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Publisher: John Wiley and Sons   (Total: 1577 journals)

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Showing 1 - 200 of 1577 Journals sorted alphabetically
Abacus     Hybrid Journal   (Followers: 12, SJR: 0.48, h-index: 22)
About Campus     Hybrid Journal   (Followers: 5)
Academic Emergency Medicine     Hybrid Journal   (Followers: 61, SJR: 1.385, h-index: 91)
Accounting & Finance     Hybrid Journal   (Followers: 46, SJR: 0.547, h-index: 30)
ACEP NOW     Free   (Followers: 1)
Acta Anaesthesiologica Scandinavica     Hybrid Journal   (Followers: 49, SJR: 1.02, h-index: 88)
Acta Archaeologica     Hybrid Journal   (Followers: 144, SJR: 0.101, h-index: 9)
Acta Geologica Sinica (English Edition)     Hybrid Journal   (Followers: 3, SJR: 0.552, h-index: 41)
Acta Neurologica Scandinavica     Hybrid Journal   (Followers: 5, SJR: 1.203, h-index: 74)
Acta Obstetricia et Gynecologica Scandinavica     Hybrid Journal   (Followers: 15, SJR: 1.197, h-index: 81)
Acta Ophthalmologica     Hybrid Journal   (Followers: 5, SJR: 0.112, h-index: 1)
Acta Paediatrica     Hybrid Journal   (Followers: 56, SJR: 0.794, h-index: 88)
Acta Physiologica     Hybrid Journal   (Followers: 6, SJR: 1.69, h-index: 88)
Acta Polymerica     Hybrid Journal   (Followers: 9)
Acta Psychiatrica Scandinavica     Hybrid Journal   (Followers: 35, SJR: 2.518, h-index: 113)
Acta Zoologica     Hybrid Journal   (Followers: 6, SJR: 0.459, h-index: 29)
Acute Medicine & Surgery     Hybrid Journal   (Followers: 3)
Addiction     Hybrid Journal   (Followers: 33, SJR: 2.086, h-index: 143)
Addiction Biology     Hybrid Journal   (Followers: 12, SJR: 2.091, h-index: 57)
Adultspan J.     Hybrid Journal   (SJR: 0.127, h-index: 4)
Advanced Energy Materials     Hybrid Journal   (Followers: 24, SJR: 6.411, h-index: 86)
Advanced Engineering Materials     Hybrid Journal   (Followers: 26, SJR: 0.81, h-index: 81)
Advanced Functional Materials     Hybrid Journal   (Followers: 50, SJR: 5.21, h-index: 203)
Advanced Healthcare Materials     Hybrid Journal   (Followers: 13, SJR: 0.232, h-index: 7)
Advanced Materials     Hybrid Journal   (Followers: 251, SJR: 9.021, h-index: 345)
Advanced Materials Interfaces     Hybrid Journal   (Followers: 6, SJR: 1.177, h-index: 10)
Advanced Optical Materials     Hybrid Journal   (Followers: 5, SJR: 2.488, h-index: 21)
Advanced Science     Open Access   (Followers: 5)
Advanced Synthesis & Catalysis     Hybrid Journal   (Followers: 17, SJR: 2.729, h-index: 121)
Advances in Polymer Technology     Hybrid Journal   (Followers: 13, SJR: 0.344, h-index: 31)
Africa Confidential     Hybrid Journal   (Followers: 19)
Africa Research Bulletin: Economic, Financial and Technical Series     Hybrid Journal   (Followers: 12)
Africa Research Bulletin: Political, Social and Cultural Series     Hybrid Journal   (Followers: 9)
African Development Review     Hybrid Journal   (Followers: 35, SJR: 0.275, h-index: 17)
African J. of Ecology     Hybrid Journal   (Followers: 15, SJR: 0.477, h-index: 39)
Aggressive Behavior     Hybrid Journal   (Followers: 15, SJR: 1.391, h-index: 66)
Aging Cell     Open Access   (Followers: 10, SJR: 4.374, h-index: 95)
Agribusiness : an Intl. J.     Hybrid Journal   (Followers: 6, SJR: 0.627, h-index: 14)
Agricultural and Forest Entomology     Hybrid Journal   (Followers: 14, SJR: 0.925, h-index: 43)
Agricultural Economics     Hybrid Journal   (Followers: 44, SJR: 1.099, h-index: 51)
AIChE J.     Hybrid Journal   (Followers: 30, SJR: 1.122, h-index: 120)
Alcoholism and Drug Abuse Weekly     Hybrid Journal   (Followers: 7)
Alcoholism Clinical and Experimental Research     Hybrid Journal   (Followers: 7, SJR: 1.416, h-index: 125)
Alimentary Pharmacology & Therapeutics     Hybrid Journal   (Followers: 34, SJR: 2.833, h-index: 138)
Alimentary Pharmacology & Therapeutics Symposium Series     Hybrid Journal   (Followers: 3)
Allergy     Hybrid Journal   (Followers: 49, SJR: 3.048, h-index: 129)
Alternatives to the High Cost of Litigation     Hybrid Journal   (Followers: 3)
American Anthropologist     Hybrid Journal   (Followers: 133, SJR: 0.951, h-index: 61)
American Business Law J.     Hybrid Journal   (Followers: 24, SJR: 0.205, h-index: 17)
American Ethnologist     Hybrid Journal   (Followers: 91, SJR: 2.325, h-index: 51)
American J. of Economics and Sociology     Hybrid Journal   (Followers: 27, SJR: 0.211, h-index: 26)
American J. of Hematology     Hybrid Journal   (Followers: 31, SJR: 1.761, h-index: 77)
American J. of Human Biology     Hybrid Journal   (Followers: 12, SJR: 1.018, h-index: 58)
American J. of Industrial Medicine     Hybrid Journal   (Followers: 16, SJR: 0.993, h-index: 85)
American J. of Medical Genetics Part A     Hybrid Journal   (Followers: 15, SJR: 1.115, h-index: 61)
American J. of Medical Genetics Part B: Neuropsychiatric Genetics     Hybrid Journal   (Followers: 3, SJR: 1.771, h-index: 107)
American J. of Medical Genetics Part C: Seminars in Medical Genetics     Partially Free   (Followers: 5, SJR: 2.315, h-index: 79)
American J. of Physical Anthropology     Hybrid Journal   (Followers: 36, SJR: 1.41, h-index: 88)
American J. of Political Science     Hybrid Journal   (Followers: 254, SJR: 5.101, h-index: 114)
American J. of Primatology     Hybrid Journal   (Followers: 15, SJR: 1.197, h-index: 63)
American J. of Reproductive Immunology     Hybrid Journal   (Followers: 3, SJR: 1.347, h-index: 75)
American J. of Transplantation     Hybrid Journal   (Followers: 16, SJR: 2.792, h-index: 140)
American J. on Addictions     Hybrid Journal   (Followers: 9, SJR: 0.843, h-index: 57)
Anaesthesia     Hybrid Journal   (Followers: 126, SJR: 1.404, h-index: 88)
Analyses of Social Issues and Public Policy     Hybrid Journal   (Followers: 10, SJR: 0.397, h-index: 18)
Analytic Philosophy     Hybrid Journal   (Followers: 16)
Anatomia, Histologia, Embryologia: J. of Veterinary Medicine Series C     Hybrid Journal   (Followers: 3, SJR: 0.295, h-index: 27)
Anatomical Sciences Education     Hybrid Journal   (Followers: 1, SJR: 0.633, h-index: 24)
Andrologia     Hybrid Journal   (Followers: 2, SJR: 0.528, h-index: 45)
Andrology     Hybrid Journal   (Followers: 2, SJR: 0.979, h-index: 14)
Angewandte Chemie     Hybrid Journal   (Followers: 159)
Angewandte Chemie Intl. Edition     Hybrid Journal   (Followers: 211, SJR: 6.229, h-index: 397)
Animal Conservation     Hybrid Journal   (Followers: 36, SJR: 1.576, h-index: 62)
Animal Genetics     Hybrid Journal   (Followers: 8, SJR: 0.957, h-index: 67)
Animal Science J.     Hybrid Journal   (Followers: 6, SJR: 0.569, h-index: 24)
Annalen der Physik     Hybrid Journal   (Followers: 5, SJR: 1.46, h-index: 40)
Annals of Anthropological Practice     Partially Free   (Followers: 2, SJR: 0.187, h-index: 5)
Annals of Applied Biology     Hybrid Journal   (Followers: 8, SJR: 0.816, h-index: 56)
Annals of Clinical and Translational Neurology     Open Access   (Followers: 1)
Annals of Human Genetics     Hybrid Journal   (Followers: 9, SJR: 1.191, h-index: 67)
Annals of Neurology     Hybrid Journal   (Followers: 44, SJR: 5.584, h-index: 241)
Annals of Noninvasive Electrocardiology     Hybrid Journal   (Followers: 2, SJR: 0.531, h-index: 38)
Annals of Public and Cooperative Economics     Hybrid Journal   (Followers: 9, SJR: 0.336, h-index: 23)
Annals of the New York Academy of Sciences     Hybrid Journal   (Followers: 5, SJR: 2.389, h-index: 189)
Annual Bulletin of Historical Literature     Hybrid Journal   (Followers: 12)
Annual Review of Information Science and Technology     Hybrid Journal   (Followers: 14)
Anthropology & Education Quarterly     Hybrid Journal   (Followers: 24, SJR: 0.72, h-index: 31)
Anthropology & Humanism     Hybrid Journal   (Followers: 17, SJR: 0.137, h-index: 3)
Anthropology News     Hybrid Journal   (Followers: 15)
Anthropology of Consciousness     Hybrid Journal   (Followers: 11, SJR: 0.172, h-index: 5)
Anthropology of Work Review     Hybrid Journal   (Followers: 11, SJR: 0.256, h-index: 5)
Anthropology Today     Hybrid Journal   (Followers: 92, SJR: 0.545, h-index: 15)
Antipode     Hybrid Journal   (Followers: 45, SJR: 2.212, h-index: 69)
Anz J. of Surgery     Hybrid Journal   (Followers: 6, SJR: 0.432, h-index: 59)
Anzeiger für Schädlingskunde     Hybrid Journal   (Followers: 1)
Apmis     Hybrid Journal   (Followers: 1, SJR: 0.855, h-index: 73)
Applied Cognitive Psychology     Hybrid Journal   (Followers: 69, SJR: 0.754, h-index: 69)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 7, SJR: 0.632, h-index: 58)
Applied Psychology     Hybrid Journal   (Followers: 140, SJR: 1.023, h-index: 64)
Applied Psychology: Health and Well-Being     Hybrid Journal   (Followers: 48, SJR: 0.868, h-index: 13)
Applied Stochastic Models in Business and Industry     Hybrid Journal   (Followers: 5, SJR: 0.613, h-index: 24)
Aquaculture Nutrition     Hybrid Journal   (Followers: 14, SJR: 1.025, h-index: 55)
Aquaculture Research     Hybrid Journal   (Followers: 31, SJR: 0.807, h-index: 60)
Aquatic Conservation Marine and Freshwater Ecosystems     Hybrid Journal   (Followers: 34, SJR: 1.047, h-index: 57)
Arabian Archaeology and Epigraphy     Hybrid Journal   (Followers: 11, SJR: 0.453, h-index: 11)
Archaeological Prospection     Hybrid Journal   (Followers: 12, SJR: 0.922, h-index: 21)
Archaeology in Oceania     Hybrid Journal   (Followers: 13, SJR: 0.745, h-index: 18)
Archaeometry     Hybrid Journal   (Followers: 27, SJR: 0.809, h-index: 48)
Archeological Papers of The American Anthropological Association     Hybrid Journal   (Followers: 14, SJR: 0.156, h-index: 2)
Architectural Design     Hybrid Journal   (Followers: 25, SJR: 0.261, h-index: 9)
Archiv der Pharmazie     Hybrid Journal   (Followers: 4, SJR: 0.628, h-index: 43)
Archives of Drug Information     Hybrid Journal   (Followers: 4)
Archives of Insect Biochemistry and Physiology     Hybrid Journal   (SJR: 0.768, h-index: 54)
Area     Hybrid Journal   (Followers: 12, SJR: 0.938, h-index: 57)
Art History     Hybrid Journal   (Followers: 224, SJR: 0.153, h-index: 13)
Arthritis & Rheumatology     Hybrid Journal   (Followers: 50, SJR: 1.984, h-index: 20)
Arthritis Care & Research     Hybrid Journal   (Followers: 28, SJR: 2.256, h-index: 114)
Artificial Organs     Hybrid Journal   (Followers: 1, SJR: 0.872, h-index: 60)
ASHE Higher Education Reports     Hybrid Journal   (Followers: 14)
Asia & the Pacific Policy Studies     Open Access   (Followers: 14)
Asia Pacific J. of Human Resources     Hybrid Journal   (Followers: 315, SJR: 0.494, h-index: 19)
Asia Pacific Viewpoint     Hybrid Journal   (SJR: 0.616, h-index: 26)
Asia-Pacific J. of Chemical Engineering     Hybrid Journal   (Followers: 7, SJR: 0.345, h-index: 20)
Asia-pacific J. of Clinical Oncology     Hybrid Journal   (Followers: 6, SJR: 0.554, h-index: 14)
Asia-Pacific J. of Financial Studies     Hybrid Journal   (SJR: 0.241, h-index: 7)
Asia-Pacific Psychiatry     Hybrid Journal   (Followers: 3, SJR: 0.377, h-index: 7)
Asian Economic J.     Hybrid Journal   (Followers: 8, SJR: 0.234, h-index: 21)
Asian Economic Policy Review     Hybrid Journal   (Followers: 4, SJR: 0.196, h-index: 12)
Asian J. of Control     Hybrid Journal   (SJR: 0.862, h-index: 34)
Asian J. of Endoscopic Surgery     Hybrid Journal   (SJR: 0.394, h-index: 7)
Asian J. of Organic Chemistry     Hybrid Journal   (Followers: 4, SJR: 1.443, h-index: 19)
Asian J. of Social Psychology     Hybrid Journal   (Followers: 5, SJR: 0.665, h-index: 37)
Asian Politics and Policy     Hybrid Journal   (Followers: 12, SJR: 0.207, h-index: 7)
Asian Social Work and Policy Review     Hybrid Journal   (Followers: 5, SJR: 0.318, h-index: 5)
Asian-pacific Economic Literature     Hybrid Journal   (Followers: 5, SJR: 0.168, h-index: 15)
Assessment Update     Hybrid Journal   (Followers: 4)
Astronomische Nachrichten     Hybrid Journal   (Followers: 2, SJR: 0.701, h-index: 40)
Atmospheric Science Letters     Open Access   (Followers: 29, SJR: 1.332, h-index: 27)
Austral Ecology     Hybrid Journal   (Followers: 13, SJR: 1.095, h-index: 66)
Austral Entomology     Hybrid Journal   (Followers: 10, SJR: 0.524, h-index: 28)
Australasian J. of Dermatology     Hybrid Journal   (Followers: 8, SJR: 0.714, h-index: 40)
Australasian J. On Ageing     Hybrid Journal   (Followers: 7, SJR: 0.39, h-index: 22)
Australian & New Zealand J. of Statistics     Hybrid Journal   (Followers: 13, SJR: 0.275, h-index: 28)
Australian Accounting Review     Hybrid Journal   (Followers: 4, SJR: 0.709, h-index: 14)
Australian and New Zealand J. of Family Therapy (ANZJFT)     Hybrid Journal   (Followers: 3, SJR: 0.382, h-index: 12)
Australian and New Zealand J. of Obstetrics and Gynaecology     Hybrid Journal   (Followers: 43, SJR: 0.814, h-index: 49)
Australian and New Zealand J. of Public Health     Hybrid Journal   (Followers: 11, SJR: 0.82, h-index: 62)
Australian Dental J.     Hybrid Journal   (Followers: 7, SJR: 0.482, h-index: 46)
Australian Economic History Review     Hybrid Journal   (Followers: 4, SJR: 0.171, h-index: 12)
Australian Economic Papers     Hybrid Journal   (Followers: 25, SJR: 0.23, h-index: 9)
Australian Economic Review     Hybrid Journal   (Followers: 6, SJR: 0.357, h-index: 21)
Australian Endodontic J.     Hybrid Journal   (Followers: 3, SJR: 0.513, h-index: 24)
Australian J. of Agricultural and Resource Economics     Hybrid Journal   (Followers: 3, SJR: 0.765, h-index: 36)
Australian J. of Grape and Wine Research     Hybrid Journal   (Followers: 5, SJR: 0.879, h-index: 56)
Australian J. of Politics & History     Hybrid Journal   (Followers: 13, SJR: 0.203, h-index: 14)
Australian J. of Psychology     Hybrid Journal   (Followers: 18, SJR: 0.384, h-index: 30)
Australian J. of Public Administration     Hybrid Journal   (Followers: 398, SJR: 0.418, h-index: 29)
Australian J. of Rural Health     Hybrid Journal   (Followers: 4, SJR: 0.43, h-index: 34)
Australian Occupational Therapy J.     Hybrid Journal   (Followers: 68, SJR: 0.59, h-index: 29)
Australian Psychologist     Hybrid Journal   (Followers: 11, SJR: 0.331, h-index: 31)
Australian Veterinary J.     Hybrid Journal   (Followers: 19, SJR: 0.459, h-index: 45)
Autism Research     Hybrid Journal   (Followers: 31, SJR: 2.126, h-index: 39)
Autonomic & Autacoid Pharmacology     Hybrid Journal   (SJR: 0.371, h-index: 29)
Banks in Insurance Report     Hybrid Journal   (Followers: 1)
Basic & Clinical Pharmacology & Toxicology     Hybrid Journal   (Followers: 10, SJR: 0.539, h-index: 70)
Basic and Applied Pathology     Open Access   (Followers: 2, SJR: 0.113, h-index: 4)
Basin Research     Hybrid Journal   (Followers: 5, SJR: 1.54, h-index: 60)
Bauphysik     Hybrid Journal   (Followers: 2, SJR: 0.194, h-index: 5)
Bauregelliste A, Bauregelliste B Und Liste C     Hybrid Journal  
Bautechnik     Hybrid Journal   (Followers: 1, SJR: 0.321, h-index: 11)
Behavioral Interventions     Hybrid Journal   (Followers: 9, SJR: 0.297, h-index: 23)
Behavioral Sciences & the Law     Hybrid Journal   (Followers: 23, SJR: 0.736, h-index: 57)
Berichte Zur Wissenschaftsgeschichte     Hybrid Journal   (Followers: 9, SJR: 0.11, h-index: 5)
Beton- und Stahlbetonbau     Hybrid Journal   (Followers: 2, SJR: 0.493, h-index: 14)
Biochemistry and Molecular Biology Education     Hybrid Journal   (Followers: 6, SJR: 0.311, h-index: 26)
Bioelectromagnetics     Hybrid Journal   (Followers: 1, SJR: 0.568, h-index: 64)
Bioengineering & Translational Medicine     Open Access  
BioEssays     Hybrid Journal   (Followers: 10, SJR: 3.104, h-index: 155)
Bioethics     Hybrid Journal   (Followers: 14, SJR: 0.686, h-index: 39)
Biofuels, Bioproducts and Biorefining     Hybrid Journal   (Followers: 1, SJR: 1.725, h-index: 56)
Biological J. of the Linnean Society     Hybrid Journal   (Followers: 15, SJR: 1.172, h-index: 90)
Biological Reviews     Hybrid Journal   (Followers: 3, SJR: 6.469, h-index: 114)
Biologie in Unserer Zeit (Biuz)     Hybrid Journal   (Followers: 42, SJR: 0.12, h-index: 1)
Biology of the Cell     Full-text available via subscription   (Followers: 9, SJR: 1.812, h-index: 69)
Biomedical Chromatography     Hybrid Journal   (Followers: 6, SJR: 0.572, h-index: 49)
Biometrical J.     Hybrid Journal   (Followers: 5, SJR: 0.784, h-index: 44)
Biometrics     Hybrid Journal   (Followers: 37, SJR: 1.906, h-index: 96)
Biopharmaceutics and Drug Disposition     Hybrid Journal   (Followers: 10, SJR: 0.715, h-index: 44)
Biopolymers     Hybrid Journal   (Followers: 18, SJR: 1.199, h-index: 104)
Biotechnology and Applied Biochemistry     Hybrid Journal   (Followers: 45, SJR: 0.415, h-index: 55)
Biotechnology and Bioengineering     Hybrid Journal   (Followers: 136, SJR: 1.633, h-index: 146)
Biotechnology J.     Hybrid Journal   (Followers: 13, SJR: 1.185, h-index: 51)
Biotechnology Progress     Hybrid Journal   (Followers: 39, SJR: 0.736, h-index: 101)
Biotropica     Hybrid Journal   (Followers: 18, SJR: 1.374, h-index: 71)
Bipolar Disorders     Hybrid Journal   (Followers: 9, SJR: 2.592, h-index: 100)
Birth     Hybrid Journal   (Followers: 35, SJR: 0.763, h-index: 64)
Birth Defects Research Part A : Clinical and Molecular Teratology     Hybrid Journal   (Followers: 2, SJR: 0.727, h-index: 77)
Birth Defects Research Part B: Developmental and Reproductive Toxicology     Hybrid Journal   (Followers: 5, SJR: 0.468, h-index: 47)
Birth Defects Research Part C : Embryo Today : Reviews     Hybrid Journal   (SJR: 1.513, h-index: 55)
BJOG : An Intl. J. of Obstetrics and Gynaecology     Partially Free   (Followers: 222, SJR: 2.083, h-index: 125)

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Journal Cover American Journal of Transplantation
  [SJR: 2.792]   [H-I: 140]   [16 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1600-6135 - ISSN (Online) 1600-6143
   Published by John Wiley and Sons Homepage  [1577 journals]
  • Utility of Protocol Kidney Biopsies for De Novo Donor Specific Antibodies
    • Authors: Sandesh Parajuli; Patrick K. Reville, Thomas M. Ellis, Arjang Djamali, Didier A. Mandelbrot
      Abstract: There is limited information about the role of protocol kidney biopsies for de novo donor specific antibodies (dnDSA) in kidney transplant recipients, especially in those with stable graft function. We initiated a routine post-transplant DSA monitoring and surveillance biopsy program for dnDSA since 2014. We identified 45 kidney transplant recipients with dnDSA detected between January 2014 and February 2017 that underwent kidney biopsy within 60 days of detection of dnDSA. 29 (64%) had stable graft function and 16 (36%) had impaired graft function at the time of dnDSA detection. Even in the group with stable graft function, we found a high rate of rejection (53%), on biopsy. 88% of patients with impaired graft function had rejection. Those patients with impaired graft function had significantly lower eGFR at 12 months post biopsy and at last follow up. Those with impaired graft function had more graft failures; however, this result was not statistically significant. The high rate of asymptomatic rejection, and the fact that outcomes in asymptomatic patients are poor, is in support of the utility of surveillance biopsies in patients with dnDSA.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-14T04:50:57.592009-05:
      DOI: 10.1111/ajt.14466
       
  • Deletion of the Activating NK Cell Receptor NKG2D Accelerates Rejection of
           Cardiac Allografts
    • Authors: Cornelia Fabritius; Paul Viktor Ritschl, Thomas Resch, Mario Roth, Susanne Ebner, Julia Günther, Vanessa Mellitzer, Anh-Vu Nguyen, Johann Pratschke, Martina Sauter, Karin Klingel, Katja Kotsch
      Abstract: It has already been shown that neutralization of the activating NK cell receptor NKG2D in combination with co-stimulation blockade prolongs graft survival of vascularized transplants. In order to clarify the underlying cellular mechanisms, we transplanted complete MHC-disparate BALB/c-derived cardiac grafts into C57BL/6 wildtypes or mice deficient for NKG2D (Klrk1-/-). Although median survival was eight days for both recipient groups, we detected already at day 5 post-transplantation significantly greater intragraft frequencies of NKp46+ NK cells in Klrk1-/- recipients than in wildtypes. This was followed by a significantly greater infiltration of CD4+, but a lesser infiltration of CD8+ T cell frequencies. Contrary to published observations, co-stimulation blockade with CTLA4-Ig resulted in a significant acceleration of cardiac rejection by Klrk1-/- recipients, and this result was confirmed by applying a neutralizing antibody against NKG2D to wildtypes. In both experimental set-ups,grafts derived from Klrk1-/- recipients were characterized by significantly higher levels of IFNγ mRNA and both CD4+ and CD8+ T cells displayed a greater capacity for degranulation and IFNγ production. In summary, our results clearly illustrate that NKG2D expression in the recipient is important for cardiac allograft survival, thus supporting the hypothesis that impairment of NK cells prevents the establishment of graft acceptance.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-14T04:50:56.052912-05:
      DOI: 10.1111/ajt.14467
       
  • Harms of Unsuccessful Donation After Circulatory Death: An Exploratory
           Study
    • Authors: Lauren J Taylor; Anne Buffington, Joseph R Scalea, Norman Fost, Kenneth D Croes, Joshua D Mezrich, Margaret L Schwarze
      Abstract: While donation after circulatory death (DCD) has expanded options for organ donation, many who wish to donate are still unable to do so. We conducted face-to-face interviews with family members (n=15) who had direct experience with unsuccessful DCD and five focus groups with professionals involved in the donation process. We used qualitative content analysis to characterize harms of non-donation as perceived by participants. Participants reported a broad spectrum of harms impacting organ recipients, donors and donor families. Harms included waste of precious life-giving organs and hospital resources, inability to honor the donor's memory and character, and impaired ability for families to make sense of tragedy and cope with loss. Donor families empathized with the initial hope and ultimate despair of potential recipients who must continue their wait on the transplant list. Focus group members reinforced these findings and highlighted the struggle of families to navigate the uncertainty regarding the timing of death during the donation process. While families reported significant harm, many appreciated the donation attempt. These findings highlight the importance of organ donation to donor families and the difficult experiences associated with current processes that could inform development of alternative donation strategies.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-14T04:45:41.770664-05:
      DOI: 10.1111/ajt.14464
       
