):378-380. doi:10.1089/lap.2006.16.378 10. Deak PA, Doros A, Lovro Z, et al. The significance of the When we compared results from kidney transplant circumaortic left renal vein and other venous variations in recipients who had a single artery anastomosis, we laparoscopic living donor nephrectomies. Transplant Proc. did not find any significant differences in serum 2011;43(4):1230-1232. doi:10.1016/j.transproceed.2011.03.069 11. Lafranca JA, van Bruggen M, Kimenai HJ, et al. Vascular multiplicity creatinine levels at 1, 6, and 12 months and graft should not be a contra-indication for live kidney donation and survival rate at 12 months (Table 5). transplantation. PLoS One. 2016;11(4):e0153460. doi:10.1371/ journal.pone.0153460 12. Kwapisz M, Kieszek R, Bieniasz M, et al. Do anatomical anomalies Conclusions affect the results of living donor kidney transplantation? Transplant Proc. 2018;50(6):1669-1673. doi:10.1016/j.transproceed. 2018.03.119 Donors with vascular anomalies are often considered 13. Zorgdrager M, Krikke C, Hofker SH, Leuvenink HG, Pol RA. Multiple unsuitable for transplant; however, these donors can renal arteries in kidney transplantation: a systematic review and be suitable sources of valuable organs. The use of meta-analysis. Ann Transplant. 2016;21:469-478. doi:10.12659/aot. 898748 modern imaging techniques before surgery could 14. Saidi R, Kawai T, Kennealey P, et al. Living donor kidney identify most arterial and venous anomalies, transplantation with multiple arteries: recent increase in modern era of laparoscopic donor nephrectomy. Arch Surg. providing valuable information for the decision 2009; 144(5):472-475. doi:10.1001/archsurg.2009.49. PMID: regarding which kidney should be removed, that 19451491 15. Popov Z, Kolevski P, Ivanovski N. Use of expanded criteria in living is, the left or right. We recommend the use of kidney donors: the crucial factor for improvement of the kidney multidetector computed tomography angiography transplant programme in Republic of Macedonia. Pril (Makedon as a standard procedure in the assessment of donor Akad Nauk Umet Odd Med Nauki). 2014;35(2):5-7. doi:10.2478/ prilozi-2014-0001 suitability. An experienced transplant team at a high 16. Ivanovski N, Popov Z, Kolevski P, Cakalaroski K, Stojkovski L. The professional level is necessary to successfully donor organ shortage in the Balkans: accept everyone! Transplant Proc. 1997;29(8):3397-3398. doi:10.1016/s0041- manage the variety of different vascular anomalies, 1345(97)01112-3 especially in living kidney donors, and to prevent 17. Troppmann C, Wiesmann K, McVicar JP, Wolfe BM, Perez RV. short- and long-term complications in kidney Increased transplantation of kidneys with multiple renal arteries in the laparoscopic live donor nephrectomy era: surgical transplant recipients. technique and surgical and nonsurgical donor and recipient outcomes. Arch Surg. 2001;136(8):897-907. doi:10.1001/archsurg. 136.8.897 References 18. Popov Z, Ivanovski N, Lekovski L, et al. [Postoperative complications following kidney transplantation]. Ann Urol (Paris). 1. Vazquez R, Garcia L, Morales-Buenrostro L, Gabilondo B, Alberu J, 2000;34(5):323-329. Vilatoba M. Renal grafts with multiple arteries: a relative 19. Popov Z, Ivanovski N, Kolevski P. [Kidney transplantation in contraindication for a renal transplant? Transplant Proc. Macedonia]. Ann Urol (Paris). 2000;34(5):294-301. 2010;42(6):2369-2371. doi:10.1016/j.transproceed.2010.05.003 20. Pandya VK, Patel AS, Sutariya HC, Gandhi SP. Evaluation of renal 2. Novick AC, Magnusson M, Braun WE. Multiple-artery renal vascular anatomy in live renal donors: role of multi detector transplantation: emphasis on extracorporeal methods of donor computed tomography. Urol Ann. 2016;8(3):270-276. doi:10. arterial reconstruction. J Urol. 1979;122(6):731-735. doi:10.1016/s 4103/0974-7796.184898 0022-5347(17)56578-7 21. Kramer A, Pippias M, Noordzij M, et al. The European Renal 3. Watson CJ, Harper SJ. Anatomical variation and its management Association-European Dialysis and Transplant Association (ERA- in transplantation. Am J Transplant. 2015;15(6):1459-1471. EDTA) Registry Annual Report 2016: a summary. Clin Kidney J. doi:10.1111/ajt.13310 2019;12(5):702-720. doi:10.1093/ckj/sfz011 770 Zivko Popov et al/Experimental and Clinical Transplantation (2020) 7: 763-770 Exp Clin Transplant
22. Benedetti E, Troppmann C, Gillingham K, et al. Short- and long- 27. Patil AB, Javali TD, Nagaraj HK, Babu S, Nayak A. Laparoscopic term outcomes of kidney transplants with multiple renal arteries. donor nephrectomy in unusual venous anatomy: donor and Ann Surg. 1995;221(4):406-414. doi:10.1097/00000658-199504000- recepient implications. Int Braz J Urol. 2017;43(4):671-678. 00012 doi:10.1590/S1677-5538.IBJU.2016.0309 23. Sagban TA, Baur B, Schelzig H, Grabitz K, Duran M. Vascular 28. Wu CT, Chiang YJ, Liu KL, Chu SH. Laparoscopic live donor challenges in renal transplantation. Ann Transplant. 2014;19:464- nephrectomy in a patient with duplex inferior vena cava. 471. doi:10.12659/AOT.890893 Transplant Proc. 2004;36(7):1912-1913. doi:10.1016/j.transproceed. 24. Ali-El-Dein B, Osman Y, Shokeir AA, Shehab El-Dein AB, Sheashaa 2004.08.097 H, Ghoneim MA. Multiple arteries in live donor renal 29. Ponticelli C, Moia M, Montagnino G. Renal allograft thrombosis. transplantation: surgical aspects and outcomes. J Urol. Nephrol Dial Transplant. 2009;24(5):1388-1393. doi:10.1093/ndt/ 2003;169(6):2013-2017. doi:10.1097/01.ju.0000067637.83503.3e gfp003 25. Serena G, Gonzalez J, Guerra G, Nuss MAA, Valdes M, Ciancio G. 30. Chen W, Kayler LK, Zand MS, Muttana R, Chernyak V, DeBoccardo Vascular Reconstructions in living unrelated kidney transplant GO. Transplant renal artery stenosis: clinical manifestations, using donor ovarian vein and recipient inferior epigastric artery diagnosis and therapy. Clin Kidney J. 2015;8(1):71-78. doi:10.1093/ with simultaneous enucleation of a complex cyst. Case Rep ckj/sfu132 Transplant. 2019;2019:3272080. doi:10.1155/2019/3272080 26. Chopin DK, Popov Z, Abbou CC, Auvert JM. Use of vena cava to obtain additional length for the right renal vein during transplantation of cadaveric kidneys. J Urol. 1989;141(5):1143- 1144. doi:10.1016/s0022-5347(17)41194-3 Artıcle
Prophylactic Wound Drainage in Renal Transplant: A Survey of Practice Patterns in Australia and New Zealand
Miho Mugino,1 Taina Lee,1 Susanna Lam,1 Ahmer Hameed,2 Charbel Sandroussi,1 Steven Chadban,3 Henry Pleass,1,2 Jerome Martin Laurence1,2
Abstract Conclusions: Although drain insertion is a common practice, transplant surgeons in Australia and New Objectives: Drains are used routinely in many centers Zealand reported sufficient uncertainty concerning at the conclusion of kidney transplant, despite a the potential benefits and harms to warrant design paucity of evidence to guide practice in kidney and conduct of a randomized controlled trial. transplant. Studies have not shown benefit from prophylactic drain placement following other Key words: Drain insertion, Kidney transplant, Surgeon major abdominal and vascular operations, and preference usage is consequently declining. Our aim was to understand practice patterns and rationale for Introduction behavior in drain placement and management in kidney transplant. Kidney transplant is conducted on an increasingly Materials and Methods: We conducted an online survey elderly and multimorbid population of people with of surgeons who routinely perform kidney transplants end-stage kidney disease. Outcomes have remained across Australia and New Zealand. stable or have improved,1 and this is attributed to Results: The response rate was 66% (43/66). Of factors that include improvements in recipient and respondents, 61% reported routine drain insertion, donor selection and perioperative care and better whereas 21% seldom inserted drains. Concerns about immunosuppressive regimens. Although vascular or bleeding and anticoagulation (63%) and routine practice (58%) were the dominant reasons for drain urologic surgical complications are rare in kidney insertion. The factors selected as most significant transplant recipients, surgical site complications such in determining drain removal were both volume as infection, dehiscence, or the development of and time (44%) and volume alone (33%). A volume of perigraft fluid collections are common. Although < 50 mL/day (51%) was the most commonly reported wound complications do not seem to have a strong threshold for removal. The postoperative period of negative effect on long-term patient or graft survival days 3 to 5 was the most commonly selected time rates, these do contribute considerably to postoperative point for drain removal (63%). Seventy-four percent of morbidity, expenditure, and patient-reported quality- respondents would consider enrolling their patients in of-life outcomes.1-4 a randomized controlled trial to determine the Drains are frequently inserted by surgeons in the benefits and harms of drain insertion. extraperitoneal space surrounding the graft.5 The From the 1Royal Prince Alfred Hospital Institute of Academic Surgery, University of Sydney, rationale for this practice is unclear; however, given Camperdown, New South Wales, Australia; the 2Department of Surgery, Westmead Hospital, University of Sydney, Westmead, New South Wales, Australia; and the 3Department of Renal that the incidence of clinically significant hemorrhage Medicine, Royal Prince Alfred Hospital, University of Sydney, Camperdown, New South Wales, or urine leak is low, drainage of lymph seems the most Australia 5-7 Acknowledgements: This project was completely supported with timely donations in kind from reasonable rationale. Perigraft fluid collections are the contributing authors. The authors have not received any funding or grants in support of the reported to occur in 0.6% to 51% of patients after presented research or for the preparation of this work and have no potential declarations of interest. Author contributions are as follows: Mugino, Lam, Hameed, Sandroussi, Chadban, kidney transplant. Most perigraft collections are not Pleass, and Laurence performed the research; Mugino, Lee, Lam, Hameed, Pleass, and Laurence associated with graft dysfunction or symptoms and analyzed the data; all authors drafted the manuscript. Corresponding author: Jerome Laurence, Royal Prince Alfred Hospital, Institute of Academic are detected incidentally on routine ultrasonographic Surgery, University of Sydney, NSW 2006, Australia imaging.8 The substantial variations of the incidence E-mail: [email protected] reported in the literature regarding perigraft collections
Experimental and Clinical Transplantation (2020) 7: 771-777 are due to variable posttransplant surveillance imaging
Copyright © Başkent University 2020 DOı: 10.6002/ect.2020.0071 Printed in Turkey. All Rights Reserved. 772 Miho Mugino et al/Experimental and Clinical Transplantation (2020) 7: 771-777 Exp Clin Transplant
protocols and the lack of any specific definition of such Local Health District. The survey was designed by collections considered significant, particularly in practicing transplant surgeons, and the questions terms of volume.9-17 included information about their training background, Data on prophylactic drainage following transplant experience, the routine use of drains in vascular,18 thyroid,19 gastrointestinal, and breast kidney transplant, and the rationale for drain usage. cancer surgery20-22 have not substantiated a benefit to The survey was designed to determine the routine drainage. Moreover, prophylactic drain demographics of the surgeons, including their field placement may increase the risks of surgical site of subspecialty and breadth of experience. The infection, cause postoperative pain, and delay practice of prophylactic drain insertion following discharge.20,21,23,24 In other areas of surgery, such as renal transplant and the reasons for the choice to use reduction mammoplasty,25 and even oncological breast (or not use) prophylactic drains were investigated. surgery and axillary dissection,26 surgical practice The online survey was tested by a group of selected patterns with respect to drains are often transplant surgeons, and their feedback was heterogeneous, and the practice of drain insertion incorporated into the final version of the survey. persists, despite substantial evidence of lack of benefit associated with drain insertion. In kidney transplant, Study population only a small number of comparative studies of drain Consultant surgeons who regularly perform kidney insertion and omission have been reported, and these transplant at transplant centers across ANZ were studies have provided conflicting results.1,5,27-29 identified through the Transplantation Society of Notwithstanding these data on the use of Australia and New Zealand. An electronic link to prophylactic drains in other contexts, the immuno - the survey was distributed via electronic mail, suppressed state in transplant may promote the individually or via their respective departments. incidence of surgical site complications such as fluid Respondents who electronically consented to accumulation,1,3,4,7,30-33 and so extrapolating data from participating in this study completed the survey and other surgery contexts to the context of the kidney identified themselves as one or more of the transplant population may be misleading. There is no following: general surgeon (upper gastrointestinal internationally accepted guideline or established surgery, transplant surgery, others), vascular consensus regarding the use of prophylactic drains in surgeon, urologist, or other. kidney transplants. However, as was seen recently in a case presented to the Supreme Court of New South Data collection Wales, “expert” witnesses frequently make claims Between November 2 and December 2, 2017, we regarding what is considered “standard of care” by a identified 66 surgeons who perform renal transplants. surgical community, even when this standard seems An electronic link to the REDCap survey was contrary to the evidence.34,35 As a consequence, we distributed via electronic mail to each surgeon or wished to clarify what practice with respect to through administrators of their department. Reminder prophylactic drain insertion was considered emails were sent weekly until a survey response was standard in Australia and New Zealand (ANZ) for obtained. Five unsuccessful attempts at reminder surgeons performing kidney transplant procedures. emails led to a “no response” from a surgeon. We used this as an opportunity to garner further Respondents who completed the questionnaire were information about attitudes, rationale for drain deidentified according to the name and transplant usage, and patterns of management. unit. No financial incentives were provided.
Materials and Methods Statistical analyses Data were exported from the REDCap program, and Survey design statistical analyses were conducted with the SPSS A web-based online survey was created via a secure Statistics package (IBM SPSS Statistics version 24). online platform, known as Research Electronic Data The Somers D test was used to test the association Capture (REDCap).36 Ethics approval for this study between an ordinal dependent variable and an was obtained from the Research Ethics and ordinal independent variable (surgeon experience Governance Office of the New South Wales Sydney and drain insertion practice). A one-way ANOVA Miho Mugino et al/Experimental and Clinical Transplantation (2020) 7: 771-777 773
was conducted to determine whether general Figure 1. Responses to Questions About the Length of Consultant Practice, Transplant Volume, and Specialty Training Background surgeons were more likely to insert a drain than non- general surgeons. Respondents were classified as surgeons trained in general surgery (n = 21) or surgeons trained in non-general surgery (vascular surgeons or urologists, n = 22), and we surveyed the likelihood of each group to insert a drain: > 90% of the time was expressed as a score of 1; > 10% of the time expressed as a score of 2; < 10% of the time expressed as a score of 3. Statistical significance was defined as P < .05.
Results respondents and demographics The response rate to the survey was 66% (43/66). The responses to questions about the length of consultant practice, transplant volume, and specialty training background are summarized in Figure 1.
Drain insertion practice The responses to questions about the estimated frequency of drain insertion and the number of drains placed are summarized in Figure 2. The vast majority of surgeons (40/43; 93%) reported placing drains (when drains were used) only in the perigraft extraperitoneal space, and 1 surgeon specifically commented that an additional drain was placed in the subcutaneous space in “obese” patients. rationale Respondents were asked to identify any and all factors that may lead to a decision to place a prophylactic drain from 4 options; also, respondents were given the opportunity to provide specific personal reasons for the decision as free text, if desired. Multiple responses were permitted. The most common responses are summarized in Figure 3A. Concerns about bleeding and anticoagulation (27/43; 63%) and routine practice (25/43; 58%) were the dominant reasons cited by respondents. Five respondents provided comments indicating that the choice to insert a prophylactic drain could arise in circumstances of “difficult bladder,” “large amount of lymphatic tissue,” “technically difficult operation,” “unit policy,” and “I never put drains unless after take back for bleeding.” Respondents were also asked to select what they perceived as the benefits of prophylactic drain insertion from 5 options (multiple (A) Years of consultant practice. (B) Surgeon kidney transplant volume per responses permitted), as well as provide additional year. (c) Surgeon training background. 774 Miho Mugino et al/Experimental and Clinical Transplantation (2020) 7: 771-777 Exp Clin Transplant
Figure 2. Responses to Questions About the Estimated Frequency of Drain Figure 3. Responses to Questions About Factors Contributing to Prophylactic Insertion and the Number of Drains Placed Drain Insertion
(A) Frequency of prophylactic drain insertion. (B) Number of drains routinely placed.
Abbreviations: OT, operating theatre; PGFC, perigraft fluid collection (A) Factors contributing to prophylactic drain insertion. (B) Perceived comments as free text, if desired. These responses are benefit of prophylactic drain insertion. *Unspecified by respondents. shown in Figure 3B. The 2 most common responses were that drain insertion reduces symptomatic perigraft fluid collections (21/43; 49%) and that the The factors selected as most significant in deter - respondents were uncertain about the benefit of mining drain removal were both volume and time drain insertion (13/43; 30%). Two respondents (19/44; 44%) and only volume (14/43; 33%). A commented in free-text format that “bleeding is volume of “< 50 mL/day” (22/43; 51%) was the most better predicted with drain inserted” and “I use drain common response. Some respondents specified to detect lymphocele postoperatively.” further (eg, “depends on the size of the patient” and “depends on fluid composition”), and 1 commented Drain management that it was decided to “remove the drain at day 5 Respondents were asked about the management of even if volume is > 50 mL/day.” When asked the drain once inserted. Responses regarding factors whether they would discharge patients with high- such as the importance of time, volume permitting output drains in situ, 16/43 (37%) responded never, safe removal, and the preferred number of post - 25/43 (58%) responded infrequently, and 2/43 (5%) transplant days for removal are shown in Figure 4. responded frequently. Twenty-five respondents Miho Mugino et al/Experimental and Clinical Transplantation (2020) 7: 771-777 775
Figure 4. Responses Regarding Factors Affecting Drain Removal (58%) believed that fluid composition was important for the decision to remove a drain, whereas 18 respondents (42%) did not think it was relevant. Thirty-five percent (15/43) of respondents indicated that they routinely test drain fluid for creatinine before removing the drain. Twenty-one percent (9/43) responded that if the fluid consisted of hemoserous fluid, then this was an indicator for safe drain removal. The number of days posttransplant was a factor for drain removal for 27/43 respondents (63%). The postoperative period of days 3 to 5 was the most commonly selected time point for drain removal (27/43; 63%). One respondent specified that drain removal was appropriate at “24 hours post-IDC removal.” One respondent commented on the choice to “shorten tract if ongoing volume > 100 mL/day, aiming to get tissue sealing before removing to prevent expanding lymphocele.”
Association of experience and training background and drain insertion practices There was no association between level of experience of surgeons and drain insertion practice (Somers D; d = .051, P = .673). General surgeons were more likely to insert drains than non-general surgeons (F = 6.121, P = .019; general surgeons, mean = 1.95 ± 0.865; non- general surgeons, mean = 1.27 ± 0.631). There was no association between the practice of drain insertion and the number of kidney transplants per year (F = 1.44, P = .251).
Willingness to participate in further study Thirty-two respondents (74%) would consider enrolling their patients in a randomized controlled trial to determine the benefits and harms of drain insertion.
Discussion
This study reports the results of a survey to assess the attitudes and preferences of surgeons in ANZ toward the use of prophylactic drains after kidney transplant. We have demonstrated that there is substantial variation in practice and rationale for the use of drains, duration of drainage, and indications for removal of the drains. More than half of respondents use drains routinely (> 90% of the time). The majority of routine drain placement was a
(A) Factors affecting timing of prophylactic drain removal. (B) Drain consequence of “unit policy or routine practice,” removal cutoff volume. (c) Timing of drain removal. suggesting that it is a consequence of established 776 Miho Mugino et al/Experimental and Clinical Transplantation (2020) 7: 771-777 Exp Clin Transplant
tradition. It must be acknowledged that drain Thirty percent of surgeons were uncertain with insertion has been a traditional, standard procedure regard to the level of prophylaxis that could be in most major surgical operations. It is not surprising, provided by drain insertion for surgical complications. given the lack of any strong evidence to the contrary, On the other hand, 48% of surgeons believed that the that the practice persists. Even in the face of surgical drain was helpful in reducing the compressive substantial evidence, traditional practices are often effect of a perigraft fluid collection, and 20% thought it defended and maintained.25 This is likely a would reduce the rate of graft loss due to the mass consequence of the conservatism among members of effect of a collection. All of these views may be correct. a highly regulated profession for which there are Clearly, practices are driven by the manner in which barriers in the process of changing/ceasing previous the surgeons view the competing risks and potential behaviors.25,37-39 A substantial minority of respondents benefits of drain insertion and the relative importance seldom or never insert drains, and the basis of this assigned to those outcomes. This survey highlights the perspective may be evidence gleaned from other clinically relevant application of surgical experience areas of surgery for which the benefits of routine and heuristics in managing these complex cases. prophylactic drainage seem questionable. Although approximately 75% of respondents indicated This survey could not resolve the clinical question willingness to participate in a randomized study, a of prophylactic drain usage because the evidence significant minority of respondents are not willing. is insubstantial. We have recently conducted a This likely reflects the lack of objective evidence against systematic review, and the results suggest that drains or for the insertion of a drain among practitioners. may be associated with a lower rate of perigraft fluid However, both groups are likely to believe that their collection. Notwithstanding the significant bias in the side of the argument would be correct. We need to design of the studies analyzed, even if correct, we do accept as a surgical community that the outcome the not know whether this would translate into any practitioner considers to be the most significant will significant clinical outcome (such as graft loss, determine which approach the practitioner may take wound infection, requirement for interventions) or and that there is no definite right or wrong answer at whether the complications of drains outweigh the this stage. benefits of reducing collections that do not have any clinical impact. Resolution of the issue would require References a multicenter, randomized controlled trial, adequately 1. Derweesh IH, Ismail HR, Goldfarb DA, et al. Intraoperative placing powered to detect relatively rare but clinically of drains decreases the incidence of lymphocele and deep vein significant outcomes. The large sample size required thrombosis after renal transplantation. BJU Int. 2008;101(11):1415- 1419. doi:10.1111/j.1464-410X.2007.07427.x for such a study may be prohibitive. Therefore, 2. Eufrasio P, Parada B, Moreira P, et al. Surgical complications in 2000 surgeons will likely remain in an environment of renal transplants. Transplant Proc. 2011;43(1):142-144. doi:10. 1016/j.transproceed.2010.12.009 clinical uncertainty with regard to the appropriate 3. Mehrabi A, Fonouni H, Wente M, et al. Wound complications use of drains. following kidney and liver transplantation. Clin Transplant. 2006;20 This survey had a response rate of 65% of Suppl 17:97-110. doi:10.1111/j.1399-0012.2006.00608.x 4. Tiong HY, Flechner SM, Zhou L, et al. A systematic approach to practicing kidney transplant surgeons in ANZ. There minimizing wound problems for de novo sirolimus-treated is a large variation in the number of transplants kidney transplant recipients. Transplantation. 2009;87(2):296-302. doi:10.1097/TP.0b013e318192dd56 performed by each survey participant. As a result, it 5. Sidebottom RC, Parsikia A, Chang PN, et al. No benefit when is difficult to determine the proportion of the placing drains after kidney transplant: a complex statistical approximately 1200 kidney transplants performed analysis. Exp Clin Transplant. 2014;12(2):106-112. 6. Webster AC, Lee VW, Chapman JR, Craig JC. Target of rapamycin annually in ANZ40 that contributed to the career inhibitors (sirolimus and everolimus) for primary immuno - experience of the respondents. Therefore, it is suppression of kidney transplant recipients: a systematic review and meta-analysis of randomized trials. Transplantation. difficult to comment on what is actually a routine 2006;81(9):1234-1248. doi:10.1097/01.tp.0000219703.39149.85 practice for all kidney transplants across Australia 7. Kakaei F, N Nikeghbalian, Ali Malekhosseini S. Current issues and future direction in kidney transplantation. In: Rath T, ed. Kidney and New Zealand. A limitation of this study is that it Transplantation Techniques. IntechOpen; 2013. doi:10.5772/ represents a snapshot in time, whereas actual 54829 patterns of practice are in constant flux. It will be 8. Ranghino, A. Segoloni GP, Lasaponara F, Biancone L. Lymphatic disorders after renal transplantation: new insights for an old interesting to repeat the survey in the future to complication. 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9. Pollak R, Veremis SA, Maddux MS, Mozes MF. The natural history of 26. Brahmbhatt RD, Huebner M, Scow JS, et al. National practice and therapy for perirenal fluid collections following renal patterns in preoperative and postoperative antibiotic prophylaxis transplantation. J Urol. 1988;140(4):716-720. doi:10.1016/s0022- in breast procedures requiring drains: survey of the American 5347(17)41795-2 Society of Breast Surgeons. Ann Surg Oncol. 2012;19(10):3205- 10. Silver TM, Campbell D, Wicks JD, Lorber MI, Surace P, Turcotte J. 3211. doi:10.1245/s10434-012-2477-1 Peritransplant fluid collections. Ultrasound evaluation and 27. Atray NK, Moore F, Zaman F, et al. Post transplant lymphocele: a clinical significance. Radiology. 1981;138(1):145-151. doi:10.1148/ single centre experience. Clin Transplant. 2004;18 Suppl 12:46-49. radiology.138.1.7005938 doi:10.1111/j.1399-0012.2004.00217.x 11. Malovrh M, Kandus A, Buturovic-Ponikvar J, et al. Frequency and 28. Cimen S, Guler S, Tennankore K, Imamoglu A, Alwayn I. Surgical clinical influence of lymphoceles after kidney transplantation. drains do not decrease complication rates but are associated with Transplant Proc. 1990;22(4):1423-1424 a reduced need for imaging after kidney transplant surgery. Ann 12. Kay R, Fuchs E, Barry JM. Management of postoperative pelvic Transplant. 2016;21:216-221. doi:10.12659/aot.898260 lymphoceles. Urology. 1980;15(4):345-347. doi:10.1016/0090- 29. Fahmy A, Youssif M, Aboyoussif T, et al. A prospective randomized 4295(80)90466-5 study comparing intraoperative placing of drains versus no drain 13. Khauli RB, Stoff JS, Lovewell T, Ghavamian R, Baker S. Post- on incidence of lymphocele formation after renal transplantation. transplant lymphoceles: a critical look into the risk factors, J Urol. 2016;195:e430. pathophysiology and management. J Urol. 1993;150(1):22-26. 30. Grim SA, Slover CM, Sankary H, Oberholzer J, Benedetti E, Clark doi:10.1016/s0022-5347(17)35387-9 NM. Risk factors for wound healing complications in sirolimus- 14. Ulrich F, Niedzwiecki S, Fikatas P, et al. Symptomatic lymphoceles treated renal transplant recipients. Transplant Proc. after kidney transplantation: multivariate analysis of risk factors 2006;38(10):3520-3523. doi:10.1016/j.transproceed.2006.10.065 and outcome after laparoscopic fenestration. Clin Transplant. 31. Pengel LH, Liu LQ, Morris PJ. Do wound complications or 2010;24(2):273-280. doi:10.1111/j.1399-0012.2009.01073.x lymphoceles occur more often in solid organ transplant recipients 15. Lucewicz A, Wong G, Lam VW, et al. Management of primary on mTOR inhibitors? A systematic review of randomized symptomatic lymphocele after kidney transplantation: a controlled trials. Transpl Int. 2011;24(12):1216-1230. doi:10.1111/j. systematic review. Transplantation. 2011;92(6):663-673. doi:10. 1432-2277.2011.01357.x 1097/TP.0b013e31822a40ef 32. Flechner SM, Zhou L, Derweesh I, et al. The impact of sirolimus, 16. Goel M, Flechner SM, Zhou L, et al. The influence of various mycophenolate mofetil, cyclosporine, azathioprine, and steroids maintenance immunosuppressive drugs on lymphocele on wound healing in 513 kidney-transplant recipients. formation and treatment after kidney transplantation. J Urol. Transplantation. 2003;76(12):1729-1734. doi:10.1097/01.TP.000 2004;171(5):1788-1792. doi:10.1097/01.ju.0000121441.76094.6f 0093502.26208.42 17. Fockens MM, Alberts VP, Bemelman FJ, van der Pant KA, Idu MM. 33. Ramos A, Asensio A, Munez E, et al. Incisional surgical site infection Wound morbidity after kidney transplant. Prog Transplant. in kidney transplantation. Urology. 2008;72(1):119-123. doi:10. 2015;25(1):45-48. doi:10.7182/pit2015812 1016/j.urology.2007.11.030 18. Karthikesalingam A, Walsh SR, Sadat U, Tang TY, Koraen L, Varty K. 34. Truskett PG. All “complex” abdominal incisional hernia repairs Efficacy of closed suction drainage in lower limb arterial surgery: using mesh must be drained: it's the law. ANZ J Surg. 2018;88(1- a meta-analysis of published clinical trials. Vasc Endovascular Surg. 2):5-6. doi:10.1111/ans.14376 2008;42(3):243-248. doi:10.1177/1538574407313514 35. Wysocki AP, McGowan B. To drain or not to drain: Supreme Court 19. Samraj K, Gurusamy KS. Wound drains following thyroid surgery. has the answer. ANZ J Surg. 2018;88(1-2):115. doi:10.1111/ans. Cochrane Database Syst Rev. 2007(4):CD006099. doi:10.1002/ 14285 14651858.CD006099.pub2 36. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. 20. Thomson DR, Sadideen H, Furniss D. Wound drainage after axillary Research electronic data capture (REDCap)--a metadata-driven dissection for carcinoma of the breast. Cochrane Database Syst methodology and workflow process for providing translational Rev. 2013(10):CD006823. doi:10.1002/14651858.CD006823.pub2 research informatics support. J Biomed Inform. 2009;42(2):377-381. 21. Ebner F, deGregorio N, Vorwerk E, Janni W, Wockel A, Varga D. doi:10.1016/j.jbi.2008.08.010 Should a drain be placed in early breast cancer surgery? Breast 37. Gupta DM, Boland RJ, Jr., Aron DC. The physician's experience of Care (Basel). 2014;9(2):116-122. doi:10.1159/000360928 changing clinical practice: a struggle to unlearn. Implement Sci. 22. Petrowsky H, Demartines N, Rousson V, Clavien PA. Evidence- 2017;12(1):28. doi:10.1186/s13012-017-0555-2 based value of prophylactic drainage in gastrointestinal surgery: 38. Helfrich CD, Rose AJ, Hartmann CW, et al. How the dual process a systematic review and meta-analyses. Ann Surg. 2004;240(6): model of human cognition can inform efforts to de-implement 1074-1084; discussion 1084-1075. doi:10.1097/01.sla.0000146149. ineffective and harmful clinical practices: a preliminary model of 17411.c5 unlearning and substitution. J Eval Clin Pract. 2018;24(1):198-205. 23. Petrosillo N, Drapeau CM, Nicastri E, et al. Surgical site infections doi:10.1111/jep.12855 in Italian hospitals: a prospective multicenter study. BMC Infect Dis. 39. Rushmer R, Davies HT. Unlearning in health care. Qual Saf Health 2008;8:34. doi:10.1186/1471-2334-8-34 Care. 2004;13 Suppl 2:ii10-15. doi:10.1136/qhc.13.suppl_2.ii10 24. Fong Y, Brennan MF, Brown K, Heffernan N, Blumgart LH. Drainage 40. ANZDATA Registry. 41st Report, Chapter 7: Kidney Transplantation. is unnecessary after elective liver resection. Am J Surg. Australia and New Zealand Dialysis and Transplant Registry; 2018. 1996;171(1):158-162. doi:10.1016/s0002-9610(99)80092-0 http://www.anzdata.org.au 25. Sugrue CM, McInerney N, Joyce CW, et al. Current practice patterns of drain usage amongst UK and Irish surgeons performing bilateral breast reductions: evidence down the drain. J Plast Surg Hand Surg. 2015;49(6):363-366. doi:10.3109/2000656X. 2015.1062386 Artıcle
Hidden Granzyme B-Mediated Injury in Chronic Active Antibody-Mediated Rejection
Brijesh Yadav,1 Narayan Prasad,1 Vikas Agarwal,2 Vinita Agarwal,3 Manoj Jain3
Abstract T cells was significantly lower in peripheral blood. Serum granzyme B level and intragraft number of + 2 Objectives: Antibody-mediated injury in chronic active granzyme B cells (counts/mm ) were also significantly antibody-mediated rejection, possibly with other higher in the chronic active antibody-mediated effector T cells, may play a role in graft injury. The role rejection group compared with that of patients of inflammatory cells in the inflammation and fibrosis with stable graft function. The intragraft granzyme + and tubular atrophy region has been recently B T cell count was positively correlated with serum advocated in the progression of injury. Cytotoxic T cells creatinine and 24-hour urine proteinuria but play a prominent role in T-cell-mediated rejection; negatively correlated with estimated glomerular however, the possible role of cytotoxic T cells in filtration rate. circulation and the intragraft compartment in chronic Conclusions: Granzyme B mediates covert graft injury active antibody-mediated rejection, a common in patients with chronic active antibody-mediated immunological cause of long-term graft failure, has rejection in addition to antibody-mediated injury. not been well-studied. Materials and Methods: We measured the frequency of Key words: Cytotoxic T cells, Intragraft granzyme B, circulating cytotoxic T cells with flow cytometry, serum mRNA expression, Stable graft function granzyme B level by enzyme-linked immunosorbent assay and intragraft granzyme B+ cell, and mRNA by Introduction immunohistochemistry and real-time polymerase chain reaction in biopsy tissue from living donor renal Chronic active antibody-mediated rejection (CABMR) allograft recipients with stable graft function and is one of the important immunological causes of graft chronic active antibody-mediated rejection. loss in the late posttransplant period. Chronic active Results: The frequency of CD3+ and CD3+CD8+ T cells antibody-mediated rejection is clinically characterized was similar in both stable graft function patients and by proteinuria, hypertension, a decline in glomerular chronic active antibody-mediated rejection patients. filtration rate, and the presence of circulating donor- The frequency of CD3+CD8+granzyme B+ cytotoxic specific antibodies. The common histological features From the 1Department of Nephrology and Renal Transplantation, the 2Department Of Clinical are multilayering in peritubular capillary basement Immunology, and the 3Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India membrane along with complement fragment C4d Acknowledgements: This project was supported by an extramural grant from the Indian deposition, glomerulitis, along with the varying Council of Medical Research and partially by an intramural research grant from the Sanjay degree of interstitial inflammation and fibrosis, and Gandhi Postgraduate Institute. Brijesh Yadav is a DST-INSPIRE fellow of the Department of 1 Science and Technology, Government of India. tubular atrophy. Patients with chronic antibody- Author contributions are as follows: Brijesh Yadav designed experiments, performed mediated rejection respond poorly to conventional experimental work, analyzed data, and drafted the manuscript; Narayan Prasad designed the experiments, ensured availability of human samples and reagents, monitored progress of work, immunosuppressive regimens and rapidly progress reviewed data, and critically reviewed the manuscript; Vikas Agarwal monitored the progress of to end-stage graft failure.2 laboratory work, helped plan experiments, provided the laboratory facility, reviewed data, and + critically reviewed the manuscript; Vinita Agarwal and Manoj Jain evaluated the A short-term interaction of naive CD8 T cells histopathological slides and performed electron microscopy. Other than described above, the with allograft peptide results in CD8+ T-cell authors have not received any funding or grants in support of the presented research or for the 3 preparation of this work and have no further declarations of potential interest. activation. The persistent allogeneic stimulation Corresponding author: Narayan Prasad, Department of Nephrology and Renal activates CD8+ T cells to synthesize and secrete Transplantation, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India 226014 granzyme B, perforin, and expression of other E-mail: [email protected] armamentaria, such as Fas ligand (FasL), granulysin,
Experimental and Clinical Transplantation (2020) 7: 778-784 lymphotoxin, tumor necrosis factor α, and interferon
Copyright © Başkent University 2020 Printed in Turkey. All Rights Reserved. DOı: 10.6002/ect.2020.0225 Brijesh Yadav et al/Experimental and Clinical Transplantation (2020) 7: 778-784 779
γ, which may lead to allograft injury.4 A few studies peritubular capillaries and donor-specific antibodies showed that inhibition of the FasL-dependent in blood. pathway could not inhibit apoptosis in the This study was approved by the institutional peritubular epithelial cell. In contrast, inhibition of the ethics committee (ethics approval code-IEC.2012-117- perforin/granzyme B pathway with concanamycin A PhD-63), and signed written consent was obtained and higher endogenous protease inhibitor 9 inhibited from patients and/or relatives. apoptosis and cell lysis, suggesting perforin/granzyme B as an indispensable pathway for allograft cell death Sample collection and rejection.5,6 Granzyme B, a serine protease of broad Renal allograft biopsy was performed with the substrate specificity, mediates cytotoxicity and induces standard graft biopsy technique, and 3 cores of biopsy apoptosis in target cells.7 Few studies have reported were obtained; 1 core was for histopathological urinary, intragraft, and circulating granzyme B as a diagnosis, and a second core was divided for reliable marker of acute rejection.8 In addition to immunofluorescence and electron microscopy antibody-mediated injury, T-cell-mediated injury also examination. The third core was used for RNA occurs in the allograft. In studies of the role of isolation for gene transcript expression analysis by inflammatory cells within interstitial and tubular real-time polymerase chain reaction (PCR). atrophy region, inflammation and fibrosis and tubular Simultaneously, venous blood was collected in atrophy were associated with poor prognosis and heparinized and plain vials for cellular flow rapid graft failure.9,10 T-cell infiltration and tubulitis are cytometry and granzyme B level analysis. Granzyme often observed in for-cause biopsies with a diagnosis of B immunostaining was performed with the paraffin antibody-mediated rejection, and such mixed T-cell block of a routine biopsy core. All SGF patients antibody-mediated pathology may occur in 10% to included in this study agreed and consented for the 90% of graft biopsies.11-13 There are relatively few graft biopsies. studies published on the changes in the cytotoxic T lymphocyte (CTL) in peripheral circulation and ımmunostaining for granzyme B in intragraft tissue intragraft tissue in CABMR. In this study, we Granzyme B immunostaining was performed with investigated the circulating and intragraft profiles of formalin-fixed, paraffin-embedded tissue sections CTL in patients with CABMR in comparison with using an anti-human mouse monoclonal antibody those of patients with stable graft function against granzyme B (1:100 dilution, Santa Cruz (SGF). Biotechnology) in steps as mentioned in our previous study.14 Materials and Methods cytotoxic t-cell staining and analysis Patient recruitment Whole blood cells were stimulated following the A total of 42 living donor first renal allograft protocol mentioned in our previous study.15 We recipients (10 SGF and 32 CABMR), without a prior stained 100 μL of stimulated blood cells for analysis. history of rejections, were included in the study. We used 10 μL of peridinin-chlorophyll-cyanine Based on histopathology reports (per the 2017 Banff 5.5-conjugated mouse monoclonal anti-human CD3 criteria), independently evaluated by the 2 and 10 μL of allophycocyanin-conjugated mouse histopathologists (Manoj Jain, Vinita Agarwal), monoclonal anti-human CD8 antibody for surface patients were categorized into 2 groups: SGF and staining following a brief incubation for 30 minutes CABMR groups.1 All CABMR cases were defined in the dark at room temperature. After red blood cell per the criteria in the Banff classification for lysis with red blood cell lysis buffer for 13 minutes, fulfillment of morphological, immunohistological, cells were fixed and permeabilized with BD and serological tests.1 Patients with SGF were those Cytofix/Cytoperm fixation/permeabilization solution, who had stable serum creatinine levels for 6 months followed by intracellular staining with 5 μL of without significant proteinuria and less than 10% phycoerythrin-conjugated mouse monoclonal anti- cortical surface area showing evidence of interstitial human granzyme B antibody for 30 minutes. An fibrosis and tubular atrophy on histology. These appropriate fluorochrome-conjugated isotype- patients had an absence of C4d staining in matched antibody against CD8 and granzyme B was 780 Brijesh Yadav et al/Experimental and Clinical Transplantation (2020) 7: 778-784 Exp Clin Transplant
used to nullify any false-positive signal and setting Fischer exact test, whenever applicable, to analyze quadrate for differentiating positive population. All the categorical variables. We used the Pearson reagents and antibodies were purchased from BD correlation matrix to analyze the correlations among Bioscience (BD Pharmingen). the different variables. P < .05 with the 2-tailed test We used a BD FACSCalibur machine to acquire was considered to be significant. 10 000 lymphocyte gated cells, and we analyzed the cells with FCS Express 6 software. The gating Results strategy was as follows: CD3+ T cells were calculated in the lymphocyte gate (gate 1); then in the CD3+ Baseline characteristics of patients T cell gate (gate 2), CD8+granzyme B+ (double- The clinical characteristics of patients with CABMR positive) T cells were considered to be CTL. and SGF are shown in Table 1. All patients were living donor organ recipients and related renal Serum granzyme B level detection donors were spouse, parent, or sibling in both of the Blood in plain vials were centrifuged at 1500 groups. Patients in the CABMR group had revolutions per minute for 5 minutes, and serum was significantly reduced estimated glomerular filtration separated and stored at -80°C until analysis. Enzyme- rate and hemoglobin and an increased level of serum linked immunosorbent assay was performed with creatinine and proteinuria. The histological grading BioLegend LEGEND MAX human granzyme B of allograft injury in both groups is shown in Table 2. ELISA kit. The minimum detection limit for the kit The histological scoring for peritubular capillaritis, was 2.4 ± 1.2 pg/mL. glomerulitis, tubulitis, tubular atrophy, and inter - stitial fibrosis was higher in CABMR compared with Granzyme B gene expression analysis by taqMan SGF patients. real-time polymerase chain reaction We used a Polytron rotor/stator homogenizer (Kinematica) to homogenize the biopsy specimens, table 1. Demographic and Clinical Characteristics of Patients With Stable and we used a Qiagen RNA extraction mini kit to Graft Function and Chronic Active Antibody-Mediated Rejection Characteristic SGF (n = 10) CABMR (n = 32) P extract the RNA, according to the manufacturer’s Patient age, y 44.30 ± 8.20 37.97 ± 12.78 .148 protocol. The purity and concentration of RNA were Donor age, y 50.50 ± 6.68 50.65 ± 10.04 .964 Patient sex, male:female 10:0 21:11 .031 determined on a NanoDrop spectrophotometer Donor sex, male:female 2:8 7:25 .90 (Thermo Scientific). We checked the integrity of the Patient relationship with donor RNA on a 1% agarose gel. To prepare copy DNA, we Spouse 6 (60%) 19 (59.3%) .80 Mother 2 (20%) 4 (12.5%) used SuperScript II RT reverse transcriptase Sister 0 (0%) 2 (6.25%) (Invitrogen) to process 200 ng of RNA and random Father 2 (20%) 5 (15.62%) Brother 0 (0%) 2 (6.25%) hexamer primer in a 20-μL reaction volume, Body mass index kg/m2 20.93 ± 4.64 21.85 ± 3.37 .492 following the manufacturer’s protocol. We used an Posttransplant biopsy interval, mo 46.70 ± 17.30 70.18 ± 34.48 .046 Applied Biosystems GenAmp 7700 sequence eGFR, mL/min/1.73 m2 70.62 ± 22.14 44.60 ± 16.62 < .001 detection system with a predesigned primer and Tacrolimus level, ng/mL 4.82 ± 0.98 5.57 ± 1.31 .102 Hemoglobin, g/dL 12.94 ± 1.60 10.25 ± 1.34 < .001 probe for granzyme B (HS01554355_m1; Applied Total leukocyte count, ×103 8.3 ± 2.1 8.03 ± 5.08 .839 Biosystems) to perform TaqMan real-time PCR with Blood urea nitrogen, mg/dL 25.79 ± 13.35 40.55 ± 11.79 .002 Baseline creatinine, mg/dL 0.81 ± 0.47 0.88 ± 0.42 .64 2 μL cDNA in a 20-μL reaction volume. We used Serum creatinine, mg/dL 1.21 ± 0.18 2.40 ± 0.80 < .001 glucose-6 phosphate dehydrogenase (Hs99999905_m1) Proteinuria, g/d 0.16 ± 0.085 2.94 ± 1.54 < .001 Urine creatinine, mg/dL 0.81 ± 0.28 0.68 ± 0.26 .178 as an endogenous housekeeping control to normalize HLA mismatch 3.41 ± 0.69 3.15 ± 0.62 .303 the RNA starting quantity. We used the 2-∆∆Ct method Induction 16 Basiliximab 2 7 .870 to calculate relative expression. Antithymocyte globulin 3 7 No induction 5 18 Statistical analyses Immunosuppression, mycophenolate + prednisolone We analyzed the data with SPSS software (version Cyclosporine 0 3 .315 20), and continuous variables were analyzed with an Tacrolimus 10 29 independent t test. Data are expressed as mean Abbreviations: CABMR, chronic active antibody-mediated rejection; eGFR, estimated glomerular filtration rate; HLA, human leukocyte antigen; SGF, values ± SD. We used the chi-square test and the stable graft function Brijesh Yadav et al/Experimental and Clinical Transplantation (2020) 7: 778-784 781
table 2. Comparison of Histological Scoring Per the 2017 Banff Criteria table 3. Circulating Cytotoxic T-Cell Frequency in Stable Graft Function and for Stable Graft Function and Chronic Active Antibody-Mediated Chronic Active Antibody-Mediated Rejection Rejection Characteristic SGF (n = 10) CABMR (n = 32) P SGF (n = 10) CABMR (n = 32) P CD3+ T cells, % 66.08 ± 6.89 66.2 ± 8.70 .96 Peritubular capillaritis CD3+CD8+ T cells, % 37.29 ± 4.11 36.70 ± 4.38 .77 ptc0 9 2 < .001 CD3+CD8+granzyme B+ T ptc1 1 7 cells, % 27.96 ± 4.86 15.38 ± 3.29 < .001 ptc2 0 8 Abbreviations: CABMR, chronic active antibody-mediated rejection; SGF, ptc3 0 15 stable graft function Glomerulitis g0 9 3 < .001 g1 1 14 ıntragraft granzyme B+ cell count was positively g2 0 12 g3 0 3 correlated with graft function parameters Tubulitis Intragraft granzyme B+ cell count (per mm2) was t0 9 11 .009 t1 1 20 positively correlated with the 24-hour proteinuria t2 0 1 level and the serum creatinine level but negatively t3 0 0 Interstitial inflammation correlated with the estimated glomerular filtration i0 8 18 < .38 rate (Figure 3). i1 2 13 i2 0 1 i3 0 0 Serum granzyme B level Intimal arteritis v0 9 14 .083 Serum granzyme B level was significantly higher in v1 1 13 the CABMR group than in the SGF group (Figure v2 0 4 v3 0 1 3D). Tubular atrophy ct0 6 6 .027 Discussion ct1 4 19 ct2 0 7 ct3 0 0 In this study, the most crucial observation was a Interstitial fibrosis ci0 10 3 < .001 lower frequency of circulating CTL and higher serum ci1 0 21 granzyme B level and intragraft granzyme B+ cell ci2 0 8 ci3 0 0 count in CABMR patients compared with results Fibrointimal thickening shown in SGF patients. These findings suggested a cv0 10 20 .072 cv1 0 8 pathogenic association of CTL with allograft injury cv2 0 4 in cases of CABMR. Ashton-Chess and colleagues cv3 0 0 Arteriolar hyalinosis have also observed that granzyme B mRNA ah0 9 24 .58 transcript expression was significantly increased in ah1 1 7 ah2 0 1 the graft and significantly decreased in the peripheral ah3 0 0 blood of patients with CABMR.17 They have also Abbreviations: CABMR, chronic active antibody-mediated rejection; SGF, emphasized that the quantification of peripheral stable graft function blood granzyme mRNA may have the potential to aid in the noninvasive diagnosis of CABMR. circulating cytotoxic t-cell profiles of the patients The persistent allo-stimulating signal leads to CTL, The frequency of CD3+ T cells and CD3+CD8+ T cells activation, and increased synthesis of granzyme was similar in both groups. However, the frequency B mRNA and protein.18,19 The low frequency of of CD3+CD8+granzyme B+ CTL was significantly circulating cell CD3+CD8+granzyme B+ T cells lower in the CABMR group than in the SGF group compared with that of SGF patients may be caused by (Table 3, Figure 1). the sequestration of granzyme B+ T cells into the intragraft tissue in cases of CABMR. CD8+ T cells in ıntragraft granzyme B+ cell count and mrNA peripheral circulation also released granzyme B into expression the serum, which may have subsequently sequestered Intragraft granzyme B+ cell count (per mm2) and into the graft and thereby mediated allograft injury. granzyme B mRNA expression were significantly The activated CTL acquire different homing transient higher in the CABMR group than in the SGF group surface molecules such as the HML-1, human (Figure 2). mucosal lymphocyte, the VLA-4 very late activation 782 Brijesh Yadav et al/Experimental and Clinical Transplantation (2020) 7: 778-784 Exp Clin Transplant
Figure 1. Frequency of Cytotoxic T Cells Analyzed by Flow Cytometry
Abbreviations: APC, allophycocyanin; CABMR, chronic active antibody-mediated rejection; FSC-H, forward scatter-height; PE, phycoerythrin; PercpCy5.5, peridinin-chlorophyll-cyanine 5.5; SGF, stable graft function; SSC-H, side scatter-height There were 10 000 lymphocytes gated in gate 1, and CD3 cells were analyzed in gate 2. In gate 2, a CD8+granzyme B+ cell was considered to be a cytotoxic T cell.
