Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.804
Filtrar
1.
Cochrane Database Syst Rev ; 8: CD009966, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32803882

RESUMO

BACKGROUND: Kidney transplantation is the preferred management for patients with end-stage kidney disease (ESKD). However, it is often complicated by worsening or new-onset diabetes. The safety and efficacy of glucose-lowering agents after kidney transplantation is largely unknown. This is an update of a review first published in 2017. OBJECTIVES: To evaluate the efficacy and safety of glucose-lowering agents for treating pre-existing and new onset diabetes in people who have undergone kidney transplantation. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 16 January 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: All randomised controlled trials (RCTs), quasi-RCTs and cross-over studies examining head-to-head comparisons of active regimens of glucose-lowering therapy or active regimen compared with placebo/standard care in patients who have received a kidney transplant and have diabetes were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Four authors independently assessed study eligibility and quality and performed data extraction. Continuous outcomes were expressed as post-treatment mean differences (MD) or standardised mean difference (SMD). Adverse events were expressed as post-treatment absolute risk differences (RD). Dichotomous clinical outcomes were presented as risk ratios (RR) with 95% confidence intervals (CI). MAIN RESULTS: Ten studies (21 records, 603 randomised participants) were included - three additional studies (five records) since our last review. Four studies compared more intensive versus less intensive insulin therapy; two studies compared dipeptidyl peptidase-4 (DPP-4) inhibitors to placebo; one study compared DPP-4 inhibitors to insulin glargine; one study compared sodium glucose co-transporter 2 (SGLT2) inhibitors to placebo; and two studies compared glitazones and insulin to insulin therapy alone. The majority of studies had an unclear to a high risk of bias. There were no studies examining the effects of biguanides, glinides, GLP-1 agonists, or sulphonylureas. Compared to less intensive insulin therapy, it is unclear if more intensive insulin therapy has an effect on transplant or graft survival (4 studies, 301 participants: RR 1.12, 95% CI 0.32 to 3.94; I2 = 49%; very low certainty evidence), delayed graft function (2 studies, 153 participants: RR 0.63, 0.42 to 0.93; I2 = 0%; very low certainty evidence), HbA1c (1 study, 16 participants; very low certainty evidence), fasting blood glucose (1 study, 24 participants; very low certainty evidence), kidney function markers (1 study, 26 participants; very low certainty evidence), death (any cause) (3 studies, 208 participants" RR 0.68, 0.29 to 1.58; I2 = 0%; very low certainty evidence), hypoglycaemia (4 studies, 301 participants; very low certainty evidence) and medication discontinuation due to adverse effects (1 study, 60 participants; very low certainty evidence). Compared to placebo, it is unclear whether DPP-4 inhibitors have an effect on hypoglycaemia and medication discontinuation (2 studies, 51 participants; very low certainty evidence). However, DPP-4 inhibitors may reduce HbA1c and fasting blood glucose but not kidney function markers (1 study, 32 participants; low certainty evidence). Compared to insulin glargine, it is unclear if DPP-4 inhibitors have an effect on HbA1c, fasting blood glucose, hypoglycaemia or discontinuation due to adverse events (1 study, 45 participants; very low certainty evidence). Compared to placebo, SGLT2 inhibitors probably do not affect kidney graft survival (1 study, 44 participants; moderate certainty evidence), but may reduce HbA1c without affecting fasting blood glucose and eGFR long-term (1 study, 44 participants, low certainty evidence). SGLT2 inhibitors probably do not increase hypoglycaemia, and probably have little or no effect on medication discontinuation due to adverse events. However, all participants discontinuing SGLT2 inhibitors had urinary tract infections (1 study, 44 participants, moderate certainty evidence). Compared to insulin therapy alone, it is unclear if glitazones added to insulin have an effect on HbA1c or kidney function markers (1 study, 62 participants; very low certainty evidence). However, glitazones may make little or no difference to fasting blood glucose (2 studies, 120 participants; low certainty evidence), and medication discontinuation due to adverse events (1 study, 62 participants; low certainty evidence). No studies of DPP-4 inhibitors, or glitazones reported effects on transplant or graft survival, delayed graft function or death (any cause). AUTHORS' CONCLUSIONS: The efficacy and safety of glucose-lowering agents in the treatment of pre-existing and new-onset diabetes in kidney transplant recipients is questionable. Evidence from existing studies examining the effect of intensive insulin therapy, DPP-4 inhibitors, SGLT inhibitors and glitazones is mostly of low to very low certainty. Appropriately blinded, larger, and higher quality RCTs are needed to evaluate and compare the safety and efficacy of contemporary glucose-lowering agents in the kidney transplant population.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/uso terapêutico , Transplante de Rim/efeitos adversos , Complicações Pós-Operatórias/tratamento farmacológico , Adamantano/efeitos adversos , Adamantano/análogos & derivados , Adamantano/uso terapêutico , Viés , Causas de Morte , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 2/sangue , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Jejum/sangue , Hemoglobina A Glicada/metabolismo , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Insulina/efeitos adversos , Insulina/uso terapêutico , Insulina Glargina/efeitos adversos , Insulina Glargina/uso terapêutico , Nitrilos/efeitos adversos , Nitrilos/uso terapêutico , Pioglitazona , Complicações Pós-Operatórias/etiologia , Pirrolidinas/efeitos adversos , Pirrolidinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Fosfato de Sitagliptina/efeitos adversos , Fosfato de Sitagliptina/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Tiazolidinedionas/efeitos adversos , Tiazolidinedionas/uso terapêutico , Transplantados , Vildagliptina
2.
Transplantation ; 104(8): 1720-1725, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32732852

