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INTRODUCTION: Steroid-based immunosuppression after transplantation increases the risk of post-transplant diabetes mellitus (PTDM), with adverse effects on patient and graft survival. In the SAILOR study, we investigated the safety and efficacy of complete steroid avoidance in immunologically low-risk kidney recipients without diabetes on the current standard-of-care maintenance regimen with tacrolimus/mycophenolate mofetil (MMF). METHODS: In this 2-year, multicenter, open-label trial, a total of 222 patients were randomized to receive either steroid avoidance protocol (tacrolimus/MMF/antithymocyte globulin [ATG] induction [n = 113]) or steroid maintenance protocol (tacrolimus/MMF/prednisolone/basiliximab-induction [n = 109]). RESULTS: At 1 year, no significant differences were found between steroid avoidance and steroid maintenance arms in the incidence of PTDM, the primary end point (12.4% vs. 18.3%, respectively, P = 0.30, CI: 16.3-4.4), or in overall biopsy-proven rejections (15% vs. 13.8%, respectively, P = 0.85). At 2 years, the composite end point of freedom from acute rejection, graft loss, and death (81% vs. 85%, respectively, P = 0.4), kidney function, or adverse events was comparable between the 2 arms. Moreover, 63.9% of the patients in the steroid avoidance arm remained free from steroids at 2 years. CONCLUSION: The SAILOR study provides further evidence for the feasibility, safety, and efficacy of early steroid-free treatment at 2 years in immunologically low-risk kidney recipients with tacrolimus/MMF maintenance regimen.
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BACKGROUND: Corticosteroids and calcineurin inhibitors (CNIs) are included in renal transplantation immunosuppressive protocols around the world. Well-known side effects are associated with the use of these drugs, including new onset of diabetes after transplantation (NODAT). Long-term patient survival rates are lower among patients with NODAT. The optimal immunosuppressive protocol would therefore include not using corticosteroids and minimization of CNI use. METHODS/DESIGN: This is a prospective, multi-centre, controlled, randomized, parallel group, open-label study involving kidney transplant patients. The study compares a steroid-free immunosuppressive protocol (study arm A), which is based on low-dose tacrolimus and mycophenolate mofetil (MMF) maintenance therapy together with antithymocyte globulin (ATG) induction, with the conventional immunosuppressive protocol (study arm B), being based on low-dose tacrolimus, MMF and steroids together with interleukin-2 receptor (IL2-R) induction. The study is designed to include most normal-risk patients. It will exclude patients seen as at a high risk of rejection. The primary objective of the study is to assess the cumulative incidence of NODAT in the two study arms 12 months after transplantation using the American Diabetes Association type 2 diabetes diagnostic criteria. The composite measure of freedom from acute rejection, graft survival and patient survival will be evaluated. Renal function and chronic changes in the transplanted kidney will be assessed. DISCUSSION: If this study confirms conceptual expectations, namely decreased incidence of NODAT, the steroid-free study protocol could be used with all patients. The regimen could be especially beneficial for patients at a high risk of diabetes mellitus. TRIAL REGISTRATION: EudraCT 2012-000451-13.
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BACKGROUND: Shipment of pancreata between distant centers is frequently associated with prolonged cold ischemia time (CIT) that leads to poorer outcomes for islet transplantation. Clinical pilot trials have indicated that oxygenation of explanted human pancreata utilizing the two-layer method (TLM) allows the use of marginal donor pancreata for islet transplantation. The present study aimed to clarify whether TLM enhances the ischemic tolerance of human pancreata. METHODS: We analyzed retrospectively the outcome of 200 human islet isolations performed after TLM preservation or storage in University of Wisconsin solution (UWS). RESULTS: Donor characteristics and digestion parameters did not vary significantly between TLM-preserved and UWS-stored pancreata. No differences were observed between experimental groups with regard to islet yield, purity, or dynamic glucose stimulation index after either short or prolonged CIT. However, CIT and stimulation index were negatively correlated in each experimental group. The isolation outcome in donors aged > or =60 years was not increased after TLM preservation when compared to UWS storage. No effect was observed regarding islet posttransplant function in recipients with established kidney grafts. CONCLUSIONS: The present study suggests that the ischemic tolerance of human pancreata cannot be extended by TLM preservation. In addition, TLM does not seem to improve the isolation outcome for pancreata from elderly donors.