Figure 2. Intragraft Granzyme B mRNA and Protein Expression Analyzed by Real-Time Polymerase Chain Reaction and Immunohistochemistry
Abbreviations: a.u., arbitrary unit; CABMR, chronic active antibody-mediated rejection; SGF, stable graft function Five high-power fields per slide (magnification, ×200) were analyzed to count the granzyme B+ cells. The result was expressed in terms of the number of granzyme B+ counts per mm2. Brijesh Yadav et al/Experimental and Clinical Transplantation (2020) 7: 778-784 783
Figure 3. Intragraft Granzyme B+ T-Cell Count Correlation With Graft Function Parameters
Abbreviations: CABMR, chronic active antibody-mediated rejection; eGFR, estimated glomerular filtration rate; SGF, stable graft function Pearson correlations for the number of intragraft granzyme B+ cell counts (per mm2) were positively correlated for (A) 24-hour proteinuria and (B) serum creatinine levels. (c) However, the estimated glomerular filtration rate was negatively correlated with granzyme B+ cell counts (per mm2). (D) Serum granzyme B level was measured by enzyme-linked immunosorbent assay. antigen, the LFA-1 leukocyte function-associated Cytotoxic T cells also mediate target cell death antigen, CD103, and the CXCR3 chemokine receptor, by activating executor caspase 3 and reactive which helps in intragraft sequestration and adherence oxygen species formation by cleavages of of CTL via the cognate receptor expressed on activated NDUFV1, NDUFS1, and NDUFS2 subunits of the endothelium and epithelial cells of allograft tissues, for NADH:ubiquinone oxidoreductase complex I inside example, the ICAM-1 intercellular adhesion molecule, mitochondria,23,25 which may lead to the death of the MCP-1 monocyte chemoattractant protein, the graft cells and graft dysfunction. Our findings also MIP-1α macrophage inflammatory protein, and suggest an association between graft dysfunction integrin αE(CD103)β7.20,21 Higher granzyme B+ cell and granzyme B-mediated injury. There was a count on immunohistochemistry in our findings also significant positive correlation between tissue suggests activation and infiltration from circulating granzyme B-positive cell count and degree of blood into the graft tissue, similar to Ashton-Chess proteinuria and serum creatinine level and a negative and colleagues.17 Although we did not stain T-cell- correlation with the decline in estimated glomerular specific markers, there may be possible involvement filtration rate in our study. of natural killer (NK) cells in granzyme B release in To circumvent the devastating effects of granzyme graft tissue. B, peritubular epithelial cells of allografts also express a higher level of granzyme inhibitor protease, serpin Protease granzyme B has a pleiotropic function proteinase inhibitor 6, which binds to granzyme B Granzyme B may have systemic and local effects covalently and inhibits granzyme B-mediated tubular leading to graft injury and activation of inflammatory cell damage; however, one of the studies has already cells in circulating blood.22 Granzyme B is a serine shown that serpin proteinase inhibitor 6 could not protease of broad substrate specificity, cleaves prevent subclinical injury in acute rejection.26 An cytoskeleton proteins, matrix metalloproteinase, inhibition of a caspase 3/reactive oxygen species nuclear lamina of a cell, and activates proinflammatory inhibitor like isatin sulfonamide, ascorbate, or cytokines interleukin 1β linked with many tocopherol may have beneficial effects in retarding inflammatory diseases.7,22 Granzyme B cleaves granzyme B-driven CABMR. However, this requires extracellular matrix protein and releases active further study before use in practice. Recently, transforming growth factor β from cells into the inflammatory cells with inflammation and fibrosis interstitial space, which may induce fibrosis and de and tubular atrophy region of the microscopy novo differentiation of regulatory T cells.23 showed association with rapid progression and graft Simultaneously, increased regulatory T cells in the local failure. In our previous study, we have demonstrated milieu at the site of injury helps in suppressing the that T-bet-positive cells in allografts were associated inflammatory cell and sustaining the inflammation for with poor prognosis.14 longer duration and perpetuating the allograft The major limitation of our study was that we had injury.17,24 not investigated perforin expression in CTL required 784 Brijesh Yadav et al/Experimental and Clinical Transplantation (2020) 7: 778-784 Exp Clin Transplant
for granzyme B delivery and coexpression of 9. Nankivell BJ, Shingde M, Keung KL, et al. The causes, significance + + and consequences of inflammatory fibrosis in kidney CD8 granzyme B (double-positive) T cells in transplantation: the Banff i-IFTA lesion. Am J Transplant. intragraft tissue. The exact mechanisms of granzyme 2018;18(2):364-376. doi:10.1111/ajt.14609 10. Roufosse C, Simmonds N, Clahsen-van Groningen M, et al. A 2018 B-induced injury, whether by caspase or reactive Reference Guide to the Banff Classification of Renal Allograft oxygen species dependent in the allograft, remain Pathology. Transplantation. 2018;102(11):1795-1814. doi:10.1097/ unclear. Therefore, a more comprehensive study is TP.0000000000002366 11. Nickeleit V, Andreoni K. The classification and treatment of required to fully understand the role of CTL and NK antibody-mediated renal allograft injury: where do we stand? cells, which release granzyme B in cases of CABMR. Kidney Int. 2007;71(1):7-11. doi:10.1038/sj.ki.5002003 12. Randhawa P. T-cell-mediated rejection of the kidney in the era of donor-specific antibodies: diagnostic challenges and clinical Conclusions significance. Curr Opin Organ Transplant. 2015;20(3):325-332. doi:10.1097/MOT.0000000000000189 + 13. Sun Q, Liu ZH, Cheng Z, et al. Treatment of early mixed cellular Higher granzyme B cell count in renal allograft and humoral renal allograft rejection with tacrolimus and tissue in patients of CABMR compared with that of mycophenolate mofetil. Kidney Int. 2007;71(1):24-30. doi:10. SGF patients indicates granzyme-mediated covert 1038/sj.ki.5001870 14. Yadav B, Prasad N, Agrawal V, et al. T-bet-positive mononuclear injury in patients with CABMR. Graft tissue granzyme cell infiltration is associated with transplant glomerulopathy and level was also associated with graft dysfunction in interstitial fibrosis and tubular atrophy in renal allograft recipients. Exp Clin Transplant. 2015;13(2):145-151. CABMR. Persistent allogeneic stimulation to the CTL 15. Prasad N, Jaiswal AK, Agarwal V, et al. Differential alteration in leads to increased synthesis and release of granzyme peripheral T-regulatory and T-effector cells with change in P- B. Activated CTL infiltrates into the different glycoprotein expression in childhood nephrotic syndrome: a longitudinal study. Cytokine. 2015;72(2):190-196. doi:10.1016/j. compartments of the allograft and mediates granzyme cyto.2014.12.028 B-dependent injury, resulting in the development of 16. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-delta delta C(T)) chronic allograft dysfunction and, ultimately, graft loss. method. Methods. 2001;25(4):402-408. doi:10.1006/meth.2001. Inhibition of granzyme B synthesis/release and 1262 17. Ashton-Chess J, Dugast E, Colvin RB, et al. Regulatory, effector, and prevention of CTL sequestration in intragraft tissue cytotoxic T cell profiles in long-term kidney transplant patients. J may be useful strategies for the prolongation of graft Am Soc Nephrol. 2009;20(5):1113-1122. doi:10.1681/ASN.2008 survival in the future. 050450 18. Soni C, Karande AA. Glycodelin A suppresses the cytolytic activity of CD8+ T lymphocytes. Mol Immunol. 2010;47(15):2458-2466. References doi:10.1016/j.molimm.2010.06.008 19. Simon T, Opelz G, Wiesel M, Ott RC, Susal C. Serial peripheral blood 1. De Serres SA, Noel R, Cote I, et al. 2013 Banff criteria for chronic active perforin and granzyme B gene expression measurements for antibody-mediated rejection: assessment in a real-life setting. Am J prediction of acute rejection in kidney graft recipients. Am J Transplant. 2016;16(5):1516-1525. doi:10.1111/ajt. 13624 Transplant. 2003;3(9):1121-1127. doi:10.1034/j.1600-6143.2003. 2. Gheith O, Al-Otaibi T, Halim MA, et al. Early versus late acute 00187.x antibody-mediated rejection among renal transplant recipients 20. Kim CH, Broxmeyer HE. Chemokines: signal lamps for trafficking of in terms of response to rituximab therapy: a single center T and B cells for development and effector function. J Leukoc Biol. experience. Exp Clin Transplant. 2017;15(Suppl 1):150-155. 1999;65(1):6-15. doi:10.1002/jlb.65.1.6 doi:10.6002/ect.mesot2016.P32 21. Smyth LJ, Kirby JA, Cunningham AC. Role of the mucosal integrin 3. Parish IA, Kaech SM. Diversity in CD8(+) T cell differentiation. Curr alpha(E)(CD103)beta(7) in tissue-restricted cytotoxicity. Clin Exp Opin Immunol. 2009;21(3):291-297. doi:10.1016/j.coi.2009.05.008 Immunol. 2007;149(1):162-170. doi:10.1111/j.1365-2249.2007. 4. Sharma VK, Bologa RM, Li B, et al. Molecular executors of cell 03385.x death: differential intrarenal expression of Fas ligand, Fas, 22. Goldbach-Mansky R, Suson S, Wesley R, Hack CE, El-Gabalawy HS, granzyme B, and perforin during acute and/or chronic rejection Tak PP. Raised granzyme B levels are associated with erosions in of human renal allografts. Transplantation. 1996;62(12):1860-1866. patients with early rheumatoid factor positive rheumatoid doi:10.1097/00007890-199612270-00031 arthritis. Ann Rheum Dis. 2005;64(5):715-721. doi:10.1136/ard.2003. 5. Wever PC, Boonstra JG, Laterveer JC, et al. Mechanisms of 007039 lymphocyte-mediated cytotoxicity in acute renal allograft 23. Jacquemin G, Margiotta D, Kasahara A, et al. Granzyme B-induced rejection. Transplantation. 1998;66(2):259-264. doi:10.1097/000 mitochondrial ROS are required for apoptosis. Cell Death Differ. 07890-199807270-00021 2015;22(5):862-874. doi:10.1038/cdd.2014.180 6. Rowshani AT, Florquin S, Bemelman F, Kummer JA, Hack CE, Ten 24. Boivin WA, Shackleford M, Vanden Hoek A, et al. Granzyme B Berge IJ. 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Liver Allografts From Older Donors With or Without Recovery of Thoracic Organs and Their Impact on Hepatic Graft and Patient Survival
Ricci Kalayanamitra,1 Ashton Brooks,2 Sushrut Trakroo,3 Zakiyah Kadry,2 Ashokkumar Jain2
Abstract in group B, respectively (P = .69). Graft survival rates at the same time points were 88.7%, 76.8%, 71.5%, and Objectives: Multiorgan procurement involving thoracic 63.1% in group A and 90.0%, 77.5%, 70.4%, and 62.5% organs prolongs the liver recovery cross-clamp time. in group B, respectively (P = .956). This may impact the outcome of hepatic allograft, Conclusions: Liver procurement with or without more so in older donors (age > 60 years). We compared recovery of thoracic organs from donors > 60 years old the outcomes of liver allografts from older donors with does not affect liver grafts and recipient outcomes and without recovery of thoracic organs. in the short-term or long-term and should be Materials and Methods: Using the Scientific Registry of encouraged. Transplant Recipients database, we compared survival outcomes of 258 adults who received a liver allograft Key words: Graft and patient survival posttransplant, from older donors with thoracic organ recovery (group Multiorgan procurement, Scientific Registry of Transplant A) with 6006 patients who received liver allografts Recipients, United Network for Organ Sharing from older donor without thoracic organ recovery (group B). Furthermore, we performed a subgroup Introduction analysis matched for recipient and donor risk factors including presence of hypertension, diabetes mellitus, There has been a steady increase in demand for solid- renal function, donor age, and use of inotropes. For organ transplants in the past 2 decades.1,2 However, the final analyses, there were 159 patients in group A the donor pool has largely remained stagnant. To and 468 in group B. decrease wait list time and mortality for liver and Results: The 1-month, 1-year, 3-year, and 5-year patient thoracic organ transplants, the number of older survival rates in group A were 95%, 91.6%, 70.1%, and candidates selected as donors is increasing.3,4 Several 65.5% compared with 95%, 92%, 70%, and 57.7% in group B, respectively (P = .695). Graft survival rates for reports have suggested that survival outcomes for group A at the same time points were 91.5%, 81.0%, recipients of thoracic organs and livers are similar 71.7%, and 57.4% compared with 91.3%, 81.1%, 61.9%, compared with younger donors, although many and 50.4% in group B, respectively (P = .791). In the authors have suggested that these improvements matched population, patient survival rates at 1 month, may be the result of a higher level of care and 1 year, 3 years, and 5 years were 95%, 83.1%, 77.1%, and consideration during the process of donor selection 68.8% compared with 94.4%, 81.6%, 72.2%, and 66.8% and recipient matching.5-9 With a shortage of donor organs, the selection of older donors is more prevalent From the 1Pennsylvania State University, College of Medicine, Hershey, Pennsylvania, USA; the 2Department of Surgery, Pennsylvania State University, College of Medicine, Hershey, than in the past. Simultaneous procurements of Pennsylvania USA; and the 3Department of Hospital Medicine, Cleveland Clinic, Cleveland, thoracic organ(s) from older donors have been Ohio, USA Acknowledgements: The authors have not received any funding or grants in support of the reported, to increase the donor pool. It is postulated presented research or for the preparation of this work and have no declarations of potential that the increase in cross-clamp time for liver recovery interest. This was a poster at the 17th Annual International Congress of International Liver Transplantation Society, Valencia, Spain and European Society for Organ Transplant (ESOT), during simultaneous thoracic organ procurement June 22-25, 2011. Work was performed at the Division of Abdominal Organ Transplantation, could potentially worsen recipient and/or graft Department of Surgery, Temple University Hospital, Philadelphia, PA. Corresponding author: Ashokkumar Jain, Pennsylvania State University, College of Medicine, outcomes, more so when older donors are used. The Department of Surgery, 500 University Drive, PO Box 850, Hershey, PA 17033-0850, USA increase in cross-clamp time could lead to primary Phone: +1 717 531 5921 E-mail: [email protected] nonfunction and may result an increase in the rate of Experimental and Clinical Transplantation (2020) 7: 785-790 30-day retransplant or mortality5-7 or cholangiopathy
Copyright © Başkent University 2020 DOı: 10.6002/ect.2020.0246 Printed in Turkey. All Rights Reserved. 786 Ricci Kalayanamitra et al/Experimental and Clinical Transplantation (2020) 7: 785-790 Exp Clin Transplant
in the long-term. After a comprehensive literature survival differences in the 2 groups. P < .05 was survey, we found no previously published studies on considered significant. survival outcomes of liver transplant recipients who had received livers from older donors with table 1. Donor Demographics simultaneous recovery of thoracic organs. Donor Factor Group A Group B P (n = 258) (n = 6006) In this study, we compared survival rates for Age ± SD, y 63.6 ± 2.7 67.7 ± 5.5 < .001* recipient and grafts for liver transplants from older Age 61 to < 65 y .001* No. (%) 182 (70.54) 2132 (35.49) donors (age > 60 years) when the liver was procured Mean age ± SD, y 62.1 ± 1.08 62.4 ± 1.1 with (group A) or without simultaneous procurement Age ≥ 65 to >70 y < .001* of thoracic organs (group B). No. (%) 76 (29.5) 3874 (64.5) Mean age ± SD, y 67 ± 2.37 70.6 ± 4.8 Female-to-male ratio 143:115 (1.24:1) 3158:2848 .37 Materials and Methods (1.14:1) Diabetes mellitus, No. (%) No 210 (81.4) 4695 (78.2) We reviewed the United Network for Organ Sharing Yes 30 (11.6) 934 (15.6) .22 Unknown 18 (7.0) 377 (6.2) (UNOS) database from 1987 to 2010 after obtaining Hypertension, No. (%) approval from the Institutional Review Board.5 The No 115 (44.6) 2115 (35.2) Yes 124 (48.0) 3486 (58.0) .005* data included all liver recoveries from donors in the Unknown 19 (7.4) 405 (6.8) United States. The study population was divided Mean donor BMI ± SD 26 ± 6.14 29 ± 6.66 .39 Inotropic support, No. (%) 117 (45.3) 2246 (37.4) .01* into 2 groups. Group A consisted of simultaneous Abbreviations: BMI, body mass index (calculated as weight in kilograms abdominal and thoracic organs procurement, and divided by height in meters squared) group B included procurement of abdominal organs Ratio is shown as No. of patients (with the reduced decimal value in only. Recipient survival, graft survival, and the rates parentheses). Group A consisted of adults who received a liver allograft from older donors with thoracic organ recovery; group B received a liver allograft of retransplant in both groups were calculated. from older donors without thoracic organ recovery. *Statistically significant. There was a total of 6322 older donors (age > 60 years) selected during the study period. There were 60 donors with inadequate data, and they were excluded from the study. Available cases for the table 2. Recipient Demographics study were divided into 2 groups. Group A (study Recipient Factos Group A Group B P (n = 258) (n = 6006) group) included 258 recipients who had received Mean age ± SD, y 53 ± 11.4 54 ± 10.8 .17 livers from deceased donors with simultaneous Male-to-female ratio 1.8:1 1.7:1 .59 Ethnicity, No. (%) thoracic organ recovery. Group B (control group) White 190 (73.6) 4536 (75.5) included 6006 recipients who had received livers from Hispanic 35 (13.6) 754 (12.6) .8 abdominal organ donors only. The demographic data African American 18 (7) 434 (7.2) Asian 15 (5.8) 282 (4.7) for donors and recipients are presented in Tables 1 and Diagnosis, No. (%) 2, respectively. We accounted for the differences in Viral infection 75 (29.1) 1756 (29.2) EtOH 45 (17.4) 899 (15) donor and recipient risk factors and matched 159 EtOH + HCV 19 (7.4) 317 (5.3) donors from group A to 468 donors from group B for Cryptogenic 22 (8.5) 685 (11.4) .4 Autoimmune hepatitis 6 (2.3) 169 (2.8) all variables (Table 3). The matched population data NASH 7 (2.7) 230 (3.8) from groups A and B were then analyzed. All HCC 34 (13.1) 625 (10.4) Metabolic syndrome 9 (3.5) 176 (2.9) patients were followed up for a mean duration of 5 Cholestasis 25 (9.7) 728 (12.1) years. All of the donors were deceased. Other 16 (6.2) 421 (7) Liver function (mean ± SD) Serum bilirubin, mg/dL 7.1 ± 9.2 7.5 ± 10.2 .59 Statistical analyses Serum albumin, g/dL 2.9 ± 0.7 2.9 ± 0.7 .64 Serum creatinine, mg/dL 1.3 ± 1 1.4 ± 1.2 .33 All data are presented as mean values with standard Mean INR ± SD 1.7 ± 0.6 1.8 ± 1.7 .39 deviation (SD). We performed comparisons of mean Mean WIT ± SD, min 44.1 ± 20.1 44.1 ± 20.6 .64 with 2-tailed t tests for continuous variables and with Abbreviations: EtOH, ethyl alcohol; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; INR, international normalized ratio; NASH, nonalcoholic the Pearson chi-square test for categorical variables. steatohepatitis; WIT, warm ischemia time We used the Kaplan-Meier method to estimate Ratio is shown as reduced decimal values. Group A consisted of adults who received a liver allograft from older donors with thoracic organ recovery; patient and graft survival, and we used the log-rank group B received a liver allograft from older donors without thoracic organ test (SPSS, version 25.0; SPSS, Inc.) to compare recovery. Ricci Kalayanamitra et al/Experimental and Clinical Transplantation (2020) 7: 785-790 787
table 3. Characteristics of Donors and Recipients 57.7% in group B, respectively (P = .695) (Figure 1). Group A Group B Also, graft survival rates at identical time points for (n = 258) (n = 468) Donor Factors group A were 91.5%, 81.0%, 71.7%, and 57.4% and for Median age ± SD, y 63.3 ± 2.4 63.2 ± 2.2 group B were 91.3%, 81.1%, 61.9%, and 50.4%, Male-to-female ratio 0.7:1 0.5:1 Ethnicity, No. (%) respectively (P = .791) (Figure 2). White 134 (84.3) 394 (84.2) Although the overall recipient and graft survival Hispanic 11(6.9) 39 (8.3) African American 7 (4.4) 23 (4.9) rates in both groups were not statistically different, Asian 7 (4.4) 12 (2.6) we did observe an apparent difference in survival at Mean BMI ± SD 25.1 ± 3.8 25.8 ± 4.8 Diabetes, No. (%) 2 (1.3) 2 (0.4) 5 years. The patient survival rate was 7.8% lower and Hypertension, No. (%) 60 (37.7) 115 (24.6) the graft survival rate was 7.3% lower in group B Cause of death, No. (%) compared with group A. All donors were > 60 years CVA 124 (78) 382 (81.6) Anoxia 4 (2.6) 32 (6.8) old in both groups. On detailed examination of Head trauma 27 (17) 53 (11.3) demographics, we found significant differences in CNS tumor 4 (2.5) 1 (0.2) Mean serum creatinine ± SD, mg/dL 0.9 ± 0.4 0.9 ± 0.2 the risk factors between groups A and B. The mean Mean aspartate aminotransferase ± SD, U/L 50.7 ± 51.4 54.4 ± 80 values for donor age and for number of donors > 65 Inotropic support, No. (%) 71 (44.7) 95 (20.3) Mean CIT ± SD, h 7.5 ± 3.9 8.1 ± 4.2 years old were significantly higher in group B. Mean Recipient Factors serum creatinine values were higher in group B but Median age ± SD, y 53.1 ± 11.3 53 ± 10.8 Male-to-female ratio 1.9:1 1.8:1 did not reach statistical significance (P = .078). Also, Ethnicity, No. (%) rates of hypertension and diabetes mellitus were White 115 (72.3) 353 (75.4) Hispanic 24 (15.1) 64 (13.7) significantly higher in group B. In group A, the African American 11 (6.9) 28 (6) need for inotropes was significantly higher (Table 1). Asian 9 (5.7) 23 (4.9) Diagnosis, No. (%) The differences between the donor and recipient Viral infection 44 (27.7) 157 (33.6) characteristics in groups A and B were compatible. EtOH 28 (17.6) 82 (17.5) EtOH + HCV 12 (7.5) 27 (5.8) Therefore, the 159 donors from group A were Cryptogenic 14 (8.8) 50 (10.7) matched for all the variables with the 468 donors in Autoimmune hepatitis 4 (2.5) 18 (3.8) group B (Table 3). This matched population was then NASH 5 (3.1) 13 (2.8) HCC 23 (14.5) 32 (6.8) reexamined with regard to patient and graft survival. Metabolic syndrome 6 (3.8) 9 (1.9) The patient survival rates for the matched Cholestasis 12 (7.5) 48 (10.3) Other 11 (6.9) 32 (6.8) population in group A at 1 month, 1 year, 3 years, and Liver function, mean ± SD 5 years were 95%, 83.1%, 77.1%, and 68.8% compared Serum bilirubin, mg/dL 6.8 ± 9 7.7 ± 11.4 Serum albumin, g/dL 2.9 ± 0.7 2.9 ± 0.8 with 94.4%, 81.6%, 72.2%, and 66.8% in group B, Serum creatinine, mg/dL 1.2 ± 0.5 1.4 ± 1.3 respectively (P = .69) (Figure 3). Graft survival rates at Mean INR ± SD 1.8 ± 0.6 1.8 ± 1 Mean WIT ± SD, min 44.1 ± 21.8 42.7 ± 20.1 1 month, 1 year, 3 years, and 5 years were 88.7%, 76.8%, Abbreviations: BMI, body mass index (calculated as weight in kilograms 71.5%, and 63.1% in group A and 90.0%, 77.5%, 68.4%, divided by height in meters squared); CIT, cold ischemia time; CNS, central and 62.5% in group B, respectively (P = .956) (Figure nervous system; CVA, cerebrovascular accident; EtOH, ethyl alcohol; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; INR, international 4). In the matched population, recipient and graft normalized ratio; NASH, nonalcoholic steatohepatitis; WIT, warm ischemia survival rates were almost identical, at each time point. time Ratio is shown as reduced decimal values. Group A consisted of adults who Figure 1. Patient Survival After Liver Transplant in Group A and Group B received a liver allograft from older donors with thoracic organ recovery; group B received a liver allograft from older donors without thoracic organ recovery.
Results
The recipient demographics are shown in Table 2. There were 254 older donors (4.12%) who were used for combined thoracic organ and liver recoveries. The overall patient survival rates at 1 month, 1 year, 3 Data for groups A and B are in percent, showing adults who received a liver allograft from older donors with thoracic organ recovery (group A) or who years, and 5 years in group A were 95.%, 91.6%, received a liver allograft from older donors without thoracic organ recovery 70.1%, and 65.5% compared with 95%, 92%, 70%, and (group B). 788 Ricci Kalayanamitra et al/Experimental and Clinical Transplantation (2020) 7: 785-790 Exp Clin Transplant
Figure 2. Graft Survival After Liver Transplant in Group A and Group B between years 1981 and 1985 to 11% between years 1986 and 1990. There was a further increase to 21% between 1990 and 1998.10 Since 1988, the UNOS database has shown a rising trend of organ use from older donors.3,5 Multiple studies have also suggested successful use of older donors for liver, heart, and lung transplants. In a review of literature for liver transplantation, Neipp and colleagues reported on 1208 transplants Data for groups A and B are in percent, showing adults who received a liver 11 allograft from older donors with thoracic organ recovery (group A) or who between 1990 and 2002. There were 67 donors who received a liver allograft from older donors without thoracic organ recovery were > 60 years old and had outcomes similar to (group B). younger donors. Macedo and colleagues observed worse outcome from donors > 50 years old.12 They Figure 3. Patient Survival After Liver Transplant for Matched Population in suggested closer monitoring of recipients when older Groups A and B donors are selected. Sampedro and colleagues showed similar outcomes for donors > 75 years old (n = 24) compared with donors < 75 years old (n = 174).13 The operative time was longer in older donors, and the authors suggest that careful donor selection may reduce recipient mortality and morbidity. Faber and colleagues examined 272 liver transplant recipients and divided the donors into the following age Data for groups A and B are in percent, showing adults who received a liver groups: < 50 years, from 50 to 59 years, from 60 to allograft from older donors with thoracic organ recovery (group A) or who 69 years, and ≥ 70 years.7 They concluded similar received a liver allograft from older donors without thoracic organ recovery (group B). rates of survival for patients and grafts; however, ischemic biliary lesion rates were significantly higher Figure 4. Graft Survival After Liver Transplant for Matched Population in with donors ≥ 70 years old.7 Chapman and Groups A and B colleagues reported on 1036 adult recipients and showed comparable outcomes in graft and patient survival from donors ≥ 60 years old, regardless of recipient age, without an increase in complication rate.14 Bertuzzo and colleagues, in a single-center European study, concluded that the outcomes from liver donors > 70 years old were comparable, with appropriate donor management.15 Data for groups A and B are in percent, showing adults who received a liver In a review of literature for heart transplant, allograft from older donors with thoracic organ recovery (group A) or who received a liver allograft from older donors without thoracic organ recovery Bennett and colleagues reported a higher relative risk (group B). of survival with donors > 50 years old; however, mortality risk without transplant was even higher.16 Loebe and colleagues compared 167 recipients of Discussion organs from donors > 50 years old with 524 recipients
of organs from donors < 35 years old and with 379 There is a growing disparity between the supply and recipients of organs from donors 35 to 50 years old.8 demand for organs for transplant. The past 3 decades They found no significant difference at midterm have shown that the annual rate of solid-organ follow-up. Blanche and colleagues reported survival transplant exceeds the annual rate of deceased donor rates after heart transplant from donors > 50 years organ donation.5 old were no different from donors < 50 years old In 2000, we reported 4000 consecutive liver (N = 267).6 However, older donors were carefully transplants from a single center between 1981 and selected in this study. Macedo and colleagues in 2010 1998. We observed that organ donation rates from reported contradictory findings, with lower rates for donors > 50 years old had increased from 6% Ricci Kalayanamitra et al/Experimental and Clinical Transplantation (2020) 7: 785-790 789
patient and graft survival from donors > 50 years In the present study, we have shown that in well- old.12 They concluded that older recipients needed matched recipients and donors, the recipient and graft younger donors and recommended more robust survival rates after liver transplant are comparable follow-up for the first 18 months after heart with those with and without simultaneous thoracic transplant. Daniel and colleagues reported similar organ procurement. conclusions, with higher mortality in donors > 50 years old and recipients > 60 years old.17 Figure 5. Trend in Older Organ Donor During the Past 30 Years For lung transplantation, DuBose and Salim suggested aggressive donor management to bridge the gap between organ supply and organ demand.18 Shigemura and colleagues reported a single-center experience with 593 lung transplants that included 87 of donors > 55 years old (14.7%).9 The outcomes were comparable with outcomes in younger donors < 55 years old. They observed increased mortality in transplants from older donors to older recipients with pulmonary hypertension or those requiring lung- cardiopulmonary bypass. However, they observed Abbreviations: UNOS, United Network for Organ Sharing that donor age > 55 years should not be an exclusion criteria.9 They concluded that careful recipient Conclusions selection criteria and meticulous surgical planning is required to improve outcomes. From 1987 to 2010, less than 9% of the donors between We reviewed the UNOS national database for all the ages of 60 and 65 years were selected for combined organ transplantation from 1988 onward and thoracic and abdominal organ procurement. Our investigated trends during the past 30 years.5 For study shows that use of liver allografts from donors liver recipients, the number of elected donors 50 to > 60 years old with or without simultaneous thoracic 64 years old has increased from 13.8% in 1990 to organ procurement has no effect on short-term or 24.4% in 2020. Simultaneously, the number of long-term and recipient or graft survival outcomes. selected donors who were ≥ 65 years old has Furthermore, survival outcomes were no different increased from 1.8% in 1990 to 7.7% in 2020. when donor characteristics were matched for age, Similarly, for heart recipients, the number of selected presence of diabetes mellitus, hypertension, use of donors between 50 and 60 years old has increased inotropes, and renal function. We conclude that from 3.7% in 1990 to 9.5% in 2000; however, there has procurement of thoracic organs with or without liver been a small decrease to 7.4% in 2020. For heart from donors > 60 years old does not affect long-term donors ≥ 65 years old, the rate of donation has been or short-term and liver graft or recipient outcomes 0.16% during the past 20 years. Interestingly, for lung and should be encouraged. recipients, the rate of donation for donors 50 to 64 years old was 1.8% in 1990 with an increase to 10.5% References in 2000, 15.8% in 2010, and 15.0% in 2020, thus far. 1. Fayek SA, Quintini C, Chavin KD, Marsh CL. The current state of For lung recipients, donors ≥ 65 years old, continues liver transplantation in the United States: perspective from to remain low (albeit, slightly better than for heart American Society of Transplant Surgeons (ASTS) Scientific Studies recipients) and accounts for 1.2% of lung transplants Committee and endorsed by ASTS Council. Am J Transplant. 2016;16(11):3093-3104. doi:10.1111/ajt.14017 in the past 20 years (Figure 5). 2. Kim WR, Therneau TM, Benson JT, et al. Deaths on the liver There is sufficient evidence to support the use of transplant waiting list: an analysis of competing risks. Hepatology. 2006;43(2):345-351. doi:10.1002/hep.21025 older donors for liver, heart, and lung transplants. 3. US Department of Health and Human Services. Health Resources Thoracic organ procurement prolongs the cross-clamp and Services Administration (HRSA). The scientific registry of transplant recipients. Accessed June 10, 2020. https://srtr. time and may adversely affect liver outcomes when the transplant.hrsa.gov/annual_reports/2011/Default.aspx liver is simultaneously recovered. However, to date, 4. Kim DY, Cauduro SP, Bohorquez HE, Ishitani MB, Nyberg SL, Rosen the data regarding simultaneous liver and thoracic CB. Routine use of livers from deceased donors older than 70: is it justified? Transpl Int. 2005;18(1):73-77. doi:10.1111/j.1432- organ procurement from older donors are scant. 2277.2004.00017.x 790 Ricci Kalayanamitra et al/Experimental and Clinical Transplantation (2020) 7: 785-790 Exp Clin Transplant
5. US Department of Health and Human Services. Health Resources 12. Macedo FI, Miranda LE, Fernandes JL, et al. Donor age as a and Services Administration (HRSA). Organ procurement and predictor of risk for short-term outcomes after liver transplant. Exp transplantation network, national data. Accessed June 10, 2020. Clin Transplant. 2010;8(3):202-209. https://optn.transplant.hrsa.gov/data/view-data-reports/ 13. Sampedro B, Cabezas J, Fabrega E, Casafont F, Pons-Romero F. national-data Liver transplantation with donors older than 75 years. Transplant 6. Blanche C, Kamlot A, Blanche DA, et al. Heart transplantation with Proc. 2011;43(3):679-682. doi:10.1016/j.transproceed.2011.01.084 donors fifty years of age and older. J Thorac Cardiovasc Surg. 14. Chapman WC, Vachharajani N, Collins KM, et al. Donor age-based 2002;123(4):810-815. doi:10.1067/mtc.2002.120009 analysis of liver transplantation outcomes: short- and long-term 7. Faber W, Seehofer D, Puhl G, et al. Donor age does not influence outcomes are similar regardless of donor age. J Am Coll Surg. 12-month outcome after orthotopic liver transplantation. 2015;221(1):59-69. doi:10.1016/j.jamcollsurg.2015.01.061 Transplant Proc. 2011;43(10):3789-3795. doi:10.1016/j. 15. Bertuzzo VR, Cescon M, Odaldi F, et al. Actual risk of using very transproceed.2011.10.048 aged donors for unselected liver transplant candidates: a 8. Loebe M, Potapov EV, Hummel M, Weng Y, Bocksch W, Hetzer R. European single-center experience in the MELD era. Ann Surg. Medium-term results of heart transplantation using older donor 2017;265(2):388-396. doi:10.1097/SLA.0000000000001681 organs. J Heart Lung Transplant. 2000;19(10):957-963. doi:10.1016/s 16. Bennett LE, Edwards EB, Hosenpud JD. Transplantation with older 1053-2498(00)00178-9 donor hearts for presumed “stable” recipients: an analysis 9. Shigemura N, Horai T, Bhama JK, et al. Lung transplantation with of the Joint International Society for Heart and Lung lungs from older donors: recipient and surgical factors affect Transplantation/United Network for Organ Sharing Thoracic outcomes. Transplantation. 2014;98(8):903-908. doi:10.1097/TP.000 Registry. J Heart Lung Transplant. 1998;17(9):901-905. 0000000000134 17. Daniel M, Chen C, Chung J, Goldberg L, Acker MA, Atluri P. 10. Jain A, Reyes J, Kashyap R, et al. Long-term survival after liver Interaction of donor and recipient age: do older heart transplant transplantation in 4,000 consecutive patients at a single center. recipients require younger hearts? Ann Thorac Surg. Ann Surg. 2000;232(4):490-500. doi:10.1097/00000658-200010000- 2019;107(1):62-66. doi:10.1016/j.athoracsur.2018.06.085 00004 18. DuBose J, Salim A. Aggressive organ donor management 11. Neipp M, Bektas H, Lueck R, et al. Liver transplantation using protocol. J Intensive Care Med. 2008;23(6):367-375. doi:10.1177/ organs from donors older than 60 years. Transpl Int. 0885066608324208 2004;17(8):416-423. doi:10.1007/s00147-004-0735-2 Artıcle
Comparison of Standard and Modified Standard Organ Procurement Techniques for Deceased Donors
Cemalettin Koc, Sami Akbulut, Sezai Yilmaz
Abstract organ retrieval had no effect on clinical outcomes in recipients after liver transplant. However, this Objectives: This study aimed to compare the impact of retrospective study requires additional prospective deceased-donor organ procurement techniques investigations to more fully understand the (standard versus modified standard) on biochemical differences. outcomes after liver transplant. Materials and Methods: From February 2006 to Key words: Deceased-donor liver transplantation, December 2013, organs were recovered from 105 Modified standard organ procurement technique, consecutive deceased donors by our transplant team. Standard organ procurement technique All organ procurement procedures were performed by a pioneer surgeon experienced in organ recovery from Introduction deceased donors. Donors were divided into those who had the abdominothoracic approach, which is referred Solid-organ transplantation has become the criterion to as the standard technique, and those who had the standard treatment modality for many diseases, abdominal approach, which is referred to as the especially chronic organ failure. The first successful modified standard technique. Both groups were kidney transplant to a human was performed in the compared in terms of age, sex, weight, height, body 1950s. Subsequently, successful liver, heart, and mass index, liver graft weight, cross-clamping time, pancreas transplant procedures were performed in cold ischemia time, and liver function tests in recipients over the first 3 postoperative days. the 1960s. At the beginning of the 1980s, successful 1 Results: Our study group included 66 male and 39 lung and intestinal transplants were done. Along female donors, with an age range of 1 to 93 years with developments in surgical techniques and the (median of 44 y, means ± standard deviation of discovery of immunosuppressive drugs to better 43.8 ± 23.7 y). Among the deceased donors, 73 prevent graft rejection, solid-organ transplantation underwent the modified standard technique and 32 has become a hope for thousands of people who have underwent the standard technique. There were no no other options for their disease.2,3 statistically significant differences between groups in Deceased organ donors are the most important terms of age, sex, weight, height, body mass index, graft source for organ transplant in Western countries, weight, cold ischemia time, and liver function tests in which is in contrast to the use of living donors in recipients over the first 3 postoperative days. We 4 observed a statistically significant difference between many underdeveloped countries. One of the main groups in terms of cross-clamping time (P < .001). differences between living and deceased donors is Conclusions: Except for the decreased cross-clamping the incision technique used during the organ time, the modified standard technique for deceased procurement process. For recovery of organs from deceased donors, thoracoabdominal cavities are From the Department of Surgery and Liver Transplant Institute, Inonu University Faculty of routinely opened via midline incision extending Medicine, Malatya, Turkey Acknowledgements: The authors have no sources of funding for this study and have no conflicts from the suprasternal notch to the symphysis pubis. of interest to declare. This study is derived from the general surgery specialization thesis of This procedure is called the thoracoabdominal Cemalettin Koc. Corresponding author: Sami Akbulut, Department of Surgery and Liver Transplant Institute, approach or the standard organ procurement Inonu University Faculty of Medicine, Elazig Yolu 10. Km, Malatya 44280, Turkey technique (SOPT).5,6 When intrathoracic organ Phone: +90 422 3410660 E-mail: [email protected] retrieval is not needed, intraabdominal organs can be Experimental and Clinical Transplantation (2020) 7: 791-795 recovered through abdominal incisions without
Copyright © Başkent University 2020 DOı: 10.6002/ect.2018.0022 Printed in Turkey. All Rights Reserved. 792 Cemalettin Koc et al/Experimental and Clinical Transplantation (2020) 7: 791-795 Exp Clin Transplant
sternotomy. This approach, which is referred to as the pancreas, and kidneys were then consecutively modified standard organ procurement technique removed.5,6 (MSOPT), can reduce time to cold preserving solution perfusion and may provide rapid organ Modified standard organ procurement technique retrieval.5 Herein, we aimed to compare the effects of The abdominal cavity was opened with a longitudinal deceased-donor recovery techniques on biochemical midline incision from xiphoid to symphysis pubis and outcomes after liver transplant. a transverse incision extending 1 cm above umbilicus to both flank regions. The inferior vena cava was Materials and Methods suspended from the superior of the left renal vein in accordance with the Cattell and Braasch maneuver. From February 2006 to December 2013, 105 The inferior mesenteric vein was suspended, and a consecutive deceased donors underwent organ cannula was inserted into it. The distal abdominal procurement procedures by the Inonu University aorta was turned and suspended near the iliac Liver Transplant Institute team. All procurement bifurcation, and a cannula was placed into it. Both procedures were performed by a pioneer surgeon hemidiaphragms were opened anteriorly, in a lunar- who is experienced in organ recovery from deceased type shape, near the costochondral region. The donors. Procurement procedures were performed opening of the inferior vena cava was detected with the abdominothoracic approach in 32 deceased in the right atrium on pericardia. After a cross-clamp donors (SOPT group) and with the abdominal was placed on the supraceliac abdominal aorta, the approach in 73 deceased donors (MSOPT group). right atrium was also opened as an extra precaution Both groups were compared in terms of age, sex, against overdistention of the liver. All inotropic weight, height, body mass index, liver graft and chronotropic medications were stopped. The weight, time to cross-clamping, cold ischemia inferior vena cava was opened from superior of time, blood group (A, B, AB, O), and liver function the left renal vein, and then the cannula of the distal tests in the first 3 posttransplant days in recipients. abdominal aorta was irrigated with 3 L of University Cross-clamping time was defined as the time of Wisconsin solution. Crushed ice was placed into between initiation of the incision and start of cold the abdominal cavity. One liter of University of perfusion. Cold ischemia time was defined as the Wisconsin solution was placed into the inferior time interval between application of deceased-donor mesenteric vein cannula for perfusion of the portal aortic cross-clamp and release of recipient cross- vein. The visceral organs were removed with en clamp. bloc dissection after perfusion was finished. All vascular pedicles of organs were dissected on the back Standard organ procurement technique table.5 A midline incision was made from the suprasternal notch to just above the symphysis pubis. Long Statistical analyses incision provides better exposure for removal of Statistical analyses were performed with SPSS heart, both kidneys, the liver, and other thora - software (SPSS: An IBM Company, version 22.0, IBM coabdominal viscera. Complete mobilization of the Corporation, Armonk, NY, USA). Quantitative distal small bowel, right colon, and duodenum was variables are presented as means and standard performed to allow for identification of the distal deviation (SD), median, and ranges. Qualitative aorta, iliac bifurcation, and the distal inferior vena variables are presented as numbers and percentages. cava. The infrarenal aorta served as the site for Kolmogorov-Smirnov normality test was used to insertion of the canula, which allowed flushing of the determine whether quantitative variables had normal organs with cold preservation solution. The distribution. The nonparametric Mann-Whitney U supraceliac aorta was encircled, followed by test was used to compare the quantitative data of 2 limited dissection of the hepatic hilum and the independent groups without normal distribution. pancreas. The portal system was cannulated Pearson chi-square and Monte Carlo simulated chi- via the inferior mesenteric vein, and the organs were square tests were used to compare qualitative data of flushed with preservation solution and topically the 2 independent groups. P < .05 was considered to cooled with slush. The thoracic organs, liver, be statistically significant. Cemalettin Koc et al/Experimental and Clinical Transplantation (2020) 7: 791-795 793
Results table 1. Comparison of Groups in Terms of Demographic and Clinical Parameters Parameter SOPT(n = 32) MSOPT(n = 73) Total (N = 105) P Value Our retrospective study included 105 deceased Sex, No. (%) Male 17 (53.1) 49 (67.1) 66 (62.9) .172 donors (66 males, 39 females), with age range from 1 Female 15 (46.9) 24 (32.9) 39 (37.1) to 93 years. The age of male deceased donors ranged Age, y Mean 41.6 44.8 43.8 .399 from 1 to 85 years (median of 47.5 y, mean ± SD of Standard 46.4 ± 22.1 y), whereas the age of female deceased deviation 19.2 25.5 23.7 Median (range) 40 (7-81) 46 (1-93) 44 (1-93) donors ranged from 1 to 93 years (median of 40 y, Weight, kg mean ± SD of 39.3 ± 25.9 y). Mean 69.7 65.8 66.9 .978 Standard Deceased donors were divided into 2 groups deviation 14.2 24.2 21.7 according to the organ procurement technique: Median (range) 70 (32-98) 70 (6-110) 70 (6-110) Height, cm MSOPT (n = 73; 69.5%) and SOPT (n = 32; 30.5%). The Mean 166.6 156.4 159.5 .362 SOPT group consisted of 17 male and 15 female Standard deviation 10.8 30.4 26.4 donors, and the MSOPT group consisted of 49 male Median (range) 169 (130-185) 167 (62-185) 168 (62-185) and 24 female donors. There were no statistically BMI, kg/m2 significant differences between groups in terms of Mean 24.7 26.1 25.7 .145 Standard age (P < .399) and sex (P < .172). There were also no deviation 3.7 4.4 4.2 statistically significant differences between groups in Median (range) 24 (14-34.7) 25 (15-40,4) 25 (14-40.4) Time to cross- terms of weight (P < .978), height (P < .362), body clamp, min mass index (P < .145), and graft weight (P < .612). Mean 128.3 46.6 71.5 < .001 Standard There was no statistically significant difference deviation 28.4 9.5 41.6 between the groups, except for cold ischemia time Median (range) 123 (56-210) 45 (30-78) 50 (30-210) (P < .055) and blood group (P < .054). The most Graft weight, g Mean 1220 1254 1238 .612 significant statistical difference between groups Standard was found in cross-clamping time. The median deviation 217 295 260 Median cross-clamping time in the MSOPT group was 45 (range) 1245 (620-1500) 1320 (670-1805 1262 (620-1805) minutes (range, 30-78 min), whereas the median Cold ischemia time, min value in the SOPT group was 123 minutes (range, Mean 433 521 494 .055 56-210 min) (P < .001). Demographic and clinical Standard deviation 257 203 223 characteristics of the deceased donors are Median summarized in Table 1. (range) 480 (120-1440) 495 (120-1440) 480 (120-1440) Blood group, Both groups were also compared and examined No. (%) A 15 (46.9) 43 (58.9) 58 (55.2) .054 in terms of liver function tests in liver grafts over the B 12 (37.5) 14 (19.2) 26 (24.8) first 3 days posttransplant in recipients. We observed AB 0 (0) 8 (11.0) 8 (7.6) no statistically significant differences in post - O 5 (15.6) 8 (11.0) 13 (12.4) Abbreviations: MSOPT, modified standard organ procurement technique; transplant liver function tests of recipients between SOPT, standard organ procurement technique organ recovery groups except for aspartate aminotransferase (AST) levels on posttransplant day Discussion 2. That is, we found no statistically significant differences between both group in terms of With improvements in surgical techniques and posttransplant day 1 AST (P < .162), day 3 AST immunosuppressive treatments for solid-organ (P = .106), day 1 alanine aminotransferase (ALT; transplant, the demand for solid organs has grown, P < .383), day 2 ALT (P = .203), day 3 ALT (P = .106), leading transplant surgeons to improve ways to day 1 international normalized ratio (INR; P < .383), recover multiple organs from deceased donors. Starzl day 2 INR (P < .959), day 3 INR (P < .483), day 1 total and associates first defined the surgical technique for bilirubin (P < .324), day 2 total bilirubin (P < .946), multiple organ procurement.7 To date, there is a lack day 3 total bilirubin (P < .600), day 1 ammonia of consensus for a standardized technique for every (P < .833), day 2 ammonia (P < .384), and day 3 aspect related to multiple organ procurement.8 ammonia (P < .733). Detailed information related to Although various transplant centers may use liver function tests are shown in Table 2. different techniques, such as single or dual organ 794 Cemalettin Koc et al/Experimental and Clinical Transplantation (2020) 7: 791-795 Exp Clin Transplant
