RESUMEN
BACKGROUND: The clinical safety and efficacy of sirolimus plus reduced-dose tacrolimus was evaluated in de novo renal allograft recipients enrolled in a comparative, open-label study. METHODS: One hundred twenty-eight renal allograft recipients were randomly assigned (1:1) to receive reduced-dose tacrolimus plus sirolimus (rTAC) or standard-dose tacrolimus and sirolimus (sTAC) for 6 months. The primary efficacy endpoint was calculated creatinine clearance values at 6 months. RESULTS: Demographic variables were similar between groups. At 6 months, mean (± standard deviation) calculated creatinine clearance was significantly improved in the rTAC group (63.8 vs 52.7 mL/min, P = .005), although mean serum creatinine values were not significantly different. Patient survival (95.2% and 96.9%) and graft survival (93.7% and 98.5%) were similar between the rTAC and sTAC groups, respectively. Acute rejection rates were 17.5% with rTAC and 7.7% with sTAC (P = .095). CONCLUSIONS: The rTAC regimen provided effective immunosuppression and was associated with improved creatinine clearance. Adequate immunosuppressant exposure must be achieved in the early postoperative period to minimize the risk of acute rejection.
Asunto(s)
Inmunosupresores/administración & dosificación , Fallo Renal Crónico/cirugía , Trasplante de Riñón , Sirolimus/administración & dosificación , Tacrolimus/administración & dosificación , Adulto , Biomarcadores/sangre , Creatinina/sangre , Monitoreo de Drogas , Quimioterapia Combinada , Europa (Continente) , Femenino , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Supervivencia de Injerto/efectos de los fármacos , Humanos , Inmunosupresores/efectos adversos , Inmunosupresores/farmacocinética , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/mortalidad , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/mortalidad , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sirolimus/efectos adversos , Sirolimus/farmacocinética , Tacrolimus/efectos adversos , Tacrolimus/farmacocinética , Factores de Tiempo , Resultado del TratamientoRESUMEN
Two Six-month pilot studies were conducted in renal (n = 17) or liver (n = 15) transplant recipients to evaluate renal function after conversion from calcineurin inhibitor (CI)- to sirolimus (SRL)-based immunosuppression. After an SRL loading dose, doses were individualized to achieve whole blood trough levels of 10-22 ng/mL. Overall, serum creatinine did not change from baseline to six months post-conversion but an improvement from 219.9 to 201.4 micromol/L at three months was noted in renal transplant recipients (p < 0.05). Another finding was a numerical increase in the mean glomerular filtration rate (GFR) from 26.8 to 33.2 mL/min/1.73 m(2) at six months among liver transplant recipients (NS). All patients survived and all grafts were functioning at the end of the study. In conclusion, renal function remained stable, with a tendency towards improvement, after abrupt conversion from CI- to SRL-based therapy in renal or liver transplant recipients with moderate renal insufficiency.
Asunto(s)
Inhibidores de la Calcineurina , Ciclosporina/uso terapéutico , Inmunosupresores/uso terapéutico , Trasplante de Riñón/fisiología , Riñón/fisiología , Trasplante de Hígado/fisiología , Sirolimus/uso terapéutico , Creatinina/sangre , Femenino , Tasa de Filtración Glomerular , Rechazo de Injerto/prevención & control , Humanos , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Proyectos Piloto , Insuficiencia Renal , Tacrolimus/uso terapéuticoRESUMEN
In 11 European centers, first cadaveric renal allograft recipients were randomized to CsA (n = 42) or sirolimus (n = 41). Dosing of these agents was concentration-controlled and open-labeled. All patients received corticosteroids and azathioprine. At 12 months, graft survival (98% sirolimus vs 93% CsA), patient survival (100% vs 98%), and incidence of biopsy-confirmed acute rejection (41% vs 38%) were similar. Serum creatinine was lower with sirolimus, significantly (P =.05) so at 3 and 4 months, and serum uric acid and magnesium were normal. Laboratory abnormalities were reported significantly more often with sirolimus, which included hypertriglyceridemia (51% vs 12%), hypercholesterolemia (44% vs 14%), thrombocytopenia (37% vs 0%), leukopenia (39% vs 14%), and, of lesser importance, increased liver enzymes and hypokalemia. These abnormalities improved 2 months after transplantation when the sirolimus target trough level was lowered from 30 to 15 ng/mL. Occurrence of cytomegalovirus was comparable (14% vs 12%), but incidence of herpes simplex (24% vs 10%, P =.08) and pneumonia (17% vs 2%, P =.03) were higher with sirolimus. No gingival hyperplasia was seen with sirolimus, tremor was rare, and hypertension was less frequent (17% vs 33%). Two malignancies were observed with CsA, none with sirolimus. Results at 12 months suggest that sirolimus can be used as base therapy in the prophylaxis of acute renal transplant rejection, and has a safety profile that differs from that of CsA.