  • Incidence and outcomes of primary central nervous system lymphoma in solid
           organ transplant recipients
    • Authors: Parag Mahale; Meredith S. Shiels, Charles F. Lynch, Eric A. Engels
      Abstract: Primary central nervous system lymphoma (PCNSL) risk is greatly increased in immunosuppressed HIV-infected people. Using data from the United States transplant registry linked with 17 cancer registries (1987-2014), we studied PCNSL and systemic non-Hodgkin lymphoma (NHL) in 288,029 solid organ transplant recipients. Transplant recipients had elevated incidence for PCNSL compared with the general population (standardized incidence ratio=65.1; N=168), and this elevation was stronger than for systemic NHL (standardized incidence ratio=11.5; N=2,043). Compared to kidney recipients, PCNSL incidence was lower in liver recipients (adjusted incidence rate ratio [aIRR]=0.52), similar in heart and/or lung recipients, and higher in other/multiple organ recipients (aIRR=2.45). PCNSL incidence was higher in Asians/Pacific Islanders than non-Hispanic whites (aIRR=2.09); after induction immunosuppression with alemtuzumab (aIRR=3.12), monoclonal antibodies (aIRR=1.83), or polyclonal antibodies (aIRR=2.03); in recipients who were Epstein-Barr virus-seronegative at the time of transplant and at risk of primary infection (aIRR=1.95); and within the first 1.5 years after transplant (aIRR>2.00). Compared to other recipients, those with PCNSL had increased risk of death (adjusted hazard ratio [aHR]=11.79) or graft failure/retransplantation (aHR=3.24). Recipients with PCNSL also had higher mortality than those with systemic NHL (aHR=1.48). In conclusion, PCNSL risk is highly elevated among transplant recipients, and it carries a poor prognosis.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-14T04:45:21.572117-05:
      DOI: 10.1111/ajt.14465
       
  • Laparoscopic Sleeve Gastrectomy Improves Renal Transplant Candidacy and
           Post-Transplant Outcomes in Morbidly Obese Patients
    • Authors: Y. Kim; A.D. Jung, V.K. Dhar, J.S. Tadros, D.P. Schauer, E.P. Smith, D.J. Hanseman, M.C. Cuffy, R.R. Alloway, A.R. Shields, S.A. Shah, E.S. Woodle, T.S. Diwan
      Abstract: Morbid obesity is a barrier to KT due to inferior outcomes, including higher rates of new-onset diabetes after transplantation (NODAT), delayed graft function (DGF), and graft failure. LSG increases transplant eligibility by reducing body mass index (BMI) in KT candidates, but the effect of surgical weight loss on post-transplant outcomes is unknown. Reviewing single-center medical records, we identified all patients who underwent LSG prior to KT from 2011-2016 (n=20). Post-LSG kidney recipients were compared with similar-BMI recipients who did not undergo LSG, using 2:1 direct matching for patient factors. McNemar's test and signed-rank test were used to compare groups. Among post-LSG patients, mean BMI was 41.5±4.4 kg/m2 at initial encounter, which decreased to 32.3±2.9 kg/m2 prior to KT (p
      PubDate: 2017-08-14T04:45:19.685146-05:
      DOI: 10.1111/ajt.14463
       
  • The Kidney Allocation System Does Not Appropriately Stratify Risk of
           Pediatric Donor Kidneys: Implications for Pediatric Recipients
    • Authors: S.M. Nazarian; A.W. Peng, B. Duggirala, M. Gupta, T. Bittermann, S. Amaral, M.H. Levine
      Abstract: Kidney Allocation System (KAS) was enacted in 2014 to improve graft utility, while facilitating transplantation of highly-sensitized patients and preserving pediatric access to high-quality kidneys. Central to this system is the Kidney Donor Profile Index (KDPI), a metric intended to predict transplant outcomes based on donor characteristics but derived using only adult donors. We posited that KAS had inadvertently altered the profile and quantity of kidneys made available to pediatric recipients. This question arose from our observation that most pediatric donors carry a KDPI over 35 and have therefore been rendered relatively inaccessible to pediatric recipients under KAS. Here we explore early trends in pediatric transplantation following KAS, including 1) use of pediatric donors, 2) use of Public Health System (PHS) high infectious risk donors, 3) wait time, and 4) living donor transplantation. We note some concerning preliminary changes following KAS implementation, including the allocation of fewer deceased donor pediatric kidneys to children and stagnation in pediatric wait times. Moreover, the poor predictive power of the KDPI for adult donors appears to be even worse when applied to pediatric donors. These early trends warrant further observation and consideration of changes in pediatric kidney allocation if they persist.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-14T04:40:25.552855-05:
      DOI: 10.1111/ajt.14462
       
  • Response to “Minimization of Ischemic Cholangiopathy in Donation after
           Cardiac Death Liver Transplantation: Is it Thrombolytic Therapy or Warm
           Ischemic Time Stringency and Donor Bile Duct Flush'
    • Authors: H. Bohorquez; G E Loss
      Abstract: We thank Giorgakis and colleagues for their interest in our recent published article (1, 2). Since the etiology of ischemic cholangiopathy (IC) in Donation after Cardiac Death (DCD) for Liver Transplantation (LT) is not well defined, hypotheses include ischemia–reperfusion injury, microvascular thrombosis, cytotoxic injury, and impaired biliary epithelial regeneration (3-5), adopting a multifaceted protocol to optimize perioperative conditions is essential. We concur with their observation that fast organ recovery with rapid decompression, in-situ aortic and portal flushing, biliary tree flushing –and in our institution, retrograde venous flushing-, keep short ischemic times, careful donor–recipient selection and pristine technical implantation are imperative to good outcomes.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-12T02:50:23.222358-05:
      DOI: 10.1111/ajt.14460
       
  • In-situ split liver splitting under extra-corporeal membrane oxygenation
           in brain-dead donor
    • Authors: Assalino Michela; Pietro Majno, Christian Toso, Thierry Berney, Raphaël Giraud, Philipp Dutkowski, Axel Andres, Barbara Wildhaber, Laure Elkrief
      Abstract: Hemodynamic instability is generally considered as a contraindication to liver splitting, in particular when using an in-situ technique. We describe the cases of two young donors with brain death in whom refractory cardiac arrest and hemodynamic instability were supported by veno-arterial extracorporeal membrane oxygenation (VA-ECMO), allowing uneventful in situ splitting. Two adult and two pediatric liver recipients were successfully transplanted with immediate graft function. Favorable outcomes were also observed for the other transplanted organs, including one heart, two lungs and four kidneys. Refractory cardiac arrest and hemodynamic instability corrected by VA-ECMO should not be considered as a contraindication to in-situ liver splitting.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-12T02:50:22.15046-05:0
      DOI: 10.1111/ajt.14461
       
  • Long- term outcome of renal transplantation from octogenarian donors: A
           multicenter controlled study
    • Authors: Piero Ruggenenti; Cristina Silvestre, Luigino Boschiero, Giovanni Rota, Lucrezia Furian, Annalisa Perna, Giuseppe Rossini, Giuseppe Remuzzi, Paolo Rigotti
      Abstract: To assess whether biopsy-guided selection of kidneys from very old brain-death donors enables more successful transplantations, this multicenter, observational study compared graft survival between 37 Recipients of one or two histologically evaluated kidneys from>80-years-old donors and 198 Reference-Recipients of non-histologically evaluated single grafts from ≤60-year-old donors (transplant period: 2006-2013 at three Italian Centers). Over a median (IQR) of 25 (13-42) months, two Recipients (5.4%) and 10 Reference-Recipients (5.1%) required dialysis [crude and donor age- and sex-adjusted HRs (95% CI): 1.55 (0.34-7.12), p=0.576 and 1.41 (0.10-19.54), p=0.798, respectively]. Shared frailty analyses confirmed similar outcomes in a 1:2 propensity score study comparing Recipients with 74 Reference-Recipients matched by center, year, donor and recipient sex and age. Serum creatinine was similar across groups over 84-month follow-up. Recipients had remarkably shorter waiting times than Reference-Recipients and Matched-Reference-Recipients [7.5 (4.0-19.5) vs 36 (19-56) and 40 (24-56) months, respectively, p
      PubDate: 2017-08-09T07:50:43.156396-05:
      DOI: 10.1111/ajt.14459
       
  • Exercise capacity in young adults after hematopoietic cell transplantation
           in childhood
    • Authors: Anders Öberg; Margareta Genberg, Andrei Malinovschi, Hans Hedenström, Per Frisk
      Abstract: A symptom-limited incremental cycle ergometer test was performed in 17 young adults treated with hematopoietic cell transplantation and total body irradiation for hematological malignancies during childhood. They were compared with 17 sex- and age-matched healthy controls. Assessments of pulmonary function, cardiac function, body composition and levels of growth hormone were also included. The median follow-up was 17.7 years. Patients achieved 63.2% of the predicted peak workload, whereas controls achieved 96.1% (p80% (p
      PubDate: 2017-08-08T18:01:27.480558-05:
      DOI: 10.1111/ajt.14456
       
  • The Kidney Allocation System Claims Equity;It Is Time to Review Utility
           and Fairness
    • Authors: G. B. Klintmalm; B. Kaplan
      Abstract: The current kidney allocation system (KAS) implemented by the United Network for Organ Sharing in December 2014 was intended to balance inequities in kidney allocation while increasing utility by transplanting kidneys expected to last the longest in patients expected to live the longest. In its first iteration, termed Life Years from Transplant (LYFT), a fairly simple system of allocation was proposed to allocate kidneys based on this principle. LYFT, as opposed to our current process, also addressed the need to have a codified system to allocate kidneys unsuitable for younger patients to older recipients, such that utility could be maximized across the spectrum of potential recipients. Due to political pressures, LYFT was not instituted and our current KAS was implemented as a compromise solution (1).
      PubDate: 2017-08-08T18:01:21.530438-05:
      DOI: 10.1111/ajt.14457
       
  • Pure Laparoscopic Living Donor Hepatectomy: Focus on 55 Donors Undergoing
           Right Hepatectomy
    • Authors: K. S. Suh; S. K. Hong, K. W. Lee, N. J. Yi, H. S. Kim, S. W. Ahn, K. C. Yoon, J. Y. Choi, D. Oh, H. Kim
      Abstract: Although laparoscopic donor hepatectomy is increasingly common, few centers with substantial experience have reported the results of pure laparoscopic donor right hepatectomy (PLDRH). Here, we report the experiences of 60 consecutive liver donors undergoing pure laparoscopic donor hepatectomy (PLDH), with most undergoing right hepatectomy. None of the 60 donors who underwent PLDH had intraoperative complications and none required transfusions, reoperation, or conversion to open hepatectomy. Forty-five donors who underwent PLDRH between November 2015 and December 2016 were compared with 42 who underwent conventional donor right hepatectomy (CDRH) between May 2013 and February 2014. The total operation time was longer (330.7 vs. 280.0 minutes; P
      PubDate: 2017-08-08T18:01:14.416063-05:
      DOI: 10.1111/ajt.14455
       
  • Heparin-binding protein, lysozyme and inflammatory cytokines in
           bronchoalveolar lavage fluid as diagnostic tools for pulmonary infection
           in lung transplanted patients
    • Authors: Anna Stjärne Aspelund; Helena Hammarström, Malin Inghammar, Hillevi Larsson, Lennart Hansson, Bertil Christensson, Lisa I. Påhlman
      Abstract: Pulmonary infection is a common complication after lung transplantation and early detection is crucial for outcome. However, the condition can be clinically difficult to diagnose and to distinguish from rejection. The aim of this prospective study was to evaluate Heparin-binding protein (HBP), lysozyme and the cytokines Interleukin (IL)-1β, IL-6, IL-8, IL-10 and Tumour Necrosis Factor (TNF) in bronchoalveolar lavage fluid (BALF) as potential biomarkers for pulmonary infection in lung transplanted (Lntx) patients.One hundred and thirteen BALF samples from 29 Lntx recipients were collected at routine scheduled bronchoscopies at 3 and 6 months, or on clinical indication. Samples were classified into no, possible, probable or definite infection at the time of sampling. Rejection was defined by biopsy results. HBP, lysozyme and cytokines were analysed in BALF and correlated to likelihood of infection and rejection. All biomarkers were significantly increased in BALF during infection, while patients with rejection presented low levels that were comparable to non-infection samples. HBP, IL-1β and IL-8 were the best diagnostic markers of infection with area under the receiver operating characteristic curve values of 0,88, 0.91 and 0.90 respectively. In conclusion, HBP, IL-1β and IL-8 could be useful diagnostic markers of pulmonary infection in Lntx patients.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-08T18:01:06.496289-05:
      DOI: 10.1111/ajt.14458
       
  • iNKT cell activation plus T-cell transfer establishes complete chimerism
           in a murine sublethal bone marrow transplant model
    • Authors: Rumi Ishii; Toshihito Hirai, Satoshi Miyairi, Kazuya Omoto, Masayoshi Okumi, Yasuyuki Ishii, Kazunari Tanabe
      Abstract: Transplant tolerance induction makes it possible to preserve functional grafts for a lifetime without immunosuppressants. One powerful method is to generate mixed hematopoietic chimeras in recipients by adoptive transfer of donor-derived bone marrow cells (BMCs). In our murine transplantation model, we established a novel method for mixed chimera generation using sublethal irradiation, CD40-CD40L blockade, and invariant natural killer T-cell activation. However, numerous BMCs that are required to achieve stable chimerism makes it difficult to apply this model for human transplantation. Here, we show that donor-derived splenic T cells could contribute to not only the reduction of BMC usage but also the establishment of complete chimerism in model mice. By cotransfer of T cells together even with one-fourth of the BMCs used in our original method, the recipient mice yielded complete chimerism and could acquire donor-specific skin-allograft tolerance. The complete chimeric mice did not show any remarks of graft versus host reaction in vivo and in vitro. Inhibition of the apoptotic signal resulted in increase in host-derived CD8+ T cells and chimerism brake. These results suggest that donor-derived splenic T cells having veto activity play a role in the depletion of host-derived CD8+ T cells and the facilitation of complete chimerism.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-02T02:06:00.160804-05:
      DOI: 10.1111/ajt.14453
       
  • Dual-Graft Adult Living Donor Liver Transplantation with ABO-Incompatible
           Graft: Short-term and Long-term Outcomes
    • Authors: J.H. Kwon; G.W. Song, S. Hwang, K. H. Kim, C.S. Ahn, D.B. Moon, T.Y. Ha, D.H. Jung, G.C. Park, S.H. Kim, W.H. Kang, H.D. Cho, E.K. Jwa, E.Y. Tak, V.A. Kirchner, S.G. Lee
      Abstract: ABO-incompatible (ABOi) dual-graft (DG) adult living donor liver transplantation (ALDLT) is not commonly performed due to its inherently intricate surgical technique and immunological complexity. Therefore, data is lacking on the short- and long-term clinical outcomes of ABOi DG ALDLT. We performed a retrospective study by reviewing the medical records of patients who underwent ABOi DG ALDLT between 2008 and 2014. Additionally, computed tomography (CT) volumetric analysis was conducted to assess the graft regeneration rate. The mean age of a total of 28 recipients was 50.2 ± 8.5 years, and the mean model for end-stage liver disease (MELD) score was 12.2 ± 4.6. The 1-, 3- and 5-year patient survival rate was 96.4% during the mean follow-up period of 57.0 ± 22.4 months. The 1-, 3- and 5-year graft survival rate was 96.4%, 94.2%, and 92.0%, respectively, and no significant differences were observed between ABO-compatible (ABOc) and ABOi grafts (p=0.145). The biliary complication rate showed no significant difference (p=0.195) between ABOc and ABOi grafts. Regeneration rates of ABOi grafts were not significantly different from those of ABOc grafts. DG ALDLT with ABOi and ABOc graft combination seems to be a feasible option for expanding the donor pool without additional donor risks.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-31T03:15:34.382811-05:
      DOI: 10.1111/ajt.14448
       
  • Kidney allograft offers: Predictors of turndown and the impact of late
           organ acceptance on allograft survival
    • Authors: J.B Cohen; J Shults, D.S Goldberg, P. L Abt, D. L Sawinski, P.P Reese
      Abstract: There is growing interest in understanding patterns of organ acceptance and reducing discard. Little is known about how donor factors, timing of procurement, and geographic location affect organ offer decisions. We performed a retrospective cohort study of 47,563 deceased donor kidney match-runs from 2007-2013. Several characteristics unrelated to allograft quality were independently associated with later acceptance in the match-run: Public Health Service increased-risk donor status (adjusted odds ratio [aOR] 2.49, 95% confidence interval [CI] 2.29-2.69), holiday or weekend procurement (aOR 1.11, 95% CI 1.07-1.16), shorter donor stature (aOR 1.53 for 180 cm, 95% CI 1.28-1.94), and procurement in an area with higher intensity of market competition (aOR 1.71, 95% CI 1.62-1.78) and with the longest waiting times (aOR 1.41, 95% CI 1.34-1.49). Later acceptance in the match-run was associated with delayed graft function but not all-cause allograft failure (adjusted hazard ratio 1.01, 95% CI 0.96-1.07). Study limitations include a lack of match-run data for discarded organs and the possibility of sequence inaccuracies for some non-local matches. Interventions are needed to reduce turndowns of viable organs, especially when decisions are driven by infectious risk, weekend or holiday procurement, geography, or other donor characteristics unrelated to allograft quality.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-31T03:15:32.726169-05:
      DOI: 10.1111/ajt.14449
       
  • Global Kidney Exchange: Financially Incompatible Pairs Are Not
           Transplantable Compatible Pairs
    • Authors: M. A. Rees; S. Paloyo, A. E. Roth, K. D. Krawiec, O. Ekwenna, C. L. Marsh, A. J. Wenig, T. B. Dunn
      Abstract: Honest debate makes ideas better; we appreciate our colleagues’ engagement. We agree with Wiseman and Gill that Global Kidney Exchange (GKE) must be conducted in an ethical manner that is sensitive to the possibilities of commodification and exploitation and, that it is important to be both careful with and transparent about how patient-donor pairs are selected from developing countries.1,2 We further agree that GKE should continue to be run in a way that enhances rather than competes with local medical services.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-31T03:15:26.664613-05:
      DOI: 10.1111/ajt.14451
       
  • Ten-Year Outcomes in a Randomized Phase II Study of Kidney Transplant
           Recipients Administered Belatacept 4-Weekly or 8-Weekly
    • Authors: F. Vincenti; G. Blancho, A. Durrbach, G. Grannas, J. Grinyó, H.–U. Meier-Kriesche, M. Polinsky, L. Yang, C. P. Larsen
      Abstract: In the phase II IM103-100 study, kidney transplant recipients were first randomized to belatacept more-intensive–based (n=74), belatacept less-intensive–based (n=71), or cyclosporine-based (n=73) immunosuppression. At 3−6 months posttransplant, belatacept-treated patients were re-randomized to receive belatacept every 4 weeks (4-weekly, n=62) or every 8 weeks (8-weekly, n=60). Patients initially randomized to cyclosporine continued to receive cyclosporine-based immunosuppression. Cumulative rates of biopsy-proven acute rejection (BPAR) from first randomization to year 10 were 22.8%, 37.0%, and 25.8% for belatacept more-intensive, belatacept less-intensive, and cyclosporine, respectively (belatacept more-intensive versus cyclosporine: HR=0.95; 95% CI 0.47−1.92; p=0.89; belatacept less-intensive versus cyclosporine: HR=1.61; 95% CI 0.85−3.05; p=0.15). Cumulative BPAR rates from second randomization to year 10 for belatacept 4-weekly, belatacept 8-weekly, and cyclosporine were 11.1%, 21.9%, and 13.9%, respectively (belatacept 4-weekly versus cyclosporine: HR=1.06, 95% CI 0.35−3.17, p=0.92; belatacept 8-weekly versus cyclosporine: HR=2.00, 95% CI 0.75−5.35, p=0.17). Renal function trends were estimated using a repeated-measures model. Estimated mean GFR values at year 10 for belatacept 4-weekly, belatacept 8-weekly, and CsA were 67.0, 68.7, and 42.7 mL/min per 1.73 m2, respectively (p
      PubDate: 2017-07-31T03:15:25.682527-05:
      DOI: 10.1111/ajt.14452
       
  • The Outstanding Questions in Transplantation: It's About Time
    • Authors: Jamil Azzi; Giorgio Raimondi, Valeria Mas, Leonardo V. Riella, Nissreen Elfadawy, Kassem Safa, David Wojciechowski, Mazhar Kanak, Rajat Nog, Jonathan Maltzman, Mandy L. Ford, Jordan S. Pober, Xung-Rong Luo, David Rothstein, Michelle L. Miller, David Matthews, William Burlingham, Megan Levings, Peter Heeger, Lauren Higdon, John Gill, Ron Gill, Maria-Luisa Alegre
      Abstract: Organ transplantation represents one of the most daring efforts of science and medicine to challenge end-stage organ diseases and ultimately death. This extraordinary gift of life would not have been possible without the early work of pioneers such as Jaboulay and Carrel in perfecting vascular anastomosis, and the scientific breakthroughs of Medawar and colleagues in understanding immune rejection. Outstanding courage and generosity of organ donors and recipients continue to inspire all of us to do more everyday.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-31T03:15:21.131672-05:
      DOI: 10.1111/ajt.14450
       
  • Living Donor Follow-up: Unfunded Mandates and the Hippocratic Oath Where
           Perfect may be the Enemy of Good'
    • Authors: D. Sudan
      Abstract: Kidney transplantation in patients with endstage renal disease (ESRD) provides far superior patient survival compared to chronic dialysis. The USRDS report from 2016 demonstrated that the average 3-year survival for patients with ESRD on hemo- or peritoneal dialysis was 56% and 67%, respectively compared to 84% and 91% 3-year survival after deceased donor (DD) and living donor (LD) kidney transplantation (KT), respectively.1 Despite superior patient survival, rates of living donation have decreased since 2005. This is somewhat surprising, given the high mortality for patients on dialysisa, the large kidney transplant waiting list b, the number of DDKT each year (which are far less than number of waitlisted candidates)c, and the high waitlist mortalityd.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-26T14:50:24.819537-05:
      DOI: 10.1111/ajt.14442
       
  • Social Media and Organ Donation: Ethically Navigating the Next Frontier
    • Authors: Macey L. Henderson; Kristel A. Clayville, Jonathan S. Fisher, Kristin K. Kuntz, Harvey Mysel, Tanjala S. Purnell, Randolph L. Schaffer, Laurence A. Sherman, Elizabeth P. Willock, Elisa J. Gordon
      Abstract: As the organ shortage continues to grow, the creation of social media communities by transplant centers and the public is rapidly expanding to increase the number of living donors. Social media communities are arranged in myriad ways, and without standardization, raising concerns about potential recipients’ and potential donors’ autonomy and quality of care. Social media communities magnify and modify extant ethical issues in deceased and living donation related to privacy, confidentiality, professionalism, and informed consent, and increase the potential for undue influence and coercion for potential living donors and transplant candidates. Currently, no national ethical guidelines have been developed in the U.S. regarding the use of social media to foster organ transplantation. We provide an ethical framework to guide transplant stakeholders in using social media for public and patient communication about transplantation and living donation, and offer recommendations for transplant clinical practice and future research.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-25T23:30:35.847603-05:
      DOI: 10.1111/ajt.14444
       
  • HCV Viremic Donors With Hepatic Bridging Fibrosis: Are We Ready To Use
           Their Livers in The Era of Direct-Acting Antivirals'
    • Authors: S. Martini; E. David, F. Tandoi, D. Dell Olio, M. Salizzoni, G. M. Saracco, R. Romagnoli
      Abstract: We read with interest the report from the American Society of Transplantation Consensus Conference on the use of hepatitis C (HCV) viremic donors in solid organ transplantation, which took place in Dallas in January 2017 (1).In the interferon-era, liver grafts from HCV-positive donors with no more than periportal fibrosis (F2 Ishak) did not show an outcome disadvantage compared with HCV-negative ones (2,3). In U.S., 16.9% of HCV-positive cirrhotics currently receive an organ from HCV-positive donors, 50% of whom are viremic and expected to transmit the infection (1). Considering the gap between organ demand and supply, the meeting participants felt that the availability of safe and effective direct-acting antivirals (DAAs) makes expansion of the criteria for transplanting HCV viremic organs into non-viremic recipients a possibility (1).This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-25T15:55:20.095039-05:
      DOI: 10.1111/ajt.14447
       
  • Indication of living Donor Liver Transplantation for Septuagenarians from
           Double Equipoise Theory
    • Authors: T. Ikegami; T. Yoshizumi, M. Ohira, N. Harada, Y. Soejima, Y. Maehara
      Abstract: We read with great interest the article by Kwon et al from Asan Medical Center (1). The authors presented outcomes of living donor liver transplantation (LDLT) for septuagenarians with a 5-year survival rate of 69.8% and concluded that they should not be excluded from LDLT. On the other hand, at Kyushu University, we have indicated different graft and recipient selection strategies of LDLT for elderly recipients ≥ 65 years with 89.9% for 5-year survival rate (2). We have performed 12 LDLTs for septuagenarian patients (1.8%) out of 670 LDLTs between October 1996 and May 2017. In this article, we compare strategies and outcomes of LDLT for septuagenarians in terms of the balance between donor risks and recipient benefits (3).This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-25T15:55:17.930762-05:
      DOI: 10.1111/ajt.14446
       