RESUMO

BACKGROUND: The impact of opioid use in lung transplant candidates on posttransplant outcomes is unknown. Studies on opioid therapy in kidney and liver transplant candidates have suggested increased risk of graft failure or death. We sought to analyze the relationship between pretransplant opioid use in lung transplant candidates and retransplant-free survival. METHODS: We retrospectively reviewed adult patients transplanted consecutively between November 2004 and August 2015. The exposure was any opioid use at time of transplant listing and primary outcome was retransplant-free survival, analyzed via Cox regression model adjusted for recipient age, gender, ethnicity, diagnosis, and bridging status. Secondary outcomes included duration of ventilation, intensive care unit and hospital length of stay, 3-month and 1-year survival, continuing opioid use at 1 year, and time to onset of chronic lung allograft dysfunction. RESULTS: The prevalence of opioid use at time of listing was 14% (61/425). Median daily oral morphine equivalent dose was 31 mg (18-54). Recipient ethnicity was associated with pretransplant opioid use. Opioid use at time of listing did not increase risk of death or retransplantation in an adjusted model (hazard ratio 1.12 [95% confidence interval 0.65-1.83], P = 0.6570). Secondary outcomes were similar between groups except hospital length of stay (opioid users 35 versus nonusers 27 d, P = 0.014). Continued opioid use at 1-year posttransplant was common (27/56, 48%). CONCLUSIONS: Pretransplant opioid use was not associated with retransplant-free survival in our cohort and should not necessarily preclude listing. Further work stratifying opioid use by indication and the association with opioid use disorder would be worthwhile.


Assuntos
Analgésicos Opioides/efeitos adversos , Rejeição de Enxerto/epidemiologia , Pneumopatias/cirurgia , Transplante de Pulmão/efeitos adversos , Dor/tratamento farmacológico , Adulto , Aloenxertos/efeitos dos fármacos , Aloenxertos/fisiopatologia , Prescrições de Medicamentos/estatística & dados numéricos , Feminino , Seguimentos , Volume Expiratório Forçado/efeitos dos fármacos , Volume Expiratório Forçado/fisiologia , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/fisiopatologia , Rejeição de Enxerto/cirurgia , Sobrevivência de Enxerto/efeitos dos fármacos , Sobrevivência de Enxerto/fisiologia , Humanos , Estimativa de Kaplan-Meier , Tempo de Internação/estatística & dados numéricos , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Pneumopatias/complicações , Pneumopatias/mortalidade , Transplante de Pulmão/normas , Masculino , Pessoa de Meia-Idade , Dor/etiologia , Período Pré-Operatório , Modelos de Riscos Proporcionais , Sistema de Registros/estatística & dados numéricos , Reoperação/estatística & dados numéricos , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
3.
J Surg Res ; 255: 575-582, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32650141

RESUMO

BACKGROUND: Necrosis of the perforator flap is a critical problem. Fasudil, an inhibitor of Rho-associated coiled-coil containing kinase, has antiapoptosis activity and attenuates oxidative stress in many diseases. We characterized the effects of fasudil through intraperitoneal injection on perforator flap survival and identified its possible mechanism. METHODS AND MATERIALS: Rats were divided into a control group (without surgery), a flap group (only surgery), and a fasudil group (surgery plus fasudil). Perforator flaps were made on the backs of the rats. The expression of vascular endothelial growth factor, the protein kinase B (PKB/Akt), endothelial nitric oxide synthase, Bax, Bcl-2, Beclin-1, P62, and LC3 II/LC3 I was determined by Western blot at day 3 after surgery. Nitric oxide (NO) components, superoxide dismutase, and malondialdehyde were also measured at day 3. The survival rate and laser Doppler perfusion imaging were performed at day 7 after surgery. RESULT: The group with fasudil treatment exhibited the higher survival rates and angiogenesis levels. Fasudil also induced the activation of Akt/eNOS/NO pathway detected by the Western blot and NO expression kit. Furthermore, Western blot results showed fasudil-attenuated apoptosis through a raised Bcl-2/Bax rate and enhanced autophagy levels through raised beclin-1, decreased p62, and the elevated rate of LC3 II/LC3 I. Finally, fasudil increased superoxide dismutase and decreased malondialdehyde. CONCLUSIONS: In conclusion, fasudil treatment decreased necrosis of perforator flaps possibly by affecting the Akt/eNOS/NO pathway, attenuating apoptosis and activating autophagy.


Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Sobrevivência de Enxerto/efeitos dos fármacos , Retalho Perfurante/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Injeções Intraperitoneais , Masculino , Necrose/tratamento farmacológico , Necrose/etiologia , Neovascularização Fisiológica/efeitos dos fármacos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Retalho Perfurante/transplante , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos
4.
Sci Rep ; 10(1): 12086, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32694579

RESUMO

The in vitro culture period prior to cell transplantation (i.e. pancreatic islet transplantation) enables cell modification and is thus advantageous. However, the islet preconditioning method has not been fully explored. Here we present a simple approach for islet preconditioning that uses the antibiotic mitomycin C (MMC), which has antitumor activity, to reduce islet immunogenicity and prevent proinflammatory events in an intraportal islet transplantation model. Freshly isolated mice islets were treated for 30 min with 10 µg/mL MMC or not, cultured for 20 h and transplanted into the livers of syngeneic or allogeneic diabetic mouse recipients. In the allogeneic model, MMC preconditioning significantly prolonged graft survival without requiring immunosuppressants. In vitro, MMC treatment suppressed the expression of proinflammatory cytokines in islet allografts, while immunohistochemical studies revealed the suppression of inflammatory cell infiltration into MMC-treated allografts relative to untreated allografts. Furthermore, MMC preconditioning significantly suppressed the mRNA expression of proinflammatory cytokines into the transplant site and induced the differentiation of regulatory T cells with the ability to suppress CD4+ T cell-mediated immune responses. In conclusion, islet preconditioning with MMC prolonged graft survival in an intraportal islet transplantation model by suppressing proinflammatory events and inducing potentially regulatory lymphocytes.