Asunto(s)
Trasplante de Riñón/inmunología , Sirolimus/uso terapéutico , Corticoesteroides/uso terapéutico , Azatioprina/uso terapéutico , Ciclosporina/uso terapéutico , Quimioterapia Combinada , Francia , Rechazo de Injerto/epidemiología , Hospitales Universitarios , Humanos , Hipercolesterolemia/inducido químicamente , Hipercolesterolemia/epidemiología , Hipertrigliceridemia/inducido químicamente , Hipertrigliceridemia/epidemiología , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Metilprednisolona/uso terapéutico , Prednisolona/uso terapéutico , Prednisona/uso terapéutico , Sirolimus/efectos adversosRESUMEN
INTRODUCTION: A previous trial in renal transplantation comparing sirolimus (rapamycin) to cyclosporine (CsA) in a triple-drug therapy regimen with azathioprine and corticosteroids found that the incidence of acute rejection was similar (approximately 40%) with a trend for better renal function with sirolimus. METHODS: In 14 European centers, first cadaveric renal allograft recipients were randomized to receive sirolimus (n = 40) or CsA (n = 38) in an open-label design. All patients received corticosteroids and mycophenolate mofetil 2 g/day. Sirolimus and CsA were concentration controlled; trough levels of mycophenolic acid and prednisolone were also measured. RESULTS: At 12 months, graft survival (92.5% sirolimus vs. 89.5% CsA), patient survival (97.5% sirolimus vs. 94.7% CsA), and the incidence of biopsy-proven acute rejection (27.5% sirolimus vs. 18.4% CsA) were not statistically different. The use of antibodies to treat suspected rejection episodes was also similar (7.5% sirolimus vs. 5.3% CsA). More sirolimus patients received bolus steroid therapy (20 vs. 11, P = 0.068). From month 2 onward, the calculated glomerular filtration rate was consistently higher in sirolimus-treated patients. The adverse events reported more frequently with sirolimus were thrombocytopenia (45% vs. 8%) and diarrhea (38% vs. 11%). In the CsA group, increased creatinine (18% vs. 39%), hyperuricemia (3% vs. 18%), cytomegalovirus infection (5% vs. 21%), and tremor (5% vs. 21%) were observed significantly more often. DISCUSSION: Patient and graft survival and the incidence of biopsy-proven acute rejection at 12 months were comparable between sirolimus and CsA, whereas safety profiles were different. These data suggest that sirolimus may be used as primary therapy for the prevention of acute rejection.