  • Microbial metabolites and graft versus host disease
    • Authors: Mary Riwes; Pavan Reddy
      Abstract: The health of mammals is a reflection of the diversity and composition of the intestinal microbiota. Alterations in the composition and functions of the intestinal microbiota have been implicated in multiple disease processes. The impact of the microbiota in health and disease is in part a function of the nutrient processing and release of metabolites. Recent studies have uncovered a major role for microbial metabolites in the function of the host immune system by which they influence disease processes such as acute graft versus host disease (GVHD), which is the main complication of allogeneic hematopoietic cell transplantation (allo-HCT). The mechanisms of acute GVHD regulation by the complex microbial community and the metabolites released by them are unclear. In this review we summarize major findings of how microbial metabolites interact with the immune system and discuss how these interactions could impact acute GVHD.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-25T15:50:24.984483-05:
      DOI: 10.1111/ajt.14443
       
  • Invited response to “Hyperfiltration after donation and living
           kidney donor risk”
    • Authors: R. W. Steiner
      Abstract: The concerns of Dr. van Londen and colleagues are well founded (1). In the future, obesity and diabetes will occur more often as young adults age and will increase the exponential growth in ESRD rates 20-30 years later. These lifetime outcomes will remain distant and difficult to predict in young candidates. The risks of post-donation hyperfiltration, i.e., an unusually high single nephron glomerular filtration rate (sngfr), have been a concern of transplant centers for decades (2).This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-25T15:50:22.843702-05:
      DOI: 10.1111/ajt.14445
       
  • PROviding Better ACcess To ORgans: A Comprehensive Overview of
           Organ-Access Initiatives from the ASTS PROACTOR Task Force
    • Authors: M. J. Hobeika; C. M. Miller, T. L. Pruett, K. A. Gifford, J. E. Locke, A. M. Cameron, M. J. Englesbe, C. S. Kuhr, J. F. Magliocca, K. R. McCune, K. L. Mekeel, S. J. Pelletier, A. L. Singer, D. L. Segev
      Abstract: The American Society of Transplant Surgeons (ASTS) PROviding better Access To Organs (PROACTOR) Task Force was created to inform ongoing ASTS organ access efforts. Task force members were charged with comprehensively cataloguing current organ access activities and organizing them according to stakeholder type. This White Paper summarizes the task force findings and makes recommendations for future ASTS organ access initiatives.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-25T15:50:19.924833-05:
      DOI: 10.1111/ajt.14441
       
  • Benefits and Limitations of Belatacept in 4 Hand Transplanted Patients
    • Authors: J Grahammer; A Weissenbacher, B G Zelger, B Zelger, C Boesmueller, M Ninkovic, A Mühlbacher, I Peschel, G Brandacher, D Öfner, S Schneeberger
      Abstract: Belatacept (CTLA4Ig) is an emerging treatment in kidney transplantation. Lack of nephrotoxicity and possibly an inhibitory effect on the development of donor specific antibodies (DSA) make it an interesting agent in hand transplantation.In order to reduce CNI immunosuppression and preserve kidney function, we have added belatacept to the therapeutic regimen of 4 hand transplanted patients at month 4, at 6, 9, and 13 years after hand/forearm transplantation. Patients received 5mg/kg belatacept every 2 weeks, the dosing interval was extended to 4 weeks after 5 applications.Belatacept was initially well tolerated in all cases. Two patients were weaned to a low-dose tacrolimus monotherapy together with monthly belatacept applications. One patient is on belatacept with lowered tacrolimus and sirolimus through levels. A fourth patient had significant levels of DSAs at time of conversion and progressed to a severe necrotizing rejection early despite an unaltered baseline immunosuppression. Finger skin necrosis and histological signs of severe chronic allograft vasculopathy eventually led to amputation of the graft.Implementation of belatacept can be beneficial in hand transplantation. However, our findings indicated both potential but also caution and reflection of the immunological state at the time of conversion.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-25T15:45:19.316344-05:
      DOI: 10.1111/ajt.14440
       
  • PD-1 expression on CD8+ T cells regulates their differentiation within
           lung allografts and is critical for tolerance induction
    • Authors: T Takahashi; H M Hsiao, S Tanaka, W Li, R Higashikubo, D Scozzi, A Bharat, J H Ritter, A S Krupnick, A E Gelman, D Kreisel
      Abstract: Immunological requirements for rejection and tolerance induction differ between various organs. While memory CD8+ T cells are considered a barrier to immunosuppression-mediated acceptance of most tissues and organs, tolerance induction after lung transplantation is critically dependent on central memory CD8+ T lymphocytes. Here we demonstrate that costimulation blockade-mediated tolerance after lung transplantation is dependent on PD-1 expression on CD8+ T cells. In the absence of PD-1 expression, CD8+ T cells form prolonged interactions with graft-infiltrating CD11c+ cells, their differentiation is skewed towards an effector memory phenotype and grafts are rejected acutely. These findings extend the notion that requirements for tolerance induction after lung transplantation differ from other organs. Thus, immunosuppressive strategies for lung transplant recipients need to be tailored based on the unique immunological properties of this organ.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-20T20:30:41.408843-05:
      DOI: 10.1111/ajt.14437
       
  • Lack of adjustment for confounding could lead to misleading conclusions
    • Authors: S. Christakoudi; M. P. Hernandez-Fuentes
      Abstract: In a recent issue Asare et al. (1) assess the utility of a previously identified signature of tolerance, based on the expression of two B-cell receptor genes (IGKV1D-13 and IGKV4-1). The authors set to determine the prevalence of “tolerance” predictions in treated stable kidney transplant recipients (KTRs) and “tolerance” frequency in patients with different immunosuppressant (IS) regimens. They illustrate (Figure 6), very successfully, that changes in the signature are compatible with known alterations of the B-cell compartment elicited by IS drugs.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-20T10:25:18.22765-05:0
      DOI: 10.1111/ajt.14439
       
  • Changing Metrics of Organ Procurement Organization Performance in Order to
           Increase Organ Donation Rates in the United States
    • Authors: D. Goldberg; M. J. Kallan, L. Fu, M. Ciccarone, J. Ramirez, P. Rosenberg, J. Arnold, G. Segal, K. P. Moritsugu, H. Nathan, R. Hasz, P. L. Abt
      Abstract: The shortage of deceased-donor organs is compounded by donation metrics that fail to account for the total pool of possible donors, leading to ambiguous donor statistics. We sought to assess potential metrics of organ procurement organizations (OPOs) utilizing data from the Nationwide Inpatient Sample (NIS) from 2009–2012 and State Inpatient Databases (SIDs) from 2008–2014. A possible donor was defined as a ventilated inpatient death ≤75 years of age, without multi-organ system failure, sepsis, or cancer, whose cause of death was consistent with organ donation. These estimates were compared to patient-level data from chart review from two large OPOs. Among 2,907,658 inpatient deaths from 2009–2012, 96,028 (3.3%) were a “possible deceased-organ donor.” The two proposed metrics of OPO performance were: (1) donation percentage (percentage of possible deceased-donors who become actual donors; range: 20.0–57.0%); and (2) organs transplanted per possible donor (range: 0.52–1.74). These metrics allow for comparisons of OPO performance and geographic-level donation rates, and identify areas in greatest need of interventions to improve donation rates. We demonstrate that administrative data can be used to identify possible deceased donors in the US and could be a data source for CMS to implement new OPO performance metrics in a standardized fashion.
      PubDate: 2017-07-20T01:01:02.854694-05:
      DOI: 10.1111/ajt.14391
       
  • American Journal of Transplantation: Volume 17, Number 8, August 2017
    • Abstract: On the cover this month: Most humans are infected with the BK polyomavirus, which resides in the urothelium. In immunocompetent individuals, the virus is easily controlled and typically inconsequential. However, in immunosuppressed patients, particularly kidney transplant recipients, immune control of the BK virus is lost, leading to polyomavirus nephropathy (PyVN). Unless recognized early, PyVN can lead to graft loss. In this issue, we present two definitive assessments (Nankivell et al, page 2065, and Drachenberg et al, page 2078) of the evolution of PyVN in kidney transplant recipients. These longitudinal clinical and histological assessments critically outline the course of BK viral reactivation and will be important for the early recognition and study of this unsolved barrier to long-term graft survival. Also this month, we begin a year-long series examining cancer in transplant recipients (see editorial by Engels, page 1967), with the first offering in the series, an overview of chemotherapy in transplant patients with malignancy (see Krisl and Doan, page 1974). Cover image by Lauren Halligan, Duke University Department of Surgery.
      PubDate: 2017-07-19T13:11:49.078692-05:
      DOI: 10.1111/ajt.14404
       
  • Innate Allorecognition by Monocytic Cells and its Role in Graft Rejection
    • Authors: Fadi G. Lakkis; Xian C. Li
      Abstract: Innate recognition of microbial products and danger molecules by monocytes and macrophages has been well established; this is mediated primarily by pattern recognition receptors and is central to activation of innate and adaptive immune cells required for productive immunity. Whether monocytes and macrophages are equipped with an allorecognition system that allows them to directly respond to allogeneic grafts is a topic of much debate. Recent studies provide compelling evidence that these cells are capable of recognizing allogeneic entities and mediate graft rejection via direct cytotoxicity and priming of alloreactive T cells. These studies have also uncovered a mechanism of innate allorecognition based on detection of the polymorphic molecule SIRPα on donor cells. Further understanding of innate allorecognition and its consequences would provide essential insights into allograft rejection and lead to better therapies for transplant patients.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-19T05:55:58.837591-05:
      DOI: 10.1111/ajt.14436
       
  • The Immunoproteasome: An Old Player with a Novel and Emerging Role in
           Alloimmunity
    • Authors: S. K Eskandari; M. A. J Seelen, G Lin, J. R Azzi
      Abstract: Modern treatment strategies for the maintenance of allograft acceptance frequently target ubiquitously-expressed pathways, leading to significant side-effects and poor long-term allograft outcomes. Constitutive proteasome inhibitors, which have recently been introduced for the treatment of antibody-mediated rejection, target the ubiquitously-expressed proteasome. To limit off-target effects and serious mechanism-based toxicity, however, these inhibitors are administered intermittently and suboptimally. Immunoproteasomes, which are an inducible subset of proteasomes enriched in immune cells, replace constitutive proteasomes after cell exposure to proinflammatory cytokines such as interferon-γ. While immunoproteasomes were first described as processors of antigen for presentation by MHC molecules, recent findings point to its broader biological roles. These vary from activating different subsets of the immune system, by controlling transcriptional activators and downstream cytokines, to affecting their differentiation and survival. These emerging roles of the immunoproteasome in activated immune cells have made it a rational candidate for the targeted treatment of immune-mediated diseases. Preclinical studies have established its role in maintaining allograft acceptance without significant short- or long-term toxicity. This review provides a brief background of the immunoproteasome and outlines its role in immunological pathways and its potential in alloimmunity.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-18T10:29:38.17577-05:0
      DOI: 10.1111/ajt.14435
       
  • Human immunology studies using organ donors: impact of clinical variations
           on immune parameters in tissues and circulation
    • Authors: D. J. Carpenter; T. Granot, N. Matsuoka, T. Senda, B. V. Kumar, J. J. C. Thome, C. L. Gordon, M. Miron, J. Weiner, T. Connors, H. Lerner, A. Friedman, T. Kato, A. D. Griesemer, D. L. Farber
      Abstract: Organ donors are sources of physiologically healthy organs and tissues for life-saving transplantation, and have been recently used for human immunology studies which are typically confined to the sampling of peripheral blood. Donors comprise a diverse population with different causes of death and clinical outcomes during hospitalization, and the effects of such variations on immune parameters in blood and tissues are not known. We present here coordinate analyses of innate and adaptive immune components in blood, lymphoid (bone marrow, spleen, lymph nodes), and mucosal (lungs, intestines) sites from a population of brain-dead organ donors (3-months-93-years; n=291) across eight clinical parameters. Overall, the blood of donors exhibited similar monocyte and lymphocyte content and low serum levels of pro-inflammatory cytokines as healthy controls; however, donor blood had increased neutrophils and serum levels of IL-8, IL-6 and MCP-1 which varied with cause of death. In tissues, the frequency and composition of monocytes, neutrophils, B lymphocytes and T cell subsets in lymphoid or mucosal sites did not vary with clinical state, and was similar in donors independent of the extent of clinical complications. Our results reveal that organ donor maintain tissue homeostasis, and are a valuable resource for fundamental studies in human immunology.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-18T10:29:12.924466-05:
      DOI: 10.1111/ajt.14434
       
  • Pancreatic Allograft Thrombosis: Suggestion for a CT grading system and
           management algorithm
    • Authors: Abdul Hakeem; John Chen, Satheesh Iype, Menna Clatworthy, Christopher Watson, Edmund M Godfrey, Sara Upponi, Kourosh Saeb-Parsy
      Abstract: Pancreatic allograft thrombosis (PAT) remains the leading cause of non-immunological graft failure. Herein we propose a new CT grading system of PAT to identify risk factors for allograft loss and outline a management algorithm by retrospective review of consecutive pancreatic transplants between 2009-2014. Triple-phase CT scans were graded independently by two radiologists as; Grade 0 – no thrombosis, Grade 1 – peripheral thrombosis, Grade 2 – intermediate non-occlusive thrombosis and Grade 3 – central occlusive thrombosis. Twenty-four of 103 (23.3%) recipients were diagnosed with PAT (including grade 1). Three grafts (2.9%) were lost due to portal vein thrombosis. On multivariate analysis, pancreas after SPK/PAK transplant, acute rejection and CT finding peri-pancreatic oedema and/or inflammatory change were significant risk factors of PAT. Retrospective review of CT images revealed more grade 1 and 2 thromboses than were initially reported. There was no significant difference in graft or patient survival, post-operative stay or morbidity of recipients with grade 1 or 2 thrombosis who were or were not anticoagulated. Our data suggest that therapeutic anticoagulation is not necessary for grade 1 and 2 arterial and grade 1 venous thrombosis. The proposed grading system can assist clinicians in decision making and provide standardised reporting for future studies.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-18T10:28:04.950358-05:
      DOI: 10.1111/ajt.14433
       
  • Multiple breath washout in Paediatric patients After lung transplantation
    • Authors: Sylvia Nyilas; Julia Carlens, Timothy Price, Florian Singer, Carsten Müller, Gesine Hansen, Gregor Warnecke, Philipp Latzin, Nicolaus Schwerk
      Abstract: Forced expiratory volume in 1 second (FEV1) from spirometry, is the most commonly used parameter to detect early allograft dysfunction after lung transplantation (LTx). There are concerns regarding its sensitivity. Nitrogen-multiple breath washout (N2-MBW) is sensitive at detecting early global (lung clearance index; LCI), and acinar (Sacin) airway inhomogeneity. We investigated whether N2-MBW indices indicate small airways pathology after LTx in children with stable spirometry. Thirty-seven children without BOS on median 1.6 (0.6–3.0) years after LTx, underwent N2-MBW and spirometry, 28 of those on two occasions (≤6 months apart) during clinically stable periods. Additional longitudinal data (11 and 8 measurements, respectively) are provided from two patients with BOS. In non-BOS patients, LCI and Sacin were significantly elevated compared to healthy controls. LCI was abnormal at the two test occasions in 81% and 71% of patients, respectively, compared to 30% and 39% of patients with abnormal FEV1/FVC. Correlations of LCI with FEV1/FVC (r=0.1, p=0.4) and FEV1 (r= −0.1, p=0.6) were poor. N2-MBW represents a sensitive and reproducible tool for early detection of airways pathology in stable transplant recipients. Moreover, indices were highly elevated in both patients with BOS. Spirometry and LCI showed poor correlation, indicating distinct and complimentary physiological measures.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-18T10:25:23.993945-05:
      DOI: 10.1111/ajt.14432
       
  • Renal Allograft Histology at 10 Years after Transplantation in the
           Tacrolimus Era: Evidence of Pervasive Chronic Injury
    • Authors: Mark D. Stegall; Lynn D. Cornell, Walter D. Park, Byron H. Smith, Fernando G. Cosio
      Abstract: Improving long-term renal allograft survival remains an important unmet need. To assess the extent of histologic injury at 10 years after transplantation in functioning grafts, we studied 575 consecutive adult solitary renal transplants performed between 2002 and 2005–77% from living donors and 92% maintained on tacrolimus-based immunosuppression. Ten-year graft survival was 59% and death-censored graft survival was 74%. Surveillance allograft biopsies were assessed at implantation, 5 years and 10 years from 145 patients that reached 10 years. At implantation, 5% of biopsies had major histologic abnormalities (cg>0, other chronic Banff scores≥2, global glomerulosclerosis>20% or mesangial sclerosis≥2). This increased to 64% at 5 years and 82% at 10 years. Major lesions at 10 years included: arteriolar hyalinosis (66%), mesangial sclerosis (67%) and global glomerulosclerosis>20% (47%) with 48% of grafts having more than one major lesion. Transplant glomerulopathy and moderate-to-severe interstitial fibrosis were uncommon (12% each). Major lesions were associated with increased proteinuria and decreased graft function. In patients with diabetes at baseline, 52% had diabetic nephropathy/mesangial sclerosis at 10 years. We conclude that almost all renal allografts sustain major histologic injury by 10 years after transplantation. Much damage appears non-immunologic suggesting that new approaches are needed to decrease late injury.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-15T12:10:32.208547-05:
      DOI: 10.1111/ajt.14431
       
  • Pre-Kidney Transplant Lower Extremity Impairment and Post-Transplant
           Mortality
    • Authors: Anthony J. Nastasi; Mara A. McAdams-DeMarco, Jennifer Schrack, Hao Ying, Israel Olorundare, Fatima Warsame, Alexandra Mountford, Christine E. Haugen, Marlís González Fernández, Silas P. Norman, Dorry L. Segev
      Abstract: Prediction models for post-kidney transplant (KT) mortality have had limited success (C-statistics≤0.70). Adding objective measures of potentially modifiable factors may improve prediction and, consequently, KT survival through intervention. The short physical performance battery (SPPB) is an easily administered objective test of lower extremity function consisting of three parts (balance, walking speed, chair stands), each with scores of 0-4, for a composite score of 0-12, with higher scores indicating better function. SPPB performance and frailty (Fried frailty phenotype) were assessed at admission for KT in a prospective cohort of 719 KT recipients at Johns Hopkins Hospital (8/2009-6/2016) and University of Michigan (2/2013-12/2016). The independent associations between SPPB impairment (SPPB composite score≤10) and composite score with post-KT mortality were tested using adjusted competing risks models treating graft failure as a competing risk. The 5-year post-KT mortality for impaired recipients was 20.6% compared to 4.5% for unimpaired recipients (P
      PubDate: 2017-07-15T12:10:29.42438-05:0
      DOI: 10.1111/ajt.14430
       
  • Minimization of Ischemic Cholangiopathy in Donation after Cardiac Death
           Liver Transplantation: Is it Thrombolytic Therapy or Warm Ischemic Time
           Stringency and Donor Bile Duct Flush'
    • Authors: Emmanouil Giorgakis; Shirin Elizabeth Khorsandi, Wayel Jassem, Nigel Heaton
      Abstract: Donation after cardiac death (DCD) liver transplantation (LT) is the fastest expanding donor pool. Despite the promise, initial DCD experience showed discouraging outcomes1. Cumulative experience from aggressive LT centers re-ignited the interest in DCD LT2, culminating in outstanding outcomes, comparable to that of donation after brain death (DBD)3.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-15T12:05:32.624411-05:
      DOI: 10.1111/ajt.14429
       
  • Splenic vein thrombosis following pancreas transplantation: identification
           of factors that support conservative management
    • Authors: Jack W. Harbell; Tara Morgan, Vickie A. Feldstein, Garrett R. Roll, Andrew Posselt, Sang-Mo Kang, Sandy Feng, Ryutaro Hirose, Chris E. Freise, Peter Stock
      Abstract: Prophylaxis for graft portal/splenic venous thrombosis following pancreas transplant varies between institutions. Similarly, treatment of venous thrombosis ranges from early re-exploration to conservative management with anticoagulation. We wished to determine the prevalence of graft splenic vein (SV) thrombosis, as well as the clinical significance of non-occlusive thrombus observed on routine imaging. Records of 112 pancreas transplant recipients over a five-year period at a single center were reviewed. Venous thrombosis was defined as absence of flow or presence of thrombus identified in any part of the graft SV on ultrasound. Thirty patients (27%) had some degree of thrombus or absence of flow in the SV on post-operative ultrasound. There were 5 graft losses in this group. Four were due to venous thrombosis, and occurred within 20 days of transplant. All patients with non-occlusive partial SV thrombus but normal arterial signal on Doppler ultrasound were successfully treated with IV heparin followed by warfarin for 3-6 months, and remained insulin independent. Findings of arterial signal abnormalities, such as absence or reversal of diastolic flow within the graft, require urgent operative intervention since this finding can be associated with more extensive thrombus that may lead to graft loss.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-14T04:35:32.391288-05:
      DOI: 10.1111/ajt.14428
       
  • Belatacept rescue therapy in kidney transplant recipients with vascular
           lesions: a case control study
    • Authors: D. Bertrand; L. Cheddani, I. Etienne, A. François, M. Hanoy, C. Laurent, L. Lebourg, F. Le Roy, L. Lelandais, M C Loron, M. Godin, D. Guerrot
      Abstract: Immunosuppression in kidney transplant recipients with decreased graft function and severe histological vascular changes can be particularly challenging. Belatacept could be a valuable option, as a rescue therapy in this context.We report a retrospective case control study comparing a CNI to belatacept switch in 17 patients with vascular damage and low eGFR to a control group of 18 matched patients with CNI continuation. Belatacept switch was performed on average 51.5 months after kidney transplantation (6.2-198 months). There was no difference between the two groups regarding eGFR at inclusion, and 3 months before inclusion. In the “CNI to belatacept switch group”, mean eGFR increased significantly from 23.5±6.7 mL/min/1.73m2 on day 0, to 30.4±9.1 ml/min/1.73m2 on month 6 (p
      PubDate: 2017-07-14T04:25:37.816382-05:
      DOI: 10.1111/ajt.14427
       
  • Outcomes in Pancreas Transplantation with Exocrine Drainage Through a
           Duodenoduodenostomy versus Duodenojejunostomy
    • Authors: J P Lindahl; R. Horneland, E Nordheim, A Hartmann, E M Aandahl, K Grzyb, H Haugaa, G Kjøsen, A Åsberg, T. Jenssen
      Abstract: Until recently, pancreas transplantation has mostly been performed with exocrine drainage via duodenojejunostomy (DJ). Since 2012, DJ was substituted with duodenoduodenostomy (DD) in our hospital, allowing endoscopic access for biopsies. This study assessed safety profiles with DD versus DJ procedures, and clinical outcomes with the DD technique in pancreas transplantation. DD patients (n=117; 62 simultaneous pancreas and kidney [SPKDD] and 55 pancreas transplantation alone [PTADD] with median follow-up 2.2 years) were compared with DJ patients (n=179; 167 SPKDJ and 12 PTADJ) transplanted in the period 1998-2012 (pre-DD era). Postoperative bleeding and pancreas graft vein thrombosis requiring relaparotomy occurred in 17% and 9% of DD patients versus 10% (p=0.077) and 6% (p=0.21) in DJ patients. Pancreas graft rejection rates were still higher in PTADD patients versus SPKDD patients (p=0.003). Hazard ratio (HR) for graft loss was 2.25 (95% CI 1.00, 5.05; p=0.049) in PTADD versus SPKDD recipients. In conclusion, compared with the DJ procedure, the DD procedure did not reduce postoperative surgical complications requiring relaparatomy or improve clinical outcomes after pancreas transplantation despite serial pancreatic biopsies for rejection surveillance. It remains to be seen whether better rejection monitoring in DD patients translates into improved long-term pancreas graft survival.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-11T04:51:20.573675-05:
      DOI: 10.1111/ajt.14420
       
  • Impact of Protease Inhibitor based Anti-Retroviral Therapy on Outcomes for
           HIV+ Kidney Transplant Recipients
    • Authors: Deirdre Sawinski; Brittany A. Shelton, Shikha Mehta, Rhiannon D. Reed, Paul A. MacLennan, Sally Gustafson, Dorry L. Segev, Jayme E. Locke
      Abstract: Excellent outcomes have been demonstrated among select HIV-positive kidney transplant (KT) recipients with well-controlled infection, but to date no national study has explored outcomes among HIV+ KT recipients by antiretroviral therapy (ART) regimen. IMS pharmacy fills (1/1/01 - 10/1/12) were linked with SRTR data. 332 recipients with pre- and post-transplant fills were characterized by ART at time of transplant as protease inhibitor (PI) or non-PI based ART (88 PI vs. 244 non-PI). Cox proportional hazards models were adjusted for recipient and donor characteristics. Comparing recipients by ART regimen, there were no significant differences in age, race, or HCV status. Recipients on PI-based regimens were significantly more likely to have an estimated post-transplant score (EPTS)> 20% (70.9% vs. 56.3%, p=0.02) than those on non-PI regimens. On adjusted analyses, PI-based regimens were associated with 1.8-fold increased risk of allograft loss (aHR: 1.84, 95%CI: 1.22-2.77, p=0.003), with the greatest risk observed in the first post-transplant year (aHR: 4.48, 95%CI: 1.75-11.48, p=0.002), and 1.9-fold increased risk of death as compared to non-PI regimens (aHR: 1.91, 95%CI: 1.02-3.59, p=0.05). These results suggest whenever possible recipients should be converted to a non-PI regimen prior to KT.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-11T04:45:22.969216-05:
      DOI: 10.1111/ajt.14419
       
