RESUMO
The delayed release of mycophenolic acid (MPA) from enteric-coated mycophenolate sodium (EC-MPS, myfortic®) may have an impact on the variability of MPA trough (C0 h) levels. A randomized, two-period crossover study was performed in 24 maintenance renal transplants to evaluate the inter- and intrasubject variability of MPA predose levels from EC-MPS and mycophenolate mofetil (MMF, CellCept®), both in combination with cyclosporine. Patients received EC-MPS (720 mg b.i.d.) and MMF (1000 mg b.i.d.) for a period of 21 d each. MPA plasma levels were measured over the final seven consecutive days at -1, 0, 1, 2, and 3 h after the morning MPA dose. Intersubject coefficients of variation (%CV) for MPA troughs were 47.5% (95% CI, 34.1-80.3) and 54.4% (40.0-86.8) for EC-MPS and MMF, respectively; intrasubject %CVs were 62.7% (55.1-72.9) and 42.8% (37.9-49.2). High MPA C0 h levels>10 µg/mL were rarely observed with both EC-MPS (1.8%) and MMF (0.6%). Mean MPA area under the curve (AUC)0-3 h was comparable between treatments, while MPA C0 h was on average 46% higher with EC-MPS. In conclusion, predose MPA trough level monitoring appears of limited value during EC-MPS and MMF therapy given the large intrasubject variability in MPA C0 h levels with both treatments.
Assuntos
Imunossupressores/farmacocinética , Transplante de Rim , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/sangue , Adolescente , Adulto , Idoso , Área Sob a Curva , Disponibilidade Biológica , Estudos Cross-Over , Feminino , Sobrevivência de Enxerto , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Ácido Micofenólico/farmacocinética , Comprimidos com Revestimento Entérico , Distribuição Tecidual , Resultado do Tratamento , Adulto JovemRESUMO
This study was conducted to evaluate the pharmacokinetics (pk) and drug interactions between cyclosporine (CsA) and sirolimus (SRL) in kidney transplant recipients. The morning (a.m.) and evening (p.m.) pk of CsA (4-5 mg/kg/dose) and SRL (2 mg, n = 20; 5 mg, n = 33) were evaluated on day 7 (n = 53). CsA showed circadian variation when comparing a.m. and p.m. administration [AUC: 8066 vs. 6699, P < 0.001 (CI 970.9; 1763.6); C0: 272 vs. 245, P = 0.007 (CI 7.5; 46.1)]. SRL showed dose-proportional pk. Significant and drug-to-drug concentration-dependent pk interactions were observed within a narrow concentration range for both drugs. A fivefold increase in SRL AUC (from a mean of 130 to 538 ng h/mL) was associated with a 25% increase in mean a.m. CsA AUC [7021 to 8811 ng h/mL, P = 0.037, CI (-3461.2; -118.9)] and with a 42% increase in mean p.m. CsA AUC [5386-7639, P = 0.024, CI (-4164.4; -340.7)]. A twofold increase in a.m. CsA AUC (from 5860 to 10 974 ng h/mL) was associated with a 70% increase in mean SRL AUC [223 to 380 ng h/mL, P = 0.0026, CI (-291.7; -22.8)]. A twofold increase in p.m. CsA AUC (from 4573 to 9692 ng h/mL) was associated with a 63% increase in mean SRL AUC [246 to 400 ng h/mL, P = 0.032, CI (-290.7; -16.6)]. CSA shows circadian pk regardless of sirolimus dose or blood concentration. Significant drug-to-drug interactions occur within narrow blood drug concentrations. The magnitude of the effect of CsA on SRL blood concentration is higher than that of SRL on CsA blood concentrations. These findings emphasize the need for therapeutic drug monitoring using this drug combination.