Assuntos
Anti-Inflamatórios/farmacologia , Sobrevivência de Enxerto/efeitos dos fármacos , Imunossupressores/farmacologia , Transplante das Ilhotas Pancreáticas , Ilhotas Pancreáticas , Mitomicina/farmacologia , Biomarcadores , Sobrevivência de Enxerto/imunologia , Imuno-Histoquímica , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transplante Heterólogo , Transplante Homólogo
5.
Rev Assoc Med Bras (1992) ; 66(3): 353-358, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32520157

RESUMO

OBJECTIVE: Melatonin has anti-inflammatory and antioxidant properties that can influence tissue growth and apoptosis. This aspect may influence the success of organ transplantation. To evaluate the relationship between melatonin and organ transplantation. METHODS: A systematic review was performed in PubMed databases using the search terms: "melatonin physiology" or "melatonin therapy" and "transplant pharmacology" or "transplant physiology" or "transplant therapy" or "Transplant therapy". Experiments on the organs of the reproductive system were not included. After analysis, five articles were selected after reading the title and abstract of 50 manuscripts. The works were divided into two aspects: a) analysis of the influence of the organ transplantation procedure on melatonin production; b) action of melatonin on organ transplantation. RESULTS: The cardiac transplantation surgical procedure, immunosuppression, and graft did not influence melatonin secretion in rodents, but there was a significant reduction of melatonin in the renal transplantation procedure in patients with renal insufficiency. Melatonin administration in experimental models decreased rejection and improved transplant success. CONCLUSION: Studies show that melatonin can reduce organ and species dependence, and the use of melatonin decreases graft rejection.


Assuntos
Antioxidantes/administração & dosagem , Rejeição de Enxerto/prevenção & controle , Melatonina/administração & dosagem , Transplante de Órgãos , Animais , Sobrevivência de Enxerto/efeitos dos fármacos , Transplante de Coração , Humanos , Imunossupressão , Transplante de Rim , Melatonina/fisiologia , Ratos
6.
Circ J ; 84(6): 965-974, 2020 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-32350231

RESUMO

BACKGROUND: During these 2 decades (1999-2019), many therapeutic strategies have been developed in the field of heart transplant (HTx) to improve post-HTx outcomes. In the present study, 116 consecutive HTx adults between 1999 and 2019 were retrospectively reviewed to evaluate the influences of a therapeutic modification on post HTx outcomes.Methods and Results:Patient survival, functional status and hemodynamics after HTx and modification of therapeutic strategies were reviewed. The overall cumulative survival rate at 10 and 20 years post-HTx was 96.4 and 76.7%, respectively. There were no significant differences in survival rate or exercise tolerance after HTx between extracorporeal and implantable continuous flow-LVAD. Post-HTx patient survival in patients, irrespective of the donor risk factors such as donor age, low LVEF, history of cardiac arrest, was equivalent across cohorts, while longer TIT and higher inotrope dosage prior to procurement surgery were significant risk factors for survival. In 21 patients given everolimus (EVL) due to renal dysfunction, serum creatinine significantly decreased 1 year after initiation. In 22 patients given EVL due to transplant coronary vasculopathy (TCAV), maximum intimal thickness significantly decreased 3 years after initiation. CONCLUSIONS: The analysis of a 20-year single-center experience with HTx in Japan shows encouraging improved results when several therapeutic modifications were made; for example, proactive use of donor hearts declined by other centers and the use of EVL in patients with renal dysfunction and TCAV.


Assuntos
Everolimo/administração & dosagem , Insuficiência Cardíaca/cirurgia , Transplante de Coração , Imunossupressores/administração & dosagem , Adulto , Seleção do Doador , Everolimo/efeitos adversos , Tolerância ao Exercício , Circulação Extracorpórea , Feminino , Sobrevivência de Enxerto/efeitos dos fármacos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Transplante de Coração/efeitos adversos , Coração Auxiliar , Hemodinâmica , Humanos , Imunossupressores/efeitos adversos , Japão , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Doadores de Tecidos/provisão & distribução , Resultado do Tratamento , Função Ventricular Esquerda , Listas de Espera
7.
Vascul Pharmacol ; 130: 106682, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32438078