table 2. Comparisons Between Groups in Terms of Liver Function Tests for perfusion, dissection in cold or warm conditions, and Recipients During First 3 Days Posttransplant single or en bloc organ removal, the same incision is SOPT MSOPT Total) P Value AST POD1 mostly used. As far as we know, our study is the first Mean 1756 2262 2121 .162 to compare procedures without sternotomy for cases Standard 5 deviation 1326 1874 1747 that do not require recovery of intrathoracic organs. Median (range) 1354 (226-5717) 1576 (123-11067) 1531 (123-11067) Our aims in this study were 2-fold. First, we AST POD2 Mean 1028 1893 1654 .012 aimed to discover any possible differences related to Standard the greater time involved from initial incision to deviation 761 1930 1730 Median (range) 873 (200-3420) 1168 (86-12734) 1091 (86-12734) cross-clamping time of the supraceliac abdominal AST POD3 aorta with SOPT (which requires sternotomy to open Mean 887 1078 1029 .106 Standard the thorax cavity). In our study, the mean cross- deviation 1375 1418 1402 Median (range) 387 (119-6410) 675 (50-7783) 483 (50-7783) clamping time was 128.3 minutes for SOPT and 46.6 ALT POD1 minutes for MSOPT, revealing the greater time for Mean 1112 1193 1170 .383 Standard opening the thorax cavity (P < .001). deviation 1238 956 1035 Our second aim of the study was to investigate Median (range) 732 (225-6679) 922 (77-5646) 879 (77-6679) ALT POD2 any clinical effects associated with the significantly Mean 781 1002 941 .203 greater cross-clamping time between the organ Standard deviation 489 740 684 Median (range) 716 (155-2098) 816 (82-4112) 801 (82-4112) recovery techniques. Most potential deceased donors ALT POD3 require various inotropic and chronotropic Mean 522 728 673 .106 Standard deviation 402 558 527 medications to stabilize the circulation system and to Median (range) 471 (125-2018) 572 (64-3056) 515 (64-3056) INR POD1 provide optimum tissue perfusion until cross- Mean 3.1 3.6 3.4 .383 clamping. Among these medications, dopamine, Standard deviation 1.4 1.6 1.6 Median (range) 3.2 (0.9-5.9) 3.3 (1.1-8.7) 3.3 (0.9-8.7) epinephrine, and norepinephrine result in splanchnic INR POD2 vasoconstriction to redirect circulation into vital Mean 2.9 3.0 3.0 .959 Standard organs and to preserve blood volume, which could deviation 1.2 1.6 1.5 reduce portal vein flow and thus result in ischemic Median (range) 2.7 (1.3-6.8) 2.8 (1.2-11.4) 2.7 (1.2-11.4) INR POD3 injury to liver cells. In our study, we aimed to inspect Mean 2.2 2.6 2.5 .483 results of ischemic injury and compared liver Standard deviation 0.9 1.4 1.3 Median (range) 2.0 (1.3-5.2) 2.3 (1.0-9.4) 2.2 (1.0-9.4) enzyme levels of recipients measured during Total bilirubin POD1 Mean 6.9 6.1 6.3 .324 postoperative days 1 to 3. All implant techniques Standard were applied by the same surgery team. Our study deviation 4.7 4.2 4.3 Median (range) 7.1 (1.5-23.8) 5.3 (0.6-20.2) 5.5 (0.6-23.8) revealed that there were no significant effects of Total bilirubin POD2 stopping inotropic and chronotropic medications at a Mean 7.1 6.4 6.6 .946 Standard median of 78 minutes earlier on liver enzyme levels. deviation 5.8 4.3 4.7 This result could be interpreted as reduced exposure Median (range) 5.0 (2.1-23.4) 5.7 (0.8-21.5) 5.3 (0.8-23.4) Total bilirubin POD3 to these medications having no significant effect Mean 8.2 7.0 7.3 .600 because of short half-lives, which may have occurred Standard deviation 7.0 5.2 5.7 in our donor groups. This study design could be Median (range) 5.3 (1.2-31) 5.9 (0.7-23) 5.7 (0.7-31) more suitable for renal transplant as kidneys are NH3 POD1 Mean 162 199 191 .833 among the organs more prone to be affected by Standard deviation 77 140 129 vasoconstrictor medications. However, our center Median (range) 145 (87-385) 141 (65-618) 143 (65-618) has a relatively limited number of renal transplant NH3 POD2 Mean 122 138 136 .384 donors, and kidneys are transplanted at various Standard deviation 28 98 90 centers throughout our country. Therefore, any Median (range) 118 (94-188) 104 (54-434) 107 (54-434) NH3 POD3 possible comments regarding renal transplant results Mean 101 137 131 .733 are limited. Standard deviation 33 98 92 Median (range) 96 (52-140) 110 (36-474) 103 (36-474) This study has some limitations. First was the Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; significant difference in cross-clamping times. The INR, international normalized ratio; MSOPT, modified standard organ sternotomy procedure lasted longer than expected procurement technique; NH3, ammonia; POD, postoperative day; SOPT, standard organ procurement technique in 5 patients in the SOPT group, resulting in a Cemalettin Koc et al/Experimental and Clinical Transplantation (2020) 7: 791-795 795
prolonged median cross-clamping time in the SOPT References group. The second limitation was the organ recovery 1. Watson CJ, Dark JH. Organ transplantation: historical perspective team’s lack of experience in using the sternotomy and current practice. Br J Anaesth. 2012;108 Suppl 1:i29-i42. device. Toward the end of the study period, the 2. Fourtounas C. Transplant options for patients with type 2 diabetes and chronic kidney disease. World J Transplant. 2014;4(2):102-110. duration was reduced by 20 to 25 minutes. Another 3. Pillai AA, Levitsky J. Overview of immunosuppression in liver limitation was the study’s retrospective design and transplantation. World J Gastroenterol. 2009;15(34):4225-4233. inclusion of only liver transplant patients. Therefore, 4. Koc S, Akbulut S, Soyer V, et al. Hepatic venous outflow obstruction after living-donor liver transplant: single center experience. Exp Clin our results must be interpreted with caution. Transplant. In press. doi: 10.6002/ect. 2017.0045. Although the MSOPT reduced cross-clamping 5 .Yilmaz M, Piskin T, Akbulut S, Ersan V, Gonultas F, Yilmaz S. Is routine sternotomy necessary for organ recovery from deceased time, there were no effects on postoperative results. donors? A comparative retrospective study. Transplant Proc. Because of its reduced operation time, MSOPT is 2012;44(6):1644-1647. suitable for procedures in which thoracic organs are 6. Sturdevant ML, Humar A. Multiorgan procurement from the deceased donor. In: Humar A, Matas AJ, Payne WD (eds.), Atlas of not targeted for retrieval. Further prospective studies Organ Transplantation. London, UK: Springer; 2006:1-33 are needed to study other abdominal organs. 7. Starzl TE, Hakala TR, Shaw BW Jr, et al. A flexible procedure for multiple cadaveric organ procurement. Surg Gynecol Obstet. 1984;158(3):223-330. 8. Keutgen XM, Petrowsky H. Procurement for visceral organ transplantation: where to cannulate and how to perfuse? Curr Opin Organ Transplant. 2014;19(2):92-99. Artıcle
Living Donor Liver Transplant in Patients With Budd-Chiari Syndrome: A Single-Center Experience at Our University Hospital
Mikal Obed,4 Mohammad Ibrahim Othman,1 Saeb Hammoudi,2 Mahmoud Abdelkader Chattab,3 Anwar Jarrad,4 Abdalla Bashir,3 Aiman Obed5
Abstract ratio was 0.9, and the median follow-up period was 89 months. Cumulative 1-, 3-, and 5-year-survival rates Objectives: Budd-Chiari syndrome is an infrequent, but were 84%, 67%, and 67%, respectively. potentially fatal, hepatic condition with the clinical Conclusions: Good survival rates are achievable with manifestation of obstructed venous drainage. This living donor liver transplant for patients with may lead to progressive hepatic congestion, portal advanced Budd-Chiari syndrome, particularly by hypertension, and, ultimately, liver failure. If medical, means of posterior cavoplasty for enlargement of the interventional, and surgical approaches are not cava orifice. Therefore, in countries with insufficient effective, liver transplant offers a rescue modality. The deceased donor programs, such as Jordan, living primary objective of this study was to report the donor liver transplant may be a lifesaving therapeutic perioperative and, above all, the vascular challenges possibility. associated with living donor liver transplant in patients with Budd-Chiari syndrome. Key words: Acute liver failure, Chronic liver failure, Materials and Methods: We retrospectively reviewed Hepatic venous outflow obstruction, Venoplasty demographic and clinical characteristics of 6 patients with Budd-Chiari syndrome who underwent living Introduction donor liver transplant at our transplant center from April 2004 to July 2020. We also evaluated all data Budd-Chiari syndrome is a multifaceted disorder regarding perioperative course, surgical outcome, and characterized by the obstruction of hepatic venous the postoperative follow-up period. drainage. This life-threatening condition may lead to Results: All patients displayed advanced liver disease progressive hepatic congestion, portal hypertension, with a Child-Pugh score C. The mean calculated Model and liver failure. This vascular obstruction may occur for End-Stage Liver Disease score was 32. The causes at the level of the hepatic venules, the large hepatic of Budd-Chiari syndrome were factor V Leiden veins, the vena cava inferior, or the right atrium.1 The thrombophilia in 1 patient, myeloproliferative disorder in 3 patients, antiphospholipid antibody syndrome in increased pressure due to clogged outflow may 1 patient, and a protein C deficiency in 1 patient. The lead to hypoxic destruction of hepatic cells, which mean age of patients was 40 years. One of the 6 eventually destroys the liver parenchyma in a patients was female. All patients had living donor liver fulminant manner.2,3 The frequency of Budd-Chiari transplant from immediate kin according to Jordanian syndrome has been globally estimated4 as 1/100 000 allocation rules. The mean graft-to-recipient weight with greater prevalence in Asia and Africa.5 This From the 1General Surgery Department, the 2Pediatric Surgery Department, the 3General and makes Budd-Chiari syndrome a rare but possibly Transplant Surgery, the 4Hepatology, Gastroenterology, and Hepatobiliary/Transplant Unit, the 6 5Hepatobiliary and Transplant Surgery, Jordan Hospital, Amman, Jordan lethal disorder. It is more common in women in their Acknowledgements: The authors have not received any funding or grants in support of the third or fourth decade of life.7 The most common presented research or for the preparation of this work and have no declarations of potential underlying causative reasons for Budd-Chiari conflicts of interest. All authors have given their final approval of the submitted version. Data sharing is not applicable to this article, since datasets were neither generated nor analyzed for syndrome are antiphospholipid antibody syndrome, the case series. primary myeloproliferative disorders, and factor V Corresponding author: Mikal Obed, Hepatology, Gastroenterology and 7,8 Hepatobiliary/Transplant Unit, Jordan Hospital, Amman, Jordan Leiden mutation. Phone: +962 6 5608030 E-mail: [email protected] The diagnosis of Budd-Chiari syndrome relies on
Experimental and Clinical Transplantation (2020) 7: 796-802 the fulfillment of 1 or more clinical characteristics
Copyright © Başkent University 2020 DOı: 10.6002/ect.2020.0331 Printed in Turkey. All Rights Reserved. Mikal Obed et al/Experimental and Clinical Transplantation (2020) 7: 796-802 797
featured in the clinical presentation, physical a case-by-case basis after they have completed all examination, radiological assessment via abdominal medical assessments. The contraindications for liver magnetic resonance imaging or computerized transplant at our university hospital are summarized tomography, and intraoperative observation and in Table 1. For our 6 cases, an accelerated donor and histopathological findings. Before liver transplant is recipient work-up was accomplished, and the ethical recommended as a rescue modality, medical treat - committee and psychiatric team accepted liver ment with anticoagulation or invasive percutaneous donation. All indications for living donor liver interventional techniques (eg, transjugular intra - transplant were approved by the Liver Transplant hepatic portosystemic shunt and surgical shunts)9 is Board. considered first. Liver transplant is the last resort9 in Manifest complete or incomplete hepatic vein cases where nonsurgical approaches fail or whenever thrombosis with or without inferior vena cava the patient faces irreversible necrosis of liver tissue involvement detected in radiological examination is or cirrhosis with liver decompensation.9-11 For these reason enough to diagnose Budd-Chiari syndrome, cases, we routinely anastomose a very short right regardless of underlying causes.13 For example, the hepatic vein directly in a posterior cavoplasty, as first CT scan of our last patient (Figure 1) showed a described by Goralczyk and associates.12 severely narrowed retrohepatic vena cava with The primary objective of this study was to report vanished hepatic veins. Moreover, the image the perioperative and, above all, the vascular revealed ascites with bilateral pleural effusion, an challenges implicated by living donor liver transplant enlarged hepatic segment one, congestion of the liver, in patients with Budd-Chiari syndrome, as exemplified and areas of necrosis. Histopathologic examination by 6 patients seen at our Liver Transplant Institute at confirmed the diagnosis: Budd-Chiari syndrome Jordan Hospital. Furthermore, we wish to point out the accompanied by severe acute centrolobular liver cell socioeconomic and health care-related significance of necrosis and vanished hepatic veins. liver transplant for countries without sufficient During the surgical procedure and mobilization deceased organ donation programs, like Jordan. of the liver, the hepatic artery, bile duct, and main portal vein were exposed and divided. All hepatic Materials and Methods veins of the diseased livers were resected directly at the inferior vena cava wall with a vascular stapler In this study, we retrospectively reviewed the device. All 6 recipients received right lobe liver demographic and surgical data of 6 patients with transplant. The short right hepatic vein orifice of the end-stage Budd-Chiari syndrome who underwent graft was directly anastomosed with the inferior vena living donor liver transplant at our institute. cava wall after the stapler line was removed from the Although this study is a retrospective clinical study, inferior vena cava and the posterior wall of the cava the approval of the local ethics committee was was widened with a running 5-0 vascular suture. All received. In advance, we obtained written informed hepatic veins with a diameter of ≥ 5 mm were consent from all patients for the publication of this anastomosed directly with the inferior vena cava report. Between April 1, 2004 and July 30, 2020, a using synthetic or homologous vascular grafts. The total of 124 living donor liver transplants were portal vein anastomoses and the hepatic artery and performed at Jordan Hospital in Amman, with 6 (5%) bile duct anastomoses were carried out using the conducted in patients with Budd-Chiari syndrome. standard end-to-end technique in all patients. Only Many patients with Budd-Chiari syndrome are the patient with narrowing inferior vena cava successfully treated at our institute with no need for received patch cavoplasty to the anterior-lateral wall surgical intervention. Liver transplant is considered with artificial vascular material. a treatment option for patients with medical and interventional treatment failure or established table 1. Exclusion Criteria for Liver Transplant in Budd-Chiari Syndrome at cirrhosis or fulminant liver failure. There are no Jordan Hospital generally recognized listing criteria for patients with Significant heart failure Budd-Chiari syndrome. Patients who qualify as Severe portopulmonary shunt Brain edema not responding to medical treatment candidates for living donor liver transplant are Uncontrolled infection discussed at our weekly transplant board meeting on Complete cava thrombosis with portal vein thrombosis 798 Mikal Obed et al/Experimental and Clinical Transplantation (2020) 7: 796-802 Exp Clin Transplant
Figure 1. Severely Narrowed Retrohepatic Vena Cava, an Enlarged Hepatic and Child-Pugh scores provided documentation of Segment One, and Occluded Hepatic Veins, Ascites, and Peripheral Edema patients’ health conditions before living donor liver transplant. All patients had severe liver disease with a Child-Pugh score C. The mean calculated MELD score was 32, with scores ranging from 27 to 40. Of 6 patients, 5 showed complete hepatic vein occlusion, whereas 1 patient had severe inferior vena cava narrowing due to external compression by an enlarged hepatic segment one (Table 2). None of our patients showed contraindications for liver transplant. Causes of Budd-Chiari syndrome in our study population included factor V Leiden thrombophilia in 1 patient, primary myeloproliferative disorder in 3 patients, antiphospholipid antibody syndrome in 1 patient, and protein C deficiency in 1 patient. Therefore, all participants in the study were consi - dered to have primary Budd-Chiari syndrome. We performed living donor liver transplant with posterior cavoplasty in all patients, meaning that all grafts were obtained from living donors. The mean graft weight was 818.8 g, whereas the mean patient weight was approximately 75 kg. Accordingly, the mean graft-to-recipient weight ratio was 0.91 (Table 3). During the surgical procedure, 2 patients received no packed red blood cells, 2 needed 3 packed red blood cell units each, 1 patient needed 4, and 1 patient received 6. All patients required fresh frozen plasma Results during the procedure, averaging at approximately 8 units per patient. The cold ischemia times averaged We reviewed baseline characteristics of 6 patients about 60 minutes (Table 3). One should keep in mind with Budd-Chiari syndrome who underwent living that 1 patient received a left anterior-lateral patch donor liver transplant at our Liver Transplantation cavoplasty due to the inferior vena cava narrowing Department at Jordan Hospital. For patient analyses, opposite to the venous anastomosis, which required the following epidemiological data were included: the longest cold ischemia time of nearly 120 minutes. age, sex, underlying disease, body weight, and All complications and posttransplant outcomes were various features of the donors. The mean age of documented and are summarized in Table 4. patients was 40 years; only 1 of the 6 patients was Postoperatively, all 6 patients received a heparin female. Model for End-Stage Liver Disease (MELD) infusion course. Our therapeutic goal was set for an
table 2. Characteristics of Patients with Budd-Chiari Syndrome Undergoing Living Donor Liver Transplant Patient 1 2 3 4 5 6 Age, years 40 40 66 29 19 48 Sex Male Male Male Male Male Female Cause of Budd-Chiari MPD MPD MPD Protein S and Factor V Leiden Anti-phospholipid syndrome C deficiency mutation antibody syndrome Vascular involvement Hepatic vein Hepatic vein Hepatic vein Hepatic vein Hepatic vein Hepatic vein and inferior vena cava Donor Brother Brother Son Brother Brother Daughter Donor age, years 39 32 30 44 24 28 MELD score 27 36 29 31 31 40 Child-Pugh score Child C Child C Child C Child C Child C Child C Abbreviations: MELD, Model for End-Stage Liver Disease; MPD, myeloproliferative disorder Mikal Obed et al/Experimental and Clinical Transplantation (2020) 7: 796-802 799
activated partial thromboplastin time of 60 to 80 therapy, as well as percutaneous transluminal seconds. angioplasty with and without stenting. Transjugular At the time of hospital discharge, all patients were intrahepatic portosystemic shunting and surgical switched from heparin to warfarin therapy with shunting are additional therapeutic possibilities.1 an additional 100 mg of acetylsalicylic acid. We Nonetheless, fatal hepatic complications often recommended a continuance of warfarin therapy for leave no option other than liver transplant. As approximately 1 year and the use of acetylsalicylic reported by Saleh and colleagues, liver transplant acid for life. All patients received tacrolimus as should be considered if all other steps of the standard immunosuppressive therapy. therapeutic algorithm fail.14 Transplant indications The median follow-up period was 89 months. for patients with Budd-Chiari syndrome include Cumulative 1-, 3-, and 5-year survival rates were fulminant liver failure, cirrhosis of the liver, and 84%, 67%, and 67%, respectively. Outcome results failure of preceding treatment attempts with showed a survival rate of 67% with good clinical portosystemic shunts or nonsurgical therapeutic outcomes. Two-thirds of patients are still alive today approaches.1,4 and doing well. Two patients are deceased, with 1 Most available studies on liver transplant in patient having a lethal myocardial infarction 15 patients with Budd-Chiari syndrome refer to records months after transplant. The second patient died on deceased donor liver transplant. However, less after a fatal sepsis and multiple organ failure 44 days scientific research has focussed on the clinical after transplant (Table 4). outcome of living donor liver transplant,6 with most evaluations of living donor liver transplant for Budd- Discussion Chiari syndrome being case reports. In 2006, Yamada and associates15 reported on 9 patients with Budd- To the best of our knowledge, this is the first study Chiari syndrome and living donor liver transplant evaluating living donor liver transplant outcomes of in which patch plasty for inferior vena cava Jordanian Budd-Chiari syndrome patients with more reconstruction was performed in 4 cases. Similarly, than a 10-year-follow-up. Presently, our center offers Mentha and associates16 published a study on one of several invasive and noninvasive therapeutic the largest sample sizes of patients (n = 248) receiving approaches in the treatment of Budd-Chiari syndrome. deceased donor liver transplant for Budd-Chiari Noninvasive modalities include anticoagulation syndrome. They reported 1-, 5-, and 10-year survival therapy, thrombolytic therapy, and diuretic drug rates of 76%, 71%, and 68%, respectively. Despite our
table 3. Perioperative Characteristics Patient Body Graft Graft-to- WIT, min CIT, min Length of ICU Length of Operation Packed Fresh Frozen Weight, Weight, Recipient- Stay, days Hospital Time, RBCs, Plasma, kg g Weight Ratio Stay, days hours units units 1 74 800 0.93 27 55 3 18 3 3 6 2 78 845 0.92 23 65 4 14 4 0 6 3 85 920 0.92 31 60 3 24 5 3 6 4 68 750 0.91 22 60 5 23 4 4 8 5 70 780 0.90 29 55 3 16 5 0 7 6 73 815 0.89 45 120 6 44 6 6 14 Abbreviations: CIT, cold ischemic time; ICU, intensive care unit; RBC, red blood cell; WIT, warm ischemic time
table 4. Outcome of Surgery Patient 1 2 3 4 5 6 Complication Wound infection Incomplete hepatic Pleural effusion Biliary Stricture vein Treatment Wound revision Warfarin therapy Aspiration ERCP with Final outcome Alive Dead Dead Alive Alive Alive Follow-up 15 years 44 days 15 months 10 years 9 years 2 years Cause of death Sepsis, multiorgan Myocardial failure infarction Abbreviations: CIT, cold ischemic time; ICU, intensive care unit; RBC, red blood cell; WIT, warm ischemic time 800 Mikal Obed et al/Experimental and Clinical Transplantation (2020) 7: 796-802 Exp Clin Transplant
limited number of patients, we showed comparable suprahepatic inferior vena cava to match the survival figures of 84%, 67%, and 67% after 1, 3, and graft vein, without requiring any resection of the 5 years. This may indicate similar outcomes in narrowed retrohepatic inferior vena cava. In 1 of the deceased donor versus living donor liver transplant. 6 patients reported here, we conducted additional Another commonality between the work of Mentha patch plasty to the left anterior-lateral wall with and associates and our findings is the early occurrence artificial vascular material, due to a narrowed area of of mortality during the first months after transplant the cava situated opposite of the venous anastomosis. due to infectious complications, multiorgan and graft Accordingly, this additional step explained the failure, or vascular complications. This implies an unusually long cold ischemia time of 120 minutes for especially vulnerable period for these patients shortly this patient (Table 3). All other patients required after transplant. The survival rates of 57 Budd-Chiari rather short cold ischemia times, as the donors’ and syndrome patients after living donor liver transplant recipients’ hepatectomies were coordinated nearly as presented by Ara and colleagues13 was quite simultaneously by 2 different teams, allowing an satisfactory. Therefore, living donor liver transplant optimized operation times (Table 3). is supported as a practical therapeutic approach in Several groups have proposed new and different patients with Budd-Chiari syndrome. techniques to overcome inferior vena cava Undoubtedly, the construction of adequate involvement, including management of the un - anastomoses with the recipient’s inferior vena cava healthy innate inferior vena cava and adequate is challenging, as it is often affected by Budd-Chiari reconstruction.18,22-28 Our study’s long-term results syndrome and, thus, in a highly stenotic condition.6 are comparable to the results of similar studies. With Karaca and colleagues17 came to a similar conclusion. the understanding that all our patients had severely The authors presented a surgical technique in which advanced liver failure with high MELD scores and the hepatic venous drainage was preserved despite a thus displayed very poor prognoses to begin with, lack of inferior vena cava from living donors. In the significant outcomes are very encouraging. deceased donor liver transplant, the recipient’s inferior vena cava is usually removed with the native Figure 2. Reconstructed Hepatic Segment V and VIII Hepatic Veins With liver, since the hepatic graft encloses a retrohepatic Synthetic Vascular Graft, With Arrow Showing Very Short Hepatic Graft Vein inferior vena cava.18,19 The piggyback liver transplant technique is the only exception to this case. In contrast, the inferior vena cava is mostly preserved in living donor liver transplant, even though it is often in narrowing condition due to massive compression by an enlarged liver.20 In our cases, we managed the reconstruction of a sufficient venous outflow by performing an anastomosis between the right hepatic vein and the recipient’s preserved inferior vena cava via posterior cavoplasty. This is a clear strength of our study. That is, we implemented the technique of posterior cavoplasty consistently in all our patients, allowing us to surmount the vascular challenges related to Budd-Chiari syndrome. We performed a venous anastomosis between the graft hepatic vein and the enlarged cava opening (Figure 2) as first described by Goralczyk and associates,12 who showed that venous outflow and portal vein pressure in those who had posterior cavoplasty was significantly better than results in the control group. Similarly, Kubo and colleagues21 reported on a formed horizontal orifice on the anterior surface of the Mikal Obed et al/Experimental and Clinical Transplantation (2020) 7: 796-802 801
One limitation of our study is the inherent bias of for countries with small or scarce deceased organ our retrospective study design. In addition, we had a donation programs. In countries like Jordan, and in modest number of patients, which could be enlarged small transplant centers like ours, living donor liver to ensure reliability. However, even with the small transplant with posterior cavoplasty for patients with size of both our university hospital in Amman and end-stage liver disease caused by Budd-Chiari its hepatobiliary surgery department, it is remarkable syndrome is extremely efficient. It provides a new that living donor liver transplant is performed, let opportunity for these patients and a chance to live alone for patients with Budd-Chiari syndrome. with acceptable long-term outcomes. Previously, patients with this syndrome were categorically sent abroad to foreign countries when Conclusions they reached decompensating liver function. A second center in Amman also offers living donor Further studies are needed to increase the knowledge liver transplantation but lacks operative experience of this clearly feasible procedure. However, we can in treating patients with Budd-Chiari syndrome. affirm that living donor liver transplant in Budd- Now, in view of our patients’ promising survival Chiari syndrome is a life-saving treatment approach, rates and their good posttransplant results, our especially in fulminant cases of hepatic failure. findings have significant health care implications, as References Jordan Hospital is a major regional health care provider for patients from various Middle Eastern 1. Obed A, Bashir A, Jarrad A. A case of live donor liver countries. All affected individuals who cannot afford transplantation in acute-on-chronic liver failure with Budd-Chiari syndrome: donor and recipient with antiphospholipid antibody clinical treatment overseas can be offered a treatment syndrome. Am J Case Rep. 2018;19:767-772. doi:10.12659/AJCR. option at home and are thereby given a chance to 909694 live. 2. Menon KV, Shah V, Kamath PS. The Budd-Chiari syndrome. N Engl J Med. 2004;350(6):578-585. doi:10.1056/NEJMra020282 Of interest, most epidemiological data in the 3. Goel RM, Johnston EL, Patel KV, Wong T. Budd-Chiari syndrome: present literature have reported on female patients, investigation, treatment and outcomes. Postgrad Med J. 2015;91(1082):692-697. doi:10.1136/postgradmedj-2015-133402 as they make up most of the diseased population. 4. Valla DC. The diagnosis and management of the Budd-Chiari However, our study comprised 83% male patients. syndrome: consensus and controversies. Hepatology. 2003;38(4): 793-803. doi:10.1053/jhep.2003.50415 This aspect delivers additional noteworthy infor - 5. Wang ZG, Jones RS. Budd-Chiari syndrome. Curr Probl Surg. mation about the management of this disease in the 1996;33(2):83-211. doi:10.1016/s0011-3840(96)80001-3 less frequently affected sex. As pointed out by Zhang 6. Valla DC. Primary Budd-Chiari syndrome. J Hepatol. 2009;50(1):195- 203. doi:10.1016/j.jhep.2008.10.007 and associates29 in 2018, the clinical characteristics of 7. Valla DC. Hepatic vein thrombosis (Budd-Chiari syndrome). Semin the obstructive lesions in Budd-Chiari patients vary Liver Dis. 2002;22(1):5-14. doi:10.1055/s-2002-23202 8. Janssen HL, Garcia-Pagan JC, Elias E, et al. Budd-Chiari syndrome: broadly between Western and Asian populations. a review by an expert panel. J Hepatol. 2003;38(3):364-371. Consequently, the clinical presentations and treatment doi:10.1016/s0168-8278(02)00434-8 9. Plessier A, Valla DC. Budd-Chiari syndrome. Semin Liver Dis. approaches for patients also differ. Although we found 2008;28(3):259-269. doi:10.1055/s-0028-1085094 hepatic thromboses as the main obstructive lesions 10. Hoekstra J, Janssen HL. Vascular liver disorders (I): diagnosis, in Western countries, Asian patients tend to display treatment and prognosis of Budd-Chiari syndrome. Neth J Med. 2008;66(8):334-339. membranous and segmental obstructions of the 11. Horton JD, San Miguel FL, Membreno F, et al. Budd-Chiari suprahepatic or retrohepatic portion of the inferior syndrome: illustrated review of current management. Liver Int. 2008;28(4):455-466. doi:10.1111/j.1478-3231.2008.01684.x vena cava. This implies that interventional 12. Goralczyk AD, Obed A, Beham A, Tsui TY, Lorf T. Posterior recanalization and surgical treatment modalities cavoplasty: a new approach to avoid venous outflow obstruction are much more relevant in Asian countries and symptoms for small-for-size syndrome in right lobe living donor liver transplantation. Langenbecks Arch Surg. than anticoagulation and transjugular intrahepatic 2011;396(3):389-395. doi:10.1007/s00423-010-0736-9 portosystemic shunt, which often suffice for Western 13. Ara C, Akbulut S, Ince V, Karakas S, Baskiran A, Yilmaz S. Living donor liver transplantation for Budd-Chiari syndrome: patients. This carries vital sociocultural implications, Overcoming a troublesome situation. Medicine (Baltimore). making living donor liver transplant an essential 2016;95(43):e5136. doi:10.1097/MD.0000000000005136 14. Saleh Y, Eldeen FZ, Kamel Y, Kabbani M, Al Sebayel M, Broering D. treatment option for the Middle Eastern Budd-Chiari Liver transplant in Budd-Chiari syndrome: a single-center syndrome population. experience in Saudi Arabia. Exp Clin Transplant. 2014;12(1):52-54. Ultimately, the findings of our small transplant doi:10.6002/ect.2013.0153 15. Yamada T, Tanaka K, Ogura Y, et al. Surgical techniques and long- center in Jordan can have major clinical consequences term outcomes of living donor liver transplantation for Budd- 802 Mikal Obed et al/Experimental and Clinical Transplantation (2020) 7: 796-802 Exp Clin Transplant
Chiari syndrome. Am J Transplant. 2006;6(10):2463-2469. 24. Yoon YI, Lee SG, Moon DB, et al. Surgical techniques and long- doi:10.1111/j.1600-6143.2006.01505.x term outcomes of living-donor liver transplantation with inferior 16. Mentha G, Giostra E, Majno PE, et al. Liver transplantation for vena cava replacement using atriocaval synthetic interposition Budd-Chiari syndrome: A European study on 248 patients from graft for Budd-Chiari syndrome. Ann Surg. 2019;269(4):e43-e45. 51 centres. J Hepatol. 2006;44(3):520-528. doi:10.1016/j.jhep.2005. doi:10.1097/SLA.0000000000002847 12.002 25. Fukuda A, Ogura Y, Kanazawa H, et al. Living donor liver 17. Karaca C, Yilmaz C, Ferecov R, et al. Living-Donor Liver transplantation for Budd-Chiari syndrome with hepatic inferior Transplantation for Budd-Chiari Syndrome: Case Series. Transplant vena cava obstruction after open pericardial procedures. Surg Proc. 2017;49(8):1841-1847. doi:10.1016/j.transproceed.2017.04.028 Today. 2013;43(10):1180-1184. doi:10.1007/s00595-012-0440-1 18. Akamatsu N, Sugawara Y, Kokudo N. Budd-Chiari syndrome and 26. Liu C, Hsia CY, Loong CC, et al. A technique of diamond-shape liver transplantation. Intractable Rare Dis Res. 2015;4(1):24-32. venoplasty to reconstruct the hepatic venous outflow in living doi:10.5582/irdr.2014.01031 donor liver transplantation for a case of Budd-Chiari syndrome. 19. Zieniewicz K, Krawczyk M, Nyckowski P, et al. Liver transplantation: Pediatr Transplant. 2009;13(1):35-38. doi:10.1111/j.1399-3046.2008. comparison of the classical orthotopic and piggyback techniques. 01059.x Transplant Proc. 2002;34(2):625-627. doi:10.1016/s0041-1345(01) 27. Lee SG. A complete treatment of adult living donor liver 02867-6 transplantation: a review of surgical technique and current 20. Sabra TA, Okajima H, Tajima T, et al. Living donor liver challenges to expand indication of patients. Am J Transplant. transplantation for adult Budd Chiari syndrome - Resection 2015;15(1):17-38. doi:10.1111/ajt.12907 without replacement of retrohepatic IVC: A case report. Int J Surg 28. Majno PE, Toso C, Berney T. Cutting the Gordian Knot of Living- Case Rep. 2018;42:50-54. doi:10.1016/j.ijscr.2017.11.050 donor Liver Transplantation for Budd-Chiari Syndrome. Ann Surg. 21. Kubo S, Ichikawa T, Takemura S, et al. Reconstruction of hepatic 2019;269(4):e46. doi:10.1097/SLA.0000000000003212 veins by anastomosis with suprahepatic IVC in the posterior 29. Zhang W, Wang QZ, Chen XW, et al. Budd-Chiari syndrome mediastinum in living donor liver transplantation for Budd-Chiari in China: A 30-year retrospective study on survival from a syndrome. Hepatogastroenterology. 2009;56(94-95):1521-1524. single center. World J Gastroenterol. 2018;24(10):1134-1143. 22. Gonultas F, Akbulut S, Barut B, et al. Usability of Inferior Vena Cava doi:10.3748/wjg.v24.i10.1134 Interposition Graft During Living Donor Liver Transplantation: Is This Approach Always Necessary? J Gastrointest Surg. 2020;24(7): 1540-1551. doi:10.1007/s11605-019-04342-6 23. Kazimi M, Karaca C, Ozsoy M, et al. Live donor liver transplantation for Budd-Chiari syndrome: anastomosis of the right hepatic vein to the right atrium. Liver Transpl. 2009;15(10):1374-1377. doi:10.1002/lt.21815 Artıcle
Evaluation of Underlying Liver Disease and Its Severity in Children Referred for Liver Transplant: a Single-Center Report From Nemazee Hospital of Shiraz
Seyed Mohsen Dehghani,1 Iraj Shahramian,2 Ali Bazi,3 Maryam Mohammadi Mofrad,1 Samira Mardani1
Abstract Pediatric End-Stage Liver Disease score in children < 12 years old was 11.4 ± 9.1. The mean Model for End- Objectives: Liver transplant has been used as a curative Stage Liver Disease score in children > 12 years old was approach for children with end-stage liver diseases. 13.7 ± 5.9. There were no differences in scores among Here, we describe the underlying causes for pediatric sex, age groups, or different etiologies. liver transplant performed at the Shiraz Organ Conclusions: Scores for disease severity were not Transplantation Center, Nemazee Hospital, Shiraz, Iran. significantly different with regard to different causes Materials and Methods: In this cross-sectional des - of underlying diseases for liver transplant in Iranian criptive study, children < 18 years old who were children. candidates for liver transplant from 2007 to 2010 at the Shiraz Organ Transplantation Center were Key words: Biliary atresia, Liver failure, Pediatric included. Patients were evaluated for their underlying diseases leading to liver failure. Disease severity was Introduction assessed and compared with Pediatric End-Stage Liver Disease model and the Model for End-Stage Liver The first pediatric liver transplant (LT) procedure Disease scores. dates back to 1963.1 Children constitute 12.5% of Results: Of 107 patients, 60.8% were males and 39.2% candidates for LT.2 In pediatric patients, LT is were females. The mean age was 11.6 ± 4.9 years. challenging, especially in younger individuals, due to Thirteen patients (12.5%) were < 2 years old, 26 (24%) special requirements regarding technical, anatomic, were 2 to 6 years old, 33 (30.8%) were 6 to 12 years old, and immunologic issues.3-7 New immunosuppression and 35 (32.7%) were 12 to 18 years old. Underlying strategies, novel surgical approaches, and better liver diseases comprised biliary atresia (27.1%), pre- and posttransplant management procedures cryptogenic cirrhosis (21.5%), autoimmune cirrhosis (13.1%), familial intrahepatic cholestasis (11.2%), have affected the survival rate of liver allograft 8,9 Wilson disease (9.3%), tyrosinemia (7.4%), neonatal recipients. hepatitis (4.7%), congenital hepatic fibrosis (3.7%), Liver transplant has dramatically improved and Caroli disease (1.9%). Jaundice (83.2%), ascites survival rate and quality of life in patients with end- (57%), and esophageal varices (43%) were the most stage liver diseases.10 Although livers from deceased common clinical findings. Mean serum direct bilirubin, donors constitute the main source (90% to 92%) of total bilirubin, international normalized ratio, and serum donated liver allografts,4,11 a significant decrease in creatinine values were 3.6 ± 0.8 mg/dL, 9.3 ± 9.1 mg/dL, mortality of patients in the preoperative period is 2.1 ± 1.1, and 0.6 ± 0.2 mg/dL, respectively. The mean due to the introduction of living donors.12
From the 1Shiraz Organ Transplantation Center, Nemazee Hospital, Shiraz University of Nevertheless, limited numbers of liver grafts still Medical Sciences, Shiraz, Iran; the 2Pediatric Ward, Amir Al-Momenin Hospital, Zabol constitute the main obstacle for higher survival rates University of Medical Science, Zabol, Iran; and the 3Clinical Research Development Unit, Amir 9 Al-Momenin Hospital, Zabol University of Medical Science, Zabol, Iran in pediatric patients. Acknowledgements: The authors have no sources of funding for this study and have no conflicts According to a report from the China Liver of interest to declare. Transplant Registry, the number of LT surgeries in Corresponding author: Iraj Shahramian, Pediatric Ward, Amir Al-Momenin Hospital, Zabol 11 University of Medical Science, Zabol, Iran China was 20 877 from 1980 to 2011. In comparison, Phone: +98 5432239031 E-mail: [email protected] the United Network for Organ Sharing and
Experimental and Clinical Transplantation (2020) 7: 803-807 Eurotransplant registries have reported 113 432
Copyright © Başkent University 2020 DOı: 10.6002/ect.2018.0047 Printed in Turkey. All Rights Reserved. 804 Seyed Mohsen Dehghani et al/Experimental and Clinical Transplantation (2020) 7: 803-807 Exp Clin Transplant
and 11 542 LT procedures, respectively, up until Statistical analyses 2011.11 These numbers are expected to gradually Statistical analyses were performed with SPSS increase with improving LT strategies in upcoming software (SPSS: An IBM Company, version 14, IBM years.13,14 Corporation, Armonk, NY, USA). Normality of data Since 1993, we have described multiple pediatric was checked by Shapiro-Wilks test. Frequencies were LT procedures in our center (the Shiraz Organ applied to present qualitative data. Means and Transplantation Center, Shiraz, Iran).15-19 In another medians were reported for PELD and MELD scores. report, which described the first 50 pediatric LT Mann-Whitney U test was applied to assess procedures performed at the Shiraz Transplantation differences in means of PELD and MELD scores Center until 2006, we provided a full view on clinical between different pathologies, male versus female, conditions of these operations.20 Here, to explore the and age groups. causes of liver failure in Iranian children, we provide a comprehensive report on the underlying causes for Results pediatric LT performed at our center. Of 107 patients, 60.8% were male and 39.2% were Materials and Methods female. Mean patient age was 11.6 ± 4.9 years, and median age was 12 years. Patients were categorized Patients into 4 age groups according to age at admission to In this cross-sectional descriptive study, patients wait list for LT. Thirteen patients (12.5%) were < 2 under 18 years old who were candidates for LT at the years old, 26 patients (24%) were 2 to 6 years old, 33 Shiraz Organ Transplantation Center were included. patients (30.8%) were 6 to 12 years old, and 35 Patients were evaluated for underlying diseases patients (32.7%) were 12 to 18 years old. leading to liver failure. Disease severity was assessed Underlying liver diseases that led to requirement by Pediatric End-Stage Liver Disease (PELD) and for LT are shown in Table 1. Biliary atresia (29/107; Model for End-Stage Liver Disease (MELD) scores. 27.1%) was the most common underlying disease. These candidates had been referred to the Shiraz Other major causes included cryptogenic cirrhosis University of Medical Sciences Liver Transplant (23/107; 21.5%) and autoimmune cirrhosis (14/107; Center in Nemazee Hospital between 2007 and 2010. 13.1%). Regarding different age categories, biliary Patients with metabolic diseases without liver atresia was the most common underlying cause in involvement who may have had liver enzyme children < 2 years old (76.9%) and 2 to 6 years old disturbances leading to secondary organ involvement (30.8%), whereas cryptogenic cirrhosis was identified were excluded from this study. In total, 107 patients as the most common cause in children 6 to 12 years met our inclusion criteria. old (33.2%) and 12 to 18 years old (34.2%) (Table 2). Jaundice was the most common clinical mani - Gathering clinical and laboratory data festation in our patients (83.2%), and ascites (57%) Patient age, sex, underlying disease, and growth and esophageal varices (43%) were the other status were obtained. Laboratory data gathered on prevalent clinical findings. Table 3 lists the clinical admission included serum albumin, total bilirubin, signs and symptoms of the study patients. Mean international normalized ratio (INR), and serum values for serum bilirubin, total bilirubin, INR, and creatinine results. table 1. Distribution of Underlying Diseases in Pediatric Candidates for Liver calculating pediatric end-stage liver disease and Transplant model for end-stage liver disease scores Underlying Disorder Percent (%) Number Biliary atresia 27.1 29 For children under 12 years old, patient priority for Cryptogenic cirrhosis 21.5 23 LT was determined according to PELD score. Based Autoimmune cirrhosis 13.1 14 on this, age, growth failure, serum albumin, total Progressive familial intrahepatic cholestasis 11.2 12 Wilson disease 9.3 10 bilirubin, and INR were used to calculate the score. Tyrosinemia 7.4 8 For children above 12 years old, we used MELD Neonatal hepatitis 4.7 5 Congenital hepatic fibrosis 3.7 4 score, which considers total bilirubin, INR, and Caroli disease 1.9 2 serum creatinine. Total 100 107 Seyed Mohsen Dehghani et al/Experimental and Clinical Transplantation (2020) 7: 803-807 805
serum creatinine were 3.6 ± 0.8 mg/dL, 9.3 ± mg/dL, table 5. Underlying Disease According to Model for End-Stage Liver Disease 2.1 ± 1.1, and 0.6 ± 0.2 mg/dL, respectively. Scoring System Underlying Disease Mean and Minimum Maximum Number For the PELD scoring system, each patient is Standard of Cases assigned a number regarding 5 criteria: age, growth Deviation status, serum albumin level, serum bilirubin level, Congenital hepatic fibrosis 13 ± 3.4 11 17 3 Autoimmune cirrhosis 15.6 ± 4.8 8 20 8 and INR. Patients with greater scores have priority Neonatal hepatitis 6 6 6 1 to be transplanted. The mean PELD score in children Progressive familial intrahepatic cholestasis 5 ± 1 6 8 4 < 12 years old was 11.4 ± 9.1. In children > 12 years Cryptogenic cirrhosis 14.7 ± 5.6 7 26 11 old, the mean MELD score was 13.7 ± 5. 9. We Wilson disease 18.2 ± 6.9 11 27 5 Tyrosinemia 6 6 6 1 observed no associations between PELD and MELD scores and age groups and males versus females. Mean MELD and PELD scores for individual Discussion pathologies are presented in Table 4 and Table 5, respectively. We observed no significant differences Advancements in technical and management between PELD or MELD scores and the different strategies have made LT an effective therapeutic causes of liver disease. option with a high cure rate in patients with end- stage liver diseases. Among 107 children (< 18 years old) on the wait list at our center from 2007 to 2010, table 2. Underlying Reasons for Liver Transplant in Children Based on Different Age Categories underlying liver diseases included biliary atresia Underlying Cause Age Group, No. (%) (27.1%), cryptogenic cirrhosis (21.5%), autoimmune < 2 years 2-6 years 6-12 years 12-18 years cirrhosis (13.1%), familial intrahepatic cholestasis Biliary atresia 10 (76.9) 8 (30.8) 4 (12) 0 (0) (11.2%), Wilson disease (9.3%), tyrosinemia (7.4%), Cryptogenic cirrhosis 0 (0) 2 (7.7) 11 (33.2) 12 (34.2) Autoimmune cirrhosis 0 (0) 2 (7.7) 5 (15.4) 9 (25.8) neonatal hepatitis (4.7%), congenital hepatic fibrosis Progressive familial (3.7%), and Caroli disease (1.9%). Our previous intrahepatic cholestasis 1 (7.7) 4 (15.4) 4 (12) 4 (11.5) Wilson disease 0 (0) 1 (3.8) 5 (15.4) 5 (14.2) report on 50 pediatric LT recipients in our center Tyrosinemia 1 (7.7) 6 (23.1) 1 (3) 1 (2.9) showed cryptogenic cirrhosis (30%), autoimmune Neonatal hepatitis 1 (7.7) 1 (3.8) 2 (6) 1 (2.9) Congenital hepatic fibrosis 0 (0) 0 (0) 1 (3) 3 (8.5) cirrhosis (24%), biliary atresia (22%), Wilson disease Caroli disease 0 (0) 2 (7.7) 0 (0) 0 (0) (14%), progressive familial intrahepatic cholestasis Total 13 (100) 26 (100) 33 (100) 35 (100) (4%), fulminant hepatitis (4%), and tyrosinemia (2%) as the major diseases.20 Although the first 3 causes were the same in these 2 consecutive reports, the table 3. Liver Disease-Related Clinical Manifestations in Patients frequency of some showed elevating trends (ie, Clinical Manifestation Percent (%) Number Jaundice 83.2 89 familial intrahepatic cholestasis and tyrosinemia). On Ascites 57 61 the other hand, rates of children with cryptogenic Esophageal varices 43 46 Gastrointestinal bleeding 24.3 26 cirrhosis, autoimmune cirrhosis, and Wilson disease Edema 14.9 16 decreased in our present report, whereas the ratio of Encephalopathy 13.1 14 Secondary bacterial peritonitis 10.3 11 biliary atresia remained similar. In another report on 138 infants and children who underwent LT (living, deceased donor, and split translations) until 2009
table 4. Underlying Disease According to Pediatric End-Stage Liver Disease from our group, Wilson disease (20.3%), cryptogenic Score cirrhosis (16.7%), autoimmune cirrhosis (14.5%), Underlying Disease Mean and Minimum Maximum Number biliary atresia (13.8%), tyrosinemia (9.4%), and Standard of Cases Deviation progressive familial intrahepatic cholestasis (8.7%) Congenital hepatic fibrosis 21 21 21 1 constituted the main underlying causes of end-stage Biliary atresia 12 ± 8.8 1 36 29 21 Autoimmune cirrhosis 17.8 ± 9.2 1 27 6 liver disease. Neonatal hepatitis 13 ± 6.6 9 23 4 In a recent 3-year study (2012-2015) from Pakistan Progressive familial intrahepatic cholestasis 12.3 ± 10.3 1 28 8 on 14 pediatric LT recipients (≤ 17 years old; median Cryptogenic cirrhosis 9.6 ± 8.4 1 28 12 age of 8.5 years old),10 28.6% children had Wilson Wilson disease 26.4 ± 11.6 11 42 5 disease and 28.6% had cryptogenic cirrhosis (ie, 4 Tyrosinemia 6.8 ± 5.2 1 13 7 Caroli disease 8.5 ± 10.6 1 16 2 patients each). Two children had Budd-Chiari 806 Seyed Mohsen Dehghani et al/Experimental and Clinical Transplantation (2020) 7: 803-807 Exp Clin Transplant