Asunto(s)
Rechazo de Injerto/prevención & control , Inmunosupresores/uso terapéutico , Trasplante de Riñón , Ácido Micofenólico/análogos & derivados , Sirolimus/uso terapéutico , Enfermedad Aguda , Adolescente , Adulto , Anciano , Niño , Ciclosporina/administración & dosificación , Ciclosporina/efectos adversos , Ciclosporina/farmacocinética , Ciclosporina/uso terapéutico , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Femenino , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Inmunosupresores/farmacocinética , Masculino , Persona de Mediana Edad , Ácido Micofenólico/administración & dosificación , Ácido Micofenólico/efectos adversos , Ácido Micofenólico/farmacocinética , Ácido Micofenólico/uso terapéutico , Sirolimus/administración & dosificación , Sirolimus/efectos adversos , Sirolimus/farmacocinética , Trasplante HomólogoRESUMEN
The immune system is closely integrated with the neuroendocrine system, and infection-induced increases in cytokines such as IL-1, IL-6 and TNF have numerous effects on the central nervous system. These include stimulation of the hypothalamus-pituitary-adrenal (HPA) axis, as well as of leptin production. The increase in leptin causes loss of appetite, which may be deleterious for children who are living under conditions of poverty, have frequent infections and are often already undernourished. These cytokines may also be involved in problems of obesity, since they activate the HPA-axis and since TNF is produced by fat cells and can cause insulin resistance. The immune system originally developed for hunter-gatherers may not be well adapted to the pathology of poverty or that of excess.
Asunto(s)
Adaptación Fisiológica , Citocinas/fisiología , Sistema Hipotálamo-Hipofisario/fisiología , Sistema Inmunológico/fisiología , Leptina/fisiología , Neurotransmisores/fisiología , Adulto , Infecciones Bacterianas/inmunología , Niño , Citocinas/biosíntesis , Citocinas/metabolismo , Humanos , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Inmunológico/metabolismo , Tolerancia Inmunológica , Recién Nacido , Insulina/biosíntesis , Resistencia a la Insulina , Leptina/metabolismo , Neurotransmisores/metabolismo , Trastornos Nutricionales/embriología , Trastornos Nutricionales/inmunología , Fenómenos Fisiológicos de la Nutrición , Obesidad/complicaciones , Obesidad/inmunología , Sistema Hipófiso-Suprarrenal/fisiología , Pobreza , Factores de Riesgo , Virosis/inmunologíaRESUMEN
BACKGROUND: Sirolimus (rapamycin) is a potent immunosuppressant with a mechanism of action different from cyclosporine (CsA) or tacrolimus. METHODS: In 11 European centers, first cadaveric renal allograft recipients were randomized to CsA (n=42) or sirolimus (n=41). Dosing of these agents was concentration-controlled and open-labeled. All patients received corticosteroids and azathioprine. RESULTS: At 12 months, graft survival (98% sirolimus vs. 90% CsA), patient survival (100% vs. 98%), and incidence of biopsy-confirmed acute rejection (41% vs. 38%) were similar. Serum creatinine was lower with sirolimus, significantly (P< or =0.05) so at 3 and 4 months, and serum uric acid and magnesium were normal. Laboratory abnormalities reported significantly more often with sirolimus included hypertriglyceridemia (51% vs. 12%), hypercholesterolemia (44% vs. 14%), thrombocytopenia (37% vs. 0%), leukopenia (39% vs. 14%), and, of lesser importance, increased liver enzymes and hypokalemia. These abnormalities improved 2 months after transplantation when the sirolimus target trough level was lowered from 30 to 15 ng/ml. Occurrence of cytomegalovirus was comparable (14% vs. 12%); incidences of herpes simplex (24% vs. 10%, P=0.08) and pneumonia (17% vs. 2%, P=0.03) were higher with sirolimus. No gingival hyperplasia was seen with sirolimus, tremor was rare, and hypertension was less frequent (17% vs. 33%). Two malignancies were observed with CsA and none with sirolimus. CONCLUSIONS: Results at 12 months suggest that sirolimus can be used as base therapy in the prophylaxis of acute renal transplant rejection, and has a safety profile that differs from CsA.