RESUMO

No data are available on rivaroxaban use in renal transplant recipients and on its surmised interaction with immunosuppressants. The aim was to investigate potential interactions between rivaroxaban and immunosuppressants in this setting. Renal transplant recipients with a stable renal function treated with rivaroxaban and tacrolimus with or without everolimus were investigated. All drugs and creatinine concentrations were determined daily for 2 weeks after the start of anticoagulation. Blood samples were drawn at 8.00 am and 3-4 h later for trough and peak concentrations, respectively. Bleeding and thrombotic events were recorded during a minimum follow-up of 6 months. In 8 renal transplant patients, rivaroxaban levels showed a predictable pharmacokinetic trend, both at Ctrough (30-61 µg/L) and at Cpeak (143-449 µg/L), with limited variability in the 25th-75th percentile range. Tacrolimus (Ctrough 3-13 µg/L; Cpeak 3-16 µg/L), everolimus (Ctrough 3-11 µg/L; Cpeak 5-17 µg/L) and creatinine concentrations were stable as well. Immunosuppressors variability before and after rivaroxaban were 30% and 30% for tacrolimus, 27% and 29% for everolimus, respectively, as well as 14% and 3% for creatinine. For rivaroxaban monitoring, the reference change value better performed in identifying significant variations of its concentration. No patient had bleeding or thrombotic events, worsening of renal graft function, and signs of immunosuppressants toxicity during a mean follow-up of 23 (9-28) months. In conclusion, rivaroxaban does not seem to interact with tacrolimus and everolimus in renal transplant recipients. Both anticoagulant and immunosuppressive effects seem warranted, without major bleeding complications and effect on the graft function.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Everolimo/farmacocinética , Inibidores do Fator Xa/farmacocinética , Imunossupressores/farmacocinética , Transplante de Rim , Rivaroxabana/farmacocinética , Tacrolimo/farmacocinética , Trombose Venosa/tratamento farmacológico , Idoso , Fibrilação Atrial/sangue , Fibrilação Atrial/diagnóstico , Coagulação Sanguínea/efeitos dos fármacos , Interações Medicamentosas , Monitoramento de Medicamentos , Everolimo/efeitos adversos , Everolimo/sangue , Inibidores do Fator Xa/efeitos adversos , Inibidores do Fator Xa/sangue , Feminino , Sobrevivência de Enxerto/efeitos dos fármacos , Hemorragia/induzido quimicamente , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/sangue , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Rivaroxabana/efeitos adversos , Rivaroxabana/sangue , Tacrolimo/efeitos adversos , Tacrolimo/sangue , Resultado do Tratamento , Trombose Venosa/sangue , Trombose Venosa/diagnóstico
8.
Transplantation ; 104(6): 1294-1303, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32433232

RESUMO

BACKGROUND: Hepatitis C virus-positive (HCV+) kidney transplant (KT) recipients are at increased risks of rejection and graft failure. The optimal induction agent for this population remains controversial, particularly regarding concerns that antithymocyte globulin (ATG) might increase HCV-related complications. METHODS: Using Scientific Registry of Transplant Recipients and Medicare claims data, we studied 6780 HCV+ and 139 681 HCV- KT recipients in 1999-2016 who received ATG or interleukin-2 receptor antagonist (IL2RA) for induction. We first examined the association of recipient HCV status with receiving ATG (versus IL2RA) using multilevel logistic regression. Then, we studied the association of ATG (versus IL2RA) with KT outcomes (rejection, graft failure, and death) and hepatic complications (liver transplant registration and cirrhosis) among HCV+ recipients using logistic and Cox regression. RESULTS: HCV+ recipients were less likely to receive ATG than HCV- recipients (living donor, adjusted odds ratio [aOR] = 0.640.770.91; deceased donor, aOR = 0.710.810.92). In contrast, HCV+ recipients who received ATG were at lower risk of acute rejection compared to those who received IL2RA (1-y crude incidence = 11.6% versus 12.6%; aOR = 0.680.820.99). There was no significant difference in the risks of graft failure (adjusted hazard ratio [aHR] = 0.861.001.17), death (aHR = 0.850.951.07), liver transplant registration (aHR = 0.580.971.61), and cirrhosis (aHR = 0.730.921.16). CONCLUSIONS: Our findings suggest that ATG, as compared to IL2RA, may lower the risk of acute rejection without increasing hepatic complications in HCV+ KT recipients. Given the higher rates of acute rejection in this population, ATG appears to be safe and reasonable for HCV+ recipients.


Assuntos
Soro Antilinfocitário/administração & dosagem , Rejeição de Enxerto/epidemiologia , Hepatite C/tratamento farmacológico , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Condicionamento Pré-Transplante/métodos , Adulto , Feminino , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Sobrevivência de Enxerto/imunologia , Hepacivirus/efeitos dos fármacos , Hepacivirus/imunologia , Hepacivirus/isolamento & purificação , Hepatite C/complicações , Hepatite C/diagnóstico , Hepatite C/imunologia , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/mortalidade , Masculino , Pessoa de Meia-Idade , Receptores de Interleucina-2/antagonistas & inibidores , Receptores de Interleucina-2/imunologia , Sistema de Registros/estatística & dados numéricos , Análise de Sobrevida , Transplantados/estatística & dados numéricos , Resultado do Tratamento , Estados Unidos/epidemiologia
9.
Transplant Proc ; 52(6): 1901-1905, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32362462

RESUMO

BACKGROUND: Intravenous immunoglobulin (Ig) therapy is used based on empirical findings for treatment of antibody-mediated rejection (AMR) in cases of renal transplantation, although its therapeutic efficacy has not been proven and the functional mechanism of an administered Ig remains elusive. In this study, the therapeutic effects of an Ig were examined in a preclinical rat renal transplant model of AMR to investigate this mechanism. METHODS: To establish an AMR renal graft model, skin graft specimens were obtained from Brown-Norway (BN) rats and transplanted to Lewis rats to produce donor-specific antibodies (DSAs), after which kidney transplantation from the Brown-Norway to Lewis rats was performed. AMR model rats were administered the Ig at a dose of 2 g/kg or saline as a control. Survival period, renal graft histopathology, complement factors, and DSA levels were assessed. RESULTS: The survival period of the group administered the Ig was significantly prolonged. Histopathological examinations of renal grafts also showed significant suppression of glomerulitis and peritubular capillaritis in the Ig group, and real-time polymerase chain reaction analysis results demonstrated significantly lower levels of expression of the complement factors C1q and C3. When the Ig was given to rats that underwent skin grafting but not renal transplantation, DSA was decreased after 6 hours and remained lower than the baseline level for at least 7 days. CONCLUSION: Ig administration suppressed DSA production. The present results showed that suppression of the complement system contributed to effective Ig treatment for AMR.