  • Sociodemographic determinants of waitlist and post-transplant survival
           among end-stage liver disease patients
    • Authors: Katherine Ross; Rachel E Patzer, David S Goldberg, Raymond J Lynch
      Abstract: While regional organ availability dominates discussions of distribution policy, community-level disparities remain poorly understood. We studied micro-geographic determinants of survival risk and their distribution across Donor Service Areas (DSAs). Scientific Registry of Transplant Recipients records for all adults waitlisted for liver transplantation 2002-2014 were reviewed. The primary exposure variables were county-level sociodemographic risk, as measured by the Community Health Score, a previously-validated composite index local health conditions, and distance to listing transplant center. Among 114,347 patients, the median CHS was 19.4 (range: 0-40). Compared the lowest risk counties (CHS 1-10), highest-risk counties (CHS 31-40) had more black (14.6% vs. 5.4%), publicly insured (44.9% vs. 33.0), and remote candidates (34.0% vs. 15.1% living>100 miles away). Higher-CHS candidates had greater waitlist mortality in Cox multivariable (HR 1.16 for CHS 31-40, 95% CI 1.11-1.21) and competing risks analysis (sHR 1.07, 95% CI 0.99-1.14). Post-transplant survival was similar across CHS quartiles. Living>25 miles from the transplant center conferred excess mortality risk (sHR 1.08, 95% CI 1.03-1.12). Proposed distribution changes would disproportionately impact DSAs with more high-CHS or distant candidates. Low-income, rural and minority patients experience excess mortality while awaiting transplant, and risk disproportionately worse outcomes with reduced organ availability under current proposals.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-11T03:05:31.763705-05:
      DOI: 10.1111/ajt.14421
       
  • Mechanical Ventilation and Extracorporeal Membrane Oxygenation as a
           Bridging Strategy to Lung Transplantation: Significant Gains in Survival
    • Authors: Awori J. Hayanga; Angela L. Du, Kyla Joubert, Tuft Marie, Rachel Baird, Joseph Pilewski, Mathew Morrell, Jonathan D'Cunha, Norihisa Shigemura
      Abstract: Mechanical ventilation (MV) and extracorporeal membrane oxygenation (ECMO) are increasingly used to bridge patients to lung transplantation. We investigated the impact of using MV, with or without ECMO, prior to lung transplantation on survival after transplantation by performing a retrospective analysis of 826 patients who underwent transplantation at our high-volume center. Recipient characteristics and posttransplant outcomes were analyzed. Most lung transplant recipients (729 patients) did not require bridging; 194 of these patients were propensity matched with patients who were bridged using MV alone (48 patients) or MV and ECMO (49 patients). There was no difference in overall survival between the MV and MV+ECMO groups (p=0.07). The MV+ECMO group had significantly higher survival conditioned on surviving to one year (median 1811 days (MV) vs. not reached (MV+ECMO), p=0.01). Recipients in the MV+ECMO group, however, were more likely to require ECMO after lung transplantation (16.7% MV vs. 57.1% MV+ECMO, p
      PubDate: 2017-07-11T03:05:30.005696-05:
      DOI: 10.1111/ajt.14422
       
  • Combined Liver Kidney transplantation for Primary Hyperoxaluria type 2: A
           case report
    • Authors: Tsering Dhondup; Elizabeth C. Lorenz, Dawn S. Milliner, John C. Lieske
      Abstract: Combined liver/kidney transplant is the preferred transplant option for most patients with primary hyperoxaluria type 1 (PH1) since orthotopic liver transplantation replaces the deficient liver-specific AGT enzyme, thus restoring normal metabolic oxalate production. However, primary hyperoxaluria type 2 (PH2) is caused by deficient glyoxylate reductase / hydroxypyruvate reductase (GRHPR), and this enzyme is widely distributed throughout the body. Though the relative abundance and activity of GRHPR in various tissues is not clear, some evidence suggests that the majority of enzyme activity may indeed reside within the liver. Thus the effectiveness of liver transplantation in correcting this metabolic disorder has not been demonstrated. Here we report a case of 44-year old man with PH2, frequent stone events, and end-stage renal disease who received a combined liver/ kidney transplant. Although requiring confirmation in additional cases, the normalization of plasma oxalate, urine oxalate and urine glycerate levels observed in this patient within a month of the transplant that remain reduced at the most recent follow-up at 13 months suggests correction of the GRHPR deficiency in PH2 can be achieved by liver transplantation.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-06T00:15:41.755144-05:
      DOI: 10.1111/ajt.14418
       
  • Maximizing utilization of the donor pool by appropriate classification of
           hepatitis C antibody positive donors
    • Authors: J. A. Anesi; D. S. Goldberg
      Abstract: The most significant issue facing solid organ transplantation (SOT) is the limited supply of donor organs. Expansion of the donor pool is needed to save more lives through SOT. Deceased donors with positive hepatitis C (HCV) serologic testing have been used inconsistently in the past due to concern for worse recipient outcomes and an inability to easily treat HCV in non-liver recipients (1).This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-05T23:56:55.217913-05:
      DOI: 10.1111/ajt.14417
       
  • Renal Consequences of Diabetes after Kidney Donation
    • Authors: Hassan N. Ibrahim; Danielle M. Berglund, Scott Jackson, David M. Vock, Robert N. Foley, Arthur J. Matas
      Abstract: Whether diabetes after donation is associated with an accelerated GFR decay in the remaining kidney has not been studied. We determined the incidence of diabetes in kidney donors, compared GFR change over time in diabetic to non-diabetic donors, and also the impact of DM on the development of proteinuria, hypertension and ESRD. Of the 4014 donors, 309(7.7%) developed diabetes at a median age of 56.0 years and after a median of 18 years post-donation. The difference in annual eGFR change between diabetic and non-diabetic donors in the seven years prior to DM development was -0.08 ml/min/year; p=0.51. After DM development, the difference was -1.10 ml/min/year for diabetics with hypertension and proteinuria, p
      PubDate: 2017-07-05T23:56:54.013492-05:
      DOI: 10.1111/ajt.14416
       
  • Life After Death- Breathing Life into Lung Transplantation from Donation
           After Circulatory Death Donors
    • Authors: S. J. Bozso; J. Nagendran
      Abstract: As there is a growing population of potential recipients that may benefit from lung transplantation, there remains a profound deficiency in donor lungs suitable for transplantation. An area of potential donor pool expansion exists in donation after circulatory death (DCD) donors. Lung transplantation utilizing DCD donors continues to be disproportionately less than donation after brain death (DBD) donors at many high-volume centers.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-05T09:55:20.660318-05:
      DOI: 10.1111/ajt.14413
       
  • Death with low MELD scores and possible implications for organ allocation
    • Authors: J. G. O'Grady; J. Lake
      Abstract: The perfect liver allocation system does not exist. The models in use reflect a balance of clinical, societal, political and regulatory priorities. MELD and its iterations perform well on transparency and accountability, which are important considerations for some stakeholders, but possibly performs less well from the patients’ perspective.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-05T09:55:19.685305-05:
      DOI: 10.1111/ajt.14414
       
  • Polyclonal Regulatory T cell Therapy for Control of Inflammation in Kidney
           Transplants
    • Authors: Sindhu Chandran; Qizhi Tang, Minnie Sarwal, Zoltan G. Laszik, Amy L. Putnam, Karim Lee, Joey Leung, Vinh Nguyen, Tara Sigdel, Erica C. Tavares, Joshua Y.C. Yang, Marc Hellerstein, Mark Fitch, Jeffrey A. Bluestone, Flavio Vincenti
      Abstract: Early subclinical inflammation in kidney transplants is associated with later graft fibrosis and dysfunction. Regulatory T cells (Tregs) can reverse established inflammation in animal models. We conducted a pilot safety and feasibility trial of autologous Treg cell therapy in three kidney transplant recipients with subclinical inflammation noted on 6-month surveillance biopsies. Tregs were purified from peripheral blood and polyclonally expanded ex vivo using medium containing deuterated glucose to label the cells. All patients received a single infusion of ~320 X106 (319, 321 and 363.8 x 106) expanded Tregs. Persistence of the infused Tregs was tracked. Graft inflammation was monitored with follow-up biopsies and urinary biomarkers. Nearly 1x109 (0.932, 0.956, 1.565 x 109) Tregs were successfully manufactured for each patient. There were no infusion reactions or serious therapy-related adverse events. The infused cells demonstrated patterns of persistence and stability similar to those observed in non-immunosuppressed subjects receiving the same dose of Tregs. Isolation and expansion of Tregs is feasible in kidney transplant patients on immunosuppression. Infusion of these cells was safe and well tolerated. Future trials will test the efficacy of polyclonal and donor alloantigen-reactive Tregs for the treatment of inflammation in kidney transplants.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-04T03:16:33.629896-05:
      DOI: 10.1111/ajt.14415
       
  • Invited response to “Potential disadvantages of over centralization of
           organ recovery centres: Response to Marsolais et al”
    • Authors: Pierre Marsolais; Emmanuel Charbonney, Karim Serri, Anne-Marie Lagacé, Francis Bernard, Martin Albert
      Abstract: Regarding the indicator of transplant per million population (tpm), we would like to reemphasize its worldwide use to report the organ donation process efficiency. This indicator encloses all potential obstacles to the donation process such as: identification of potential donors, conversion rate, support to donor's families, quality of donor support and organisational efficiency. The tpm is used by international organisations such as “Le Comité européen sur la transplantation d'organes” as their main measure since 2003 (3).This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-27T09:45:36.348331-05:
      DOI: 10.1111/ajt.14411
       
  • Mechanistic sharing between NK cells in ABMR and effector T cells in TCMR
    • Authors: Michael D. Parkes; Philip F. Halloran, Luis G. Hidalgo
      Abstract: Human organ allograft rejection depends on effector lymphocytes: NK cells in antibody-mediated rejection (ABMR) and effector T cells in T cell-mediated rejection (TCMR). We hypothesized that NK cell CD16a stimulation and CD8 T cell TCR/CD3 stimulation represent highly similar effector systems, and should lead to shared molecular changes between ABMR and TCMR. We studied similarity between soluble proteins and the transcripts induced in CD16a stimulated NK cells and TCR/CD3-stimulated T cells in vitro. Of 30 soluble mediators tested, CD16a-activated NK cells and CD3/TCR activated T cells produced the same limited set of five mediators—CCL3, CCL4, CSF2, IFNG, and TNF—and failed to produce 25 others. Many transcripts increased in stimulated NK cells were also increased in CD3-stimulated CD8 T cells (FDR
      PubDate: 2017-06-27T09:45:29.49303-05:0
      DOI: 10.1111/ajt.14410
       
  • Unlocking the potential of organ donation
    • Authors: J. M. Smits
      Abstract: In the 8th century AD, under the reign of the Abbasid caliph Harun al-Rashid, the House of Wisdom was inaugurated in Baghdad.1 This was a center of learning and transmission of classical wisdom, where scholars from all parts of the world gathered to learn and to transmit all the world's knowledge.So it is an ancient, albeit brilliant, concept to bring together all the beautiful minds and by exchanging and confronting opinions and ideas, gain new knowledge.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-27T09:45:24.091222-05:
      DOI: 10.1111/ajt.14412
       
  • Hyperfiltration after donation and living kidney donor risk
    • Authors: M. van Londen; J. van der Weijden, G. Navis
      Abstract: The editorial by Dr. Steiner states that follow-up on living kidney donors in all current studies is too short for a good estimation of life-time End-Stage Renal Disease (ESRD) risks. We agree that follow-up should be longer, in order to allow development of ESRD, but would like to add an important additional argument for this statement.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-26T01:52:43.683913-05:
      DOI: 10.1111/ajt.14409
       
  • Mannose-binding lectin deficient donors increase the risk of bacterial
           infection and bacterial infection-related mortality after liver
           transplantation
    • Authors: J Lombardo; G Sanclemente, J Colmenero, M Español-Rego, M T Arias, P Ruiz, E Mauro, L Sastre, G Crespo, A Rimola, A Moreno, F Lozano, M Navasa
      Abstract: Mannose-binding lectin (MBL) is synthesized by the liver and binds to microbes. MBL2 gene polymorphisms produce intermediate/low/null- or normal-MBL serum levels (MBL-deficient or MBL-sufficient phenotypes, respectively). We aimed to evaluate the incidence and severity of infection, rejection and survival within 1 year after liver transplantation (LT) according to donor and recipient MBL2 gene polymorphisms. A repeated-event analysis for infection episodes (negative binomial regression, Andersen–Gill model) was performed in 240 LT. Four-hundred twenty-eight infectious episodes (310 bacterial, 15 fungal, 65 CMV-related and 38 viral non-CMV) and 48 rejection episodes were recorded. The main bacterial infections were urinary (n=82, 26%) and pneumonia (n=69, 22%). LT recipients of MBL-deficient livers had a higher risk of bacterial infection [IRR: 1.48(1.04-2.09); p=0.028], pneumonia [IRR: 2.4(1.33-4.33); p=0.013] and septic shock [IRR=5.62(1.92-16.4); p=0.002] compared to recipients of MBL-deficient livers. The 1-year bacterial infection-related mortality was higher in recipients of MBL-deficient vs. MBL-sufficient livers (65.8% vs. 56.1%, respectively p=0.0097). The incidence of rejection, viral or fungal infection was similar in both groups. Recipient MBL2 genotype did not significantly increase the risk of bacterial infection. LT recipients of MBL-deficient livers have a higher risk of bacterial infection, pneumonia, septic shock and one-year bacterial infection-related mortality after LT.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-26T01:52:42.81139-05:0
      DOI: 10.1111/ajt.14408
       
  • Mechanical Circulatory Support in the Treatment of Advanced Heart Failure
    • Authors: Amanda W. Cai; Sabrina Islam, Shelley R. Hankins, Wade Fischer, Howard J. Eisen
      Abstract: According to the Centers for Disease Control (CDC), heart failure (HF) remains a pervasive condition with high morbidity and mortality, affecting 5.8 million people in the United States (US) and 23 million worldwide. For patients with refractory end-stage HF, heart transplantation is the gold standard for definitive treatment. However, the demand for heart transplantation has consistently exceeded the availability of donor hearts, with approximately 2,331 orthotopic heart transplantations performed in the US in 2015 despite an estimated 100,000 to 250,000 patients with New York Heart Association (NYHA) class IIIB or IV symptoms that are refractory to medical treatment and potential transplant candidates. 1, 2, 3 As such, the need for mechanical circulatory support (MCS) to treat patients with end-stage heart failure has become paramount. In this review, we focus on the history, advancements, and current use of durable MCS device therapy in the treatment of advanced heart failure.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-22T19:50:26.871734-05:
      DOI: 10.1111/ajt.14403
       
  • Flawed Assumptions: Ethical Problems with Proposed Presumed Consent
           Legislation
    • Authors: C. R. Bruce; P. Koch
      Abstract: At present, there is a House bill in the Texas Legislature that would shift Texas from an opt-in organ donation model – a model requiring explicit consent for organ donation from the donor or donor's family – to an opt-out, or presumed consent, model. Under this new bill, the state would assume that a person agreed to organ donation unless the donor registered an objection. If passed, this law would be the first-of-its-kind in the United States, and it represents the direct inverse of the nation's current opt-in model as outlined by the Uniform Anatomical Gift Act (although the bill does not violate federal law). (1) Recently, lawmakers in other states such as Delaware and New York have proposed similar bills. Proponents’ intentions are clear: to increase the number of available organs. They argue that data from other countries suggest that a shift from opt-in to opt-out could increase organ procurement. (2)This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-22T12:05:22.077086-05:
      DOI: 10.1111/ajt.14402
       
  • Sustained Post-Transplant Diabetes is Associated with Long-Term Major
           Cardiovascular Events Following Liver Transplantation
    • Authors: Giorgio A. Roccaro; David S. Goldberg, Wei-Ting Hwang, Renae Judy, Arwin Thomasson, Stephen E. Kimmel, Kimberly A. Forde, James D. Lewis, Yu-Xiao Yang
      Abstract: Cardiovascular disease is a leading cause of death among liver transplant (LT) recipients. With a rising burden of post-transplant metabolic disease, increases in cardiovascular-related morbidity and mortality may reduce life expectancy following liver transplantation. It is unknown if the risk of long-term major cardiovascular events (MCE) differs among LT recipients with varying diabetic states. We performed a retrospective cohort study of LT recipients from 2003 to 2013, to compare the incidence of MCE among patients 1) without diabetes, 2) with pre-transplant diabetes 3) with de novo transient post-transplant diabetes, and 4) with de novo sustained post-transplant diabetes. We analyzed 994 eligible patients (39% normal, 24% pre-transplant diabetes, 16% transient post-transplant diabetes, and 20% sustained post-transplant diabetes). Median follow up was 54.7 months. Overall, 12% of patients experienced a MCE. Adjusting for demographic and clinical variables, sustained post-transplant diabetes was the only state associated with a significantly increased risk of MCE (SHR 1.95, 95% CI 1.20-3.18). Patients with sustained post-transplant diabetes mellitus had a 13% and 27% cumulative incidence of MCE at 5 and 10 years. While pre-transplant diabetes has traditionally been associated with cardiovascular disease, the long-term risk of MCE is greatest in LT recipients with sustained post-transplant diabetes mellitus.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-22T10:20:19.639722-05:
      DOI: 10.1111/ajt.14401
       
  • Selective CD28 blockade results in superior inhibition of donor-specific T
           follicular helper cell and antibody responses relative to CTLA-4-Ig
    • Authors: I R Badell; G M La Muraglia, D Liu, M E Wagener, G Ding, M L Ford
      Abstract: Donor-specific antibodies (DSA) are a barrier to improved long-term outcomes following kidney transplantation. Costimulation blockade with CTLA-4-Ig has shown promise as a potential therapeutic strategy to control DSA. T follicular helper (Tfh) cells, a subset of CD4+ T cells required for optimum antibody production, are reliant on the CD28 costimulatory pathway. We have previously shown that selective CD28 blockade leads to superior allograft survival through improved control of CD8+ T cells relative to CTLA-4-Ig, but the impact of CD28-specific blockade on CD4+ Tfh cells is unknown. Thus, we identified and characterized donor-reactive Tfh cells in a murine skin transplant model, and then utilized this model to evaluate the impact of selective CD28 blockade with an anti-CD28 domain antibody (dAb) on the donor-specific Tfh-mediated immune response. We observed that the anti-CD28 dAb led to superior inhibition of donor-reactive CXCR5+PD-1hi Tfh and CD95+GL7+ germinal center B cells, and DSA formation as compared to CTLA-4-Ig. Interestingly, donor-reactive Tfh cells differentially upregulated CTLA-4 expression, suggesting an important role for CTLA-4 in mediating the superior inhibition observed with the anti-CD28 dAb. Therefore, selective CD28 blockade as a novel approach to control Tfh cell responses and prevent DSA after kidney transplantation warrants further study.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-21T18:20:32.429431-05:
      DOI: 10.1111/ajt.14400
       
  • Intra-abdominal cooling system limits ischemia-reperfusion injury during
           robot-assisted renal transplantation
    • Authors: Raphael P. H. Meier; Vincent Piller, Monika E. Hagen, Charles Joliat, Jean-Bernard Buchs, Antonio Nastasi, Raphael Ruttimann, Nicolas C. Buchs, Solange Moll, Jean-Paul Vallée, François Lazeyras, Philippe Morel, Leo Bühler
      Abstract: Robot-assisted kidney transplantation is feasible; however, concerns have been raised about possible increases in warm ischemia times. We describe a novel intra-abdominal cooling system to continuously cool the kidney during the procedure.Porcine kidneys were procured by standard open technique. Groups were as follow: Robotic renal transplantation with (n=11) and without (n=6) continuous intra-abdominal cooling and conventional open technique with intermittent 4°C saline cooling (n=6). Renal cortex temperature, magnetic resonance imaging and histology were analyzed. Robotic renal transplantation required a longer operative time, either with or without the cooling system, compared to the open approach (70.4±17.7 min and 74.0±21.5 min vs. 49.4±12.4 min, p-values
      PubDate: 2017-06-21T18:16:14.350271-05:
      DOI: 10.1111/ajt.14399
       
  • The prognostic importance of bronchoalveolar lavage fluid CXCL9 during
           
    • Authors: M Y Shino; S S Weigt, N Li, A Derhovanessian, D M Sayah, R Saggar, Richard H. Huynh, A L Gregson, A Ardehali, D J Ross, J P Lynch, R M Elashoff, J A Belperio
      Abstract: The clinical significance and treatment strategies for minimal acute rejection (grade A1), the most common form of acute rejection (AR), remains controversial. In this retrospective single-center cohort study of 441 lung transplant recipients, we formally evaluate the association between minimal AR and chronic lung allograft dysfunction (CLAD) and test a novel hypothesis using BAL CXCL9 concentration during minimal AR as a biomarker of subsequent CLAD development. In univariable and multivariable models adjusted for all histopathologic injury patterns, minimal AR was not associated with CLAD development. However, minimal AR with elevated BAL CXCL9 concentrations markedly increased CLAD risk in a dose-response manner. Minimal AR with CXCL9 concentrations greater than the 25th, 50th, and 75th percentile had an adjusted HRs for CLAD of 1.1 (95% CI 0.8-1.6), 1.6 (95% CI 1.1-2.3) and 2.2 (95% CI 1.4-3.4), respectively. Thus, we demonstrate the utility of BAL CXCL9 measurement as a prognostic biomarker that allows discrimination of recipients at increased risk of CLAD development after minimal AR. BAL CXCL9 measurement during transbronchial biopsies may provide clinically useful prognostic data and potentially guide treatment decisions for this common form of AR, as a possible strategy to minimize CLAD development.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-21T18:16:02.973038-05:
      DOI: 10.1111/ajt.14397
       
  • Evaluation of strategies for increasing transplantation should be based on
           a current and precise assessment of the state of organ donation
    • Authors: K. J. O'Connor; A. K. Glazier
      Abstract: In the article “Regional Differences in Communication Process and Outcomes of Requests for Solid Organ Donation”, Traino et al claim to “explore regional differences in communication in requests for organ donation.” (1) However, old data and incomplete analysis make the conclusions of unclear value to furthering meaningful improvement in the field.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-21T18:16:00.317714-05:
      DOI: 10.1111/ajt.14398
       
  • HCV-positive Donor Organs in Solid Organ Transplantation: “Mind the
           Gap!”
    • Authors: J. A. Fishman; X. Forns
      Abstract: The shortage of organs for transplantation is a major impediment to access to life-saving therapy. The availability of antiviral therapies that control hepatitis B (HBV) and HIV, or cure hepatitis C (HCV), have changed traditional equations in transplantation, allowing infected individuals access to transplantation without unimpeded viral replication during immunosuppression. The availability of these therapies also permits use of organs from donors actively or potentially infected with these viruses.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-20T13:24:11.700195-05:
      DOI: 10.1111/ajt.14396
       
  • Allospecific Memory B Cell Responses are Dependent on Autophagy
    • Authors: Miguel Fribourg; Jie Ni, F. Nina Papavasiliou, Zhenyu Yue, Peter S. Heeger, Jeremy S. Leventhal
      Abstract: Long-lived, donor-reactive memory B cells (Bmem) can produce alloantibodies that mediate transplant injury. Autophagy, an intrinsic mechanism of cell organelle/component recycling, is required for Bmem survival in infectious and model antigen systems but whether autophagy impacts alloreactive Bmem is unknown. We studied mice with an inducible yellow fluorescent protein (YFP) reporter expressed under the Activation-Induced Cytidine Deaminase (AID) promoter active in B cells undergoing germinal center reactions. Up to 12 months after allogeneic sensitization, splenic YFP+ B cells were predominantly IgD-IgM-IgG+ and expressed CD73, CD80, and PD-L2, consistent with Bmem. Labeled cells contained significantly more cells with autophagosomes, and autophagosomes per cell than unlabeled, naïve B cells. To test for a functional link, we quantified alloantibody formation in mice with B cells conditionally deficient in the requisite autophagy gene ATG7. These experiments revealed absent B cell ATG7: a) prevented B cell autophagy, b) inhibited secondary alloantibody responses without altering primary alloantibody formation and c) diminished frequencies of alloreactive Bmem. Pharmacological autophagy inhibition with 3-methyladenine had similar effects on wild type mice. Together with new documentation of increased autophagosomes within human Bmem, our data indicate that targeting autophagy has potential for eliminating donor-reactive Bmem in transplant recipients.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-16T09:10:23.811549-05:
      DOI: 10.1111/ajt.14394
       
  • Retransplantation after a failed donation after circulatory determination
           of death liver transplant: MELD exception priority and second chances
    • Authors: Peter L. Abt; David S. Goldberg
      Abstract: Increased utilization of higher-risk liver allografts is hampered by concerns about an increased risk of post-transplant graft failure and subsequent death if the patient is not retransplanted. This dilemma faces clinicians considering broader use of livers from donation after circulatory determination of death (DCDD) donors. In the setting of primary non-function or early hepatic artery thrombosis (HAT), there is a mechanism for standardized awarding of Model for End-Stage Liver Disease (MELD) exception points.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-16T09:10:21.954096-05:
      DOI: 10.1111/ajt.14395
       
  • Donor Recipient Matching Based on Predicted Recognizable HLA Epitopes
           Predicts the Incidence of De Novo Donor-Specific HLA Antibodies Following
           Renal Transplantation
    • Authors: Nils Lachmann; Matthias Niemann, Petra Reinke, Klemens Budde, Danilo Schmidt, Fabian Halleck, Axel Pruß, Constanze Schönemann, Eric Spierings, Oliver Staeck
      Abstract: De novo donor-specific HLA antibodies (dnDSA) are recognized as risk factor for premature allograft failure. Determinants of DSA specificity are generated via the indirect allorecognition pathway. Here, we present supportive data for the relevance of predicted indirectly recognizable HLA epitopes (PIRCHE) to predict dnDSA following kidney transplantation.A total of 2,787 consecutive kidney transplants performed 1995-2015 without preformed DSA have been analyzed. De novo DSA were detected by single antigen bead assay. HLA epitope mismatches were determined by the HLAMatchmaker and PIRCHE approach and correlated in uni- and multivariate analyses with 10-year allograft survival and incidence of dnDSA.The PIRCHE-II score moderately predicted allograft survival. However, the predictive value of elevated PIRCHE-II scores>9 for the incidence of dnDSA was statistically significant (p
      PubDate: 2017-06-14T09:21:23.12071-05:0
      DOI: 10.1111/ajt.14393
       
  • The incremental cost of Incompatible Living Donor Kidney Transplant: A
           National Cohort Analysis
    • Authors: David Axelrod; Krista L. Lentine, Mark A. Schnitzler, Xun Luo, Huiling Xiao, Babak J. Orandi, Allan Massie, Jacqueline Garonzik-Wang, Mark D. Stegall, Stanley C. Jordan, Jose Oberholzer, Ty B. Dunn, Lloyd E. Ratner, Sandip Kapur, Ronald P. Pelletier, John P. Roberts, Marc L. Melcher, Pooja Singh, Debra L. Sudan, Marc P. Posner, Jose M. El-Amm, Ron Shapiro, Matthew Cooper, George S. Lipkowitz, Michael A. Rees, Christopher L. Marsh, Bashir R. Sankari, David A. Gerber, Paul W. Nelson, Jason Wellen, Adel Bozorgzadeh, A. Osama Gaber, Robert A. Montgomery, Dorry L. Segev
      Abstract: Incompatible living donor kidney transplant (ILDKT) has been established as an effective option for end stage renal disease (ESRD) patients with willing but HLA incompatible live donors, reducing mortality and improving quality of life. Depending upon antibody titer, ILDKT can require highly resource intensive procedure including intravenous immunoglobulin, plasma exchange and/or cell depleting antibody treatment as well as protocol biopsies and DSA testing. This study sought to compare the cost and Medicare reimbursement, exclusive of organ acquisition payment, for ILDKT recipients (N=926) with varying antibody titers to matched compatible transplants (N=2762) performed between 2002-2011. Data were assembled from a national cohort study of ILDKT and a unique dataset linking hospital cost accounting data, and Medicare claims. Overall, ILDKT transplants were 41% more expensive than their compatible counterparts ($151,024 vs. $106,636, p
      PubDate: 2017-06-14T09:21:21.121475-05:
      DOI: 10.1111/ajt.14392
       
  • T cell subsets predicting belatacept-resistant rejection: Finding the root
           where the trouble starts
    • Authors: T. Wekerle
      Abstract: The potential of costimulation blockade to revolutionize post-transplant immunosuppression has remained largely unfulfilled to date. Belatacept, the only costimulation blocker approved in organ transplant recipients, has not replaced the 30-plus-year-old CNIs as the mainstay of immunosuppression and is currently used infrequently. Modulating pathogenic immune responses through the interruption of costimulatory signals, which a naïve T cell requires for its full activation, has captivated immunologists since the demonstration that such costimulation blockade leads to antigen-specific immunomodulation (at least in vitro). CD28 was identified as a key T cell costimulatory receptor and its blockade became a primary goal. Direct blockade of the CD28 receptor has been challenging (as conventional anti-CD28 antibodies typically retain some stimulating activity) and thus indirect blockade via ligation of the ligands CD80 and CD86 (B7-1 and B7-2) through CTLA4-Ig fusion proteins was developed as alternative.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-14T09:21:18.747479-05:
      DOI: 10.1111/ajt.14390
       
  • Equitable access is not a secondary goal of organ allocation
    • Authors: K. Ladin; D. Hanto
      Abstract: We appreciate the thoughtful comments expressed by Ms. Glazier.1 We agree that maintaining local priority for allocation of livers will not address broad health inequalities. In fact, we argue that this is not the purpose of organ allocation.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-08T22:25:26.745173-05:
      DOI: 10.1111/ajt.14387
       
  • Utilization of Organs from Donors According to Hepatitis C Antibody and
           Nucleic Acid Testing Status: Time for Change
    • Authors: C E Kling; J D Perkins, C S Landis, A P Limaye, L Sibulesky
      Abstract: Previous studies have grouped all HCV antibody (Ab) positive donors. Only recently has testing for donor hepatitis C virus (HCV) nucleic acid (NAT) become routine and the impact of Ab and NAT status on organ utilization is unknown. Using the United Network for Organ Sharing (UNOS) database, we identified 9290 donors from 2015 to 2016 for whom both HCV Ab and NAT data were available, and compared organ utilization by HCV status. 93.8% of donors were Ab- NAT-, 0.15% were Ab- NAT+, 1.8% were Ab+ NAT- and 4.2% were Ab+ NAT+. Ab- NAT- donors donated at the highest rate for all organs except livers, where Ab+ NAT- donors donated at a higher rate (81.2% vs 73.2%, p=0.03). Livers were discarded for reasons related to abnormal biopsies in Ab+ NAT+ donors, whereas kidneys from Ab or NAT positive donors were discarded for reasons related to HCV status. Using a propensity-matched model, we estimated that using Ab+ NAT- donors at the same rate as Ab- NAT- donors could result in 48 more kidney donors, 37 more heart donors and 15 more lung donors annually. We urge use of HCV Ab+ NAT- donors into appropriately selected and consenting recipients.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-08T20:37:48.87137-05:0
      DOI: 10.1111/ajt.14386
       
  • Harnessing scientific and technological advances to improve equity in
           kidney allocation policies
    • Authors: Anat R Tambur; Benoit Audry, Corinne Antoine, Caroline Suberbielle, Denis Glotz, Christian Jacquelinet
      Abstract: We reported that current assignment of HLA-DQ is a barrier to organ allocation. Here we simulated the impact of incorporating HLA-DQ antigens and antibodies as A/B and αβ allelic variants, respectively, on calculated PRA and probability of finding potential compatible donors (PCD). A cohort of 1224 donors and 2075 sensitized candidates was analyzed using HLA-DQαβ allelic (study) versus serologic (current practice) nomenclature. A significant (p
      PubDate: 2017-06-08T18:50:42.794314-05:
      DOI: 10.1111/ajt.14389
       
  • Everolimus-based immunosuppression in liver transplant recipients
    • Authors: Faouzi Saliba
      Abstract: My co-authors and I thank Dr Cholongitas for such thoughtful comments (1) on the findings of the randomized SIMCER trial (2). We concur with many of the points raised. To clarify, the remark ‘A similar improvement in renal function may not be achieved in patients with … substantially impaired renal function at the time of transplant’ refers to the improved estimated GFR (eGFR) observed in the everolimus-treated cohort versus the control arm given standard tacrolimus therapy, rather than to an improvement within the everolimus cohort versus baseline.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-08T17:37:53.771011-05:
      DOI: 10.1111/ajt.14388
       
  • Response to: Prophylactic Ureteric Stents in Renal Transplant Recipients:
           A Multicentre Randomised Controlled Trial of Early Versus Late Removal
    • Authors: J.A. Richards; K. Jones, Z. Moinuddin, G.J. Pettigrew
      Abstract: This study was powered on “stent complications”, rather than major ureteric complications (MUC). On an intention to treat basis there was no significant benefit from early stent removal (p = 0.055), but when looking overall at patients with early stent removal (irrespective of intention to treat), they did demonstrate a decrease in “stent complications” (predominantly reduced urinary tract infections (UTIs) 7.6% versus 24.6%). Despite being underpowered to look at MUC, there was a significant increase in overall urological complications with early stent removal.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-29T06:16:36.947257-05:
      DOI: 10.1111/ajt.14378
       
  • It is bad policy and contrary to federal law to prioritize local
           allocation of livers to address geographically based social inequities
    • Authors: Alexandra K. Glazier
      Abstract: In the article “Geographic Disparities in Liver Availability: Accidents of geography or consequences of poor social policy” Ladin et al argue that those who live in underserved areas, with high rates of preventable deaths from gunshot wounds, motor vehicle accidents and reduced medical services, may have a “special claim” to local organs in order to adjust for the geographically based “poor social policies” that contribute to low access to healthcare (1).This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-29T01:30:23.346349-05:
      DOI: 10.1111/ajt.14384
       
  • Skin Cancers in Organ Transplant Recipients
    • Authors: Amit Mittal; Oscar R. Colegio
      Abstract: Long-term utilization of immunosuppression in organ transplant recipients (OTRs) leads to decreased immune-mediated tumor surveillance and development of malignant tumors. A delicate balance needs to be maintained in the intensity of immunosuppression to keep the risk of malignancy low without jeopardizing life-saving graft function. OTRs are prone to developing skin cancers which exhibit unique epidemiologic, pathophysiologic and prognostic characteristics. In this review, we discuss the most commonly reported skin cancers in OTRs: squamous cell carcinoma (SCC), basal cell carcinoma (BCC), Kaposi's sarcoma, Merkel cell carcinoma and malignant melanoma (MM). Tumors in this high-risk population are aggressive and may respond poorly to standard therapies. However, new targeted therapies are promising. Checkpoint inhibitor antibodies have been used for treatment of cutaneous SCC, Merkel cell carcinoma, and MM; epidermal growth factor receptor inhibitors for cutaneous SCC; hedgehog pathway inhibitors for BCC; and BRAF and MEK inhibitors are being used increasingly in the management of MM. Guidelines for dermatologic screening is variable and primarily based on expert opinion. Prospective evidence-based trials by multidisciplinary groups are needed to better define surveillance schedules for pre-transplant and post-transplant cutaneous malignancies.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-29T01:25:31.690654-05:
      DOI: 10.1111/ajt.14382
       
  • Waitlist Outcomes for Patients Relisted following Failed Donation after
           Cardiac Death Liver Transplant: Implications for Awarding MELD Exception
           Scores
    • Authors: Kristopher P. Croome; David D. Lee, Justin H. Nguyen, Andrew P. Keaveny, C Burcin Taner
      Abstract: Understanding of outcomes for patients re-listed for ischemic cholangiopathy (IC) following a donation after cardiac death (DCD) liver transplant (LT) will help standardization of MELD exception scheme for re-transplantation. Early relisting (E-RL) for DCD graft failure due to PNF or HAT was defined as re-listing ≤ 14 days after DCD-LT, late relisting (L-RL) due to biliary complications was defined as re-listing 14 days- 3 years after DCD-LT. Of 3908 DCD-LT performed nationally between 2002-2016, 540 (13.8%) patients were re-listed within 3 years of transplant. 168 patients (4.3%) in the E-RL and 372 patients (9.5%) in the L-RL group. E-RL and L-RL groups had waitlist mortality rate of 15.4% and 10.5% at 3 months and 16.1% and 14.3% at 1 year. Waitlist mortality in the L-RL group was higher than mortality/de-listed rate for patients with exception points for both hepatocellular carcinoma (HCC) and hepatopulmonary syndrome (HPS) at 3-12 month time points (p
      PubDate: 2017-05-29T01:25:24.33761-05:0
      DOI: 10.1111/ajt.14383
       
  • The American Society of transplantation consensus conference on the use of
           hepatitis C viremic donors in solid organ transplantation
    • Authors: J. Levitsky; R.N. Formica, R.D. Bloom, M. Charlton, M Curry, J. Friedewald, J. Friedman, D. Goldberg, S. Hall, M Ison, T. Kaiser, D. Klassen, G. Klintmalm, J. Kobashigawa, A. Liapakis, K. O'Conner, P. Reese, K. Shelat, D. Stewart, N. Terrault, N. Theodoropoulos, J. Trotter, E. Verna, M. Volk
      Abstract: The availability of direct acting antiviral agents for the treatment of hepatitis C virus (HCV) has resulted in a profound shift in the approach to the management of this infection. These changes have impacted the practice of solid organ transplantation by altering the framework by which patients with end stage organ disease are managed and receive organ transplants. The high level of safety and efficacy of these medications in patients with chronic HCV infection provide the opportunity to explore their use in the setting of transplanting organs from HCV viremic patients into HCV non-viremic recipients. Because these organs are frequently discarded and typically come from younger donors, this approach has the potential to save lives on the solid organ transplant waiting list. Therefore, an urgent need exists for prospective research protocols that study the risk versus benefit of utilizing organs for hepatitis C infected donors. In response to this rapidly changing practice and the need for both urgent scientific study and consensus on how these investigations should proceed, the American Society of Transplantation convened a meeting of experts to review current data and develop the framework for the future study of utilizing HCV viremic organs in solid organ transplantation.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-29T01:20:40.254406-05:
      DOI: 10.1111/ajt.14381
       
  • Novel Donor Transfer Algorithm for Multi-organ and Facial Allograft
           Procurement
    • Authors: J. Rodrigo Diaz-Siso; Natalie M. Plana, Benjamin Schleich, Helen Irving, Bruce E. Gelb, Eduardo D Rodriguez
      Abstract: The non-life-saving nature of facial transplantation (FT) has raised concerns over the procurement of a facial allograft (FA) and allocated solid organs (SO) from a single donor. In response, FT teams have described their experiences performing simultaneous and asynchronous procurement. One unanimous conclusion is that the safe procurement of life-saving organs must be given priority during the donor operation.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-28T08:35:30.926149-05:
      DOI: 10.1111/ajt.14380
       
  • Lessons learned: Early termination of a randomized trial of calcineurin
           inhibitor and corticosteroid avoidance using Belatacept
    • Authors: Kenneth A. Newell; Aneesh K. Mehta, Christian P. Larsen, Peter G. Stock, A. Bradley Farris, Shikha G. Mehta, David Ikle, Brian Armstrong, Yvonne Morrison, Nancy Bridges, Mark Robien, Roslyn B. Mannon
      Abstract: The intent of this NIH-sponsored study was to compare a belatacept-based immunosuppressive regimen with a maintenance regimen of tacrolimus and mycophenolate (MMF). Nineteen primary, EBV-immune renal transplant recipients with a negative cross-match were randomized to one of three groups. All patient groups received perioperative steroids and maintenance MMF. Patients in groups 1 and 2 were induced with alemtuzumab and maintained on tacrolimus or belatacept, respectively. Patients in group 3 were induced with basiliximab, received 3 months of tacrolimus, and maintained on belatacept. There was one death with a functioning allograft due to endocarditis (group 1). There were three graft losses due to vascular thrombosis (all group 2) and one graft loss due to glomerular disease (group 1). Biopsy-proven acute cellular rejection was more frequent in the belatacept treated groups, with 10 treated episodes in 7 subjects compared to 1 episode in group 1. However, eGFR was similar between groups at week 52. There were no episodes of PTLD or opportunistic infections in any group. Protocol enrollment was halted prematurely due to high rate of serious adverse events. Such negative outcomes pose challenges to clinical investigators who ultimately must weigh the risk and benefit in randomized trials.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-28T08:35:29.01655-05:0
      DOI: 10.1111/ajt.14377
       
  • New Insights into the Alleged KDPI Labeling Effect on Kidney Utilization
    • Authors: Darren E. Stewart; Victoria C. Garcia, Mark I. Aeder, David K. Klassen
      Abstract: The Kidney Donor Profile Index (KDPI) became a driving factor in deceased donor kidney allocation on December 4, 2014 with the implementation of the kidney allocation system (KAS). On April 20, 2016, the annual recalibration of the Kidney Donor Risk Index (KDRI) into KDPI was incorrectly programmed in DonorNet, resulting in erroneously-high KDPI values from between 1 and 21 percentage points (e.g., actual KDPI of 70% was displayed as 86%). The error was corrected on May 19, 2016, less than 24 hours after being recognized. During this 30-day period, the distribution of recipients largely resembled pre-KAS patterns. The observed discard rate of 22.9% was higher than the post-KAS average of 19.6% (OR=1.22) but far lower than the projected rate of 31.4% (OR=1.96) based on the usual discard rate by KDPI relationship, suggesting clinicians and patients did not rely heavily on this single number (KDPI) in kidney utilization decisions. Still, risk-adjusted analyses suggest the elevated discard rate was most likely attributable to the erroneously-high KDPIs, not a shift in donor characteristics or random chance. The rise in discard rate was sharply higher for kidneys whose inflated KDPI crossed the 85% policy threshold (OR=1.46, p=0.049) vs. those that did not (OR=1.06, p=0.631).This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-28T08:35:24.932716-05:
      DOI: 10.1111/ajt.14379
       
  • Learning from lessons on applying information technology in organ
           transplant: a stepping stone to achieve Electronic Health Record
           meaningful use
    • Authors: H Pirnejad; Z Niazkhani
      Abstract: We read with interest the paper by Zier et al. on automated referral of impending brain deaths to an organ procurement organization (OPO) using a electronic clinical decision support system (CDSS) (1). The paper reports on the evaluation of a home-grown CDSS and how it worked as an effective tool for implementation of a recognized best practice in the organ donation process i.e. timely referral of potential organ donors to an OPO. This is very valuable because effective management of scarce resources of deceased donors can provide ample opportunities for saving lives of potential organ recipients. We thank authors for sharing their experience of CDSS use in the organ transplant domain. This study, however, has cited some of CDSS applications in medical domains other than organ transplantation. Therefore, we would like to draw the authors’ attention to recent reviews on the application and impact of transplant specific CDSSs in the organ transplant domain (2, 3).This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-28T08:30:30.294942-05:
      DOI: 10.1111/ajt.14373
       
  • Effects of DNA Methylation on Progression to Interstitial Fibrosis and
           Tubular Atrophy in Renal Allograft Biopsies: A Multi-omics Approach
    • Authors: Sai Vineela Bontha; Daniel G. Maluf, Kellie J. Archer, Catherine I. Dumur, Mikhail Dozmorov, Anne King, Enver Akalin, Thomas F. Mueller, Lorenzo Gallon, Valeria R. Mas
      Abstract: Progressive fibrosis of the interstitium is the dominant final pathway in renal destruction in native and transplanted kidneys. Over time, the continuum of molecular events following immunological and non-immunological insults lead to interstitial fibrosis and tubular atrophy (IFTA) and culminate in kidney failure. We hypothesize that these insults trigger changes in DNA methylation (DNAm) patterns which in turn could exacerbate injury and slow down the regeneration processes, leading to fibrosis development and graft dysfunction. Herein, we analyzed biopsy samples from kidney allografts collected after 24-months post transplantation and used an integrative multi-omics approach to understand the underlying molecular mechanisms. The role of DNAm and microRNAs on the graft gene expression was evaluated. Enrichment analyses of differentially methylated CpG sites were performed using GenomeRunner. CpGs were strongly enriched in regions that were variably methylated among tissues implying high tissue specificity in their regulatory impact. Corresponding to this methylation pattern, gene expression data were related to immune response (activated state) and nephrogenesis (inhibited state). Preimplantation biopsies showed similar DNAm patterns to normal allograft biopsies at 2-years post-transplantation. Our findings demonstrate for the first time a relationship among epigenetic modifications and development of interstitial fibrosis, graft function, and inter-individual variation on long-term outcomes.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-28T08:30:29.511525-05:
      DOI: 10.1111/ajt.14372
       
  • Impact of a National Controlled Donation After Circulatory Death (DCD)
           Programme on Organ Donation in the UK: A 10 Year Study
    • Authors: Russell Hodgson; Alastair L Young, Magdy A Attia, J Peter A Lodge
      Abstract: Organ transplantation is the most successful treatment for some forms of organ failure yet a lack of organs means many die on the waiting list. In the UK, the Organ Donation Taskforce was set up to identify barriers to organ donation and in 2008 released its first report (ODTR). This study assesses the success since the ODTR and examines the impact of the UK's controlled Donation after Circulatory Death (DCD) programme and the controversies surrounding it. There were 12864 intended Donation after Brain Death (DBD) or DCD donors from April 2004 to March 2014. When the 5 years preceding the ODTR was compared to the 5 years following, intended DCD donors increased 292% (1187 to 4652), and intended DBD donors increased 11% (3327 to 3698). Organs retrieved per intended DBD donor remained static (3.30 to 3.26), whereas there was a decrease in DCD (1.54 to 0.99) due to a large rise in donors that didn't proceed to donation (325 to 2464). The majority of DCD donors who proceeded did so within 30 minutes from time of withdrawal. Our study suggests further work on converting eligible referrals to organ donation and explororing methods of converting DCD to DBD donors.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-28T08:30:26.566286-05:
      DOI: 10.1111/ajt.14374
       
  • Everolimus-based immunosuppression in liver transplant recipients
    • Authors: Evangelos Cholongitas
      Abstract: We read with great interest the randomized study by Saliba et al(1) regarding the impact on renal function of everolimus-based therapy [i.e. everolimus plus mycophenolic (MPA) with low-exposure tacrolimus discontinued by month 4 post-liver transplantation (LT)] vs tacrolimus-based therapy.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-28T08:30:24.753727-05:
      DOI: 10.1111/ajt.14375
       
  • Cytomegalovirus-induced polyarteritis nodosa (PAN) in a liver transplant
           recipient
    • Authors: Kerolos Abadeer; Aslam Nabeel, Cherise Cortese, Hani M. Wadei
      Abstract: Polyarteritis nodosa (PAN) is a necrotizing vasculitis that has been associated with viral infections especially hepatitis B virus. We hereby report a case of tissue invasive cytomegalovirus (CMV)-induced PAN in a liver transplant recipient presenting with acute kidney injury and active urinary sediment. Treatment directed against both PAN and CMV resulted in improvement in kidney function, normalization of urinary indices and resolution of the CMV infection. No recurrence of either PAN or CMV occurred after 3 year follow-up period.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-28T08:30:23.576498-05:
      DOI: 10.1111/ajt.14376
       
  • ESRD in living donors from prior to 1987: Obtaining waitlist priority
    • Authors: R. Hays; C. Lillesand, D. A. Mandelbrot
      Abstract: Since 1996, living kidney donors who later developed ESRD have been eligible to receive priority status on the UNOS/OPTN kidney transplant waitlist. In 2015, Potluri et al showed that this system is generally effective: living donors receiving priority points were transplanted faster than controls.1 Others have noted limited data on living donor ESRD trajectory and treatment access, due to the lack of a system to follow living donor outcomes long-term.2-3This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-25T04:11:09.396033-05:
      DOI: 10.1111/ajt.14369
       
  • Belatacept Combined with Transient Calcineurin Inhibitor Therapy Prevents
           Rejection and Promotes Improved Long-Term Renal Allograft Function
    • Authors: A B Adams; J Goldstein, C Garrett, R Zhang, R E Patzer, K A Newell, N A Turgeon, A S Chami, A Guasch, A D Kirk, S O Pastan, T C Pearson, C P Larsen
      Abstract: Belatacept, a T cell costimulation-blocker demonstrated superior renal function, lower cardiovascular risk, and improved graft/patient survival in renal transplant recipients. Despite the potential benefits, adoption of belatacept has been limited in part due to concerns regarding higher rates and grades of acute rejection in clinical trials. Since July 2011 we have utilized belatacept-based immunosuppression regimens in clinical practice. In this retrospective analysis of 745 patients undergoing renal transplantation at our center, we compared patients treated with belatacept (n=535) to a historical cohort receiving a tacrolimus-based protocol (n=205). Patient and graft survival were equivalent between all groups. An increased rate of acute rejection was observed in an initial cohort treated with a protocol similar to the low-intensity regimen from the BENEFIT trial vs the historical tacrolimus group (50.5% vs 20.5%). The addition of a transient course tacrolimus reduced rejection rates to acceptable levels (16%). Treatment with belatacept was associated with superior eGFR (belatacept 63.8ml/min vs tacrolimus 46.2ml/min at 4 years, p
      PubDate: 2017-05-23T06:50:43.661862-05:
      DOI: 10.1111/ajt.14353
       
  • Thymic-peripheral crosstalk in lymphodepletion therapy
    • Authors: M. E. Snyder; D. L. Farber
      Abstract: T cell depletion is widely used as induction therapy in solid organ transplants and particularly in kidney transplantation, to reduce the episodes of acute cellular rejection. The resultant reduction in T cell numbers is usually temporary, as T cells are actively replenished due to thymic output and/or lymphopenia-induced proliferation of remaining, depletion-resistant T cells. However, the extent of T cell replenishment and the persistence of lymphopenia varies between individuals, with potential impacts on protective or pathogenic immune responses.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-22T10:00:22.167412-05:
      DOI: 10.1111/ajt.14370
       
  • Breast cancer and transplantation
    • Authors: Germaine Wong; Eric Au, Sunil V Badve, Wai H Lim
      Abstract: Breast cancer is an important cancer among solid organ transplant recipients. While the incidence of breast cancer in solid organ transplant recipients is comparable to the age matched general population, the outcomes are generally poor. Interventions such as cancer screening which preclude the development of late stage disease through early detection are not well-studied, and clinical practice guidelines for cancer screening rely solely on recommendations from the general population. Among those with a prior breast cancer history, disease recurrence after transplantation is a rare but fearful event. Once disease recurs, the risk of death is high. The focus of this review is to present the epidemiology of breast cancer in solid organ transplant recipients, screening and preventive strategies for those who may be at risk, novel genomic profiling for determining tumor progression and the newer targeted interventions for recipients who have developed breast cancers after solid organ transplantation.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-19T11:10:28.069542-05:
      DOI: 10.1111/ajt.14368
       
  • Brain-dead Donors with Ornithine Transcarbamylase Deficiency: A Big
           Learning Opportunity in Clinical Evaluation
    • Authors: F Caballero; J Ris, M Puig, J Leal, S Benito
      Abstract: We have read with interest the report by Ramanathan et al regarding a case of ornithine transcarbamylase (OTC) deficiency unmasked post–liver transplantation (1). This serves as a big learning opportunity in clinical organ donor evaluation. A consequence of this disorder is hyperammonemia. Acute high levels in serum ammonia can cause severe neurological findings such as cerebral edema and brain death (2-4).This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-19T10:25:30.148185-05:
      DOI: 10.1111/ajt.14367
       
