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Showing 1 - 200 of 1583 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: 54, SJR: 1.385, h-index: 91)
Accounting & Finance     Hybrid Journal   (Followers: 44, SJR: 0.547, h-index: 30)
ACEP NOW     Free  
Acta Anaesthesiologica Scandinavica     Hybrid Journal   (Followers: 50, SJR: 1.02, h-index: 88)
Acta Archaeologica     Hybrid Journal   (Followers: 141, 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: 54, SJR: 0.794, h-index: 88)
Acta Physiologica     Hybrid Journal   (Followers: 7, 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: 5, SJR: 0.459, h-index: 29)
Acute Medicine & Surgery     Hybrid Journal   (Followers: 2)
Addiction     Hybrid Journal   (Followers: 32, SJR: 2.086, h-index: 143)
Addiction Biology     Hybrid Journal   (Followers: 11, 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: 25, SJR: 0.81, h-index: 81)
Advanced Functional Materials     Hybrid Journal   (Followers: 49, SJR: 5.21, h-index: 203)
Advanced Healthcare Materials     Hybrid Journal   (Followers: 13, SJR: 0.232, h-index: 7)
Advanced Materials     Hybrid Journal   (Followers: 253, 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: 4)
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: 33, SJR: 0.275, h-index: 17)
African J. of Ecology     Hybrid Journal   (Followers: 14, SJR: 0.477, h-index: 39)
Aggressive Behavior     Hybrid Journal   (Followers: 15, SJR: 1.391, h-index: 66)
Aging Cell     Open Access   (Followers: 9, 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: 29, 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: 128, 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: 28, 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 Orthopsychiatry     Hybrid Journal   (Followers: 4, SJR: 0.756, h-index: 69)
American J. of Physical Anthropology     Hybrid Journal   (Followers: 36, SJR: 1.41, h-index: 88)
American J. of Political Science     Hybrid Journal   (Followers: 248, 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: 15, SJR: 2.792, h-index: 140)
American J. on Addictions     Hybrid Journal   (Followers: 9, SJR: 0.843, h-index: 57)
Anaesthesia     Hybrid Journal   (Followers: 115, SJR: 1.404, h-index: 88)
Analyses of Social Issues and Public Policy     Hybrid Journal   (Followers: 11, 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: 155)
Angewandte Chemie Intl. Edition     Hybrid Journal   (Followers: 211, SJR: 6.229, h-index: 397)
Animal Conservation     Hybrid Journal   (Followers: 34, 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: 43, 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: 16, SJR: 0.137, h-index: 3)
Anthropology News     Hybrid Journal   (Followers: 14)
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: 93, SJR: 0.545, h-index: 15)
Antipode     Hybrid Journal   (Followers: 44, 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: 67, SJR: 0.754, h-index: 69)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 7, SJR: 0.632, h-index: 58)
Applied Psychology     Hybrid Journal   (Followers: 137, 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: 13, 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: 215, SJR: 0.153, h-index: 13)
Arthritis & Rheumatology     Hybrid Journal   (Followers: 49, 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: 311, 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: 3, 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: 13, 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: 12, 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: 6, 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: 22, 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: 17, SJR: 0.384, h-index: 30)
Australian J. of Public Administration     Hybrid Journal   (Followers: 381, 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: 66, 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: 3, 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: 8, 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: 14, 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: 36, 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: 137, 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: 10, SJR: 2.592, h-index: 100)
Birth     Hybrid Journal   (Followers: 34, 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)

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Journal Cover American Journal of Transplantation
  [SJR: 2.792]   [H-I: 140]   [15 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  [1583 journals]
  • 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
    • 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
    • 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
    • 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
    • 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
  • American Journal of Transplantation: Volume 17, Number 6, June 2017
    • Abstract: On the cover this month: Transplantation has long been known for its innovation in multidisciplinary care and long-term follow-up. This care is highly detailed and resource-intensive. In this month's AJT, Schmid et al (page 1594) report on a randomized controlled trial in living donor renal transplant recipients testing the effectiveness of telemedicine to facilitate outpatient case management. They demonstrate that it leads to a reduction in healthcare utilization, reduced healthcare costs, lower nonadherence, and better disease-specific quality of life. As the number of patients surviving with transplants continues to grow, innovations like these will be important in continuing high-quality, lifelong, multidisciplinary care. Cover design by Lauren Halligan, Duke University Department of Surgery.
      PubDate: 2017-05-23T08:38:04.08854-05:0
      DOI: 10.1111/ajt.14330
  • 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
  • A Very Different Paradigm for Living Kidney Donor Risk
    • Authors: R. W. Steiner
      PubDate: 2017-05-18T09:20:22.117301-05:
      DOI: 10.1111/ajt.14313
  • 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
    • 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
  • Costimulation blockade; America first, Canada second what about
    • 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
  • Risk of End-Stage Renal Disease in HIV-Positive Potential Live Kidney
    • Authors: A. D. Muzaale; K. N. Althoff, C. J. Sperati, A. G. Abraham, L. M. Kucirka, A. B. Massie, M. M. Kitahata, M. A. Horberg, A. C. Justice, M. J. Fischer, M. J. Silverberg, A. A. Butt, S. L. Boswell, A. R. Rachlis, A. M. Mayor, M. J. Gill, J. J. Eron, S. Napravnik, D. R. Drozd, J. N. Martin, R. J. Bosch, C. M. Durand, J. E. Locke, R. D. Moore, G. M. Lucas, D. L. Segev
      Abstract: New federal regulations allow HIV-positive individuals to be live kidney donors; however, potential candidacy for donation is poorly understood given the increased risk of end-stage renal disease (ESRD) associated with HIV infection. To better understand this risk, we compared the incidence of ESRD among 41 968 HIV-positive participants of North America AIDS Cohort Collaboration on Research and Design followed for a median of 5 years with the incidence of ESRD among comparable HIV-negative participants of National Health and Nutrition Examination III followed for a median of 14 years. We used risk associations from multivariable Cox proportional hazards regression to derive cumulative incidence estimates for selected HIV-positive scenarios (no history of diabetes, hypertension, AIDS, or hepatitis C virus coinfection) and compared these estimates with those from similarly selected HIV-negative scenarios. For 40-year-old HIV-positive individuals with health characteristics that were similar to those of age-matched kidney donors, viral load
      PubDate: 2017-05-12T01:05:02.93503-05:0
      DOI: 10.1111/ajt.14235
  • 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
    • 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
  • Uptake of Cancer Screening Tests Among Recipients of Solid Organ
    • Authors: S. A. Acuna; R. Sutradhar, X. Camacho, C. Daly, M. E. Del Giudice, S. J. Kim, N. N. Baxter
      Abstract: Population-based cancer screening recommendations are also suggested for solid organ transplant recipients (SOTR); however, recommendation adherence is unknown. In a population-based cohort of SOTR in Ontario between 1997 and 2010, we determined the uptake of breast, cervical, and colorectal cancer screening tests and identified factors associated with up-to-date screening using recurrent event analysis. We identified 4436 SOTR eligible for colorectal, 2252 for cervical, and 1551 for breast cancer screening. Of those, 3437 (77.5%), 1572 (69.8%), and 1417 (91.4%), respectively, were not up-to-date for cancer screening tests during the observation period. However, these rates are likely an overestimate due to the inability to differentiate between tests done for screening or for diagnosis. SOTR with fewer comorbidities had higher rates of becoming screen up-to-date. Assessment by a primary care provider (PCP) was associated with becoming up-to-date with cancer screening (breast relative risk [RR] = 1.40, 95% confidence interval [CI]: 1.12–1.76, cervical RR = 1.29, 95% CI: 1.06–1.57, colorectal RR = 1.30, 95% CI: 1.15–1.48). Similar results were observed for continuity of care by transplant specialist at a transplant center. In conclusion, cancer screening for most SOTR does not adhere to standard recommendations. Involvement of PCPs in posttransplant care and continuity of care at a transplant center may improve the uptake of screening.