Assuntos
Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/efeitos dos fármacos , Imunoglobulinas Intravenosas/farmacologia , Isoanticorpos/efeitos dos fármacos , Transplante de Rim/efeitos adversos , Adulto , Animais , Proteínas do Sistema Complemento/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Humanos , Isoanticorpos/imunologia , Masculino , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos Lew , Resultado do Tratamento
10.
Transplantation ; 104(7): e208-e213, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32235257

RESUMO

BACKGROUND: Histologic criteria for diagnosing acute rejection in vascularized composite tissue allograft (VCA) have been established by the Banff 2007 Working Classification of Skin-Containing Composite Tissue Allograft, but the role of early vascular lesions in graft rejection warrants additional analysis. METHODS: We performed a retrospective study of 34 skin biopsies performed over 430 d for rejection surveillance, in Canada's first face allotransplant recipient. Three observers reviewed all biopsies to assess the nature and intensity of the inflammatory skin infiltrate. A complete histological and immunohistochemical review of the vascular components was performed with a focus on lymphocytic vasculitis, intravascular fibrin, vessel caliber, extent of injury, C4d positivity, and inflammatory cell phenotyping. We then correlated these data points to clinical and immunosuppression parameters. RESULTS: Acute vascular damage in biopsies that would be classified as mild acute rejection correlates with troughs in immunosuppression and subsides when immunosuppressive tacrolimus doses are increased. Grade 0 Banff rejection and Grade I without lymphocytic vasculitis were almost indistinguishable, whereas Grade I with lymphocytic vasculitis was an easy and reproducible histologic finding. CONCLUSIONS: Our results highlight the possible relevance of vascular injury in the context of VCA, as its presence might underlie a more aggressive form of immune rejection. If these findings are validated in other VCA patients, vascular injury in mild rejection might warrant a different clinical approach.


Assuntos
Transplante de Face/efeitos adversos , Rejeição de Enxerto/diagnóstico , Imunossupressores/administração & dosagem , Tacrolimo/administração & dosagem , Vasculite/complicações , Idoso , Biópsia , Canadá , Aloenxertos Compostos/irrigação sanguínea , Aloenxertos Compostos/patologia , Relação Dose-Resposta a Droga , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/patologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Sobrevivência de Enxerto/imunologia , Humanos , Imunossupressores/farmacocinética , Masculino , Estudos Retrospectivos , Índice de Gravidade de Doença , Pele/irrigação sanguínea , Pele/patologia , Tacrolimo/farmacocinética , Transplante Homólogo/efeitos adversos , Resultado do Tratamento , Vasculite/diagnóstico , Vasculite/tratamento farmacológico , Vasculite/imunologia
11.
Transplantation ; 104(4): 881-887, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32224815

RESUMO

BACKGROUND: Tacrolimus (TAC) is the most important agent for maintenance immunosuppression and prevention of immunologic injury to the renal allograft, yet there remains no consensus on how best to monitor drug therapy. Both high TAC intrapatient variability and low TAC time in therapeutic range (TTR) have been associated with risk of de novo donor-specific antibodies (dnDSA). In this study, we hypothesized that the risk associated with high TAC coefficient of variation (CV) is a result of low TAC TTR rather than the variability itself. METHODS: We analyzed the risk of dnDSA, acute rejection, or death-censored graft loss by non-dosed-corrected TAC CV and TAC TTR during the first posttransplant year in a cohort of 538 patients with a median follow-up period of 4.1 years. RESULTS: Patients with CV >44.2% and TTR <40% (high intrapatient variability and low TTR) had a high risk of dnDSA (adjusted OR = 4.93, 95% confidence interval = 2.02-12.06, P < 0.001) and death-censored graft loss by 5 years (adjusted HR = 4.00, 95% confidence interval = 1.31-12.24, P = 0.015) when compared with patients with CV >44.2% and TTR ≥40% (high intrapatient variability and optimal TTR), while the latter patients had similar risk to patients with CV <44.2% (lower intrapatient variability). CONCLUSIONS: These data suggest that previously reported immunologic risk associated with high TAC intrapatient variability is due to time outside of therapeutic range rather than variability in and of itself when evaluating absolute non-dose-corrected TAC levels irrespective of reason or indication.


Assuntos
Inibidores de Calcineurina/uso terapêutico , Monitoramento de Medicamentos , Rejeição de Enxerto/prevenção & controle , Antígenos HLA/imunologia , Imunossupressores/uso terapêutico , Isoanticorpos/sangue , Transplante de Rim , Tacrolimo/uso terapêutico , Adulto , Biomarcadores/sangue , Inibidores de Calcineurina/efeitos adversos , Inibidores de Calcineurina/sangue , Feminino , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/mortalidade , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/sangue , Transplante de Rim/efeitos adversos , Transplante de Rim/mortalidade , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Tacrolimo/efeitos adversos , Tacrolimo/sangue , Fatores de Tempo , Resultado do Tratamento
12.
Transplantation ; 104(5): 970-980, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32317615