syndrome (14.2%), and 1 child had biliary atresia 16, although 10 patients had scores of > 28 and 3 had (7.1%).10 In a report from the United States on 196 LT PELD scores of -11 to 6.9 procedures on 155 children, biliary atresia comprised Both the PELD and MELD scoring systems have the dominant cause of liver failure in both infants been used for prognostic analyses in previous (< 12 mo old) and children (1-18 years old).9 Other studies.31-34 Patients within both age groups (< 1 year causes included metabolic disease, fulminate old and 1-18 years old) with higher PELD scores hepatitis, cystic fibrosis, cryptogenic cirrhosis, and showed lower overall and 1-year survival rates than tumors.9 In a study from Turkey, Aydogdu and patients with lower PELD scores.9 The negative colleagues described 67 LT procedures (32 deceased correlation of PELD score with 1-year survival has and 35 living grafts) in 61 pediatric patients.22 The most also been described by Barshes and associates.29 A common causes included metabolic liver disease MELD score of > 20 in children with biliary atresia (27.8%), biliary atresia (22.9%), and cryptogenic was shown to be significantly associated with lower cirrhosis (18%). Some other causes were also described, 2-year mortality rate.24 Although patient age is a including autoimmune and viral hepatitis (9.8% and factor incorporated into calculation of PELD score, 6.5%, respectively) and fulminant liver disease we recognized no statistically significant difference in (8.1%).22 these scores with regard to age groups or males versus In the China Liver Transplant Registry report, females. This observation indicates that prognosis of biliary atresia and Wilson disease were the most these patients could be dependent on some other frequent causes for LT in pediatric patients.11 In pathologic factors (ie, underlying pathologies, genetic general, biliary atresia is the most common cause for alternations, acquired and environmental factors, and LT.23-25 This is followed by congenital disorders, with therapeutic interventions). hereditary deficiency of α1-antitrypsin, as the most In our study, we detected no significant dif - frequent cause for LT.26,27 Comparisons of these ferences in PELD/MELD scores among different studies indicate a variable and wide picture on underlying conditions. However, the highest PELD causes of liver failure in children; therefore, clinicians score was seen in children with biliary atresia and must consider the different etiologies for liver failure cryptogenic cirrhosis. Accordingly, the highest MELD in children. score was also found in patients with cryptogenic The PELD and MELD models for predicting cirrhosis, whereas children with autoimmune requirements for LT based on severity and mortality cirrhosis showed the second highest MELD score. risk of end-stage liver disorders28,29 have successfully Among those with the same pathology, there was decreased mortality rates in both pediatric and adult no significant difference between MELD and patients on wait lists for LT.30 In our study, mean PELD scores in children < 12 or > 12 years old. PELD score was 11.4 ± 9.5 (range, 1-42) in children Nevertheless, it is recommended to explore the < 12 years old and mean MELD score was 13.7 ± 5.9 effects of other mentioned factors in determining (range, 6-27) in patients > 12 years old (P > .05). The clinical severity of end-stage liver diseases. higher score in children older than 12 years indicated more severe conditions and higher preference for LT. Conclusions A possible explanation for this observation may be due to different causes of liver failure among those Our study showed a variety of underlying causes < 12 or > 12 years old. In our study, the most common necessitating LT in Iranian children. The most cause for children > 12 years old was cryptogenic common reasons for this were identified as biliary cirrhosis, whereas biliary atresia was the most atresia, cryptogenic cirrhosis, and autoimmune common cause in those < 12 years old. cirrhosis. There was no significant difference between Other reports have shown median PELD score of these pathologies, as well as other pathologies, 23 (range, 1-54) in 61 pediatric LT recipients in regarding sex, age, or PELD/MELD scores. This Turkey.22 In a study of pediatric LT in the United highlights the possible role of other independent States,9 19 children (> 1 year old) had PELD score factors modulating progression of liver failure in > 28, whereas 11 and 7 children had scores of 7 to 16 these conditions. Accordingly, improved current and 17 to 27 at the time of LT, respectively.9 Among prioritization criteria are needed for patients on 74 infants (<1 year old), most had PELD score of 7 to wait lists for LT by identifying, validating, and Seyed Mohsen Dehghani et al/Experimental and Clinical Transplantation (2020) 7: 803-807 807
incorporating more clinical and genetic parameters 18. Malek-Hosseini SA, Lahsaie M, Salahi H. Living-related liver transplantation in children: The Shiraz experience. Med J Islamic into our scoring systems. Republic Iran. 2003;17(1). 19. Malek Hoseini SA, Bahador A, Salahi H, et al. Liver transplantation References in Iran. Transplant Proc. 2003. 35(7):2779-80. 20. Dehghani SM, Bahador A, Gholami S. Pediatric liver transplantation in Iran: Evaluation of the first 50 cases. Pediatr 1. Starzl TE, Marchioro TL, Vonkaulla KN, Hermann G, Brittain RS, Transplant. 2007;11:256-260. Waddell WR. Homotransplantation of the Liver in Humans. Surg 21. Bahador A, Salahi H, Nikeghbalian S, et al. Pediatric liver Gynecol Obstet. 1963;117:659-676. transplantation in Iran: a 9-year experience. Transplant Proc. 2. Karjoo M, Banikazemi M, Saeidi M, Kiani MA. Review of natural 2009;41(7):2864-2867. history, benefits and risk factors pediatric liver transplantation. Int 22. Aydogdu S, Arikan C, Kilic M, et al. Outcome of pediatric liver J Pediatr. 2016;4(3):1529-1544. transplant recipients in Turkey: single center experience. Pediatr 3. Pashev V, Naychov Z, Uzunova J, Spasov L. [10 years of experience Transplant. 2005;9(6):723-728. in living donation for liver transplantation in pediatric patients - a 23. Kalayoglu M, D'Alessandro AM, Knechtle SJ, et al. Long-term single centre study]. Khirurgiia (Sofiia). 2016;82(1):4-15. results of liver transplantation for biliary atresia. Surgery. 4. Przybyszewski EM, Verna EC, Lobritto SJ, et al. Durable clinical and 1993;114(4):711-718. immunologic advantage of living donor liver transplantation in 24. van der Doef HPJ, van Rheenen PF, van Rosmalen M, Rogiers X, children. Transplantation. 2018;102(6):953-960. Verkade HJ, for pediatric liver transplantation centers of E. Wait-list 5. Couchonnal E, Rivet C, Ducreux S, et al. Deleterious impact of C3d- mortality of young patients with Biliary atresia: Competing risk binding donor-specific anti-HLA antibodies after pediatric liver analysis of a Eurotransplant registry-based cohort. Liver Transpl. transplantation. Transpl Immunol. 2017;45:8-14. 2018;24(6):810-819. 6. Alexopoulos SP, Nekrasov V, Cao S, et al. Effects of recipient size 25. Vieira SMG, Schwengber FP, Melere M, Ceza MR, Souza M, Kieling and allograft type on pediatric liver transplantation for biliary CO. The first episode of spontaneous bacterial peritonitis is a atresia. Liver Transpl. 2017;23(2):221-233. threat event in children with end-stage liver disease. Eur J 7. Feier FH, Seda-Neto J, da Fonseca EA, et al. Analysis of factors Gastroenterol Hepatol. 2018;30(3):323-327. associated with biliary complications in children after liver 26. Whitington PF, Balistreri WF. Liver transplantation in pediatrics: transplantation. Transplantation. 2016;100(9):1944-1954. indications, contraindications, and pretransplant management. J 8. Otte JB. Pediatric liver transplantation: Personal perspectives on Pediatr. 1991;118(2):169-177. historical achievements and future challenges. Liver Transpl. 27. Oishi K, Arnon R, Wasserstein MP, Diaz GA. Liver transplantation 2016;22(9):1284-1294. for pediatric inherited metabolic disorders: Considerations for 9. D'Alessandro AM, Knechtle SJ, Chin LT, et al. Liver transplantation indications, complications, and perioperative management. in pediatric patients: twenty years of experience at the University Pediatr Transplant. 2016;20(6):756-769. of Wisconsin. Pediatr Transplant. 2007;11(6):661-670. 28. Lauferman L, Dip M, Halac E, et al. Waiting list outcome of 10. Bhatti AB, Dar FS, Hashmi SS, Zia H, Malik MI, Shah NH. Paediatric PELD/MELD exceptions: A single-center experience in Argentina. living donor liver transplantation: a single centre experience from Pediatr Transplant. 2018;22(2). Pakistan. J Coll Physicians Surg Pak. 2016;26(6):476-480. 29. Barshes NR, Lee TC, Udell IW, et al. The pediatric end-stage liver 11. Wang H, Jiang W, Zhou Z, Long J, Li W, Fan ST. Liver transplantation disease (PELD) model as a predictor of survival benefit and in mainland China: the overview of CLTR 2011 annual scientific posttransplant survival in pediatric liver transplant recipients. Liver report. Hepatobiliary Surg Nutr. 2013;2(4):188-197. Transpl. 2006;12(3):475-480. 12. Emre S. Living-donor liver transplantation in children. Pediatr 30. Dip M, Cejas N, Cervio G, et al. Results after the adoption of a Transplant. 2002;6(1):43-46. MELD/PELD-based liver allocation policy in Argentina. Pediatr 13. Dehghani SM, Efazati N, Shahramian I, Haghighat M, Imanieh MH. Transplant. 2015;19(1):56-61. 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Utility of Transjugular Intrahepatic Portosystemic Shunt Placement for Maintaining Portal Vein Patency in Candidates on Wait Lists Who Develop Thrombus
Mustafa Alani,1 Michael Rowley,2 Paul Kang,3 Steve Chen,4 Kevin Hirsch,4 Anil Seetharam5,6
Abstract (20.8%) with complete thrombosis had improve - ment/resolution of portal vein thrombosis. Nine Objectives: Although no longer a contraindication to patients (30%) required hospitalization within 3 liver transplant, portal vein thrombosis may lead to months for hepatic encephalopathy. There were 3 longer operative time and complexities in venous deaths (10%) not related to transjugular intrahepatic reconstruction. Strategies to maintain preoperative portosystemic shunt placement (10%). Nine patients patency include systemic anticoagulation and/or underwent liver transplant after shunt placement transjugular intrahepatic portosystemic shunt (median 2.9 mo; range, 0.3-32 mo); all 9 received end- placement. The former may not be ideal in cirrhotic to-end anastomosis without need for intraoperative patients prone to luminal gastrointestinal tract thrombectomy. bleeding, and factors that predict improvements in Conclusions: Transjugular intrahepatic portosystemic portal vein thrombosis with the latter have not been shunt placement may be effective as monotherapy for well defined. Our goal was to evaluate the effectiveness maintaining or restoring portal vein patency in of transjugular intrahepatic portosystemic shunt selected liver transplant candidates, even in those with placement as monotherapy to improve and/or resolve complete portal vein thrombosis. Further studies are portal vein thrombosis in otherwise eligible liver needed to define potential responders to this transplant candidates with partial or complete portal approach. vein thrombosis and to identify factors predicting success. Key words: Cirrhosis, Liver transplant, Portal vein Materials and Methods: We identified 30 patients from thrombosis 2010 to 2015 who had transjugular intrahepatic Introduction portosystemic shunt placement for primary indication to maintain portal vein patency. The prevalence of portal vein thrombosis (PVT) in Results: The main portal vein was completely thrombosed in 5 of 30 (16.6%), nearly completely patients with cirrhosis at evaluation or at the time of 1 2 thrombosed in 9 of 30 (30%), and partially throm - liver transplant varies from 5% to 26%. Pathogenesis bosed in 16 patients (53.3%). Twenty-four patients is multifactorial and related to several factors: altered (80%) had improvement and/or resolution of portal balance of coagulation factors, increases in intrahepatic vein thrombosis after transjugular intrahepatic resistance to portal flow, and endothelial injury due portosystemic shunt placement, with 18 of these to elevated portal pressure.3,4 Liver transplant in a (75%) having complete resolution. All 5 patients patient with PVT was first reported in Pittsburgh, 5 From the 1Gastroenterology Department, St. Joseph's Hospital and Medical Center, Creighton Pennsylvania (USA). Since then, various surgical University, Phoenix, Arizona; the 2Gastroenterology Department, University of Texas- and medical strategies have been proposed to treat Southwestern Medical Center, Dallas, Texas; the 3Department of Epidemiology and Biostatistics, PVT, facilitating end-to-end portal inflow when University of Arizona, Phoenix, Arizona; the 4Department of Interventional Radiology, Banner University Medical Center, Phoenix, Arizona; the 5Banner Transplant and Advanced Liver feasible. Intraoperative methods are associated with Disease Center, Phoenix, Arizona; and the 6University of Arizona College of Medicine, Phoenix, significant complications, including prolonged Arizona, USA Acknowledgements: The authors have no sources of funding for this study and have no conflicts operative times, increased postoperative com - of interest to declare. plications, and higher in-hospital mortality rates.3,5-8 Corresponding author: Anil Seetharam, Banner University Medical Center, Banner Transplant and Advanced Liver Disease Center, 1441 N 12th St, Phoenix, AZ 85006, USA The primary goal of management of PVT in Phone: +1 602 521 5800 E-mail: [email protected] patients on liver transplant wait lists is to achieve
Experimental and Clinical Transplantation (2020) 7: 808-813 partial or complete recanalization to ensure portal
Copyright © Başkent University 2020 DOı: 10.6002/ect.2019.0153 Printed in Turkey. All Rights Reserved. Mustafa Alani et al/Experimental and Clinical Transplantation (2020) 7: 808-813 809
flow to the allograft or to prevent propagation of portal vein micropuncture access/wire placement thrombus, particularly into the confluence with the to facilitate access.12,13 After 2012, most of these superior mesenteric vein. Two primary treatment procedures have been performed with intravascular strategies for patients with PVT on wait lists are ultrasonography guidance.14,15 anticoagulation therapy and transjugular intrahepatic Transluminal angioplasty of the intrahepatic tract portosystemic shunt (TIPS) placement. Complete followed by deployment of a Viatorr (Gore Medical, recanalization rate with systemic anticoagulation Flagstaff, AZ, USA)-covered stent across the tract agents has been reported to be as high as 40%3; was carried out (nominal diameter of 10 mm). The however, studies are mixed with regard to optimal appropriate stent length was determined by agents and the duration/intensity for this simultaneous portovenogram (utilizing a marker indication.9,10 A major practical concern with the use band flush catheter) and inferior venacavagram of anticoagulant therapy is risk of inducing portal via a 10-French angle-tipped Ring set sheath. hypertensive-related bleeding and the need for Stents were placed from the portal vein extending repeated transfusion. Portal vein recanalization with slightly into the inferior vena cava. Most stents TIPS placement has been reported in patients with were dilated initially to 8 mm, and pressures were PVT.11 However, in most studies, TIPS was indicated measured. If the portosystemic gradient (PSG) was to treat severe complications of portal hypertension, greater than 12 mm Hg, then the stents were further and PVT was identified incidentally during work-up dilated to 9 or 10 mm to achieve a PSG of less than prior to TIPS placement. To our knowledge, few 12 mm Hg. A small number of patients with studies have examined TIPS placement with primary preexisting hepatic encephalopathy were only intent to maintain/restore PVT patency for future dilated initially to 6 mm. Repeat PSG, right atrial liver transplant. In this study, we report the efficacy pressure, and a venogram were obtained after and intermediate-term follow-up of 30 consecutive balloon dilation of the stent. patients receiving TIPS to maintain portal vein Techniques used in our center to clear the patency for future liver transplant. thrombus before placement of TIPS depend on thrombus acuity. For acute thromboses, we obtain Materials and Methods dual right intrajugular access and utilize intra vascular ultrasonography to guide access from the hepatic vein Patient selection to the portal vein (usually the right hepatic vein to After institutional review board approval, we right portal vein) and place a Viatorr TIPS to secure conducted a retrospective review of 34 consecutive access. Initially, the stent is not dilated to restrict the patients with cirrhosis who were on the transplant ability of thrombus to migrate and embolize. We wait list and who had undergone TIPS placement at then perform thrombolysis, thrombectomy, and our institution (2010-2015) for primary indication to angioplasty to clear the thrombus and establish good maintain portal vein patency. Four patients were splenic and mesenteric venous inflow into the portal excluded from our evaluation because of use of veins (Figures 1 to 6). This may be performed with concomitant systemic anticoagulation agents. or without main portal vein stent placement. Finally, the TIPS stent is dilated to achieve a right atrial PSG transjugular intrahepatic portosystemic shunt of 12 mm Hg or less to prevent thrombosis of the placement portovenous system after recanalization. Transjugular intrahepatic portosystemic shunt For cases of chronic thrombosis, we again obtain placement was performed utilizing the Ring dual right intrajugular access and utilize intra - Transjugular Intrahepatic Access Set with aColapinto vascular ultrasonography to guide access from the needle (Cook Medical, Bloomington, IN, USA), with hepatic vein to the portal vein (usually right hepatic the procedure routinely performed from the right vein to right portal vein). This also frequently hepatic vein to the proximal right portal vein. Before requires recanalization of the splenic vein; mesenteric 2012, this procedure was performed with fluoroscopic and portal veins may be assisted with trans-splenic guidance with wedged CO2 portovenograms and/or transhepatic access followed by angioplasty (Parallax, Waltham, MA, USA) and assisted by and stent placement to restore normal venous transabdominal ultrasonography and/or direct anatomy and flow. 810 Mustafa Alani et al/Experimental and Clinical Transplantation (2020) 7: 808-813 Exp Clin Transplant
Figure 1. Liver Transplant Candidate With Cirrhosis, Patent Intrahepatic Portal Figure 4. Transjugular Intrahepatic Portosystemic Shunt and Portal Vein Stent Vein (Arrow), and Distal Narrowing/Portal Vein Thrombus Deployed With Good Flow Demonstrated in the Splenic Vein and Superior Mesenteric Vein
Figure 2. Venogram Demonstrating Portal Vein Thrombus and Extensive Portosystemic Collaterals Figure 5. Good Flow Demonstrated in the Transjugular Intrahepatic Portosystemic Shunt and Portal Vein Stent
Figure 3. Obtaining Transjugular Intrahepatic Portosystemic Shunt Access With Transhepatic-Assisted Guidance Figure 6. Liver Transplant Candidate With Transjugular Intrahepatic Portosystemic Shunt Deployed and Patent Portal and Mesenteric Veins Mustafa Alani et al/Experimental and Clinical Transplantation (2020) 7: 808-813 811
radiographic assessment and clinical variables 18 patients (75%) had complete resolution of PVT. Improvement, resolution, or worsening of PVT was All 5 patients (20.8%) with complete PVT had assessed by review of cross-sectional follow-up improvement/resolution. imaging at 6 months after TIPS placement based on assessment by United Network for Organ Sharing- table 1. Baseline Characteristics certified abdominal radiologists. Our secondary Variable Total (N = 30) objective included an analysis of baseline factors Mean age (SD), y 55.2 (8.75) Male patient, No. (%) 16 (53.3) predicting response with TIPS monotherapy. Non-White ethnicity, No. (%) 10 (33.3) Response with TIPS was operationally defined as Cause of liver disease, No. HCV 14 improvement, resolution, or prevention of further NASH 6 extension of thrombus while on the liver transplant Alcohol 3 PBC 2 wait list as assessed with multiphasic cross-sectional Autoimmune 1 imaging follow-up at 6 months after TIPS placement. Other 4 Preplacement demographics included age, biologic Mean hemoglobin (SD), g/dL 10.2 (2.50) Mean INR (SD) 1.54 (0.39) sex, race, cause of cirrhosis, biologic Model for Mean creatinine (SD), mg/dL 0.90 (0.38) End-Stage Liver Disease (MELD), hemoglobin, Mean albumin (SD), g/dL 2.87 (0.79) Mean bilirubin (SD), mg/dL 2.75 (2.85) creatinine, international normalized ratio, total Bilirubin > 2.0 mg/dL, No. (%) 13 (43.3) bilirubin, albumin, thrombus extension, and history Mean MELD score (SD) 13.2 (3.69) Pre-TIPS hepatic encephalopathy, Yes (%) 13 (43.3) of hepatic encephalopathy. Degree of PVT before procedure, No. (%) Partial 16 (53.3) Near complete 9 (30.0) Statistical analyses Complete 5 (16.7) Demographic results along with TIPS procedure PVT grade by Yerdel classification, No. (%) 1 14 (46.7) variables were recorded and analyzed to assess 2 7 (23.3 baseline differences between those who did and those 3 7 (23.3) 4 2 (6.67) who did not respond to the procedure. Categorical Extension of clot into superior variables were analyzed using the Fisher exact test. mesenteric/splenic vein, Yes (%) 17 (56.7) Mean PSG before TIPS (SD), mm Hg 15.6 (4.69) Continuous variables were compared using the Mean PSG after TIPS (SD), mm Hg 6.67 (2.86) Wilcoxon rank sum test. P < .05 was considered Mean change in PSG (SD), mm Hg 8.96 (3.81) significant. Data were analyzed with STATA software Shunt size, No. (%) < 8 mm 9 (30.0) version 14 (StataCorp, College Station, TX, USA) 8 mm 17 (56.7) 10 mm 4 (13.3) Mean 3-mo post TIPS MELD (SD) 13.5 (2.83) Results Transplant, Yes (%) 9 (30.0) Death, Yes (%) 3 (10.0) Baseline demographics Abbreviations: HCV, hepatitis C virus; INR, international normalized ratio; MELD, Model for End-Stage Liver Disease; NASH, nonalcoholic Thirty patients underwent TIPS for primary steatohepatitis; PBC, primary biliary cholangitis; PSG, portosystemic indication to maintain or restore PVT patency gradient; PVT, portal vein thrombosis; SD, standard deviation; TIPS, transjugular intrahepatic portosystemic shunt (baseline characteristics are listed in Table 1). The main portal vein was completely thrombosed in 5 of 30 patients (16.6%), with near complete occlusion in The portal vein remained patent on the first cross- 9 of 30 patients (30%) and partially thrombosed sectional image after TIPS placement in 17 patients portal vein in 16 patients (53.3%). Mean MELD (56%) (median of 1.4 mo after placement). The portal (± standard deviation) for the cohort was 13.2 ± 3.69, vein remained completely patent in 19 patients (63%) and average reduction in PSG with TIPS placement (median duration of 7.1 mo) during the available was 8.96 ± 3.81 mm Hg. follow-up interval. Nine patients (30%) required hospitalization within 3 months for hepatic efficacy of transjugular intrahepatic portosystemic encephalopathy. There were 3 deaths (10%), which shunt for portal vein thrombosis patency and were not related to TIPS. Nine patients underwent predictors of response liver transplant post-TIPS (median of 2.9 mo; range, Of 30 patients, 24 (80%) responded with improvement 0.3-32 mo), and all 9 received end-to-end anastomoses or resolution of PVT (Table 2). Of the 24 responders, (Table 3). 812 Mustafa Alani et al/Experimental and Clinical Transplantation (2020) 7: 808-813 Exp Clin Transplant
table 2. Outcomes table 3. Characteristics of Transplant Patients Variable No Response Response P Value Patient Pre-TIPS 3 mo PVT SMV TIPS to End-to-End Group (n = 6) Group (n = 24) MELD Post-TIPS Grade* Extension LT Anastomosis Mean age (SD), years 48.7 (11.4) 56.9 (7.36) .07 MELD Duration Male patient, No. (%) 3 (50.0) 13 (54.2) NS 1 9 12 1 Yes 8 mo Yes Ethnicity, No. (%) 2 12 14 1 No 4 d Yes White 5 (83.3) 15 (62.9) 3 18 16 2 No 17 d Yes Non-White 1 (16.7) 9 (37.5) 4 10 12 3 Yes 11 mo Yes Mean hemoglobin (SD), g/dL 8.63 (1.64) 10.6 (2.54) .09 5 18 16 1 Yes 8 d Yes Mean INR (SD) 1.65 (0.50) 1.52 (0.37) .54 6 14 15 1 No 2 mo Yes Mean creatinine (SD), mg/dL 0.93 (0.35) 0.89 (0.39) .87 7 6 8 2 Yes 3 mo Yes Mean albumin (SD), g/dL 2.70 (0.58) 2.91 (0.84) .62 8 15 15 2 No 32 mo Yes Mean bilirubin (SD), mg/dL 2.42 (1.34) 2.84 (3.13) .56 9 18 16 1 Yes 5 mo Yes Bilirubin level, No. (%) Abbreviations: LT, liver transplant; MELD, Model for End-Stage Liver < 2.0 mg/dL 2 (33.3) 15 (62.5) Disease; PVT, portal vein thrombosis; SMV, superior mesenteric vein; TIPS, > 2.0 mg/dL 4 (66.7) 9 (37.5) transjugular intrahepatic portosystemic shunt Mean MELD score (SD) 14.5 (3.51) 12.9 (3.74) .32 *Based on Yerdel classification. Pre-TIPS hepatic encephalopathy, Yes (%) 3 (50.0) 10 (41.7) NS Degree of PVT before procedure, No. (%) .043 Discussion Partial 6 (100.0) 10 (41.7) Near complete 9 (37.5) Complete 5 (20.8) Portal vein thrombosis is increasingly recognized in PVT grade by Yerdel classification, No. (%) NS patients with cirrhosis, especially in patients on the Grade 1 3 (50.0) 11 (45.8) transplant wait list. Nonphysiologic techniques used Grade 2 2 (33.3) 5 (20.8) to restore portal vein flow (hemitranspositions Grade 3 1 (16.7) 6 (25.0) Grade 4 2 (8.33) and cavoportal and renoportal anastomoses) are Extension of clot into superior associated with significantly increased morbidity and mesenteric/splenic vein, Yes (%) 3 (50.0) 14 (58.3) NS 15,16 Mean PSG before TIPS (SD), mortality. Furthermore, the use of anticoagulation mm Hg 17.5 (3.21) 15.2 (4.94) .17 agents for patients with chronic PVT is still Mean PSG after TIPS (SD), mm Hg 8.0 (3.16) 6.33 (2.76) .25 controversial, and, in many candidates, systemic Mean change in PSG (SD), mm Hg 9.5 (2.58) 8.83 (4.10) .69 anticoagulation is relatively contraindicated due to Shunt size, No. (%) < .001 17 < 8 mm 1 (16.7) 8 (33.3) high risk of luminal gastrointestinal tract bleeding. 8 mm 5 (83.3) 12 (50.0) The use of TIPS for treatment of chronic PVT has 10 mm 4 (16.7) Extent of PVT on 1st follow-up been utilized by many transplant centers as a method image, No. (%) < .001 to improve portal vein patency or prevent None 1 (16.7) 17 (70.8) Minimal 5 (83.3) 9 (25.0) progression of the thrombus to maintain transition Partial 1 (4.17) of the patient to liver transplant. Near complete/complete Extent of PVT 6 mo post-TIPS, No. (%) .001 In this series, we found efficacy of TIPS None 1 (16.7) 18 (75.0) monotherapy in maintaining and/or restoring PVT Minimal 5 (20.8) patency in liver transplant candidates. Interestingly, Partial 3 (50.0) Near complete/complete 2 (33.3) 1 (4.17) the grade of PVT and/or extension to superior Mean 3-mo post-TIPS MELD (SD) 14.2 (2.56) 13.4 (2.93) .49 mesenteric vein had no effect on the rate of response Transplant, Yes (%) 2 (33.3) 7 (29.2) 1.0 Death, Yes (%) 0 (0.0) 3 (12.5) 1.0 to TIPS for this indication. Our study has several Type of response, No. (%) limitations: principally, it is a retrospective analysis Resolved 18 (75.0) < .001 Near resolution 4 (16.7) from a single center with a relatively small sample Improved 2 (8.33) size and short follow-up duration. In this No change 6 (100.0) investigation, median MELD score was low (13), yet Abbreviations: INR, international normalized ratio; MELD, Model for End- Stage Liver Disease; NS, not significant; PSG, portosystemic gradient; PVT, 30% of patients received a liver transplant within a portal vein thrombosis; SD, standard deviation; TIPS, transjugular median of 3 months; this is a notably higher rate of intrahepatic portosystemic shunt transplant for patients with MELD score of < 15. There are many regions in the United States and There were no differences in baseline demog - worldwide where a patient with a low MELD score raphics, TIPS procedural variables, or Yerdel grade would have to wait much longer for liver transplant, of PVT between the responder and nonresponder and a 63% 7-month patency rate may not be groups (Table 2). sufficient to justify TIPS placement. However, Mustafa Alani et al/Experimental and Clinical Transplantation (2020) 7: 808-813 813
presented results call out the need for further 9. Huard G, Bilodeau M. Management of anticoagulation for portal vein thrombosis in individuals with cirrhosis: a systematic review. prospective investigations to evaluate predictors of Int J Hepatol. 2012;2012:672986. response to TIPS monotherapy for PVT patency and 10. DeLeve LD, Valla DC, Garcia-Tsao G; American Association for the Study of Liver Diseases. Vascular disorders of the liver. Hepatology. the long-term durability of this approach in liver 2009;49(5):1729-1764. transplant candidates. 11. Rana A, Hardy MA, Halazun KJ, et al. Survival outcomes following liver transplantation (SOFT) score: a novel method to predict patient survival following liver transplantation. Am J Transplant. References 2008;8(12):2537-2546. 12. Rees CR, Niblett RL, Lee SP, Diamond NG, Crippin JS. Use of carbon 1. Englesbe MJ, Schaubel DE, Cai S, Guidinger MK, Merion RM. Portal dioxide as a contrast medium for transjugular intrahepatic vein thrombosis and liver transplant survival benefit. Liver Transpl. portosystemic shunt procedures. J Vasc Interv Radiol. 1994;5(2): 2010;16(8):999-1005. 383-386. 2. Gayowski TJ, Marino IR, Doyle HR, et al. A high incidence of native 13. Ferral H, Bilbao JI. The difficult transjugular intrahepatic portal vein thrombosis in veterans undergoing liver portosystemic shunt: alternative techniques and "tips" to transplantation. J Surg Res. 1996;60(2):333-338. successful shunt creation. Semin Intervent Radiol. 2005;22(4):300- 3. Chen H, Turon F, Hernandez-Gea V, et al. Nontumoral portal vein 308. thrombosis in patients awaiting liver transplantation. Liver Transpl. 14. Farsad K, Fuss C, Kolbeck KJ, et al. Transjugular intrahepatic 2016;22(3):352-365. portosystemic shunt creation using intravascular ultrasound 4. Cherqui D, Duvoux C, Rahmouni A, et al. Orthotopic liver guidance. J Vasc Interv Radiol. 2012;23(12):1594-1602. transplantation in the presence of partial or total portal vein 15. Pillai AK, Andring B, Faulconer N, et al. Utility of intravascular US- thrombosis: problems in diagnosis and management. World J guided portal vein access during transjugular intrahepatic Surg. 1993;17(5):669-674. portosystemic shunt creation: retrospective comparison with 5. Kakaei F, Nikeghbalian S, Salahi H, et al. Liver transplantation in conventional technique in 109 patients. J Vasc Interv Radiol. the presence of old portal vein thrombosis. Int J Organ Transplant 2016;27(8):1154-1159. Med. 2010;1(1):44-48. 16. Paskonis M, Jurgaitis J, Mehrabi A, et al. Surgical strategies for liver 6. Seu P, Shackleton CR, Shaked A, et al. Improved results of liver transplantation in the case of portal vein thrombosis--current role transplantation in patients with portal vein thrombosis. Arch Surg. of cavoportal hemitransposition and renoportal anastomosis. Clin 1996;131(8):840-844; discussion 844-845. Transplant. 2006;20(5):551-562. 7. Salem R, Vouche M, Baker T, et al. Pretransplant portal vein 17. Manzanet G, Sanjuan F, Orbis P, et al. Liver transplantation in recanalization-transjugular intrahepatic portosystemic shunt in patients with portal vein thrombosis. Liver Transpl. 2001;7(2):125- patients with complete obliterative portal vein thrombosis. 131. Transplantation. 2015;99(11):2347-2355. 8. Hibi T, Nishida S, Levi DM, et al. When and why portal vein thrombosis matters in liver transplantation: a critical audit of 174 cases. Ann Surg. 2014;259(4):760-766. Artıcle
Evaluation of Neuroimaging Findings of Central Nervous System Complications in Heart Transplant Recipients
Hale Turnaoglu,1 Ahmet Muhtesem Agildere,1 Feride Kural Rahatli,1 FuldemYildirim Donmez,1 Ruhsen Ocal,2 Taner Sezer,3 Ufuk Can,2 Atilla Sezgin,4 Sait Aslamaci4
Abstract neurologic complications in our heart transplant recipients. The other complications were hemorrhagic Objectives: In this study, we presented neuroradiologic stroke, intracranial abscess, and intracranial dis - findings and diagnoses of neurologic complications in semination of sinusoidal fungal infection. Neurologic a series of heart transplant recipients. complications are common in heart transplant recipients Materials and Methods: A retrospective review was and should be identified promptly for early treatment. conducted at Başkent University Hospital. We searched For the recognition of these complications, computed the hospital and radiology databases and identified tomography should be performed for initial evaluation 109 heart transplant recipients. Thirty-one of these to rule out edema or hemorrhage. However, in the recipients had neuroradiologic evaluations secondary to presence of serious neurologic symptoms that cannot presentation of neurologic symptoms after heart be explained by computed tomography, magnetic transplant, with 18 patients evaluated with computed resonance imaging should be indicated. tomography and 22 patients evaluated with magnetic resonance imaging (overlap of imaging-defined groups Key words: Heart transplantation, Neurologic occurred in 9 recipients). Computed tomography and complications, PRES, Stroke magnetic resonance imaging studies were retrieved from the Picture Archiving and Communication System, Introduction with each type of imaging retrospectively evaluated on consensus by 2 radiologists. Currently, heart transplantation remains the best Results: Radiopathologic findings related to symptoms long-term therapy for patients with end-stage heart were detected in 12 of the 31 study patients. The most failure who have failed conventional medical common abnormality was posterior reversible leuko- therapies.1 Patients who are candidates for heart encephalopathy syndrome (5 patients, 4.6%). The other transplant have an increased prevalence of vascular abnormalities were ischemic stroke (3 patients, 2.8%), risk factors, such as hypertension, hypercho - hemorrhagic stroke (1 patient, 0.9%), intracranial lesterolemia, diabetes, obesity, and smoking. As a abscess (2 patients, 1.8%), and intracranial dissem - ination of sinusoidal fungal infection and related result, neurologic complications occur more hemorrhagic infarct (1 patient, 0.9%). The other 19 commonly with heart transplant compared with heart transplant recipients who underwent computed other transplant procedures.2 Frequency of these tomography and/or magnetic resonance imaging for complications depends on follow-up, ranging from neurologic complaints showed no neuroradiologic 23% to 81%. Ischemic stroke is the most common findings related to neurologic symptoms. cerebrovascular complication in heart transplant Conclusions: Posterior reversible leukoencephalopathy recipients.1,3 Posterior reversible leukoencephalopathy syndrome and ischemic stroke were the most common syndrome (PRES) is another common neurologic
From the 1Department of Radiology, the 2Department of Neurology, the 3Department of complication in these patients. Other early and late Pediatric Neurology, and the 4Department of Cardiovascular Surgery, Baskent University cerebrovascular complications include hemorrhagic Faculty of Medicine, Ankara, Turkey Acknowledgements: The authors have no sources of funding for this study and have no conflicts stroke, transient ischemic attack, and less often of interest to declare. central nervous system (CNS) infections, mass, and Corresponding author: Hale Turnaoglu, Baskent University Faculty of Medicine, Ankara lymphoproliferative disorders.1,4,5 Hospital, Department of Radiology, Mareşal Fevzi Çakmak Cad. 10. Sok. No: 45, 06490 Bahcelievler, Ankara, Turkey Neurologic complications are associated with Phone: +90 312 2036868 ext: 1165 E-mail: [email protected] significant morbidity and increased mortality in
3 Experimental and Clinical Transplantation (2020) 7: 814-822 heart transplant recipients. The clinical presentation
Copyright © Başkent University 2020 DOı: 10.6002/ect.2018.0118 Printed in Turkey. All Rights Reserved. Hale Turnaoglu et al/Experimental and Clinical Transplantation (2020) 7: 814-822 815
ranges from generalized encephalopathy to focal Erlangen, Germany) system. In all patients, T1- neurologic deficits,3,6 but the diagnosis is often weighted axial and sagittal images (time of repetition difficult because systemic and metabolic disorders [TR]/time of echo [TE]/number of excitations and immunosuppressive therapy may obscure [NEX]/slice thickness = 500-580/13-15/2/5-5.5), symptoms of an underlying CNS lesion.7,8 Prompt T2-weighted coronal images (TR/TE/NEX/slice neuroradiologic diagnosis is crucial for the proper thickness = 4100-5160/99-103/2/5-5.5), and fluid- treatment of serious neurologic complications. The attenuated inversion recovery axial images role of neuroradiology in this population includes (TR/TE/NEX/slice thickness = 9000-10 000/105- the early detection and monitoring of the progression 140/2/5-5.5) were acquired. Echo planar images of complications, evaluation of treatment response, were obtained with diffusion gradients at 1.5T in x, y, and localization of the appropriate site for and z planes using 5-mm-thick sections with 1.5 mm stereotactic or open biopsy in specific cases.9,10 Brain of skip at b = 0, 500, and 1000 s/mm2. Apparent computed tomography (CT) and/or magnetic diffusion coefficient maps were automatically resonance imaging (MRI) studies are often necessary generated. T1-weighted images in axial and coronal after the clinical examination and electrodiagnostic planes were obtained after intravenous gadolinium and laboratory tests when neurologic symptoms administration (0.1 mmol/kg) in patients with present in heart transplant recipients. In this study, possible abscess or encephalitis. Patients were we reviewed the neuroradiologic findings and sedated when needed; these patients were monitored diagnoses of neurologic complications in a series of by electrocardiography and pulse oximetry with an heart transplant recipients. anesthesiologist present throughout the examination. Images of CT and MRI studies were retrieved from Materials and Methods the Picture Archiving and Communication System and were retrospectively evaluated on consensus by A retrospective review was conducted on all patients 2 radiologists. who underwent heart transplantation at Başkent University Hospital. Institutional review board Results approval was obtained before the study. We searched the hospital and radiology databases and identified In the 31 heart transplant recipients who underwent 109 heart transplant recipients. Of these, 31 recipients CT and/or MRI, mean age at the onset of symptoms received neuroradiologic evaluation secondary to was 30.4 years (range, 7.5-59 y). The patient group presentation of neurologic symptoms after heart consisted of 16 male (51.6%) and 15 female (48.4%) transplant. These symptoms were evaluated with CT heart transplant recipients. Overall time from in 18 recipients and with MRI in 22 recipients (with transplant to onset of symptoms was 3 days to 7 overlap of imaging-defined groups in 9 recipients). years (mean of 15.5 mo). Underlying diseases that These 31 patients made up our study group. had resulted in heart failure varied widely. Causes of Demographic and clinical factors, such as age, heart failure in the 31 study patients are shown in sex, reason for transplant, symptoms at time of Table 1. All patients were under mycophenolate presentation, time from transplant to onset of mofetil (a selective immunosuppressant agent) symptoms, physical findings, medications, and and/or tacrolimus (a calcineurin inhibitor) and/or additional diseases of recipients, were recorded. prednisolone (a systemic corticosteroid) therapy. Computed tomography scans were performed Patients presented with various symptoms. Two using 4-detector CT (Somatom 4; Siemens, Erlangen, patients were evaluated for possible metastasis and Germany) or 16-detector CT (Sensation 16; Siemens). aspergillosis, although they did not have any With 16- or 4- detector CT, images were obtained at a 3- or 2.5-mm slice thickness for the posterior fossa table 1. Underlying Diseases Leading to Heart Transplant in Our Patient and a 5- or 6-mm slice thickness for the supra - Group (N = 31) Underlying Disease No. of Patients (%) tentorial region. Contrast medium was administered Dilated cardiomyopathy 21 (67.7%) in patients when needed. Restrictive cardiomyopathy 4 (12.9%) Heart failure 3 (9.7%) Magnetic resonance imaging studies were Complex congenital heart diseases 2 (6.5%) performed on a Siemens 1.5T (Magnetom Avanto, Myocarditis 1 (3.2%) 816 Hale Turnaoglu et al/Experimental and Clinical Transplantation (2020) 7: 814-822 Exp Clin Transplant
symptoms. Details of the indications for CT and/or intracranial abscesses, CT showed the hypodense MRI examinations are shown in Table 2. cystic masses with vague or no prominent Radiopathologic findings related to symptoms enhancement. In the patient with intracranial were detected in 12 of the 31 heart transplant dissemination of sinusoidal fungal infection, MRI recipients who underwent CT and/or MRI. The showed hyperintensities in the affected areas. diagnosis, symptoms, and time from transplant to In the remaining 19 heart transplant recipients onset of symptoms are listed in Table 3. Among who underwent CT and/or MRI for neurologic patients with neuroradiologic findings, the most complaints, no neuroradiologic findings related to common abnormality was PRES in 5 patients (4.6%). neurologic symptoms were detected. The most Other findings were ischemic stroke (3 patients, common complaint was headache (n = 7; Table 2). In 2.8%), hemorrhagic stroke (1 patient, 0.9%), intra - this patient group, time from transplant to onset of cranial abscess (2 patients, 1.8%), and intracranial symptoms was 5 days to 6 years (mean of 14.5 mo). dissemination of sinusoidal fungal infection and Some of these recipients showed chronic ischemic- related hemorrhagic infarct (1 patient, 0.9%). For hemorrhagic findings such as microangiopathic patients who had PRES, CT, MRI, and diffusion- ischemic gliosis (n = 2), lacunar infarct (n = 2), weighted MRI studies revealed vasogenic edema encephalomalacia (n = 3), and chronic hemorrhagic within the affected regions, with nonenhancing areas area (n = 1) on CT and/or MRI. In addition, cerebral of low attenuation in CT and multiple areas of and/or cerebellar atrophy was observed at varying increased signal intensity in the subcortical white degrees in 7 of these patients (age range, 19-57 y, matter on T2-weighted images on MRI. For patients mean age of 40 y). who had ischemic stroke, CT showed loss of gray- white matter differentiation and cortical hypodensity Discussion with associated parenchymal swelling with resultant gyral effacement. In patients with no evidence of Neurologic complications, which occur frequently in stroke on CT, MRI and/or diffusion-weighted MRI heart transplant recipients (23%-81%), markedly revealed the infarction. In the patient with increase mortality and morbidity.3 Neurologic hemorrhagic stroke, CT easily disclosed the affected complications in such patients are influenced by their regions as hyperdense areas. In the patients who had primary disease, prior cardiovascular and CNS status, the surgical procedure and postoperative
table 2. Indications for Computed Tomography and/or Magnetic course, and posttransplant medications. The most Resonance Imaging in Our Heart Transplant Patient Group (N= 31) common complication in heart transplant recipients Symptom No Neuroradiologic Positive is ischemic stroke, which has been shown to occur in Finding Neuroradiologic (n = 19, 61.3%) Finding (n = 12, 38.7%) 3% to 10% of patients,3,11 followed by drug toxicity Seizure 4 5 and related PRES.7 Most strokes are due to ischemic Headache 7 Altered mental status 4 infarctions; however, hemorrhagic strokes can also Visual disturbance 1 2 occur in 0.6% to 2.5% of heart transplant recipients.12 Numbness 1 1 Tremor 1 Other early and late cerebrovascular complications Dizziness 1 Sudden arm/leg weakness 1 include CNS infections, mass, and lympho - Foot drop 1 proliferative disorders.1,4,5 In our series of heart No symptom 2 transplant recipients with serious neurologic
table 3. Diagnosis, Symptoms, and Mean Time From Transplant to Onset of Symptoms of Heart Transplant Recipients Who Had Neuroradiologic Findings on Computed Tomography and/or Magnetic Resonance Imaging Neuroradiologic Diagnosis Symptom Mean Time From Transplant to Onset of Symptom Posterior reversible encephalopathy syndrome Seizures (n = 4); visual problems (n = 1) 1.5 months (5 days to 3 months) Ischemic cerebrovascular events Altered mental status (n = 1); numbness 10 months (5 days to 2.3 years) (n = 1); visual problems (n = 1) Hemorrhagic cerebrovascular event Altered mental status (n = 1) 16 days Intracranial abscess Seizures (n = 1); altered mental status (n = 1) 3 months (2 to 3.5 months) Intracranial dissemination of sinusoidal Altered mental status (n = 1) 7 years fungal infection and hemorrhagic infarct Hale Turnaoglu et al/Experimental and Clinical Transplantation (2020) 7: 814-822 817
symptoms evaluated by neuroimaging, PRES was In our series, 3 patients who developed ischemic more commonly seen (4.6%), although ischemic stroke had dilated cardiomyopathy contributing to stroke (2.8%) and hemorrhagic stroke (0.9%) also heart failure, with stroke occurring within 10 days of occurred. In addition, we observed occurrences of transplant in 2 patients and during the late period in intracranial abscess (1.8%) and intracranial 1 patient. Reasons contributing to ischemic stroke dissemination of sinusoidal fungal infection and were embolism in 2 patients and undetermined cause related hemorrhagic infarct (0.9%). in 1 patient (Figure 1). Cardiovascular risk factors for ischemic stroke are Hemorrhagic stroke is usually caused by present in many heart transplant patients, including coagulation disorders, high pressure of the cardio - hypertension, hyperlipidemia, atrial fibrillation, and pulmonary bypass, and uncontrolled blood diabetes mellitus.12 Preoperative left ventricular pressure.16 In heart transplant recipients, early assist device support, preoperative intraaortic perioperative hemorrhagic stroke may occur in the balloon pump support, prolonged cardiopulmonary setting of pretransplant low cardiac output followed bypass time, postoperative hepatic failure, older age, by posttransplant relative hyperperfusion associated the presence of extracranial carotid artery stenosis with disordered cerebral autoregulatory pressor over 50%, pretransplant ventilator dependence, response.14 Lobar hemorrhagic stroke has been postoperative dialysis, infection requiring antibiotics reported without coagulation disorders and before discharge, pacemaker implantation, and uncontrolled blood pressure in up to 5% of patients, drug-treated hypertension during follow-up can all probably due to a mechanism of hyperperfusion.18 contribute to increased risk of cerebral infarction.2,11,13 After heart transplant, hemorrhagic stroke is most Furthermore, transplant-associated ischemic stroke is commonly located in the deep (basal ganglia, more common in patients transplanted for dilated thalamus, pons, and cerebellum) versus in the cardiomyopathy, prior valvular disease, or congen - cerebral lobes.1,3,11,15-18 In our series, 1 patient ital heart diseases.3,13 presented with multiple cerebral and cerebellar In heart and liver allograft recipients, strokes hematomas in both deep and lobar localizations and occur earlier after transplant, whereas they tend to had subarachnoid hemorrhage due to throm - occur later after kidney transplant.14 According to the bocytopenia and probably due to mechanism of results of studies providing specific information hyperperfusion (Figure 2). about stroke pathogenesis after heart transplant, the Computed tomography and MRI are primary ischemic stroke subtype distribution is different from imaging methods used in patients who have the distribution observed in the general population. suspected cerebrovascular diseases. The role of Specifically, large artery atherosclerosis (5%), small immediate CT in the management of acute cerebral vessel disease (5%), and cardioembolism (15%) are infarction is crucial. Intracerebral hemorrhage can be seen less often, but unusual causes (35%) and un - rapidly diagnosed or excluded by CT. The CT determined causes (40%) occur more frequently.1,11,15-17 findings in acute cerebral infarction evolve with time.