      PubDate: 2017-05-09T01:05:02.432192-05:
      DOI: 10.1111/ajt.14272
  • 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
  • Cum hoc sed non propter hoc
    • Authors: C.-C. Chen; E. Pouliquen, L. Kessler, V. Dubois, O. Thaunat
      Abstract: We are thankful to Carter and colleagues for their interest in our recently published paper (1). Analyzing the cases of 42 pancreas islet recipients from the GRAGIL network, we confirmed that pancreas islet grafting is an HLA-sensitizing event. In our cohort, ∼1/3 of islet graft recipients developed alloantibodies directed against mismatched HLA molecules expressed by the graft.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-03T08:20:49.581647-05:
      DOI: 10.1111/ajt.14288
  • A memory B cell crossmatch assay for quantification of donor-specific
           memory B cells in the peripheral blood of HLA-immunized individuals
    • Authors: G. E. Karahan; Y. J. H. de Vaal, J. Krop, C. Wehmeier, D. L. Roelen, F. H. J. Claas, S. Heidt
      Abstract: Humoral responses against mismatched donor HLA are routinely measured as serum HLA antibodies, which are mainly produced by bone-marrow residing plasma cells. Individuals with a history of alloimmunization but lacking serum antibodies may harbor circulating dormant memory B cells, which may rapidly become plasma cells upon antigen re-encounter. Currently available methods to detect HLA-specific memory B cells are scarce and insufficient in quantifying the complete donor-specific memory B cell response due to their dependence on synthetic HLA molecules. Here we present a highly sensitive and specific tool for quantifying donor-specific memory B cells in peripheral blood of individuals using cell lysates covering the complete HLA class I and class II repertoire of an individual. Using this ELISPOT assay, we found a median frequency of 31 HLA class I and 89 HLA class II-specific memory B cells per million IgG producing cells directed at paternal HLA in peripheral blood samples of women (n=22) with a history of pregnancy using cell lysates from spouses. The donor-specific memory B cell ELISPOT can be utilized in HLA diagnostic laboratories as a cross-match assay to quantify donor-specific memory B cells in patients with a history of sensitizing events.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-03T08:16:17.216854-05:
      DOI: 10.1111/ajt.14293
  • B Cell Receptor Genes Associated with Tolerance Identify a Cohort of
           Immunosuppressed Patients with Improved Renal Allograft Graft Function
    • Authors: A. Asare; S. Kanaparthi, N. Lim, D. Phippard, F. Vincenti, J. Friedewald, M. Pavlakis, E. Poggio, P. Heeger, R. Mannon, B. E. Burrell, Y. Morrison, N. Bridges, I. Sanz, A. Chandraker, K. A. Newell, L. A. Turka
      Abstract: We previously reported that two B cell receptor genes, IGKV1D-13 and IGKV4-1, were associated with tolerance following kidney transplantation. To assess the potential utility of this “signature” we conducted a prospective, multicenter study to determine the frequency of patients predicted tolerant within a cohort of patients deemed to be candidates for immunosuppressive minimization. At any single time point 25 – 30% of patients were predicted to be tolerant, while 13.7% consistently displayed the tolerance “signature” over the two-year study. We also examined the relationship of the presence of the tolerance “signature” on drug usage and graft function. Contrary to expectations, the frequency of predicted tolerance was increased in patients receiving tacrolimus and reduced in those receiving corticosteroids, MMF, or Thymoglobulin as induction. Surprisingly, patients consistently predicted to be tolerant displayed a statistically and clinically significant improvement in eGFR that increased over time following transplantation. These findings indicate that the frequency of patients consistently predicted to be tolerant is sufficiently high to be clinically relevant and confirm recent findings by others that immunosuppressive agents impact putative biomarkers of tolerance. The association of a B cell-based “signature” with graft function suggests that B cells may contribute to the function/survival of transplanted kidneys.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-02T11:05:15.49861-05:0
      DOI: 10.1111/ajt.14283
  • Chronic allograft deterioration -NDASH- a clinical reality in vascularized
           composite allotransplantation
    • Authors: N. Krezdorn; B. Pomahac
      Abstract: The first successful transplantation of a vascularized composite tissue allotransplantation (VCA)-NDASH- a hand -NDASH- was achieved in 1998. However, it was not until the first partial face transplant was performed in France in 2005 that the world first witnessed with fascination the vast implications of vascularized composite allotransplantation (VCA). Since then, there have been over 107 upper extremities and 35 face transplantations, with the longest follow up of 18 years for hand transplantation (1), and 10 years for face transplantation. Given the facts that the average half life of a kidney transplant is about 10 years, and the numbers of VCA are so small, the true half life of VCA remains subject to speculation.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-02T10:18:55.029315-05:
      DOI: 10.1111/ajt.14291
  • 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
    • 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
  • Real time central assessment of kidney transplant indication biopsies by
           microarrays: The INTERCOMEX Study
    • Authors: Philip F. Halloran; Jeff Reeve, Enver Akalin, Olivier Aubert, Georg A. Bohmig, Daniel Brennan, Jonathan Bromberg, Gunilla Einecke, Farsad Eskandary, Clement Gosset, Jean-Paul Duong Van Huyen, Gaurav Gupta, Carmen Lefaucheur, Andrew Malone, Roslyn B. Mannon, Daniel Seron, Joana Sellares, Matthew Weir, Alexandre Loupy
      Abstract: We performed a prospective trial to assess the feasibility of real-time central molecular assessment of kidney transplant biopsies from 10 North American and European centers. Biopsies taken one day to 34 years post-transplant were stabilized in RNAlater, couriered overnight at ambient temperature to the central laboratory, and processed (29 hour workflow) using microarrays to assess T cell-mediated and antibody-mediated rejection (TCMR, ABMR). Of 538 biopsies submitted, 519 (96%) were sufficient for microarray analysis (average length 3mm). Automated reports were generated without knowledge of histology and HLA antibody, assigning diagnoses based on Molecular Microscope Diagnostic System (MMDx) classifier algorithms derived by machine learning and signed out by one observer. Agreement between MMDx and histology (balanced accuracy) was TCMR 77%, ABMR 77%, and no rejection 76%. A classification tree derived to provide automated sign-outs predicted the observer sign-outs with>90% accuracy. In 451 biopsies where feedback was obtained, clinicians indicated that MMDx more frequently agreed with clinical judgement (87%) than did histology (80%) (p=0.0042). In 81% of feedback forms, clinicians reported that MMDx would increase confidence in management compared to conventional assessment alone. We conclude that real-time central molecular assessment is feasible and offers a useful new dimension in biopsy interpretation. Clinicaltrials. govNCT#01299168.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-27T18:39:05.366494-05:
      DOI: 10.1111/ajt.14329
  • Complement dependence of murine costimulatory blockade-resistant cellular
           cardiac allograft rejection
    • Authors: Nicholas Chun; Robert L. Fairchild, Yansui Li, Jinhua Liu, Ming Zhang, William M. Baldwin, Peter. S. Heeger
      Abstract: Building upon studies showing that ischemia/reperfusion-(IR)-injury is complement-dependent, we tested links among complement activation, transplant associated ischemia-reperfusion injury, and murine cardiac allograft rejection. We transplanted BALB/c hearts subjected to 8h cold ischemic storage (CIS) into CTLA4Ig-treated WT or c3-/- B6 recipients. Whereas allografts subjected to 8h CIS rejected in WT recipients with a median survival time (MST) of 37d, identically treated hearts survived >60d in c3-/- mice (p60d in mannose binding lectin-(mb1-/-/mbl2-/- recipients, and 42d in factor-B-(cfb)-/- recipients (n=4-6/group, p60d, p
      PubDate: 2017-04-26T03:30:45.999082-05:
      DOI: 10.1111/ajt.14328
  • Chronic Antibody-Mediated Rejection in Nonhuman Primate Renal Allografts:
           Validation of Human Histological and Molecular Phenotypes
    • Authors: B. A. Adam; R. N. Smith, I. A. Rosales, M. Matsunami, B. Afzali, T. Oura, A. B. Cosimi, T. Kawai, R. B. Colvin, M. Mengel
      Abstract: Molecular testing represents a promising adjunct for the diagnosis of antibody-mediated rejection (AMR). Here we apply a novel gene expression platform in sequential formalin-fixed paraffin-embedded (FFPE) samples from nonhuman primate (NHP) renal transplants. We analyzed 34 previously-described gene transcripts related to AMR in humans in 197 archival NHP samples, including 102 from recipients that developed chronic AMR, 80 from recipients without AMR, and 15 normal native nephrectomies. Three endothelial genes (VWF, DARC, CAV1), derived from 10-fold cross-validation ROC curve analysis, demonstrated excellent discrimination between AMR and non-AMR samples (AUC=0.92). This 3-gene set correlated with classic features of AMR, including glomerulitis, capillaritis, glomerulopathy, C4d, and DSA (r=0.39-0.63, p
      PubDate: 2017-04-26T03:28:32.886227-05:
      DOI: 10.1111/ajt.14327
  • Kidney paired donation program versus global kidney exchange in India
    • Authors: Vivek Kute; Rahul M. Jindal, Narayan Prasad
      Abstract: We read with interest the recent article on global kidney exchange (GKE) to overcome financial incompatibility in developing country for living kidney transplantation.
      Authors proposed that enabling GKE will overcome “poverty barrier” in developing countries and “immunologic barrier” in developed countries. The need for renal replacement therapy in India is staggering; only 2% of patients with renal failure were managed with kidney transplantation2.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-22T03:10:42.89402-05:0
      DOI: 10.1111/ajt.14324
  • Comment: Kidney exchange to overcome financial barriers to kidney
    • Authors: L. S. Baines; R. M. Jindal
      Abstract: Rees et al. have shown the feasibility of global kidney exchange (GKE) to overcome financial cost and address the current shortage of organs for transplantation. Wiseman and Gill, question their interpretation of definition of “financial incompatibility”. The authors1 do not factor in the well documented cognitive and emotional aspects of kidney transplantation. Particularly, relevant to kidney transplantation is how patients calculate risk and the emotional turmoil characterised by anxiety and fear which are directly correlated to post-transplant adherence.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-22T03:10:41.818484-05:
      DOI: 10.1111/ajt.14325
  • Living Donor Uterus Transplantation: A Single Center's Observations and
           Lessons Learned from Early Setbacks to Technical Success
    • Authors: G. Testa; E. C. Koon, L. Johannesson, G. McKenna, T. Anthony, G. B. Klintmalm, R. T. Gunby, A. M. Warren, J. M. Putman, G. dePrisco, J. M. Mitchell, K. Wallis, M. Olausson
      Abstract: Uterus transplantation is a vascularized composite allograft transplantation. It allows women who do not have a uterus to become pregnant and deliver a baby. In this paper we analyze the first 5 cases of Living Donor Uterus Transplantation performed in the US. The first 3 recipients lost their uterus grafts at day 14, 12 and 6 after transplant. Vascular complications, related to both inflow and outflow problems, were identified as the primary reason for the graft losses. Two recipients, 6 and 3 months post-transplant have functioning grafts with regular menstrual cycles. Ultimate success will be claimed only after a live birth. This paper is an in-depth analysis of evaluation, surgical technique and follow-up of these five living donor uterus transplants. The lessons learned were instrumental in allowing us to evolve from failure to technical and functional success. We aim to share our conclusions and build on the knowledge in the evolving field of uterus transplantation.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-22T03:10:38.630208-05:
      DOI: 10.1111/ajt.14326
  • 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
  • Considering tangible benefit for interdependent donors: Extending a
           risk-benefit framework in donor selection
    • Authors: Sarah E. Van Pilsum Rasmussen; Macey L. Henderson, Jeffrey Kahn, Dorry Segev
      Abstract: From its infancy, live donor transplantation has operated within a framework of acceptable risk to donors. Such a framework presumes that risks of living donation are experienced by the donor while all benefits are realized by the recipient, creating an inequitable distribution that demands minimization of donor risk. We suggest that this risk-tolerance framework ignores tangible benefits to donor. A previously proposed framework more fully considers potential benefits to the donor and argues that risks and benefits must be balanced. We expand on this approach, and posit that donors sharing a household with and/or caring for a potential transplant patient may realize tangible benefits that are absent in a more distantly related donation (e.g. cousin, non-directed). We term these donors, whose wellbeing is closely tied to their recipient, “interdependent donors.” A flexible risk-benefit model that combines risk assessment with benefits to interdependent donors will contribute to donor evaluation and selection that more accurately reflects what is at stake for donors. In so doing, a risk-benefit framework may allow some donors to accept greater risk in donation decisions.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-20T01:26:06.855545-05:
      DOI: 10.1111/ajt.14319
  • Prevention of the Osmotic Demyelination Syndrome after Liver
           Transplantation: A Multidisciplinary Perspective
    • Authors: J F Crismale; K A Meliambro, S DeMaria, D B Bronster, S Florman, T D Schiano
      Abstract: The osmotic demyelination syndrome (ODS) is a serious neurologic condition that occurs in the setting of rapid correction of hyponatremia. It presents with protean manifestations, from encephalopathy to the “locked-in” syndrome. ODS can complicate liver transplantation (LT), and its incidence may increase with the inclusion of serum sodium as a factor in the Model for End-Stage Liver Disease score. A comprehensive understanding of risk factors for the development of ODS in the setting of LT, along with recommendations to mitigate the risk of ODS, are necessary. The literature to date on ODS in the setting of LT was reviewed. Major risk factors for the development of ODS include severe pre-transplant hyponatremia (Serum sodium [SNa] < 125 mEq/L), the magnitude of change in SNa pre- vs. post-transplant, higher positive intraoperative fluid balance, and the presence of postoperative hemorrhagic complications. Strategies to reduce the risk of ODS include correcting hyponatremia pre-transplant via fluid restriction and/or ensuring an appropriate rate of increase from the preoperative SNa via close attention to fluid and electrolyte management both during and after surgery. Multidisciplinary management involving transplant hepatology, nephrology, neurology, surgery, and anesthesiology/critical care is key to performing LT safely in patients with hyponatremia.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-19T06:16:53.896931-05:
      DOI: 10.1111/ajt.14317
  • Blood chimerism in dizygotic monochorionic twins during five years
    • Authors: Morten Hanefeld Dziegiel; Morten Høgh Hansen, Sofie Haedersdal, Angela Natalie Barrett, Klaus Rieneck, Katharina Maria Main, Anne Todsen Hansen, Frederik Banch Clausen
      Abstract: Dizygotic monochorionic twin pregnancies can result in blood chimerism due to in utero twin-to-twin exchange of stem cells. In this case, we examined the proportion of allogeneic red blood cells (RBCs) by flow cytometry and the proportion of allogeneic nucleated cells by digital PCR at seven months and again at five years. We found an increase in the proportion of allogeneic cells from 63% to 89% in one twin, and a similar increase in autologous cells in the other twin from 57% to 84%. A paradigm for stem cell therapy could be modelled on this case: induction of tolerance and chimerism by antenatal transfusion of donor stem cells. The procedure would hold the promise of transplantation and tolerance induction without myelo-ablative conditioning for inheritable benign hematological diseases like sickle cell disease and thalassemia.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-19T06:16:52.729092-05:
      DOI: 10.1111/ajt.14318
  • Rat hindlimb cryopreservation and transplantation – A step towards
           “organ banking”
    • Authors: Amir Arav; Or Friedman, Yehudit Natan, Eyal Gur, Nir Shani
      Abstract: In 2016 over 5 million reconstructive procedures were performed in the USA. The recent successes of clinical vascularized composite allotransplantations (VCA), hand and face transplantations included, established the tremendous potential of these life-enhancing reconstructions. Nevertheless, Due to limited availability and lifelong immunosuppression, application is limited. Long term banking of composite transplants may increase the availability of esthetically compatible parts with partial or complete HLA matching, reducing the risk of rejection and the immunosuppressive burden. The study purpose was to develop efficient protocols for the cryopreservation and transplantation of a complete rodent limb. Directional freezing is a method in which a sample is cooled at a constant velocity linear temperature gradient enabling precise control of the process and ice crystal formation. Vitrification is an alternative cryopreservation method in which the sample solidifies without the formation of ice crystals. Testing both methods on a rat hindlimb composite tissue transplantation model, we found reliable, reproducible and stable ways to preserve composite tissue. We believe that with further research and development cryopreservation may lead to composite tissue “banks”. This may lead to a paradigm shift from few and far apart emergent surgeries to wide scale, well planned, and better controlled elective surgeries.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-19T06:16:49.471082-05:
      DOI: 10.1111/ajt.14320
  • Reply to Comment on the Article “OPTN/SRTR 2015 Annual Data Report:
    • Authors: R Kandaswamy; P G Stock, S K Gustafson, M Skeans, B Thompson, B L Kasiske
      Abstract: The OPTN/SRTR Annual Data Report surveys all solid-organ transplants, and deceased donor recovery and transplant economics, and attempts to maintain methodological consistency across chapters. We include multivisceral transplants in each organ-specific chapter, unless otherwise noted in a figure caption, as the most practical approach for including all transplants in the survey.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-19T06:12:53.094356-05:
      DOI: 10.1111/ajt.14321
  • Effect of Empagliflozin on Tacrolimus-induced Pancreas Islet Dysfunction
           and Renal Injury
    • Authors: J. Jin; L. Jin, K. Luo, S. W. Lim, B. H. Chung, C. W. Yang
      Abstract: An inhibitor of sodium glucose co-transporter type 2 (SGLT-2) is recommended in type 2 diabetes mellitus (DM) but its use is still undetermined in Tacrolimus (TAC)-induced DM. We evaluated the effect of empagliflozin (Em) on TAC-induced pancreatic islet dysfunction and renal injury in experimental model of TAC-induced DM and in vitro. TAC induced a two-fold increase in SGLT-2 expression, while Em decreased SGLT-2 expression and further increased urinary glucose excretion compared to the TAC group. Em reduced hyperglycemia and increased plasma insulin level, pancreatic islet size and glucose-stimulated insulin secretion (GSIS) compared to the TAC group. In kidney, Em alleviated TAC-induced renal dysfunction and decreased albumin excretion and histological injury compared with the TAC group. Increased oxidative stress and apoptotic cell death by TAC was remarkably decreased with Em in serum, pancreatic and renal tissues. In vitro study, TAC decreased cell viability and increased reactive oxygen species (ROS) production in both insulin secreting beta cell derived (INS-1) and human kidney-2 (HK-2) cell lines. Addition of Em increased cell viability and decreased ROS production in HK-2 but not in INS-1 cell lines. This suggests that Em is effective in controlling TAC-induced hyperglycemia and has direct protective effect on TAC-induced renal injury.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-19T04:20:44.226709-05:
      DOI: 10.1111/ajt.14316
  • 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
      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
  • A Transplant Specific Quality Initiative – Introducing TransQIP: a joint
           effort of the ASTS and ACS
    • Authors: Justin Parekh; Clifford Ko, Jacqueline Lappin, Stuart Greenstein, Ryutaro Hirose
      Abstract: In an attempt to improve surgical quality in the field of transplantation, the American College of Surgeons (ACS) and American Society and Transplant Surgeons have initiated a national quality improvement program in transplantation. This transplant specific quality improvement program, called TransQIP, has been built from the ground up by transplant surgeons and captures detailed information on donor and recipient factors as well as transplant specific outcomes. It is built upon the existing ACS/NSQIP infrastructure and is designed to capture 100% of liver and kidney transplants performed at participating sites. TransQIP has completed its alpha pilot and will embark upon its beta phase at approximately 30 centers in the spring of 2017. Going forward, we anticipate TransQIP will help satisfy Centers for Medicare and Medicaid Services (CMS) requirements for a quality improvement program, surgeon requirements for maintenance of certification and qualify as a clinical practice improvement activity under the Merit-Based Incentive Payment System (MIPS). Most importantly, we believe TransQIP will provide insight into surgical outcomes in transplantation that will allow the field to provide better care to our patients.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-19T02:45:33.90814-05:0
      DOI: 10.1111/ajt.14315
  • The Resurgence of Xenotransplantation
    • Authors: Peter J. Cowan; A. Joseph Tector
      Abstract: There has been an upsurge of interest in xenotransplantation in recent years. This resurgence can attributed to a combination of factors. First, there has been a dramatic improvement in efficacy in several preclinical models, with maximum xenograft survival times increasing to 950 days for islets, 945 days for hearts, and 310 days for kidneys. Second, the rapid development of genome editing technology (particularly the advent of CRISPR/Cas9) has revolutionized the capacity to generate new donor pigs with multiple protective genetic modifications; what once took many years to achieve can now be performed in months, with much greater precision and scope. Third, the spectre of porcine endogenous retrovirus (PERV) has receded significantly. There has been no evidence of PERV transmission in clinical trials and preclinical models, and improved screening methods and new options for the treatment or even elimination of PERV are now available. Balancing these positive developments are several remaining challenges, notably the heavy and often clinically inapplicable immunosuppression required to prevent xenograft rejection. Nonetheless, the potential for xenotransplantation as a solution to the shortage of human organs and tissues for transplantation continues to grow.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-11T02:55:38.028569-05:
      DOI: 10.1111/ajt.14311
  • 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
      Abstract: Early referral of patients to an organ procurement organization (OPO) may positively impact 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 three years prior to installation of the initial CDS (pre-CDS) and for one year after implementation of the final CDS (post-CDS) were reviewed. Mean time to OPO notification decreased from 30.2 hours pre-CDS to 1.7 hours post-CDS (p=0.015). Notification within one hour 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 (7 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 clinical decision support system in a pediatric hospital setting improved timely OPO notification and was associated with increased organ donation.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-11T02:55:35.585216-05:
      DOI: 10.1111/ajt.14312
  • Risk of thyroid cancer among solid organ transplant recipients
    • Authors: Cari M. Kitahara; Elizabeth L. Yanik, Paul W. Ladenson, Brenda Y. Hernandez, Charles F. Lynch, Karen S. Pawlish, Eric A. Engels
      Abstract: Solid organ transplant recipients have an elevated incidence of thyroid cancer. We evaluated a wide range of potential risk factors in a cohort of 229,300 U.S. solid organ transplant recipients linked with 15 stage/regional cancer registries (1987-2012). Incidence rate ratios (IRRs) were adjusted for age, sex, race/ethnicity, transplanted organ, year of transplant, and time since transplant. Hazards ratios (HRs) for death and/or graft failure were adjusted for age, sex, race/ethnicity, transplanted organ, and year of transplant. Following transplant, 356 thyroid cancers were diagnosed. Thyroid cancer incidence was 2.50-fold higher in transplant recipients than the general population (95%CI 2.25-2.77). Among recipients of different organs, kidney recipients had the highest incidence of thyroid cancer (IRR=1.26, 95%CI 1.03-1.53). Elevated thyroid cancer incidence was associated with cholestatic liver disease/cirrhosis as an indication for liver transplant (IRR=1.69, 95%CI 1.09-2.63), hypertensive nephrosclerosis as an indication for kidney transplant (IRR=1.41, 95%CI 1.03-1.94), and longer prior dialysis among kidney recipients (5+ versus
      PubDate: 2017-04-11T02:35:44.010448-05:
      DOI: 10.1111/ajt.14310
  • Depletion-resistant CD4 T cells enhance thymopoiesis during lymphopenia
    • Authors: Katayoun Ayasoufi; Ran Fan, Anna Valujskikh
      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 to 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. Following mATG depletion, residual CD4 T cells migrated into the thymus following lymphoablation and enhanced thymopoiesis. Conversely, depletion of CD4 T cells prior to 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 following lymphoablation. Targeting thymopoiesis through manipulating functions of depletion-resistant helper T cells may thus improve therapeutic benefits and minimize risks of lymphoablation in clinical settings.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-11T02:10:45.921485-05:
      DOI: 10.1111/ajt.14309
  • Geographic Disparities in Liver Availability: Accidents of geography or
           consequences of poor social policy'
    • Authors: Keren Ladin; Gregory Zhang, Douglas W. Hanto
      Abstract: Recently, a redistricting proposal intended to equalize MELDs recommended expanding liver sharing to mitigate geographic variation in liver transplantation. Yet, it is unclear whether variation in liver availability is arbitrary and a disparity requiring rectification, or whether it reflects differences in access to care. We evaluate the proposal's claim that organ supply is an “accident of geography” by examining the relationship between local organ supply and the uneven landscape of social determinants and policies that contribute to differential death rates across the United States. We show that higher mortality leading to greater availability of organs may partly result from disproportionate risks incurred at the local-level. Disparities in public safety laws, healthcare infrastructure, and public funding may influence the risk of death and subsequent availability of deceased donors. These risk factors are disproportionately prevalent in regions with high organ supply. Policies calling for organ redistribution from high-supply to low-supply regions may exacerbate existing social and health inequalities by redistributing the single benefit (greater organ availability) of greater exposure to environmental and contextual risks (e.g. violent death, healthcare scarcity). Variation in liver availability may not be an “accident of geography”, but rather a byproduct of disadvantage.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-08T01:51:13.712352-05:
      DOI: 10.1111/ajt.14301
  • Post-Transplant Lymphoproliferative Disorder Following Clinical Islet
           Transplantation: Report of the First Two Cases
    • Authors: Anthea Peters; Tolu Olateju, Jean Deschenes, Santosh H Shankarnarayan, Neil Chua, A M James Shapiro, Peter Senior
      Abstract: We report the first two cases of post-transplant lymphoproliferative disorder (PTLD) in recipients of islet transplants worldwide. First, a 44-year old recipient of 3 islet infusions developed PTLD 80 months after his initial transplant, presenting with abdominal pain and diffuse terminal ileum thickening on imaging. He was treated with surgical excision, reduction of immunosuppression and rituximab. Seven months later he developed central nervous system PTLD, presenting with vertigo and diplopia; immunosuppression was discontinued, resulting in graft loss, and he was given high-dose methotrexate and consolidative autologous stem cell transplant. He remains in remission 37 months after initial diagnosis. Second, a 58-year old female recipient of 2 islet infusions developed PTLD 24 months after initial islet infusion, presenting with pancytopenia secondary to extensive bone marrow involvement. Immunosuppression was discontinued, resulting in graft loss, and she received rituximab and chemotherapy, achieving complete remission. Both cases were monomorphic B-cell PTLD subtype by histology and negative for EBV in tissue or blood. These cases document the first occurrences of this rare complication in islet transplant, likely secondary to prolonged, intensive immunosuppression, and highlight the variable clinical manifestations of PTLD. Further studies are needed to determine incidence rate and risk factors in islet transplantation.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-08T01:51:10.393344-05:
      DOI: 10.1111/ajt.14303
  • Vascularized Composite Allograft (VCA) Donation and Transplantation: A
           Survey of Public Attitudes in the United States
    • Authors: James R. Rodrigue; David Tomich, Aaron Fleishman, Alexandra K. Glazier
      Abstract: Vascularized composite allograft (VCA) transplantation has emerged as a groundbreaking surgical intervention to return identity and function following traumatic injury, congenital deformity, or disfigurement. While public attitudes toward traditional organ/tissue donation are favorable, little is known about attitudes toward VCA donation and transplantation. A survey was conducted of 1,485 U.S. residents in August 2016 to assess VCA donation attitudes. Participants also completed the Revised Health Care System Distrust Scale. Most respondents were willing to donate hands/forearms (67.4%) and legs (66.8%), and almost half (48.0%) were willing to donate the face. Three-quarters (74.4%) of women were willing to donate the uterus; 54.4% of men were willing to donate the penis. VCA donation willingness was more likely among whites and Hispanics (p
      PubDate: 2017-04-08T01:51:07.244451-05:
      DOI: 10.1111/ajt.14302
  • HLA mismatching favoring host-versus-graft NK cell activity via KIR3DL1 is
           associated with improved outcomes following lung transplantation
    • Authors: John R. Greenland; Haibo Sun, Daniel Calabrese, Tiffany Chong, Jonathan P. Singer, Jasleen Kukreja, Steven R. Hays, Jeffrey A. Golden, George H. Caughey, Jeffrey M. Venstrom, Raja Rajalinginam
      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) NK cell activity mediated by KIR3DL1 ligand. Because natural killer (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 (ACR) and CLAD-free survival across 252 KIR3DL1+ recipients from UCSF. For validation, we assessed survival and freedom from BOS, retransplantation, or death in 12,845 non-KIR typed recipients from the 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 (HR 0.57, 95% 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.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-04T08:25:28.982171-05:
      DOI: 10.1111/ajt.14295
  • Normothermic Ex Vivo Kidney Perfusion Following Static Cold Storage
           -NDASH- Brief, Intermediate, or Prolonged Perfusion for Optimal Renal
           Graft Reconditioning'
    • Authors: J. Moritz Kaths; Juan Echeverri, Ivan Linares, Jun Yu Cen, Sujani Ganesh, Matyas Hamar, Peter Urbanellis, Paul Yip, Rohan John, Darius Bagli, Istvan Mucsi, Anand Ghanekar, David Grant, Lisa A. Robinson, Markus Selzner
      Abstract: Normothermic ex vivo kidney perfusion (NEVKP) demonstrated superior results compared to hypothermic storage in donation after circulatory death (DCD) kidney transplantation. It is unknown whether an optimal perfusion time exists following hypothermic storage to allow for the recovery of renal grafts from cold ischemic injury. In a porcine model of DCD kidney autotransplantation, the impact of initial static cold storage (SCS) (8h) followed by various periods of NEVKP recovery was investigated: group A) 8hSCS only (control), group B) 8hSCS+1hNEVKP (brief NEVKP), group C) 8hSCS+8hNEVKP (intermediate NEVKP), and group D) 8hSCS+16hNEVKP (prolonged NEVKP). All grafts were preserved and transplanted successfully. One animal in group D) was sacrificed and excluded by postoperative day 3 due to hind limb paralysis, but demonstrated good renal function. Postoperative graft assessment during 8 days follow up demonstrated lowest levels of peak serum creatinine for intermediate (C) and prolonged NEVKP (D) (p=0.027). Histological assessment on day 8 demonstrated a significant difference in tubular injury (p=0.001) with highest values for group B. These results suggest that longer periods of NEVKP following SCS are feasible and safe for postponing surgical transplant procedure and superior to brief NEVKP reducing the damage caused during cold ischemic storage of renal grafts.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-04T08:25:25.126069-05:
      DOI: 10.1111/ajt.14294
  • BK virus nephropathy: histological evolution by sequential pathology
    • Authors: Brian J. Nankivell; Jasveen Renthawa, Raghwa N. Sharma, Kathy Kable, Philip J. O'Connell, Jeremy R. Chapman
      Abstract: Reactivation of BK virus in renal allografts causes a destructive chronic infection. This single-centre, retrospective, cohort study describes the evolution of BK virus allograft nephropathy (BKVAN) from 63 kidneys (n=61 patients) using sequential histopathology (n=454 biopsies, averaging 7.8±2.6/kidney) followed for 60.1 months. Uninfected protocol biopsies formulated time-matched control Banff scores (n=975).This article is protected by copyright. All rights reserved.
      PubDate: 2017-03-30T10:05:29.236753-05:
      DOI: 10.1111/ajt.14292
  • Prolonged cold ischemia time results in local and remote organ dysfunction
           in a murine model of vascularized composite transplantation
    • Authors: Néha Datta; Sean G. Devaney, Ronald W. Busuttil, Kodi Azari, Jerzy W. Kupiec-Weglinski
      Abstract: Vascularized composite allotransplantation (VCA) is a viable reconstructive option for complex tissue defects. Although grafts with large muscular component may be uniquely susceptible to ischemia/reperfusion (I/R) syndrome, the safe cold ischemia time in VCA has not been established. We investigated the effects of cold ischemia on innate immune response and recipient survival in a murine orthotopic hindlimb transplantation model. Surprisingly, mice receiving grafts exposed to 6h or longer of cold storage demonstrated reduced survival and massive elevations in serum creatinine, BUN and creatine kinase, as compared to 1h of cold storage recipients. This was accompanied by progressive increase in macrophage and neutrophil cell infiltration in muscle biopsies, altered platelet endothelial cell adhesion molecule-1 (PECAM-1) expression and ultimate renal injury. Multiplex immunoassay analysis identified 21 cytokines in serum and 18 cytokines in muscle biopsies that are likely essential in the complex response to I/R-triggered injury in VCA. In conclusion, this study in a mouse model of orthotopic hindlimb transplantation, is the first to document that prolonged cold ischemia triggers progressive I/R injury with vascular endothelial damage, and may lead to irrecoverable local and remote organ damage. These experimental findings are important in guiding future therapies for human VCA recipientsThis article is protected by copyright. All rights reserved.
      PubDate: 2017-03-30T10:00:32.203923-05:
      DOI: 10.1111/ajt.14290
  • Incidence and predictors of cancer following kidney transplantation in
    • Authors: A Francis; D W Johnson, J C Craig, G Wong
      Abstract: Cancer risk is increased substantially in adult kidney transplant recipients, but the long-term risk of cancer in childhood recipients is unclear. Using the Australian and New Zealand Dialysis and Transplant Registry, the overall and site-specific incidences of cancer after transplantation in childhood recipients were compared with population-based data using standardized incidence ratios (SIR). Among 1734 childhood recipients (median age 14 years, 57% male, 85% white), 289 (16.7%) developed cancer (196 non-melanoma skin cancers, 143 non-skin cancers) over a median follow-up of 13.4 years. The 25-year cumulative incidences of any cancer were 27% (95% confidence intervals, 24-30%), 20% (17-23%) for non-melanoma skin cancer and 14% (12-17%) for non-skin cancer (including melanoma). The SIR for non-skin cancer was 8.23 (6.92-9.73), with the highest risk for post-transplant lymphoproliferative disease (SIR 45.80, 32.71-62.44) and cervical cancer (29.4, 95%CI 17.5-46.5). Increasing age at transplantation (adjusted hazard ratio [aHR] per year 1.10, 95%CI 1.06-1.14), white race (aHR 3.36, 95%CI 1.61-6.79) and having a functioning transplant (aHR 2.27, 95%CI 1.47-3.71) were risk factors for cancer. Cancer risk, particularly for viral related cancers, is increased substantially after kidney transplantation during childhood.This article is protected by copyright. All rights reserved.
      PubDate: 2017-03-29T09:36:04.683335-05:
      DOI: 10.1111/ajt.14289
  • Novel magnetic resonance imaging for assessment of bronchial stenosis in
           lung transplant recipients
    • Authors: Kamran Mahmood; Lukas Ebner, Mu He, Scott Haile Robertson, Ziyi Wang, H Page McAdams, Momen M Wahidi, Scott L Shofer, Yuh-Chin T Huang, Bastiaan Driehuys
      Abstract: Bronchial stenosis in lung transplant recipients is a common disorder that adversely affects clinical outcomes. It is evaluated by spirometry, CT scan and bronchoscopy with significant limitations. We hypothesize that magnetic resonance imaging (MRI) employing both ultrashort echo time (UTE) scans and hyperpolarized (HP) 129Xe gas can offer structural and functional assessment of bronchial stenosis seen after lung transplantation.Six patients with lung transplantation-related bronchial stenosis underwent HP 129Xe MRI and UTE MRI. Three patients subsequently underwent airway stent placement and had repeated MRI at 4 week follow up.HP 129Xe MRI depicted decreased ventilation distal to the stenotic airway. After airway stent placement, MRI showed that low-ventilation regions had decreased (35% vs. 27.6%, P =0.006) and normal-ventilation regions increased (17.9% vs 27.6%, P = 0.04) in the stented lung. Improved gas transfer was also seen on 129Xe MRI. There was a good correlation between UTE MRI and independent bronchoscopic airway diameter assessment (Pearson correlation coefficient = 0.92).This pilot study shows that UTE and HP 129Xe MRI are feasible in patients with bronchial stenosis related to lung transplantation, and may provide structural and functional airway assessment to guide treatment. These conclusions need to be confirmed by larger studies.This article is protected by copyright. All rights reserved.
      PubDate: 2017-03-29T09:25:47.267626-05:
      DOI: 10.1111/ajt.14287
  • 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
      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
  • Inferior outcomes on the waiting list in low volume pediatric heart
           transplant centers
    • Authors: Abbas Rana; Charles D. Fraser, Brandi B. Scully, Jeffrey S. Heinle, E. Dean McKenzie, William J. Dreyer, Michael Kueht, Hao Liu, Eileen D. Brewer, Todd K. Rosengart, Christine A. O'Mahony, John A. Goss
      Abstract: Low case volume has been associated with poor outcomes in a wide spectrum of procedures. Our objective is to study the association of low case volume and worse outcomes in pediatric heart transplant centers, taking the novel approach of including waitlist outcomes in the analysis.We studied a cohort of 6,482 candidates listed in the Organ Procurement and Transplantation Network for pediatric heart transplantation between 2002 and 2014; 4,665 of the candidates (72%) were transplanted. Candidates were divided into groups according to the average annual transplant volume performed in the listing center during the study period:> 10, 6-10, 3-5, and 10 annual transplants) (p
      PubDate: 2017-03-01T21:30:28.634137-05:
      DOI: 10.1111/ajt.14252
  • Transplantation in Africa
    • Authors: Lara C. Pullen
      Pages: 1431 - 1432
      Abstract: This issue of “The AJT Report” looks at the state of transplantation surgery in Africa, and the future of the specialty in the region. We also review the growing crisis of end-stage kidney disease in sub-Saharan countries and what healthcare authorities have done to address the problem.
      PubDate: 2017-05-23T08:38:09.465554-05:
      DOI: 10.1111/ajt.14331
  • Timing Is Everything
    • Authors: Maria-Luisa Alegre
      Pages: 1433 - 1433
      Abstract: Druzd and colleagues show that internal clocks govern entry and egress of lymphocytes within lymph nodes, imparting a time-dependent impact to the magnitude of an immune response.
      PubDate: 2017-05-23T08:38:13.274064-05:
      DOI: 10.1111/ajt.14332
  • Metrics and Data Analysis in Transplantation: Quality Improvement via
    • Authors: J. A. Fishman
      Pages: 1435 - 1436
      Abstract: Refinement of transplant analytics should reflect changes in clinical practice and allow meaningful comparisons between programs that could improve transplant outcomes. See the review from Kotton et al on page 1439.
      PubDate: 2017-02-24T18:40:40.350692-05:
      DOI: 10.1111/ajt.14219
  • The Effects of Center Volume on Mortality in Pediatric Heart
           Transplantation- The Rest of the Story
    • Authors: C. E. Canter
      First page: 1437
      Abstract: Paul Harvey was an American radio commentator in the latter part of the twentieth century. He would present vignettes and would finish them with the tag line “now you know the rest of the story”. In this issue Rana, et al (1) have analyzed the effects of center transplant volume on outcomes with pediatric heart transplantation. Instead of focusing on outcomes after transplantation, their primary aim was to analyze center volume effects on waitlist mortality- the rest of the story.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-25T10:00:57.040828-05:
      DOI: 10.1111/ajt.14277
  • Transplant Infectious Diseases: A Review of the Scientific Registry of
           Transplant Recipients Published Data
    • Authors: C. N. Kotton; S. Huprikar, D. Kumar
      Pages: 1439 - 1446
      Abstract: The Scientific Registry of Transplant Recipients (SRTR) serves to collect data on organ transplants performed in the United States. Although the infectious diseases data are limited and include mostly pretransplant serologies and other nonspecific infection-related outcomes, this multicenter data collection allows for insightful national data and the ability to monitor trends over time. We reviewed the published concise reports for each organ type in SRTR reports containing data from 2005 to 2014, and summarized our findings with respect to cytomegalovirus (CMV), Epstein-Barr virus, posttransplant lymphoproliferative disorder (PTLD), hepatitis B virus (HBV), hepatitis C virus (HCV), HIV, general infection, and prophylaxis. Our review highlights a few developments. While rates of donor–recipient CMV serology combinations remain fairly constant over time, there are generally more seronegative donors and recipients among living donor transplants. There has been a reduction in PTLD for pediatric transplant recipients. There has also been a slight reduction in anti-HBV core antibody–positive donor organs and stable reporting of HCV-positive donor organs and HIV-positive recipients.
      PubDate: 2017-02-23T12:25:24.005707-05:
      DOI: 10.1111/ajt.14195
  • How Spain Reached 40 Deceased Organ Donors per Million Population
    • Authors: R. Matesanz; B. Domínguez-Gil, E. Coll, B. Mahíllo, R. Marazuela
      Pages: 1447 - 1454
      Abstract: With 40 donors and more than 100 transplant procedures per million population in 2015, Spain holds a privileged position worldwide in providing transplant services to its patient population. The Spanish success derives from a specific organizational approach to ensure the systematic identification of opportunities for organ donation and their transition to actual donation and to promote public support for the donation of organs after death. The Spanish results are to be highlighted in the context of the dramatic decline in the incidence of brain death and the changes in end-of-life care practices in the country since the beginning of the century. This prompted the system to conceive the 40 donors per million population plan, with three specific objectives: (i) promoting the identification and early referral of possible organ donors from outside of the intensive care unit to consider elective non-therapeutic intensive care and incorporate the option of organ donation into end-of-life care; (ii) facilitating the use of organs from expanded criteria and non–standard risk donors; and (iii) developing the framework for the practice of donation after circulatory death. This article describes the actions undertaken and their impact on donation and transplantation activities.
      PubDate: 2017-01-09T01:00:00.805742-05:
      DOI: 10.1111/ajt.14104
  • The Road to HLA Antibody Evaluation: Do Not Rely on MFI
    • Authors: H. C. Sullivan; R. S. Liwski, R. A. Bray, H. M. Gebel
      Pages: 1455 - 1461
      Abstract: Technological advances in HLA laboratory testing undoubtedly improved the sensitivity and specificity of HLA antibody assessment but not without introducing a set of challenges regarding data interpretation. In particular, the introduction of solid-phase single-antigen bead (SAB) antibody assessment brought the belief that mean fluorescence intensity (MFI) was a quantifiable value. As such, MFI levels heavily influenced HLA antibody reporting, monitoring, and clinical practice. However, given that SAB testing was neither intended for nor approved to be quantifiable, is the use of MFI in current clinical and laboratory practice valid' What, if anything, does this numerical value actually reveal about the pathogenic potential of the antibody' What are the pitfalls and caveats associated with reporting MFI' Herein, we travel the road to HLA antibody assessment and explore the reliability of MFI values to make clinical decisions.
      PubDate: 2017-03-17T09:49:13.809981-05:
      DOI: 10.1111/ajt.14229
  • A Soluble Form of P Selectin Glycoprotein Ligand 1 Requires Signaling by
           Nuclear Factor Erythroid 2–Related Factor 2 to Protect Liver Transplant
           Endothelial Cells Against Ischemia–Reperfusion Injury
    • Authors: C. Zhang; Y. Zhang, Y. Liu, Y. Liu, S. Kageyama, X.–d. Shen, F. Gao, S. Zheng, R. W. Busuttil, G. D. Shaw, H. Ji, J. W. Kupiec-Weglinski
      Pages: 1462 - 1475
      Abstract: Liver endothelial cell (LEC) damage is essential in the pathogenesis of ischemia–reperfusion injury (IRI) in transplant recipients. We analyzed the mechanism of LEC resistance against IRI by using a novel recombinant soluble form of P selectin glycoprotein ligand 1, tandem P selectin glycoprotein ligand immunoglobulin (TSGL-Ig), in a mouse model of hepatic cold preservation (4°C in University of Wisconsin solution for 20 h) and syngeneic orthotopic liver transplantation (OLT). Unlike controls, TSGL-Ig protected orthotopic liver transplants against ischemia–reperfusion (IR) stress, shown by depressed serum alanine aminotransferase levels, well-preserved hepatic architecture, and improved survival (42% vs. 92%). TSGL-Ig suppressed neutrophil/macrophage sequestration and proinflammatory cytokine/chemokine programs in OLT. Treatment with TSGL-Ig mitigated LEC activation (P and E selectin, VCAM-1 and intercellular adhesion molecule 1 expression). In parallel in vitro studies, TSGL-Ig diminished cellular damage in H2O2-stressed LEC cultures (lactic acid dehydrogenase and alanine aminotransferase levels). Increased thioredoxin, glutamate-cysteine ligase, NAD(P)H quinone dehydrogenase 1, and hypoxia-inducible factor 1α expression, along with transcription factor nuclear factor erythroid 2–related factor 2 (Nrf2), implied that TSGL-Ig exerts antioxidant functions in IR-stressed OLT and H2O2-stressed LECs. Indeed, Nrf2-deficient livers suffered fulminant IRI compared with WT despite concomitant TSGL-Ig therapy. Thus, TSGL-Ig is not only acting as a competitive antagonist blocking leukocyte migration into IR-stressed liver, but it may also act directly as an agonist stimulating Nrf2-mediated cytoprotection in LECs. This study supports the role of P selectin signaling in hepatic homeostasis in OLT, with broad implications for tissue damage conditions.
      PubDate: 2017-02-06T09:05:43.858933-05:
      DOI: 10.1111/ajt.14159
  • Renal Allograft Survival in Nonhuman Primates Infused With Donor
           Antigen-Pulsed Autologous Regulatory Dendritic Cells
    • Authors: M. B. Ezzelarab; D. Raich-Regue, L. Lu, A. F. Zahorchak, A. Perez-Gutierrez, A. Humar, M. Wijkstrom, M. Minervini, R. W. Wiseman, D. K. C. Cooper, A. E. Morelli, A. W. Thomson
      Pages: 1476 - 1489
      Abstract: Systemic administration of autologous regulatory dendritic cells (DCreg; unpulsed or pulsed with donor antigen [Ag]), prolongs allograft survival and promotes transplant tolerance in rodents. Here, we demonstrate that nonhuman primate (NHP) monocyte-derived DCreg preloaded with cell membrane vesicles from allogeneic peripheral blood mononuclear cells induce T cell hyporesponsiveness to donor alloantigen (alloAg) in vitro. These donor alloAg-pulsed autologous DCreg (1.4–3.6 × 106/kg) were administered intravenously, 1 day before MHC-mismatched renal transplantation to rhesus monkeys treated with costimulation blockade (cytotoxic T lymphocyte Ag 4 immunoglobulin [CTLA4] Ig) and tapered rapamycin. Prolongation of graft median survival time from 39.5 days (no DCreg infusion; n = 6 historical controls) and 29 days with control unpulsed DCreg (n = 2), to 56 days with donor Ag-pulsed DCreg (n = 5) was associated with evidence of modulated host CD4+ and CD8+ T cell responses to donor Ag and attenuation of systemic IL-17 production. Circulating anti-donor antibody (Ab) was not detected until CTLA4 Ig withdrawal. One monkey treated with donor Ag-pulsed DCreg rejected its graft in association with progressively elevated anti-donor Ab, 525 days posttransplant (160 days after withdrawal of immunosuppression). These findings indicate a modest but not statistically significant beneficial effect of donor Ag-pulsed autologous DCreg infusion on NHP graft survival when administered with a minimal immunosuppressive drug regimen.
      PubDate: 2017-02-02T09:23:20.515192-05:
      DOI: 10.1111/ajt.14182
  • Renal Operational Tolerance Is Associated With a Defect of Blood Tfh Cells
           That Exhibit Impaired B Cell Help
    • Authors: A. Chenouard; M. Chesneau, L. Bui Nguyen, S. Le Bot, M. Cadoux, E. Dugast, C. Paul, S. Malard-Castagnet, S. Ville, P. Guérif, J.-P. Soulillou, N. Degauque, R. Danger, M. Giral, S. Brouard
      Pages: 1490 - 1501
      Abstract: Renal operationally tolerant patients (TOL) display a defect in B cell differentiation, with a deficiency in plasma cells. Recently described, T follicular helper (Tfh) cells play a critical role in B cell differentiation. We analyzed blood Tfh subsets in TOL and transplanted patients with stable graft function under immunosuppression (STA). We observed a reduced proportion of blood activated and highly functional Tfh subsets in TOL, without affecting Tfh absolute numbers. Functionally, Tfh cells from TOL displayed a modified gene expression profile, failed to produce interleukin-21, and were unable to induce IgG production by naive B cells. This Tfh defect is linked to a low incidence of postgraft de novo donor-specific antibody (dnDSA) immunization, suggesting that the lack of Tfh cells in TOL may induce a protolerogenic environment with reduced risk of developing dnDSA. Finally, we showed that elevated Tfh in STA precedes the occurrence of dnDSA during an alloresponse. These data provide new insights into the mechanisms of antibody response in operational tolerance. Disrupted homeostasis and impaired Tfh function in TOL could lead to a reduced risk of developing dnDSA and suggest a predictive role of blood Tfh cells on the occurrence of dnDSA in transplant recipients.
      PubDate: 2017-01-19T10:05:50.073885-05:
      DOI: 10.1111/ajt.14142
  • T Cells Promote Bronchial Epithelial Cell Secretion of Matrix
           Metalloproteinase-9 via a C-C Chemokine Receptor Type 2 Pathway:
           Implications for Chronic Lung Allograft Dysfunction
    • Authors: M. Pain; P.-J. Royer, J. Loy, A. Girardeau, A. Tissot, P. Lacoste, A. Roux, M. Reynaud-Gaubert, R. Kessler, S. Mussot, C. Dromer, O. Brugière, J.-F. Mornex, R. Guillemain, M. Dahan, C. Knoop, K. Botturi, C. Pison, R. Danger, S. Brouard, A. Magnan,
      Pages: 1502 - 1514
      Abstract: Chronic lung allograft dysfunction (CLAD) is the major limitation of long-term survival after lung transplantation. CLAD manifests as bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS). Alloimmune reactions and epithelial-to-mesenchymal transition have been suggested in BOS. However, little is known regarding the role of allogenicity in epithelial cell differentiation. Primary human bronchial epithelial cells (BECs) were treated with activated T cells in the presence or absence of transforming growth factor (TGF)-β. The expression of epithelial and mesenchymal markers was investigated. The secretion of inflammatory cytokines and matrix metalloproteinase (MMP)-9 was measured in culture supernatants and in plasma from lung transplant recipients (LTRs): 49 stable, 29 with BOS, and 16 with RAS. We demonstrated that C-C motif chemokine 2 secreted by T cells supports TGF-β–induced MMP-9 production by BECs after binding to C-C chemokine receptor type 2. Longitudinal investigation in LTRs revealed a rise in plasma MMP-9 before CLAD onset. Multivariate analysis showed that plasma MMP-9 was independently associated with BOS (odds ratio [OR] = 6.19, p = 0.002) or RAS (OR = 3.9, p = 0.024) and predicted the occurrence of CLAD 12 months before the functional diagnosis. Thus, immune cells support airway remodeling through the production of MMP-9. Plasma MMP-9 is a potential predictive biomarker of CLAD.
      PubDate: 2017-01-23T10:50:41.668148-05:
      DOI: 10.1111/ajt.14166
  • The Influence of Race and Common Genetic Variations on Outcomes After
           Pediatric Heart Transplantation
    • Authors: D. J. Green; M. M. Brooks, G. J. Burckart, R. E. Chinnock, C. Canter, L. J. Addonizio, D. Bernstein, J. K. Kirklin, D. C. Naftel, D. M. Girnita, A. Zeevi, S. A. Webber
      Pages: 1525 - 1539
      Abstract: Significant racial disparity remains in the incidence of unfavorable outcomes following heart transplantation. We sought to determine which pediatric posttransplantation outcomes differ by race and whether these can be explained by recipient demographic, clinical, and genetic attributes. Data were collected for 80 black and 450 nonblack pediatric recipients transplanted at 1 of 6 centers between 1993 and 2008. Genotyping was performed for 20 candidate genes. Average follow-up was 6.25 years. Unadjusted 5-year rates for death (p = 0.001), graft loss (p = 0.015), acute rejection with severe hemodynamic compromise (p = 0.001), late rejection (p = 0.005), and late rejection with hemodynamic compromise (p = 0.004) were significantly higher among blacks compared with nonblacks. Black recipients were more likely to be older at the time of transplantation (p < 0.001), suffer from cardiomyopathy (p = 0.004), and have public insurance (p < 0.001), and were less likely to undergo induction therapy (p = 0.0039). In multivariate regression models adjusting for age, sex, cardiac diagnosis, insurance status, and genetic variations, black race remained a significant risk factor for all the above outcomes. These clinical and genetic variables explained only 8–19% of the excess risk observed for black recipients. We have confirmed racial differences in survival, graft loss, and several rejection outcomes following heart transplantation in children, which could not be fully explained by differences in recipient attributes.
      PubDate: 2017-01-23T10:40:27.666774-05:
      DOI: 10.1111/ajt.14153
  • Effect of Replacing Race With Apolipoprotein L1 Genotype in Calculation of
           Kidney Donor Risk Index
    • Authors: B. A. Julian; R. S. Gaston, W. M. Brown, A. M. Reeves-Daniel, A. K. Israni, D. P. Schladt, S. O. Pastan, S. Mohan, B. I. Freedman, J. Divers
      Pages: 1540 - 1548
      Abstract: Renal allografts from deceased African American donors with two apolipoprotein L1 gene (APOL1) renal-risk variants fail sooner than kidneys from donors with fewer variants. The Kidney Donor Risk Index (KDRI) was developed to evaluate organ offers by predicting allograft longevity and includes African American race as a risk factor. Substituting APOL1 genotype for race may refine the KDRI. For 622 deceased African American kidney donors, we applied a 10-fold cross-validation approach to estimate contribution of APOL1 variants to a revised KDRI. Cross-validation was repeated 10 000 times to generate distribution of effect size associated with APOL1 genotype. Average effect size was used to derive the revised KDRI weighting. Mean current-KDRI score for all donors was 1.4930 versus mean revised-KDRI score 1.2518 for 529 donors with no or one variant and 1.8527 for 93 donors with two variants. Original and revised KDRIs had comparable survival prediction errors after transplantation, but the spread in Kidney Donor Profile Index based on presence or absence of two APOL1 variants was 37 percentage points. Replacing donor race with APOL1 genotype in KDRI better defines risk associated with kidneys transplanted from deceased African American donors, substantially improves KDRI score for 85–90% of kidneys offered, and enhances the link between donor quality and recipient need.
      PubDate: 2017-01-03T10:20:36.399293-05:
      DOI: 10.1111/ajt.14113
  • Relationship Among Viremia/Viral Infection, Alloimmunity, and Nutritional
           Parameters in the First Year After Pediatric Kidney Transplantation
    • Authors: R. Ettenger; H. Chin, K. Kesler, N. Bridges, P. Grimm, E. F. Reed, M. Sarwal, R. Sibley, E. Tsai, B. Warshaw, A. D. Kirk
      Pages: 1549 - 1562
      Abstract: The Immune Development in Pediatric Transplantation (IMPACT) study was conducted to evaluate relationships among alloimmunity, protective immunity, immune development, physical parameters, and clinical outcome in children undergoing kidney transplantation. We prospectively evaluated biopsy-proven acute rejection (BPAR), de novo donor-specific antibody (dnDSA) formation, viremia, viral infection, T cell immunophenotyping, and body mass index (BMI)/weight Z scores in the first year posttransplantation in 106 pediatric kidney transplant recipients. Outcomes were excellent with no deaths and 98% graft survival. Rejection and dnDSAs occurred in 24% and 22%, respectively. Pretransplant cytomegalovirus (CMV) and Epstein–Barr virus (EBV) serologies and subsequent viremia were unrelated to BPAR or dnDSA. Viremia occurred in 73% of children (EBV, 34%; CMV, 23%; BMK viremia, 23%; and JC virus, 21%). Memory lymphocyte phenotype at baseline was not predictive of alloimmune complications. Patients who developed viral infection had lower weight (−2.1) (p = 0.028) and BMI (−1.2) (p = 0.048) Z scores at transplantation. The weight difference persisted to 12 months compared with patients without infection (p = 0.038). These data indicate that there is a high prevalence of viral disease after pediatric kidney transplantation, and underweight status at transplantation appears to be a risk factor for subsequent viral infection. The occurrence of viremia/viral infection is not associated with alloimmune events.
      PubDate: 2017-02-01T10:41:30.603264-05:
      DOI: 10.1111/ajt.14169
  • Reactivation of Latent HPV Infections After Renal Transplantation
    • Authors: F. Hinten; L. B. Hilbrands, K. A. P. Meeuwis, J. IntHout, W. G. V. Quint, A. J. Hoitsma, L. F. A. G. Massuger, W. J. G. Melchers, J. A. Hullu
      Pages: 1563 - 1573
      Abstract: Female renal transplant recipients (RTRs) have an increased risk for developing human papillomavirus (HPV)–related (pre)malignant lesions of the genital tract. This study aims to assess the genital prevalence of HPV before and after renal transplantation (RT). In female patients who were counseled for RT at the Radboud University Medical Center Nijmegen, the Netherlands, gynecological examination was performed at first visit, and 1 and 2 years later. HPV self-sampling and questionnaires on sexual behavior were performed every 3 months. In 65 patients who underwent RT, the high-risk human papillomavirus (hrHPV) prevalence as assessed with the highly sensitive SPF10 -LiPA25 test increased significantly from 19% before to 31% after RT (p = 0.045). Based upon the clinically validated Cobas 4800 HPV test, the hrHPV prevalence increased from 10% before to 14% after RT (p = 0.31). During follow-up, no changes in sexual behavior were reported. Thirty-three patients who did not undergo RT showed a hrHPV prevalence of 21% at study entry and of 27% after 12 months with the sensitive test, and a stable prevalence of 16% with the clinically validated test. The results of this study indicate that activation of latent HPV infections may contribute to the increased risk of HPV-related (pre)malignant lesions in female RTRs.