RESUMO

BACKGROUND: Calcineurin inhibitors successfully control rejection of transplanted organs but also cause nephrotoxicity. This study, using a rhesus monkey renal transplantation model, sought to determine the applicability of a new immunomodulatory drug inhibiting the store-operated calcium release-activated calcium channel of lymphocytes to control transplant rejection without nephrotoxicity. METHODS: Animals underwent kidney transplantation and were treated with tacrolimus alone (n = 3), a CRACM1 inhibitor (PRCL-02) (n = 6) alone, or with initial tacrolimus monotherapy followed by gradual conversion at 3 weeks to PRCL-02 alone (n = 3). PRCL-02 was administered via a surgically inserted gastrostomy tube BID. RESULTS: Dose-related drug exposure in monkeys was established and renal transplants were then performed using PRCL-02 monotherapy. Oral dosing of PRCL-02 was well tolerated and resulted in suppressed T-cell proliferation in in vitro MLR comparable to animals in the tacrolimus control arm. Animals receiving tacrolimus monotherapy were e on day 100 without rejection. PRCL-02 monotherapy only marginally prolonged graft survival (MST = 13.16 d; group 2) compared with untreated controls. Animals treated initially with tacrolimus and converted to PRCL-02 monotherapy had a mean graft survival of 35.3 days which was prolonged compared with PRCL-02 monotherapy but not compared with the tacrolimus-treated group. Pharmacokinetic studies showed inconsistent drug exposures despite attempts to adjust dose and exposure which may have contributed to the rejections. CONCLUSIONS: We conclude that, in this nonhuman primate model of kidney transplantation, PRCL-02 demonstrated evidence of in vivo immunosuppressive activity but was inferior to tacrolimus treatment with respect to suppressing immune transplant rejection.


Assuntos
Canais de Cálcio Ativados pela Liberação de Cálcio/uso terapêutico , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Imunossupressão/métodos , Transplante de Rim , Tacrolimo/uso terapêutico , Animais , Inibidores de Calcineurina/uso terapêutico , Modelos Animais de Doenças , Rejeição de Enxerto/diagnóstico , Macaca mulatta , Masculino , Transplante Homólogo , Resultado do Tratamento
13.
Transplant Proc ; 52(3): 780-784, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32111386

RESUMO

BACKGROUND: The recommended standard immunosuppressive therapy for renal transplant recipients comprises an initial induction therapy mainly with an interleukin-2-receptor antibody (IL2-RA) and a triple maintenance therapy. With tacrolimus and mycophenolate acid it is unknown whether IL2-RA application affects the short- and long-term results. This question is addressed in the present analysis. METHODS: From July 2007 to June 2019 a total of 127 living donor kidney transplant recipients meeting the center-specific definition of immunologic low risk situation (first transplantation, HLA-mismatch ≤3, panel reactive antibody ≤10%) were identified. In 83 recipients with a first-degree relationship to the donor we omitted the IL2-RA induction (IL2-RA-). The remaining 44 recipients, mostly not first-degree relatives, served as controls (IL2-RA+). Biopsy-proven acute rejection and long-term patient and graft survival rates were compared. RESULTS: Biopsy-proven acute rejection rates after 3 months were similar in both groups with 4.8% (IL2-RA-) vs 13.7% (IL2-RA+; P = .0937), including borderline rejection rates of 18.0% (IL2-RA-) vs 18.3% (IL2-RA+; P = 1.000), respectively. Ten-year long-term survival rates were comparable between the IL2-RA- and the IL2-RA+ group with 95.6% vs 93.5% (patient survival; P = .5465) and 92.1% vs 90.6% (death-censored graft survival; P = .8893). CONCLUSION: For low-risk living donor kidney transplant recipients with first-degree relationship to the donor, it is safe to omit induction therapy with IL2-RA.


Assuntos
Basiliximab/uso terapêutico , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Imunossupressores/uso terapêutico , Transplante de Rim , Adulto , Feminino , Rejeição de Enxerto/epidemiologia , Humanos , Quimioterapia de Indução/métodos , Transplante de Rim/mortalidade , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Tacrolimo/uso terapêutico
14.
Transfusion ; 60(4): 769-778, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32187691

RESUMO

BACKGROUND: Platelet engraftment following cord blood (CB) transplantation remains a significant hurdle to this day. The uncontrolled growth of ice, a process referred to as ice recrystallization, is one of several mechanisms that lead to cell loss and decreased potency during freezing and thawing. We hypothesized that reducing cell damage induced by ice recrystallization in CB units (CBUs) would reduce losses of stem and progenitor cells and therefore improve engraftment. We previously demonstrated that the ice recrystallization inhibitor (IRI) N-(2-fluorophenyl)-D-gluconamide (IRI 2) increases the postthaw recovery of CB progenitors. Herein, we set out to ascertain whether IRI 2 can enhance platelet and bone marrow engraftment activity of hematopoietic stem cells (HSCs) in cryopreserved CBUs using a serial transplantation model. STUDY DESIGN AND METHODS: CBUs were processed following standard volume/red blood cell reduction procedure and portions frozen with dimethyl sulfoxide (DMSO) supplemented or not with IRI 2. Thawed CB samples were serially transplanted into immunodeficient mice. RESULTS: Our results show that supplementation of DMSO with IRI 2 had several beneficial effects. Specifically, higher levels of human platelets were observed in the peripheral blood (p < 0.05; n = 4) upon transplant of CBUs preserved with the IRIs. In addition, human BM chimerism and the number of human CFU progenitors in the bone marrow were superior in IRI 2 recipients compared to DMSO recipients. Moreover, IRI 2 had no negative impact on the multilineage differentiation and self-renewal activities of HSCs. DISCUSSION: Taken together, these results demonstrate that supplementation of a hematopoietic graft with IRI can improve the postthaw engraftment activities of HSCs.