  • Solid renal masses in transplanted allograft kidneys: A closer look at the
           epidemiology and management
    • Authors: John J. Griffith; Katherine A. Amin, Nikhil Waingankar, Susan M. Lerner, Veronica Delaney, Scott A. Ames, Ketan Badani, Michael A. Palese, Reza Mehrazin
      Abstract: The objective of this review is to explore the available literature on solid renal masses (SRM) in transplant allograft kidneys to better understand the epidemiology and management of these tumors. A literature review using PubMed was performed according to the PRISMA methodology. Fifty-six relevant studies were identified from 1988-2015. A total of 174 SRMs in 163 patients, were identified with a mean tumor size of 2.75 cm (0.5-9.0cm). Tumor histology was available in 164 (94.3%) tumors: clear cell renal cell carcinoma (RCC) (45.7%), papillary RCC (42.1%), chromophobe RCC (3%), and others (9.1%). Tumors were managed by partial nephrectomy (67.5%), radical nephrectomy (19.4%), percutaneous radiofrequency ablation (10.4%), and percutaneous cryoablation (2.4%). Of the 131 patients (80.3%) who underwent nephron-sparing interventions, 10 (7.6%) returned to dialysis and 8 (6.1%) developed tumor recurrence over a mean follow-up of 2.85 years. Of the 110 patients (67.5%) who underwent partial nephrectomy, 3.6% developed a local recurrence during a mean follow up of 3.12 years. The current management of SRMs in allograft kidneys mirrors management in the non-transplant population with notable findings including an increased rate of papillary RCC and similar recurrence rates after partial nephrectomy in the transplant population despite complex surgical anatomy.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-19T10:05:23.575744-05:
      DOI: 10.1111/ajt.14366
       
  • The Living Donor Collective: A Scientific Registry for Living Donors
    • Authors: B L Kasiske; S K Asrani, M A Dew, M L Henderson, C Henrich, A Humar, A K Israni, K L Lentine, A J Matas, K A Newell, D LaPointe Rudow, A B Massie, JJ Snyder, S J Taler, J F Trotter, A D Waterman,
      Abstract: In the setting of an overall decline in living organ donation and new questions about long-term safety, a better understanding of outcomes after living donation has become imperative. Adequate information on outcomes important to donors may take many years to ascertain and may only be evident by comparing large numbers of donors with suitable controls. Previous studies have been unable to fully answer critical questions, primarily due to lack of appropriate controls, inadequate sample size, and/or follow-up duration too short to allow detection of important risks attributable to donation. The Organ Procurement and Transplantation Network does not follow donors long term and has no prospective control group with which to compare post-donation outcomes. There is a need to establish a national living donor registry, and to prospectively follow donors over their lifetimes. In addition, there is a need to better understand the reasons many potential donors who volunteer to donate do not donate, and whether the reasons are justified. Therefore, the US Health Resources and Services Administration asked the Scientific Registry of Transplant Recipients to establish a national registry to address these important questions. Here, we discuss the efforts, challenges, and opportunities inherent in establishing the Living Donor Collective.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-18T10:06:28.094358-05:
      DOI: 10.1111/ajt.14365
       
  • Potential disadvantages of over centralization of organ recovery centres:
           Response to Marsolais et al
    • Authors: Matthew J. Weiss; Andrew Healey, Sonny Dhanani, Jean-François Lizé
      Abstract: As physicians involved in the Canadian organ donation system, we read with interest the report by Marsolais et al (1). While the team at Hôpital Sacre-Coeur de Montréal deserves to be congratulated for their excellence in the organ donation, the described model has potential disadvantages, and we believe its advantages have been overstated.Marsolais et al. chose people transplanted per million (tpm) as their primary outcome, which is less frequently reported than donors per million. We disagree that tpm is the correct statistic, and we also disagree with how it was calculated.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-16T09:50:47.457322-05:
      DOI: 10.1111/ajt.14357
       
  • BK Virus Nephropathy Revisited
    • Authors: Michael Mengel
      Abstract: More than 20 years after its first description and increased morbidity under powerful immunosuppression, the understanding of the pathogenesis of BK polyomavirus induced allograft nephropathy (BKVN) has changed clinical practice in renal transplantation. Screening programs were introduced at most transplant centers causing the prevalence of BKVN to decrease. However, BK viremia is still found in 10-30% of renal allograft recipients with 1-10% developing BKVN.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-16T09:50:46.460962-05:
      DOI: 10.1111/ajt.14358
       
  • The National Landscape of Living Kidney Donor Follow-up in the United
           States
    • Authors: Macey L. Henderson; Alvin G. Thomas, Ashton Shaffer, Allan B. Massie, Xun Luo, Courtenay M. Holscher, Tanjala S. Purnell, Krista Lentine, Dorry L. Segev
      Abstract: In 2013, OPTN/UNOS mandated that transplant centers collect data on living kidney donors (LKDs) at 6-months, 1-year, and 2-years post-donation, with policy-defined thresholds for the proportion of complete living donor follow-up (LDF) data submitted in a timely manner (60 days before or after the expected visit date). While mandated, it was unclear how centers across the country would perform in meeting thresholds, given potential donor and center-level challenges of LDF. To better understand the impact of this policy, we studied SRTR data for 31,615 LKDs between 1/2010-6/2015, comparing proportions of complete and timely LDF form submissions pre- and post-policy implementation. We also used multilevel logistic regression to assess donor- and center-level characteristics associated with complete and timely LDF submissions. Complete and timely 2-year LDF increased from 33% pre-policy (1/2010-1/2013) to 54% post-policy (2/2013-6/2015) (p
      PubDate: 2017-05-16T09:50:44.650228-05:
      DOI: 10.1111/ajt.14356
       
  • Report from the American society of transplantation conference on donor
           heart selection in adult cardiac transplantation in the U.S
    • Authors: J. Kobashigawa; K. Khush, M. Colvin, M. Acker, A. Van Bakel, H. Eisen, Y. Naka, J. Patel, D. A. Baran, T. Daun, M. Luu, M. Olymbios, J. Rogers, V. Jeevanandam, F. Esmailian, F. D. Pagani, B. Lima, J. Stehlik
      Abstract: Cardiac transplantation remains the only definitive treatment for end-stage heart failure. Transplantation rates are limited by a shortage of donor hearts. This shortage is magnified because many hearts are discarded due to strict selection criteria and concern for regulatory reprimand for less than optimal post-transplant outcomes. There is no standardized approach to donor selection despite proposals to liberalize acceptance criteria. A donor heart selection conference was organized to facilitate discussion, and generate ideas for future research. The event was attended by 66 participants from 41 centers with considerable experience in cardiac donor selection. There were state-of-the-art presentations on donor selection, with subsequent break-out sessions on standardizing the process and increasing utilization of donor hearts. Participants debated misconceptions and established agreement on donor and recipient risk factors for donor selection, and identified the components necessary for a future donor risk score. Ideas for future initiatives include modification of regulatory practices to consider extended criteria donors when evaluating outcomes, and prospective studies aimed at identifying the factors leading to non-acceptance of available donor hearts. With agreement on the most important donor and recipient risk factors, it is anticipated that a consistent approach to donor selection will improve rates of heart transplantation.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-16T09:50:34.861749-05:
      DOI: 10.1111/ajt.14354
       
  • Modelling the iatrogenic pancreatic cancer risk after islet
           autotransplantation in mouse
    • Authors: E Dugnani; V Pasquale, D Liberati, A Citro, E Cantarelli, S Pellegrini, P Marra, T Canu, G Balzano, M Scavini, A Esposito, C Doglioni, L Piemonti
      Abstract: Iatrogenic pancreatic cancer metastasis after islet infusion is a potential risk of islet autotransplantation performed after pancreatectomy. To model this risk islets and/or pancreatic exocrine clusters obtained from a genetically engineered mouse model for pancreatic ductal adenocarcinoma (the LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre, termed KPC mouse) were transplanted via the portal vein in syngeneic wild type (WT) severely diabetic recipients in the following treatment groups: group A (n=11) received KPC exocrine clusters in volume equal to 250 equivalent islets (IEQs); group B (n=12) received 250 WT IEQs mixed with KPC exocrine clusters (1:1 volume ratio); group C (n=5) received 250 KPC IEQs and group D (n=7) received 250 wild type IEQs. The incidence of hepatic metastasis was assessed by magnetic resonance imaging and histology over the 13 months of follow-up. Overall survival was not different in the four groups. No mice developed liver metastases during the follow-up. Two mice developed spontaneous tumors: a liver hepatocellular tumor in group A and a malignant lymphoma in group D. Islets and/or exocrine clusters obtained by KPC mouse, a model which develops pancreatic cancer with 100% penetrance, do not retain the same risk of tumor development when transplanted via the portal vein in syngeneic diabetic recipient.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-16T09:46:29.839482-05:
      DOI: 10.1111/ajt.14360
       
  • Living Donor Liver Transplantation for Patients Older Than Age 70 Years: A
           Single-Center Experience
    • Authors: J. H. Kwon; Y. I. Yoon, G. W. Song, K. H. Kim, D. B. Moon, D. H. Jung, G. C. Park, E. Y. Tak, V. A. Kirchner, S. G. Lee
      Abstract: Over the past two decades, the age of liver transplantation (LT) recipients has been increasing. We reviewed our experience with LT for patients aged 70 years or older (range: 70-78) and investigated the feasibility of performing LT, especially living donor LT (LDLT), for older patients. We retrospectively reviewed the medical records of 25 patients (15 LDLT recipients, 10 DDLT recipients), aged 70 years or older who underwent LT from January 2000 to April 2016. Their perioperative morbidity rate was 28.0% and the in-hospital mortality rate was 16.0%. This result was comparable to that of matched 60-year-old patients (n=73) (p=0.726, p=0.816). For the 70-year-old patient group, the 1- and 5-year patient survival rates were 84.0% and 69.8%, whereas the 1- and 5-year graft survival rates were 83.5% and 75.1%, respectively. Comparisons of patient and graft survival rates between matched patients 60 years old and 70 years old showed no statistically significant differences (p= 0.372, p = 0.183). Our experience suggests that patients 70 years or older should not be excluded from LT, or even LDLT, solely based on age and implies that careful selection of recipients and donors as well as meticulous surgical technique are necessary for successful results.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-16T09:46:19.915091-05:
      DOI: 10.1111/ajt.14355
       
  • Proteoforms in Peripheral Blood Mononuclear Cells as Novel Rejection
           Biomarkers in Liver Transplant Recipients
    • Authors: T. K. Toby; M. Abecassis, K. Kim, P. M. Thomas, R. T. Fellers, R. D. LeDuc, N. L. Kelleher, J. Demetris, J. Levitsky
      Abstract: Biomarker profiles of acute rejection in liver transplant recipients could enhance the diagnosis and management of recipients. Our aim was to identify diagnostic proteoform signatures of acute rejection in circulating immune cells, using an emergent “top down” proteomics methodology. We prepared differentially processed and cryopreserved cell lysates from 26 non-viral liver transplant recipients by molecular weight-based fractionation and analyzed them by mass spectrometry of whole proteins in three steps: 1) Nanocapillary liquid chromatography coupled with high-resolution tandem mass spectrometry; 2) database searching to identify and characterize intact proteoforms; 3) data processing through a hierarchical linear model matching the study design to quantify proteoform fold changes in patients with rejection vs. normal liver function vs. acute dysfunction without rejection. Differentially expressed proteoforms were seen in patients with rejection vs. normal and non-specific controls, most evidently in the cell preparations stored in traditional serum-rich media. Mapping analysis of these proteins back to genes through gene ontology and pathway analysis tools revealed multiple signaling pathways, including inflammation mediated by cytokines and chemokines. Larger studies are needed to validate these novel rejection signatures and test their predictive value for use in clinical management.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-16T09:32:29.763969-05:
      DOI: 10.1111/ajt.14359
       
  • The impact of left ventricular diastolic dysfunction on lung transplant
           outcome in patients with pulmonary arterial hypertension
    • Authors: Avital Avriel; Anat Hershko Klement, Sindhu R. Johnson, Marc Perrot, John Granton
      Abstract: Diastolic dysfunction may influence perioperative outcome, early graft function and long-term survival. We compared the outcomes of DLTx for PAH patients with pre-operative LV diastolic dysfunction to those without diastolic dysfunction. Of 116 consecutive patients with PAH (who underwent transplantation between January 1995 and December 2013), 44 met our inclusion and exclusion criteria. Fourteen patients (31.8%) with diastolic dysfunction pre-LTx had a higher BMI [29 (IQR 21.5-32.6) vs. 22.4 (IRQ 19.9-25.3)], mean pulmonary arterial pressure (54.6 ± 10 mmHg vs. 47 ± 11.3 mmHg) and right atrial pressure (16.5 ± 5.2 mmHg vs. 10.6 ± 5.2 mmHg). They received extracorporeal life support more frequently [33% vs 7% (p=0.02)], had worse Apache II score, 21.7 ± 7.4 vs 15.3 ± 5.3 (p=0.02), and a trend toward worse ventilator-free days 2.5 (IQR 6.5 – 32.5) vs. 17 (IQR 3 – 23) (p=0.08). There was no effect on development of primary graft dysfunction or ICU / hospital survival. One-year survival was worse (HR 4.45, 95% CI 1.3-22, p=0.02). Diastolic dysfunction was the only variable that correlated with overall survival (HR 5.4, 95% CI 1.3-22, P=0.02). Diastolic dysfunction leads to early post-operative morbidity and worse survival in PAH patients after double lung transplant.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-16T00:25:28.200844-05:
      DOI: 10.1111/ajt.14352
       
  • Costimulation blockade; America first, Canada second what about
           Norway'
    • Authors: Karsten Midtvedt; Hallvard Holdaas, Stein Bergan, Anders Åsberg
      Abstract: We read with interest the letter by Gill et al “commenting on costimulation blockade in large markets only» (1). They pinpoint the fact that the United States for long times have been the testing ground for development and commercialization of new therapeutics. This is a problem for therapeutics with small target patient populations such as immunosuppressant drugs. The authors anticipate that this will be a bigger issue in the future arguing that establishing a market foothold for new transplant therapeutics in the U.S. market likely will be even more difficult with the availability of generic immunosuppressant drugs.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-16T00:20:29.550474-05:
      DOI: 10.1111/ajt.14351
       
  • Increased Pre-Transplant Frequency of CD28+ CD4+ TEM Predicts
           Belatacept-Resistant Rejection in Human Renal Transplant Recipients
    • Authors: Miriam Cortes-Cerisuelo; Sonia J. Laurie, David V. Mathews, Pamela D. Winterberg, Christian P. Larsen, Andrew B. Adams, Mandy L. Ford
      Abstract: While most human T cells express the CD28 costimulatory molecule constitutively, it is well-known that age, inflammation, and viral infection can drive the generation of CD28null T cells. In vitro studies have demonstrated that CD28null cell effector function is not impacted by the presence of the CD28 costimulation blocker belatacept. As such, a prevailing hypothesis suggests that CD28null cells may precipitate costimulation blockade-resistant rejection. However, CD28+ cells possess more proliferative and multi-functional capacity, factors that may increase their ability to successfully mediate rejection. Here, we performed a retrospective immunophenotypic analysis of adult renal transplant recipients who experienced acute rejection on belatacept treatment as compared to those that did not. Intriguingly, our findings suggest that patients possessing higher frequency of CD28+ CD4+ TEM prior to transplant were more likely to experience acute rejection following treatment with a belatacept-based immunosuppressive regimen. Mechanistically, CD28+ CD4+ TEM contained significantly more IL-2 producers. In contrast, CD28null CD4+ TEM isolated from stable belatacept-treated patients exhibited higher expression of the 2B4 coinhibitory molecule as compared to those isolated from patients who rejected. These data raise the possibility that pre-transplant frequencies of CD28+ CD4+ TEM could be used as a biomarker to predict risk of rejection following treatment with belatacept.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-14T04:26:50.838281-05:
      DOI: 10.1111/ajt.14350
       
  • Belatacept Resistant Rejection is Associated with CD28+ Memory CD8 T cells
    • Authors: D V Mathews; W C Wakwe, S C Kim, M C Lowe, C Breeden, M E Roberts, A B Farris, E A Strobert, J B Jenkins, C P Larsen, M L Ford, R Townsend, A B Adams
      Abstract: Recently newer therapies have been designed to more specifically target rejection in an effort to improve efficacy and limit unwanted toxicity. Belatacept, a CD28-CD80/86 specific reagent is associated with superior patient survival and graft function than traditional therapy but its adoption as a mainstay immunosuppressive therapy has been tempered by increased rejection rates. It is essential that the underlying mechanisms associated with this rejection be elucidated before belatacept is more widely employed. To that end we designed a study in a non-human primate kidney transplant model where animals were treated with either a belatacept- or a tacrolimus-based immunosuppressive regimen. Interestingly we found that elevated pre-transplant frequencies of CD28+CD8+TEMRA cells are associated with rejection on belatacept but not tacrolimus treatment. Further analysis showed that the CD28+CD8+TEMRA cells rapidly lose CD28 expression after transplant in those animals that go on to reject with the allograft infiltrate being predominantly CD28-. These data suggest that CD28+ memory T cells may be resistant to belatacept, capable of further differentiation including loss of CD28 expression while maintaining effector function. The unique signaling requirements of CD28+ memory T cells provide opportunities for the development of targeted therapies, which may synergize with belatacept to prevent costimulation independent rejection.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-14T04:22:24.054518-05:
      DOI: 10.1111/ajt.14349
       
  • An Interventional Study Using Cell Mediated Immunity to Personalize
           therapy for Cytomegalovirus infection after Transplantation
    • Authors: Deepali Kumar; Muhtashim Mian, Lianne Singer, Atul Humar
      Abstract: Cell mediated immune responses predict clinical CMV events but have not been adopted into routine practice due to lack of interventional studies. Our objective was to demonstrate the safety and feasibility of early discontinuation of antivirals based on the real-time measurement of CMV-specific CMI in patients with CMV viremia. Transplant patients were enrolled at the onset of CMV viremia requiring antiviral therapy. CD8 T-cell responses were determined using the Quantiferon-CMV assay, and results were used to guide subsequent management. A total of 27 patients (median viral load at onset 10,900 IU/ml) were treated until viral load negative. At end of treatment 14/27 (51.9%) had a positive CMV-CMI response and had antivirals discontinued. The remaining 13/27 (48.1%) patients had a negative CMV-CMI response and received two months of secondary antiviral prophylaxis. In those with a positive CMI and early discontinuation of antivirals, only a single patient experienced a low-level asymptomatic recurrence. In contrast, recurrence was observed in 69.2% of CMI negative patients despite more prolonged antivirals (p=0.001). In conclusion, this is the first study to demonstrate the feasibility and safety of real-time CMV-specific CMI assessment to guide changes to the management of CMV infection.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-13T03:52:40.930053-05:
      DOI: 10.1111/ajt.14347
       
  • Ultrasound Imaging based on Molecular Targeting for Quantitative
           Evaluation of Hepatic Ischemia Reperfusion Injury
    • Authors: Chen Qiu; Tinghui Yin, Yingcai Zhang, Yufan Lian, Yujia You, Kun Wang, Rongqin Zheng, Xintao Shuai
      Abstract: The present study aimed to quantitatively diagnose and monitor the therapy response of hepatic ischemia reperfusion injury (IRI) with targeted ultrasound (US) imaging. Targeted microbubbles (MBs) were fabricated, and the binding of ICAM-1 antibodies to MBs was observed. To establish a quantitative method based on targeted US imaging, contrast-enhanced ultrasound (CEUS) was applied on IRI rats. After andrographolide treatment, the IRI rats were subjected to the quantitative targeted US imaging for a therapeutic effect. Effective binding of ICAM-1 antibodies to MBs was observed. According to the quantitative targeted US imaging, the ICAM-1 normalized intensity difference (NID) in IRI rats (38.74 ± 15.08%) was significantly higher than that in the control rats (10.08 ± 2.52%, P = 0.048). Furthermore, different degrees of IRI (mild IRI, moderate to severe IRI) were distinguished by the use of NID (37.14 ± 2.14, 22.34 ± 1.08, P = 0.002). Analysis of mRNA expression demonstrated the accuracy of analyzing the NID using quantitative targeted US imaging (R2 = 0.7434, P < 0.001). Andrographolide treatment resulted in obviously weakened NID of ICAM-1 (17.7 ± 4.8% vs 34.2 ± 6.6%, P < 0.001). The study showed the potential of the quantitative targeted US imaging method for the diagnosis and therapeutic monitoring of IRI.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-10T08:40:39.04981-05:0
      DOI: 10.1111/ajt.14345
       
  • Successful Treatment of KSHV Inflammatory Cytokine Syndrome (KICS) after
           Kidney-Liver Transplant: Correlations with HHV8 miRNome and Specific
           T-Cell Response
    • Authors: Alessandra Mularoni; Alessia Gallo, Giovanni Riva, Patrizia Barozzi, Monica Miele, Giovanni Cardinale, Giovanni Vizzini, Riccardo Volpes, Paolo Grossi, Daniele Di Carlo, Angelo Luca, Tommaso Trenti, Mario Luppi, Pier Giulio Conaldi
      Abstract: In post-transplant patients, HHV-8/KSHV infection is known to cause aggressive tumors, as well as severe non-neoplastic complications. These latter syndromes are driven by HHV-8/KSHV lytic reactivations and related hyper-inflammatory host responses, typically characterized by high viral loads, elevated levels of cytokines and other inflammation biomarkers, cytopenia, organ failure, high fever, and worsening conditions (with no evidence of B-cell neoplasias). These disorders are associated with a high mortality rate, often due to lack of prompt diagnosis, effective therapeutic approaches, and adequate follow up. Indeed, these features resemble most of those defining the so-called KSHV inflammatory cytokine syndrome (KICS), which was recently recognized in HIV-positive patients. Here we describe, for the first time, a case of KICS-like non-neoplastic recurrent complication occurring in an HIV-negative post-transplant patient, which was successfully treated by combination of anti-CD20 monoclonal therapy, antivirals, and modification of immunosuppressive regimen. In addition to clinical and laboratory findings collected during 3-year-long follow up, we also report novel experimental data on HHV-8-specific T-cell dynamics and circulating miRNA profile, showing correlations with clinical course and other laboratory markers (including viral load, CRP and cytokine levels), thus providing useful information about abnormal cellular and cytokine dynamics underlying of HHV-8-associated inflammatory disorders in post-transplant patients.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-10T08:40:22.923355-05:
      DOI: 10.1111/ajt.14346
       
  • Pancreas-after-Islet (PAI) transplantation in non-uremic Type 1 diabetes:
           A strategy for restoring durable insulin independence
    • Authors: S A Wisel; J M Gardner, G R Roll, J Harbell, C E Freise, S Feng, S M Kang, R Hirose, D B Kaufman, A Posselt, P G Stock
      Abstract: Islet transplantation offers a minimally-invasive approach for beta cell replacement in diabetic patients with hypoglycemic unawareness. Attempts at insulin independence may require multiple islet re-infusions from distinct donors, thus increasing the risk for allogeneic sensitization. Currently, solid organ pancreas transplant is the only remaining surgical option following failed islet transplantation in the US. However, the immunologic impact of repeated exposure to donor antigens on subsequent pancreas transplantation is unclear. Here we describe a case series of seven patients undergoing solid organ pancreas transplant following islet graft failure, with long-term follow-up of pancreatic graft survival and renal function. Despite highly variable panel-reactive antibody (PRA) levels prior to pancreas transplant (mean 27±35%), all seven patients achieved stable and durable insulin independence with a mean follow-up of 6.7 years. Mean hemoglobin A1c (HgbA1c) values improved significantly from post-islet, pre-pancreas levels (mean 8.1±1.5%) to post-pancreas levels (mean 5.3±0.1%; p=0.0022). Three patients experienced acute rejection episodes successfully managed with thymoglobulin and methylprednisolone, and none of these pre-uremic type 1 diabetic recipients developed Stage 4 or 5 chronic kidney disease postoperatively. These results support pancreas-after-islet (PAI) transplantation with aggressive immunosuppression and protocol biopsies as a viable strategy to restore insulin independence after islet graft failure.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-10T08:25:33.288289-05:
      DOI: 10.1111/ajt.14344
       
  • Regulatory T cells Promote Natural Killer Cell Education in Mixed Chimeras
    • Authors: Benedikt Mahr; Nina Pilat, Svenja Maschke, Nicolas Granofszky, Christoph Schwarz, Lukas Unger, Karin Hock, Andreas M Farkas, Christoph Klaus, Heinz Regele, Thomas Wekerle
      Abstract: Therapeutic administration of regulatory T cells (Tregs) leads to engraftment of conventional doses of allogeneic bone marrow (BM) in non-irradiated recipient mice conditioned with costimulation blockade and mTOR inhibition. The mode of action responsible for this Treg effect is poorly understood but may encompass the control of costimulation blockade-resistant natural killer (NK) cells. We show that transient NK cell depletion at the time of BM transplantation (BMT) led to BM engraftment and persistent chimerism without Treg transfer, but failed to induce skin graft tolerance. In contrast, the permanent absence of anti-donor NK reactivity in mice grafted with F1 BM was associated with both chimerism and tolerance comparable to Treg therapy, implying that NK cell tolerization is a critical mechanism of Treg therapy. Indeed, NK cells of Treg-treated BM recipients reshaped their receptor repertoire in the presence of donor MHC in a manner suggesting attenuated donor-reactivity. These results indicate that adoptively transferred Tregs prevent BM rejection, at least in part, by suppressing NK cells and promote tolerance by regulating the appearance of NK cells expressing activating receptors to donor class I MHC.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-10T08:25:30.516579-05:
      DOI: 10.1111/ajt.14342
       
  • Broken Chains and Reneging: A Review of 1,748 Kidney Paired Donation
           Transplants
    • Authors: Nick Cowan; H. Albin Gritsch, Nima Nisseri, Joe Sinacore, Jeffrey Veale
      Abstract: Concerns regarding the potential for broken chains and reneges within kidney paired donation (KPD) and its effect on chain length have been previously raised. While these concerns have been tested in simulation studies, “real world” data has yet to be evaluated. The purpose of this study was to evaluate the actual rate and cause of broken chains within a large KPD program. All patients undergoing renal transplantation through the National Kidney Registry from 2008 through May 2016 were included for analysis. Broken chains and loops were identified. A total of 344 chains and 78 loops were completed during the study period yielding a total of 1,748 transplants. Twenty broken chains and one broken loop were identified. The mean chain length (# of transplants) within broken chains was 4.8 compared to 4.6 of completed chains (p=0.78). The most common causes of a broken chain were donor medical issues incurred while acting as a bridge donor (n=8), donors electing not to proceed (n=6), and kidneys being declined by the recipient surgeon (n=4). All recipients involved in a broken chain have subsequently received a transplant. Based on the results broken chains are infrequent, rarely due to lack of donor motivation, and have no significant impact on chain length.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-10T08:25:23.759596-05:
      DOI: 10.1111/ajt.14343
       
  • Prolonged Survival Following Pig-to-Primate Liver Xenotransplantation
           Utilizing Exogenous Coagulation Factors and Co-Stimulation Blockade
    • Authors: J.A. Shah; M. S. Patel, N. Elias, N. Navarro-Alvarez, I. Rosales, R.A. Wilkinson, N. J. Louras, M. Hertl, J.A. Fishman, R.B. Colvin, A.B. Cosimi, J. F. Markmann, D. H. Sachs, P.A. Vagefi
      Abstract: Since the first attempt in 1968, survival following pig-to-primate liver xenotransplantation (LXT) has been limited. We evaluated a model utilizing α-1,3-galactosyltransferase knockout donors, continuous post-transplant infusion of human prothrombin concentrate complex and immunosuppression including anti-thymocyte globulin, FK-506, methylprednisone and co-stimulation blockade (belatacept, n=3 or anti-CD40mAb, n=1) to extend survival. Baboon #1 remained well until POD25 when euthanasia was required due to cholestasis and plantar ulcers. Baboon #2 was euthanized following a seizure on POD5, despite normal LFTs and no apparent pathology. Baboon # 3 demonstrated initial stable liver function, but was euthanized on POD8 due to worsening LFTs. Pathology revealed C4d positivity, extensive hemorrhagic necrosis and a focal CMV inclusion. Baboon # 4 was clinically well with stable LFTs until POD29, when euthanasia was again necessitated by plantar ulcerations as well as rising LFTs. Final pathology was C4d negative and without evidence of rejection, inflammation or TMA. Thus, nearly one-month rejection-free survival has been achieved following LXT in 2 of 4 continuous recipients, demonstrating that the porcine liver can support life in primates for several weeks and is encouraging for potential clinical application of LXT as a bridge to allotransplantation for patients with acute-on-chronic or fulminant hepatic failure.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-10T08:20:30.010639-05:
      DOI: 10.1111/ajt.14341
       
  • Comprehensive Review on Colorectal Cancer and Transplant
    • Authors: S. Prenner; J. Levitsky
      Abstract: Colon cancer (CRC) is a common malignancy worldwide. Some studies suggest that organ recipients are at a higher risk for CRC than the general population. The underlying transplant indications and their inherent risk factors for CRC may drive the variation in incidence rates that are seen in patients receiving different allografts. Recipients with cystic fibrosis are now recognized as a population at high risk for CRC at a young age. Transplant recipients have high mortality following a CRC diagnosis, even if it is detected at an early stage. Certain types of immunosuppression have been shown to accelerate cancer transformation and may contribute to the more aggressive phenotype seen in organ recipients. Given the high incidence and progressive nature of post-transplant CRC, shorter screening intervals with a modality that can detect early stage polyps may be essential to prevent mortality. Future research is needed to better elucidate the role of immunosuppression in carcinogenesis. This comprehensive review examines CRC risk, screening, and management specific to organ transplant candidates and recipients.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-04T09:41:39.740429-05:
      DOI: 10.1111/ajt.14340
       
  • A multicenter study on long-term outcomes after lung transplantation
           
    • Authors: V. van Suylen; B. Luijk, R.A.S. Hoek, E.A. Graaf, E.A. Verschuuren, C. Van De Wauwer, J.A. Bekkers, R.C.A. Meijer, W. Bij, M.E. Erasmus
      Abstract: The implementation of donation after circulatory death category 3 (DCD3) was one of the attempts to reduce the gap between supply and demand of donor lungs. In the Netherlands, the total number of potential lung donors was greatly increased by the availability of DCD3 lungs in addition to the initial standard usage of donation after brain death (DBD) lungs. From the three lung transplant centers in the Netherlands, 130 DCD3 recipients were one-to-one nearest neighbor propensity score matched with 130 DBD recipients. The primary end points were primary graft dysfunction (PGD), post-transplant lung function, freedom from chronic lung allograft dysfunction (CLAD) and overall survival. PGD did not differ between the groups. Post-transplant lung function was comparable after bilateral lung transplantation, but seemed worse after DCD3 single lung transplantation. The incidence of CLAD (p=0.17) nor the freedom from CLAD (p=0.36) nor the overall survival (p=0.40) was significantly different between both groups. The presented multicenter results are derived from a national context where one third of the lung transplantations is performed with DCD3 lungs. We conclude that the long-term outcome after lung transplantation with DCD3 donors is similar to DBD donors and that DCD3 donation can substantially enlarge the donor pool.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-04T02:25:32.511338-05:
      DOI: 10.1111/ajt.14339
       
  • In vitro induction of human regulatory T-cells (iTregs) using conditions
           of low tryptophan plus kynurenines
    • Authors: K L Hippen; R S O'Connor, A M Lemire, A Saha, E A Hanse, N C Tennis, S C Merkel, A Kelekar, J L Riley, B L Levine, C H June, L S Kean, M L MacMillan, J S Miller, J E Wagner, D H Munn, B R Blazar
      Abstract: Thymic regulatory T cells (tTreg) or induced Tregs (iTregs) suppress murine acute graft-versus-host disease (GVHD). Previously we demonstrated that plasmacytoid dendritic cell (pDC) indoleamine 2,3-dioxygenase (IDO) fosters the in vitro development of human iTregs via tryptophan depletion and kynurenine (Kyn) metabolites. We now show that stimulation of naïve CD4+ T cells in low tryptophan (Low Trp) plus Kyn supports human iTreg generation. In vitro, low Trp+Kyn iTreg and tTregs potently suppress Teffector cell proliferation equivalently but are phenotypically distinct. As compared to tTreg or Teffector, bioenergetics profiling reveals that Low Trp+Kyn iTreg have increased basal glycolysis and oxidative phosphorylation and also use glutaminolysis as an energy source. Low Trp+Kyn iTreg viability was reliant on IL-2 in vitro. Although in vivo IL-2 administration increased Low Trp+Kyn iTreg persistence upon adoptive transfer into immune deficient mice given peripheral blood mononuclear cells to induce GVHD, IL-2 supported iTregs did not improve recipient survival. We conclude that Low Trp+Kyn create suppressive iTregs that have high metabolic needs that will need to be addressed prior to clinical translation.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-04T02:20:28.048886-05:
      DOI: 10.1111/ajt.14338
       
  • Neuroinvasive St. Louis Encephalitis Virus Infection in Solid Organ
           Transplant Recipients
    • Authors: Carlos A. Hartmann; Holenarasipur R. Vikram, Maria T. Seville, Robert Orenstein, Shimon Kusne, Janis E. Blair, Thomas E. Grys, Roberto L. Patron
      Abstract: In the summer of 2015, 3 unrelated solid organ transplant recipients had meningoencephalitis suggestive of West Nile virus (WNV) infection in Phoenix, Arizona. Testing was inconclusive but was later confirmed as St. Louis encephalitis (SLE). We retrospectively reviewed clinical manifestations, treatment, and outcomes of these transplant recipients. Common symptoms were fever, rigors, diarrhea, headache, and confusion. One patient died 3 days after hospitalization. Therapy for the 2 patients was initiated with interferon alfa-2b (IFN) and intravenous immunoglobulin G (IVIG) (IFN+IVIG in combination). Both patients tested positive for WNV by serologic assay, but SLE virus (SLEV) infection was later confirmed by plaque reduction neutralization test at a reference laboratory. Clinical improvement was observed within 72 hours after IFN+IVIG initiation. SLEV has been an uncommon cause of neuroinvasive disease in the United States. Accurate, timely diagnosis is hindered because of similar clinical presentation of neuroinvasive WNV and SLE, serologic cross-reactivity, and lack of a commercially available serologic assay for SLEV. There is currently no approved therapy for flaviviral neuroinvasive disease. Anecdotal reports indicate varying success with IFN, IVIG, or IFN+IVIG in WNV neuroinvasive disease. The same regimen might be of value for immunocompromised persons with neuroinvasive SLEV infection.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-27T19:12:55.194864-05:
      DOI: 10.1111/ajt.14336
       
  • Cutaneous Toxicities from Transplant-related Medications
    • Authors: M Ilyas; O. R Colegio, B Kaplan, A Sharma
      Abstract: Despite the abundance of information on cutaneous malignancies associated with solid organ transplantation in the transplant literature, there is limited information regarding non-malignant skin changes after transplantation. There are numerous skin toxicities secondary to immunosuppressive and other transplant-related medications that can vary in presentation, severity, and prognosis. In order to limit associated morbidity and mortality, SOTR care providers should effectively identify and manage cutaneous manifestations secondary to drug toxicity. Toxicities from the following transplant related medications will be discussed: Antithymocyte globulins; Systemic steroids; Cyclosporine; Tacrolimus; Azathioprine; Mycophenolate mofetil; mTOR inhibitors: Sirolimus and Everolimus; Basiliximab and Daclizumab; Belatacept; Voriconazole.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-27T19:06:28.257913-05:
      DOI: 10.1111/ajt.14337
       
  • Zika Virus RNA in an Asymptomatic Donor's Vitreous: Risk for
           Transmission'
    • Authors: E. Heck; H. D. Cavanagh, D. M. Robertson
      Abstract: Intense interest in the spread of Zika virus and its complications has brought Zika to the forefront of multiple areas of medicine and disease prevention.(1, 2) To date, there has been only one report of Zika virus present in human aqueous from a patient with uveitis.(1) Here we report the first finding of an asymptomatic cornea donor whose vitreous tested positive for Zika.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-27T18:57:29.077178-05:
      DOI: 10.1111/ajt.14334
       
  • Lepromatous leprosy in a renal transplant recipient
    • Authors: Sema Aytekin; Şirin Yaşar, Fatih Göktay, Filiz Cebeci, Aslı Duran, Pembegül Güneş, Gülizar Manga Şahin
      Abstract: Leprosy is a chronic granulomatous disease caused by acid fast bacillus Mycobacterium Leprae. It is rare in organ transplant patients; cases have been reported in three heart, one liver, and 12 renal transplantation patients in Worldwide (1,2). We report on a patient with lepromatous leprosy presenting six years after renal transplantation.A 38-year-old male was admitted with multiple erythematous lesions appeared over the patient's face, extremities, and trunk.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-27T18:56:36.350143-05:
      DOI: 10.1111/ajt.14335
       
  • Deciphering tacrolimus-induced toxicity in pancreatic β-cells
    • Authors: J Triñanes; A E Rodriguez-Rodriguez, Y Brito-Casillas, A Wagner, A P J De Vries, G Cuesto, A Acebes, E Salido, A Torres, E Porrini
      Abstract: β-cell transcription factors like: FoxO1, MafA, PDX-1, NeuroD, are dysfunctional in type 2 diabetes (T2DM). PTDM resembles T2DM and reflects interaction between pre-transplant insulin resistance and immunosuppressants, mainly calcineurin inhibitors. We evaluated the effect of tacrolimus, cyclosporine-A and metabolic stressors (glucose+palmitate) on insulinoma β-cells (INS-1) in vitro and in pancreata of obese and lean Zucker rats. Cells were cultured for five days with 100μM palmitate and 22mM glucose; cyclosporin-A (250ng/mL) or tacrolimus (15ng/mL) were added the last 48h. Glucose+palmitate increased nuclear FoxO1 and decreased nuclear MafA. Tacrolimus on top of glucose+palmitate magnified these changes in nuclear factors whereas cyclosporin-A did not. On top of glucose+palmitate, both drugs reduced insulin content and tacrolimus also affected insulin secretion. Tacrolimus withdrawal or conversion to cyclosporin-A restored these changes. Similar results were observed in pancreata of obese animals on calcineurin inhibitors. Tacrolimus and cyclosporin-A, on top of glucose+palmitate induced a comparable inhibition of calcineurin-NFAT. Thus, tacrolimus potentiates glucolipotoxicity in β-cells, possibly by sharing common pathways of β-cell dysfunction. Tacrolimus-induced β-cell dysfunction is potentially reversible. The inhibition of calcineurin-NFAT pathway may contribute to the diabetogenic effect of calcineurin inhibitors but does not explain the stronger of tacrolimus compared with cyclosporine-A.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-22T03:01:06.8005-05:00
      DOI: 10.1111/ajt.14323
       
  • 2017 American Transplant Congress Focuses on Hot Issues
    • Authors: Lara C. Pullen
      Pages: 1963 - 1964
      Abstract: This month, “The AJT Report” features research presented at this year's American Transplant Congress, held April 29–May 3 in Chicago, and highlights some evolving trends impacting the field of transplantation.
      PubDate: 2017-07-19T13:11:43.984705-05:
      DOI: 10.1111/ajt.14405
       
  • Immune-Electrical Connection
    • Authors: Maria-Luisa Alegre
      Pages: 1965 - 1965
      Abstract: Macrophages interact with cardiomyocytes in the AV node via Cx43 gap junctions and assist normal AV nodal conduction, and macrophage depletion promotes AV block.
      PubDate: 2017-07-19T13:11:52.096327-05:
      DOI: 10.1111/ajt.14406
       
  • Cancer in Solid Organ Transplant Recipients: There Is Still Much to Learn
           and Do
    • Authors: E. A. Engels
      Pages: 1967 - 1969
      Abstract: Eric Engels introduces a 12-month series of articles about cancer, a major complication of solid organ transplantation. See the initial article in this series by Krisl and Doan on page 1974.
      PubDate: 2017-04-10T08:20:27.848511-05:
      DOI: 10.1111/ajt.14140
       
  • Chemotherapy and Transplantation: The Role of Immunosuppression in
           Malignancy and a Review of Antineoplastic Agents in Solid Organ Transplant
           Recipients
    • Authors: J. C. Krisl; V. P. Doan
      Pages: 1974 - 1991
      Abstract: It is estimated that solid organ transplant recipients have a two- to fourfold greater overall risk of malignancy than the general population. Some of the most common malignancies after transplant include skin cancers and posttransplant lymphoproliferative disorder. In addition to known risk factors such as environmental exposures, genetics, and infection with oncogenic viruses, immunosuppression plays a large role in the development of cancer through the loss of the immunosurveillance process. The purpose of this article is to explain the role of immunosuppression in cancer and to review the classes of chemotherapeutics. The field of anticancer drugs is continually expanding and developing, with limited data on use in transplant recipients. This article aims to provide information on class review, adverse effects, dose adjustments, and drug interactions that are pertinent to the care of transplant recipients.
      PubDate: 2017-04-10T08:26:07.8363-05:00
      DOI: 10.1111/ajt.14238
       
  • Complement Polymorphisms in Kidney Transplantation: Critical in Graft
           Rejection'
    • Authors: L. A. Michielsen; A. D. Zuilen, I. S. Muskens, M. C. Verhaar, H. G. Otten
      Pages: 2000 - 2007
      Abstract: The complement system, as part of the innate immune system, plays an important role in renal transplantation. Complement is involved in the protection against foreign organisms and clearance of apoptotic cells but can also cause injury to the renal allograft, for instance, via antibody binding or in ischemia–reperfusion injury. Numerous polymorphisms in complement factors have been identified thus far; some of them result in different functionalities or alter complement levels. In this review, we provide an overview of the literature on the role of complement polymorphisms in renal transplantation. Furthermore, we discuss functional complement polymorphisms that have not yet been investigated in kidney transplantation. By investigating multiple polymorphisms both in donor and recipient at the same time, a complotype can be constructed. Because the combination of multiple polymorphisms is likely to have a greater impact than a single one, this could provide valuable prognostic information.
      PubDate: 2017-02-25T15:25:27.151126-05:
      DOI: 10.1111/ajt.14199
       
  • Depletion-Resistant CD4 T Cells Enhance Thymopoiesis During Lymphopenia
    • Authors: K. Ayasoufi; R. Fan, A. Valujskikh
      Pages: 2008 - 2019
      Abstract: Lymphoablation is routinely used in transplantation, and its success is defined by the balance of pathogenic versus protective T cells within reconstituted repertoire. While homeostatic proliferation and thymopoiesis may both cause T cell recovery during lymphopenia, the relative contributions of these mechanisms remain unclear. The goal of this study was to investigate the role of the thymus during T cell reconstitution in adult allograft recipients subjected to lymphoablative induction therapy. Compared with euthymic mice, thymectomized heart allograft recipients demonstrated severely impaired CD4 and CD8 T cell recovery and prolonged heart allograft survival after lymphoablation with murine anti-thymocyte globulin (mATG). The injection with agonistic anti-CD40 mAb or thymus transplantation only partially restored T cell reconstitution in mATG-treated thymectomized mice. After mATG depletion, residual CD4 T cells migrated into the thymus and enhanced thymopoiesis. Conversely, depletion of CD4 T cells before lymphoablation inhibited thymopoiesis at the stage of CD4−CD8−CD44hiCD25+ immature thymocytes. This is the first demonstration that the thymus and peripheral CD4 T cells cooperate to ensure optimal T cell reconstitution after lymphoablation. Targeting thymopoiesis through manipulating functions of depletion-resistant helper T cells may thus improve therapeutic benefits and minimize the risks of lymphoablation in clinical settings.
      PubDate: 2017-05-17T06:26:16.610196-05:
      DOI: 10.1111/ajt.14309
       
  • Origin of Enriched Regulatory T Cells in Patients Receiving Combined
           Kidney–Bone Marrow Transplantation to Induce Transplantation Tolerance
    • Authors: B. Sprangers; S. DeWolf, T. M. Savage, T. Morokata, A. Obradovic, S. A. LoCascio, B. Shonts, J. Zuber, S. P. Lau, R. Shah, H. Morris, V. Steshenko, E. Zorn, F. I. Preffer, S. Olek, D. M. Dombkowski, L. A. Turka, R. Colvin, R. Winchester, T. Kawai, M. Sykes
      Pages: 2020 - 2032
      Abstract: We examined tolerance mechanisms in patients receiving HLA-mismatched combined kidney–bone marrow transplantation (CKBMT) that led to transient chimerism under a previously published nonmyeloablative conditioning regimen (Immune Tolerance Network study 036). Polychromatic flow cytometry and high-throughput sequencing of T cell receptor-β hypervariable regions of DNA from peripheral blood regulatory T cells (Tregs) and CD4 non-Tregs revealed marked early enrichment of Tregs (CD3+CD4+CD25highCD127lowFoxp3+) in blood that resulted from peripheral proliferation (Ki67+), possibly new thymic emigration (CD31+), and, in one tolerant subject, conversion from non-Tregs. Among recovering conventional T cells, central memory CD4+ and CD8+ cells predominated. A large proportion of the T cell clones detected in posttransplantation biopsy specimens by T cell receptor sequencing were detected in the peripheral blood and were not donor-reactive. Our results suggest that enrichment of Tregs by new thymic emigration and lymphopenia-driven peripheral proliferation in the early posttransplantation period may contribute to tolerance after CKBMT. Further, most conventional T cell clones detected in immunologically quiescent posttransplantation biopsy specimens appear to be circulating cells in the microvasculature rather than infiltrating T cells.
      PubDate: 2017-04-10T08:30:36.364058-05:
      DOI: 10.1111/ajt.14251
       
  • Allo-HLA Cross-Reactivities of CMV-, FLU- and VZV-Specific Memory T Cells
           Are Shared by Different Individuals
    • Authors: H. van den Heuvel; K.M. Heutinck, E.M.W. van der Meer-Prins, S.L. Yong, P.P.M.C. van Miert, J.D.H. Anholts, M.E.I. Franke-van Dijk, X.Q. Zhang, D.L. Roelen, R.J.M. ten Berge, F.H.J. Claas
      First page: 2033
      Abstract: Virus-specific T cells can recognize allogeneic HLA (allo-HLA) through TCR cross-reactivity. The allospecificity often differs per individual (“private cross-reactivity”), but can also be shared by multiple individuals (“public cross-reactivity”). However, only a few examples of the latter have been described. Since these could facilitate alloreactivity prediction in transplantation, we aimed to identify novel public cross-reactivities of human virus-specific CD8+ T cells directed against allo-HLA by assessing their reactivity in mixed-lymphocyte reactions. Further characterization was done by studying TCR usage with primer-based DNA sequencing, cytokine production with enzyme-linked immunosorbent assays (ELISAs), and cytotoxicity with 51Chromium-release assays. We identified three novel public allo-HLA cross-reactivities of human virus-specific CD8+ T cells. CMV B35/IPS CD8+ T cells cross-reacted with HLA-B51 and/or HLA-B58/B57 (23% of tetramer-positive individuals), FLU A2/GIL CD8+ T cells with HLA-B38 (90% of tetramer-positive individuals) and VZV A2/ALW CD8+ T cells with HLA-B55 (two unrelated individuals). Cross-reactivity was tested against different cell types including endothelial and epithelial cells. All cross-reactive T cells expressed a memory phenotype, emphasizing the importance for transplantation. We conclude that public allo-HLA cross-reactivity of virus-specific memory T cells is not uncommon, which may create novel opportunities for alloreactivity prediction and risk estimation in transplantation.This article is protected by copyright. All rights reserved.
      PubDate: 2017-03-23T01:05:30.605475-05:
      DOI: 10.1111/ajt.14279
       
  • Cytomegalovirus-Responsive CD8+ T Cells Expand After Solid Organ
           Transplantation in the Absence of CMV Disease
    • Authors: L. E. Higdon; J. Trofe-Clark, S. Liu, K. B. Margulies, M. K. Sahoo, E. Blumberg, B. A. Pinsky, J. S. Maltzman
      Pages: 2045 - 2054
      Abstract: Cytomegalovirus (CMV) is a major cause of morbidity and mortality in solid organ transplant recipients. Approximately 60% of adults are CMV seropositive, indicating previous exposure. Following resolution of the primary infection, CMV remains in a latent state. Reactivation is controlled by memory T cells in healthy individuals; transplant recipients have reduced memory T cell function due to chronic immunosuppressive therapies. In this study, CD8+ T cell responses to CMV polypeptides immediate-early-1 and pp65 were analyzed in 16 CMV-seropositive kidney and heart transplant recipients longitudinally pretransplantation and posttransplantation. All patients received standard of care maintenance immunosuppression, antiviral prophylaxis, and CMV viral load monitoring, with approximately half receiving T cell–depleting induction therapy. The frequency of CMV-responsive CD8+ T cells, defined by the production of effector molecules in response to CMV peptides, increased during the course of 1 year posttransplantation. The increase commenced after the completion of antiviral prophylaxis, and these T cells tended to be terminally differentiated effector cells. Based on this small cohort, these data suggest that even in the absence of disease, antigenic exposure may continually shape the CMV-responsive T cell population posttransplantation.
      PubDate: 2017-03-13T17:46:00.888938-05:
      DOI: 10.1111/ajt.14227
       
  • Thrombalexin: Use of a Cytotopic Anticoagulant to Reduce Thrombotic
           Microangiopathy in a Highly Sensitized Model of Kidney Transplantation
    • Authors: M. Manook; J. Kwun, C. Burghuber, K. Samy, M. Mulvihill, J. Yoon, H. Xu, A. L. MacDonald, K. Freischlag, V. Curfman, E. Branum, D. Howell, A. B. Farris, R. A. Smith, S. Sacks, A. Dorling, N. Mamode, S. J. Knechtle
      Pages: 2055 - 2064
      Abstract: Early activation of coagulation is an important factor in the initiation of innate immunity, as characterized by thrombotic microangiopathy (TMA). In transplantation, systemic anticoagulation is difficult due to bleeding. A novel “cytotopic” agent, thrombalexin (TLN), combines a cell-membrane-bound (myristoyl tail) anti-thrombin (hirudin-like peptide [HLL]), which can be perfused directly to the donor organ or cells. Thromboelastography was used to measure time to clot formation (r-time) in both rhesus and human blood, comparing TLN versus HLL (without cytotopic tail) versus negative control. Both TLN- and HLL-treated rhesus or human whole blood result in significantly prolonged r-time compared to kaolin controls. Only TLN-treated human endothelial cells and neonatal porcine islets prolonged time to clot formation. Detection of membrane-bound TLN was confirmed by immunohistochemistry and fluorescence activated cell sorter. In vivo, perfusion of a nonhuman primate kidney TLN-supplemented preservation solution in a sensitized model of transplantation demonstrated no evidence of TLN systemically. Histologically, TLN was shown to be present up to 4 days after transplantation. There was no platelet deposition, and TMA severity, as well as microvascular injury scores (glomerulitis + peritubular capillaritis), were less in the TLN-treated animals. Despite promising evidence of localized efficacy, no survival benefit was demonstrated.
      PubDate: 2017-03-23T10:10:43.633369-05:
      DOI: 10.1111/ajt.14234
       