Figure 1. 57-Year-Old Male Patient Presenting With Altered Mental Status
Axial computed tomography (CT) images show large hypodense area that involved both the gray and white matter in the middle cerebral artery distribution in the right hemisphere and a hypodense area in the left cerebellum (thick arrows in A and B). A hyperattenuating middle cerebral artery is also seen (thin arrows in A and B). Diffusion-weighted (c) and apparent diffusion coefficient (D) magnetic resonance images (obtained 1.5 h after CT) demonstrate cytotoxic brain edema in multiple areas, consistent with ischemic stroke. 818 Hale Turnaoglu et al/Experimental and Clinical Transplantation (2020) 7: 814-822 Exp Clin Transplant
Figure 2. 7-Year-Old Girl Presenting With Altered Mental Status 16 Days After presentation at 7.5 years posttransplant has also been Heart Transplant reported.24 Posterior reversible leukoencephalopathy syn - drome has been extensively described after bone marrow, liver, renal, and lung transplant but less in heart transplant recipients.4,25 In PRES, the abnormalities are usually seen in a symmetric bilateral distribution involving mainly the parietal and occipital lobes, but involvement of temporal and frontal cortex and additional areas of the brain, including brain stem, cerebellum, and basal ganglia, has also been reported.26-28 The pathophysiology of Axial computed tomography images in A and B show multiple hyperdense PRES and state of brain blood flow remain areas consistent with parenchymal hematomas (thick arrows) and controversial. In early studies, vasoconstriction seen subarachnoid hemorrhage (thin arrows) in both hemispheres due to thrombocytopenia and with a mechanism of hyperperfusion. Brain has an by catheter angiography prompted the authors to edematous appearance. postulate that reduced brain perfusion led to the imaging features. In contrast, animal studies have Almost 60% of CT scans obtained within the first few suggested that experimentally induced hypertension hours after cerebral infarction are normal. Acute above the autoregulatory limit led to hyperperfusion, strokes are identified more often and localized more break down of the blood-brain barrier, and accurately with MRI than with CT scans. With the use hemispheric edema.29,30 In PRES, hyperperfusion or of diffusion-weighted MRI, signal intensity changes hypoperfusion has been demonstrated in various can be detected within minutes of arterial occlusion. diseases, including molar pregnancy, eclampsia, Acute infarcts have lower apparent diffusion aneurysmal subarachnoid hemorrhage, after coefficients than noninfarcted brain and may be a chemotherapy, and in autoimmune diseases, and sensitive indicator of early cytotoxic brain edema.19 with various imaging methods such as single-photon After the exclusion of intracerebral hemorrhage by CT emission CT and magnetic resonance perfusion.31-38 in patients suspected of cerebrovascular disease, In addition, relative cerebral blood volume has been patients should immediately undergo MRI and/or shown to be reduced moderately in areas of PRES diffusion-weighted MRI. (average of 65%) compared with normal uninvolved Posterior reversible leukoencephalopathy syn - regions in 2 studies.33,38 In their comparison of drome is a clinical/radiologic syndrome characterized anterior versus posterior hemispheric flow, Brubaker by alterations in mental status, personality changes, and associates found that magnetic resonance headaches, visual disturbances, and seizures. These perfusion demon strated significant posterior brain symptoms can occur in the early postoperative hypoperfusion with increased mean transit time, period or later, emerging due to immunosuppressive reduced cerebral blood volume, and reduced cerebral treatment and accompanied by distinctive MRI blood flow.37 After heart transplant, patients have findings.20 Despite the proven efficacy of calcineurin shown residual frontal hypoperfusion on single- inhibitors (cyclosporine and tacrolimus) to prevent photon emission CT with 99m tchexamethyl- acute rejection episodes and to enhance graft propylene-amineoxime,39 and these cerebral survival, recipients may develop PRES.21,22 Posterior anomalies may be because of long-standing cerebral reversible leukoencephalopathy syndrome occurs hypoperfusion resulting from severe heart disease or more frequently in the presence of high blood levels microemboli caused by a cardiovascular bypass.12 On of drugs; however, some patients have levels within the basis of these results, cerebral hyperperfusion the therapeutic range.23 This syndrome may also be followed by hypoperfusion resulting from severe heart related to other changes induced by calcineurin disease may be a trigger of PRES in heart transplant inhibitors, including kidney insufficiency, hyper - recipients. Therefore, frontal involvement may be more tension, hypomagnesemia, hypocholesterolemia, and common in heart transplant recipients. Indeed, in our high doses of cortisone.4 Although it has been reported series, 3 of 5 patients with PRES had frontal that 82% of cases occur within 90 days of transplant, involvement (Figure 3). Hale Turnaoglu et al/Experimental and Clinical Transplantation (2020) 7: 814-822 819
Figure 3. Magnetic Resonance Images of an 11-Year-Old Girl Presenting With Seizures 11 Days After Heart Transplant
Bilateral cerebral hyperintensities on fluid-attenuated inversion recovery (FLAIR) images in the frontal and occipital cortex (thin arrows), and right thalamus (thick arrows) are shown, consistent with posterior reversible encephalopathy syndrome (A and B). Diffusion-weighted images (DWI; c) and apparent diffusion coefficient (D) images demonstrate edema. Six months later, edema vanished on FLAIR (e) and regressed on DWI (F).
In patients with PRES, radiologic findings may ranges. The onset of these symptoms was within the suggest reversible intracranial vasogenic edema. first 3 months after transplant. Patients were treated Brain CT results of patients with PRES are often symptomatically, resulting in clinical resolution of normal. However, T2-weighted MRIs show high symptoms. Follow-up MRIs also revealed resolution signals in affected areas. These findings are best of previous edema and cortical abnormalities. demonstrated as hyperintense signals on fluid- More potent and effective immunosuppressive attenuated inversion recovery sequence.26 Increased regimens have reduced the risk of graft rejection; diffusion on diffusion-weighted MRI may suggest however, these regimens have increased the vasogenic edema from endothelial damage rather susceptibility of transplant recipients to a variety of than cytotoxic edema from regional ischemia.40 These opportunistic CNS infections. These potentially life- symptoms typically reverse promptly when the threatening infections may be nonspecific and far immunosuppressive treatment is changed or when from acute or obvious in transplant recipients.43 Viral drug doses are reduced.4 The clinical resolution of and fungal pathogens are more often implicated in symptoms may then permit confirmation of PRES.41 opportunistic CNS infections in allograft recipients Early recognition is essential, and delayed diagnosis than bacteria and protozoa.25 Central nervous system may lead to status epilepticus, intracranial involvement is often metastatic from another site as hemorrhage, ischemic infarction leading to neurologic part of systemic dissemination. Spread can also occur damage, or death.42 directly from sinuses.43 The two most common In heart transplant recipients who are receiving pathogens are Cryptococcus and Aspergillus species. calcineurin inhibitors, central neurologic alterations Munoz and associates reported that, among solid- should prompt radiologic imaging to investigate organ transplant recipients, heart transplant recipients PRES. Magnetic resonance imaging should be the have the highest incidence of toxoplasmosis.44 diagnostic procedure of choice. In our patients, Orofacial aspergillosis is a rare clinical condition, associated seizures, hypertension, and renal which primarily affects, the paranasal sinuses, impairment pointed toward anticalcineurin toxicity, nasal cavity, mouth, facial skin, and orbit. The although tacrolimus levels were within therapeutic fungal lesions in the nasal, oral, and sinusoidal 820 Hale Turnaoglu et al/Experimental and Clinical Transplantation (2020) 7: 814-822 Exp Clin Transplant
cavities may be the indirect result of thrombotic Figure 4. Contrast-Enhanced Computed Tomography Scan of a 59-Year-Old Male Patient With History of Pulmonary Aspergillosis, Presenting With vascular infarction or dissemination to brain Seizures 3.5 Months After Heart Transplant parenchyma.45 Opportunistic CNS infections occur in about 5% to 10% of all renal transplant recipients.46 In heart transplant recipients, to our knowledge, the rates are unknown. Fungal CNS infections are fortunately becoming less common in transplant patients, but they still carry high mortality, and early and accurate diagnosis is of great importance.47 Neuroimaging studies may show evidence of an abscess, encephalitis, or even brain infarction.9 The most common imaging characteristics of cerebral aspergillosis at CT or MRI are multiple lesions with infarction or hemorrhage in a random distribution due to the angioinvasive nature of the infection.48 Abscesses may appear radiologically identical to other brain abscesses as classic ring-enhancing lesions with striking high signal intensity on Peripheral enhancing nodular hypodense lesion in the right frontal lobe is diffusion-weighted imaging. However, contrast seen (arrow). This patient had surgery, and Aspergillus fumigatus was material enhancement may be vague or absent. A isolated. hypointense ring is often seen in the periphery of the lesions on T2-weighted MRIs. In cases where CNS Of 31 study patients, 19 heart transplant aspergillosis is secondary to paranasal sinus disease, recipients who underwent CT and/or MRI for associated invasive rhinosinusitis, osteomyelitis, neurologic complaints showed no radiopathologic local dural enhancement, and subdural empyema finding related to symptoms. The most common may also be present.48 Two patients in our heart complaint was headache in these patients. In their transplant study group presented with abscesses study, Donmez and colleagues reported similar within 3 months after heart transplant, which were findings for liver transplant recipients and suggested diagnosed with CT. One patient had multiple that headaches not accompanied by other complaints hypodense cystic masses with no prominent or objective signs could be evaluated initially by peripheral enhancement, and the other patient had 1 CT.49 Other symptoms in our recipients were tremor, lesion with vague peripheral enhancement after dizziness, sudden arm/leg weakness, and foot drop, contrast medium administration. In one of these which were probably related to side effects of drugs patients, Aspergillus fumigatus was isolated (Figure 4). and transient ischemic attacks. Imaging studies in Another patient was diagnosed with orofacial these patients showed chronic ischemic-hemorrhagic aspergillosis, which presented 7 years after heart findings, including microangiopathic ischemic transplant. The patient’s MRI showed extensive gliosis, lacunar infarct, encephalomalacia, and swelling and edema of right hemi-face, including chronic hemorrhagic area. Also, cerebral-cerebellar orbita, infraorbital region, dorsum nasi, anterior of atrophy was observed at varying degrees in patients maxilla, parotid gland, infratemporal fossa, pterygoid at younger ages than in the normal population. These muscles, and neck. T2-weighted images showed a findings are related to advanced heart failure, hypointense nodular lesion in the right maxillary decreased cerebral blood flow and hypoperfusion, sinus suggesting fungal infection. Focal hyperintense underlying atherosclerosis, and antithrombotic drug signals consistent with focal cerebritis were present use in these patients. in the right temporal lobe, in the contiguity of To investigate neurologic complications, CT is cavernous sinus. Acute infarction findings were preferred for initial evaluation to rule out edema or shown on the right cerebellum, vermis, and pons hemorrhage. In the presence of serious neurologic (Figure 5). symptoms that cannot be explained by CT findings, Hale Turnaoglu et al/Experimental and Clinical Transplantation (2020) 7: 814-822 821
Figure 5. Magnetic Resonance Image of a 55-Year-Old Male Patient Presenting With Swelling of the Right Hemi-Face and Altered Mental Status
Extensive swelling and edema of right hemi-face, including orbita, infraorbital region, dorsum nasi, anterior of maxilla, parotid gland, infratemporal fossa, pterygoid muscles, and neck, are seen on the T1-weighted fat-saturated coronal images (A and B). On the T2-weighted fat-saturated axial image, a hypointense nodular lesion in the right maxillary sinus, suggesting fungal infection, is observed (arrow in c). Hyperintensities on the fluid-attenuated inversion recovery image (D) and diffusion restriction on the diffusion-weighted image (e) consistent with acute infarction are seen in the right cerebellum, vermis, and pons (arrows). Cause was determined as aspergillosis. patients should have MRIs. However, agitated, References lethargic, or potentially seizing patients might not 1. van de Beek D, Kremers W, Daly RC, et al. Effect of neurologic remain still or safely undergo sedation for relatively complications on outcome after heart transplant. Arch Neurol. lengthy routine MRI protocols. Therefore, some of 2008;65(2):226-231. 2. Heroux A, Pamboukian SV. Neurologic aspects of heart our heart transplant recipients with neurologic transplantation. Handb Clin Neurol. 2014;121:1229-1236. complications were evaluated only by CT. A shorter 3. Perez-Miralles F, Sanchez-Manso JC, Almenar-Bonet L, Sevilla- MRI protocol may be devised in many instances, Mantecon T, Martinez-Dolz L, Vilchez-Padilla JJ. Incidence of and risk factors for neurologic complications after heart such as limiting the study to diffusion-weighted, transplantation. Transplant Proc. 2005;37(9):4067-4070. gradient-echo, and T2-weighted images.49 4. Navarro V, Varnous S, Galanaud D, et al. Incidence and risk factors for seizures after heart transplantation. J Neurol. 2010;257(4):563-568. 5. Jaiswal A, Sabnani I, Baran DA, Zucker MJ. A unique case of Conclusions rituximab-related posterior reversible encephalopathy syndrome in a heart transplant recipient with posttransplant lymp - hoproliferative disorder. Am J Transplant. 2015;15(3):823-826. The most common neurologic complications in our 6. Wright AJ, Fishman JA. Central nervous system syndromes in solid heart transplant recipients were PRES and ischemic organ transplant recipients. Clin Infect Dis. 2014;59(7):1001-1011. stroke. Other complications included hemorrhagic 7. Senzolo M, Ferronato C, Burra P. Neurologic complications after solid organ transplantation. Transpl Int. 2009;22(3):269-278. stroke, intracranial abscess, and intracranial 8. Server A, Bargallo N, Floisand Y, Sponheim J, Graus F, Hald JK. dissemination of sinusoidal fungal infection. Imaging spectrum of central nervous system complications of hematopoietic stem cell and solid organ transplantation. Neurologic complications are common in heart Neuroradiology. 2017;59(2):105-126. transplant recipients and should be identified 9. Zivkovic S. Neuroimaging and neurologic complications after promptly for early treatment. To investigate these organ transplantation. J Neuroimaging. 2007;17(2):110-123. 10. Guarino M, Benito-Leon J, Decruyenaere J, et al. EFNS guidelines complications, CT is preferred for initial evaluation on management of neurological problems in liver transplantation. to rule out edema or hemorrhage. However, when Eur J Neurol. 2006;13(1):2-9. 11. Zierer A, Melby SJ, Voeller RK, et al. Significance of neurologic serious neurologic symptoms cannot be explained by complications in the modern era of cardiac transplantation. Ann CT findings, MRI should be indicated. Thorac Surg. 2007;83(5):1684-1690. 822 Hale Turnaoglu et al/Experimental and Clinical Transplantation (2020) 7: 814-822 Exp Clin Transplant
12. Pizzi M, Ng L. Neurologic complications of solid organ 33. Bartynski WS, Boardman JF. Catheter angiography, MR transplantation. Neurol Clin. 2017;35(4):809-823. angiography, and MR perfusion in posterior reversible 13. Morgan CT, Manlhiot C, McCrindle BW, Dipchand AI. Outcome, encephalopathy syndrome. AJNR Am J Neuroradiol. 2008;29(3): incidence and risk factors for stroke after pediatric heart 447-455. transplantation: An analysis of the International Society for Heart 34. Apollon KM, Robinson JN, Schwartz RB, Norwitz ER. Cortical and Lung Transplantation Registry. J Heart Lung Transplant. blindness in severe preeclampsia: computed tomography, 2016;35(5):597-602. magnetic resonance imaging, and single-photon-emission 14. Sila CA. Spectrum of neurologic events following cardiac computed tomography findings. Obstet Gynecol. 2000;95(6 Pt transplantation. Stroke. 1989;20(11):1586-1589. 2):1017-1019. 15. Adair JC, Call GK, O'Connell JB, Baringer JR. Cerebrovascular 35. Lewis DH, Hsu S, Eskridge J, et al. Brain SPECT and transcranial syndromes following cardiac transplantation. Neurology. 1992; Doppler ultrasound in vasospasm-induced delayed cerebral 42(4):819-823. ischemia after subarachnoid hemorrhage. J Stroke Cerebrovasc Dis. 16. Belvis R, Marti-Fabregas J, Cocho D, et al. Cerebrovascular disease 1992;2(1):12-21. as a complication of cardiac transplantation. Cerebrovasc Dis. 36. Naidu K, Moodley J, Corr P, Hoffmann M. Single photon emission 2005;19(4):267-271. and cerebral computerised tomographic scan and transcranial 17. Guillon B, Wiertlewski S, Trochu JN, et al. [Late cerebrovascular Doppler sonographic findings in eclampsia. Br J Obstet Gynaecol. complications of cardiac transplantation]. Rev Neurol (Paris). 1997;104(10):1165-1172. 2000;156(3):264-269. 37. Brubaker LM, Smith JK, Lee YZ, Lin W, Castillo M. Hemodynamic 18. Acampa M, Lazzerini PE, Guideri F, Tassi R, Martini G. Ischemic and permeability changes in posterior reversible encephalopathy stroke after heart transplantation. J Stroke. 2016;18(2):157-168. syndrome measured by dynamic susceptibility perfusion- 19. Davis WL, Jacobs J. Cerebral vasculature: normal anatomy and weighted MR imaging. AJNR Am J Neuroradiol. 2005;26(4):825-830. pathology. In: Osborn AG, ed. Diagnostic Neuroradiology. St. Louis, 38. Engelter ST, Petrella JR, Alberts MJ, Provenzale JM. Assessment of MO: Mosby; 1994:154-385. cerebral microcirculation in a patient with hypertensive 20. Kwon S, Koo J, Lee S. Clinical spectrum of reversible posterior encephalopathy using MR perfusion imaging. AJR Am J leukoencephalopathy syndrome. Pediatr Neurol. 2001;24(5):361- Roentgenol. 1999;173(6):1491-1493. 364. 39. Burra P, Senzolo M, Pizzolato G, et al. Frontal cerebral blood flow 21. Chow KM, Szeto CC. Posterior leukoencephalopathy with is impaired in patients with heart transplantation. Transpl Int. cyclosporine. Clin Nephrol. 2003;60(4):297-298; author reply 298. 2002;15(9-10):459-462. 22. Munoz R, Espinoza M, Espinoza O, Andrade A, Bravo E, Gonzalez 40. Coley SC, Porter DA, Calamante F, Chong WK, Connelly A. F. Cyclosporine-associated leukoencephalopathy in organ Quantitative MR diffusion mapping and cyclosporine-induced transplant recipients: experience of three clinical cases. Transplant neurotoxicity. AJNR Am J Neuroradiol. 1999;20(8):1507-1510. Proc. 2006;38(3):921-923. 41. Singh N, Bonham A, Fukui M. Immunosuppressive-associated 23. Wijdicks EF, Wiesner RH, Krom RA. Neurotoxicity in liver transplant leukoencephalopathy in organ transplant recipients. recipients with cyclosporine immunosuppression. Neurology. Transplantation. 2000;69(4):467-472. 1995;45(11):1962-1964. 42. Stott VL, Hurrell MA, Anderson TJ. Reversible posterior 24. Tsagalou EP, Anastasiou-Nana MI, Margari ZJ, Vassilopoulos D. leukoencephalopathy syndrome: a misnomer reviewed. 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Therapeutic Potential of Bama Pig Adipose-Derived Mesenchymal Stem Cells for the Treatment of Carbon Tetrachloride-Induced Liver Fibrosis
Xinran Wu,3* Shuang Zhang,2* Junhui Lai,1 Huidi Lu,1 Yuchen Sun,1 Weijun Guan1
Abstract Key words: Animal model, Carbon tetrachloride-treated mice, Hepatic differentiation Objectives: Liver fibrosis is inevitable in the healing process of liver injury. Liver fibrosis will develop Introduction into liver cirrhosis unless the damaging factors are removed. This study investigated the potential therapy The liver is the largest solid organ in the human body of Bama pig adipose-derived mesenchymal stem and is responsible for multiple, essential functions.1 cells in a carbon tetrachloride-induced liver fibrosis Exposure of livers to xenobiotics, drugs, and viruses Institute of Cancer Research strain mice model. eventually leads to chronic hepatitis and liver Materials and Methods: Adipose-derived mesenchymal cirrhosis. These diseases are most likely to cause stem cells were injected intravenously into the tails of hepatocellular carcinoma, even organ damage, and mice of the Institute of Cancer Research strain that had eventually lead to inflammation, fibrosis, and loss of been treated with carbon tetrachloride for 4 weeks. Survival rate, migration, and proliferation of adipose- an ability of regeneration. More than 450 million derived mesenchymal stem cells in the liver were people will develop cirrhosis as a consequence of observed by histochemistry, fluorescent labeling, and these diseases, which demonstrates the relevance of serological detection. liver pathologies as causes of mortality and public Results: At 1, 2, and 3 weeks after adipose-derived health expenses. mesenchymal stem cell injection, liver fibrosis was At present, liver transplant is the best treatment significantly ameliorated. The injected adipose- for cirrhosis and liver fibrosis. However, the shortage derived mesenchymal stem cells had hepatic of organ donors, huge cost of treatment, and lifelong differentiation potential in vivo, and the survival rate immunosuppression may limit this option. Stem cell of adipose-derived mesenchymal stem cells declined transplant has been widely used in the treatment over time. Conclusions: The findings in this study confirmed that of liver diseases because of its advantages such adipose-derived mesenchymal stem cells derived from as abundant source, low immunogenicity, less the Bama pig can be used in the treatment of liver trauma, and simple operation. Stem cell grafting fibrosis, and the grafted adipose-derived mesenchy- is therefore considered an effective alternative mal stem cells can migrate, survive, and differentiate to the treatment of liver fibrosis.2 Mesenchymal stromal into hepatic cells in vivo. cells (MSCs) are easily obtained, are efficiently From the 1Department of Animal Genetic Resources, Institute of Animal Science, Chinese cultured, and can functionally differentiate into Academy of Agricultural Sciences, Haidian District, Beijing, China; the 2Scientific Experimental Research Center, Harbin Sport University, Nangang District, Harbin, Heilongjiang Province, hepatocytes and therefore provide an effective China; and the 3Sport and Exercise Sciences Centre, University of Malaya, Kuala Lumpur, treatment for liver cirrhosis and fibrosis in animal Malaysia 3 Acknowledgements: *Xinran Wu and Shuang Zhang contributed equally to this work. This models. Additionally, ethical and religious concerns research was supported by the National Natural Science Foundation of China (Grant No. are not likely because MSCs are obtained by 31472099), the Agricultural Science and Technology Innovation Program (cxgc-ias-01), and the National Infrastructure of Animal Germplasm Resources project (2016). Other than autologous transplant. described above, the authors have not received any funding or grants in support of the presented Many adipose-derived cell types and experimental research or for the preparation of this work and have no further declarations of potential interest. Corresponding author: Weijun Guan, Department of Animal Genetic Resources, Institute of models have been used to test the efficacy of cell Animal Science, Chinese Academy of Agricultural Sciences, Haidian District, Beijing, China therapies for many diseases, such as spinal cord E-mail: [email protected] injury, neurodegenerative disease, autoimmune
Experimental and Clinical Transplantation (2020) 7: 823-831 diseases, and metabolic diseases, leading to divergent
Copyright © Başkent University 2020 DOı: 10.6002/ect.2020.0108 Printed in Turkey. All Rights Reserved. 824 Xinran Wu et al/Experimental and Clinical Transplantation (2020) 7: 823-831 Exp Clin Transplant
results on the actual role of adipose-derived ıdentification of adipose-derived mesenchymal mesenchymal stem cells (ADSCs) as a new treatment stem cells with flow cytometry analysis alternative.4-7 We used surface markers and flow cytometry to In this study, we used the carbon tetrachloride establish the characteristics of the cells. Cells at (CCl4)-induced model of liver fibrosis to investigate passage 8 were incubated with the following the effect of Bama pig ADSC transplant on liver antibodies: CD29, CD44, CD105, vimentin, and CD34. function in mice with hepatic fibrosis. Our objective Cells were washed with phosphate-buffered saline was to open a new direction and theoretical basis for and then stained with fluorescein isothiocyanate- the clinical treatment of liver fibrosis. conjugated or Cy5-conjugated secondary antibody. For controls, there were no second antibodies. The Materials and Methods results were obtained by an EPICS-XL flow cytometer. Animals Research animals were 6-week-old male mice of the ıdentification of adipose-derived mesenchymal Institute of Cancer Research strain. Mice were stem cells with karyotype analysis purchased from Beijing HFK Bioscience Cells at passage 8 were treated in a hypertonic (http://www.labagd.com). All protocols in the condition and stained with Giemsa. We used the oil- experiments were in accordance with the relevant immersion technique to examine numbers and shape provisions of the Institutional Animal Ethics of chromosomes. Committee. Multipotential differentiation of adipose-derived ısolation, culture, and purification of adipose- mesenchymal stem cells: adipogenic differentiation derived mesenchymal stem cells and confirmation Adipose tissues were recovered from the visceral When the cells reached 70% confluence, we changed (omental) region of the pig under aseptic conditions. the medium to adipocyte-inducing medium. Control Briefly, the extracellular matrix was dissociated with group cells were fed with a DMEM medium. Ten 0.1% (mg/mL) type I collagenase (Sigma). After days later, the induced cells were stained with Oil centrifugation, the supernatant was discarded and Red O, and the adipogenic-specific genes for the deposits were dissolved in the complete medium. lipoprotein lipase (LPL) and peroxisome proliferator- When the cells reached 70% to 80% confluence, activated receptor gamma (PPARγ) were detected by digestion and passage were carried out with 0.125% polymerase chain reaction (PCR). trypsin. The cells are usually homogenous after 3 passages. ınsulin-secreting cells differentiation and confirmation ıdentification of adipose-derived mesenchymal When the cells reached 80% confluence, the medium stem cells with surface marker detection was replaced with an induced medium with 90% Cells were incubated in the following antibodies Dulbecco’s modified Eagle medium nutrient mixture (from Abcam): CD29 (1:100), CD44 (1:100), CD105 F-12, 10 ng/mL hepatocyte growth factor (PeproTech), (1:100), and vimentin (1:100). Then, we stained the 10 ng/mL activin A (Sigma), 1 mmol/L β- cells with fluorescein isothiocyanate-conjugated or mercaptoethanol (Sigma), 10 mmol/L nicotinamide, Cy5-conjugated secondary antibodies (Bioss) and and 2% B-27 supplement (Gibco). Control group cells used a confocal microscope (Nikon model TE-2000- were cultured with a complete medium. The insulin E) to examine the stained cells. gene (INS) and the insulin promoter factor gene (PDX1) were evaluated by reverse transcriptase-PCR ıdentification of adipose-derived mesenchymal (RT-PCR). stem cells with reverse transcription-polymerase chain reaction Neurogenic differentiation of adipose-derived We used TRIzol reagent (Invitrogen) to obtain RNA mesenchymal stem cells and confirmation from cells of passages 4, 14, 20, and 26, and we used When the cells reached 70% confluence, we changed gel electrophoresis to examine the products. the medium to the neurogenic induction medium. Xinran Wu et al/Experimental and Clinical Transplantation (2020) 7: 823-831 825
Induction was divided into 2 steps. Briefly, in step 1, transplant of adipose-derived mesenchymal stem the cells were incubated with the first neurogenic cells to carbon tetrachloride-injured mice of the induction medium for 7 days. Then, in step 2, the ınstitute of cancer research strain cells were incubated with the second neurogenic For cell transplant, 1.5 × 107 ADSCs (P8) suspended induction medium for 7 days. The cells were in 50 μL of phosphate-buffered saline were injected confirmed by immunofluorescent assays of intravenously into mice that were treated with CCl4 neural markers for the genes for microtubule- for 4 weeks (n = 30). For control, 50 μL of phosphate- associated protein 2 (MAP2), glial fibrillary buffered saline were injected (n = 15). The mice were acidic protein (GFAP), and β-tubulin. The given an additional 1-, 2-, and 3-week injection of neural-specific genes for neurofibromatosis-related CCl4 after cell transplant. Animal livers and protein (NF) and MAP2 were examined by peripheral blood samples were collected at different RT-PCR. intervals. chronic liver fibrosis model in mice and model ın vivo detection of differentiated adipose-derived evaluation mesenchymal stem cells The experimental group mice were treated Adipose-derived mesenchymal stem cells are known with 200 μL of 10% CCl4 solution twice weekly to differentiate into hepatic cells in vivo. Adipose- by an intraperitoneal injection, whereas the derived mesenchymal stem cells were positive for control group mice were injected with 200 μL the antibody CD44 and negative for the antibody mineral oil in the same form twice weekly.8 CK18, whereas hepatic cells were positive for the Four weeks later, some mice were used for antibody CK18 and negative for the antibody CD44. serological tests and immunohistochemical We used an immunohistochemistry assay to evaluate assay. Samples of 3 normal mice were set as a the differentiated hepatic cells. We used a confocal control group, and the results were set as a normal microscope (Nikon) to examine the results, according range of the relevant parameter. This range was to standard protocols. calculated by using the mean values (±2SD) for each test. Statistical analyses To assess the extent of liver fibrosis under the We used analysis of variance to analyze the data. We enzymatic level, serum alanine transaminase, aspartate used the Tukey-Kramer test to evaluate the statistical transaminase, albumin-to-globulin ratio, albumin, significance. P < .05 was considered significant. We total protein, and globulin levels were measured. used JMP Software (SAS Institute) to perform all Serum was obtained after centrifugation at -80 °C. statistical analyses. Livers from the experimental group and control group were obtained. For the immunohistochemical Results assay, 8-μm liver tissue sections were embedded in paraffin and stained with the antibody for characterization of mesenchymal stem cells smooth muscle actin, hematoxylin-eosin, and Masson derived from pig adipose tissue stain. To examine the results, we used a confocal Cells recovered from pig adipose tissue by adherence microscope (Nikon) and a light microscope showed a typical characterization of ADSCs, (Nikon Eclipse model 90i) according to standard especially with regard to the proliferation pattern protocols. and the phenotype as assessed by cell morphology, RT-PCR, flow cytometry, colony-forming units, cell labeling with cM-Diı indocarbocyanine dye karyotype, immunofluorescence, and multiple To analyze biodistribution after injection, we used differentiation potential. CM-DiI indocarbocyanine dye to label the ADSCs Primary cells began to adhere to plates and and injected 1.5 × 107 labeled ADSCs into the extend toward the spindle after 48 hours. Cells experimental group.9 Three mice were evaluated at expanded rapidly, and the transplant reached 90% 1, 2, and 3 weeks after cell injection. We applied confluence 7 days later (Figure 1). When the cells an immunohistochemical method to detect the proliferated to passage 28, signs such as transplanted cells. vacuolization and karyotype began to appear. 826 Xinran Wu et al/Experimental and Clinical Transplantation (2020) 7: 823-831 Exp Clin Transplant
Figure 1. Morphology of Adipose-Derived Mesenchymal Stem Cells
Adipose-derived mesenchymal stem cells have a morphology similar to fibroblasts. Scale bars in (A) and (B) are 50 μm, and scale bars in (c) and (D) are 100 μm.
Passages 4, 14, 20, and 26 were detected by RT-PCR, Differentiation potential of adipose-derived and these were positive for CD29, CD44, CD71, CD73, mesenchymal stem cells CD90, and CD105 but negative for the endothelial We evaluated the multipotential differentiation of marker CD31 (Figure 2). The results of flow cytometry ADSCs by inducing the cells into 3 germ layers. For showed phenotypic characteristics of homogeneous mesoderm, adipogenic differentiation was observed. cell populations. The results showed that 81.43% For the ectoderm, neurogenic differentiation was of the cells were positive for CD29 (Figure 3A), 88.88% observed. For the entoderm, insulin-secreting of the cells were positive for CD44 (Figure 3B), 18.38% differentiation was observed. There were some lipid of the cells were positive for CD105 (Figure 3C), and droplets in adipogenic differentiation, and the results 85.85% of the cells were positive for vimentin (Figure were confirmed by Oil Red O staining and RT-PCR 3D), whereas CD34 expression was 11.6% (Figure 3E). (Figure 6A and 6B). Insulin-secreting differentiation The results of immunofluorescence revealed that the was shown by RT-PCR (Figure 7). Neurogenic ADSCs expressed CD29, CD44, CD105, and vimentin (Figure 4). The results of karyotyping showed that Figure 3. Characterization of a Fetal Pig Adipose-Derived Mesenchymal Stem the number of diploid chromosomes was 2n = 38, Cells by Flow Cytometry Analysis including a pair of sex chromosomes. There was no missing or broken diploid chromosome ploidy (Figure 5).
Figure 2. Gene Expression Profiles of Fetal Pig Adipose-Derived Mesenchymal Stem Cells as Shown by Reverse Transcriptase-Polymerase Chain Reaction
Abbreviations: FL1-3, fluorescent light channels 1-3 (A) CD29 (81.43%), (B) CD44 (88.88%), (c) CD105 (18.38%), (D) vimentin (85.85%), and (e) CD34 (11.6%). Xinran Wu et al/Experimental and Clinical Transplantation (2020) 7: 823-831 827
differentiation was detected by RT-PCR and Using immunohistochemistry, we found out that immunofluorescence (Figure 8). necrosis caused by CCl4 treatment was mitigated by ADSC injection. Staining with Masson stain and Figure 4. Immunofluorescent Staining: Adipose-Derived Mesenchymal Stem hematoxylin-eosin showed that the transplant of Cells at Passage 19 ADSCs could ameliorate CCl4-induced fibrous deposition (Figure 9A).
Figure 6. Adipogenic Differentiation of Mesenchymal Stem Cells
(A) Ten days after induction, cells at passage 15 were positive for Oil Red O; scale bar = 100 μm. Ten days after induction, adipose-derived mesenchymal stem cells were magnified under a microscope; scale bar = 25 μm. Ten days after induction, cells were positive for Oil Red O; scale bar = 25 μm. (B) Specific genes for LPL and PPARγ were detected by reverse transcriptase- polymerase chain reaction in the induced group.
Abbreviations: DAPI, diamidinophenylindole Figure 7. Insulin-Secreting Cell Differentiation of the Adipose-Derived In vitro, cytoplasm was stained with antibodies to CD29, CD44, CD105, Mesenchymal Stem Cells and vimentin. Nuclear material was counterstained with DAPI. Scale bars = 50 μm.
Figure 5. Normal Chromosome Structure and Morphology of Fetal Pig Adipose-Derived Mesenchymal Stem Cells at Passage 10.2 (n = 38)
(A) Induction of 2-week adipose-derived mesenchymal stem cells at passage 15; scale bar = 100 μm. (B) The specific genes for insulin (INS) and insulin promoter factor (PDX1) were detected by reverse transcriptase-polymerase chain reaction in the induced group.
Adipose-derived mesenchymal stem cell transplant Serological analysis showed that the transplanted decreased carbon tetrachloride-induced chronic cells significantly improved the impaired liver fibrosis in mouse livers function (Figure 9B). Colorimetric assays showed To discover whether the transplanted ADSCs could that injection of the cells remarkably reduced mitigate liver injury, we compared the histological aspartate transaminase, alanine transaminase, the difference of liver tissue in transplanted and albumin-to-globulin ratio, albumin, total protein, and nontransplanted CCl4-treated mice. As shown in globulin content and collagen production in the Figure 9, the mice without transplant showed more CCl4-damaged liver tissues. In brief, these results severe fibrous liver dysfunction compared with suggested that cell transplant may inhibit CCl4- normal mice. After transplant of ADSCs, mice with induced fibrous deposition and may have antifibrotic liver injury showed reduced vacuolar degeneration. and anti-inflammatory functions. 828 Xinran Wu et al/Experimental and Clinical Transplantation (2020) 7: 823-831 Exp Clin Transplant
Figure 8. Neurogenic Differentiation of the Adipose-Derived Mesenchymal Stem Cells
Abbreviations: DAPI, diamidinophenylindole (A) Immunofluorescence assay of the induced adipose-derived mesenchymal stem cells. (B) Reverse transcriptase- polymerase chain reaction showed the expression of neurogenic cell-specific genes.