Assuntos
Plaquetas/citologia , Criopreservação/métodos , Sangue Fetal/transplante , Sobrevivência de Enxerto , Gelo/efeitos adversos , Animais , Crioprotetores/farmacologia , Cristalização , Dimetil Sulfóxido/farmacologia , Sobrevivência de Enxerto/efeitos dos fármacos , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/normas , Humanos , Camundongos
15.
Sci Rep ; 10(1): 4464, 2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32161272

RESUMO

Adenosine is widely known as a potent modulator of innate and acquired immunity. It is released during transplants, and acts on four subtype receptors. In previous studies, we demonstrated that pharmacological preconditioning (PPC), pre-administration of the selective A1 receptor (A1R) agonist led to A1R desensitization, is followed by upregulation of the adenosine A2A receptor. This immunosuppressive effect resulted in lymphopenia, and it reduced T-cell reactivity. The aim of the current study was to challenge the immunosuppressive effects of A1R-PPC in models of allogeneic grafts. PPC mice were treated by intraperitoneal injection using specific adenosine A1R agonist 24 h and 12 h before starting any procedure. We challenged our method in novel allogeneic muscle and skin grafts models. Mice and grafts were assessed by complete blood counts, MLR from PPC splenocytes, and pathological evaluation. We found a significant reduction in WBC and lymphocyte counts in PPC-treated mice. Two-way MLR with splenocytes from PPC grafted mice showed decreased proliferation and anergy. Histology of PPC allogeneic grafts revealed profoundly less infiltration and even less muscle necrosis compared to vehicle treated allografts. Similar results observed in PPC skin transplantation. To conclude, PPC moderated graft rejection in separate allogeneic challenges, and reduced lymphocytes infiltration and ischemic damage.


Assuntos
Agonistas do Receptor A1 de Adenosina/farmacologia , Sobrevivência de Enxerto/efeitos dos fármacos , Sobrevivência de Enxerto/imunologia , Imunossupressão , Imunossupressores/farmacologia , Condicionamento Pré-Transplante , Animais , Células Sanguíneas/efeitos dos fármacos , Células Sanguíneas/imunologia , Células Sanguíneas/metabolismo , Proliferação de Células , Camundongos , Modelos Animais , Receptor A1 de Adenosina/metabolismo , Transplante de Pele , Condicionamento Pré-Transplante/métodos , Transplante Homólogo
16.
Transplant Proc ; 52(5): 1376-1379, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32213293

RESUMO

BACKGROUND: Pancreas transplant is an effective treatment for insulin-dependent diabetic individuals with end-stage renal disease, yet immunosuppression-associated adverse events may adversely affect patient and graft survival. The aim of the study was to document whether mammalian target of rapamycin inhibitors (mTORi) are safe and effective as a second-line drug after pancreas transplant. METHODOLOGY: An observational single-center study was performed in a cohort of 490 simultaneous pancreas-kidney transplant and 45 pancreas-after-kidney transplant individuals after conversion to mTORi (n = 13) owing to adverse events of either tacrolimus or mycophenolate. RESULTS: mTORi conversion was performed 11.5 ± 10.1 (range, 1-28) months after pancreas transplant, mainly owing to cytomegalovirus infection and gastrointestinal intolerance. We frequently observed clinical complications after mTORi conversion, yet creatinine, eGFR, proteinuria, fasting plasma glucose, HbA1c, and C-peptide remained stable throughout the study (mean follow-up 8.2 ± 5, range 1-17) years, as did the lipid profile (P > .05). However, graft loss occurred in almost 20% of patients owing to chronic alterations. LIMITATIONS: The small number of patients and a single-center cohort were limitations of the study. CONCLUSIONS: Late mTORi conversion is a safe and effective approach when tacrolimus or mycophenolate-mediated adverse events occur after pancreas transplant.


Assuntos
Everolimo/uso terapêutico , Imunossupressores/uso terapêutico , Transplante de Pâncreas/métodos , Sirolimo/uso terapêutico , Adulto , Substituição de Medicamentos/métodos , Feminino , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Imunossupressão/métodos , Transplante de Rim , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
17.
J Vis Exp ; (156)2020 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-32090989

RESUMO

The use of biocompatible materials for circumferential esophageal reconstruction is a technically challenging task in rats and requires an optimal implant technique with nutritional support. Recently, there have been many attempts at esophageal tissue engineering, but the success rate has been limited due to difficulty in early epithelization in the special environment of peristalsis. Here, we developed an artificial esophagus that can improve the regeneration of the esophageal mucosa and muscle layers through a two-layered tubular scaffold, a mesenchymal stem cell-based bioreactor system, and a bypass feeding technique with modified gastrostomy. The scaffold is made of polyurethane (PU) nanofibers in a cylindrical shape with a three-dimensional (3D) printed polycaprolactone strand wrapped around the outer wall. Prior to transplantation, human-derived mesenchymal stem cells were seeded into the lumen of the scaffold, and bioreactor cultivation was performed to enhance cellular reactivity. We improved the graft survival rate by applying surgical anastomosis and covering the implanted prosthesis with a thyroid gland flap, followed by temporary nonoral gastrostomy feeding. These grafts were able to recapitulate the findings of initial epithelialization and muscle regeneration around the implanted sites, as demonstrated by histological analysis. In addition, increased elastin fibers and neovascularization were observed in the periphery of the graft. Therefore, this model presents a potential new technique for circumferential esophageal reconstruction.