Asunto(s)
Inmunosupresores/uso terapéutico , Trasplante de Riñón , Sirolimus/uso terapéutico , Adulto , Anciano , Ciclosporina/uso terapéutico , Femenino , Humanos , Inmunosupresores/efectos adversos , Riñón/fisiopatología , Masculino , Persona de Mediana Edad , Concentración Osmolar , Pacientes Desistentes del Tratamiento , Proyectos Piloto , Sirolimus/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: T-cell activation through T-cell receptor engagement requires co-stimulatory molecules and also adhesion molecules such as ICAM-1. Moreover ICAM-1 mediates leukocyte invasion from the blood into tissue during inflammatory processes. In animal studies using mouse monoclonal antibodies against ICAM-1 (enlimomab), renal allograft survival has been improved and reperfusion damage from ischemia reduced. The European Anti-ICAM-1 Renal Transplant Study (EARTS) was a randomized, double-blind, parallel-group, placebo-controlled study lastingl year and performed in 10 transplant centers in Europe. METHODS: A total of 262 recipients of cadaveric kidneys were given either enlimomab or a placebo for 6 days and were given triple immunosuppressive therapy of cyclosporine, azathioprine, and prednisolone. The primary efficacy endpoint was the incidence of the first acute rejection within 3 months, and each event was assessed by a committee including investigators and independent pathologists. RESULTS: There was no significant difference in the incidences of first acute rejection at 3 months between the placebo and enlimomab groups (39% vs. 45%), and enlimomab did not reduce the risk of delayed onset of graft function (DGF) (26% vs. 31%). Neither was there a difference in patient survival (95% vs. 91%) or graft survival (89% vs. 84%) at 1 year. Fatal events occurred in 19 (7%) patients (7 placebo, 12 enlimomab). Clinically, the most important non-fatal adverse events were infections; however, there was no statistically significant difference between the incidences in the two groups (70% vs. 79%). CONCLUSION: Short term enlimomab induction therapy after renal transplantation did not reduce the rate of acute rejection or DGF.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Rechazo de Injerto/prevención & control , Molécula 1 de Adhesión Intercelular/inmunología , Trasplante de Riñón , Riñón/fisiopatología , Enfermedad Aguda , Adolescente , Adulto , Anciano , Animales , Cadáver , Femenino , Supervivencia de Injerto , Humanos , Inmunización Pasiva , Masculino , Ratones , Persona de Mediana EdadAsunto(s)
Supervivencia de Injerto , Trasplante de Riñón/estadística & datos numéricos , Adolescente , Adulto , Anciano , Cadáver , Niño , Preescolar , Quimioterapia Combinada , Femenino , Rechazo de Injerto/epidemiología , Rechazo de Injerto/terapia , Hospitales Universitarios , Humanos , Inmunosupresores/uso terapéutico , Lactante , Trasplante de Riñón/mortalidad , Trasplante de Riñón/fisiología , Donadores Vivos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de Supervivencia , Suecia , Factores de Tiempo , Donantes de TejidosAsunto(s)
Rechazo de Injerto/inducido químicamente , Supervivencia de Injerto/efectos de los fármacos , Trasplante de Corazón/fisiología , Antagonistas de los Receptores H2 de la Histamina/toxicidad , Inmunosupresores/antagonistas & inhibidores , Animales , Suero Antilinfocítico/uso terapéutico , Cimetidina/toxicidad , Femenino , Trasplante de Corazón/inmunología , Inmunosupresores/uso terapéutico , Masculino , Omeprazol/toxicidad , Ranitidina/toxicidad , Ratas , Ratas Endogámicas , Trasplante HomólogoRESUMEN
The postoperative alterations of absolute levels of lymphocyte phenotype subsets in peripheral blood were studied in recipients of living donor renal allografts and in kidney donors. The results were expressed as per cent changes of the preoperative values. The lymphocyte subsets, CD3, CD4 and CD8 cells, decreased to approximately 50% following the surgical trauma, with rapid recovery to preoperative levels within 1 week in kidney donors and in recipients without rejection episodes. In contrast, the T-cell levels in recipients with rejection episodes remained low after 1 week, before clinical signs of rejection, and was predictive for the later occurrence of acute rejection episodes. The T-cell levels in the recipients with rejection episodes remained low during the first 6 weeks, maybe due to the rejection treatments given during this period. The B-lymphocytes were not affected in any of the recipient groups. The alterations observed were not explained by CMV infections, which occurred mainly after the observation period of 6 weeks. In conclusion, the operation per se induced alterations in circulating T-lymphocyte subsets and low T-cell levels after 1 week were predictive of rejection episodes.
Asunto(s)
Rechazo de Injerto/inmunología , Trasplante de Riñón , Subgrupos de Linfocitos T/inmunología , Adulto , Anciano , Antígenos CD/inmunología , Linfocitos B/inmunología , Biomarcadores , Femenino , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Trasplante HomólogoAsunto(s)
Inmunosupresores/uso terapéutico , Trasplante de Páncreas/inmunología , Adulto , Suero Antilinfocítico/uso terapéutico , Azatioprina/uso terapéutico , Enfermedades Transmisibles/epidemiología , Creatinina/sangre , Ciclosporina/sangre , Ciclosporina/uso terapéutico , Resistencia a Medicamentos , Quimioterapia Combinada , Femenino , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/epidemiología , Humanos , Masculino , Metilprednisolona/uso terapéutico , Complicaciones Posoperatorias/epidemiología , Prednisolona/uso terapéutico , ReoperaciónRESUMEN
In a prospective study before, and during 1 year following, kidney transplantation, physical strength and performance were tested in patients over the age of 60 and in younger control patients. Quadriceps strength increased significantly in the control patients (+3.3 +/- 3.2 kg, n = 11, P = 0.007) but remained stable in the successfully grafted elderly patients (-0.1 +/- 4.2 kg, n = 16). Grip strength tended to increase in the control patients (P = 0.064) but not in the elderly. Stepping up on a chair--a test of strength and coordination in combination--could be performed by all control patients on all occasions. Fourteen of 16 elderly patients managed it before transplant, but only 3/12 after 3 weeks, 5/13 after 6 months, and 10/16 after 1 year. Forced expiratory volume during 1 s and working capacity on the ergometer bicycle also tended to decline during 1 year. We conclude that the average elderly person does not gain strength during 1 year after successful kidney transplantation.
Asunto(s)
Ejercicio Físico/fisiología , Trasplante de Riñón/fisiología , Músculo Esquelético/fisiología , Adolescente , Adulto , Factores de Edad , Anciano , Prueba de Esfuerzo , Femenino , Humanos , Enfermedades Renales/cirugía , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Pruebas de Función RespiratoriaRESUMEN
The cell-mediated immune response was studied, using mixed lymphocyte reactivity (MLR) and cell-mediated lympholysis (CML) tests, in patients with well-functioning kidney grafts from living donors at 6 and 12 months and at 2-5 years after transplantation. The patients were allocated to treatment with cyclosporin A (CyA) and prednisolone (group A) or with CyA, prednisolone and azathioprine (group B). The MLR towards a third party were in the range of that of untreated controls while the anti-donor activities were reduced after 6 months in both groups. The CML activities in group A towards a third party were in the range of that of untreated controls at all times, while the anti-donor activities were decreased. By contrast, the CML activities in group B towards a third party were decreased during the first year and were in the range of that of normal controls at 2-5 years. The anti-donor CML activities were low at all times in group B. In summary, the two CyA protocols allowed the induction of donor-specific unresponsiveness within the first post-transplant year. The anti-third party activities were low during the first post-transplant year in recipients with triple therapy but not in those without azathioprine.