Figure 9. Evaluation of the Recovery From Liver Failure
Abbreviations: ADSCs, adipose-derived mesenchymal stem cells; A/G, albumin/globulin ratio; ALB, albumin; ALT, alanine transaminase; AST, aspartate transaminase; GLOB, globulin; TP, total protein (A) To assess the effect of ADSCs in fibrosis, we used Masson stain and hematoxylin-eosin to analyze liver samples after transplant for 1, 2, and 3 weeks. (B) Immunohistochemical analysis of ALT, AST, GLOB, ALB, and TP expression. All results showed that ADSCs could ameliorate liver fibrosis. Xinran Wu et al/Experimental and Clinical Transplantation (2020) 7: 823-831 829
Distribution of adipose-derived mesenchymal stem postinfusion, which suggested that the differentiated cells after intraportal transplant ability of ADSCs decreased over time. We analyzed a group of 3 mice at 1, 2, and 3 weeks after transplant. Injected cells were confirmed by Discussion immunohistochemistry (Figure 10). One week after transplant, 50% of the cells were observed on each We studied the biological characteristics of ADSCs slide. We observed that most cells were around the and analyzed the transdifferentiated ability of portal vein, although we also observed aggregated ADSCs in the injured liver model. For the first part, cells. After 2 weeks, only 20% of cells were observed we displayed the following 2 features of ADSCs: a in the liver slices. After 3 weeks, the number of cells strong ability to self-renew and proliferate, which dropped to 5% (Figure 10A). We did not detect the allows these cells to be a valuable resource for cell cells in the vascular system, and this may be because therapy; and the ability to differentiate in vitro into 3 these cells were not integrated into the parenchyma. germ layers including ectoderm, mesoderm, and entoderm, which indicates a powerful therapeutic Adipose-derived mesenchymal stem cells potential for these cells,10,11 particularly in paralytic differentiated into hepatic-like cells in injured liver stroke, meniscus repair, and myocardial infarction. To test whether ADSCs were able to differentiate into Recently, reports have been published on the ability hepatic-like cells after injection into the injured liver, of ADSCs to differentiate into hepatocytes in vitro we incubated liver samples with pig-specific and in vivo. Our results presented here were based antibodies to CD44 and CK18 (Figure 10B). We on these findings.12-15 compared the number of positive cells to CD44 and Adipose-derived mesenchymal stem cells were
CK18 in liver tissues of CCl4-injured mice with ADSC obtained easily from adipose tissue and demonstrated transplant during 5, 6, and 7 weeks. As presented in large-scale in vitro proliferation; also, these cells were Figure 4C, after 1 week of infusion, the number of induced into functional hepatic-like cells in an efficient CK18-positive cells increased. Over time, the number manner. All these factors were important in of CK18-positive cells declined at 6 and 7 weeks regeneration treatments. The differentiated cells can
Figure 10. Detection of the Differentiation of Adipose-Derived Mesenchymal Stem Cells
Abbreviations: ADSCs, adipose-derived mesenchymal stem cells (A) ADSC cells stained with CM-DiI indocarbocyanine dye were decreased over time. (B) A portion of ADSCs could differentiate into hepatocytes in honors. (c) ADSC transplant decreased the expression of tumor necrosis factor-α. 830 Xinran Wu et al/Experimental and Clinical Transplantation (2020) 7: 823-831 Exp Clin Transplant
express the specific genes ALB and AFP and can be signal pathways are involved during the recovery positive for the antibody ALB, with albumin and what are they? Which factors play the main production and urea secretion. In addition, the cells function during the recovery? What are the have a glycogen storage capacity that balances differences between cell therapy and tissue self- glucose in vivo. recovery? It is clear that further research is required. We analyzed the distribution of ADSCs after tail We propose that ADSCs may be a new source of vein injection by CM-DiI indocarbocyanine dye adult stem cells. Compared with bone marrow labeling and immunofluorescence (with pig-specific MSCs, ADSCs have an advantage because ADSCs antibodies to CD44 and CK18). At 1, 2, and 3 weeks originate from “waste” tissue. However, more after the transplant, the results showed the analyses are needed before ADSCs may be used as a persistence of injection into the parenchyma of liver, standard alternative source of stem cells; for whereas the cells remaining in the liver were example, further studies are needed to evaluate the obviously reduced over time, which revealed that efficacy of ADSCs for the treatment of disease. We most ADSCs were removed from the liver. Therefore, evaluated the efficacy of ADSCs in the treatment of the reason for failure of cells to enter the liver liver regeneration. First, ADSCs have a selective parenchyma may be attributable to the lack of recruitment characteristic and these cells could be adhesion molecules. induced into hepatic-like cells that are positive for Through immunofluorescence, we observed a CK18 in the injured liver. Second, we observed the morphological improvement of the liver after cell decline of liver enzyme levels, inflammatory factors, transplant. Transforming growth factor-β, smooth and recovery of liver fibrosis following infusion muscle actin, and collagen I staining demonstrated of ADSCs. Third, we confirmed ADSCs could the reduction of the injured area. These results differentiate into hepatocytes in mice, but the revealed that these cells could improve liver fibrosis. numbers are reduced over time. However, further Stem cell therapy has great potential for use in the assessment of the mechanisms is required. In brief, treatment of liver fibrosis and tissue regeneration.16,17 the data showed the transplant of ADSCs to be We also used biochemical assay to analyze the functional. However, the mouse liver-infused therapeutic potential of ADSCs. Parameters such as mechanism of donor cells and recipient liver aspartate transaminase, alanine transaminase, cells and the principle of in vivo homing and albumin/globulin ratio, albumin, total protein, and differentiation potential of injected ADSCs are not yet globulin declined in the injured group after cell fully clear. More work is required to identify the injection, showing that ADSCs could regenerate the cellular and molecular mechanism(s) involved in the liver. Parekkadan and colleagues stated that engrafted animal model. ADSCs did not usually differentiate into hepatocytes.18 To detect the possibility of transdifferentiation in mice, Conclusions we conducted immunofluorescence staining for pig- specific antibodies CD44 and CK18. Adipose-derived We investigated the effectiveness of Bama pig ADSCs mesenchymal stem cells were positive for CD44 on the treatment of CCl4-induced liver fibrosis. The (green), and hepatocytes were positive for CK18 mouse liver fibrosis model was successfully induced
(red). The results showed that ADSCs could by CCl4 and evaluated by staining with Masson stain transdifferentiate into hepatocytes, but the numbers and hematoxylin-eosin. The characterization and would reduce over time. pluripotent differentiation of ADSCs were analyzed Mesenchymal stem cells have been shown to experimentally, and ADSCs can differentiate into secrete a wide range of chemokines, growth factors, functional hepatocytes with a high inductive rate. and active cytokines and therefore may mediate a At 1, 2, and 3 weeks after ADSC transplant, we congenital immune system function and regulate evaluated liver function by serological test, and the liver regeneration in vivo.18-21 Furthermore, MSCs results showed that the transplant of ADSCs could have been reported to inhibit proliferation and ameliorate liver injury caused by CCl4. These fibrogenesis of activated hepatic stellate cells.18 findings offer novel insight regarding the usefulness Several questions remain. How do the factors of MSCs as a resource for clinical therapy for liver participate in the recovery of liver injury? How many fibrosis. Xinran Wu et al/Experimental and Clinical Transplantation (2020) 7: 823-831 831
References 12. Schwartz RE, Reyes M, Koodie L, et al. Multipotent adult progenitor cells from bone marrow differentiate into functional 1. Peres LA, Bredt LC, Cipriani RF. Acute renal injury after partial hepatocyte-like cells. J Clin Invest. 2002;109(10):1291-1302. hepatectomy. World J Hepatol. 2016;8(21):891-901. doi:10.4254/ doi:10.1172/JCI15182 wjh.v8.i21.891 13. Lee KD, Kuo TK, Whang-Peng J, et al. In vitro hepatic differentiation 2. Zhang Z, Wang FS. Stem cell therapies for liver failure and cirrhosis. of human mesenchymal stem cells. Hepatology. 2004;40(6):1275- J Hepatol. 2013;59(1):183-185. doi:10.1016/j.jhep.2013.01.018 1284. doi:10.1002/hep.20469 3. Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of 14. Lange C, Bassler P, Lioznov MV, et al. Hepatocytic gene expression adult human mesenchymal stem cells. Science. 1999;284 in cultured rat mesenchymal stem cells. Transplant Proc. (5411):143-147. doi:10.1126/science.284.5411.143 2005;37(1):276-279. doi:10.1016/j.transproceed.2004.11.087 4. Sakaida I, Terai S, Yamamoto N, et al. Transplantation of bone 15. Lange C, Bassler P, Lioznov MV, et al. Liver-specific gene expression in mesenchymal stem cells is induced by liver cells. World J marrow cells reduces CCl4-induced liver fibrosis in mice. Hepatology. 2004;40(6):1304-1311. doi:10.1002/hep.20452 Gastroenterol. 2005;11(29):4497-4504. doi:10.3748/wjg.v11.i29.4497 5. Oyagi S, Hirose M, Kojima M, et al. Therapeutic effect of 16. Cao H, Yang J, Yu J, et al. Therapeutic potential of transplanted transplanting HGF-treated bone marrow mesenchymal cells into placental mesenchymal stem cells in treating Chinese miniature CCl4-injured rats. J Hepatol. 2006;44(4):742-748. doi:10.1016/j. pigs with acute liver failure. BMC Med. 2012;10:56. doi:10.1186/ jhep.2005.10.026 1741-7015-10-56 6. Abdel Aziz MT, Atta HM, Mahfouz S, et al. Therapeutic potential of 17. Liu Y, Han ZP, Zhang SS, et al. Effects of inflammatory factors on bone marrow-derived mesenchymal stem cells on experimental mesenchymal stem cells and their role in the promotion of tumor liver fibrosis. Clin Biochem. 2007;40(12):893-899. doi:10.1016/j. angiogenesis in colon cancer. J Biol Chem. 2011;286(28):25007- clinbiochem.2007.04.017 25015. doi:10.1074/jbc.M110.213108 7. Banas A, Teratani T, Yamamoto Y, et al. Rapid hepatic fate 18. Parekkadan B, van Poll D, Megeed Z, et al. Immunomodulation of specification of adipose-derived stem cells and their therapeutic activated hepatic stellate cells by mesenchymal stem cells. potential for liver failure. J Gastroenterol Hepatol. 2009;24(1):70-77. Biochem Biophys Res Commun. 2007;363(2):247-252. doi:10.1016/j. doi:10.1111/j.1440-1746.2008.05496.x bbrc.2007.05.150 8. Khurana S, Mukhopadhyay A. Characterization of the potential 19. Parekkadan B, van Poll D, Suganuma K, et al. Mesenchymal stem subpopulation of bone marrow cells involved in the repair of cell-derived molecules reverse fulminant hepatic failure. PLoS One. injured liver tissue. Stem Cells. 2007;25(6):1439-1447. doi:10. 2007;2(9):e941. doi:10.1371/journal.pone.0000941 1634/stemcells.2006-0656 20. Caplan AI, Dennis JE. Mesenchymal stem cells as trophic 9. Gutfilen B, Rossini A, Martins FP, da Fonseca LM. Tc-99m- mediators. J Cell Biochem. 2006;98(5):1076-1084. doi:10.1002/jcb. leukocytes: is it an intracellular labelling? J Clin Lab Immunol. 20886 1999;51(1):1-7 21. Sadat S, Gehmert S, Song YH, et al. The cardioprotective effect of 10. Lazarus HM, Haynesworth SE, Gerson SL, Rosenthal NS, Caplan AI. mesenchymal stem cells is mediated by IGF-I and VEGF. Biochem Ex vivo expansion and subsequent infusion of human bone Biophys Res Commun. 2007;363(3):674-679. doi:10.1016/j.bbrc. marrow-derived stromal progenitor cells (mesenchymal 2007.09.058 progenitor cells): implications for therapeutic use. Bone Marrow Transplant. 1995;16(4):557-564 11. Cowan CM, Shi YY, Aalami OO, et al. Adipose-derived adult stromal cells heal critical-size mouse calvarial defects. Nat Biotechnol. 2004;22(5):560-567. doi:10.1038/nbt958 Case RepoRt
Successful Kidney Transplant From a Brain Stem-Dead Donor Due To Lethal Methanol Poisoning
Afshar Zomorrodi, Farzad Kakaei
Abstract Case Report
Kidney replacement is the best treatment modality A 38-year-old man, following ingestion of methanol for chronic renal failure; however, the greatest obstacle alcohol, presented with blurred vison to a poisoning for transplant is the scarce number of donor organs. In center. After dialysis and treatment, the the United States and Europe, less than 1% of organs patient developed deep coma and was formally for transplant are provided from patients with diagnosed with brain death. He was referred lethal poisoning. In this paper, we present a successful to our organ transplant department. Kidney kidney transplant from a donor with methanol function (acute tubular necrosis) was stabilized, poisoning. A 38-year-old-man who had methanol poisoning developed brain stem death after and a retrieved kidney was grafted to a 27-year-old unsuccessful treatment and was a candidate to be a man with chronic renal failure. Due to proliferative kidney donor for transplant to a 27-year-old male glomerulonephritis, he was treated with 3 medicines, patient with chronic renal failure. Three weeks after which included tacrolimus, mycophenolic acid, kidney transplant, the recipient was discharged with and prednisolone. After 3 weeks, the transplant good kidney function. We suggest that it may be recipient was discharged with creatinine level of possible to consider lethal methanol poisoning for 1.5 mg/dL. kidney donation. Discussion Key words: Chronic renal failure, Extended criteria donor, Renal replacement, Renal transplant Organ shortages remain a problem in kidney
Introduction transplant. In the United States and Europe, brain death donors due to poisoning provide less than 1% A main issue for kidney transplant, which is the of organs available for transplant.1 There have been best treatment for chronic renal failure, is organ rare cases of kidney, heart, and pancreas donations shortage. In the United States and Europe, less from brain-dead donors with methanol, cyanide, and than 1% of organs for transplant are provided from carbon dioxide poisoning.2 donors after poisoning brain death.1 Here, we Kidney transplant from donors with methanol describe a 38-year-old man with methanol poisoning poisoning has been reported in the United States, who, after 7 days of unsuccessful treatment for Spain, and Belgium.3-7 After absorption in the methanol poising and who lapsed into a deep gastrointestinal tract, methanol is changed to coma, was referred to our center with diagnosis formate in the liver, which is responsible for the of brain death. A kidney was retrieved from the toxicity of methanol.8 The first case of a kidney donor. donor with methanol poisoning in a recipient with long-term kidney function was reported by From the Organ Transplantation Center, Imam Reza Hospital, Tabriz Medical Science 9 University, Tabriz, Iran Friedlaender and associates. The first renal and Acknowledgements: The authors have no sources of funding for this study and have no conflicts pancreas transplant in a donor with brain death after of interest to declare. Corresponding author: Afshar Zomorrodi, Organ Transplant Department, Imam Reza methanol ingestion was reported by Chari and Hospital, Tabriz Medical Science University, Tabriz, Iran colleagues.10 The recipients did not develop any Phone: +98 9141147229 E-mail: [email protected] signs or symptoms of methanol poising after Experimental and Clinical Transplantation (2020) 7: 832-833 transplant.11
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Conclusions 5. Leikin JB, Heyn-Lamb R, Aks S, Erickson T, Snyder J. The toxic patient as a potential organ donor. Am J Emerg Med. 1994;12(2): 151-154. Brain dead donors due to poisoning could be another 6. Lopez-Navidad A, Caballero F, Gonzalez-Segura C, Cabrer C, Frutos 2 MA. Short- and long-term success of organs transplanted from source of organ donations. We suggest that organ acute methanol poisoned donors. Clin Transplant. 2002;16(3):151- transplant centers consider brain dead patients 162. with poisoning for possible organ donation. Donors 7. Caballero F, Lopez-Navidad A, Cotorruelo J, Txoperena G. Ecstasy- induced brain death and acute hepatocellular failure: multiorgan with brain death after methanol poisoning should donor and liver transplantation. Transplantation. 2002;74(4):532- especially be considered for kidney donations. 537. 8. Barceloux DG, Bond GR, Krenzelok EP, Cooper H, Vale JA, American Academy of Clinical Toxicology Ad Hoc Committee on the References Treatment Guidelines for Methanol P. American Academy of Clinical Toxicology practice guidelines on the treatment of 1. Hantson P. Organ donation after fatal acute poisoning. J Toxicol methanol poisoning. J Toxicol Clin Toxicol. 2002;40(4):415-446. Clin Toxicol. 2002;40:301-303. 9. Friedlaender MM, Rosenmann E, Rubinger D, et al. Successful renal 2. Wood DM, Dargan PI, Jones AL. Poisoned patients as potential transplantation from two donors with methanol intoxication. organ donors: postal survey of transplant centres and intensive Transplantation. 1996;61(10):1549-1552. care units. Crit Care. 2003;7(2):147-154. 10. Chari RS, Hemming AW, Cattral M. Successful kidney pancreas 3. Hantson P, Vekemans MC, Squifflet JP, Mahieu P. Outcome transplantation from donor with methanol intoxication. following organ removal from poisoned donors: experience with Transplantation. 1998;66(5):674-675. 12 cases and a review of the literature. Transpl Int. 1995;8(3):185- 11. Gunka I, Samlik J, Mazur M, Pokorna E, Kuman M, Kubisova M. 189. [Kidney transplantation from donors dying of methanol 4. Hantson P, Vanormelingen P, Lecomte C, et al. Fatal methanol intoxication]. Rozhl Chir. 2013;92(4):201-204. poisoning and organ donation: experience with seven cases in a single center. Transplant Proc. 2000;32(2):491-492. Case RepoRt
En Bloc Kidney Transplant From a Pediatric Donor to a Pediatric Recipient Through a Total Extraperitoneal Approach: A Case Report
Kwangho Yang,1 Dongil Kim,1 Soohong Kim,1 Hyojung Ko,1 Jaeryong Shim,1 Taebeom Lee,1 Jeho Ryu,1 Seongheon Kim,2 Byunghyun Choi1
Abstract Introduction
En bloc kidney transplant remains a technically The results of pediatric kidney transplant have 1 challenging procedure, especially in pediatric improved in the past few decades. However, en bloc transplants. The intra-abdominal approach has been kidney transplant (EBKT) remains a technically the preferred operation for very young children. challenging procedure, especially in pediatric donors However, the transverse incision could result in more and pediatric recipients.2 Pediatric patients who are on abdominal muscle damage and intra-abdominal the wait list for kidney transplant have a higher adhesions. If the extraperitoneal approach, which is the probability of transplant from pediatric deceased standard method for adult kidney transplant, could be donors because of changes in the allocation system in performed in pediatric recipients, then adverse Korea since October 2018. Therefore, the likelihood of effects after a transverse incision could be avoided. A EBKT from pediatric donors to pediatric recipients 30-month-old female recipient (13.1 kg) underwent an en bloc kidney transplant from a 36-month-old female has increased. Traditionally, transverse incision was donor (13.3 kg) who had cardiac arrest of unknown preferred over midline incision for infants and origin. The kidneys were retrieved with the en bloc younger children, even though the transverse technique using a bladder patch. A right Gibson incision incision could result greater severity of abdominal was made along the lateral fascia of the rectus muscle of muscle damage.3 Moreover, the transperitoneal the recipient to prevent muscle fiber damage. The approach is often selected for EBKT in pediatric inferior vena cava and aorta of the donor were patients, especially when the patient’s body weight is anastomosed to the inferior vena cava and right less than 20 kg.4 The transperitoneal approach has common iliac artery of the recipient, respectively. The been considered advantageous, as it allows sufficient bladder patch with 2 ureteral openings was directly space for dual kidney grafts. Nevertheless, because anastomosed to the bladder of the recipient. Urination was excellent immediately after the operation. The all kidney transplant procedures are performed in recipient recovered quickly. The total extraperitoneal the retroperitoneal space, the total extraperitoneal approach is feasible and has some advantages over the approach (as in adult kidney transplant) remains an transverse incision, even in pediatric recipients. important option by which to reduce the risk of muscle injury and other adverse effects such as intra- Key words: Abdominal muscle damage, Pediatric kidney abdominal adhesion, bleeding, and delayed transplant detection of urinary leakage.
From the 1Department of Surgery, Pusan National University Yangsan Hospital, Pusan Case Report National University School of Medicine; and the 2Department of Pediatrics, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Korea Acknowledgements: The authors have not received any funding or grants in support of the This report was approved by the Institutional Review presented research or for the preparation of this work and have no further declarations of potential interest. We thank Dr. Rune Horneland, a transplant surgeon at Oslo University Hospital in Board (approval No. 05-2020-116). Norway, who recommended this technique to us for the pediatric kidney transplant. Dr. Horneland performs this same technique as a chief surgeon of the pediatric transplant unit at his hospital. Corresponding author: Byung Hyun Choi, Department of Surgery, Yangsan Busan National Deceased donor and bench procedure Univ. Hospital, Beomeo-ri, Mulgeum-eup, Yangsan-si, Gyeongsangnam-do, Korea A 36-month-old female patient with no medical Phone: +82 55 360 2478 E-mail: [email protected] history of disease was referred to the emergency
Experimental and Clinical Transplantation (2020) 7: 834-837 room to treat sudden cardiac arrest. The pulse was
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recovered after resuscitation; however, ischemic normal saline) was administered at 30 mL every 4 brain damage was exaggerated, resulting in brain hours (without Foley catheter clamping) directly to death. Her height was 110 cm, and her weight was the bladder to resolve the hematoma, which 13.3 kg. Only the kidneys were allocated for disappeared after 5 days. transplant. En bloc kidney grafts were retrieved with However, ascites of unknown origin with mild a bladder patch that included the openings of the elevation of liver enzyme occurred; therefore, ureters. The grafts weighed 127 g each. ultrasonography-guided ascites aspiration was We performed the standard bench procedure for performed. The creatinine level of ascites was very EBKT. All lumbar arteries were ligated, and the low (< 0.1 mg/dL); therefore, urinary leakage to the upper openings of the aorta and inferior vena cava abdominal cavity was ruled out. Liver enzymes also (IVC) were closed with continuous sutures. Ureteral decreased thereafter. openings and remnant bladder tissue removal were confirmed. Figure 1. En Bloc Kidney Transplant Performed Through the Right Gibson Incision Recipient profile A The recipient was a 30-month-old girl under peritoneal dialysis for end-stage renal disease of unknown origin. She had no other medical diseases, except for mild developmental delay. Her height was 88 cm, and her weight was 13.1 kg. surgical procedure A right Gibson incision was attempted along the lateral border of the rectus fascia to prevent muscle fiber damage. The retroperitoneal space was secured B by gentle dissection of the perineum at the medial side. The IVC and right common iliac artery were dissected for anastomosis. The graft IVC was anastomosed to the IVC of the recipient, and the graft aorta was anastomosed to the recipient’s right common iliac artery. The cold ischemic time was 131 minutes, and the anastomotic time was 35 minutes. Urinary output was observed immediately after anastomosis. The anastomosis of the bladder patch of the graft (a) No perfusion defect was observed immediately after the perfusion. (B) En bloc kidney after bladder-to-bladder anastomosis. to the bladder of the recipient was performed by inserting a single, double J catheter. The catheter could not pass through the other ureteral opening; however, Figure 2. Serum Blood Urea Nitrogen and Creatinine Level During Admission the urination was excellent. Therefore, the catheter was not forcibly inserted to prevent ureteral injury. The total operation took 3.5 hours with an estimated blood loss of 150 mL (Figure 1). postoperative course Urination was normal, and the serum creatinine level was quickly normalized after transplant (Figure 2). Hematuria was observed within 3 postoperative days, and hematoma (2.4 cm × 2.2 cm × 4.3 cm) was observed in the bladder by ultrasonography. Abbreviations: BUN, blood urea nitrogen; GFR, glomerular filtration rate Therefore, urokinase (100,000 U mix to 100 mL of The level quickly normalized after the transplant and was maintained. 836 Kwangho Yang et al/Experimental and Clinical Transplantation (2020) 7: 834-837 Exp Clin Transplant
Doppler ultrasonography and mercaptoacetyl - (2 mg/kg) were started 1 day before transplant, and triglycine kidney scans were performed to evaluate mycophenolate mofetil was started after fasting the graft (Figure 3). The perfusion and spectral and then discontinued postoperatively. Diltiazem wave were within the normal range on Doppler (2 mg/kg), a calcium channel blocker, was also ultrasonography, and the uptake and excretion were administered to prevent vascular spasm intrao - also within the normal range in the mercaptoacetyl - peratively and to increase the tacrolimus level. triglycine kidney scan. Discussion Figure 3. Serum Blood Urea Nitrogen and Creatinine Level During Admission A A pediatric en bloc kidney graft compared with an adult living donor kidney for adult recipients has been shown to result in similar positive outcomes.5 However, EBKT from pediatric donor to pediatric recipient is still considered a “marginal” transplant procedure because of the technical complexity, and special considerations for pediatric recipients must be considered; such potential complications are absent in these procedures for adult recipients.2 Surgeons prefer the transverse incision for younger patients because the shape of the abdomen of younger children is circular compared with the oval shape of adults. Therefore, the transperitoneal approach is the preferred method for surgical visibility.3 In contrast, the extraperitoneal approach is the standard incision technique for kidney transplant in adult recipients.6 Because the vessels B and bladder for transplant are all located in the extraperitoneal space, the extraperitoneal approach enables surgeons to avoid the risks of adhesion or intra-abdominal organ injuries. These observations tell us that, if we have access to sufficient space to locate the graft in the extraperitoneal cavity in pediatric recipients, then the peritoneal cavity need not be opened. According to our experience, the space was sufficiently larger than the space made through an intra-abdominal approach. Moreover, we expect this approach to provide a better view for graft biopsy. We had always thought that the transperitoneal approach was better than the extraperitoneal (a) The spectral wave was normal, and the resistive index ratio was within the normal range on Doppler ultrasonography. (B) The perfusion and approach in pediatric patients. Therefore, we excretion of radioactive material were easily observed in the performed all EBKT procedures on pediatric mercaptoacetyltriglycine kidney scan. recipients using the transperitoneal approach. The transperitoneal approach has a benefit in native Immunosuppressants nephrectomy, which is frequently requested by We used the standard steroid-based immunosup - pediatric nephrologists. However, in this case, there pressant protocol, including basiliximab induction was no need for nephrectomy because the patient did (10 mg on the day of operation and on postoperative not have a typical pediatric body shape, and the day 4), tacrolimus, and mycophenolate mofetil. longitudinal distance was sufficient. Therefore, we Tacrolimus (0.1 mg/kg every 12 h) and corticosteroid chose the extraperitoneal approach. Kwangho Yang et al/Experimental and Clinical Transplantation (2020) 7: 834-837 837
Another advantage of the total extraperitoneal difficulty. Furthermore, the method is more advan - approach was observed in this case. Large volume tageous than the intra-abdominal approach. ascites of unknown origin occurred after drain removal; however, the ascites was not caused by References kidney grafts because the grafts were totally 1. Verghese PS. Pediatric kidney transplantation: a historical review. separated by the peritoneal membrane, as confirmed Pediatr Res. 2017;81(1-2):259-264. doi:10.1038/pr.2016.207 in the ascitic fluid analysis. If transverse incision had 2. Afanetti M, Niaudet P, Niel O, Saint Faust M, Cochat P, Berard E. Pediatric en bloc kidney transplantation into pediatric recipients: been made as usual, then the drain could not have the French experience. Pediatr Transplant. 2012;16(2):183-186. been removed until the complete disappearance of doi:10.1111/j.1399-3046.2012.01654.x ascites. 3. Lloyd DA. Abdominal surgery: general principle of access. In: Spitz L, Coran AG, eds. Operative Pediatric Surgery. 6th ed. Hodder However, surgeons should remain aware that Arnold; 2006. pediatric kidney recipients have a higher risk of other 4. Hebert SA, Swinford RD, Hall DR, Au JK, Bynon JS. Special considerations in pediatric kidney transplantation. Adv Chronic concurrent abdominal diseases, which could increase Kidney Dis. 2017;24(6):398-404. doi:10.1053/j.ackd.2017.09.009 the likelihood of other types of abdominal surgeries 5. Sureshkumar KK, Habbach A, Tang A, Chopra B. Long-term during their lifetimes.4 Therefore, the intra-abdo - outcomes of pediatric en bloc compared to living donor kidney transplantation: a single-center experience with 25 years follow- minal cavity must be preserved, intact without up. Transplantation. 2018;102(5):e245-e248. doi:10.1097/TP.000 adhesion, if possible. 0000000002104 6. Park SC, Kim SD, Kim JI, Moon IS. Minimal skin incision in living In conclusion, the total extraperitoneal approach kidney transplantation. Transplant Proc. 2008;40(7):2347-2348. for pediatric EBKT to a pediatric recipient is a feasible doi:10.1016/j.transproceed.2008.07.028 surgical procedure without increasing the surgical Case RepoRt
Pediatric Pure Red Cell Aplasia Caused by Tacrolimus After Living-Donor Liver Transplant
Suguru Watanabe, Rieko Sakamoto, Hidekazu Yamamoto, Masayuki Imaya, Takahiro Yamashita, Tadashi Anann, Kimitoshi Nakamura
Abstract transplant, clinicians should consider switching from tacrolimus to another immunosuppressant.
Pure red cell aplasia is a relatively rare disease Key words: characterized by selective suppression of erythroid Anemia, Hypoplasia, Immunosuppression
precursors in the bone marrow. This disease can also Introduction develop secondary to several other diseases and as a side effect of certain drugs. Tacrolimus, a potent Pure red cell aplasia (PRCA) is a relatively rare immunosuppressant, is widely used in organ trans - disease characterized by selective suppression of plant. Several cases of pure red cell aplasia due to erythroid precursors in the bone marrow. Pure red tacrolimus administration in organ transplant recipients have been reported. Here, we report a case of reversible cell aplasia is clinically manifested by normocytic, pure red cell aplasia that developed during tacrolimus normochromic anemia, low red blood cell (RBC) therapy following living-donor liver transplant. The counts, normal leukocyte and thrombocyte counts, patient, a 1-year-old girl diagnosed with progressive and lack of erythroblasts in the bone marrow. This familial intrahepatic cholestasis type II, underwent disease can also develop secondary to lymphoma, living-donor liver transplant when she was 10 months thymoma, viral infection, malignancy, rheumatoid old. She was started on 3 immunosuppressants disease, and drug side effects. Some medications, posttransplant: tacrolimus (0.1 mg/kg/day twice such as diphenylhydantoin, azathioprine, and daily), mycophenolate mofetil, and prednisolone isoniazid, have been suspected to cause PRCA.1 (0.2 mg/kg/day). One year after transplant, she Tacrolimus, a potent immunosuppressant, is developed severe progressive anemia. Her hemoglobin concentration was extremely low (5.4 g/dL). A bone widely used in organ transplant, but its hematologic marrow biopsy revealed severe hypoplasia of the toxicity has not been adequately evaluated. There erythroblasts with no abnormality of other myelocytes. have been previous reports of PRCA due to These findings were suggestive of pure red cell aplasia; tacrolimus administration in organ transplant we suspected that tacrolimus had caused this based on recipients.2-5 Here, we report a case of reversible similar previous cases of tacrolimus-associated pure PRCA that developed during tacrolimus therapy red cell aplasia. Accordingly, tacrolimus was switched following living-donor liver transplant. to cyclosporine after this diagnosis. One week after this switch, the patient’s red blood cell counts, Case Report reticulocytes, and hemoglobin concentration increased.
Although tacrolimus is considered to have no significant potential for myelosuppression, cases of Written informed consent had been obtained from tacrolimus-related pure red cell aplasia have occurred. the parents of the patient. The patient, a 1-year-old In patients who develop pure red cell aplasia during girl diagnosed with progressive familial intrahepatic tacrolimus treatment following living-donor liver cholestasis type II, underwent living-donor liver transplant when she was 10 months old. The From the Department of Pediatrics, Kumamoto University, Kumamoto, Japan Acknowledgements: The authors have no sources of funding for this study and have no conflicts blood typing was identical, and recovery was of interest to declare. uneventful. She was started on 3 immunosuppressants Corresponding author: Rieko Sakamoto, 1-1-1 Honjo Chuo-ku, Kumamoto-shi, Kumamoto- ken, 860-0811 Japan post transplant: tacrolimus (0.1 mg/kg/day twice Phone: +81 96 373 5191 E-mail: [email protected] daily), mycophenolate mofetil, and prednisolone
Experimental and Clinical Transplantation (2020) 7: 838-841 (0.2 mg/kg/day). Her blood tacrolimus levels
Copyright © Başkent University 2020 DoI: 10.6002/ect.2019.0075 Printed in Turkey. All Rights Reserved. Suguru Watanabe et al/Experimental and Clinical Transplantation (2020) 7: 838-841 839
remained in the normal range (5-10 ng/mL) At 1 month after admission, her anemia did throughout treatment. not improve, and she needed 2 units of packed One year after transplant, she developed severe RBC transfusions every few weeks to maintain a progressive anemia. Her hemoglobin concentration hemoglobin concentration of > 8.0 mg/dL. Because was extremely low (5.4 g/dL), but leukocyte and we suspected that the anemia was caused by platelet counts were normal. She was transfused 1 a bone marrow function disorder, a bone marrow unit of packed RBCs. After a few days, she was biopsy was performed 1.5 months after hospital admitted to our hospital for diagnostic investigation admission. and treatment. Mycophenolate mofetil, acyclovir, The bone marrow biopsy revealed severe and sulfamethoxazole trimethoprim were stopped hypoplasia of the erythroblasts with no abnormality because they were suspected to have induced the of other myelocytes. The findings were suggestive of anemia. Her clinical course during hospitalization is PRCA. We suspected that tacrolimus caused PRCA shown in Figure 1. based on similar previous cases of TAC-associated On admission, physical examination showed no PRCA.2-5 Accordingly, tacrolimus was switched to remarkable abnormal changes except pallor and cyclosporine after this diagnosis. diarrhea. Her hemoglobin concentration was 6.2 g/dL, One week after the switch to cyclosporine, RBC reticulocyte count was 2.6 × 103/μL, and total counts, reticulocytes, and hemoglobin concentration leukocyte and platelet counts were 5100/μL and increased. She was discharged after a 2-month 4.2 × 105/μL, respectively. Although the haptoglobin hospitalization. level was < 2 mg/dL, a peripheral blood smear examination did not indicate hemolysis, and Coombs Discussion test was negative. Erythropoietin levels were high at 140 mIU/mL. Serum iron, vitamin B12, and folic acid Pure red cell aplasia is a condition in which erythroid levels were within reference ranges, whereas ferritin precursors in the bone marrow are selectively levels were mildly elevated (226 μg/dL). Parvovirus suppressed but normal myeloid and megakaryocyte B19 DNA, Epstein-Barr virus, and cytomegalovirus maturation results are displayed. Pure red cell tests were negative. Fecal analysis and urinalysis aplasia can be inherited as a primary hematologic showed normal findings. Antinuclear antibodies and disorder or can develop secondary to lymphoma, rheumatoid factor were negative. Chest magnetic viral infections, malignancy, rheumatoid disease, and resonance imaging did not show any tumors such as drug side effects. Diphenylhydantoin, azathioprine, thymoma or lymphoma. and isoniazid have been suspected to cause PRCA.1
Figure 1. Clinical Course During Hospitalization
Abbreviations: CyA, cyclosporine; LDLT, living-donor liver transplant; PSL, prednisolone; TAC, tacrolimus 840 Suguru Watanabe et al/Experimental and Clinical Transplantation (2020) 7: 838-841 Exp Clin Transplant
Tacrolimus-induced PRCA has also been shown in tacrolimus stimulates TGF-β1 hyperexpression in patients after organ transplant. mammalian cells in a dose-dependent manner.9,10 Tacrolimus is widely used in organ transplant due Increased TGF-β signaling inhibits hematopoiesis at to its potent immunosuppressant effect. Tacrolimus the stem cell level and controls RBC differentiation. can bind to FK506-binding protein, which is Thus, PRCA may be caused by excessive TGF-β expressed on the surface of CD4-positive T cells and production induced by high tacrolimus concentrations. mediates inhibition of the gene transcription for In our patient, the tacrolimus blood level was within interleukin 2 and other transcription factors essential normal range; however, it has been reported that to early T-cell activation. Although tacrolimus is tacrolimus blood level may not be a reliable indicator considered to have no significant potential for of systemic tacrolimus exposure.11 myelosuppression, tacrolimus-related PRCA has been reported. Conclusions A MEDLINE search for articles in English published between 1990 and 2017 yielded only 7 cases A periodic blood test that includes blood imaging of tacrolimus-induced PRCA in 4 publications.2-5 The should be conducted for patients treated with main characteristics of the 7 cases are listed in Table 1. tacrolimus. In patients who develop PRCA during Two of the 7 patients were children, and 2 were tacrolimus treatment following living-donor liver male. All patients were administered prednisolone transplant, clinicians should consider switching from with tacrolimus, and tacrolimus was sequentially tacrolimus to another immunosuppressant. switched to cyclosporine after PRCA diagnosis. All patients showed complete recovery of hemoglobin References levels within a few weeks after the switch. There 1. Means RT, Jr. Pure red cell aplasia. Blood. 2016;128(21):2504- were no noted similarities with regard to tacrolimus 2509. dosing period, age of PRCA onset, and concomitant 2. Misra S, Moore TB, Ament ME, Busuttil RW, McDiarmid SV. Red cell use of medications other than prednisolone among aplasia in children on tacrolimus after liver transplantation. Transplantation. 1998;65(4):575-577. the 7 patients. Tacrolimus concentration was checked 3. Suzuki S, Osaka Y, Nakai I, et al. Pure red cell aplasia induced by in 3 patients, with 2 showing levels > 10 ng/mL. FK506. Transplantation. 1996;61(5):831-832. 4. Patil MR, Choudhury AR, Chohwanglim M, Divyaveer S, Mahajan The mechanism by which tacrolimus causes PRCA C, Pandey R. Post renal transplant pure red cell aplasia-is is unclear, and some cases could not be treated with tacrolimus a culprit? Clin Kidney J. 2016;9(4):603-605. 5. Gregoor PS, Weimar W. Tacrolimus and pure red-cell aplasia. Am J erythropoietin and granulocyte-colony stimulating Transplant. 2005;5(1):195-196. factor. In vitro studies showed that tacrolimus 6. Zhu X, Imamura M, Hashino S, et al. Enhancing and suppressive concentrations of > 10 ng/mL in 24 hours can effects of immunosuppressants cyclosporin A, FK506, and KM2210 on the colony formation of murine bone marrow cells. 6 suppress burst-forming unit-erythroid activity. These Ann Hematol. 1995;71(6):301-306. are the earliest committed erythroid progenitors and 7. Gao X, Lee HY, da Rocha EL, et al. TGF-beta inhibitors stimulate red blood cell production by enhancing self-renewal of BFU-E are defined based on their capability to produce erythroid progenitors. Blood. 2016;128(23):2637-2641. large colonies of methylcellulose-based erythroid 8. Keller JR, Mantel C, Sing GK, Ellingsworth LR, Ruscetti SK, Ruscetti FW. Transforming growth factor beta 1 selectively regulates early cells. The burst-forming unit-erythroid population is murine hematopoietic progenitors and inhibits the growth of IL- suppressed by transforming growth factor-beta 3-dependent myeloid leukemia cell lines. J Exp Med. 1988;168(2): (TGF-β).7,8 Some reports have indicated that 737-750.
table 1. Reported Cases of Pure Red Cell Aplasia Induced by Tacrolimus Study Year Sex Age Organ for Transplant Dosing Period of Concomitant Tacrolimus Tacrolimus Until Medications Concentration, Onset ng/mL Misra et al2 1998 F 16 mo Liver 8 mo PSL, co-trim, Mg 5-22.5 Misra et al2 1998 F 5 years Liver 47 mo PSL, co-trim, Mg 6.4-9.5 Suzuki et al3 1996 M 34 years Kidney 11 days PSL 5-15 Suzuki et al3 1996 F 40 years Kidney 9 mo MMF, PSL, co-trim, VGCV Patil et al4 2016 M 30 years Kidney 2 mo MMF, PSL, co-trim, VGCV Patil et al4 2016 F 35 years Kidney 40 mo PSL, MMF Gregoor and Weimar5 2005 F 20 years Kidney 1 mo MMF, PSL, co-tri, PPI Abbreviations: co-trim, co-trimoxazole; F, female; M, male; Mg, magnesium; MMF, mycophenolate mofetil; PPI, proton pump inhibitor; PSL, prednisolone; VGCV, valganciclovir Suguru Watanabe et al/Experimental and Clinical Transplantation (2020) 7: 838-841 841
9. Maluccio M, Sharma V, Lagman M, et al. Tacrolimus enhances 11. Scholten EM, Cremers SC, Schoemaker RC, et al. AUC-guided transforming growth factor-beta1 expression and promotes dosing of tacrolimus prevents progressive systemic overexposure tumor progression. Transplantation. 2003;76(3):597-602. in renal transplant recipients. Kidney Int. 2005;67(6):2440-2447. 10. Khanna A, Cairns V, Hosenpud JD. Tacrolimus induces increased expression of transforming growth factor-beta1 in mammalian lymphoid as well as nonlymphoid cells. Transplantation. 1999;67(4):614-619. Case RepoRt
Liver Transplant for Nonresectable Colorectal Cancer Liver Metastases in South Africa: A Single-Center Case Series
Jean Botha,1,2 Georgia Demetriou,1,3 June Fabian,1 Harriet Etheredge1,3
Abstract Recurrence occurred in all patients at a median time of 6 months after transplant (range, 3-13 months). Objectives: Publication in 2013 of the first Secondary Conclusions: To our knowledge, this is the only Cancer cohort study returned attention to liver published case series of patients undergoing liver transplant for nonresectable colorectal cancer, transplant for nonresectable colorectal carcinoma in demonstrating excellent outcomes for a procedure Africa and is internationally unique in its use of that was historically contraindicated. The Wits Donald expanded criteria and marginal grafts for this type of Gordon Medical Centre in Johannesburg, South Africa, transplant. Despite the use of such grafts in our hosts the largest liver transplant program in sub- recipients, thus far, these outcomes align with those of Saharan Africa. The persistent shortage of deceased the 2013 Secondary Cancer cohort studies from donor organs in our setting has compelled us to Norway. innovate solutions unique to our context, which allows us to perform as many transplants as possible and Key words: Chemotherapy, Norwegian Secondary Cancer maximize our resource utilization. Therefore, we study initiated a research study to transplant organs in Introduction patients with nonresectable colorectal carcinoma with
expanded criteria using marginal deceased donor Historically, liver transplant for colorectal metastases organs that would otherwise have been discarded. Materials and Methods: Institutional Review Board was abandoned as a therapeutic option after a series approval was obtained for this study. We used criteria of inferior outcomes during the 1990s. At the time, from the 2013 Secondary Cancer cohort study to most deaths resulted from perioperative com - determine eligibility of patients with nonresectable plications and were not due to disease recurrence. colorectal carcinoma for liver transplant. Unlike the However, over the past 2 decades, both the fields of study from 2013, we utilized expanded criteria and liver transplant and oncology have evolved, and marginal liver allografts for transplant. today, liver transplant is an established therapeutic Results: Five patients have undergone liver transplant option for primary carcinomas of the liver and liver for nonresectable colorectal carcinoma. At a median metastases from neuroendocrine tumors. These follow-up of 36 months (range, 10-52 months), 4 of the primary liver carcinomas include hepatocellular 5 (80%) patients are alive. The patient who died had progressive disease on chemotherapy pretransplant carcinoma, cholangiocarcinoma, hepatoblastoma, and was the only patient who tested positive for the and hemangioendothelioma. Secondary carcinomas Kirsten rat sarcoma viral oncogene homolog mutant. include metastases from neuroendocrine tumors.1 The recent expansion of oncological indications From the 1Wits Donald Gordon Medical Centre, Faculty of Health Sciences, University of the for liver transplant has been facilitated by an overall Witwatersrand, Johannesburg, South Africa; the 2Department of Surgery, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; and the 3Department improvement in survival from liver transplant, of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, improved diagnostic modalities to determine the Johannesburg, South Africa Acknowledgements: The authors have not received any funding or grants in support of the extent of metastatic involvement of the liver and presented research or for the preparation of this work and have no potential declarations of other organs, and improved chemotherapeutic interest. Corresponding author: June Fabian, Research Office, Wits Donald Gordon Medical Centre, 18 agents that allow for effective multimodal treatment Eton Road, Parktown, Johannesburg, South Africa, 2193 strategies to enhance patient survival.1 By defining Phone: +27 11 356 6395 E-mail: [email protected] stringent inclusion criteria for transplant candidates Experimental and Clinical Transplantation (2020) 7: 842-846 with these types of cancers, a minimum 5-year
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survival rate of 60% is achievable. Arguably, this of population-based registries prevents us from survival benchmark renders such transplants feasible establishing true incidence rates.5,6 In South Africa, the and ethically justifiable but also requires careful most recent report from the pathology-based National consideration, given the local and regional circu - Cancer Registry confirmed that CRC is the sixth most mstances of each transplant program.2 common malignancy in women and the fourth most In 2013, results from the original Norwegian common malignancy in men.7 Approximately 20% of Secondary Cancer study (SECA-I) placed liver South Africans with CRC present with advanced transplant for nonresectable colorectal carcinoma disease, primarily in the form of colorectal liver (NRCRC) back into the spotlight, challenging the metastases.8 For patients with resectable colorectal transplant community to reconsider the exclusion of liver metastases, complete resection of the liver such patients from transplant.3 The Norwegian metastases is the only treatment associated with long- SECA-I study capitalized on the unusual organ term survival. Internationally, the 5-year survival rate donor situation in Norway, where deceased donor for patients with liver resection is reported at 46% (DD) organ supply exceeds demand. It was on this versus a 5-year survival rate of 6% without liver basis that surplus DD liver grafts were implanted resection. Moreover, one-sixth of patients can into 21 patients with NRCRC who fulfilled specific expect 10-year survival after resection, if selected inclusion criteria, although these criteria were appropriately. In patients with NRCRC starting relatively broad. After transplant, the SECA-I first-line chemotherapy, 5-year survival rate is 10%, cohort demonstrated an overall 5-year survival rate and median survival after starting second-line of 60% after a median follow-up of 27 months chemotherapy is 10 to 12 months.9 (interquartile range, 8-60 months) compared with a In South Africa, outcomes of metastatic CRC are 10% rate of 5-year survival for patients on palliative congruent with those reported internationally, with a chemotherapy. 5-year survival rate after liver resection of 57%.8 The findings of the SECA-I study provided a basis However, this survival rate was reported as a subset for the Norwegian team to refine the inclusion of a larger cohort in which only 23% of patients criteria for the second study (SECA-II), which has (n = 60) presented with resectable liver metastases. recently shown improved outcomes over SECA-I, The remaining patients (77%; n = 203) presented with with a 5-year survival rate of 83% after a median NRCRC and were treated with chemotherapy alone, follow-up time of 36 months (interquartile range, and the 5-year survival rate was between 10% and 5-60 months). Both SECA studies reported disease 15%.8 Hence, prognosis for patients with NRCRC is recurrence after liver transplant; however, the rates dismal, both locally and internationally. of recurrence differed substantially. The SECA-I The Transplant Unit at Wits Donald Gordon study demonstrated a recurrence rate of 90% in Medical Centre in Johannesburg, South Africa, was patients (19/21). With more stringent inclusion established in 2004 and has achieved acceptable criteria, recurrence rate in the SECA-II cohort outcomes over a relatively short time. The most dropped to 33% (5/15). Most recurrences were recent annual report showed an overall unadjusted resectable pulmonary metastases, and both SECA recipient survival rate at 1 year of 83% (95% CI, 74% studies demonstrated disease-free survival after to 89%) and at 3 years of 75% (95% CI, 65% to 83%). surgery for recurrent disease. Although the results of In contrast to the organ-replete milieu of the the SECA-I and SECA-II studies are promising, the Norwegian SECA studies, severe organ shortages consensus in the scientific community is that further persist in South Africa, with lower DD rates than most studies in diverse patient cohorts are needed to other countries with transplant programs. To address validate these findings before endorsing NRCRC as organ shortages, our transplant unit performs split an indication for liver transplant, particularly in liver grafts whenever possible, and we have transplants programs with DD organ shortages.4 introduced an adult living donor liver transplant Colorectal cancer (CRC) is one of the most program that is still in its early stages. Despite organ common malignancies in high-income countries, and shortages, two-thirds of our adults on the wait list approximately half of those affected develop liver are transplanted within 60 days of listing.10 Although metastases. In sub-Saharan Africa, the incidence of these numbers may seem counterintuitive, these CRC appears to be increasing, but the absence results may be affected by the lack of access to 844 Jean Botha et al/Experimental and Clinical Transplantation (2020) 7: 842-846 Exp Clin Transplant
appropriate specialist care centers, the low referral exclude interval development of extrahepatic rates for those with end-stage liver disease, and an malignant disease. overall relatively low number of transplants in South At the time of transplant, standard immuno - Africa. Although we perform liver transplant for the suppression was administered and comprised previously mentioned oncological indications, this intraoperative methylprednisolone and, from post - report describes our first experience of liver transplant day 1, combination oral prednisone, transplant in a case series of South African patients mycophenolate mofetil, and tacrolimus (targeted to with NRCRC. levels 10-15 μmol/L, for the first 6 weeks after In 2016, we were approached by a colleague with transplant). Tacrolimus was then substituted for NRCRC who was eligible for liver transplant everolimus (targeted to levels of 5-8 μmol/L), and according to the SECA-I criteria. Given our pervasive oral corticosteroids were withdrawn within 6 DD organ shortage and the fact that NRCRC is not months. Patients who received an ABO incompatible an established transplant indication, we approached (ABOi) allograft additionally underwent a course of our Institutional Review Board for permission to plasma exchange until the relevant isoagglutinin perform a transplant for this patient with one levels were less than a ratio of 1:4, and this was proviso: we would not compromise wait list status followed by 2 doses of rituximab, 1 week apart. The of patients with recognized indications for liver study protocol conformed to the ethical guidelines of transplant. The only way we could achieve this would the 2013 Declaration of Helsinki. be to transplant a DD organ that would otherwise have been discarded. After extensive deliberation, Results our Institutional Review Board approved these transplants, with the conditions that the staged patient overview research study was subjected to careful oversight and Five patients who met the inclusion criteria that each recipient was fully aware of the organ underwent liver transplant for NRCRC in this series. allocation process.11 We were permitted to undertake An overview of patient demographics and clinical the first case (approval number M151137), and, after profiles can be found in Table 1. The median time providing our results to the Institutional Review from resection of the primary tumor to transplant Board, we subsequently received permission to was 14 months (interquartile range, 5-53 months). perform a further 4 cases, all of which are detailed According to the TNM Classification of Malignant in the present report. Given our outcomes, our Tumors standard for stages of a primary tumor, 4 of Institutional Review Board approved this program the 5 patients had T3 tumors. One patient was staged as an ongoing research study in our Transplant Unit, as T0, after completion of first-line chemotherapy. In the first of its kind in sub-Saharan Africa. Because all 5 patients, the liver metastases were diagnosed at this was a research project, patients were required to the same time as, or within 12 months of, the primary undergo a research information process and to colorectal tumor, hence designated as synchronous provide research-related consent, over and above lesions. standard transplant consent procedures. Donor overview Materials and Methods All of the liver allografts for this series were procured from deceased adult donors. No living donor We used the SECA-I criteria to determine eligibility of allografts were used. South African has an “opt-in” patients with NRCRC: hepatic-only CRC metastases policy for organ donation, and consent was obtained confirmed by magnetic resonance imaging, computed for the donor next-of-kin in all cases. All donors were tomography scan, and fluorodeoxyglucose positron diagnosed with brainstem death, as donation after emission tomography scan; prior resection of the circulatory death is not widely practiced in South primary tumor; completion of, at least, first-line Africa. chemotherapy; and fulfillment of the standard criteria for liver transplant at our center. At the time of the Clinical outcome transplant procedure, repeat computed tomography At a median follow-up of 38 months (range, 10-54 scans of chest and abdomen were performed to months), 4 of the 5 patients (80%) were alive (Figure 1). Jean Botha et al/Experimental and Clinical Transplantation (2020) 7: 842-846 845
table 1. Patient Demographics and Clinical Profile Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Age 62 67 36 59 35 Sex Male Male Male Male Female Primary tumor Locatıon Sigmoid Rectum Rectum Colon Sigmoid TNM stage T0, N0 T3, N0 T3, N0 T3, N1 T3, N2 Interval to transplant, mo 5 53 5 14 31 KRAS Wild Wild Wild Mutant Wild Chemotherapy 1st line FOLFOX FOLFOX + Bev FOLFOXIRI + Bev FOLFOX FOLFOX + Cetux 2nd line FOLFIRI + Cetux FOLFIRI + Bev FOLFIRI + Cetux FOLFIRI + Bev Capecitabine + Cetux 3rd line Capecitabine Response Yes Yes Yes No Yes CEA at transplant 14 356 1 4 8 Liver resection No No No Yes × 2 Yes × 2 RFA or SIRT RFA and SIRT RFA Hepatic tumor No. of lesions 15 3 5 10 8 Diameter largest, cm > 5 < 5 > 5 > 5 > 5 Time Sync Sync Sync Sync Sync Fong score12 4 3 3 4 4 Liver graft type Deceased Deceased Deceased Deceased Deceased ECD Type 75-yr-old donor ABOi > 40% steatosis ABOi ABOi Abbreviations: ABOi, ABO incompatible; Bev, bevacizumab; CEA, carcinoembryonic antigen; Cetux, cetuximab; ECD, expanded criteria donor (ie, a deceased donor graft that increases the risk of early graft failure, or inferior graft and recipient survival compared with an ideal graft); FOLFIRI, folinic acid, fluorouracil, and irinotecan combination regimen; FOLFOX, folinic acid, fluorouracil, and oxaliplatin combination regimen; FOLFOXIRI, folinic acid, fluorouracil, oxaliplatin, and irinotecan combination regimen; Fong score,12 a clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer; KRAS, Kirsten rat sarcoma viral oncogene homolog; RFA, radio-frequency ablation; Sync, synchronous lesion (liver metastases diagnosed at the same time or within 12 months of the primary colorectal tumor); SIRT, selective internal radiation therapy; TNM, the TNM Classification of Malignant Tumors standard for stages of a primary tumor
The patient who died had progressive disease on months). Pulmonary recurrence occurred in 3 chemotherapy pretransplant and was the only patients, of which 2 had subsequently undergone patient who tested positive for the Kirsten rat pulmonary resections and are presently free of sarcoma viral oncogene homolog (KRAS) mutant. disease. The remaining patient is on chemotherapy. Prior to transplant, this patient had undergone 2 liver One patient developed paraaortic lymph node resections complicated by bleeding, which made the recurrence, as detected on routine computed assessment of extrahepatic disease at the time of tomography scan, and is presently undergoing transplant difficult. The patient subsequently chemotherapy. developed rapid recurrence of disease and died 10 months after transplant. Discussion
Figure 1. Survival of Nonresectable Colorectal Carcinoma Orthotopic Liver To the best of our knowledge, this is the only Transplant published case series of patients undergoing liver transplant for NRCRC in Africa. Despite the use of organs that would otherwise have been discarded, thus far, the outcomes we achieved align with those in the SECA studies from Norway. It is notable that 2 of our recipients received a marginal graft (one graft was retrieved from a 75-year-old donor, and the other graft showed more than 40% macrovesicular steatosis). The remaining 3 recipients received ABOi grafts, and all 3 of these Abbreviations: DFS, disease-free survival; NRCRC, nonresectable colorectal carcinoma; OLTx, orthotopic liver transplantation; Txp, transplant recipients were alive at the time of writing. Additionally, none of the recipients of an ABOi graft Colorectal cancer recurrence after transplant has developed antibody-mediated rejection. Recurrence of CRC occurred in all patients at a In many Asian countries, ABOi living donation median time of 6 months after transplant (range, 3-13 has been a successful alternative to DD donation in 846 Jean Botha et al/Experimental and Clinical Transplantation (2020) 7: 842-846 Exp Clin Transplant
the face of extreme DD shortages. Antithetically, 3. Hagness M, Foss A, Line PD, et al. Liver transplantation for nonresectable liver metastases from colorectal cancer. Ann Surg. countries such as the United States discourage ABOi 2013;257(5):800-806. doi:10.1097/SLA.0b013e3182823957 transplants because outcomes may not be equivalent 4. Line PD, Hagness M, Dueland S. The potential role of liver transplantation as a treatment option in colorectal liver to ABO-compatible transplants, and this may also metastases. Can J Gastroenterol Hepatol. 2018;2018:8547940. reflect a clinical practice attuned to a more readily doi:10.1155/2018/8547940 available pool of compatible DD grafts. Moreover, 5. Bray F, Soerjomataram I. The changing global burden of cancer: transitions in human development and implications for cancer the United States has the capacity to rapidly procure prevention and control. In: Gelband H, Jha P, Sankaranarayanan matching DD organs across a sharing network R, Horton S, eds. Cancer: Disease Control Priorities. 3rd ed. The International Bank for Reconstruction and Development/The supported by excellent infrastructure. World Bank; 2015. Accessed March 15, 2019. http://www.ncbi.nlm. In our setting, given the proviso that we only use nih.gov/books/NBK343643 grafts that would otherwise be discarded, ABOi DD 6. Bray F, Jemal A, Grey N, Ferlay J, Forman D. Global cancer transitions according to the Human Development Index (2008- transplant is a likely consequence for our patients 2030): a population-based study. Lancet Oncol. 2012;13(8):790- with extended oncological indications for liver 801. doi:10.1016/S1470-2045(12)70211-5 7. National Institute for Communicable Diseases. Summary statistics transplant, such as NRCRC. of cancer diagnosed histologically in 2014. Accessed August 1, In this small proof-of-concept case series, survival 2020. https://www.nicd.ac.za/wp-content/uploads/2017/03/ 2014-NCR-tables-1.pdf exceeded that of palliative chemotherapy. Going 8. Brand M, Gaylard P, Ramos J. Colorectal cancer in South Africa: an forward, we plan to adapt our program to fit the assessment of disease presentation, treatment pathways and 5- SECA-II inclusion criteria, and we will continue to year survival. S Afr Med J. 2018;108(2):118-122. doi:10.7196/SAMJ. 2017.v108i2.12338 carefully monitor our outcomes. Ultimately, we hope 9. Dueland S, Guren TK, Hagness M, et al. Chemotherapy or liver that this strategy, as well as the use of selection criteria transplantation for nonresectable liver metastases from colorectal cancer? Ann Surg. 2015;261(5):956-960. doi:10.1097/SLA.00000 like those used in transplant for hepatocellular 00000000786 carcinoma, cholangiocarcinoma, and neuroendocrine 10. Fabian J, Loveland J, Maher H, et al. Wits Transplant Annual Data Report 2018 Adult and Paediatric Liver Transplantation. Wits J Clin metastases, may provide long-term survival com - Med. 2019;1:109-121. 10.18772/26180197.2019.v1n3a2 parable to standard indications for liver transplant. 11. Etheredge HR, Botha J, Cleaton-Jones P. Liver transplantation for non-resectable colorectal liver metastases at a single centre in South Africa: a report of the ethics and regulatory approval References process. S Afr J Bioethics Law. 2017;10(1):5-7. 12. Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score 1. Foss A, Adam R, Dueland S. Liver transplantation for colorectal for predicting recurrence after hepatic resection for metastatic liver metastases: revisiting the concept. Transpl Int. 2010;23(7):679- colorectal cancer: analysis of 1001 consecutive cases. Ann Surg. 685. doi:10.1111/j.1432-2277.2010.01097.x 1999;230(3):309-318. doi:10.1097/00000658-199909000-00004 2. Mazzaferro V, Battiston C, Sposito C. Pro (with caution): extended oncologic indications in liver transplantation. Liver Transpl. 2018;24(1):98-103. doi:10.1002/lt.24963 Case RepoRt
Role of Fluorodeoxyglucose Positron Emission Tomogram Scan in Sirolimus-Induced Lung Toxicity: A Rare Case Report
Sarfraz Saleemi,1 Bader Alothman,1 Faisal Albaiz,1 Sami Alrasheedi,1 Yaser Z. Shah,2 Aman Saleemi3
Abstract Key words: Computed tomography scan, FDG-PET scan, Pneumonitis, Transplant Lung toxicity is a rare but serious side effect of Introduction sirolimus, a mammalian target of rapamycin inhibitor used as an immunosuppressive agent in solid-organ transplant recipients. We report a case of 67-year-old Sirolimus is a potent immunosuppressive agent that man who had living-related renal transplant 12 years works as a mammalian target of rapamycin (mTOR) previously that was complicated by chronic allograft inhibitor. It is widely used in solid-organ transplant dysfunction. He presented with fever, cough, and recipients to prevent graft rejection and to avoid shortness of breath, and his chest imaging showed possible side effects associated with other immuno - bilateral patchy and ground glass opacities. Before suppressive therapies.1 However, there have been symptoms of lung toxicity, the patient’s sirolimus levels rare but serious pulmonary adverse events reported were in the range of high normal. Bronchoalveolar that are related to sirolimus use.2,3 The patient lavage ruled out infection, and a transbronchial biopsy usually presents with dry cough, fever, and was inconclusive. A fluorodeoxyglucose positron dyspnea.4 Chest imaging does not show any specific emission tomogram scan showed high uptake in the area of lung opacities with a standard uptake value of pattern. It may include interstitial changes and areas 4.7. His symptoms improved after he was switched from of patchy or ground-glass opacities. The diagnosis is sirolimus to tacrolimus, and a thoracic computed made after exclusion of infection, autoimmune, and tomography scan after 6 weeks showed complete toxic causes. Treatment is mainly discontinuation of resolution. Pulmonary toxicity should be considered sirolimus. Reducing the dose of sirolimus concomitant in any patient on sirolimus with respiratory symptoms with use of steroids has shown success in resolving and opacities on chest imaging. The role of the pneumonitis. The role of fluorodeoxyglucose fluorodeoxyglucose positron emission tomogram scan positron emission tomogram (FDG-PET) scans in the in evaluation of sirolimus-induced lung toxicity has assessment of sirolimus-induced lung toxicity has not been previously described, and this is the first not been described in the literature. report of this type of scan finding indicating intense inflammation in this condition. We report a case of sirolimus toxicity with its clinical and radiological features, diagnostic work- From the 1Section of Pulmonary Medicine, Department of Medicine, King Faisal Specialist, up, FDG-PET features, and management. Hospital & Research Center, Riyadh, Saudi Arabia; the 2Section of Adult Transplant Nephrology, Organ Transplant Center, King Faisal Specialist, Hospital & Research Center, Riyadh, Saudi Arabia; and the 3University of Medicine and Health Sciences, St. Kitts Case Report Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest. Author contributions are as follows: S. Saleemi provided concept and design A 67-year-old man, who had living-related kidney and draft preparation; B. Alothman and F. Albaiz collected data and provided draft review; S. transplant donated from his daughter for end-stage Alrasheedi and Y. Z. Shah provided draft review and revision for important intellectual contents; A. Saleemi provided draft and image editing and formatting and graph preparation; all authors renal disease due to diabetes and hypertension 12 have read and approved the manuscript. years previously, presented with fever, cough, and Corresponding author: Sarfraz Saleemi, Section of Pulmonary Medicine, Department of Medicine MBC 46, King Faisal Specialist, Hospital & Research Center, Riyadh 11211, PO Box exertional dyspnea. He was initially prescribed 3354, Saudi Arabia tacrolimus and mycophenolate; however, because of Phone: +966 503194569 E-mail: [email protected] complications of chronic allograft dysfunction, Experimental and Clinical Transplantation (2020) 7: 847-850 tacrolimus was changed to sirolimus. His sirolimus
Copyright © Başkent University 2020 DoI: 10.6002/ect.2020.0306 Printed in Turkey. All Rights Reserved. 848 Sarfraz Saleemi et al/Experimental and Clinical Transplantation (2020) 7: 847-850 Exp Clin Transplant
levels had been stable until a few weeks before densities (Figure 1A). Sputum culture was negative. presentation, when levels were at a higher therapeutic Empirical broad-spectrum antibiotics did not show range. clinical or radiological response. An FDG-PET scan On examination, he had tachypnea and his showed increased uptake in the area of lung opacities oxygen saturation was 87% breathing room air. with standard uptake value of 4.7, indicating intense Auscultation of chest revealed basal fine crackles. inflammation (Figure 2). Laboratory data showed normal white blood cell Bronchoscopy, bronchoalveolar lavage, and count but elevated C-reactive protein. A chest transbronchial biopsy were performed. Cell count radiography and computed tomography (CT) scan in lavage fluid showed 54% neutrophils, 12% showed multiple areas of ground glass and patchy lymphocytes, 14% monocytes, 3% eosinophils, and
Figure 1. Computed Tomography Scan Results
(a) Lung opacities. (B) Resolved lung opacities after sirolimus discontinuation.
Figure 2. Fluorodeoxyglucose Positron Emission Tomogram Results
(a) Axial view, showing fluorodeoxyglucose uptake in the areas of lung opacities (arrows). (B) Coronal view. Sarfraz Saleemi et al/Experimental and Clinical Transplantation (2020) 7: 847-850 849
5% lining cells. The fluid was negative for bacterial, proliferation of T cells and B cells and blocks the fungal, and mycobacterial cultures. Cytology was activation of specific protein kinase, causing arrest of negative for malignant cells, and special stains for acid cell cycle in G1 phase. It has antiatherogenic and fast bacillus and fungus were negative. There was no antineoplastic characteristics that promote evidence of virus cytopathy. Bronchoalveolar lavage immunologic tolerance, reducing the incidence of aspergillus galactomannan test was negative. No chronic allograft nephropathy. The lack of acute or evidence of virus or atypical bacteria was observed by chronic nephrotoxicity has given this drug an multiplex polymerase chain reaction. A serum advantage over calcineurin inhibitors. The most TB-QuantiFERON test was nonreactive. Possibility common side effects of sirolimus are hyperlipidemia of posttransplant lymphoproliferative disorders and myelosuppression, but other side effects such as was suggested, but there was no evidence on impaired wound healing, edema, thrombotic transbronchial biopsy. Transbronchial biopsy showed microangiopathy, and pneumonitis have been alveolated lung tissue with infiltration of foamy reported.6 Although rare, sirolimus can cause serious macrophages and no evidence of malignant cells. pulmonary toxicity. Patients usually present with Epstein-Barr virus by in situ hybridization was nonspecific symptoms, including fever, cough, negative. shortness of breath, and fatigue. Serum sirolimus level was 8.5 ng/mL (therapeutic There are no specific radiologic and pathologic range, 4-11.9 ng/mL). Sirolimus levels in the findings in sirolimus lung toxicity.7 Chest imaging weeks preceding admission for symptoms of lung features of ground glass and interstitial opacities toxicity were in the range of high normal (Figure 3A). have been described. Lung biopsy features of After infections were ruled out, he was diagnosed organizing pneumonia, interstitial pneumonitis, focal to have sirolimus-induced lung injury. Sirolimus necrotizing vasculitis, and nonspecific granulomatous was discontinued and switched to tacrolimus. inflammation have also been shown. Bronchoalveolar The patient continued to show clinical improvement, lavage is mostly lymphocytic, and it is a useful and his oxygen saturation became normal. procedure to rule out infection.8 On follow-up after 6 weeks, the patient was The diagnosis is mostly of exclusion, and clinical asymptomatic. A chest CT scan showed complete and radiological improvement after discontinuation resolution of lung opacities (Figure 1B), and of drug is confirmatory.9 There is no role of steroids C-reactive protein level returned to normal in sirolimus lung toxicity except in patients who (Figure 3B). develop diffuse alveolar damage. Several risk factors have been speculated in the Discussion development of lung toxicity, including initial loading dose, late switch to sirolimus, recent increase in dose, Sirolimus is a potent immunosuppressive agent used serum level, allograft dysfunction, hypervolemia, in solid-organ transplant recipients. It is produced by older age, male sex, and concomitant immunosup - a strain of Streptomyces hygroscopicus and is an mTOR pressive treatment.10 There is no relation to the inhibitor.5 It is also an inhibitor of antigen-induced duration of sirolimus use.
Figure 3. Sirolimus (a) and C-Reactive Protein (B) Levels 850 Sarfraz Saleemi et al/Experimental and Clinical Transplantation (2020) 7: 847-850 Exp Clin Transplant
The pathophysiological mechanism of pneumonitis 2. Sola E, Lopez V, Burgos D, et al. Pulmonary toxicity associated with sirolimus treatment in kidney transplantation. Transplant Proc. is not well understood. It is thought that an 2006;38(8):2438-2440. doi:10.1016/j.transproceed.2006.08.037 autoimmune response probably plays a part. In 3. Singh U, Gupta A, Jasuja S. Sirolimus-induced pneumonitis. Indian J Nephrol. 2009;19(2):80-81. doi:10.4103/0971-4065.53329 addition, delayed hypersensitivity and idiosyncratic 4. Pham PT, Pham PC, Danovitch GM, et al. Sirolimus-associated mechanism may have roles in some patients.11 pulmonary toxicity. Transplantation. 2004;77(8):1215-1220. doi:10. The role of FDG-PET scan in the assessment of 1097/01.tp.0000118413.92211.b6 5. Sehgal SN. Sirolimus: its discovery, biological properties, and patients with suspected sirolimus lung toxicity has mechanism of action. Transplant Proc. 2003;35(3 Suppl):7S-14S. not been reported. A high standard uptake value on doi:10.1016/s0041-1345(03)00211-2 6. Augustine JJ, Bodziak KA, Hricik DE. Use of sirolimus in solid organ FDG-PET scan can indicate intense inflammation in transplantation. Drugs. 2007;67(3):369-391. doi:10.2165/00003495- lung parenchyma and may explain high levels of C- 200767030-00004 reactive protein. 7. Champion L, Stern M, Israël-Biet D, et al. Brief communication: sirolimus-associated pneumonitis: 24 cases in renal transplant recipients. Ann Intern Med. 2006;144(7):505 doi:10.7326/0003- Conclusions 4819-144-7-200604040-00009 8. Chhajed PN, Dickenmann M, Bubendorf L, Mayr M, Steiger J, Tamm M. Patterns of pulmonary complications associated with Pulmonary complications of sirolimus should be sirolimus. Respiration. 2006;73(3):367-374. doi:10.1159/000087945 9. Alkhunaizi AM, Al-Khouzaie TH, Alsagheir AI. Sirolimus-induced considered in any patient with solid-organ transplant interstitial lung disease and resolution after conversion to on sirolimus who presents with respiratory symptoms everolimus. Resp Med Case Rep. 2020;30:101109. doi: and chest imaging abnormalities, especially interstitial 10.1016/j.rmcr.2020.101109 10. Morath C, Schwenger V, Ksoll-Rudek D, et al. Four cases of and ground glass opacities. An FDG-PET scan may sirolimus-associated interstitial pneumonitis: identification of risk play a role in identifying pneumonitis induced by factors. Transplant Proc. 2007;39(1):99 doi:10.1016/j.transproceed. 2006.10.219 sirolimus. 11. Morelon E, Stern M, Israël-Biet D, et al. Characteristics of sirolimus- associated interstitial pneumonitis in renal transplant patients. References Transplantation. 2001;72(5):787-790. doi:10.1097/00007890- 200109150-00008
1. Lee VW, Chapman JR. Sirolimus: its role in nephrology. Nephrology (Carlton). 2005;10(6):606-614. doi:10.1111/j.1440-1797.2005.00493.x Letter to editor
Ex Vivo Lung Perfusion Using Whole Blood: How?
Mohamed S. A. Mohamed
Dear Editor: the estimated cardiac output, depending on the applied protocol. In addition, the blood would also The ex vivo lung perfusion (EVLP) procedure has contain large amounts of inflammatory cytokines emerged and established itself as a safe and reliable and death signals that could lead to deterioration method for the reconditioning of marginal lung of the graft instead of improvement. Although grafts. Many clinical centers worldwide have preclinical animal studies have reported a significant reported the successful and valuable application of improvement with this method, the used blood was this procedure.1 Preclinical studies have continued collected from “healthy” animal donors that were further investigations and refining of the technology. “killed” through collecting their blood (shock). In One of the main points of discussion and controversy addition, posttransplant results with regard to this is the nature of the used perfusate, whether it practice are scarce, thus not fully supporting or should be whole blood, acellular perfusate, or a ruling out the questioned effects. mixture of red blood cells and acellular perfusate. The next option could be the use of donated Although each point of view has advantages and matching blood, which would mean exposing the disadvantages, some published studies and unpub - marginal graft and its stimulated resident leukocytes lished observations have reported a significant to the plasma of another individual followed by the benefit of the use of whole blood over red blood cells new host. A matter that may matter! or acellular perfusates.2,3 This commentary explores The last option could be the use of the recipient’s the applicability, rather than the evidence-based own blood. For this, there are 2 important concerns. significance, on the human level. First, whether the clinical status of the terminally ill In general, the blood could be obtained from the patient would allow that. If yes, this could lead to the donor, from matching donated blood, or from the 2nd concern; exposing the marginal graft to the recipient. Perhaps it could be possible to obtain blood immune discrepancy of the new host before any for perfusion from the brain-dead donor before graft reconditioning, which might not be a good idea. excision, while the donor is on support devices. This Therefore, although the use of the acellular perfusates would allow the blood to contain the important has already achieved outstanding clinical results, the supporting hormones and mediators that resist benefits of the whole blood perfusate should be and/or improve the graft edema.4 However, in further investigated. In addition, and if its application practice, this would be challenging as brain-dead would be recommended, the above-mentioned donors are usually multiorgan donors, where the technical alerts should be considered during the lungs are the last to be recovered, and the perfusion conduction of the clinical studies. technique aims to maintain flow of 40% to 100% of In 2014, an emerging EVLP protocol was 1 From MSAM for Medical Development, Bredstedt, Germany described. This protocol advised the use of an Acknowledgements: The intellectual properties included in this manuscript belong solely to the acellular (supplemented) perfusate. However, with author. Reproduction or use of any of these ideas requires the author’s written permission. No funding was provided for the development of this work. The author has no conflicts of interest regard to the use of whole blood perfusion, the to disclose.. following considerations were advised: (1) the EVLP Corresponding author: Mohamed S. A. Mohamed, MSAM for Medical Development, Theodor Storm Str. 1, 25821, Bredstedt, Germany should run for at least 4 hours; (2) during the first 2 E-mail: [email protected] hours, donor blood together with a cytokine filter
Experimental and Clinical Transplantation (2020) 7: 851-852 could be used; and (3) after graft conditioning has
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been established, the recipient’s blood could be used 4. Woolf PD. Endocrinology of shock. Ann Emerg Med. 1986;15(12): 1401-1405. for the other 2 hours, to allow for a pretransplant 5 .Lei J, Wendt CH, Fan D, Mariash CN, Ingbar DH. Developmental graft/host degree of adaptation or at least controlled acquisition of T3-sensitive Na-K-ATPase stimulation by rat alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2007;292(1):L6-14. prediction of the interaction. Because the reported 6. Minakata Y, Suzuki S, Grygorczyk C, Dagenais A, Berthiaume Y. superiority of whole blood perfusion has been Impact of beta-adrenergic agonist on Na+ channel and Na+-K+- ascribed to multiple hormones in the plasma, ATPase expression in alveolar type II cells. Am J Physiol. 1998;275(2):L414-422. 4-8 especially during shock, supplementation of an 7. Matthay MA, Folkesson HG, Clerici C. Lung epithelial fluid acellular perfusate with those hormones may transport and the resolution of pulmonary edema. Physiol Rev. 2002;82(3):569-600. provide the same clinical benefits, without the 8. Barquin N, Ciccolella DE, Ridge KM, Sznajder JI. Dexamethasone exposure to any other possible hazard.9-11 upregulates the Na-K-ATPase in rat alveolar epithelial cells. Am J Physiol. 1997;273(4):L825-830. 9. Mohamed MS. A cocktail solution for the ex vivo preservation and References perfusion of the lung; Shehata solution. Transplant Open. 2016;1:1- 13. 1. Mohamed MS. Ex vivo lung perfusion and transplant: state of the 10. Mohamed MSA. Ex vivo lung perfusion; this idea deserves testing. art and view to the future. Exp Clin Transplant. 2015;13(6):493-499. Eur J Cardiothorac Surg. 2017;52(3):607. 2. White CW, Hasanally D, Mundt P, et al. A whole blood-based 11. Mohamed MS. Insulin supplementation of the lung graft cold perfusate provides superior preservation of myocardial function preservation solution. Ann Thorac Surg. 2016;101(1):411-412. during ex vivo heart perfusion. J Heart Lung Transplant. 2015;34(1): 113-121. 3. Loor G, Howard BT, Spratt JR, et al. Prolonged EVLP using OCS lung: cellular and acellular perfusates. Transplantation. 2017; 101(10):2303-2311. Index to Volume XVIII Issue VII
Author Index
A Amiri M 313 Beasley GM 93 Abbasi S 757 Anann T 838 Becchetti C 737 Abu Gazala S 382 Anders RA 463 Becker K 751 Acharya R 707 Andorno E 522 Behboudi B 696 Afshari A 757 Anwar N 136 Belen Apak FB 141 Agarwal S 707 Arandi N 719 Bellini MI 169 Agarwal V 778 Ardelt M 481 Benot AR 149 Agarwal V 778 Arinsoy T 98 Bermúdez LE 512 Aghdaie MH 505 Arshad A 292 Berry P 636 Agildere AM 814 Arslan B 712 Berti L 247 Agostinho N 725 Arslan H 270, 275, 306 Bhat AS 250 Ağalar C 182, 712 Arslan İ 498 Biancone L 116 Ahluwalia J 390 Aslamaci S 814 Bias TE 153 Ahmad N 255 Asma S 267 Biela Boaretto RB 436 Ahmad N 572 Astarcıoglu İ 182, 712 Binsalih S 106 Ahmadinejad Z 196 Atar S 267 Black SM 491 Ahn HJ 120 Atsushi Y 258 Blancho G 353 Ajayi T 463 Aubin H 533 Bloom AI 382 Akarsu M 182 Augustine T 732 Boeken U 533 Akateh C 491 Ayoobzadehshirazi A 339 Boffini M 133 Akbulut S 791 Ayvazoglu Soy E 201, 270, 275 Boga C 267 Akcay S 275 470, 543, 564, 689, 744 Bokos J 539 Akdur A 53,270, 275, 543, 564, 689, 744 Azari F 585 Bombardi M 60 Akgun AN 210 Azarpira MR 505 Bonizzoli M 60 Akhyari P 533 Azarpira N 215, 505 Boscolo A 123 Aki SZ 98 Azmi M 252 Bosio A 116 Aksoy SO 712 Azouley D 491 Boteon A 396 Al Ali AS 177 Botha J 842 Al Maeeni SM 177 B Boyacioglu S 210 Al Midani A 157, 519, 636 Bacakoglu A 182 Boyle SM 153 Al Oudah N 106 Badawy A 258 Branchereau J 353 Al Sayyari A 106 Baek J 19 Broering D 188 Al Sayyed MH 65 Baek SH 19 Brooks A 785 Al Sereidi HM 177 Bagante F 491 Brooks J 284, 751 Al-hamoudi W 188 Baghernezhad M 339 Buchholz BM 396 Al-Qaoud T 300 Bahador A 65 Budimir-Bekan I 749 Alabbad S 188 Balradja I 707 Burra P 737 Alani M 808 Banerjee S 549 Buscemi V 522 Albaiz F 847 Behera A 645 Butala BP 549 Albenmousa A 188 Banga N 519 Butler PEM 519 Albertoni L 123 Barale M 116 Alejo JL 585 Baratto F 123 C Aleksandar T 450 Barbas AS 93 Cabello MDN 149 Alexopoulos SP 701 Barbieri S 737 Cabral Dias Filho A 436 Alfieri C 385 Barut B 89 Cacciarelli T 605 Alothman B 847 Barzin G 696 Cakalaroski K 763 Alrasheedi S 847 Bashir A 796 Cameron AM 463 Alshalabi O 270, 543, 744 Basic-Jukic N 242 Can U 814 Altinors N 53 Batgi H 359 Cantarovich D 353 Altundag O 201, 470 Bath N 300 Cao T 71 Altuntas F 359 Bazargan-Hejazi S 339 Carcano G 247 Alzoebie LA 177 Bazi A 803 Cattelan A 737 Amico F 247 Beal EW 491 Centonze L 653
February, pp. 1-138 April, pp. 139-268 June, pp. 269-415 August, pp. 417-540 October, pp. 541-658 November, pp. 659-750 December, pp. 751-852 Cereda M 653 Diena D 116 Fukuda M 485 Cevik A 618 Diez A 39 Fukuhara H 682 Ceylaner G 444 Ding GY 83 Fukumitsu K 258 Chadban S 725, 771 Diviacco P 522 Futamura K 682 Chaluvashetty SB 645 Dobrindt EM 591 Chang CH 224 Dodani S 252 G Chaparro C 410 Dohi T 345 Gandhi S 549 Chattab MA 796 Dondorf F 481 Gangwani G 261 Chen H 368 Donohue C 636 Garcia JER 149 Chen S 808 Dor FJMF 169 Garcia JR 149 Chen TL 224 Doyle A 153 García PK 512 Chen X 529 Du X 368 Garonzik-Wang J 463 Cheng D 368 Durlik M 8 Gasparov S 749 Cheng K 671 Duseja AK 645 Gauttier V 353 Chikkala BR 707 Gavelli F 133 Cho D 392 E Gehring B 557 Cho JH 515 Ebadi P 757 Georgiades C 463 Cho SU 120 Ebrahimi A 196, 696 Geramizadeh B 206, 719 Cho Y 120 Egeli T 182 Germani G 737 Choi B 834 Eghbal MH 598 Ghamdi G 106 Choi EK 19 Elbeialy MAK 474 Ghinolfi D 60 Choi JH 19 Elessawi DF 375 Gholami S 65, 339 Choi JY 515 Elhalel-Dranitzky M 382 Ghorbani F 334, 429 Chopra B 144 Ellidokuz H 182, 712 Ghorbani-Dalini S 505 Ciftci O 210 Elsaid K 474 Ghuman S 261 Cillo U 737 Elsheikh Y 188 Goggins W 39 Comert S 53 Engineer DP 549 Gomez EG 149 Contreras K 512 Erbel S 533 Gomez MR 234 Cortesi C 676 Erdogmus S 444 Gontero P 116 Coskun M 564, 689 Ersoy A 498 González C 512 Croner RS 481 Erten Y 98 Gordana Ž 450 Cruddas L 519 Erturk S 444 Goto N 682 Çalışkan K 306 Esfandiari E 505 Gourevitch D 396 Etezadi F 34 Grutters JC 234 D Etheredge H 842 Guan W 823 D’Souza K 725 Eurich D 591 Guimera Garcia J 458 Dahiya D 645 Ezzat A 659 Gulsen S 53 Dal MS 359 Gupta A 261 Dalmasso E 116 F Gupta S 390 Dalyanoglu H 533 Fabian J 842 Gupta S 707 Dar F 255 Fakhar N 313 Gurakar A 463 Das A 645 Fan HL 128 Das D 707 Fan J 83 H Dashti H 196, 313 Farshi A 729 Haberal AN 210 Davis NF 13 Felgendreff P 481 Haberal KM 275 De Carlis L 522, 653 Feltracco P 737 Haberal M 53, 139, 141, 201, 210, 269, 270, De Carlis R 522, 653 Feng S 71 275, 306, 470, 541, 543, 564, 689, 744 De Simone P 60 Ferede AA 13 Hakim D 585 Deger SM 98 Fernando B 636 Hakim N 585 Dehghani M 65 Ferrarese A 737 Halawa A 659 Dehghani SM 65, 649, 803 Feurer ID 701 Hameed A 771 DeLeonibus A 284 Fidan K 157 Hammoudi S 796 Demetriou G 842 Filipec Kanizaj T 407 Hanlon LV 725 Demiroğlu YZ 306 Filippou D 414 Haque A 255 Derici S 182, 712 Fischer-Fröhlich CL 334, 429 Harada N 485 Dey R 707 Forde J 13 Harhay MN 153 Di Sandro S 522, 653 Fourtounas K 572 Hari Krishna Reddy M 110 Dicocco P 585 Fu PY 83 Harman A 689 Díaz-Ramírez GS 402 Fukuda A 325 Harwood S 27 Has Cuhadar M 267 K Kirwan CJ 27 Hata K 258 Kabei K 1 Kitchens WH 741 Heaton N 255 Kadry Z 345, 785 Ko H 834 Heidari M 757 Kahraman G 744 Koc C 791 Hekimoglu K 270 Kaido T 258 Kocman B 407, 749 Hernández JPC 149 Kakaei F 832 Kohli HS 390 Hervás PL 638 Kalayanamitra R 785 Koizumi N 164 Hervouet J 353 Kalra N 645 Korneffel K 557 Hijdra D 234 Kaman L 645 Kosoku A 1 Hirama T 410 Kamalifar S 505 Kozanoglu I 267 Hiramitsu T 682 Kamel I 463 Krok KL 345 Hirata Y 612 Kamo N 258 Kulkarni MJ 250 Hirsch K 808 Kanda A 682 Kumada N 1 Hodson J 292 Kang P 808 Kumar ACV 110 Hou G 368 Kapolou V 414 Kumru G 444 Kural Rahatli F 814 Hoveidaei AH 649 Karakaya E 53, 270, 564, 689, 744 Hsiao TI 536 Kurt Azap O 275 Katano T 612 Huang XW 83 Kute VB 549 Khan TFT 572 Kutlay S 444 Karam G 353 I Kutlutürk K 89 Karamchandani DM 345 Ietto G 247 Kwakkel-van Erp JM 234 Karimi M 313 Ikegami T 485 Kwon CHD 392 Karimi MH 215, 757 Imanieh MH 649 Kasahara M 325 Imaya M 838 L Kastelan Z 242 Iovino D 247 Lacerda CM 641 Kaya AH 359 Ipek P 618 Lai HC 128 Kayaalp C 89 Iravani Saadi M 719 Lai J 823 Kayıkcı Ö 359 Irie R 325 Laios K 414 Kazemi MJ 206 Isaac JR 396 Laiq SM 252 Kervella D 353 İskender D 359 Lam S 771 Kessaris N 157, 169 Itoh S 485 Langabeer SE 657 Kessler R 265 Ivan M 450 Laurence JM 725, 771 Keven K 444 Ivanovski N 763 Lauterio A 522, 653 Khajavi MR 34 Ivanovski O 763 Lee HY 626 Iwai T 1 Khalaileh A 382 Lazzeri C 60 Izzy M 701 Khalil A 39 Le Bas-Bernardet S 353 Khalil K 292 Lee CH 19 J Khan A 224 Lee DH 153 Jadrijevic S 407, 749 Khan TFT 136 Lee J 120 Jafarian A 313, 696 Khani F 313 Lee J 120 Jain A 345, 785 Khedr MS 659 Lee T 725, 771 Jain M 778 Khosravi B 65 Lee T 834 Jakhete N 463 Khosravi MB 598 Leitão L 641 Jarrad A 796 Khoury T 382 Leite RF 577 Javaherian M 313 Kızıl Çakar M 359 Li PC 224 Jaye DL 741 Kim A 463 Li Y 71 Jee D 19 Kim CD 515 Liao CC 224 Jeng LB 224 Kim D 834 Liao X 345 Jeong KH 515 Kim HT 626 Lichtenberg A 533 Jeong W 120 Kim JM 392 Lim JH 515 Jing T 71 Kim KJ 19 Little D 13 Joh JW 392 Kim KY 515 López Buenadicha A 526 John R 410 Kim S 120 Lopez Hervás P 526 Jones G 519, 636 Kim S 19 Lovric-Kujundzic S 242 Joseph MPC 577 Kim S 834 Lu H 823 Jowkar S 598 Kim S 834 Luijk HD 234 Jucá N 641 Kim YL 515 Luu H 463 Jung HY 515 Kirincich J 242 Lytsikas-Sarlis P 414 Jung SM 120 Kirnap M 270 M Moray G 201, 210, 270, 470, 543, 564, 744 Ozbilgin M 182 Ma M 463 Morelli F 653 Ozdogu H 267 Ma T 71 Mori M 485 Ozturk M 267 Magliocca JF 741 Moris D 539 Öllinger R 591 Makarem J 696 Moroni G 385 Özelsancak R 306 Malat G 153 Mosca PJ 93 Malek Hosseini SA 65, 206, 339 Mrzljak A 407, 749 P Malik A 605 Mu J 71 Pan Z 417 Maluf D 320, 585 Mubarak M 252 Pandey Y 707 Mani A 339 Muderrisoglu H 210 Parisotto C 169 Mardani S 803 Mugino M 771 Park GE 392 Marín-Zuluaga JI 402 Muiesan P 396 Park JS 120 Marks SD 157 Muñoz-Maya O 402 Park S 19 Martin O 585 Muo CH 224 Park SH 515 Martinez Moreno AI 458 Muşabak U 275 Park UJ 626 Martínez-Casas OY 402 Pasaoglu H 98 N Pasaoglu OT 98 Massard G 265 Nadeem N 572 Passerini P 385 Masuda S 485 Naganuma T 1 Patel HV 549 Matas AJ 48 Nagra A 157 Patrucco F 133 Matejak-Górska M 8 Najafi A 696 Pawlik TM 491 Matsuoka L 701 Najafizadeh K 429 Peck KR 392 Matthias M 157 Nakamura K 838 Pehlivan S 498 Mattiazzi A 676 Nakatani T 1 Pelletier S 320 Mavrommatis E 414 Namdaroğlu S 359 Peris A 60 Maximo Silva AC 577 Narumi S 682 Peromingo R 526 Meek B 234 Nashwa RK 375 Pestana JOM 577 Mehdi SH 252 Nasim A 252 Pezzati D 60 Mehdiani A 533 Nasiri M 215 Philosophe B 463 Mehta N 261 Nassiri Toosi M 313, 696 Picton M 732 Meneghini 385 Nawano T 682 Pieras Ayala E 458 Menin E 123 Nayebpour M 164 Pile T 27 Merdin A 359 Nekoei SM 505 Piscoran O 732 Merhav H 382 Nemr WA 375 Pleass HCC 725, 771 Mesnard B 353 Nickkholgh A 320 Popov Z 763 Messa P 385 Nikeghbalian S 65, 334, 339 Pourfakhr P 34 Micozkadıoğlu H 306 Nishide S 1 Powelson J 39 Migliaccio ML 60 Núñez J 638 Power R 13 Migliorisi C 653 Nuño Vazquez-Garza J 526, 638 Prasad N 778 Miranda LE 641 Pratschke J 591 Mikulic D 407, 749 O Puerta A 638 Min JH 120 O’Kelly P 13 Preto M 116 Minault D 353 Obed A 796 Prudhomme T 353 Mirza I 136 Obed M 796 Puerta Vicente A 526 Mishra VV 549 Ocal H 618 Pustavoitau A 463 Mitro G 284, 751 Ocal R 814 Puza CJ 93 Miyahara G 612 Ogbemudia AE 353 Moayedi J 206 Oguz A 201 Q Moazzami B 313 Oh SK 120 Qian Y 529 Modi PR 549 Okada M 682 Mohamed MSA 851 Okada N 612 R Mohammadi Mofrad M 803 Okajima H 258 Radic J 242 Mohammadpour Z 196, 696 Omameuda T 612 Raftery M 27 Mohan P 13 Onishi Y 612 Rahatli S 201, 470 Mohanty T 390 Ors Sendogan D 444 Ram R 110 Moini M 696 Ortiz J 164, 284, 557, 751 Ramírez IC 402 Moinuddin Z 732 Othman MI 796 Rampoldi A 653 Mojtabaee M 334, 429 Ottmann S 463 Ramsi MA 177 Mor-Yosef-Levi I 382 Oudijk EJ 234 Ramzi M 719 Ranganna K 153 Santiago RM 410 Song Y 417 Rasekh R 65 Santos-Sánchez Ó 402 Sonmez E 53 Rauchfuss F 481 Saracino G 585 Soufi H 649 Redfield III R 300 Saredi G 247 Spasovski G 763 Rees M 284, 557, 751 Sarialioglu F 141 Srinavasan P 255 Rega SA 701 Sata N 612 Stankov O 763 Regalia A 385 Sauer I 591 Stavridis S 763 Renaudin K 353 Sayin CB 275, 564 Stern S 382 Restrepo-Gutiérrez JC 402 Scalea JR 536 Stironja I 407 Ridout D 157 Scheiber D 533 Sturdevant M 188 Riera Mari V 458 Schirmer J 577 Sun H 368 Righi D 116 Schizas D 414 Sun Y 823 Riley III TR 345 Schmuck RB 591 Sundaram CP 39 Rinaldi M 133 Schreibman I 345 Sung EG 19 Rincon Cintra da Cruz P 436 Schreurs I 234 Sureshkumar KK 144 Risvanli A 618 SecoAntunes AR 265 Surowiecka A 8 Rizvi SJ 549 Sedigh O 116 Suyani E 98 Rodríguez MP 512 Sedki M 676 Rogal S 605 Seetharam A 808 T Roh YN 626 Segura JS 149 Taber T 39 Roozbeh J 339 Seker I 618 Tahir W 255 Rosa JV 149 Sengul S 444 Takeda M 325 Rospert D 557 Senzolo M 737 Takeishi K 485 Rossi L 116 Serrano OK 48 Takemoto Y 1 Rowley M 808 Sethi J 390 Takou A 659 Roy A 645 Settmacher U 481 Talluri S 153 Roza BA 577 Sevinc Aİ 712 Taneja S 645 Rreka E 60 Sezer T 814 Taniere P 396 Rudarakanchana N 157 Sezgin A 814 Tapia MJR 149 Ruiz P 676 Shafiei M 34 Tautenhahn HM 481 Ryu J 834 Shah PR 549 Tekgunduz E 359 Ryu S 120 Shah YZ 847 Tekkarışmaz N 306 Shahbazov R 320, 585 Tepebasi S 267 S Shahramian I 803 Thuraisingham R 27 Saadat I 215 Shahsavari H 313 Tian Y 345 Saberi B 463 Shaikh OS 605 Timurkaan N 618 Sadegh-Beigee F 334 Shamsaeefar A 65 Tolan HK 89 Sadeghi L 505 Sharfuddin A 39 Tomosugi T 682 Sagol O 712 Shariat Moharari R 34, 696 Torgay A 543, 564 Sahmeddini MA 598 Sharif A 292 Toshima T 485 Sakuma Y 612 Sharma V 605 Tozzi M 247 Saidi S 763 Shim J 834 Trakroo S 785 Sakamoto R 838 Shimada H 1 Troisi RI 188 Sakamoto S 325 Shimizu S 325 Tsai JL 112 Saleemi A 847 Shorbagy MS 474 Tsai SF 112 Saleemi S 847 Simonato E 133 Tsakotos G 414 Saleh A 659 Singh V 645 Tseng WC 128 Saleh M 474 Sinn DH 392 Tsilimigras DI 539 Saleh Y 188 Sipahi NF 533 Tsoucalas G 414 Salehipour M 757 Sirin H 712 Tugtepe H 157 Salimi J 696 Siva Kumar V 110 Tumin D 491 Salsamendi J 676 Skrtic A 407, 749 Turkoz Sucak G 98 Saluzzo F 737 Slavica S 450 Turnaoglu H 814 Samadi K 598 Smyth G 13 Tzukert K 382 Sanada Y 612 Soldini G 247 Sanders-Pinheiro H 577 Solidoro P 133 U Sandroussi C 771 Sollinger HW 300 Uchida H 325 Sangeetha Lakshmi B 110 Song K 83 Uchida J 1 Santana VBBM 436 Song LE 515 Uchiyama T 325 Uemoto S 258 Westenfeld R 533 Yildirim S 275, 543, 564 Ulubay G 270 Woo KS 626 Yildiz A 498 Ulusal Okyay G 98 Wu M 633 Yilmaz C 53 Unek T 182, 712 Wu W 83 Yilmaz KC 210 Uthman E 106 Wu X 823 Yilmaz S 89, 791 Wu Y 71 Yoo I 120 V Wu ZF 128 Yoshiya S 485 van Dellen D 732 Yoshizumi T 485 van Kessel DA 234 X You Y 120 van Moorsel CHM 234 Xia Q 529 Vargas DC 512 Xie Y 71 Z Varley R 732 Xu M 83 Zakaria H 188 Varma S 707 Zanettini Riccetto CL 436 Vatansever N 498 Y Zani E 247 Veltzke-Schlieker W 591 Yadav A 261 Zanoni F 385 Verma S 707 Yadav B 778 Zanus G 123 Vernadakis S 539 Yaghobi R 206, 719, 757 Zare M 339 Verran DJ 725 Yagi S 258 Zelaschi B 123 Vidya B 110 Yamada N 612 Zhang H 529 Vilar JA 638 Yamamoto H 838 Zhang J 417 Vilar Tabanera A 526 Yamashita T 838 Zhang J 529 Vilca-Melendez H 255 Yanagi Y 325 Zhang M 265 Vuletic T 749 Yang HR 224 Zhang S 823 Yang K 834 Zhao Y 83 W Yao W 368 Zheng Q 633 Wadhwa N 261 Yaqoob MM 27 Zhong M 83 Walsh AL 13 Yaqub MS 39 Zhou J 83 Wang J 320 Yarbug Karakayali F 564 Zhu D 633 Washburn K 491 Yeh CC 128 Zhu L 71 Watanabe S 838 Yeh CC 224 Zidan A 188 Watarai Y 682 Yeral M 267 Ziogas IA 701 Wedd JP 741 Yi W 671 Zomorrodi A 729, 832 Wenig AJ 164 Yildirim Donmez F 814 48-52 Retransplant Outcomes Compared With First Experimental and Kidney Transplants: Important Observations Not Reported in the Scientific Registry of Transplant Clinical Transplantation Recipients Annual Report Oscar K. Serrano, Arthur J. Matas Official Journal of the Middle East Society for Organ Transplantation 53-59 Balloon Kyphoplasty Is a Safe and Effective Option for the Treatment of Vertebral Compression Volume: 18 Issue: 1 February 2020 Fractures in Solid-Organ Transplant Recipients Contents Erkin Sonmez, Serhat Comert, Aydincan Akdur, Emre Karakaya, Salih Gulsen, Cem Yilmaz, Artıcle Nur Altinors, Mehmet Haberal
1-7 Conversion From Cyclosporine to Once-Daily 60-64 Comorbidities and Age in Brain-Dead Donors and Tacrolimus on 50:1 mg Basis: A Short-Term Pilot Liver Transplantation: A 15-Year Retrospective Study Investigation Hisao Shimada, Junji Uchida, Akihiro Kosoku, Tomoaki Chiara Lazzeri, Manuela Bonizzoli, Davide Ghinolfi, Iwai, Kazuya Kabei, Shunji Nishide, Paolo De Simone, Daniele Pezzati, Erion Rreka, Toshihide Naganuma, Norihiko Kumada, Marco Bombardi, Maria Luisa Migliaccio, Adriano Peris Yoshiaki Takemoto, Tatsuya Nakatani 65-70 Single Center Long-Term Results of Pediatric Liver 8-12 Influence of Peritoneal or Hemodialysis on Results of Transplantation Simultaneous Pancreas and Kidney Transplant Mohammad Hussein Al Sayyed, Alireza Shamsaeefar, Agnieszka Surowiecka, Marta Matejak-Górska, Saman Nikeghbalian, Seyyed Mohsen Dehghani, Marek Durlik Ali Bahador, Masood Dehghani, Razieh Rasekh, Siavash Gholami, Bahareh Khosravi, 13-18 Warm Ischemia Time at Vascular Anastomosis is an Seyyed Ali Malek Hosseini Independent Predictor for Delayed Graft Function in Kidney Transplant Recipients 71-82 Changes to Liver Structure and Energy Metabolism Atakelet A. Ferede, Anna L. Walsh, Niall F. Davis, During Cold Storage of Transplanted Liver in Mice Gordon Smyth, Ponnusamy Mohan, Richard Power, Liang Zhu, Shanshan Feng, Yunhong Wu, Jingzhou Mu, James Forde, Patrick O’Kelly, Dilly Little Tangtang Jing, Yan Xie, Yan Li, Tingting Cao, Tonghui Ma 19-26 Effects of Blood Transfusion on Hepatic Ischemia- Reperfusion Injury-Induced Renal Tubular Injury 83-88 In Situ Normothermic Regional Perfusion for Liver Saeyoung Kim, Jongyoon Baek, Sangyoung Park, Eun- Donation From China Category III (Organ Donation Kyung Choi, Suk-Hwan Baek, After Brain Death Followed by Circulatory Death): A Joon-Hyuk Choi, Chae-Hoon Lee, Eon-Gi Sung, Single-Center Cohort Study Keuk-Jun Kim, Daelim Jee Guang-Yu Ding, Yun Zhao, Wei Wu, Ming Zhong, Pei-Yao Fu, Ming Xu, Jian Zhou, Jia Fan, 27-33 Treating Posttransplant Anemia With Erythropoietin Xiao-Wu Huang, Kang Song Improves Quality of Life but Does Not Affect Progression of Chronic Kidney Disease 89-92 Ectopic Balloon Device Placement to Correct the Taryn Pile, Martin Raftery, Raj Thuraisingham, Positional Hepatic Venous Outflow Obstruction in Christopher J. Kirwan, Steven Harwood, Liver Transplantation Muhammed M. Yaqoob Hüseyin Kerem Tolan, Bora Barut, Koray Kutlutürk, Cüneyt Kayaalp, Sezai Yilmaz 34-38 Half Saline-Bicarbonate Solution as Intraoperative Fluid Replacement Therapy Leads to Less Acidosis 93-97 Type of Organ Transplanted Impacts the Risk and Better Early Renal Function During Deceased- and Presentation of Cutaneous Squamous Cell Donor Transplant Carcinoma in Transplant Recipients Pejman Pourfakhr, Mohaddese Shafiei, Charles J. Puza, Georgia M. Beasley, Andrew S. Barbas, Farhad Etezadi, Mohammad Reza Khajavi, Paul J. Mosca Reza Shariat Moharari 98-105 Early Diagnostic Markers for Detection of Acute 39-47 Correlation and Prediction of Living-Donor Kidney Injury in Allogeneic Hematopoietic Stem Remaining Function by Using Predonation Cell Transplant Recipients Computed Tomography-Based Volumetric Serpil Muge Deger, Yasemin Erten, Elif Suyani, Measurements: Role of Remaining Kidney Volume Sahika Zeynep Aki, Gulay Ulusal Okyay, Ali Khalil, Muhammad Sohail Yaqub, Tim Taber, Ozge T. Pasaoglu, Hatice Pasaoglu, Turgay Arinsoy, John Powelson, William Goggins, Chandru P. Sundaram, Gulsan Turkoz Sucak Alejandro Diez, Asif Sharfuddin Case Report Volume: 18 Issue: 2 April 2020 Contents 106-109 Acute Cellular Rejection With Severe Interstitial Lymphoplasmacytic Infiltrate and Edema Associated Edıtorıal With Minimal Change Disease Ghormullah Ghamdi, Nourah Al Oudah, 139-140 COVID-19 Update Elmontasir Uthman, Salih Binsalih, Abdulla Al Sayyari Mehmet Haberal