Assuntos
Materiais Biocompatíveis/administração & dosagem , Esôfago/cirurgia , Sobrevivência de Enxerto , Procedimentos Cirúrgicos Reconstrutivos/métodos , Engenharia Tecidual/métodos , Tecidos Suporte , Animais , Esôfago/fisiologia , Sobrevivência de Enxerto/efeitos dos fármacos , Sobrevivência de Enxerto/fisiologia , Humanos , Células-Tronco Mesenquimais/fisiologia , Nanofibras/administração & dosagem , Poliésteres/administração & dosagem , Ratos , Ratos Sprague-Dawley
18.
Nephrol Dial Transplant ; 35(2): 336-345, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32030416

RESUMO

BACKGROUND: Belatacept (bela) rescue therapy seems to be a valuable option for calcineurin inhibitor chronic toxicity in kidney transplantation. Nevertheless, the risk of infection associated with bela is not well reported. METHODS: We report the rate of opportunistic infections (OPI) after a switch to bela in a multicentric cohort of 280 kidney transplant patients. RESULTS: Forty-two OPI occurred in 34 patients (12.1%), on average 10.8 ± 11.3 months after the switch. With a cumulative exposure of 5128 months of bela treatment, we found an incidence of 0.008 OPI/month of exposure, and 9.8 OPI/100 person-years. The most common OPI was cytomegalovirus (CMV) disease in 18/42 OPI (42.9%) and pneumocystis pneumonia in 12/42 OPI (28.6%). Two patients presented a progressive multifocal leucoencephalopathy and two patients developed a cerebral Epstein-Barr virus-induced post-transplant lymphoproliferative disease. OPI led to death in 9/34 patients (26.5%) and graft failure in 4/34 patients (11.8%). In multivariate analysis, estimated glomerular filtration rate <25/mL/min/1.73 m2 on the day of the switch and the use of immunosuppressive agents before transplantation were associated with the occurrence of OPI. We found a higher rate of infection-related hospitalization (24.1 versus 12.3/100 person-years, P = 0.0007) and also a higher rate of OPI (13.2 versus 6.7/100 person-years, P = 0.005) in the early conversion group (within 6 months). CONCLUSIONS: The risk of OPI is significant post-conversion to bela and may require additional monitoring and prophylactic therapy, particularly regarding pneumocystis pneumonia and CMV disease. These data need to be confirmed in a larger case-control study.


Assuntos
Abatacepte/efeitos adversos , Rejeição de Enxerto/tratamento farmacológico , Sobrevivência de Enxerto/efeitos dos fármacos , Imunossupressores/efeitos adversos , Transplante de Rim/efeitos adversos , Transtornos Linfoproliferativos/epidemiologia , Infecções Oportunistas/epidemiologia , Feminino , França/epidemiologia , Taxa de Filtração Glomerular , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/patologia , Humanos , Incidência , Transtornos Linfoproliferativos/etiologia , Transtornos Linfoproliferativos/patologia , Masculino , Pessoa de Meia-Idade , Infecções Oportunistas/etiologia , Infecções Oportunistas/patologia , Estudos Retrospectivos
19.
Transplant Proc ; 52(2): 556-558, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32035673

RESUMO

BACKGROUND: Calcineurin inhibitors have been implicated in acute and chronic kidney disease after liver transplant (LT). Everolimus (EVR) is a mammalian target of rapamycin inhibitor efficacious in preventing acute cellular rejection while preserving renal function among LT recipients. We evaluated the benefits on renal function of EVR immunosuppression in LT recipients. METHODS: We performed a retrospective and observational study in 477 LT recipients in Virgen de las Nieves Hospital from 2002 to 2019 on the use of EVR with tacrolimus minimization or withdrawal in LT recipients with renal dysfunction. The study included 100 patients starting EVR (20.96%); in 66 (66%) the indication was renal dysfunction. The change in renal function was assessed by estimated glomerular filtration rate. Statistical analyses were performed using SPSS 17.0 software (IBM, Munich, Germany). RESULTS: Fifty 8 patients received mycophenolate mofetil (87.8%), and tacrolimus therapy was stopped in 27 patients (40.9%). Induction therapy with basiliximab was administered in 41 patients (62.12%). There was significant difference between estimated glomerular filtration rate at the time of starting EVR and the first month at last follow-up (49.42 mL/min/1.73 m2 vs 75.27 mL/min/1.73 m2; P < .001) and at end of follow-up (24 months) (49.42 mL/min/1.73 m2 vs 64.32 mL/min/1.73 m2; P = .001). The rate of incidence of adverse events was 48.48% (32/66). Seven patients died during follow-up (10.6%), but there were no EVR-related deaths. Eleven patients (16.6%) developed biopsy-proven acute rejection. CONCLUSION: This study showed that EVR is associated with a beneficial effect on glomerular filtration rate in both the short and long term in LT recipients.


Assuntos
Everolimo/administração & dosagem , Imunossupressores/administração & dosagem , Transplante de Fígado/efeitos adversos , Complicações Pós-Operatórias/tratamento farmacológico , Insuficiência Renal Crônica/tratamento farmacológico , Adulto , Basiliximab/administração & dosagem , Biópsia , Inibidores de Calcineurina/efeitos adversos , Quimioterapia Combinada , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Imunossupressão/métodos , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Complicações Pós-Operatórias/induzido quimicamente , Insuficiência Renal Crônica/induzido quimicamente , Estudos Retrospectivos , Sirolimo/administração & dosagem , Tacrolimo/administração & dosagem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA