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Von Tokarski F, Fillon A, Maisons V, Thoreau B, Bayer G, Gatault P, Longuet H, Sautenet B, Buchler M, Vigneau C, Fakhouri F, Halimi JM. Thrombotic microangiopathies after kidney transplantation in modern era: nosology based on chronology. BMC Nephrol 2023; 24:278. [PMID: 37730583 PMCID: PMC10512637 DOI: 10.1186/s12882-023-03326-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 09/07/2023] [Indexed: 09/22/2023] Open
Abstract
BACKGROUND Thrombotic microangiopathies (TMAs) are rare but can be severe in kidney transplant. recipients (KTR). METHODS We analysed the epidemiology of adjudicated TMA in consecutive KTR during the. 2009-2021 period. RESULTS TMA was found in 77/1644 (4.7%) KTR. Early TMA (n = 24/77 (31.2%); 1.5% of all KTR) occurred during the first two weeks ((median, IQR) 3 [1-8] days). Triggers included acute antibody-mediated rejection (ABMR, n = 4) and bacterial infections (n = 6). Graft survival (GS) was 100% and recurrence rate (RR) was 8%. Unexpected TMA (n = 31/77 (40.2%); 1.5/1000 patient-years) occurred anytime during follow-up (3.0 (0.5-6.2) years). Triggers included infections (EBV/CMV: n = 10; bacterial: n = 6) and chronic active ABMR (n = 5). GS was 81% and RR was 16%. Graft-failure associated TMA (n = 22/77 (28.6%); 2.2% of graft losses) occurred after 8.8 (4.9-15.5) years). Triggers included acute (n = 4) or chronic active (n = 14) ABMR, infections (viral: n = 6; bacterial: n = 5) and cancer (n = 6). 15 patients underwent transplantectomy. RR was 27%. Atypical (n = 6) and typical (n = 2) haemolytic and uremic syndrome, and isolated CNI toxicity (n = 4) were rare. Two-third of biopsies presented TMA features. CONCLUSIONS TMA are mostly due to ABMR and infections; causes of TMA are frequently combined. Management often is heterogenous. Our nosology based on TMA timing identifies situations with distinct incidence, causes and prognosis.
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Affiliation(s)
- Florent Von Tokarski
- Service de Néphrologie-HTA, Dialyses, Transplantation Rénale, Hôpital Bretonneau Et Hôpital Clôcheville, CHU Tours, 2 Bd Tonnellé, 37044, Tours, Tours Cedex, France
| | - Alexandre Fillon
- Service de Néphrologie-HTA, Dialyses, Transplantation Rénale, Hôpital Bretonneau Et Hôpital Clôcheville, CHU Tours, 2 Bd Tonnellé, 37044, Tours, Tours Cedex, France
| | - Valentin Maisons
- Service de Néphrologie-HTA, Dialyses, Transplantation Rénale, Hôpital Bretonneau Et Hôpital Clôcheville, CHU Tours, 2 Bd Tonnellé, 37044, Tours, Tours Cedex, France
| | - Benjamin Thoreau
- Service de Néphrologie-HTA, Dialyses, Transplantation Rénale, Hôpital Bretonneau Et Hôpital Clôcheville, CHU Tours, 2 Bd Tonnellé, 37044, Tours, Tours Cedex, France
| | - Guillaume Bayer
- Service de Néphrologie-HTA, Dialyses, Transplantation Rénale, Hôpital Bretonneau Et Hôpital Clôcheville, CHU Tours, 2 Bd Tonnellé, 37044, Tours, Tours Cedex, France
| | - Philippe Gatault
- Service de Néphrologie-HTA, Dialyses, Transplantation Rénale, Hôpital Bretonneau Et Hôpital Clôcheville, CHU Tours, 2 Bd Tonnellé, 37044, Tours, Tours Cedex, France
- EA4245, François-Rabelais University, Tours, France
| | - Hélène Longuet
- Service de Néphrologie-HTA, Dialyses, Transplantation Rénale, Hôpital Bretonneau Et Hôpital Clôcheville, CHU Tours, 2 Bd Tonnellé, 37044, Tours, Tours Cedex, France
| | - Bénédicte Sautenet
- Service de Néphrologie-HTA, Dialyses, Transplantation Rénale, Hôpital Bretonneau Et Hôpital Clôcheville, CHU Tours, 2 Bd Tonnellé, 37044, Tours, Tours Cedex, France
- Inserm U1246, Hôpital Bretonneau, CHU Tours, Tours, France
| | - Matthias Buchler
- Service de Néphrologie-HTA, Dialyses, Transplantation Rénale, Hôpital Bretonneau Et Hôpital Clôcheville, CHU Tours, 2 Bd Tonnellé, 37044, Tours, Tours Cedex, France
- EA4245, François-Rabelais University, Tours, France
| | - Cécile Vigneau
- Service de Néphrologie, CHU Pontchaillou, 35033, Rennes, France
- Université Rennes 1, Inserm IRSET, UMR 1085, 35033, Rennes, France
| | - Fadi Fakhouri
- Department of medicine, Service of Nephrology, CHUV and Université de Lausanne, Lausanne, Switzerland
| | - Jean-Michel Halimi
- Service de Néphrologie-HTA, Dialyses, Transplantation Rénale, Hôpital Bretonneau Et Hôpital Clôcheville, CHU Tours, 2 Bd Tonnellé, 37044, Tours, Tours Cedex, France.
- EA4245, François-Rabelais University, Tours, France.
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Ferrer-Fàbrega J, Folch-Puy E, Lozano JJ, Ventura-Aguiar P, Cárdenas G, Paredes D, García-Criado Á, Bombí JA, García-Pérez R, López-Boado MÁ, Rull R, Esmatjes E, Ricart MJ, Diekmann F, Fondevila C, Fernández-Cruz L, Fuster J, García-Valdecasas JC. Current Trends in Organ Preservation Solutions for Pancreas Transplantation: A Single-Center Retrospective Study. Transpl Int 2022; 35:10419. [PMID: 35418805 PMCID: PMC8995432 DOI: 10.3389/ti.2022.10419] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 02/25/2022] [Indexed: 12/14/2022]
Abstract
Due to the high vulnerability of the pancreas to ischemia-reperfusion injury, choices regarding preservation solution markedly affect pancreas transplant success. A retrospective single-center analysis of 380 pancreas transplants (2000–2019) was performed to correlate current preservation solutions with transplant outcomes. Early graft failure requiring transplantectomy within 30 days post-transplant occurred in 7.5% for University of Wisconsin (UW) group (n = 267), 10.8% of Celsior (CS) group (n = 83), 28.5% of Histidine-Tryptophan-Ketoglutarate (HTK) group (n = 7), and none for Institut Georges Lopez-1 (IGL-1) group (n = 23). The most common causes of technical failures in this cohort included abdominal hemorrhage (8.4%); graft pancreatitis (3.7%); fluid collections (2.6%); intestinal complications (6.6%); and vascular thrombosis (20.5%). Although IGL-1 solution provided lower surgical complication rates, no significant differences were found between studied groups. Nevertheless, HTK solution was associated with elevated pancreatitis rates. The best graft survival was achieved at 1 year using UW and IGL-1, and at 3 and 5 years using IGL-1 (p = 0.017). There were no significant differences in patient survival after a median follow-up of 118.4 months. In this setting therefore, IGL-1 solution appears promising for perfusion and organ preservation in clinical pancreas transplantation, compared to other commonly used solutions.
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Affiliation(s)
- Joana Ferrer-Fàbrega
- Hepatobiliopancreatic Surgery and Liver and Pancreatic Transplantation Unit, Clinic Institute of Digestive and Metabolic Diseases (ICMDiM), Hospital Clínic, University of Barcelona, Barcelona, Spain.,August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - Emma Folch-Puy
- Experimental Pathology Department, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain.,August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - Juan José Lozano
- Bioinformatics Platform, Network for Biomedical Research in Hepatic and Digestive Diseases (CIBERehd), Barcelona, Spain.,Network for Biomedical Research in Hepatic and Digestive Diseases (CIBERehd), Barcelona, Spain
| | - Pedro Ventura-Aguiar
- Renal Transplant Unit, Nephrology and Kidney Transplant Department, Hospital Clínic, University of Barcelona, Barcelona, Spain.,August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - Gabriel Cárdenas
- Hepatobiliopancreatic Surgery and Liver and Pancreatic Transplantation Unit, Clinic Institute of Digestive and Metabolic Diseases (ICMDiM), Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - David Paredes
- Donation and Transplant Coordination Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Ángeles García-Criado
- Department of Radiology, Hospital Clínic, University of Barcelona, Barcelona, Spain.,August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - Josep Antoni Bombí
- Department of Pathology, Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Rocío García-Pérez
- Hepatobiliopancreatic Surgery and Liver and Pancreatic Transplantation Unit, Clinic Institute of Digestive and Metabolic Diseases (ICMDiM), Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Miguel Ángel López-Boado
- Hepatobiliopancreatic Surgery and Liver and Pancreatic Transplantation Unit, Clinic Institute of Digestive and Metabolic Diseases (ICMDiM), Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Ramón Rull
- Hepatobiliopancreatic Surgery and Liver and Pancreatic Transplantation Unit, Clinic Institute of Digestive and Metabolic Diseases (ICMDiM), Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Enric Esmatjes
- Diabetes Unit, Department of Endocrinology and Nutrition, Hospital Clínic, University of Barcelona, Barcelona, Spain.,August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - Maria José Ricart
- Renal Transplant Unit, Nephrology and Kidney Transplant Department, Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Fritz Diekmann
- Renal Transplant Unit, Nephrology and Kidney Transplant Department, Hospital Clínic, University of Barcelona, Barcelona, Spain.,August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - Constantino Fondevila
- Hepatobiliopancreatic Surgery and Liver and Pancreatic Transplantation Unit, Clinic Institute of Digestive and Metabolic Diseases (ICMDiM), Hospital Clínic, University of Barcelona, Barcelona, Spain.,Network for Biomedical Research in Hepatic and Digestive Diseases (CIBERehd), Barcelona, Spain.,August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - Laureano Fernández-Cruz
- Hepatobiliopancreatic Surgery and Liver and Pancreatic Transplantation Unit, Clinic Institute of Digestive and Metabolic Diseases (ICMDiM), Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Josep Fuster
- Hepatobiliopancreatic Surgery and Liver and Pancreatic Transplantation Unit, Clinic Institute of Digestive and Metabolic Diseases (ICMDiM), Hospital Clínic, University of Barcelona, Barcelona, Spain.,Network for Biomedical Research in Hepatic and Digestive Diseases (CIBERehd), Barcelona, Spain.,August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - Juan Carlos García-Valdecasas
- Hepatobiliopancreatic Surgery and Liver and Pancreatic Transplantation Unit, Clinic Institute of Digestive and Metabolic Diseases (ICMDiM), Hospital Clínic, University of Barcelona, Barcelona, Spain.,Network for Biomedical Research in Hepatic and Digestive Diseases (CIBERehd), Barcelona, Spain.,August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
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Balani SS, Jensen CJ, Kouri AM, Kizilbash SJ. Induction and maintenance immunosuppression in pediatric kidney transplantation-Advances and controversies. Pediatr Transplant 2021; 25:e14077. [PMID: 34216190 DOI: 10.1111/petr.14077] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 05/04/2021] [Accepted: 05/26/2021] [Indexed: 12/16/2022]
Abstract
Advances in immunosuppression have improved graft survival in pediatric kidney transplant recipients; however, treatment-related toxicities need to be balanced against the possibility of graft rejection. Several immunosuppressive agents are available for use in transplant recipients; however, the optimal combinations of agents remain unclear, resulting in variations in institutional protocols. Lymphocyte-depleting antibodies, specifically ATG, are the most common induction agent used for pediatric kidney transplantation in the US. Basiliximab may be used for induction in immunologically low-risk children; however, pediatric data are scarce. CNIs and antiproliferative agents (mostly Tac and mycophenolate in recent years) constitute the backbone of maintenance immunosuppression. Steroid-avoidance maintenance regimens remain controversial. Belatacept and mTOR inhibitors are used in children under specific circumstances such as non-adherence or CNI toxicity. This article reviews the indications, mechanism of action, efficacy, dosing, and side effect profiles of various immunosuppressive agents available for pediatric kidney transplantation.
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Affiliation(s)
- Shanthi S Balani
- Pediatric Nephrology, University of Minnesota, Minneapolis, MN, USA
| | - Chelsey J Jensen
- Solid Organ Transplant, University of Minnesota, Minneapolis, MN, USA
| | - Anne M Kouri
- Pediatric Nephrology, University of Minnesota, Minneapolis, MN, USA
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Zhao F, Wang X, Liang T, Bao D, Wang Y, Du Y, Li H, Du J, Chen A, Fu Z, Xie Z, Liang G. Effect of Hyperbaric Oxygen on Tissue Damage and Expression of Adhesion Molecules and C3 in a Rat Model of Renal Ischemia-Reperfusion Injury After Kidney Transplantation. Ann Transplant 2020; 25:e919385. [PMID: 32499475 PMCID: PMC7297207 DOI: 10.12659/aot.919385] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND The aim of this study was to investigate the protective effect and mechanism of hyperbaric oxygen (HBO) in a rat model of renal ischemia-reperfusion injury following kidney transplantation. MATERIAL AND METHODS Sprague Dawley rats were randomly divided into 3 groups (n=18): sham group, kidney transplantation group, and HBO treatment group. Six rats in each group were sacrificed at 1, 3, and 5 hours after reperfusion, and serum and renal tissue were then collected. The serum creatinine levels and histopathological changes of the renal tissue were detected. ICAM-1, VCAM-1, and C3 expression levels were also detected by immunohistochemical staining or real-time polymerase chain reaction. RESULTS Renal function was damaged in the kidney transplantation group and the HBO treatment group compared with sham group (P<0.05). Renal histopathological changes, including tubular cell swelling, tubular dilatation, and hyaline casts, were remarkably reduced in the HBO treatment group compared to the kidney transplantation group. In the immunohistochemical examination, the expression levels of ICAM-1, VCAM-1, and C3 were obviously increased in the kidney transplantation group and the HBO treatment group; moreover, the levels in the HBO treatment group were significantly lower than in the kidney transplantation group (P<0.05). In addition, the ICAM-1 and C3 mRNA levels were increased in the kidney transplantation group and HBO treatment group, but the levels of in the HBO treatment group them were significantly decreased compared to the kidney transplantation group that at 3 and 5 hours after reperfusion (P<0.05). CONCLUSIONS HBO treatment exerted a protective effect on renal function through inhibition of adhesion molecule overexpression and complement system activation in a rat model of renal ischemia-reperfusion injury after kidney transplantation.
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Affiliation(s)
- Faliang Zhao
- Medical College of Soochow University, Suzhou, Jiangsu, China (mainland).,Urological Department, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China (mainland)
| | - Xin Wang
- Urological Department, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China (mainland)
| | - Tiancai Liang
- Urological Department, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China (mainland)
| | - Dingsu Bao
- Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, China (mainland)
| | - Yuanliang Wang
- Urological Department, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China (mainland)
| | - Yang Du
- Urological Department, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China (mainland)
| | - Hao Li
- Urological Department, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China (mainland)
| | - Jiang Du
- Urological Department, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China (mainland)
| | - Anjian Chen
- Urological Department, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China (mainland)
| | - Zifeng Fu
- Urological Department, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China (mainland)
| | - Zhihui Xie
- Department of Hyperbaric Oxygen, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China (mainland)
| | - Guobiao Liang
- Medical College of Soochow University, Suzhou, Jiangsu, China (mainland).,Urological Department, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China (mainland)
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Chai YX, Ji JL, Li SJ, Cao YW, Sun XX, Wang QH, Huang T, Dong Z, Wang HY. Efficacy of anti-T-lymphocyte globulin-Fresenius as an induction agent in deceased-donor renal transplantation: A cohort study. Exp Ther Med 2020; 19:2384-2390. [PMID: 32104307 DOI: 10.3892/etm.2020.8451] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2019] [Accepted: 09/24/2019] [Indexed: 11/06/2022] Open
Abstract
Anti-T-lymphocyte globulin (ATG) is frequently used in the induction regimen of renal transplantation, but its dose has not been standardized. In the present study, the efficacy of different ATG-Fresenius (ATG-F) doses was assessed in recipients of renal transplantation. A total of 131 adult recipients of renal transplantation who received ATG-F induction between August 2015 and July 2018 were included. The incidence of biopsy-confirmed acute rejection, graft function, as well as graft and patient survival within 12 months post-transplant, was assessed, and adverse events, including hematologic and infection-associated side effects, were compared between patients receiving a cumulative ATG-F dose of <7 or ≥7 mg/kg. The incidence of biopsy-confirmed acute rejection was similar between patients receiving cumulative doses of <7 and ≥7 mg/kg (7.5 vs. 4.7%, P=0.766). The incidence of infection within 12 months was lower in the ATG-F <7 mg/kg group compared with that in the ≥7 mg/kg group (26.9 vs. 50.0%, P=0.006), but the incidence of pneumonia did not differ between the ATG-F <7 and ≥7 mg/kg groups (10.4 vs. 20.3%, P=0.117). The incidence of urinary infection was higher in the ≥7 mg/kg group than in the <7 mg/kg group (20.4 vs. 7.46%, P=0.033), while the extent and duration of anemia and lymphopenia was similar between groups. There was no difference in graft function, delayed graft function, as well as overall and graft survival between the groups. In conclusion, a moderate reduction in the cumulative ATG-F dose was not associated with an increased risk of acute rejection, while the risk of infection was reduced. Optimization of the ATG-F dose for induction may facilitate the reduction of the risk of infection without compromising the induction efficacy in renal transplant recipients.
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Affiliation(s)
- Yun-Xia Chai
- Department of Kidney Transplantation, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
| | - Jian-Lei Ji
- Department of Kidney Transplantation, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
| | - Shu-Juan Li
- Department of Kidney Transplantation, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
| | - Yan-Wei Cao
- Department of Kidney Transplantation, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
| | - Xiao-Xia Sun
- Department of Kidney Transplantation, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
| | - Qing-Hai Wang
- Department of Kidney Transplantation, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
| | - Tao Huang
- Department of Kidney Transplantation, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
| | - Zhen Dong
- Department of Kidney Transplantation, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
| | - Hong-Yang Wang
- Department of Kidney Transplantation, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
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Molina M, Guerrero-Ramos F, Fernández-Ruiz M, González E, Cabrera J, Morales E, Gutierrez E, Hernández E, Polanco N, Hernández A, Praga M, Rodriguez-Antolín A, Pamplona M, de la Rosa F, Cavero T, Chico M, Villar A, Justo I, Andrés A. Kidney transplant from uncontrolled donation after circulatory death donors maintained by nECMO has long-term outcomes comparable to standard criteria donation after brain death. Am J Transplant 2019; 19:434-447. [PMID: 29947163 DOI: 10.1111/ajt.14991] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 06/22/2018] [Accepted: 06/22/2018] [Indexed: 01/25/2023]
Abstract
Uncontrolled donation after circulatory death (uDCD) increases organ availability for kidney transplant (KT) with short-term outcomes similar to those obtained from donation after brain death (DBD) donors. However, heterogeneous results in the long term have been reported. We compared 10-year outcomes between 237 KT recipients from uDCD donors maintained by normothermic extracorporeal membrane oxygenation (nECMO) and 237 patients undergoing KT from standard criteria DBD donors during the same period at our institution. We further analyzed risk factors for death-censored graft survival in the uDCD group. Delayed graft function (DGF) was more common in the uDCD group (73.4% vs 46.4%; P < .01), although glomerular filtration rates at the end of follow-up were similar in the 2 groups. uDCD and DBD groups had similar rates for 10-year death-censored graft (82.1% vs 80.4%; P = .623) and recipient survival (86.2% vs 87.6%; P = .454). Donor age >50 years was associated with graft loss in the uDCD group (hazard ratio: 1.91; P = .058), whereas the occurrence of DGF showed no significant effect. uDCD KT under nECMO support resulted in similar graft function and long-term outcomes compared with KT from standard criteria DBD donors. Increased donor age could negatively affect graft survival after uDCD donation.
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Affiliation(s)
- María Molina
- Department of Nephrology, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (imas12), Madrid, Spain
| | - Félix Guerrero-Ramos
- Department of Urology, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (imas12), Madrid, Spain
| | - Mario Fernández-Ruiz
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (imas12), Madrid, Spain
| | - Esther González
- Department of Nephrology, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (imas12), Madrid, Spain
| | - Jimena Cabrera
- Programa de Prevención y Tratamiento de las Glomerulopatías, Centro de Nefrología, Hospital de Clínicas, Universidad de la República, Montevideo, Uruguay.,Department of Nephrology, Hospital Evangelico, Montevideo, Uruguay
| | - Enrique Morales
- Department of Nephrology, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (imas12), Madrid, Spain
| | - Eduardo Gutierrez
- Department of Nephrology, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (imas12), Madrid, Spain
| | - Eduardo Hernández
- Department of Nephrology, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (imas12), Madrid, Spain
| | - Natalia Polanco
- Department of Nephrology, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (imas12), Madrid, Spain
| | - Ana Hernández
- Department of Nephrology, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (imas12), Madrid, Spain
| | - Manuel Praga
- Department of Nephrology, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (imas12), Madrid, Spain.,School of Medicine, Universidad Complutense, Madrid, Spain
| | - Alfredo Rodriguez-Antolín
- Department of Urology, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (imas12), Madrid, Spain
| | - Manuel Pamplona
- Department of Urology, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (imas12), Madrid, Spain
| | - Federico de la Rosa
- Department of Urology, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (imas12), Madrid, Spain
| | - Teresa Cavero
- Department of Nephrology, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (imas12), Madrid, Spain
| | - Mario Chico
- Department of Intensive Care Medicine, Hospital Universitario "12 de Octubre", Madrid, Spain
| | | | - Iago Justo
- Department of Abdominal Organ Transplantation and General and Digestive Surgery, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (imas12), Madrid, Spain
| | - Amado Andrés
- Department of Nephrology, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (imas12), Madrid, Spain.,School of Medicine, Universidad Complutense, Madrid, Spain
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7
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Tacrolimus and Single Intraoperative High-dose of Anti-T-lymphocyte Globulins Versus Tacrolimus Monotherapy in Adult Liver Transplantation. Ann Surg 2018; 268:776-783. [PMID: 30307410 DOI: 10.1097/sla.0000000000002943] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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8
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Does Rabbit Antithymocyte Globulin (Thymoglobuline®) Have a Role in Avoiding Delayed Graft Function in the Modern Era of Kidney Transplantation? J Transplant 2018; 2018:4524837. [PMID: 30112193 PMCID: PMC6077603 DOI: 10.1155/2018/4524837] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 06/20/2018] [Indexed: 12/16/2022] Open
Abstract
Delayed graft function (DGF) increases the risk of graft loss by up to 40%, and recent developments in kidney donation have increased the risk of its occurrence. Lowering the risk of DGF, however, is challenging due to a complicated etiology in which ischemia-reperfusion injury (IRI) leads to acute tubular necrosis. Among various strategies explored, the choice of induction therapy is one consideration. Rabbit antithymocyte globulin (rATG [Thymoglobuline]) has complex immunomodulatory effects that are relevant to DGF. In addition to a rapid and profound T-cell depletion, rATG inhibits leukocyte migration and adhesion. Experimental studies of rATG have demonstrated attenuated IRI-related tissue damage in reperfused tissues, consistent with histological evidence from transplant recipients. Starting rATG intraoperatively instead of postoperatively can improve kidney graft function and reduce the incidence of DGF. rATG is effective in preventing acute rejection in kidney transplant recipients at high immunological risk, supporting delayed calcineurin inhibitor (CNI) introduction which protects the graft from early insults. A reduced rate of DGF has been reported with rATG (started intraoperatively) and delayed CNI therapy compared to IL-2RA induction with immediate CNI in patients at high immunological risk, but not in lower-risk patients. Overall, induction with rATG induction is the preferred choice for supporting delayed introduction of CNI therapy to avoid DGF in high-risk patients but shows no benefit versus IL-2RA in lower-risk individuals. Evidence is growing that intraoperative rATG ameliorates IRI, and it seems reasonable to routinely start rATG before reperfusion.
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Cillo U, Bechstein WO, Berlakovich G, Dutkowski P, Lehner F, Nadalin S, Saliba F, Schlitt HJ, Pratschke J. Identifying risk profiles in liver transplant candidates and implications for induction immunosuppression. Transplant Rev (Orlando) 2018; 32:142-150. [DOI: 10.1016/j.trre.2018.04.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 04/03/2018] [Accepted: 04/05/2018] [Indexed: 12/16/2022]
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Cheng R, Kransdorf EP, Wei J, Patel JK, Kobashigawa JA, Azarbal B. Angiogenesis on coronary angiography is a marker for accelerated cardiac allograft vasculopathy as assessed by intravascular ultrasound. Clin Transplant 2017; 31. [PMID: 28786501 DOI: 10.1111/ctr.13069] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/01/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND Errant neovascularization and coronary artery fistulae (CAF) are frequently observed after cardiac transplantation. The relationship between angiographic neovascularization/CAF and coronary plaque progression is unknown. METHODS Angiography and intravascular ultrasound were routinely performed at 4-6 weeks and 1-year post-transplant. Pts were divided into three groups: no angiographic angiogenesis (Group 1), neovascularization only (Group 2), and CAF (Group 3). First-year changes in maximal intimal thickness (MIT), maximal intimal area (MIA), and percent atheroma volume (PAV) were compared between groups. RESULTS The 106 pts were included, 40/106 in Group 1, 42/106 in Group 2, and 24/106 in Group 3. Respectively, first-year ΔMIT was 0.14 ± 0.13 mm, 0.32 ± 0.26 mm, and 0.50 ± 0.34 mm, P < .001. ΔMIA was 0.6 ± 0.6 mm2 , 1.7 ± 1.8 mm2 , and 3.0 ± 2.6 mm2 , P < .001. ΔPAV was 2.3 ± 2.5%, 6.0 ± 5.1%, and 9.6 ± 9.0%, P < .001. Rapid plaque progression occurred in 1/40 (2.5%) pts in Group 1, 12/42 (28.6%) in Group 2, and 12/24 (50%) in Group 3, P < .001. Multivariate analysis identified both antithymocyte globulin and presence of CAF as independently associated with rapid plaque progression: OR 0.29 (P = .038) and 4.04 (P = .014). CONCLUSION Neovascularization and CAF are commonly present on surveillance angiography after cardiac transplantation and may signify amplified angiogenesis. Their presence is associated with accelerated coronary plaque progression by IVUS.
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Affiliation(s)
| | | | - Janet Wei
- Cedars-Sinai Heart Institute, Los Angeles, CA, USA
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11
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Ruan V, Czer LSC, Awad M, Kittleson M, Patel J, Arabia F, Esmailian F, Ramzy D, Chung J, De Robertis M, Trento A, Kobashigawa JA. Use of Anti-Thymocyte Globulin for Induction Therapy in Cardiac Transplantation: A Review. Transplant Proc 2017; 49:253-259. [PMID: 28219580 DOI: 10.1016/j.transproceed.2016.11.034] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 11/16/2016] [Indexed: 01/20/2023]
Abstract
The most common causes of death after heart transplantation (HTx) include acute rejection and multi-organ failure in the early period and malignancy and cardiac allograft vasculopathy (CAV) in the late period. Polyclonal antibody preparations such as rabbit anti-thymocyte globulin (ATG) may reduce early acute rejection and the later occurrence of CAV after HTx. ATG therapy depletes T cells, modulates adhesion and cell-signaling molecules, interferes with dendritic cell function, and induces B-cell apoptosis and regulatory and natural killer T-cell expansion. Evidence from animal studies and from retrospective clinical studies in humans indicates that ATG can be used to delay calcineurin inhibitor (CNI) exposure after HTx, thus benefiting renal function, and to reduce the incidence of CAV and ischemia-reperfusion injury in the transplanted heart. ATG may reduce de novo antibody production after HTx. ATG does not appear to increase cytomegalovirus infection rates with longer prophylaxis (6-12 months). In addition, ATG may reduce the risk of lymphoproliferative disease and does not appear to confer an additive effect on acquiring lymphoma after HTx. Randomized, controlled trials may provide stronger evidence of ATG association with patient survival, graft rejection, renal protection through delayed CNI initiation, as well as other benefits. It can also help establish optimal dosing and patient criteria to maximize treatment benefits.
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Affiliation(s)
- V Ruan
- Division of Cardiology, Cedars-Sinai Medical Center, and Cedars-Sinai Heart Institute, Los Angeles, California
| | - L S C Czer
- Division of Cardiology, Cedars-Sinai Medical Center, and Cedars-Sinai Heart Institute, Los Angeles, California.
| | - M Awad
- Division of Cardiology, Cedars-Sinai Medical Center, and Cedars-Sinai Heart Institute, Los Angeles, California
| | - M Kittleson
- Division of Cardiology, Cedars-Sinai Medical Center, and Cedars-Sinai Heart Institute, Los Angeles, California
| | - J Patel
- Division of Cardiology, Cedars-Sinai Medical Center, and Cedars-Sinai Heart Institute, Los Angeles, California
| | - F Arabia
- Division of Cardiothoracic Surgery, Cedars-Sinai Medical Center, and Cedars-Sinai Heart Institute, Los Angeles, California
| | - F Esmailian
- Division of Cardiothoracic Surgery, Cedars-Sinai Medical Center, and Cedars-Sinai Heart Institute, Los Angeles, California
| | - D Ramzy
- Division of Cardiothoracic Surgery, Cedars-Sinai Medical Center, and Cedars-Sinai Heart Institute, Los Angeles, California
| | - J Chung
- Division of Cardiothoracic Surgery, Cedars-Sinai Medical Center, and Cedars-Sinai Heart Institute, Los Angeles, California
| | - M De Robertis
- Division of Cardiothoracic Surgery, Cedars-Sinai Medical Center, and Cedars-Sinai Heart Institute, Los Angeles, California
| | - A Trento
- Division of Cardiothoracic Surgery, Cedars-Sinai Medical Center, and Cedars-Sinai Heart Institute, Los Angeles, California
| | - J A Kobashigawa
- Division of Cardiology, Cedars-Sinai Medical Center, and Cedars-Sinai Heart Institute, Los Angeles, California
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Yeung MY, Gabardi S, Sayegh MH. Use of polyclonal/monoclonal antibody therapies in transplantation. Expert Opin Biol Ther 2017; 17:339-352. [PMID: 28092486 DOI: 10.1080/14712598.2017.1283400] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION For over thirty years, antibody (mAb)-based therapies have been a standard component of transplant immunosuppression, and yet much remains to be learned in order for us to truly harness their therapeutic capabilities. Current mAbs used in transplant directly target and destroy graft-destructive immune cells, interrupt cytokine and costimulation-dependent T and B cell activation, and prevent down-stream complement activation. Areas covered: This review summarizes our current approaches to using antibody-based therapies to prevent and treat allograft rejection. It also provides examples of promising novel mAb therapies, and discusses the potential for future mAb development in transplantation. Expert opinion: The broad capability of antibodies, in parallel with our growing ability to synthetically modulate them, offers exciting opportunities to develop better biologic therapeutics. In order to do so, we must further our understanding about the basic biology underlying allograft rejection, and gain better appreciation of how characteristics of therapeutic antibodies affect their efficacy.
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Affiliation(s)
- Melissa Y Yeung
- a Transplantation Research Center, Renal Division , Brigham and Women's Hospital, Harvard Medical School , Boston , Massachusetts , United States
| | - Steven Gabardi
- a Transplantation Research Center, Renal Division , Brigham and Women's Hospital, Harvard Medical School , Boston , Massachusetts , United States
| | - Mohamed H Sayegh
- a Transplantation Research Center, Renal Division , Brigham and Women's Hospital, Harvard Medical School , Boston , Massachusetts , United States.,b Faculty of Medicine, Professor of Medicine and Immunology , American University of Beirut , Beirut , Lebanon
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13
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Jurenec F, Mihovilović K, Špiranec K, Sinđić A, Knotek M. In Vitro Effects of Thymoglobulin in Human Embryonic Kidney Cell Line (HEK293) in Culture. Transplant Proc 2016; 48:2840-2844. [PMID: 27788827 DOI: 10.1016/j.transproceed.2016.07.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Revised: 06/23/2016] [Accepted: 07/05/2016] [Indexed: 11/15/2022]
Abstract
BACKGROUND Anti-thymocyte globulins are polyclonal T-cell-depleting immunoglobulins used in induction of immunosuppression in kidney transplant recipients. Thymoglobulin is purified rabbit immunoglobulin (Ig)G, obtained by immunization of rabbits with fetal human thymus, which depletes T lymphocytes by complement-dependent lysis and apoptosis, reduces production of cytokines, and decreases expression of adhesion molecules in endothelial cells. METHODS To determine possible direct effects of Thymoglobulin on kidney cells during transplantation, we used the Human Embryonic Kidney cell line (HEK293) in culture. We measured membrane potential of the cells by use of the slow whole patch-clamp technique. We determined effects of Thymoglobulin on cell death and proliferation during hypoxia/re-oxygenation injury, using a hypoxic chamber. RESULTS Depolarizations of HEK293 cells caused by Thymoglobulin were concentration-dependent and membrane potential-dependent, showing direct effects of Thymoglobulin on the HEK293 cells, whereas rabbit anti-thymocyte globulin produced against Jurkat cells (ATG-F) and normal rabbit IgG had no effects. To determine the effects of Thymoglobulin in hypoxia/re-oxygenation conditions, cells were incubated for 24 hours with Thymoglobulin in an atmosphere with 5% CO2-95% N2 at 37°C followed by 1 hour in atmosphere with 5% CO2-95% air at 37°C. The effects of hypoxia/re-oxygenation were detected by calculating cell death and determining the cell growth, using scratch test. CONCLUSIONS Thymoglobulin prevented the cell death induced by hypoxia and re-oxygenation conditions. In addition, it accelerated the cell growth (improved scratch wound-healing). This is the first study to show the direct effects of Thymoglobulin on kidney-derived epithelial cells, which may lead to better understanding of its effects in kidney transplantation.
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Affiliation(s)
- F Jurenec
- Department of Urology, University Hospital Merkur, Zagreb, Croatia
| | - K Mihovilović
- Department of Medicine, University Hospital Merkur, Zagreb, Croatia
| | - K Špiranec
- Department of Anatomy, Histology, and Embryology, Faculty of Veterinary Medicine, University of Zagreb, Zagreb, Croatia
| | - A Sinđić
- Croatian Institute for Brain Research, Department of Physiology and Immunology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - M Knotek
- Renal Division, Department of Medicine, University Hospital Merkur and School of Medicine, Zagreb, Croatia.
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Kremer J, Muschitz GK, Aumayr K, Moser P, Szabo G, Weymann A, Zuckermann A, Podesser BK. Influence of antithymocyte globulin treatment of brain-dead organ donor on inflammatory response in cardiac grafts: an experimental study in mice. Transpl Int 2016; 29:1329-1336. [PMID: 27571572 DOI: 10.1111/tri.12851] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 05/05/2016] [Accepted: 08/25/2016] [Indexed: 11/27/2022]
Abstract
The expression of proinflammatory cytokines in donor hearts after antithymocyte globulin (ATG) treatment given prior to organ removal was evaluated to analyze changes in inflammatory response. Adult female OF-1 mice were randomized into brain death (BD) groups (BD Control, BD ATG) with or without treatment, and Controls (Control, ATG). BD induction was performed through gradual inflation of an intracranial positioned balloon catheter. At the end of a 6-h observation period, ATG (1 mg/kg BW) was given intravenously. After 45 min, the donor hearts were removed. Proinflammatory markers IL-2 and IL-6 were examined using ELISA and immunohistochemistry staining. After single administration of ATG, the inflammatory reaction in the myocardium showed a significant reduction in IL-2 expression (BD Control vs. BD ATG, P = 0.033). Our investigation showed expected increase in proinflammatory mediators after BD. This increase was abolished by single infusion of ATG, indicated by significant reduction in IL-2 levels in the myocardium. We observed a reduction of IL-6 deposition in media cells in ATG-treated specimens. Further research is necessary to evaluate the role of ATG in donor management considering a potentially positive effect of ATG on IL-2-directed inflammatory response and possible reduction of IL-6-mediated vascular changes.
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Affiliation(s)
- Jamila Kremer
- Department of Cardiac Surgery, Heart and Marfan Center, University of Heidelberg, Heidelberg, Germany.,Ludwig Boltzmann Cluster for Cardiovascular Research, Core Unit for Biomedical Research, Medical University Vienna, Vienna, Austria
| | - Gabriela K Muschitz
- Ludwig Boltzmann Cluster for Cardiovascular Research, Core Unit for Biomedical Research, Medical University Vienna, Vienna, Austria.,Division of Plastic and Reconstructive Surgery, Department of Surgery, Medical University Vienna, Vienna, Austria
| | - Klaus Aumayr
- Department of Clinical Pathology, Medical University Vienna, Vienna, Austria
| | - Philipp Moser
- Ludwig Boltzmann Cluster for Cardiovascular Research, Core Unit for Biomedical Research, Medical University Vienna, Vienna, Austria.,Center of Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Gabor Szabo
- Department of Cardiac Surgery, Heart and Marfan Center, University of Heidelberg, Heidelberg, Germany
| | - Alexander Weymann
- Department of Cardiac Surgery, Heart and Marfan Center, University of Heidelberg, Heidelberg, Germany
| | - Andreas Zuckermann
- Division of Cardiac Surgery, Department of Surgery, Medical University Vienna, Vienna, Austria
| | - Bruno K Podesser
- Ludwig Boltzmann Cluster for Cardiovascular Research, Core Unit for Biomedical Research, Medical University Vienna, Vienna, Austria
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Cytomegalovirus Infection After Intestinal/Multivisceral Transplantation: A Single-Center Experience With 210 Cases. Transplantation 2016; 100:451-60. [PMID: 26247555 DOI: 10.1097/tp.0000000000000832] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Cytomegalovirus (CMV) infection is the most prevalent infectious complication after solid organ transplantation, and recipients of isolated intestinal transplantation (IIT)/multivisceral transplantation (MVT) are among those at the highest risk. Limited clinical data exist regarding CMV infection after IIT/MVT. The aim of this study is to analyze risk factors for posttransplant CMV infection and to assess the efficacy and validity of our prophylaxis and treatment regimens in intestinal transplantation. METHODS Medical records of 210 IIT/MVT patients were retrospectively reviewed. Posttransplant CMV prophylaxis regimen consisted of ganciclovir followed by 1 year of valganciclovir. The addition of CMV immunoglobulin (CMVIG) was decided according to donor/recipient CMV serostatus (D/R). All results of CMV PCR and/or pp65 antigenemia, and pathological reports were reviewed. Time to the incidence of CMV infection (viremia and/or tissue invasive disease) and risk factors for CMV infection were investigated. RESULTS CMV infection was observed in 34 of 210 (16%) with a median onset of 347 days. Rejection was significantly associated with CMV infection (P = 0.01, odds ratio = 2.61). In the high-risk serostatus group (D+/R-), prophylactic CMVIG and induction with high-dose rabbit antithymocyte globulin (>10 mg/kg) were associated with a lower CMV infection rate on univariate analysis. The CMVIG remained to be an independent factor on multivariate analysis (P = 0.04, hazard ratio = 0.93/dose). Mortality associated with CMV infection occurred in 4, and CMV infection adversely affected patient survival (P = 0.001, hazard ratio = 2.71). CONCLUSIONS Prophylaxis with CMVIG and appropriate induction with rabbit antithymocyte globulin may be important to reduce CMV infection in high-risk serostatus group (D+/R-).
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Does Delayed Graft Function Still Herald a Poorer Outcome in Kidney Transplantation? CURRENT TRANSPLANTATION REPORTS 2016. [DOI: 10.1007/s40472-016-0110-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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17
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Azarbal B, Cheng R, Vanichsarn C, Patel JK, Czer LS, Chang DH, Kittleson MM, Kobashigawa JA. Induction Therapy With Antithymocyte Globulin in Patients Undergoing Cardiac Transplantation Is Associated With Decreased Coronary Plaque Progression as Assessed by Intravascular Ultrasound. Circ Heart Fail 2016; 9:e002252. [PMID: 26747860 DOI: 10.1161/circheartfailure.115.002252] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Antithymocyte globulin (ATG) is used as induction therapy after cardiac transplant for enhancing immunosuppression and delaying the initiation of nephrotoxic drugs. It is unknown if ATG induction is associated with decreased coronary plaque progression by intravascular ultrasound (IVUS). METHODS AND RESULTS Patients transplanted between March 2010 and December 2012 with baseline and 1-year IVUS were included. All patients transplanted were included in a secondary analysis. Change in plaque progression was measured in a blinded fashion on matched coronary segments and contrasted between patients induced with ATG and those who were not. One hundred and three patients were included in IVUS arms. Mean age at transplant was 55.8 ± 12.6 years, and 33.0% were female. Patients induced with ATG were more sensitized (54.3% versus 14.3%). Plaque progression was attenuated in patients who received ATG by changes in maximal intimal area (1.0 ± 1.2 versus 2.3 ± 2.6 mm(2); P = 0.001), maximal percent stenosis (6.3 ± 7.9 versus 12.8 ± 12.3%; = 0.003), maximal intimal thickness (0.2 ± 0.2 versus 0.3 ± 0.3 mm; P = 0.035), and plaque volume (0.5 ± 0.7 versus 1.0 ± 1.3 mm(3)/mm; P = 0.016). Rapid plaque progression by maximal percent stenosis (≥ 20%) occurred less frequently in the ATG arm (4.3% versus 26.3; P = 0.003). Survival (P = 0.242) and any treated rejection (P = 0.166) were not statistically different between groups. Patients receiving ATG had a higher rate of first-year infection (P = 0.003), perhaps related to increased intravenous antibiotic use immediately postoperatively, and a trend toward more biopsy-proven rejection (P = 0.073). CONCLUSIONS Induction therapy with ATG is associated with reduced first-year coronary plaque progression as assessed by IVUS, despite an increased prevalence of sensitized patients with a trend toward more rejection.
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Affiliation(s)
- Babak Azarbal
- From the Cedars-Sinai Heart Institute, Los Angeles, CA.
| | - Richard Cheng
- From the Cedars-Sinai Heart Institute, Los Angeles, CA
| | | | | | | | - David H Chang
- From the Cedars-Sinai Heart Institute, Los Angeles, CA
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van Heurn LWE, Talbot D, Nicholson ML, Akhtar MZ, Sanchez-Fructuoso AI, Weekers L, Barrou B. Recommendations for donation after circulatory death kidney transplantation in Europe. Transpl Int 2015; 29:780-9. [PMID: 26340168 DOI: 10.1111/tri.12682] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Revised: 06/19/2015] [Accepted: 08/26/2015] [Indexed: 12/29/2022]
Abstract
Donation after circulatory death (DCD) donors provides an invaluable source for kidneys for transplantation. Over the last decade, we have observed a substantial increase in the number of DCD kidneys, particularly within Europe. We provide an overview of risk factors associated with DCD kidney function and survival and formulate recommendations from the sixth international conference on organ donation in Paris, for best-practice guidelines. A systematic review of the literature was performed using Ovid Medline, Embase and Cochrane databases. Topics are discussed, including donor selection, organ procurement, organ preservation, recipient selection and transplant management.
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Affiliation(s)
| | - David Talbot
- Department of Liver/Renal Transplant, Freeman Hospital, Newcastle Upon Tyne, UK
| | - Michael L Nicholson
- Department of Surgery, NIHR Cambridge Biomedical Research Centre, Cambridge, UK
| | | | | | - Laurent Weekers
- Department of Nephrology-Dialysis-Transplantation, University of Liège, CHU Sart Tilman, Liège, Belgium
| | - Benoit Barrou
- Department of Urology - Transplantation, GHzu Pitié Salpêtriere, Paris, France
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Werner I, Seitz-Merwald I, Kiessling AH, Kur F, Beiras-Fernandez A. ATG-Fresenius inhibits blood circulating cell proliferation in a dose-dependent manner: an experimental study. Transplant Proc 2015; 46:3000-3. [PMID: 25420810 DOI: 10.1016/j.transproceed.2014.07.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
INTRODUCTION Antithymocyte globulin (ATG)-Fresenius (Neovii-Biotech, Graefelfing, Germany), a highly purified rabbit polyclonal antihuman T-lymphocyte immunoglobulin resulting from immunization of rabbits with the Jurkat T-lymphoblast cell line, is currently used for the prevention of acute rejection in patients receiving solid organ transplants. Our aim was to investigate the in vitro activity of ATG-Fresenius regarding the proliferation of peripheral blood mononuclear cells (PBMCs), an important mechanism of rejection after solid organ transplantation. METHODS PBMCs were isolated from 6 healthy donors. Proliferation was assayed using [(3)H] thymidine incorporation. For analysis of mitogen-stimulated proliferation, the PBMCs were incubated at 37°C with various concentrations of ATG-Fresenius in the absence/presence of 40 μg/mL phytohemagglutinin. For analysis of the mixed lymphocyte reaction, PBMCs were incubated at 37°C with various concentrations of ATG-Fresenius for 3 days. On day 3, PBMCs (stimulator cells) from allogeneic donors were incubated with 25 μg/mL mitomycin C. The responder cells (preincubated with ATG-Fresenius) were then cultured at 37°C with the stimulator cells for 6 days. Groups were compared using ANOVA and the Tukey-Kramer multiple comparison test. RESULTS Preincubation of PBMCs with ATG results in concentration-dependent inhibition of phytohemagglutinin-stimulated proliferation. The effect was more pronounced after 2 and 3 days of treatment with ATG compared with 1 day. There was a concentration-dependent decrease in the mixed lymphocyte reaction-induced proliferation (up to 80%) at ATG-Fresenius concentrations as low as 0.05 to 0.5 μg/mL. No further effect on proliferation at ATG-Fresenius concentrations of 0.5 to 50 μg/mL was seen, and higher concentrations (>100 μg/mL) totally inhibited proliferation. CONCLUSIONS Our in vitro results provide more evidence of the beneficial effect of ATGs in the early phase of solid organ transplantation, by reducing effector cell proliferation.
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Affiliation(s)
- I Werner
- Department of Thoracic and Cardiovascular Surgery, University Hospital Frankfurt, Goethe University, Frankfurt/Main, Germany
| | | | - A H Kiessling
- Department of Thoracic and Cardiovascular Surgery, University Hospital Frankfurt, Goethe University, Frankfurt/Main, Germany
| | - F Kur
- Department of Cardiac Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - A Beiras-Fernandez
- Department of Thoracic and Cardiovascular Surgery, University Hospital Frankfurt, Goethe University, Frankfurt/Main, Germany.
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Salvadori M, Rosso G, Bertoni E. Update on ischemia-reperfusion injury in kidney transplantation: Pathogenesis and treatment. World J Transplant 2015; 5:52-67. [PMID: 26131407 PMCID: PMC4478600 DOI: 10.5500/wjt.v5.i2.52] [Citation(s) in RCA: 259] [Impact Index Per Article: 25.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Revised: 01/12/2015] [Accepted: 04/29/2015] [Indexed: 02/05/2023] Open
Abstract
Ischemia/reperfusion injury is an unavoidable relevant consequence after kidney transplantation and influences short term as well as long-term graft outcome. Clinically ischemia/reperfusion injury is associated with delayed graft function, graft rejection, chronic rejection and chronic graft dysfunction. Ischemia/reperfusion affects many regulatory systems at the cellular level as well as in the renal tissue that result in a distinct inflammatory reaction of the kidney graft. Underlying factors of ischemia reperfusion include energy metabolism, cellular changes of the mitochondria and cellular membranes, initiation of different forms of cell death-like apoptosis and necrosis together with a recently discovered mixed form termed necroptosis. Chemokines and cytokines together with other factors promote the inflammatory response leading to activation of the innate immune system as well as the adaptive immune system. If the inflammatory reaction continues within the graft tissue, a progressive interstitial fibrosis develops that impacts long-term graft outcome. It is of particular importance in kidney transplantation to understand the underlying mechanisms and effects of ischemia/reperfusion on the graft as this knowledge also opens strategies to prevent or treat ischemia/reperfusion injury after transplantation in order to improve graft outcome.
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Mohty M, Bacigalupo A, Saliba F, Zuckermann A, Morelon E, Lebranchu Y. New directions for rabbit antithymocyte globulin (Thymoglobulin(®)) in solid organ transplants, stem cell transplants and autoimmunity. Drugs 2015; 74:1605-34. [PMID: 25164240 PMCID: PMC4180909 DOI: 10.1007/s40265-014-0277-6] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In the 30 years since the rabbit antithymocyte globulin (rATG) Thymoglobulin® was first licensed, its use in solid organ transplantation and hematology has expanded progressively. Although the evidence base is incomplete, specific roles for rATG in organ transplant recipients using contemporary dosing strategies are now relatively well-identified. The addition of rATG induction to a standard triple or dual regimen reduces acute cellular rejection, and possibly humoral rejection. It is an appropriate first choice in patients with moderate or high immunological risk, and may be used in low-risk patients receiving a calcineurin inhibitor (CNI)-sparing regimen from time of transplant, or if early steroid withdrawal is planned. Kidney transplant patients at risk of delayed graft function may also benefit from the use of rATG to facilitate delayed CNI introduction. In hematopoietic stem cell transplantation, rATG has become an important component of conventional myeloablative conditioning regimens, following demonstration of reduced acute and chronic graft-versus-host disease. More recently, a role for rATG has also been established in reduced-intensity conditioning regimens. In autoimmunity, rATG contributes to the treatment of severe aplastic anemia, and has been incorporated in autograft projects for the management of conditions such as multiple sclerosis, Crohn’s disease, and systemic sclerosis. Finally, research is underway for the induction of tolerance exploiting the ability of rATG to induce immunosuppresive cells such as regulatory T-cells. Despite its long history, rATG remains a key component of the immunosuppressive armamentarium, and its complex immunological properties indicate that its use will expand to a wider range of disease conditions in the future.
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Affiliation(s)
- Mohamad Mohty
- Department of Hematology and Cellular Therapy, CHU Hôpital Saint Antoine, 184, rue du Faubourg Saint Antoine, 75571, Paris Cedex 12, France,
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Chen GD, Lai XQ, Ko DSC, Qiu J, Wang CX, Han M, Li J, Huang G, He XS, Chen LZ. Comparison of efficacy and safety between rabbit anti-thymocyte globulin and anti-T lymphocyte globulin in kidney transplantation from donation after cardiac death: a retrospective cohort study. Nephrology (Carlton) 2015; 20:539-43. [PMID: 25808082 DOI: 10.1111/nep.12469] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/19/2015] [Indexed: 12/01/2022]
Abstract
AIM To compare the efficacy and safety between rabbit anti-thymocyte globulin (Thymoglobulin) and anti-T lymphocyte globulin (ATG-Fresenius, ATG-F) in donation after cardiac death (DCD) kidney transplantation. METHODS We retrospectively analyzed 255 cases of DCD kidney transplantation performed at our hospital from February 2007 to October 2013. The patients were divided into two groups based on their induction therapies with Thymoglobulin (n = 188) or ATG-F (n = 67). Clinical data were collected and compared between the two groups. RESULTS Delayed graft function (DGF) occurred in 36 (19.1%) patients in the Thymoglobulin group versus 17 (25.4%) patients in the ATG-F group (P = 0.281). However, if we subgroup the patients with increased risk factors for DGF, the DGF rate was 9/40 (22.5%) in the Thymoglobulin group versus 9/16 (56.3%) in the ATG-F group (P = 0.015). Duration of DGF was significantly shorter in the Thymoglobulin group (11.7 days vs. 16.1 days). The acute rejection rate was significantly lower in the Thymoglobulin group (9.6% vs. 19.4%, P = 0.035). One-year graft and patient survival were both comparable between the Thymoglobulin and ATG-F groups. The adjusted odds ratio of DGF was 4.283 (1.137-16.13) between the ATG-F and Thymoglobulin groups in patients with increased risk factors for DGF. CONCLUSION Compared with ATG-F, Thymoglobulin may reduce duration of DGF and acute rejection rate after DCD kidney transplantation. Moreover, Thymoglobulin significantly reduced DGF in patients with increased risk factors for DGF.
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Affiliation(s)
- Guo-Dong Chen
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Xing-Qiang Lai
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Dicken Shiu-Chung Ko
- Departments of Urology and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Jiang Qiu
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Chang-Xi Wang
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Ming Han
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Jun Li
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Gang Huang
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Xiao-Shun He
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Li-Zhong Chen
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
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Zhang CB, Tang YC, Xu XJ, Guo SX, Wang HZ. Hydrogen gas inhalation protects against liver ischemia/reperfusion injury by activating the NF-κB signaling pathway. Exp Ther Med 2015; 9:2114-2120. [PMID: 26136944 DOI: 10.3892/etm.2015.2385] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2013] [Accepted: 05/30/2014] [Indexed: 11/05/2022] Open
Abstract
Hydrogen has been demonstrated to function as a novel antioxidant and exert therapeutic antioxidant activity in a number of diseases. The present study was designed to investigate the effect of hydrogen inhalation on liver ischemia/reperfusion (I/R) injury in rats. The portal triad to the left lobe and the left middle lobe of the liver were completely occluded for 90 min. This was followed by reperfusion for 180 min. The rats subsequently underwent syngeneic orthotopic liver transplantation. Inhalation of various concentrations (1, 2 and 3%) of hydrogen gas and its administration for different durations (1, 3 and 6 h) immediately prior to the I/R injury allowed the optimal dose and duration of administration to be determined. Liver injury was evaluated through biochemical and histopathological examinations. The expression levels of proinflammatory cytokines, including tumor necrosis factor (TNF)-α and interleukin (IL)-6, were measured by enzyme-linked immunosorbent assay and quantitative polymerase chain reaction (qPCR). Liver nuclear factor κB (NF-κB) was detected by qPCR and western blot analysis. Inhalation of hydrogen gas at 2% concentration for 1 h significantly reduced the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, the expression of cytokines, including IL-6, TNF-α, early growth response protein 1 (Egr-1) and IL-1β, and morphological damage. In addition, the mRNA and protein expression levels of NF-κB, heme oxygenase-1 (HO-1), B-cell lymphoma 2 (Bcl-2) and zinc finger protein A20 (A20) in rats where only the donors received hydrogen were significantly increased compared with those in rats where both the donor and recipient, or only the recipient received hydrogen. The results indicate that hydrogen inhalation at 2% concentration for 1 h prior to liver transplantation protected the rats from ischemia/reperfusion injury by activation of the NF-κB signaling pathway.
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Affiliation(s)
- Chao-Bin Zhang
- Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China
| | - Yi-Chen Tang
- Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China
| | - Xue-Jun Xu
- Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China
| | - Shi-Xiang Guo
- Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China
| | - Huai-Zhi Wang
- Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China
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Halldorson JB, Bakthavatsalam R, Montenovo M, Dick A, Rayhill S, Perkins J, Reyes J. Differential rates of ischemic cholangiopathy and graft survival associated with induction therapy in DCD liver transplantation. Am J Transplant 2015; 15:251-8. [PMID: 25534449 DOI: 10.1111/ajt.12962] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2014] [Revised: 07/09/2014] [Accepted: 08/04/2014] [Indexed: 01/25/2023]
Abstract
Transplantation utilizing donation after circulatory death (DCD) donors is associated with ischemic cholangiopathy (IC) and graft loss. The University of Washington (UW) DCD experience totals 89 DCD liver transplants performed between 2003 and 2011. Overall outcome after DCD liver transplantation at UW demonstrates Kaplan-Meier estimated 5-year patient and graft survival rates of 81.6% and 75.6%, respectively, with the great majority of patient and graft losses occurring in the first-year posttransplant from IC. Our program has almost exclusively utilized either anti-thymocyte globulin (ATG) or basiliximab induction (86/89) for DCD liver transplantations. Analysis of the differential effect of induction agent on graft survival demonstrated graft survival of 96.9% at 1 year for ATG versus 75.9% for basiliximab (p = 0.013). The improved survival did not appear to be from a lower rate of rejection (21.9% vs. 22.2%) but rather a differential rate of IC, 35.2% for basiliximab versus 12.5% for ATG (p = 0.011). Multivariable analysis demonstrated induction agent to be independently associated with graft survival and IC free graft survival when analyzed against variables including donor age, fWIT, donor cold ischemia time and transplant era.
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Affiliation(s)
- J B Halldorson
- Division of Transplantation, University of California, San Diego, CA
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25
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Rafiei M, Kittleson M, Patel J, Osborne A, Chang D, Czer L, Reinsmoen N, Esmailian F, Kobashigawa J. Anti-Thymocyte Gamma-Globulin May Prevent Antibody Production After Heart Transplantation. Transplant Proc 2014; 46:3570-4. [DOI: 10.1016/j.transproceed.2014.08.042] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Accepted: 08/19/2014] [Indexed: 10/24/2022]
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Outcome and cost analysis of induction immunosuppression with IL2Mab or ATG in DCD kidney transplants. Transplantation 2014; 97:1161-5. [PMID: 24573113 DOI: 10.1097/01.tp.0000442505.10490.20] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Kidney transplantation from DCD now represents a significant part of the overall transplant activity in the UK. Outcome of different induction immunosuppression regimes and related cost benefit analysis has been reported by very few studies.This is a single centre study on frequency-matched patients who received a DCD kidney transplant between August 2007 and August 2009. METHODS Data on 45 patients divided in 2 groups were collected prospectively and analyzed retrospectively. Group A (24 patients) received IL2Mab and Group B (21 patients) ATG as induction immunosuppression. Patient and graft survival were similar in both groups. RESULTS In the ATG-induced group, there was a significant lower rate of DGF, BPAR, and infections requiring readmission.A cost analysis was performed including all immunosuppression-related costs, and it has shown remarkable savings in the ATG-induced group. CONCLUSION Considering that the number of DCD kidney transplants is destined to rise in the UK, we believe that ATG is a valid option to continue optimizing outcomes of DCD kidney transplant. In our experience, ATG proved to be safe, effective, and contributed to significant cost savings.
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Harrison JJ, Hamandi B, Li Y, Famure O, Kim SJ. Timing of rabbit antithymocyte globulin induction therapy in kidney transplantation: an observational cohort study. Transplant Res 2014; 3:1. [PMID: 24387192 PMCID: PMC3882095 DOI: 10.1186/2047-1440-3-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2013] [Accepted: 12/23/2013] [Indexed: 12/28/2022] Open
Abstract
Background Literature on the timing of rabbit antithymocyte globulin (rATG) induction and its effects on kidney transplant outcomes is limited. The manufacturer recommends that the first dose be given intra-operatively, however this may present clinical practice risks and challenges. Our objective was to assess the impact of the timing of the first dose of rATG on kidney transplant outcomes. Methods Incident kidney transplant recipients (KTR) from January 2002 to December 2009 receiving the first dose of rATG post-operatively (Post, n = 353) or before reperfusion (Pre, n = 124) were evaluated. Outcomes assessed included eGFR at 1-year, delta eGFR (12 versus 1 month), and incidence of biopsy-proven acute rejection, graft loss, death, and a composite of the time-to-event outcomes. The impact of timing on outcomes was adjusted for potential confounders and assessed using linear and Cox regression models. Results Among 435 KTR surviving with function to 12 months post-transplant, there was no significant difference in mean estimated glomerular filtration rate or eGFR (55.0 versus 56.7 mL/min, P = 0.46) and delta eGFR (1.8 versus 0.3 mL/min, P = 0.40) in Post versus Pre groups, respectively. At a median follow-up of 3 years, the composite endpoint (time to first biopsy-proven acute rejection, graft loss, or death) was similar by timing group (adjusted HR = 0.94; 95% CI: 0.58, 1.53, P = 0.81) in the total study population. Conclusions Timing of rATG had no appreciable impact on clinically relevant endpoints in this study cohort. These results support consideration of more flexible timing of the first dose of rATG induction in KTR.
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Affiliation(s)
| | | | | | | | - S Joseph Kim
- Division of Nephrology and the Kidney Transplant Program, Toronto General Hospital University Health Network 585 University Avenue, 11C-1183, M5G 2 N2 Toronto, Ontario, Canada.
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Nagai S, Yoshida A, Kohno K, Altshuler D, Nakamura M, Brown KA, Abouljoud MS, Moonka D. Peritransplant absolute lymphocyte count as a predictive factor for advanced recurrence of hepatitis C after liver transplantation. Hepatology 2014; 59:35-45. [PMID: 23728831 DOI: 10.1002/hep.26536] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Revised: 05/07/2013] [Accepted: 05/14/2013] [Indexed: 12/11/2022]
Abstract
UNLABELLED Lymphocytes play an active role in natural immunity against hepatitis C virus (HCV). We hypothesized that a lower absolute lymphocyte count (ALC) may alter HCV outcome after liver transplantation (LT). The aim of this study was to investigate the impact of peritransplant ALC on HCV recurrence following LT. A total of 289 LT patients between 2005 and 2011 were evaluated. Peritransplant ALC (pre-LT, 2-week, and 1-month post-LT) and immunosuppression were analyzed along with recipient and donor factors in order to determine risk factors for HCV recurrence based on METAVIR fibrosis score. When stratifying patients according to pre- and post-LT ALC (<500/μL versus 500-1,000/μL versus >1,000/μL), lymphopenia was significantly associated with higher rates of HCV recurrence with fibrosis (F2-4). Multivariate Cox regression analysis showed posttransplant ALC at 1 month remained an independent predictive factor for recurrence (P = 0.02, hazard ratio [HR] = 2.47 for <500/μL). When peritransplant ALC was persistently low (<500/μL pre-LT, 2-week, and 1-month post-LT), patients were at significant risk of developing early advanced fibrosis secondary to HCV recurrence (F3-4 within 2 years) (P = 0.02, HR = 3.16). Furthermore, severe pretransplant lymphopenia (<500/μL) was an independent prognostic factor for overall survival (P = 0.01, HR = 3.01). The use of rabbit anti-thymocyte globulin induction (RATG) had a remarkable protective effect on HCV recurrence (P = 0.02, HR = 0.6) despite its potential to induce lymphopenia. Subgroup analysis indicated that negative effects of posttransplant lymphopenia at 1 month (<1,000/μL) were significant regardless of RATG use and the protective effects of RATG were independent of posttransplant lymphopenia. CONCLUSION Peritransplant ALC is a novel and useful surrogate marker for prediction of HCV recurrence and patient survival. Immunosuppression protocols and peritransplant management should be scrutinized depending on peritransplant ALC.
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Affiliation(s)
- Shunji Nagai
- Division of Transplant and Hepatobiliary Surgery, Henry Ford Transplant Institute, Henry Ford Hospital, Detroit, MI
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In vitro effects of ATG-Fresenius on immune cell adhesion. Transplant Proc 2013; 45:1846-9. [PMID: 23769055 DOI: 10.1016/j.transproceed.2013.01.079] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2012] [Accepted: 01/24/2013] [Indexed: 11/23/2022]
Abstract
INTRODUCTION ATG-Fresenius, a purified rabbit polyclonal anti-human T-lymphocyte immunoglobulin is used for induction immunosuppression as well as prevention and treatment of acute rejection episodes among patients receiving solid organ transplants. The aim of this study was to investigate the in vitro activity of ATG-Fresenius upon immune cell adhesion, which may explain its activity to mitigate ischemia-reperfusion injury. MATERIALS AND METHODS Human vascular endothelial cells (HUVEC) and peripheral blood mononuclear cells (PBMCs) isolated from umbilical vein or peripheral blood were incubated 20 to 24 hours before analysis. HUVEC were incubated with 10 and 100 μg/mL ATG-Fresenius or reference polyclonal rabbit immunoglobulin G. Analysis of immune cell adhesion to endothelial cells was studied in cocultures of PBMCs and adherent HUVEC. Endothelial cell expression of adhesion molecules CD62E and CD54 was determined by flow cytometry. The numbers of T-, B- and natural killer cells attached to HUVEC were also determined by flow cytometry. Groups were compared using one-way analysis of variance. RESULTS We showed that ATG-Fresenius binds to endothelial cells particularly activated ones expressing increased levels of E-selectin and ICAM-1. The increased binding of ATG-Fresenius to activated endothelial cells was consistent with its known binding to Intercellular Adhesion Molecule 1 (ICAM-1) and selectins. We also showed that ATG-Fresenius inhibited adhesion of prestimulated immune cells to activated endothelium. CONCLUSION We demonstrated dose-dependent binding of ATG-Fresenius to activated endothelial cells.
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Aliabadi A, Grömmer M, Cochrane A, Salameh O, Zuckermann A. Induction therapy in heart transplantation: where are we now? Transpl Int 2013; 26:684-95. [DOI: 10.1111/tri.12107] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2013] [Revised: 03/20/2013] [Accepted: 04/04/2013] [Indexed: 11/28/2022]
Affiliation(s)
- Arezu Aliabadi
- Department of Cardiothoracic Surgery; Medical University of Vienna; Vienna; Austria
| | - Martina Grömmer
- Department of Cardiothoracic Surgery; Medical University of Vienna; Vienna; Austria
| | | | - Olivia Salameh
- Department of Cardiothoracic Surgery; Medical University of Vienna; Vienna; Austria
| | - Andreas Zuckermann
- Department of Cardiothoracic Surgery; Medical University of Vienna; Vienna; Austria
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Powell JT, Tsapepas DS, Martin ST, Hardy MA, Ratner LE. Managing renal transplant ischemia reperfusion injury: novel therapies in the pipeline. Clin Transplant 2013; 27:484-91. [PMID: 23614480 DOI: 10.1111/ctr.12121] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/27/2013] [Indexed: 01/26/2023]
Abstract
Ischemia reperfusion injury (IRI) is an early, non-specific inflammatory response that follows perfusion of warm blood into a cold asanguinous organ following transplantation. The occurrence of IRI may have a pivotal impact on acute and long-term renal allograft function. Initially, IRI contributes to delayed graft function (DGF), a term typically defined as the need for dialysis within one wk after renal transplantation. DGF frequently leads to prolonged hospital stay, increased healthcare costs, and potentially worse prognosis. Strategies to prevent IRI have so far been fairly limited, poorly defined, inadequately studied, and mostly anecdotal. The purpose of this review is to summarize the existing and novel therapies, which may mitigate IRI in renal transplantation. Agents currently in the pipeline include: Diannexin, which reduces endothelial cell injury by shielding phosphatidylserine; YSPSL, which mimics the binding portion of P-selectin glycoprotein ligand-1 to competitively inhibit translocation of P-selectin and recruitment of polymorphonuclear leukocytes to the surface of endothelial cells; and I5NP, a synthetic small interfering ribonucleic acid that results in the inhibition of p53 expression. These agents represent an exciting frontier in transplant pharmacotherapy; they are in various phases of investigation and may have broader benefits in reducing complications of DGF.
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Affiliation(s)
- Jaclyn T Powell
- Department of Pharmacy, New York Presbyterian Hospital, Columbia University Medical Center, New York, NY, USA.
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Treatment with antithymocyte globulin ameliorates intestinal ischemia and reperfusion injury in mice. Surgery 2012; 152:843-50. [DOI: 10.1016/j.surg.2012.03.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2011] [Accepted: 03/01/2012] [Indexed: 11/19/2022]
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Zheng FJ, Shi L, Yang J, Deng XH, Wu YQ, Yan XQ, Huang N. Effect of Tea Polyphenols on the Adhesion of Highly Metastatic Human Lung Carcinoma Cell Lines to Endothelial Cells in Vitro. Asian Pac J Cancer Prev 2012; 13:3751-5. [DOI: 10.7314/apjcp.2012.13.8.3751] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Page EK, Dar WA, Knechtle SJ. Tolerogenic therapies in transplantation. Front Immunol 2012; 3:198. [PMID: 22826708 PMCID: PMC3399382 DOI: 10.3389/fimmu.2012.00198] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2012] [Accepted: 06/22/2012] [Indexed: 01/08/2023] Open
Abstract
Since the concept of immunologic tolerance was discovered in the 1940s, the pursuit of tolerance induction in human transplantation has led to a rapid development of pharmacologic and biologic agents. Short-term graft survival remains an all-time high, but successful withdrawal of immunosuppression to achieve operational tolerance rarely occurs outside of liver transplantation. Collaborative efforts through the NIH sponsored Immune Tolerance Network and the European Commission sponsored Reprogramming the Immune System for Establishment of Tolerance consortia have afforded researchers opportunity to evaluate the safety and efficacy of tolerogenic strategies, investigate mechanisms of tolerance, and identify molecular and genetic markers that distinguish the tolerance phenotype. In this article, we review traditional and novel approaches to inducing tolerance for organ transplantation, with an emphasis on their translation into clinical trials.
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Perioperative Minimal Induction Therapy: A Further Step toward More Effective Immunosuppression in Transplantation. J Transplant 2012; 2012:426042. [PMID: 22685630 PMCID: PMC3364007 DOI: 10.1155/2012/426042] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2011] [Revised: 02/21/2012] [Accepted: 03/12/2012] [Indexed: 01/07/2023] Open
Abstract
Dual induction with low doses of rabbit anti-human thymoglobulin (RATG) and basiliximab effectively and safely prevented allograft rejection in high-risk renal transplant recipients. To assess whether treatment timing affects efficacy and tolerability, in this single-center, matched-cohort study, we compared posttransplant outcomes in 25 patients and 50 gender-, age-, and treatment-matched reference patients induced with the same course of 7 daily RATG infusions (0.5 mg/kg/day) started before or after engraftment, respectively. All subjects received basiliximab (20 mg) before and 4 days after transplantation, withdrew steroids within 6 days after surgery, and were maintained on steroid-free immunosuppression with cyclosporine and mycophenolate mofetil or azathioprine. Over 12 months after transplant, 1 patient (4%) and 13 reference patients (26%) had acute rejection episodes. One patient and 5 reference-patients required dialysis therapy because of delayed graft function. In all patients circulating CD4+ and CD8+ T lymphocytes were fully depleted before engraftment. Both treatments were well tolerated. In kidney transplantation, perioperative RATG infusion enhances the protective effect of low-dose RATG and basiliximab induction against graft rejection and delayed function, possibly because of more effective inhibition of early interactions between circulating T cells and graft antigens.
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Cicora F, Roberti J, Lausada N, González P, Guerrieri D, Stringa P, Cicora P, Vásquez D, González I, Palti G, Intile D, Raimondi C. Donor preconditioning with rabbit anti-rat thymocyte immunoglobulin ameliorates ischemia reperfusion injury in rat kidney transplantation. Transpl Immunol 2012; 27:1-7. [PMID: 22484297 DOI: 10.1016/j.trim.2012.03.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2012] [Revised: 03/20/2012] [Accepted: 03/21/2012] [Indexed: 12/14/2022]
Abstract
A major concern in transplantation is the preservation of organ function. Ischemia time and microcirculatory disturbance of the organ cannot be avoided and may result in ischemia reperfusion injury (IRI), increasing the risk of delayed graft function (DGF) and acute and chronic rejection. Anti-thymocyte immunoglobulin (rATG) is a polyclonal antibody preparation with multiple effects when administered to recipients. Our objective has been to evaluate whether the administration of rATG to kidney donors instead of recipients, in an experimental model of syngeneic rat transplantation, ameliorates IRI and facilitates immediate graft function recovery. Urea and creatinine levels and necrosis severity scores were significantly lower in kidneys from donors that had received rATG (urea: control: 211±8mg/dl vs. treatment: 110±15mg/dl, p<0.001; creatinine: control: 4.6±0.24mg/dl vs. treatment: 2.6±0.22mg/dl, p<0.001; necrosis severity scores: control: 2.3 vs. treatment: 1.6, p<0.05). TUNEL staining showed 80±13 positive cells in control group and 9±3 (p<0.001) in treatment group. In situ expression of proinflammatory cytokines TNF-α, IL-6, IL-21 and TGF-β1 was reduced in rATG group (p<0.01); the same was observed for KIM-1 and caspase 8 (p<0.001). Cytoprotective genes Bcl2 and HO-1 were upregulated in situ in treatment group (p<0.001). In situ expression of IL-17, caspase 9, IL-23a, CxCl3 and ICAM1 showed no difference between groups (p>0.05). Findings suggest ATG administered to donors may ameliorate the IRI process in kidney transplantation, expressed by lower necrosis and apoptosis scores and the improvement of renal function, which may be explained through the diminished in situ expression of inflammatory mediators.
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Differential Regulation of the Nuclear Factor-κB Pathway by Rabbit Antithymocyte Globulins in Kidney Transplantation. Transplantation 2012; 93:589-96. [DOI: 10.1097/tp.0b013e31824491aa] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
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Abstract
The last two decades have witnessed a pandemic in antibody development, with over 600 entering clinical studies and a total of 28 approved by the FDA and European Union. The incorporation of biologics in transplantation has made a significant impact on allograft survival. Herein, we review the armamentarium of clinical and preclinical biologics used for organ transplantation--with the exception of belatacept--from depleting and IL-2R targeting induction agents to costimulation blockade, B-cell therapeutics, BAFF and complement inhibition, anti-adhesion, and anti-cytokine approaches. While individual agents may be insufficient for tolerance induction, they provide possibilities for reduction of steroid or calcineurin inhibitor use, alternatives to rejection episodes refractory to conventional therapies, and specialized immunosuppression for highly sensitized patients.
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Affiliation(s)
- Eugenia K Page
- Department of Surgery, Emory University Hospital, Atlanta, GA, USA
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40
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Antithymocyte globulin induction therapy for adult heart transplantation: A UK national study. J Heart Lung Transplant 2011; 30:770-7. [DOI: 10.1016/j.healun.2011.01.716] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2010] [Revised: 01/04/2011] [Accepted: 01/28/2011] [Indexed: 11/20/2022] Open
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Stevens RB, Lane JT, Boerner BP, Miles CD, Rigley TH, Sandoz JP, Nielsen KJ, Skorupa JY, Skorupa AJ, Kaplan B, Wrenshall LE. Single-dose rATG induction at renal transplantation: superior renal function and glucoregulation with less hypomagnesemia. Clin Transplant 2011; 26:123-32. [PMID: 21401720 DOI: 10.1111/j.1399-0012.2011.01425.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
UNLABELLED BACKGROUND Rabbit anti-thymocyte globulin (rATG) induction reduces reperfusion injury and improves renal function in kidney recipients by means of properties unrelated to T-cell lysis. Here, we analyze intensive rATG induction (single dose, rATG(S) , vs. divided dose, rATG(D) ) for improved renal function and protection against hyperglycemia. METHODS Patients without diabetes (n = 98 of 180) in a prospective randomized trial of intensive rATG induction were followed for six months for the major secondary composite end point of impaired glucose regulation (hyperglycemia and new-onset diabetes after transplantation, NODAT). Prospectively collected data included fasting blood glucose and HbA(1c). Serum Mg(++) was routinely collected and retrospectively analyzed. RESULTS Induction with rATG(S) produced less impaired glucose regulation (p = 0.05), delayed NODAT development (p = 0.02), less hyperglycemia (p = 0.02), better renal function (p = 0.04), and less hypomagnesemia (p = 0.02), a factor associated with a lower incidence of NODAT. Generalized linear modeling confirmed that rATG(S) protects against a synergistic interaction between tacrolimus and sirolimus that otherwise increased hypomagnesemia (p = 0.008) and hyperglycemia (p = 0.03). CONCLUSIONS rATG(S) initiated before renal reperfusion improved early renal function and reduced impaired glucose regulation, an injury by diabetogenic maintenance agents (tacrolimus and sirolimus).
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Affiliation(s)
- R Brian Stevens
- Departments of Surgery, University of Nebraska Medical Center, Omaha, NE 68198-3285, USA.
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Cantarovich D, Rostaing L, Kamar N, Saint-Hillier Y, Ducloux D, Mourad G, Garrigue V, Wolf P, Ellero B, Cassuto E, Albano L, Soulillou JP. Corticosteroid avoidance in adult kidney transplant recipients under rabbit anti-T-lymphocyte globulin, mycophenolate mofetil and delayed cyclosporine microemulsion introduction. Transpl Int 2010; 23:313-24. [DOI: 10.1111/j.1432-2277.2009.00971.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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