  • BK Virus Nephropathy: Histological Evolution by Sequential Pathology
    • Authors: B. J. Nankivell; J. Renthawa, R. N. Sharma, K. Kable, P. J. O'Connell, J. R. Chapman
      Pages: 2065 - 2077
      Abstract: Reactivation of BK virus in renal allografts causes a destructive chronic infection. This single-center retrospective cohort study describes the evolution of BK virus allograft nephropathy (BKVAN) from 63 kidneys (from 61 patients) using sequential histopathology (454 biopsies, averaging 7.8 ± 2.6 per kidney) followed for 60.1 mo. Uninfected protocol biopsies formulated time-matched control Banff scores (n = 975). Interstitial inflammation occurred in 73% at diagnosis, correlating with viral histopathology (r = 0.413, p = 0.008) and amplifying early injury with accelerated interstitial fibrosis and tubular atrophy (IF/TA, p = 0.017) by 3 mo. Prodromal simian virus 40 large T antigen (SV40T)–negative inflammation with viremia preceded the histological diagnosis in 23.8%. Persistent subacute injury from viral cytopathic effect was associated with acute tubular necrosis and ongoing interstitial inflammation, culminating in IF/TA in 86.9%. Overall, cellular interstitial infiltration mitigated the intensity of subsequent tubular injury, SV40T, and tissue viral load, assessed by sequential paired histology (p < 0.001). Graft loss was predicted by high-level viremia (hazard ratio [HR] 4.996, 95% CI 2.19–11.396, p < 0.001), deceased donor (HR 3.201, 95% CI 1.149–8.915, p = 0.026), and late acute rejection (HR 3.124, 95% CI 1.037–9.413, p = 0.043). Transplant failure occurred in 38.1%, with uncontrolled infection (58.3%) and SV40T-negative chronic rejection (41.7%) causing losses. BKVAN is characterized by subacute virus-induced tubular injury, inflammation, and progressive nephron destruction. Effective antiviral therapy remains an unmet clinical need.
      PubDate: 2017-05-05T08:40:26.16104-05:0
      DOI: 10.1111/ajt.14292
       
  • Histological evolution of BK virus associated nephropathy: Importance of
           integrating clinical and pathological findings
    • Authors: Cinthia B. Drachenberg; John C. Papadimitriou, Muhammad R. Chaudhry, Richard Ugarte, Manju Mavanur, Beje Thomas, Charles Cangro, Nadiesda Costa, Emilio Ramos, Matthew R. Weir, Abdolreza Haririan
      First page: 2078
      Abstract: Long term clinicopathological studies of BK-associated nephropathy (PyVAN) are not available. We studied 206 biopsies (71 patients), followed 3.09±1.46y after immunosuppression reduction. The biopsy features (% SV40+staining and inflammation +/- acute rejection) were correlated with viral load dynamics and serum creatinine to define the clinicopathological status (PyVCPS).Incidence of acute rejection was 28% in the 2ndbiopsy and 50% subsequently (25% mixed TCMR+AMR; rejection overall affected 38% of patients (>50% AMR). Graft loss was 15.4% (0.8-5.3y after PyVAN); 76% had complete viral clearance (mean 28weeks). The only predictors of graft loss were acute rejection (TCMR p=0.008, any type p=0.07), and increased “t” and “ci” in the 2ndbiopsy (p=0.006 and 0.048). Higher peak viremia correlated with poorer viral clearance (p=.002).Presumptive and proven PyVAN had similar presentation, evolution and outcome. Late PyVAN (>2 years,9.8%) justifies BK viremia evaluation at any point with graft dysfunction and/or biopsy evaluation.This study describes the histological evolution of PyVAN and corresponding clinicopathological correlations. Although the pathological features overall reflect the viral and immunological interactions, the PyVAN course remains difficult to predict based on any single feature. Appropriate clinical management requires repeat biopsies and determination of the PyVCPS at relevant time points, for corresponding personalized immunosuppression adjustment.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-19T03:10:46.469491-05:
      DOI: 10.1111/ajt.14314
       
  • Donor Specificity but Not Broadness of Sensitization Is Associated With
           Antibody-Mediated Rejection and Graft Loss in Renal Allograft Recipients
    • Authors: C. Wehmeier; G. Hönger, H. Cun, P. Amico, P. Hirt-Minkowski, A. Georgalis, H. Hopfer, M. Dickenmann, J. Steiger, S. Schaub
      Pages: 2092 - 2102
      Abstract: Panel-reactive antibodies are widely regarded as an important immunological risk factor for rejection and graft loss. The broadness of sensitization against HLA is most appropriately measured by the “calculated population-reactive antibodies” (cPRA) value. In this study, we investigated whether cPRA represent an immunological risk in times of sensitive and accurate determination of pretransplantation donor-specific HLA antibodies (DSA). Five hundred twenty-seven consecutive transplantations were divided into four groups: cPRA 0% (n = 250), cPRA 1–50% (n = 129), cPRA 51–100% (n = 43), and DSA (n = 105). Patients without DSA were considered as normal risk and received standard immunosuppression without T cell–depleting induction. Patients with DSA received an enhanced induction therapy and maintenance immunosuppression. Surveillance biopsies were performed at 3 and 6 months. Median follow-up was 5.7 years. Among the three cPRA groups, there were no differences regarding the 1-year incidence of ABMR (p = 0.16) and TCMR (p = 0.75). The 5-year allograft survival rates were similar and around 87% (p = 0.28). The estimated glomerular filtration rate at last follow-up was 50–53 mL/min (p = 0.45). On multivariable Cox proportional hazard analysis, the strongest independent predictor for ABMR and (death-censored) graft survival was pretransplantation DSA. cPRA were not predictive for ABMR, TCMR, or (death-censored) graft survival. We conclude that with current DSA assignment, the broadness of sensitization measured by cPRA does not imply an immunological risk.
      PubDate: 2017-03-27T09:25:56.051048-05:
      DOI: 10.1111/ajt.14247
       
  • Orthogonal Comparison of Molecular Signatures of Kidney Transplants With
           Subclinical and Clinical Acute Rejection: Equivalent Performance Is
           Agnostic to Both Technology and Platform
    • Authors: S. M. Kurian; E. Velazquez, R. Thompson, T. Whisenant, S. Rose, N. Riley, F. Harrison, T. Gelbart, J. J. Friedewald, j. charette, S. Brietigam, J. Peysakhovich, M. R. First, M. M. Abecassis, D. R. Salomon
      Pages: 2103 - 2116
      Abstract: We performed orthogonal technology comparisons of concurrent peripheral blood and biopsy tissue samples from 69 kidney transplant recipients who underwent comprehensive algorithm-driven clinical phenotyping. The sample cohort included patients with normal protocol biopsies and stable transplant (sTx) function (n = 25), subclinical acute rejection (subAR, n = 23), and clinical acute rejection (cAR, n = 21). Comparisons between microarray and RNA sequencing (RNA-seq) signatures were performed and demonstrated a strong correlation between the blood and tissue compartments for both technology platforms. A number of shared differentially expressed genes and pathways between subAR and cAR in both platforms strongly suggest that these two clinical phenotypes form a continuum of alloimmune activation. SubAR is associated with fewer or less expressed genes than cAR in blood, whereas in biopsy tissues, this clinical phenotype demonstrates a more robust molecular signature for both platforms. The discovery work done in this study confirms a clear ability to detect gene expression profiles for sTx, subAR, and cAR in both blood and biopsy tissue, yielding equivalent predictive performance that is agnostic to both technology and platform. Our data also provide strong biological insights into the molecular mechanisms underlying these signatures, underscoring their logistical potential as molecular diagnostics to improve clinical outcomes following kidney transplantation.
      PubDate: 2017-04-03T08:45:40.186713-05:
      DOI: 10.1111/ajt.14224
       
  • The Effect of Cortex/Medulla Proportions on Molecular Diagnoses in Kidney
           Transplant Biopsies: Rejection and Injury Can Be Assessed in Medulla
    • Authors: K. S. Madill-Thomsen; R. C. Wiggins, F. Eskandary, G. A. Böhmig, P. F. Halloran
      Pages: 2117 - 2128
      Abstract: Histologic assessment of kidney transplant biopsies relies on cortex rather than medulla, but for microarray studies, the proportion cortex in a biopsy is typically unknown and could affect the molecular readings. The present study aimed to develop a molecular estimate of proportion cortex in biopsies and examine its effect on molecular diagnoses. Microarrays from 26 kidney transplant biopsies divided into cortex and medulla components and processed separately showed that many of the most significant differences were in glomerular genes (e.g. NPHS2, NPHS1, CLIC5, PTPRO, PLA2R1, PLCE1, PODXL, and REN). Using NPHS2 (podocin) to estimate proportion cortex, we examined whether proportion cortex influenced molecular assessment in the molecular microscope diagnostic system. In 1190 unselected kidney transplant indication biopsies (Clinicaltrials.govNCT01299168), only 11% had
      PubDate: 2017-03-23T09:30:29.821159-05:
      DOI: 10.1111/ajt.14233
       
  • Prophylactic Ureteric Stents in Renal Transplant Recipients: A Multicenter
           Randomized Controlled Trial of Early Versus Late Removal
    • Authors: P. Patel; I. Rebollo-Mesa, E. Ryan, M. D. Sinha, S. D. Marks, N. Banga, I. C. Macdougall, M. C. Webb, G. Koffman, J. Olsburgh
      Pages: 2129 - 2138
      Abstract: Prophylactic ureteric stenting in renal transplantation reduces major urological complications; however, morbidity is related to the indwelling duration of a stent. We aimed to determine the optimal duration for stents in this clinical setting. Patients (aged 2–75 years) from six UK hospitals who were undergoing renal transplantation were recruited and randomly assigned to either early stent removal at 5 days (without cystoscopy) or late removal at 6 weeks after transplantation (with cystoscopy). The primary outcome was a composite of stent-related complications defined as pain, visible hematuria, migration, fragmentation, and urinary tract infections (UTIs) within 3 mo of transplantation. Between May 2010 and Nov 2013, we randomly assigned 227 participants, with 205 included in the final analysis of the primary outcome. Stent-related complications were significantly higher in the late versus early stent removal groups (36 of 126 [28.6%] vs. 6 of 79 [7.6%]; p < 0.001). The majority of stent complications consisted of UTIs, with an incidence of 31 of 126 (24.6%) in the late group compared with 6 of 79 (7.6%) in the early group (p = 0.004). We found early stent removal on day 5 significantly reduced stent-related complications and improved quality of life in the first 3 mo after transplantation (ISRCTN09184595).
      PubDate: 2017-03-17T09:47:32.375534-05:
      DOI: 10.1111/ajt.14223
       
  • OPO Strategies to Prevent Unintended Use of Kidneys Exported for High PRA
           (>98% cPRA) Recipients
    • Authors: A. S. Paramesh; N. Neidlinger, M. Salvatore, A. Smith, A. Friedman, W. Payne, T. Taber, C. Wright
      Pages: 2139 - 2143
      Abstract: Since the advent of the Kidney Allocation System (KAS), matched candidates with high (>98%) panel reactive antibody (hPRA) are given priority over local candidates with lower PRA. This often leads to exporting of kidneys. Data for these kidneys are not detailed on routine reports. Twenty-two organ procurement organizations prospectively submitted data from August 2015 to July 2016, describing allocation practices of kidneys to hPRA patients and outcomes of these kidneys. Five hundred twenty out of 6924 procured kidneys were exported for hPRA recipients. Of these, 402 (77.3%) were transplanted into the intended recipient (IR); 100 (19.2%) were transplanted into unintended recipients (UR), and 18 (3.5%) were discarded. The most common reason for use in an UR was a positive crossmatch (XM) (63%). The most common reasons for discard were donor quality (44%) and ischemic time (39%). Prior to kidney export, when tissue crossmatching was done, 96.2% of the kidneys went to the IR, versus 80.7% following virtual CM, versus 56.7% when no crossmatching was performed (p < 0.0001). A significant number of kidneys exported for hPRA patients are not being used in the IR or are being discarded. The most common reason for this is positive tissue XM. We report that unintended use of the kidney was minimized when tissue was shipped and XM results were known prior to exporting the kidney.
      PubDate: 2017-03-03T09:35:24.591157-05:
      DOI: 10.1111/ajt.14220
       
  • Justifying Nonstandard Exception Requests for Pediatric Liver Transplant
           Candidates: An Analysis of Narratives Submitted to the United Network for
           Organ Sharing, 2009–2014
    • Authors: E. R. Perito; H. J. Braun, J. L. Dodge, S. Rhee, J. P. Roberts
      Pages: 2144 - 2154
      Abstract: Nonstandard exception requests (NSERs), for which transplant centers provide patient-specific narratives to support a higher Model for End-stage Liver Disease/Pediatric End-stage Liver Disease score, are made for>30% of pediatric liver transplant candidates. We describe the justifications used in pediatric NSER narratives 2009–2014 and identify justifications associated with NSER denial, waitlist mortality, and transplant. Using United Network for Organ Sharing data, 1272 NSER narratives from 1138 children with NSERs were coded for analysis. The most common NSER justifications were failure-to-thrive (48%) and risk of death (40%); both associated with approval. Varices, involvement of another organ, impaired quality of life, and encephalopathy were justifications used more often in denied NSERs. Of the 25 most prevalent justifications, 60% were not associated with approval or denial. Waitlist mortality risk was increased when fluid overload or “posttransplant complication outside standard criteria” were cited and decreased when liver-related infection was noted. Transplant probability was increased when the narrative mentioned liver-related infections, and fluid overload for children
      PubDate: 2017-02-28T11:25:30.438534-05:
      DOI: 10.1111/ajt.14216
       
  • Safety and Outcomes in 100 Consecutive Donation After Circulatory Death
           Liver Transplants Using a Protocol That Includes Thrombolytic Therapy
    • Authors: H. Bohorquez; J. B. Seal, A. J. Cohen, A. Kressel, E. Bugeaud, D. S. Bruce, I. C. Carmody, T. W. Reichman, N. Battula, M. Alsaggaf, G. Therapondos, N. Bzowej, G. Tyson, S. Joshi, R. Nicolau-Raducu, N. Girgrah, G. E. Loss
      Pages: 2155 - 2164
      Abstract: Donation after circulatory death (DCD) liver transplantation (LT) reportedly yields inferior survival and increased complication rates compared with donation after brain death (DBD). We compare 100 consecutive DCD LT using a protocol that includes thrombolytic therapy (late DCD group) to an historical DCD group (early DCD group n = 38) and a cohort of DBD LT recipients (DBD group n = 435). Late DCD LT recipients had better 1- and 3-year graft survival rates than early DCD LT recipients (92% vs. 76.3%, p = 0.03 and 91.4% vs. 73.7%, p = 0.01). Late DCD graft survival rates were comparable to those of the DBD group (92% vs. 93.3%, p = 0.24 and 91.4% vs. 88.2%, p = 0.62). Re-transplantation occurred in 18.4% versus 1% for the early and late DCD groups, respectively (p = 0.001). Patient survival was similar in all three groups. Ischemic-type biliary lesions (ITBL) occurred in 5%, 3%, and 0.2% for early DCD, late DCD, and DBD groups, respectively, but unlike in the early DCD group, in the late DCD group ITBL was endoscopically managed and resolved in each case. Using a protocol that includes a thrombolytic therapy, DCD LT yielded patient and graft survival rates comparable to DBD LT.
      PubDate: 2017-04-11T09:50:28.932363-05:
      DOI: 10.1111/ajt.14261
       
  • Improving the Outcomes of Organs Obtained From Controlled Donation After
           Circulatory Death Donors Using Abdominal Normothermic Regional Perfusion
    • Authors: E. Miñambres; B. Suberviola, B. Dominguez-Gil, E. Rodrigo, J. C. Ruiz-San Millan, J. C. Rodríguez-San Juan, M. A. Ballesteros
      Pages: 2165 - 2172
      Abstract: The use of donation after circulatory death (DCD) has increased significantly during the past decade. However, warm ischemia results in a greater risk for transplantation. Indeed, controlled DCD (cDCD) was associated with inferior outcomes compared with donation after brain death. The use of abdominal normothermic regional perfusion (nRP) to restore blood flow before organ recovery in cDCD has been proposed as better than rapid recovery to reverse the effect of ischemia and improve recipients’ outcome. Here, the first Spanish series using abdominal nRP as an in situ conditioning method is reported. A specific methodology to avoid restoring circulation to the brain after death determination is described. Twenty-seven cDCD donors underwent abdominal nRP during at least 60 min. Thirty-seven kidneys, 11 livers, six bilateral lungs, and one pancreas were transplanted. The 1-year death-censored kidney survival was 91%, and delayed graft function rate was 27%. The 1-year liver survival rate was 90.1% with no cases of ischemic cholangiopathy. Transplanted lungs and pancreas exhibited primary function. The use of nRP may represent an advance to increase the number and quality of grafts in cDCD. Poor results in cDCD livers could be reversed with nRP. Concerns about restoring brain circulation after death are easily solved.
      PubDate: 2017-03-28T01:00:26.59644-05:0
      DOI: 10.1111/ajt.14214
       
  • Laparoscopic Biopsies in Pancreas Transplantation
    • Authors: P. D. Uva; J. S. Odorico, A. Giunippero, I. C. Cabrera, A. Gallo, L. R. Leon, E. Minue, F. Toniolo, I. Gonzalez, E. Chuluyan, D. H. Casadei
      Pages: 2173 - 2177
      Abstract: As there is no precise laboratory test or imaging study for detection of pancreas allograft rejection, there is increasing interest in obtaining pancreas tissue for diagnosis. Pancreas allograft biopsies are most commonly performed percutaneously, transcystoscopically, or endoscopically, yet pancreas transplant surgeons often lack the skills to perform these types of biopsies. We have performed 160 laparoscopic pancreas biopsies in 95 patients. There were 146 simultaneous kidney–pancreas biopsies and 14 pancreas-only biopsies due to pancreas alone, kidney loss, or extraperitoneal kidney. Biopsies were performed for graft dysfunction (89) or per protocol (71). In 13 cases, an additional laparoscopic procedure was performed at the same operation. The pancreas diagnostic tissue yield was 91.2%; however, the pancreas could not be visualized in eight cases (5%) and in 6 cases the tissue sample was nondiagnostic (3.8%). The kidney tissue yield was 98.6%. There were four patients with intraoperative complications requiring laparotomy (2.5%) with two additional postoperative complications. Half of all these complications were kidney related. There were no episodes of pancreatic enzyme leak and there were no graft losses related to the procedure. We conclude that laparoscopic kidney and pancreas allograft biopsies can be safely performed with very high tissue yields.
      PubDate: 2017-04-04T11:00:31.782513-05:
      DOI: 10.1111/ajt.14259
       
  • Improved Time to Notification of Impending Brain Death and Increased Organ
           Donation Using an Electronic Clinical Decision Support System
    • Authors: J. L. Zier; A. B. Spaulding, M. Finch, T. Verschaetse, R. Tarrago
      Pages: 2186 - 2191
      Abstract: Early referral of patients to an organ procurement organization (OPO) may positively affect donation outcomes. We implemented an electronic clinic decision support (CDS) system to automatically notify our OPO of children meeting clinical triggers indicating impending brain death. Medical records of all patients who died in a pediatric critical care unit or were referred for imminent death for 3 years prior to installation of the initial CDS (pre-CDS) and for 1 year after implementation of the final CDS (post-CDS) were reviewed. Mean time to OPO notification decreased from 30.2 h pre-CDS to 1.7 h post-CDS (p = 0.015). Notification within 1 h of meeting criteria increased from 36% pre-CDS to 70% post-CDS (p = 0.003). Although an increase in donor conversion from 50% pre-CDS to 90% post-CDS did not reach statistical significance (p = 0.0743), there were more organ donors post-CDS (11 of 24 deaths) than pre-CDS (seven of 57 deaths; p = 0.002). Positive outcomes were achieved with the use of a fully automated CDS system while simultaneously realizing few false-positive notifications, low costs, and minimal workflow interruption. Use of an electronic CDS system in a pediatric hospital setting improved timely OPO notification and was associated with increased organ donation.
      PubDate: 2017-05-09T09:45:25.441906-05:
      DOI: 10.1111/ajt.14312
       
  • HLA Mismatching Favoring Host-Versus-Graft NK Cell Activity Via KIR3DL1 Is
           Associated With Improved Outcomes Following Lung Transplantation
    • Authors: J. R. Greenland; H. Sun, D. Calabrese, T. Chong, J. P. Singer, J. Kukreja, S. R. Hays, J. A. Golden, G. H. Caughey, J. M. Venstrom, R. Rajalingam
      Pages: 2192 - 2199
      Abstract: Chronic lung allograft dysfunction (CLAD) is linked to rejection and limits survival following lung transplantation. HLA-Bw4 recipients of HLA-Bw6 grafts have enhanced host-versus-graft (HVG) natural killer (NK) cell activity mediated by killer cell immunoglobulin-like receptor (KIR)3DL1 ligand. Because NK cells may promote tolerance by depleting antigen-presenting cells, we hypothesized improved outcomes for HLA-Bw4 recipients of HLA-Bw6 grafts. We evaluated differences in acute cellular rejection and CLAD-free survival across 252 KIR3DL1+ recipients from University of California, San Francisco (UCSF). For validation, we assessed survival and freedom from bronchiolitis obliterans syndrome (BOS), retransplantation, or death in 12 845 non-KIR typed recipients from the United Network for Organ Sharing (UNOS) registry. Cox proportional hazards models were adjusted for age, gender, ethnicity, transplant type, and HLA mismatching. HVG-capable subjects in the UCSF cohort had a decreased risk of CLAD or death (hazard ratio [HR] 0.57, 95% confidence interval [CI] 0.36–0.88) and decreased early lymphocytic bronchitis. The HVG effect was not significant in subjects with genotypes predicting low KIR3DL1 expression. In the UNOS cohort, HVG-capable subjects had a decreased risk of BOS, retransplant, or death (HR 0.95, 95% CI 0.91–0.99). Survival improved with the higher-affinity Bw4-80I ligand and in Bw4 homozygotes. Improved outcomes in HVG-capable recipients are consistent with a protective NK cell role. Augmentation of NK activity could supplement current immunosuppression techniques.
      PubDate: 2017-05-11T09:12:17.722958-05:
      DOI: 10.1111/ajt.14295
       
  • Allosensitization Following Bone Graft
    • Authors: E. D. O'Sullivan; R. K. Battle, S. Zahra, J. F. Keating, L. P. Marson, D. M. Turner
      Pages: 2207 - 2211
      Abstract: It is recognized that patients may become sensitized to donor-specific HLA antigens as a result of previous antigenic exposures, classically through previous transplantation, pregnancy, or blood transfusion. We present an unusual case of a patient who unexpectedly developed a range of anti-HLA antibodies following orthopedic surgery where a bone graft was deployed intraoperatively. We describe the case of a 52-year-old man awaiting a renal transplantation, undergoing elective orthopedic surgery requiring a small-volume bone graft. His postoperative antibody profile was found to be substantially changed compared to his previous negative samples, with the presence of HLA-DR, DQ, and DP specificities, at levels that would be likely to give a positive flow cytometry crossmatch and therefore according to local procedures required listing as unacceptable antigens for organ allocation. We perform a literature review of all previous cases of allosensitization following bone graft. This case is the first to demonstrate allosensitization following minor surgery with ;low-volume bone graft. Previous evidence is very limited and pertains only to massive osteochondral surgery for trauma or malignancy, and is confounded by potential concomitant blood transfusion. Clinicians should be aware of the risk of allosensitization where bone grafts are used.
      PubDate: 2017-03-17T09:50:23.455892-05:
      DOI: 10.1111/ajt.14231
       
  • Improved Fetal Hemoglobin With mTOR Inhibitor–Based Immunosuppression in
           a Kidney Transplant Recipient With Sickle Cell Disease
    • Authors: N. Gaudre; P. Cougoul, P. Bartolucci, G. Dörr, A. Bura-Riviere, N. Kamar, A. Del Bello
      Pages: 2212 - 2214
      Abstract: Fetal hemoglobin induction is a key point in the management of sickle cell disease (SCD). We report the case of a kidney transplant recipient with SCD who was treated with everolimus, a mammalian target of rapamycin inhibitor. At 10 months after initiating therapy, the patient's fetal hemoglobin level was dramatically increased (from 4.8% to 15%) and there was excellent tolerance to treatment.
      PubDate: 2017-03-30T10:15:25.811032-05:
      DOI: 10.1111/ajt.14263
       
  • Vital Signs: Health Care–Associated Legionnaires’ Disease Surveillance
           Data From 20 States and a Large Metropolitan Area—United States, 2015
    • Authors: E. A. Soda; A. E. Barskey, P. P. Shah, S. Schrag, C. G. Whitney, M. J. Arduino, S. C. Reddy, J. M. Kunz, C. M. Hunter, B. H. Raphael, L. A. Cooley
      Pages: 2215 - 2220
      Abstract: BackgroundLegionnaires’ disease, a severe pneumonia, is typically acquired through inhalation of aerosolized water containing Legionella bacteria. Legionella can grow in the complex water systems of buildings, including health care facilities. Effective water management programs could prevent the growth of Legionella in building water systems.MethodsUsing national surveillance data, Legionnaires’ disease cases were characterized from the 21 jurisdictions (20 U.S. states and one large metropolitan area) that reported exposure information for ≥90% of 2015 Legionella infections. An assessment of whether cases were health care–associated was completed; definite health care association was defined as hospitalization or long-term care facility residence for the entire 10 days preceding symptom onset, and possible association was defined as any exposure to a health care facility for a portion of the 10 days preceding symptom onset. All other Legionnaires’ disease cases were considered unrelated to health care.ResultsA total of 2,809 confirmed Legionnaires’ disease cases were reported from the 21 jurisdictions, including 85 (3%) definite and 468 (17%) possible health care–associated cases. Among the 21 jurisdictions, 16 (76%) reported 1–21 definite health care–associated cases per jurisdiction. Among definite health care–associated cases, the majority (75, 88%) occurred in persons aged ≥60 years, and exposures occurred at 72 facilities (15 hospitals and 57 long-term care facilities). The case fatality rate was 25% for definite and 10% for possible health care–associated Legionnaires’ disease.Conclusions and Implications for Public Health PracticeExposure to Legionella from health care facility water systems can result in Legionnaires’ disease. The high case fatality rate of health care–associated Legionnaires’ disease highlights the importance of case prevention and response activities, including implementation of effective water management programs and timely case identification.
      PubDate: 2017-07-19T13:11:49.119197-05:
      DOI: 10.1111/ajt.14407
       
  • Rare Late Complication After Percutaneous Liver Biopsy
    • Authors: L. W. Unger; W. Matzek, G. Berlakovich
      Pages: 2221 - 2223
      PubDate: 2017-07-19T13:11:47.254462-05:
      DOI: 10.1111/ajt.14371
       
 
 
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