110-111 Sensorineural Deafness Following Tacrolimus Use Revıew Boju Sangeetha Lakshmi, Bhukya Vidya, Mogili Hari Krishna Reddy, Anil C. Venkata Kumar, 141-143 Can Hepatitis A Vaccine Provide Protection Against Rapur Ram, Vishnubotla Siva Kumar COVID-19? Faik Sarialioglu, Fatma Burcu Belen Apak, 112-115 Recovery of Renal Function in a Kidney Transplant Mehmet Haberal Patient After Receiving Hemodialysis for 4 Months Jun-Li Tsai, Shang-Feng Tsai Artıcle 144-148 Impact of Donor Ethnicity on Long-Term Kidney 116-119 Self-Expandable Covered Metallic Stent (UVENTA) Transplant Outcomes: Analysis by Kidney Donor to Treat a Ureteral Stricture After Renal Transplant: Profile Index Categories A Case Report Kalathil K. Sureshkumar, Bhavna Chopra Omid Sedigh, Maurizio Barale, Mirko Preto, Andrea Bosio, Davide Diena, Laura Rossi, 149-152 A Single-Center Experience With Third and Fourth Dorico Righi, Luigi Biancone, Paolo Gontero, Kidney Transplants and Second Kidney Transplant Ettore Dalmasso After Pancreas-Kidney Transplant: Surgical Aspects and Outcomes 120-122 Liver Donation After Brain Death Following Joseba Salguero Segura, José Valero Rosa, Intentional Ingestion of 99% E-Cigarette Liquid Enrique Gomez Gomez, María Dolores Navarro Cabello, Nicotine 10 mL Jesus Ruiz Garcia, Alberto Rodriguez Benot, Jinwoong Lee, Yeonho You, Jung Soo Park, José Enrique Robles Garcia, María José Requena Tapia, Jin Hong Min, Insool Yoo, Wonjoon Jeong, Yongchul Cho, Juan Pablo Campos Hernández Seung Ryu, Seungwhan Kim, Sung Uk Cho, Se Kwang Oh, Junwan Lee, Hong Joon Ahn, 153-156 Safety and Efficacy of Universal Postoperative Sang Min Jung Decolonization for Kidney Transplant Recipients Dong Heun Lee, Gregory Malat, Suzanne M. Boyle, 123-127 Early Use of Etanercept for Graft-Versus-Host Sindhura Talluri, Tiffany E. Bias, Meera N. Harhay, Disease After Liver Transplant: the Importance of Karthik Ranganna, Alden Doyle Broad Spectrum Infective Prophylaxis Annalisa Boscolo, Eugenia Menin, Beatrice Zelaschi, 157-163 Low-Dose Aspirin Reduces the Rate of Renal Laura Albertoni, Giacomo Zanus, Fabio Baratto Allograft Thrombosis in Pediatric Renal Transplant Recipients 128-132 Overdose of Tacrolimus as the Trigger Causing Ammar Al Midani, Nung Rudarakanchana, Progression of Posterior Reversible Encephalopathy Arvind Nagra, Kibriya Fidan, Halil Tugtepe, Syndrome and Subsequent Hepatic Infarction After Mary Matthias, Deborah Ridout, Nicos Kessaris, Liver Transplant: A Case Report Stephen D. Marks Wei-Cheng Tseng, Hou-Chuan Lai, Chun-Chang Yeh, Hsiu-Lung Fan, Zhi-Fu Wu 164-168 Evaluation of Whether Kidney Paired Donations Improve Overall Transplant Center Performance 133-135 Vanishing Middle Bronchus in Bilateral Lung Alexandra J. Wenig, Naoru Koizumi, Mehdi Nayebpour, Transplant After Ex Vivo Lung Perfusion Jorge Ortiz Filippo Patrucco, Erika Simonato, Massimo Boffini, Mauro Rinaldi, Francesco Gavelli, Paolo Solidoro 169-176 Social Media Use Among Transplant Professionals in Europe: a Cross-Sectional Study From the European Leter to Edıtor Society of Organ Transplantation 136-138 Recipient Warm Ischemia and Delayed Graft Maria Irene Bellini, Chiara Parisotto, Frank J. M. F. Dor, Function Nicos Kessaris Taqi F. Toufeeq Khan, Irfan Mirza, Nisar Anwar 177-181 United Arab Emirates’ Future Perspective: Converting Potential Organ Donors Into Actual Organ Donors in an Academic Setting Musaab Ali Ramsi, Shaima Mohamed Al Maeeni, Hend Mohamed Al Sereidi, Alyaa Saeed Al Ali, Lama Azzam Alzoebie 182-187 Analysis of Causes and Risk Factors for Late Case Report Mortality After Liver Transplant: How Can We Obtain Better Long-Term Survival? 242-246 A Kidney Transplant Recipient With Fulminant Tufan Egeli, Tarkan Unek, Cihan Agalar, Serhan Derici, Progressive Multifocal Leukoencephalopathy- Mucahit Ozbilgin, Mesut Akarsu, Aylin Bacakoglu, Immune Reconstitution Inflammatory Syndrome: A Hulya Ellidokuz, Ibrahim Astarcioglu Rare Clinical Outcome and Review of the Literature Jason Kirincich, Nikolina Basic-Jukic, Josipa Radic, 188-195 Is It Justified to Use Liver Grafts From Living Donors Sanja Lovric-Kujundzic, Zeljko Kastelan for Retransplant? A Single-Center Experience Hazem Zakaria, Yahia Saleh, Ahmed Zidan, 247-249 Retrograde Intrarenal Surgery Through an Incision Mark Sturdevant, Saleh Alabbad, Yasser Elsheikh, of the Ureter as a Good Treatment Option for Large Waleed Al-hamoudi, Ali Albenmousa, Ureteropelvic Impacted Stones in Transplanted Roberto Ivan Troisi, Dieter Broering Kidneys Giuseppe Ietto, Giovanni Saredi, Gabriele Soldini, 196-200 Invasive Fungal Infections With Good Survival Domenico Iovino, Francesco Amico, Elia Zani, Following Liver Transplant: A Single-Center Lorenzo Berti, Matteo Tozzi, Giulio Carcano Experience From a Developing Country Amirpasha Ebrahimi, Habibolah Dashti, 250-251 Cissus quadrangularis-Induced Thrombocytopenia Zinat Mohammadpour, Zahra Ahmadinejad in a Renal Allograft Recipient Manjunath Jeevanna Kulkarni, Archana Shrinivas Bhat 201-205 Single-Center Experience of Recurrence Patterns and Survival Analyses of Patients With Hepatocellular 252-254 Kaposi Varicelliform Eruption Associated With Carcinoma and Liver Transplant Chickenpox in a Liver Transplant Recipient Samed Rahatli, Ebru H. Ayvazoglu Soy, Arzu Oguz, Maliha Azmi, Asma Nasim, Sunil Dodani, Ozden Altundag, Gokhan Moray, Mehmet Haberal Syed Mudassir Laiq, Syed Haider Mehdi, Muhammed Mubarak 206-209 Significance of Occult Hepatitis C Virus Infection in Liver Transplant Patients With Cryptogenic 255-257 Occlusive Hepatic Artery Thrombus in a Deceased- Cirrhosis Donor Liver Procured From a Donor With Blunt Ramin Yaghobi, Mohammad Javad Kazemi, Abdominal Trauma Following a Road Traffic Bita Geramizadeh, Seyed Ali Malek Hosseini, Collision Accident Javad Moayedi Niaz Ahmad, Wasif Tahir, Ali Haque, Faisal Dar, Hector Vilca-Melendez, Parthi Srinavasan, Nigel Heaton 210-214 Relation of Preoperative and Postoperative Echocardiographic Parameters With Rejection and 258-260 Evans Syndrome After Successful Mortality in Liver Transplant Patients Immunosuppressant-Free Living-Donor Liver Kerem Can Yilmaz, Orcun Ciftci, Arzu Neslihan Akgun, Transplant Haldun Muderrisoglu, Sedat Boyacioglu, Amr Badawy, Toshimi Kaido, Yoshizawa Atsushi, Asuman Nihan Haberal, Gokhan Moray, Shintaro Yagi, Koichiro Hata, Naoko Kamo, Mehmet Haberal Ken Fukumitsu, Hideaki Okajima, Shinji Uemoto
215-223 Gene Expression Profile of Toll-Like Receptor/ 261-264 Percutaneous Recanalization of Anastomotic Portal Adaptor/Interferon Regulatory Factor/Cytokine Axis Vein in a Pediatric Patient After Liver Transplant During Liver Regeneration After Partial Ischemia- Without Any Recognizable Portal Vein Remnant on Reperfusion Injury Imaging Meysam Nasiri, Mohammad-Hossein Karimi, Arun Gupta, Gaurav Gangwani, Naimish Mehta, Negar Azarpira, Iraj Saadat Nishant Wadhwa, Samarjit Ghuman, Ajit Yadav
224-233 De Novo Malignancy After Heart, Kidney, and Liver 265-266 Multiple Lung Transplant in a Patient Within 25 Transplant: A Nationwide Study in Taiwan Years: A Case Report Chun-Chieh Yeh, Arshad Khan, Chih-Hsin Muo, Min Zhang, Ana Rita SecoAntunes, Romain Kessler, Horng-Ren Yang, Ping-Chun Li, Chao-Hsiang Chang, Gilbert Massard Ta-Liang Chen, Long-Bin Jeng, Chien-Chang Liao Letter to Edıtor 234-241 Lung Transplant Patients Show a Dissimilar 267-268 Problems With Unrelated Donors For Stem Cell Peripheral B-Cell Subset Ratio Compared With Transplant and Proposed Solutions: A Single-Center Healthy Controls Experience Inge Schreurs, Bob Meek, Daniëlle Hijdra, Ilknur Kozanoglu, Hakan Ozdogu, Suheyl Asma, Maria Rodriguez Gomez, Coline H. M. van Moorsel, Mahmut Yeral, Sevtap Atar, Songul Tepebasi, H. D. Luijk, Johanna M. Kwakkel-van Erp, Medine Has Cuhadar, Murat Ozturk, Can Boga Erik-Jan Oudijk, Diana A. van Kessel, Jan C. Grutters Volume: 18 Issue: 3 June 2020 325-333 Efficacy of Antithymocyte Globulin Treatment for Contents Severe Centrilobular Injury Following Pediatric Liver Transplant: Clinical Significance of Monitoring 269 Memoriam Lymphocyte Subset Dr. Pekka Juha Häyry Hajime Uchida, Seisuke Sakamoto, Seiichi Shimizu, Mehmet Haberal Masahiro Takeda, Yusuke Yanagi, Akinari Fukuda, Toru Uchiyama, Rie Irie, Mureo Kasahara Artıcle 334-338 Liver Procurement from Poisoned Donors: 270-274 Coronavirus Disease (COVID-19) in Kidney A Survival Study and Liver Transplant Patients: A Single-Center Meysam Mojtabaee, Fariba Ghorbani, Experience Saman Nikeghbalian, Carl-Ludwig Fischer-Fröhlich, Aydincan Akdur, Emre Karakaya, Farahnaz Sadegh-Beigee Ebru H. Ayvazoglu Soy, Omar Alshalabi, Mahir Kirnap, Hande Arslan, Gaye Ulubay, Koray Hekimoglu, 339-344 Psychologic Evaluation in Liver Transplantation: Gokhan Moray, Mehmet Haberal Assessment of Psychologic Profile of End-Stage Liver Disease Patients Before and After Transplant 275-283 Incidence and Immunologic Analysis of Coronavirus Mohammad Baghernezhad, Arash Mani, Disease (COVID-19) in Hemodialysis Patients: Anaheed Ayoobzadehshirazi, Jamshid Roozbeh, A Single-Center Experience Maasoomeh Zare, Saman Nikeghbalian, Hande Arslan, Ugur Musşabak, Ebru H. Ayvazoglu Soy, Seyed Ali Malek-Hosseini, Siavash Gholam, Ozlem Kurt Azap, Burak Sayin, Sule Akcay, Shahrzad Bazargan-Hejazi K. Murat Haberal, Aydincan Akdur, Sedat Yildirim, Mehmet Haberal 345-352 Incidence of Post-Liver Transplant Hepatic Dysfunction After Sustained Virologic Response 284-291 Alemtuzumab Induction Is Associated With Following Direct-Acting Anti-Hepatitis C Therapy Equalization of Graft Outcomes Between Elderly and Ashokkumar Jain, Thomas R. Riley III, Nonelderly Kidney Transplant Recipients: A Single- Karen L. Krok, Ian Schreibman, Center Report Dipti M. Karamchandani, Xiaojie Liao, Ye Tian, Anthony DeLeonibus, Graham Mitro, Joseph Brooks, Takehiko Dohi, Zakiyah Kadry Michael Rees, Jorge Ortiz 353-358 Total Pancreatectomy and Pancreatic Allotransplant 292-299 Changes in Body Mass Index and Outcomes After in a Porcine Experimental Model Kidney Transplant: A Single-Center, Retrospective, Thomas Prudhomme, Delphine Kervella, Observational Study Ann Etohan Ogbemudia, Vanessa Gauttier, Adam Arshad, James Hodson, Khalid Khalil, Karine Renaudin, Benoit Mesnard, David Minault, Adnan Sharif Jérémy Hervouet, Stéphanie Le Bas-Bernardet, Diego Cantarovich, Georges Karam, Gilles Blancho, 300-305 Salvage Renal Autotransplant Following Previous Julien Branchereau Renal Vein Stenting in Nutcracker Syndrome Talal Al-Qaoud, Natalie Bath, Robert Redfield III, 359-367 Impact of Guideline-Driven Approach in Follow- Hans W. Sollinger Up of Long-Term Complications After Allogeneic Hematopoietic Cell Transplant: Single Center 306-312 Risk Factors for Urinary Tract Infection After Kidney Experience Transplant: A Retrospective Analysis Ali Hakan Kaya, Sinem Namdaroğlu, Ömür Kayıkcı, Nihan Tekkarışmaz, Rüya Özelsancak, Alparslan Merdin, Hikmettullah Batgi, Dicle İskender, Hasan Micozkadıoğlu, Kenan Çalışkan, Mehmet Sinan Dal, Merih Kızıl Çakar, Emre Tekgunduz, Yusuf Ziya Demiroğlu, Ayşe Hande Arslan, Fevzi Altuntas Mehmet Haberal 368-374 Monitoring Early-Stage Acute Rejection by Imaging 313-319 Factors Associated With Length of Hospital Stay CXCR3-Positive Cell Infiltration: Evaluation of Following Liver Transplant Surgery 125Iodine-Labeled CXCL10 Mahmoud Amiri, Mohssen Nassiri Toosi, Hukui Sun, Wenliang Yao, Dayan Cheng, Bobak Moazzami, Ali Jafarian, Hooman Shahsavari, Hongyan Chen, Xiangde Du, Guihua Hou Mohammad Javaherian, Habibollah Dashti, Nasir Fakhar, Mehrdad Karimi, Farah Khani 375-381 Histologic Evaluations of Xenotransplanted Rabbit Knees by In Vitro-Propagated Human Amniotic 320-324 Intervention on Spontaneous Splenorenal Shunt May Epithelial Cells: A Preclinical Study Decrease the Incidence of Acute Kidney Injury After Dina F. Elessawi, Radwan K. Nashwa, Waleed A. Nemr Liver Transplant Arash Nickkholgh, Jingzhou Wang, Rauf Shahbazov, Shawn Pelletier, Daniel Maluf Case Report Volume: 18 Issue: 4 August 2020 Contents 382-384 Repeat Kidney Transplant in a Patient With a Double Inferior Vena Cava and Difficult Venous Access: A Revıew Case Report Shira Stern, Hadar Merhav, Samir Abu Gazala, 417-428 Systematic Review and Meta-Analysis of Clinical Allan-Isaac Bloom, Tawfik Khoury, Outcomes of Penetrating Keratoplasty Versus Deep Irit Mor-Yosef-Levi, Michal Elhalel-Dranitzky, Anterior Lamellar Keratoplasty for Keratoconus Keren Tzukert, Abed Khalaileh Yaowen Song, Jing Zhang, Zhiqiang Pan
385-389 Delayed Diagnosis of West Nile Virus Infection in Artıcle a Kidney Transplant Patient Due to Inaccuracies in Commonly Available Diagnostic Tests 429-435 Impact of Recruitment Maneuvers to Cover Adverse Francesca Zanoni, Carlo Alfieri, Gabriella Moroni, Effects of Donor Transfer Patrizia Passerini, Anna Regalia, Maria Meneghini, Fariba Ghorbani, Katayoun Najafizadeh, Piergiorgio Messa Carl-Ludwig Fischer-Fröhlich, Meysam Mojtabaee
390-391 Fever of Unknown Origin in a Renal Transplant 436-443 Donor Age Amplifies the Detrimental Effects of Recipient: Lactate Dehydrogenase as an Important Cold Ischemia Time on Long-Term Kidney Allograft Clue to Diagnosis Survival Independently of the Occurrence of Delayed Jasmine Sethi, Krishan Lal Gupta, Tirthankar Mohanty, Graft Function or Early Acute Rejection Shefali Gupta, Jasmina Ahluwalia, Harbir Singh Kohli Pedro Rincon Cintra da Cruz, Aderivaldo Cabral Dias Filho, 392-395 Infectious Complications in Patients Who Received Viviane Brandão Bandeira Mello Santana, High-Volume Plasma Exchange Prior to Liver Rubia Bethania Biela Boaretto, Transplant: A Case Report Cassio Luis Zanettini Riccetto Ga Eun Park, Kyong Ran Peck, Jong Man Kim, Choon Hyuck David Kwon, Jae-Won Joh, Duck Cho, 444-449 Fabry Disease Screening in Patients With Kidney Dong Hyun Sinn Transplant: A Single-Center Study in Turkey Siyar Erdogmus, Sim Kutlay, Gizem Kumru, 396-401 Autotransplantation of the Liver for Ex Vivo Damla Ors Sendogan, Sehsuvar Erturk, Resection of Intrahepatic Caval Leiomyosarcoma: A Kenan Keven, Gulay Ceylaner, Sule Sengul Case Report Bettina M. Buchholz, Amanda Pinter Carvalheiro da 450-457 Transplanted Kidney Increases Nitric Oxide Silva Boteon, Phillipe Taniere, John R. Isaac, David Formation With Metabolic Acidosis Reduction Gourevitch, Paolo Muiesan Tomić Aleksandar, Žunić Gordana, Spasić Slavica, Marjanović Ivan 402-406 Disseminated Cryptococcosis After Liver Transplant: A Case Report 458-462 Prevalence of BK Virus in Renal Transplant at Gabriel Sebastián Díaz-Ramírez, a Single Center: Experience With Our Ureteral Omar Yesid Martínez-Casas, Reimplantation Surgical Technique Juan Ignacio Marín-Zuluaga, Ana I. Martinez Moreno, Jordi Guimera Garcia, Octavio Muñoz-Maya, Óscar Santos-Sánchez, Vicente Riera Mari, Enrique Pieras Ayala Isabel Cristina Ramírez, Juan Carlos Restrepo-Gutiérrez 463-469 Accuracy of Milan, University of California San 407-409 Adrenalectomy for Bilateral Metachronous Adrenal Francisco, and Up-To-7 Criteria in Predicting Recurrence of Hepatocellular Carcinoma After Liver Tumor Recurrence Following Deceased-Donor Transplant: A Case Report Liver Transplant in Patients With Hepatocellular Danko Mikulic, Ivan Stironja, Stipislav Jadrijevic, Carcinoma Anita Skrtic, Anna Mrzljak, Tajana Filipec Kanizaj, Behnam Saberi, Jacqueline Garonzik-Wang, Michelle Branislav Kocman Ma, Tokunbo Ajayi, Amy Kim, Harry Luu, Neha Jakhete, Aliaksei Pustavoitau, Robert A. Anders, 410-413 Pulmonary Blastomycosis Following Eculizumab Christos Georgiades, Ihab Kamel, Shane Ottmann, Therapy in a Lung Transplant Recipient Benjamin Philosophe, Andrew M. Cameron, Takashi Hirama, Rex Michael Santiago, Rohan John, Ahmet Gurakar Cecilia Chaparro 470-473 Posttransplant Malignancies in Adult Renal and Letter to Edıtor Hepatic Transplant Patients Samed Rahatli, Ozden Altundag, Ebru Ayvazoglu Soy, 414-415 Transplantation in Ancient Greek Medicine Gokhan Moray, Mehmet Haberal Konstantinos Laios, Vassiliki Kapolou, Pavlos Lytsikas-Sarlis, Evangelos Mavrommatis, Georgios Tsakotos, Gregory Tsoucalas, Demetrios Schizas, Demetrios Filippou 474-480 Respiratory Complications Among Living 522-525 Successful Transplant of a Liver Graft After Liver Donors: A Single-Center Retrospective Giant Hepatic Artery Aneurysm Resection and Observational Study Reconstruction Mohammed S. Shorbagy, Mohamed Saleh, Riccardo De Carlis, Enzo Andorno, Vincenzo Buscemi, Marwa A. K. Elbeialy, Kamal Elsaid Andrea Lauterio, Pietro Diviacco, Stefano Di Sandro, Luciano De Carlis 481-484 Liver Transplant Due to Flupirtine-Induced Acute Liver Failure 526-528 Luschka Duct Leak: An Unexpected Cause of Felix Dondorf, Roland S. Croner, Choleperitoneum After Liver Transplant Hans-Michael Tautenhahn, Philipp Felgendreff, Alberto Vilar Tabanera, Ana Puerta Vicente, Michael Ardelt, Utz Settmacher, Falk Rauchfuss Adolfo López Buenadicha, Roberto Peromingo, Pedro Lopez Hervás, Javier Nuño Vazquez-Garza 485-490 Use of Mycophenolate Mofetil Suspension as Part of Induction Therapy After Living-Donor Liver 529-532 Graft Hepatic Artery Rupture Due to Carbapenem- Transplant Resistant Klebsiella pneumoniae Infection After Noboru Harada, Tomoharu Yoshizumi, Shohei Yoshiya, Liver Transplant Kazuki Takeishi, Takeo Toshima, Shinji Itoh, Yongbing Qian, Haomin Zhang, Xiaosong Chen, Toru Ikegami, Mio Fukuda, Satohiro Masuda, Jianjun Zhang, Qiang Xia Masaki Mori 533-535 Successful Heart Transplant in a Childhood Cancer 491-497 Defining a Liver Transplant Benefit Threshold for Survivor With Chemoradiotherapy-Induced the Model for End-Stage Liver Disease-Sodium Score Cardiomyopathy Eliza W. Beal, Clifford Akateh, Dmitry Tumin, Nihat Firat Sipahi, Payam Akhyari, Hug Aubin, Fabio Bagante, Sylvester M. Black, Kenneth Washburn, Arash Mehdiani, Sophia Erbel, Ralf Westenfeld, Daniel Azouley, Timothy M. Pawlik Daniel Scheiber, Hannan Dalyanoglu, Artur Lichtenberg, Udo Boeken 498-504 Level of Daily Life Activities and Learning Needs in Renal Transplant Patients 536-538 Hypoglycemia Following Pancreas Transplant: Seda Pehlivan, Nursel Vatansever, İlknur Arslan, A Diagnostic Challenge in the Immediate Abdülmecit Yildiz, Alparslan Ersoy Posttransplant Setting Tiffany I. Hsiao, Joseph R. Scalea 505-511 ROCK Y-27632 Inhibitor, Ascorbic Acid, and Trehalose Increase Survival of Human Wharton Jelly Letter to Edıtor Mesenchymal Stem Cells After Cryopreservation Sulmaz Kamalifar, Negar Azarpira,Ladan Sadeghi, 539-540 Organ Donation After Circulatory Death in Greece: Sadegh Ghorbani-Dalini, Seideh Masoomeh Nekoei, Time to Consider Mahdokht H. Aghdaie, Elaheh Esfandiari, Dimitrios Moris, Diamantis I. Tsilimigras, John Bokos, Mohamad Reza Azarpira Spyridon Vernadakis
Case Report Volume: 18 Issue: 5 October 2020 512-514 Abdominoplasty in Hemodialysis Patients Before Contents Transplant Paola Karina García, Diana Carolina Vargas, 541-542 In Memoriam Kateir Contreras, Camilo González, John S. Najarian Martha Patricia Rodríguez, Luis Eduardo Bermúdez Mehmet Haberal
515-518 Severe Respiratory Syncytial Virus Pneumonia in a Artıcle Kidney Transplant Recipient With Desensitization: Case Report and Comprehensive Review of the 543-548 The ewN Anterior Less Invasive Crescentic Incision Literature for Living Donor Nephrectomy Eun Song Lee, Kyu Yeun Kim, Kye-Hwa Jeong, Mehmet Haberal, Ebru H. Ayvazoglu Soy, Jeong-Hoon Lim, Hee-Yeon Jung, Ji-Young Choi, Aydincan Akdur, Omar Alshalabi, Sedat Yildirim, Jang-Hee Cho, Sun-Hee Park, Yong-Lim Kim, Gokhan Moray, Adnan Torgay Chan-Duck Kim 549-556 Two Decades of Deceased Donor Kidney 519-521 A Rare Presentation of Escherichia coli Necrotizing Transplantation at Ahmedabad, India Fasciitis in Renal Transplantation Vivek B. Kute, Himanshu V. Patel, Pranjal R. Modi, Lucinda Cruddas, Ammar Al-Midani,Neal Banga, Sayyad J. Rizvi, Pankaj R. Shah, Divyesh P. Engineer, Gareth Jones, Peter EM Butler Subho Banerjee, Bina P. Butala, Shruti Gandhi, Vineet V. Mishra 557-563 BK Virus in Renal Transplant Patients Using 618-625 Effects of Ovarian Transplant on Alemtuzumab for Induction Immunosuppression Anti-Müllerian Hormone, Kisspeptin-1, Katie Korneffel, Bradley Gehring, Daniel Rospert, and Kisspeptin-1 Receptor Levels in Rats Michael Rees, Jorge Ortiz Ali Risvanli, Halis Ocal, Necati Timurkaan, Pinar Ipek, Aydin Cevik, Ibrahim Seker 564-571 Liver and Kidney Transplant During a 6-Month Period in the COVID-19 Pandemic: A Single-Center 626-632 Effect of Opt-out System for Organ Donation After Experience Brain Death on Ethical Legitimacy and Potential Aydincan Akdur, Emre Karakaya, Efficacy in a Mathematical Model Ebru H. Ayvazoglu Soy, Feza Yarbug Karakayali, Sang Woo Kim, Hyun Yong Lee, Ui Jun Park, Sedat Yildirim, Adnan Torgay, Cihat Burak Sayin, Hyoung Tae Kim, Young-Nam Roh Mehmet Coskun, Gokhan Moray, Mehmet Haberal Case Report 572-576 Steroid-Sparing and Steroid-Based Immunosuppression in Kidney Transplant: Is 633-635 Ultrasonography-Based Dynamic Assessment on There a Difference in Outcomes and Recipient an Adult for Postoperative Effects of Double Kidney Comorbidities? Transplant From a Nadeem Ahmad, Taqi F Toufeeq Khan, 6-Month-Old Donor Nayab Nadeem, Konstantinos Fourtounas Dongyong Zhu, Qichao Zheng, Meng Wu
577-584 Nonadherence to Immunosuppressive Medications 636-637 Use of Thromboelastography to Guide Platelet Following Pediatric Kidney Transplantation Within Infusion in a Patient with Wiskott-Aldrich Syndrome Full Cost Coverage Health System: Prevalence and Undergoing Renal Transplant Correlates Ammar Al Midani, Ciara Donohue, Peter Berry, Ana Carolina Maximo Silva, Helady Sanders-Pinheiro, Gareth Jones, Bimbi Fernando Renata Fabiana Leite, Marina Pontello Cristelli Joseph, Jose Osmar Medina Pestana, Janine Schirmer, 638-640 Cystic Duct Bile Leak in Graft: An Unexpected Bartira de Aguiar Roza Origin for Choleperitoneum After Liver Transplant Ana Puerta, Jordi Núñez, José Alberto Vilar, 585-590 Laparoscopic Versus Finger-Assisted Open Donor Pedro López Hervás, Javier Nuño Nephrectomy Technique: A Possible Safe Alternative Rauf Shahbazov, Daniel Maluf, Feredun Azari, 641-644 Dissection of the Hepatic Artery: A Rare Cause of David Hakim, Oscar Martin, Pierpaolo Dicocco, Late Ischemia After Liver Transplant Jennifer L. Alejo, Giovanna Saracino, Nadey Hakim Luiz Eduardo Miranda, Laécio Leitão, Norma Jucá, Cláudio Moura Lacerda 591-597 Ischemic-Type Biliary Lesions After Liver Transplant: Factors Causing Early-Onset Versus 645-648 Intrahepatic Arterioportal Fistula: A Rare Cause of Late-Onset Disease Portal Hypertension After Deceased Donor Liver Eva Maria Dobrindt, Dennis Eurich, Transplant Wilfried Veltzke-Schlieker, Johann Pratschke, Akash Roy, Sunil Taneja, Arunanshu Behera, Igor Sauer, Robert Öllinger, Rosa Bianca Schmuck Lileswar Kaman, Naveen Kalra, Sreedhara B. Chaluvashetty, Ashim Das, Divya Dahiya, 598-604 Preconditioning Effect of Remifentanil Versus Ajay K. Duseja, Virendra Singh Fentanyl in Prevalence of Early Graft Dysfunction in Patients After Liver Transplant: A Randomized 649-652 Successful Treatment of Idiopathic Clinical Trial Thrombocytopenic Purpura After Liver Transplant: Sanaz Jowkar, Mohammad Bagher Khosravi, A Case Report Mohammad Ali Sahmeddini, Amir Human Hoveidaei, Hoda Soufi, Mohammad Hossein Eghbal, Kazem Samadi Seyed Mohsen Dehghani, Mohammad Hadi Imanieh
605-611 Liver Transplant From Increased-Risk Donors in the 653-656 Endovascular Treatment of Acute Posttransplant Era of Direct-Acting Antivirals for Hepatitis C Portal Vein Thrombosis Due to Portal Steal From Obaid S. Shaikh, Shari Rogal, Anam Malik, Mesocaval And Coronary Portosystemic Shunts Vivek Sharma, Thomas Cacciarelli Leonardo Centonze, Stefano Di Sandro, Marco Cereda, Andrea Lauterio, Riccardo De Carlis, Carmelo Migliorisi, 612-617 Liver Transplant for Posthepatectomy Liver Failure Francesco Morelli, Antonio Rampoldi, Luciano De Carlis in Hepatoblastoma Yuta Hirata, Yukihiro Sanada, Takahiko Omameuda, Letter to Edıtor Takumi Katano, Go Miyahara, Naoya Yamada, 657-658 Absence of Polycythemia Vera in Postrenal Noriki Okada, Yasuharu Onishi, Yasunaru Sakuma, Transplant Erythrocytosis Naohiro Sata Stephen E. Langabeer Volume: 18 Issue: 6 November 2020 712-718 Comparison of Resection and Liver Transplant in Contents Treatment of Hepatocellular Carcinoma Suleyman Ozkan Aksoy, Tarkan Unek, Revıew Ali İbrahim Sevinc, Baha Arslan, Haluk Sirin, Zekai Serhan Derici, Hulya Ellidokuz, Ozgul Sagol, 659-670 Update on the Management of BK Virus Infection Cihan Agalar, İbrahim Astarcıoglu Ahmed Saleh, Mohamed Salah El Din Khedr, Abeer Ezzat, Anna Takou, Ahmed Halawa 719-724 Genetic Variation of Costimulatory Molecules, Including Cytotoxic T-Lymphocyte Antigen Artıcle 4, Inducible T-Cell Costimulator, Cluster Differentiation 28, and Programmed Cell Death 1 671-675 Diagnostic Value of Flow Cytometry in Kidney Genes, in Iranian Patients With Leukemia Transplant Recipients With Active Pulmonary Mani Ramzi, Nargess Arandi, Mahdiyar Iravani Saadi, Tuberculosis Ramin Yaghobi, Bita Geramizadeh Wang Yi, Ke Cheng
676-681 Computed Tomography-Guided Kidney Transplant Case Report Biopsy Outcomes: A Single-Center Experience Camilo Cortesi, Mai Sedki, Phillip Ruiz, 725-728 Renal Transplant Artery Autologous Saphenous Vein Jason Salsamendi, Adela Mattiazzi Graft Aneurysms: Late Presentation and the Need for Recall and Surveillance 682-688 Changes in Muscle Quality and Body Composition Lucy Victoria Hanlon, Nelson Agostinho, 1 Year After Hand-Assisted Laparoscopic Donor Kenneth D’Souza, Taina Lee, Steven Chadban, Nephrectomy in Living Kidney Donors Henry Claud Capron Pleass, Deborah Jean Verran, Hiroki Fukuhara, Takaaki Nawano, Akiko Kanda, Jerome Martin Laurence Toshihide Tomosugi, Manabu Okada, Kenta Futamura, Takahisa Hiramitsu, Norihiko Goto, Shunji Narumi, 729-731 A Massive Chylous Ascites With Severe Morbidity Yoshihiko Watarai After Laparoscopic Donor Nephrectomy and Successful Treatment With Total Parenteral 689-695 Our Living Donor Protocol for Liver Transplant: A Nutrition and Octreotide Single-Center Experience Afshar Zomorrodi, Alireza Farshi Emre Karakaya, Aydincan Akdur, Ebru H. Ayvazoglu Soy, Ali Harman, Mehmet Coskun, 732-736 Kidney Transplantation From a 5-Day-Old Donor Mehmet Haberal With a Single Functioning Kidney Rebecca Varley, Oana Piscoran, Michael Picton, 696-700 Comparison of Coagulation Conditions in Patients Zia Moinuddin, David van Dellen, Titus Augustine With Liver Cirrhosis Due to Primary Sclerosing Cholangitis and Nonbiliary Causes of Cirrhosis 737-740 Geotrichum capitatum Invasive Infection Early After Before Orthotopic Liver Transplant Liver Transplant Atabak Najafi, Ali Jafarian, Jalil Makarem, Chiara Becchetti, Alberto Ferrarese, Gilda Barzin, Javad Salimi, Mohsen Nasiri-Toosi, Annamaria Cattelan, Stefania Barbieri, Paolo Feltracco, Majid Moini, Amirpasha Ebrahimi, Behnam Behboudi, Francesca Saluzzo, Umberto Cillo, Marco Senzolo, Zinat Mohammadpour, Reza Shariat Moharari Giacomo Germani, Patrizia Burra
701-706 Sex and Gender Disparities in Pretransplant 741-743 A Mimic of Posttransplant Lymphoproliferative Characteristics and Relationships with Postoperative Disease Following Liver Transplant Outcomes in Liver Transplant Recipients with William H. Kitchens, David L. Jaye, Joel P. Wedd, Alcoholic Liver Disease Joseph F. Magliocca Lea Matsuoka, Manhal Izzy, Irene D. Feurer, Scott A. Rega, Ioannis A. Ziogas, 744-748 Oxalosis Crystals' Redeposition in Cardiac Tissue Sophoclis P. Alexopoulos Leading to New-Onset Fatal Cardiac Complication After Liver Transplant in Primary Oxalosis Patient: 707-711 Outcome of Pediatric Liver Transplants in Patients Case Report With Less Than 10 kg of Body Weight Is Not Worse Omar AlShalabi, Ebru H. Ayvazoglu Soy, Yuktansh Pandey, Sharat Varma, Aydincan Akdur, Emre Karakaya, Gokhan Kahraman, Bhargava Ram Chikkala, Rajgopal Acharya, Gokhan Moray, Mehmet Haberal Sapana Verma, Inbaraj Balradja, Dibyajyoti Das, Rajesh Dey, Shaleen Agarwal, Subhash Gupta Letter to Edıtor
749-750 Traumatic Neuroma and Liver Retransplant Anna Mrzljak, Anita Skrtic, Slavko Gasparov, Branislav Kocman, Stipislav Jadrijevic, Tara Vuletic, Ivan Budimir Bekan, Danko Mikulic Volume: 18 Issue: 7 December 2020 808-813 Utility of Transjugular Intrahepatic Portosystemic Contents Shunt Placement for Maintaining Portal Vein Artıcle Patency in Candidates on Wait Lists Who Develop Thrombus 751-756 Alemtuzumab Induction and Steroid Minimization Mustafa Alani, Michael Rowley, Paul Kang, in IgA Nephropathy: A Matched-Cohort Analysis Steve Chen, Kevin Hirsch, Anil Seetharam Kevin Becker, Joseph Brooks, Graham Mitro, Michael Rees, Jorge Ortiz 814-822 Evaluation of Neuroimaging Findings of Central Nervous System Complications in Heart Transplant 757-762 Gene Expression of Toll-Like Receptors 2 and 4 in Recipients Renal Transplant Rejection Hale Turnaoglu, Ahmet Muhtesem Agildere, Mozhdeh Heidari, Padideh Ebadi, Sanaz Abbasi, Feride Kural Rahatli, FuldemYildirim Donmez, Afsoon Afshari, Ramin Yaghobi, Mehdi Salehipour, Ruhsen Ocal, Taner Sezer, Ufuk Can, Atilla Sezgin, Mohammad Hossein Karimi Sait Aslamaci
763-770 Management of Multiple Renal Arteries and Unusual 823-831 Therapeutic Potential of Bama Pig Adipose-Derived Venous Anatomy During Kidney Transplant: From Mesenchymal Stem Cells for the Treatment of a Simple Technical Problem to a Graft-Saving Carbon Tetrachloride-Induced Liver Fibrosis Procedure Xinran Wu, Shuang Zhang, Junhui Lai, Huidi Lu, Zivko Popov, Oliver Stankov, Sotir Stavridis, Yuchen Sun, Weijun Guan Skender Saidi, Ognen Ivanovski, Goce Spasovski, Koco Cakalaroski, Ninoslav Ivanovski Case Report
771-777 Prophylactic Wound Drainage in Renal Transplant: 832-833 Successful Kidney Transplant From a Brain Stem- A Survey of Practice Patterns in Australia and New Dead Donor Due To Lethal Methanol Poisoning Zealand Afshar Zomorrodi, Farzad Kakaei Miho Mugino, Taina Lee, Susanna Lam, Ahmer Hameed, Charbel Sandroussi, Steven Chadban, 834-837 En Bloc Kidney Transplant From a Pediatric Henry Pleass, Jerome Martin Laurence Donor to a Pediatric Recipient Through a Total Extraperitoneal Approach: A Case Report 778-784 Hidden Granzyme B-Mediated Injury in Chronic Kwangho Yang, Dongil Kim, Soohong Kim, Hyojung Ko, Active Antibody-Mediated Rejection Jaeryong Shim, Taebeom Lee, Jeho Ryu, Seongheon Kim, Brijesh Yadav, Narayan Prasad, Vikas Agarwal, Byunghyun Choi Vinita Agarwal, Manoj Jain 838-841 Pediatric Pure Red Cell Aplasia Caused by 785-790 Liver Allografts From Older Donors With or Tacrolimus After Living-Donor Liver Transplant Without Recovery of Thoracic Organs and Their Suguru Watanabe, Rieko Sakamoto, Impact on Hepatic Graft and Patient Survival Hidekazu Yamamoto, Masayuki Imaya, Ricci Kalayanamitra, Ashton Brooks, Sushrut Trakroo, Takahiro Yamashita, Tadashi Anann, Zakiyah Kadry, Ashokkumar Jain Kimitoshi Nakamura
791-795 Comparison of Standard and Modified Standard 842-846 Liver Transplant for Nonresectable Colorectal Organ Procurement Techniques for Deceased Cancer Liver Metastases in South Africa: A Single- Donors Center Case Series Cemalettin Koc, Sami Akbulut, Sezai Yilmaz Jean Botha, Georgia Demetriou, June Fabian, Harriet Etheredge 796-802 Living Donor Liver Transplant in Patients With Budd-Chiari Syndrome: A Single-Center Experience 847-850 Role of Fluorodeoxyglucose Positron Emission at Our University Hospital Tomogram Scan in Sirolimus-Induced Lung Toxicity: Mikal Obed, Mohammad Ibrahim Othman, A Rare Case Report Saeb Hammoudi, Mahmoud Abdelkader Chattab, Sarfraz Saleemi, Bader Alothman, Faisal Albaiz, Anwar Jarrad, Abdalla Bashir, Aiman Obed Sami Alrasheedi, Yaser Z. Shah, Aman Saleemi
803-807 Evaluation of Underlying Liver Disease and Its Letter to Edıtor Severity in Children Referred for Liver Transplant: a Single-Center Report From Nemazee Hospital of 851-852 Ex Vivo Lung Perfusion Using Whole Blood: How? Shiraz Mohamed S. A. Mohamed Seyed Mohsen Dehghani, Iraj Shahramian, Ali Bazi, Maryam Mohammadi Mofrad, Samira Mardani Financial Disclosure, Copyright Transfer, and Ethical Conduct Form
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POST-GRADUATE DEGREE PROGRAMS AT POST-GRADUATE DEGREE PROGRAMS AT MASTER MASTER LEVEL: LEVEL: - Anatomy - International Financial Reporting and Auditing - Medical Biology - American Culture and Literature - Medical Genetics - Museology - Nursing - Capital Markets - Nutrition And Genetics - Capital Markets (Distance Education) - Phsiotherapy And Rehabilitation - Banking and Finance - Public Health - Banking and Finance (Distance Education) - Exercise And Sportive Performance - Civil Law - Audiology And Speech- Voice Dıisorders - Medical Law - Audiology - Economics - Economy Law POST-GRADUATE DEGREE PROGRAMS AT - Health Care Management DOCTORATE LEVEL: - Insurance and Risk Management - Endodontics - International Trade and Marketing - Medical Biology - Business Administration - Medical Genetics - Business Administration (Distance Learning) - Nursing - Accounting and Finance - Nutrition and Dietetics - Marketing - Oral and Maxillofacial Surgery - Composition - Orthodontics - Musicology - Pediatric Dentistry - Performance - Periodontology - Psychology - Pharmacology - Public Law - Prosthodontics - Public Relations and Publicity - Public Health - Radio, Television and Cinema - Audiology - Social Work - Sociology Institute of Health Sciences - Interior Archictecture and Environmental Design Phone: +90 312 2466709 - Management Information Systems Web site: http://sabe.baskent.edu.tr/kw/index.php - Human Resource Management E-mail: [email protected] - Management Information Systems Address: Başkent Üniversitesi Bağlıca Kampüsü Sağlık Bilimleri - Technology and Knowledge Management Fakültesi Binası Fatih Sultan Mahallesi Eskişehir Yolu 18.km 06790 Etimesgut / ANKARA - Turkish Language and Literature POST-GRADUATE DEGREE PROGRAMS AT Institute of European Union and International DOCTORATE LEVEL: Relations: - Banking and Finance Tel: +90 312 2466841 – +90 312 2466666/2147 - Civil Law Web site: http://abu.baskent.edu.tr/kw/index.php - Business Administration E-mail: [email protected] - Accounting and Finance Address: Başkent Üniversitesi Bağlıca Kampüsü Sağlık Bilimleri Fakültesi Binası Fatih Sultan Mahallesi Eskişehir Yolu 18.km - Management and Organizations 06790 Etimesgut / ANKARA - Turkish Language and Literature
Institute of Social Sciences: INSTITUTE OF TRANSPLANTATION AND GENE Tel: +90 312 2466711 - +90 312 2466712 SECIENCES Web site: http://sbe.baskent.edu.tr/kw/index.php E-mail: sbe@ baskent.edu.tr Address: Başkent Üniversitesi Bağlıca Kampüsü Sağlık Bilimleri Institute of Transplantation and Gene Sciences: Fakültesi Binası Fatih Sultan Mahallesi Eskişehir Yolu 18.km Tel: +90 312 2466666 Web site: http://tgbe.baskent.edu.tr/kw/index.php 06790 Etimesgut / ANKARA E-mail: [email protected] Address: Atatürk Mahallesi İstiklal Caddesi N0: 27 06980 Kahramankazan/ ANKARA INSTITUTE OF EDUCATIONAL SCIENCES
POST-GRADUATE DEGREE PROGRAMS AT INSTITUTE OF BURN, FIRE AND NATURAL DISASTER MASTER LEVEL: - Computer Education and Instructional Technologies Institute of Transplantation and Gene Sciences: Education Tel: +90 312 2466666 - Computer Education and Instructional Technologies Web site: http://tgbe.baskent.edu.tr/kw/index.php Education (Distance Learning) E-mail: [email protected] - Curriculum and Instruction Address: Atatürk Mahallesi İstiklal Caddesi N0: 27 06980 - Educational Administration and Supervision Kahramankazan/ ANKARA - Educational Administration (Distance Learning) - English Language Teaching - Mathematics and Science DISTANCE EDUCATION RESEARCH AND APPLICATION - Elemantary Education Mathematics Teaching CENTER - Pre-School Education - Turkish Language Teaching Institute of Transplantation and Gene Sciences: - Teaching Turkish as a Foreign Language Tel: +90 312 2466666- 6849/ 6616 Web site: http://buzem.baskent.edu.tr/index.php/en/latest- announcements POST-GRADUATE DEGREE PROGRAMS AT DOCTORATE E-mail: [email protected] LEVEL: Address: Başkent University, Rectorate Building, Floor: -1, - Educational Administration Room: AB 107 - Elementary Mathematics Education Bağlıca Kampüsü Fatih Sultan Mahallesi Eskişehir Yolu 18.km 06790 Etimesgut / ANKARA Institute of Educational Sciences: Tel: +90 312 2466623 Web site: http://egbilens.baskent.edu.tr/kw/index.php E-mail: [email protected] Address: Başkent Üniversitesi Bağlıca Kampüsü Sağlık Bilimleri Fakültesi Binası Fatih Sultan Mahallesi Eskişehir Yolu 18.km 06790 Etimesgut / ANKARA
INSTITUTE OF EUROPEAN UNION AND INTERNATIONAL RELATIONS
POST-GRADUATE DEGREE PROGRAMS AT MASTER LEVEL: - European Union - International Relations POST-GRADUATE DEGREE PROGRAMS AT DOCTORATE LEVEL: - Political Science www.baskent.edu.tr