      PubDate: 2017-02-02T09:10:40.257722-05:
      DOI: 10.1111/ajt.14181
  • The Value of Protocol Biopsies to Identify Patients With De Novo
           Donor-Specific Antibody at High Risk for Allograft Loss
    • Authors: C. A. Schinstock; F. Cosio, W. Cheungpasitporn, D. M. Dadhania, M. J. Everly, M. D. Samaniego-Picota, L. Cornell, M. D. Stegall
      Pages: 1574 - 1584
      Abstract: De novo donor-specific antibody (dnDSA) is associated with antibody-mediated rejection (AMR) and allograft loss, yet the allograft histology associated with dnDSA remains unclear. The aim of this study was to examine the allograft histology associated with dnDSA in patients with serial surveillance biopsies. We retrospectively studied adult conventional solitary kidney transplant recipients from October 2007 to May 2014. The definition of dnDSA was new donor-specific antibody (DSA) with mean fluorescence intensity (MFI)>1000. The incidence of dnDSA was 7.0% (54 of 771) over mean follow-up of 4.2 ± 1.9 years. Patients with dnDSA had reduced death-censored allograft survival (87.0% vs. 97.0% no dnDSA, p < 0.01). Moreover, 94% of patients received a biopsy after dnDSA (mean of three biopsies per patient). AMR was present in 25.0% and 52.9% of patients at dnDSA detection and at 1 year, respectively. Patients with both class I and II dnDSA had the highest rate of allograft loss. The higher the sum MFI at dnDSA detection, the higher the incidence of AMR. In conclusion, patients with dnDSA without AMR at time of detection may benefit from a follow-up biopsy within 1 year because AMR can be missed initially. In addition, the dnDSA class and sum MFI at baseline appear to be prognostic. The higher the sum MFI of dnDSA at baseline, the higher the incidence of AMR.
      PubDate: 2017-01-25T14:40:28.893597-05:
      DOI: 10.1111/ajt.14161
  • Variation in Access to Kidney Transplantation Across Renal Programs in
           Ontario, Canada
    • Authors: K. L. Naylor; S. N. Dixon, A. X. Garg, S. J. Kim, P. G. Blake, G. E. Nesrallah, M. K. McCallum, C. D'Antonio, A. H. Li, G. A. Knoll
      Pages: 1585 - 1593
      Abstract: In the United States, kidney transplant rates vary significantly across end-stage renal disease (ESRD) networks. We conducted a population-based cohort study to determine whether there was variability in kidney transplant rates across renal programs in a health care system distinct from the United States. We included incident chronic dialysis patients in Ontario, Canada, from 2003 to 2013 and determined the 1-, 5-, and 10-year cumulative incidence of kidney transplantation in 27 regional renal programs (similar to U.S. ESRD networks). We also assessed the cumulative incidence of kidney transplant for “healthy” dialysis patients (aged 18–50 years without diabetes, coronary disease, or malignancy). We calculated standardized transplant ratios (STRs) using a Cox proportional hazards model, adjusting for patient characteristics (maximum possible follow-up of 11 years). Among 23 022 chronic dialysis patients, the 10-year cumulative incidence of kidney transplantation ranged from 7.4% (95% confidence interval [CI] 4.8–10.7%) to 31.4% (95% CI 16.5–47.5%) across renal programs. Similar variability was observed in our healthy cohort. STRs ranged from 0.3 (95% CI 0.2–0.5) to 1.5 (95% CI 1.4–1.7) across renal programs. There was significant variation in kidney transplant rates across Ontario renal programs despite patients having access to the same publicly funded health care system.
      PubDate: 2017-01-09T12:00:01.094249-05:
      DOI: 10.1111/ajt.14133
  • Telemedically Supported Case Management of Living-Donor Renal Transplant
           Recipients to Optimize Routine Evidence-Based Aftercare: A Single-Center
           Randomized Controlled Trial
    • Authors: A. Schmid; S. Hils, A. Kramer-Zucker, L. Bogatyreva, D. Hauschke, S. De Geest, P. Pisarski
      Pages: 1594 - 1605
      Abstract: Improving mid-term and long-term outcomes after solid organ transplantation is imperative, and requires both state-of-the-art transplant surgery and optimization of routine, evidence-based aftercare. This randomized, controlled trial assessed the effectiveness of standard aftercare versus telemedically supported case management, an innovative aftercare model, in 46 living-donor renal transplant recipients during the first posttransplant year. The model includes three components: (i) chronic care case management initiated after discharge, (ii) case management initiated in emerging acute care situations, and (iii) a telemedically equipped team comprising a transplant nurse case manager and two senior transplant physicians (nephrologist, surgeon). Analyses revealed a reduction of unplanned inpatient acute care, with considerable cost reductions, in the intervention group. The prevalence of nonadherence over the 1-year study period was 17.4% in the intervention group versus 56.5% in the standard aftercare group (p = 0.013). Only the intervention group achieved their pre-agreed levels of adherence, disease-specific quality of life, and return to employment. This comparative effectiveness study provides the basis for multicenter study testing of telemedically supported case management with the aim of optimizing posttransplant aftercare. The trial was registered with the German Clinical Trials Register (, DKRS00007634.
      PubDate: 2017-01-05T10:35:24.930035-05:
      DOI: 10.1111/ajt.14138
  • Left Lobe Auxiliary Liver Transplantation for End-stage Hepatitis B Liver
    • Authors: S.-F. Wang; X.-P. Chen, Z.-S. Chen, L. Wei, S.-L. Dong, H. Guo, J.-P. Jiang, W.-H. Teng, Z.-Y. Huang, W.-G. Zhang
      Pages: 1606 - 1612
      Abstract: Auxiliary liver transplantation (ALT) for hepatitis B virus (HBV)-related liver cirrhosis previously showed poor results, because the native liver was a significant source of HBV recurrence and the graft could be rapidly destroyed by HBV infection in an immunosuppressive condition. Four patients with HBV-related liver cirrhosis were unable to undergo orthotopic liver transplantation because the only available grafts of left lobe were too small. Under entecavir-based anti-HBV treatment, they underwent ALT in which the recipient left liver was removed and the small left lobe graft was implanted in the corresponding space. The mean graft weight/recipient weight was 0.49% (range, 0.38%–0.55%). One year after transplantation, the graft sizes were increased to 273% and the remnant livers were decreased to 44%. Serum HBV DNA was persistently undetectable. Periodic graft biopsy showed no signs of tissue injury and negative immunostaining for hepatitis B surface antigen and hepatitis B core antigen. After a mean follow-up period of 21 months, all patients live well with normal graft function. Our study suggests that ALT for HBV-related liver cirrhosis is feasible under entecavir-based anti-HBV treatment. Successful application of small left livers in end-stage liver cirrhosis may significantly increase the pool of left liver grafts for adult patients.
      PubDate: 2017-01-18T09:20:40.257631-05:
      DOI: 10.1111/ajt.14143
  • The First 2 Years of Activity of a Specialized Organ Procurement Center:
           Report of an Innovative Approach to Improve Organ Donation
    • Authors: P. Marsolais; P. Durand, E. Charbonney, K. Serri, A.-M. Lagacé, F. Bernard, M. Albert
      Pages: 1613 - 1619
      Abstract: The number of patients requiring organ transplants continues to outgrow the number of organs donated each year. In an attempt to improve the organ donation process and increase the number of organs available, we created a specialized multidisciplinary team within a specialized organ procurement center (OPC) with dedicated intensive care unit (ICU) beds and operating rooms. The OPC was staffed with ICU nurses, operating room nurses, organ donor management ICU physicians, and multidisciplinary staff. All organ donors within a designated geographic area were transferred to and managed within the OPC. During the first 2 years of operation, 126 patients were referred to the OPC. The OPC was in use for a total of 3527 h and involved 253 health workers. We retrieved 173 kidneys, 95 lungs, 68 livers, 37 hearts, and 13 pancreases for a total of 386 organs offered for transplantation. This translates to a total of 124.6 persons transplanted per million population, which compares most favorably to recently published numbers in developed countries. The OPC clearly demonstrates potential to increase the number of deceased donor organs available for transplant. Further studies are warranted to better understand the exact influence of the different components of the OPC on organ procurement.
      PubDate: 2017-01-07T22:15:26.417631-05:
      DOI: 10.1111/ajt.14139
  • Regional Differences in Communication Process and Outcomes of Requests for
           Solid Organ Donation
    • Authors: H. M. Traino; A. J. Molisani, L. A. Siminoff
      Pages: 1620 - 1627
      Abstract: Although federal mandate prohibits the allocation of solid organs for transplantation based on “accidents of geography,” geographic variation of transplantable organs is well documented. This study explores regional differences in communication in requests for organ donation. Administrative data from nine partnering organ procurement organizations and interview data from 1339 family decision makers (FDMs) were compared across eight geographically distinct US donor service areas (DSAs). Authorization for organ donation ranged from 60.4% to 98.1% across DSAs. FDMs from the three regions with the lowest authorization rates reported the lowest levels of satisfaction with the time spent discussing donation and with the request process, discussion of the least donation-related topics, the highest levels of pressure to donate, and the least comfort with the donation decision. Organ procurement organization region predicted authorization (odds ratios ranged from 8.14 to 0.24), as did time spent discussing donation (OR = 2.11), the number of donation-related topics discussed (OR = 1.14), and requesters’ communication skill (OR = 1.14). Standardized training for organ donation request staff is needed to ensure the highest quality communication during requests, optimize rates of family authorization to donation in all regions, and increase the supply of organs available for transplantation.
      PubDate: 2017-01-23T10:45:27.188623-05:
      DOI: 10.1111/ajt.14165
  • Monitoring of Human Uterus Transplantation With Cervical Biopsies: A
           Provisional Scoring System for Rejection
    • Authors: J. Mölne; V. Broecker, J. Ekberg, O. Nilsson, P. Dahm-Kähler, M. Brännström
      Pages: 1628 - 1636
      Abstract: Until now, absolute uterine factor infertility has been the major untreatable form of female infertility. Uterus transplantation has recently proven to be the first successful treatment for absolute uterine factor infertility, with demonstration of live births. In this study, live donation uterus transplantation was performed in nine women. In total, 163 cervical biopsies (149 protocol, 14 follow-up) were taken to detect histopathological signs of rejection. Based on experience from animal experiments, we used a three-grade scoring system to evaluate biopsies systematically. Nine episodes of rejection were diagnosed in five patients: grade 1 in six episodes, grade 2 in two episodes, and grade 3 in one episode. Treatment decisions were based on histopathology, and all rejection episodes were reversed after treatment. The biopsies were reviewed retrospectively, and immunohistochemistry was performed to characterize the inflammatory infiltrates. A borderline category was introduced to avoid overtreatment of patients. Based on our review of all biopsies, we put forward a simple grading system for monitoring of rejection and to guide immunosuppressive treatment in uterus transplantation.
      PubDate: 2017-01-03T11:31:08.099878-05:
      DOI: 10.1111/ajt.14135
  • Association of Higher CD4+CD25highCD127low, FoxP3+, and IL-2+ T Cell
           Frequencies Early After Lung Transplantation With Less Chronic Lung
           Allograft Dysfunction at Two Years
    • Authors: J. Salman; F. Ius, A.-K. Knoefel, W. Sommer, T. Siemeni, C. Kuehn, I. Tudorache, M. Avsar, T. Nakagiri, G. Preissler, R. Hatz, M. Greer, T. Welte, A. Haverich, G. Warnecke
      Pages: 1637 - 1648
      Abstract: Regulatory T cells (Treg) can regulate alloantigens and may counteract chronic lung allograft dysfunction (CLAD) in lung transplantation. We analyzed Treg in peripheral blood prospectively and correlated percentages of subpopulations with the incidence of CLAD at 2 years. Among lung-transplanted patients between January 2009 and July 2011, only patients with sufficient Treg measurements were included into the study. Tregs were measured immediately before lung transplantation, at 3 weeks and 3, 6, 12, and 24 months after transplantation and were defined as CD4+CD25high T cells and further analyzed for CTLA4, CD127, FoxP3, and IL-2 expressions. Between January 2009 and July 2011, 264 patients were transplanted at our institution. Among the 138 (52%) patients included into the study, 31 (22%) developed CLAD within 2 years after transplantation. As soon as 3 weeks after lung transplantation, a statistically significant positive association was detected between Treg frequencies and later absence of CLAD. At the multivariate analysis, increasing frequencies of CD4+CD25highCD127low, CD4+CD25highFoxP3+ and CD4+CD25highIL-2+ T cells at 3 weeks after lung transplantation emerged as protective factors against development of CLAD at 2 years. In conclusion, higher frequencies of specific Treg subpopulations early after lung transplantation are protective against CLAD development.
      PubDate: 2017-01-24T09:35:34.032897-05:
      DOI: 10.1111/ajt.14148
  • Noneligible Donors as a Strategy to Decrease the Organ Shortage
    • Authors: K. P. Croome; D. D. Lee, A. P. Keaveny, C. B. Taner
      Pages: 1649 - 1655
      Abstract: Organ procurement organization (OPO) performance is generally evaluated by the number of organ procurement procedures divided by the number of eligible deaths (donation after brain death [DBD] donors aged 70 years) is not tracked. The present study aimed to investigate the variability in the proportion of noneligible liver donors by the 58 donor service areas (DSAs). Patients undergoing liver transplant (LT) between 2011 and 2015 were obtained from the United Network for Organ Sharing Standard Transplant Analysis and Research file. LTs from noneligible and eligible donors were compared. The proportion of noneligible liver donors by DSA varied significantly, ranging from 0% to 19.6% of total liver grafts used. In transplant programs, the proportion of noneligible liver donors used ranged from 0% to 35.3%. On linear regression there was no correlation between match Model for End-Stage Liver Disease score for programs in a given DSA and proportion of noneligible donors used from the corresponding DSA (p = 0.14). Noneligible donors remain an underutilized resource in many OPOs. Policy changes to begin tracking noneligible donors and learning from OPOs that have high noneligible donor usage are potential strategies to increase awareness and pursuit of these organs.
      PubDate: 2017-01-31T10:37:23.980049-05:
      DOI: 10.1111/ajt.14163
  • Breg dependent islet transplant tolerance is also NK-cell dependent
    • Authors: C. Schuetz; K. M. Lee, R. Scott, L. Kojima, L. Washburn, L. Liu, W.-H. Liu, H. Tector, J. Lei, H. Yeh, J. I. Kim, J. F. Markmann
      First page: 1656
      Abstract: Immunologic tolerance to solid organ and islet cell grafts has been achieved in various rodent models using antibodies directed at CD45RB and Tim-1. We have shown that this form of tolerance depends on regulatory B-cells. To elucidate further the mechanism by which Bregs induce tolerance we investigated the requirement of NK and NKT cells in this model. To do so, hyperglycemic B6, μMT, Beige or CD1d-/- mice received Balb/c islet grafts and treatment with the tolerance inducing regimen consisting of anti-CD45RB and anti –TIM1. B6 mice depleted of both NK and NKT cells by anti-NK1.1 antibody and mice deficient in NK activity (Beige) did not develop tolerance following dual antibody treatment. In contrast, transplant tolerance induction was successful in CD1d-/- recipients (deficient in NK-T cells), indicating that NK but not NKT cells are essential in B-cell dependent tolerance. In addition, reconstitution of Beige host with NK cells restored the ability to induce transplant tolerance with dual antibody treatment. Transfer of tolerance by B-cells from tolerant mice was also dependent on host Nk1.1+ cells. In conclusion, these results show that regulatory function of B-cells is dependent on NK cells in this model of transplantation tolerance.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-11T09:55:30.776002-05:
      DOI: 10.1111/ajt.14265
  • Impact of CXCR4/CXCL12 Blockade on Normal Plasma Cells In Vivo
    • Authors: N. Moore; M. Moreno Gonzales, K. Bonner, B. Smith, W. Park, M. Stegall
      Pages: 1663 - 1669
      Abstract: Plasma cells (PCs) are a major source of alloantibody in transplant patients and are resistant to current therapy. Because receptor–ligand interactions in stromal microenvironments play important roles in the localization, development, and survival of normal PCs, we hypothesized that interfering with CXCR4/CXCL12 interactions with plerixafor might cause PC depletion and enhance the efficacy of the proteasome inhibitor bortezomib. PCs in mouse spleen, bone marrow, and peripheral blood demonstrated CXCR4 expression. We then treated with plerixafor in doses ranging from 240 μg/kg in a single dose to a 1-mg/kg daily dose for 10 days. CXCR4/CXCL12 blockade with plerixafor resulted in increased mobilization of PCs into the peripheral blood. Splenectomy completely abrogated this effect, suggesting that all plerixafor-mobilized cells were from the spleen. The total number of PCs in the spleen and marrow remained constant despite treatment with plerixafor. Bortezomib caused a reduction in PCs, but adding plerixafor did not increase killing. We conclude that CXCR4/CXCL12 interactions are important for the retention of a subpopulation of PCs in the spleen, but this interaction has minimal effect on PCs in the marrow. The lack of enhancement of bortezomib-mediated depletion suggests that factors other than CXCR4/CXCL12 interactions are responsible for drug resistance.
      PubDate: 2017-03-22T09:46:02.388981-05:
      DOI: 10.1111/ajt.14236
  • Successful Renal Transplantation in Small Children With a Completely
           Thrombosed Inferior Vena Cava
    • Authors: P. Verghese; E. Minja, V. Kirchner, B. Chavers, A. Matas, S. Chinnakotla
      Pages: 1670 - 1673
      Abstract: In small children with end-stage renal disease, an adult-sized kidney transplant is the best option. However, in the face of a completely thrombosed inferior vena cava (IVC), such transplants can be challenging, given the difficulty of achieving adequate renal venous outflow and the risk of graft thrombosis. Using a new technique to anastomose the renal vein to the right hepatic vein/IVC junction, we successfully implanted an adult-sized graft in two small children (9.8 and 14 kg) who had end-stage renal disease and a completely thrombosed IVC. After mobilizing the right lobe of the liver and obtaining total vascular occlusion of the liver, we used a Fogarty catheter to dilate the retrohepatic IVC. In the right hepatic vein, we made a venotomy and extended it inferiorly onto the retrohepatic IVC. To that venotomy, we anastomosed the donor left renal vein, using continuous 7-0 Prolene sutures. Both patients attained excellent renal allograft function: One had a serum creatinine level of 0.30 mg/dL at 6 mo after transplant, and the other had a level of 0.29 mg/dL at 1 year. In these two small children with completely thrombosed IVC, our technique for transplanting an adult-sized kidney provided adequate venous outflow.
      PubDate: 2017-02-28T11:15:41.790353-05:
      DOI: 10.1111/ajt.14213
  • BK Polyomavirus Genomic Integration and Large T Antigen Expression:
           Evolving Paradigms in Human Oncogenesis
    • Authors: D. J. Kenan; P. A. Mieczkowski, E. Latulippe, I. Côté, H. K. Singh, V. Nickeleit
      Pages: 1674 - 1680
      Abstract: Human polyomaviruses are ubiquitous, with primary infections that typically occur during childhood and subsequent latency that may last a lifetime. Polyomavirus-mediated disease has been described in immunocompromised patients; its relationship to oncogenesis is poorly understood. We present deep sequencing data from a high-grade BK virus–associated tumor expressing large T antigen. The carcinoma arose in a kidney allograft 6 years after transplantation. We identified a novel genotype 1a BK polyomavirus, called Chapel Hill BK polyomavirus 2 (CH-2), that was integrated into the BRE gene in chromosome 2 of tumor cells. At the chromosomal integration site, viral break points were found, disrupting late BK gene sequences encoding capsid proteins VP1 and VP2/3. Immunohistochemistry and in situ hybridization studies demonstrated that the integrated BK virus was replication incompetent. We propose that the BK virus CH-2 was integrated into the human genome as a concatemer, resulting in alterations of feedback loops and overexpression of large T antigen. Collectively, these findings support the emerging understanding that viral integration is a nearly ubiquitous feature in polyomavirus-associated malignancy and that unregulated large T antigen expression drives a proliferative state that is conducive to oncogenesis. Based on the current observations, we present an updated model of polyomavirus-mediated oncogenesis.
      PubDate: 2017-02-21T10:52:13.332939-05:
      DOI: 10.1111/ajt.14191
  • Zika Virus Transmission—Region of the Americas, May 15,
           2015–December 15, 2016
    • Authors: J. Ikejezie; C. N. Shapiro, J. Kim, M. Chiu, M. Almiron, C. Ugarte, M. A. Espinal, S. Aldighieri
      Pages: 1681 - 1686
      Abstract: This report updates the most recent surveillance data for Zika virus.
      PubDate: 2017-05-23T08:38:05.904141-05:
      DOI: 10.1111/ajt.14333
  • The First Transplant Surgeon: The Flawed Genius of Nobel Prize Winner,
           Alexis Carrel, edited by David Hamilton. World Scientific, London, 2017.
           587 pages
    • Authors: D. K. C. Cooper
      Pages: 1687 - 1687
      PubDate: 2017-03-30T10:15:22.22356-05:0
      DOI: 10.1111/ajt.14264
  • Fever in a Kidney Transplant Recipient
    • Authors: P. Sanghi; G. Gupta, H. D. Massey, D. Kumar
      Pages: 1688 - 1690
      PubDate: 2017-05-23T08:38:05.209066-05:
      DOI: 10.1111/ajt.14285
  • Fluctuation Does Not Mean Variability: A Pharmacokinetic Point of View
    • Authors: F. Lemaitre; C. Tron, M. Rayar
      Pages: 1691 - 1692
      PubDate: 2017-03-17T09:25:24.363827-05:
      DOI: 10.1111/ajt.14237
  • Reply to “Fluctuation Does Not Mean Variability: A Pharmacokinetic
           Point of View”
    • Authors: S. Tremblay; V. Nigro, E. S. Woodle, R. R. Alloway
      Pages: 1693 - 1693
      PubDate: 2017-03-22T09:50:32.131484-05:
      DOI: 10.1111/ajt.14248
  • Viva España—Lessons From the Spanish Organ Donation System
    • Authors: A. Sharif
      Pages: 1694 - 1694
      PubDate: 2017-03-22T09:45:28.263674-05:
      DOI: 10.1111/ajt.14246
  • About the opt-out system, live transplantation and information to the
           public on organ donation in Spain … Y olé!
    • Authors: R. Matesanz; R. Marazuela, E. Coll, B. Mahíllo, B. Domínguez-Gil
      First page: 1695
      Abstract: We have read with interest Sharif's letter regarding our publication on the strategies developed in Spain to progress towards self-sufficiency in transplantation.1 The recognition of the efforts made along the years to achieve high levels of deceased donation (43.4 donors pmp in 2016), well summarized by his ‘Viva España’, is highly appreciated.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-02T10:18:56.383556-05:
      DOI: 10.1111/ajt.14296
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