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Transplante das Ilhotas Pancreáticas/métodos , Preservação de Órgãos/instrumentação , Adenosina/farmacologia , Adulto , Idoso , Alopurinol/farmacologia , Feminino , Glutationa/farmacologia , Humanos , Insulina/farmacologia , Ilhotas Pancreáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Preservação de Órgãos/métodos , Soluções para Preservação de Órgãos/farmacologia , Pâncreas/metabolismo , Projetos Piloto , Rafinose/farmacologia , Estudos Retrospectivos , Manejo de Espécimes , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVE: In clinical islet transplantation, the instant blood-mediated inflammatory reaction (IBMIR) is a major factor contributing to the poor initial engraftment of the islets. This reaction is triggered by tissue factor and monocyte chemoattractant protein (MCP)-1, expressed by the transplanted pancreatic islets when the islets come in contact with blood in the portal vein. All currently identified systemic inhibitors of the IBMIR are associated with a significantly increased risk of bleeding or other side effects. To avoid systemic treatment, the aim of the present study was to render the islet graft blood biocompatible by applying a continuous heparin coating to the islet surface. RESEARCH DESIGN AND METHODS: A biotin/avidin technique was used to conjugate preformed heparin complexes to the surface of pancreatic islets. This endothelial-like coating was achieved by conjugating barely 40 IU heparin per full-size clinical islet transplant. RESULTS: Both in an in vitro loop model and in an allogeneic porcine model of clinical islet transplantation, this heparin coating provided protection against the IBMIR. Culturing heparinized islets for 24 h did not affect insulin release after glucose challenge, and heparin-coated islets cured diabetic mice in a manner similar to untreated islets. CONCLUSIONS: This novel pretreatment procedure prevents intraportal thrombosis and efficiently inhibits the IBMIR without increasing the bleeding risk and, unlike other pretreatment procedures (e.g., gene therapy), without inducing acute or chronic toxicity in the islets.
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Heparina/farmacologia , Transplante das Ilhotas Pancreáticas/métodos , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/patologia , Sistema ABO de Grupos Sanguíneos/imunologia , Animais , Células Endoteliais/efeitos dos fármacos , Sobrevivência de Enxerto , Humanos , Inflamação/imunologia , Inflamação/patologia , Inflamação/prevenção & controle , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/cirurgia , Transplante das Ilhotas Pancreáticas/imunologia , Transplante das Ilhotas Pancreáticas/patologia , Camundongos , Modelos Biológicos , Perfusão , Suínos , Técnicas de Cultura de Tecidos , Transplante Autólogo/imunologia , Transplante Autólogo/métodos , Transplante Autólogo/patologia , Transplante Heterólogo/imunologia , Transplante Heterólogo/métodos , Transplante Heterólogo/patologiaRESUMO
There are strong indications that only a small fraction of grafts successfully engraft in clinical islet transplantation. One explanation may be the instant blood-mediated inflammatory reaction (IBMIR) elicited by tissue factor, which is produced by the endocrine cells. In the present study, we show that islets intended for islet transplantation produce tissue factor in both the transmembrane and the alternatively spliced form and that the membrane-bound form is released as microparticles often associated with both insulin and glucagon granules. A low-molecular mass factor VIIa (FVIIa) inhibitor that indirectly blocks both forms of tissue factor was shown in vitro to be a promising drug to eliminate the IBMIR. Thrombin-antithrombin complex (TAT) and FVIIa-antithrombin complex (FVIIa-AT) were measured in nine patients who together received 20 infusions of isolated human islets. Both the TAT and FVIIa-AT complexes increased rapidly within 15-60 min after infusion. When the initial TAT and FVIIa-AT levels were plotted against the increase in C-peptide concentration after 7 days, patients with an initially strong IBMIR showed no significant increase in insulin synthesis after 7 days. In conclusion, tissue factor present in both the islets and the culture medium and elicits IBMIR, which affects the function of the transplanted islets.
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Transplante das Ilhotas Pancreáticas , Ilhotas Pancreáticas/fisiologia , Tromboplastina/fisiologia , Adulto , Processamento Alternativo/fisiologia , Antitrombina III/fisiologia , Fator VIIa/antagonistas & inibidores , Fator VIIa/fisiologia , Feminino , Humanos , Imuno-Histoquímica , Inflamação/fisiopatologia , Ilhotas Pancreáticas/ultraestrutura , Masculino , Pessoa de Meia-Idade , Peptídeo Hidrolases/fisiologia , Fatores de TempoRESUMO
A complete registration of all deceased patients at intensive care units in the Southern Health region of Sweden has shown that 3,114 patients died during the five years from 1999 to 2003. Only 174 cases (5.6 per cent) were classified as potential organ donors according to the definition of total brain infarction (brain death) without medical contra-indications against organ donation. Consent for organ donation was given in slightly more than half of these cases. In 42 per cent of the cases relatives were not aware of the attitude of the deceased, and in 40 per cent of these cases they used their right of veto against organ donation. Corresponding registration, as part of the computerised system for quality assurance for intensive care (PASIVA), may become a national and complete quality assurance for organ donation in Sweden.