Asunto(s)
Azatioprina/uso terapéutico , Ciclosporina/uso terapéutico , Trasplante de Riñón/inmunología , Prednisolona/uso terapéutico , Adulto , Niño , Preescolar , Citotoxicidad Inmunológica , Quimioterapia Combinada , Femenino , Humanos , Inmunidad Celular/efectos de los fármacos , Inmunosupresores/uso terapéutico , Prueba de Cultivo Mixto de Linfocitos , MasculinoRESUMEN
The alterations in the absolute levels of lymphocyte phenotype subsets were measured in a rat model for heart allograft acceptance induced by antithymocyte globulin (ATG). In untreated, allografted rats all T lymphocytes decreased with 50% within 3 days after transplantation and recovered within 1 week. ATG alone induced a depletion of 75% of the T lymphocytes, which did not normalise until 60 days after treatment. During the first 10 days, ATG-treated rats with an accepted allograft had higher levels of T lymphocytes than those with rejections while the T lymphocytes recovered faster after day 10 in the later rats. The study demonstrates different alterations in T lymphocytes phenotype subsets between rejecting rats and rats with long-term accepted allograft. It also shows that the operation trauma with rejection as well as the ATG treatment strongly influence the T cell subsets.
Asunto(s)
Suero Antilinfocítico/uso terapéutico , Rechazo de Injerto/patología , Supervivencia de Injerto/efectos de los fármacos , Fenotipo , Subgrupos de Linfocitos T/citología , Animales , Femenino , Trasplante de Corazón/inmunología , Masculino , Modelos Biológicos , Ratas , Ratas Endogámicas , Subgrupos de Linfocitos T/efectos de los fármacos , Trasplante Homólogo/inmunologíaAsunto(s)
Antígenos CD/análisis , Rechazo de Injerto , Trasplante de Riñón/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Adulto , Biomarcadores , Antígenos CD4/análisis , Antígenos CD8/análisis , Femenino , Antígenos HLA-DR/análisis , Humanos , Terapia de Inmunosupresión , Masculino , Persona de Mediana EdadAsunto(s)
Suero Antilinfocítico/inmunología , Subgrupos de Linfocitos T/inmunología , Animales , Anticuerpos Monoclonales , Antígenos CD/análisis , Antígenos CD19 , Antígenos de Diferenciación de Linfocitos B/análisis , Antígenos CD4/análisis , Antígenos CD5 , Citometría de Flujo/métodos , Cinética , Masculino , Ratas , Ratas Endogámicas , Valores de Referencia , Factores de TiempoRESUMEN
The angiotensin-converting enzyme inhibitor captopril has been suggested to have an immunomodulatory effect both in clinical and experimental studies. To further investigate this possible effect in organ transplantation, captopril was given to inbred rats before transplantation of an allogeneic heart. Captopril was found to prolong graft survival significantly compared to untreated controls. In rats treated with a tolerogenic dose of ATG, additional captopril administration tended to increase the proportion of rats with long-term functioning grafts, but this did not reach statistical significance. It is concluded that captopril displays an immunosuppressive effect that seems to be weak, since no augmentation of ATG-induced transplantation unresponsiveness was seen.
Asunto(s)
Suero Antilinfocítico/uso terapéutico , Captopril/uso terapéutico , Supervivencia de Injerto/efectos de los fármacos , Trasplante de Corazón , Linfocitos T/inmunología , Animales , Masculino , Ratas , Ratas Endogámicas , Trasplante HomólogoRESUMEN
Adjuvant treatment with ursodeoxycholic acid (UDCA) for liver-transplant recipients has been reported to reduce the frequency of acute rejection episodes. To explore this effect further, UDCA was given to rats in an experimental heart transplantation model, with or without concomitant immunosuppressive treatment with antihymocyte globulin (ATG). UDCA was administered orally 7 days before and 14 days after transplantation. Rats treated with UDCA alone or in combination with ATG were compared with untreated controls and ATG-treated recipients. Adjuvant treatment with UDCA was found to induce prolonged graft survival and increase the amount of transplant tolerance in rats. Serum levels of bilirubin and aminotransferases were not altered irrespective of the UDCA dose given. The results indicate that UDCA has an immunomodulatory capacity that might not be restricted to the liver, but also might apply to other transplanted organs as well.