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Doadores de Tecidos , Obtenção de Tecidos e Órgãos , Família/psicologia , Humanos , Unidades de Terapia Intensiva/normas , Unidades de Terapia Intensiva/estatística & dados numéricos , Garantia da Qualidade dos Cuidados de Saúde , Sistema de Registros , Inquéritos e Questionários , Suécia , Doadores de Tecidos/psicologia , Doadores de Tecidos/estatística & dados numéricos , Obtenção de Tecidos e Órgãos/normas , Obtenção de Tecidos e Órgãos/estatística & dados numéricosRESUMO
BACKGROUND: The procedure of human islet isolation needs further optimization and standardization. Here, we describe techniques to enhance enzymatic digestion and minimize mechanical forces during the digestion process. The isolation protocol has also been modified to meet current GMP (cGMP) standards. Moreover, the impact of donor- and process-related factors was correlated to the use of islets for clinical transplantation. METHODS: One hundred twelve standardized consecutive islet isolations were evaluated. Metyltioninklorid and indermil (topical tissue adhesive) were applied to detect leakage of collagenase injected and to repair the damaged pancreatic glands. The effects of dye and glue were evaluated in terms of islet yield, islet function using the perifusion assay, and success rate of the isolation. To analyze key factors for successful isolations, both univariate and multivariate regression analysis were performed. RESULTS: Both Metyltioninklorid and Indermil were effective to prevent leakage of enzyme solutions from the pancreatic glands. Both islet yield and success rate were higher when these tools were applied (4,516.1+/-543.0 vs. 3,447.7+/-323.5, P=0.02; 50.0% vs. 21.3%, P=0.02, respectively). No adverse effects on islet function or collagenase activity were observed. Multivariate regression analysis identified the maximal recorded amylase >100 U/L (P=0.026), BMI (P=0.03), and the use of catecholamine (P=0.04) as crucial donor-related factors. In addition, cold ischemia time (P=0.005), the dissection procedure using whole glands with duodenum (P=0.02), and the local procurement team (P=0.03) were identified as crucial isolation-related variables. CONCLUSIONS: A standardized technique of islet isolation is presented applying novel means to improve enzymatic digestion and to meet cGMP standards.
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Ilhotas Pancreáticas/citologia , Coleta de Tecidos e Órgãos/métodos , Humanos , Transplante das Ilhotas Pancreáticas , Modelos Logísticos , Pessoa de Meia-Idade , Análise Multivariada , Doadores de Tecidos , Obtenção de Tecidos e ÓrgãosRESUMO
BACKGROUND: Islet-produced tissue factor (TF) triggers an adverse clotting reaction, the instant blood-mediated inflammatory reaction (IBMIR), providing a likely explanation for the need of tissue from multiple donors in clinical islet transplantation. In this study, the authors investigated whether compounds previously shown to affect TF and macrophage chemoattractant protein (MCP)-1 expression in monocytes and endothelial cells have the same effect in human islet cells. METHODS: Islets were cultured in the presence of l-arginine, cyclosporine A, enalapril, or nicotinamide for 48 hr, after which the TF content and MCP-1 expression were assessed. The effect of nicotinamide on IBMIR was evaluated by exposing the treated islets to fresh human ABO-compatible blood in an in vitro loop model. RESULTS: Nicotinamide was the only compound that significantly reduced both TF and MCP-1. This reduction was dose-dependent. The level of MCP-1 was strongly correlated with TF expression (r2=0.98). In addition, the level of TF was also correlated with the ability of the islets to initiate IBMIR (r2=0.94). CONCLUSIONS: TF and MCP-1 expression in human islets can be decreased by adding nicotinamide to the culture medium. These observations indicate that the adverse effects of IBMIR in clinical islet transplantation could be reduced without endangering the recipient using antithrombotic drugs.
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Transplante das Ilhotas Pancreáticas/fisiologia , Ilhotas Pancreáticas/fisiologia , Niacinamida/farmacologia , Tromboplastina/metabolismo , Arginina/farmacologia , Células Cultivadas , Quimiocina CCL2/metabolismo , Ciclosporina/farmacologia , Enalapril/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Ilhotas Pancreáticas/efeitos dos fármacos , Cinética , Tromboplastina/antagonistas & inibidoresRESUMO
BACKGROUND: Considering the fact that donor age is a major risk factor for graft survival, and taking into account the importance attached to the principle of autonomy in the Swedish Health Care Law, we decided that allocation of kidneys from marginal donors should be restricted to patients who have given their informed consent. Written information was given to the patients on the waiting list for kidney transplantation in the southern part of Sweden. Patients were asked to state whether they would accept either a single kidney or dual transplantation kidneys from marginal donors. The aim of this study was to investigate the views of patients on the information they received about kidneys from marginal donors and their reaction to being asked to make a decision on this issue. METHODS: A questionnaire was posted to 61 patients who had already replied to the question of whether or not they would accept kidneys from a marginal donor for themselves. The median age of the patients was 52 years (range 22-74 years). Answers were given anonymously. RESULTS: Among the 53 respondents, 48 considered the information to be comprehensible. The extent of the information was considered sufficient by 43 patients. No patient thought that the information was too extensive. According to 41 patients, it is totally right to be asked to make a decision on this type of issue. Two patients thought it was totally wrong. Finally, 33 patients thought it was easy to make a decision on this issue. CONCLUSIONS: This study indicates that patients on the waiting list for kidney transplantation accept information on donor-related risk factors and most patients want to be involved in the decision concerning transplantation with a kidney from a marginal donor.