Assuntos
Ciclosporina/farmacocinética , Rejeição de Enxerto/prevenção & controle , Imunossupressores/farmacocinética , Transplante de Rim , Sirolimo/farmacocinética , Adulto , Ritmo Circadiano , Ciclosporina/administração & dosagem , Ciclosporina/sangue , Ciclosporina/uso terapêutico , Relação Dose-Resposta a Droga , Esquema de Medicação , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/sangue , Imunossupressores/uso terapêutico , Masculino , Sirolimo/administração & dosagem , Sirolimo/sangue , Sirolimo/uso terapêuticoRESUMO
This study was conducted to evaluate time-dependent pharmacokinetic changes and drug interactions over the first 6 months after transplantation in kidney transplant recipients receiving tacrolimus (TAC), prednisone (PRED) and mycophenolate mofetil (MMF) or sirolimus (SRL). Pharmacokinetic assessments were carried out at day 7 and months 1, 3, and 6 in kidney transplant recipients receiving TAC plus PRED with either MMF (2 g/day, n = 13) or SRL (15 mg loading dose, 5 mg for 7 days followed by 2 mg/day, n = 12). There were no differences in the main demographic characteristics or in mean PRED doses during the first 6 months after transplant. From day 7 to month 6, there was a 65% increase in TAC dose corrected exposure (dose corrected area under the curve; AUC) in patients receiving MMF (P = 0.005) and a 59% increase in TAC dose corrected exposure in patients receiving SRL (P = 0.008). From day 7 to month 6, there was a 72% increase in mycophenolate dose corrected exposure (P = 0.001) and a 65% increase in SRL dose corrected exposure (P = 0.008). TAC dose corrected exposure was 23% lower in patients receiving SRL compared with MMF (P = 0.012) on average over the study period. PRED dose reduction was associated with increase in TAC (in patients receiving SRL, P = 0.040) and mycophenolic acid (MPA) (P = 0.070) drug exposures. Tercile distribution of TAC drug exposure showed a positive correlation with mean SRL exposures (P = 0.016). Conversely, tercile distribution of SRL drug exposure showed a positive correlation with mean TAC exposures (P = 0.004). Time-dependent increases in TAC, MPA and SRL drug exposures occur up to 6 months after transplantation. Drug-to-drug interactions indicate that intense therapeutic drug monitoring is required to avoid under- or over-immunosuppression.
Assuntos
Imunossupressores/farmacocinética , Transplante de Rim , Tacrolimo/farmacocinética , Adulto , Área Sob a Curva , Relação Dose-Resposta a Droga , Interações Medicamentosas , Monitoramento de Medicamentos/métodos , Feminino , Seguimentos , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/farmacologia , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/farmacocinética , Ácido Micofenólico/farmacologia , Prednisona/administração & dosagem , Prednisona/farmacologia , Sirolimo/administração & dosagem , Sirolimo/farmacocinética , Sirolimo/farmacologia , Tacrolimo/administração & dosagem , Fatores de Tempo , Distribuição TecidualRESUMO
BACKGROUND: To evaluate the effect of 1 year systemic arterial hypertension on 3-year allograft survival in children with kidney transplantation. METHODS: A retrospective study was carried out of pediatric patients submitted to kidney transplantation at the Universidade Federal de São Paulo (UNIFESP) between January, 1998 and January, 2003. Patients were classified as normotensive or hypertensive according to presence of hypertension within the first year after transplantation. Survival analyses were performed with the Kaplan-Meier survival method, and survival curves were compared with the log-rank test. A p value of < 0.05 was considered statistically significant. RESULTS: Prior to transplantation there were 86 patients (64%) and after 1 year, 70 children (52%) were classified as hypertensive, respectively. Overall, the 3-year graft survival was of 92.5%. Survival of the normotensive group was 95.3% and 90.0% for the hypertensive group; the difference was not statistically significant. CONCLUSION: Although the difference between the two groups was not statistically significant the higher survival of the normotensive group seems to be clinically significant and allows hypothesizing that arterial hypertension could be a risk factor for pediatric graft survival. However, due to limitations of the study it is impossible to affirm that hypertension is an independent risk factor for lower graft survival.
Assuntos
Sobrevivência de Enxerto , Hipertensão/complicações , Transplante de Rim , Adolescente , Brasil/epidemiologia , Criança , Pré-Escolar , Métodos Epidemiológicos , Humanos , Hipertensão/diagnóstico , Hipertensão/epidemiologia , Hipertensão/etiologia , Fatores de Risco , Fatores de Tempo , Transplante HomólogoRESUMO
OBJETIVO: Avaliar a influência da hipertensão arterial sistêmica com um ano de transplante renal na sobrevida do enxerto renal três anos após o transplante em crianças. MÉTODOS: Estudo observacional e retrospectivo na série de pacientes transplantados renais pediátricos da Universidade Federal de São Paulo (UNIFESP) no período de janeiro/1998 a janeiro/2003. Ao final do primeiro ano pós-transplante, os pacientes foram classificados em dois grupos: normotensos e hipertensos. A análise estatística de sobrevida foi através do método de Kaplan-Meier. A comparação entre grupos foi realizada utilizando-se o teste do "log-rank". Para os testes adotamos o limite de 5 por cento (α < 0,05) para rejeição da hipótese de nulidade. RESULTADOS: Antes do transplante 86 pacientes (64 por cento) e após um ano 70 indivíduos (52 por cento) foram classificados como hipertensos, respectivamente. A sobrevida do enxerto renal após três anos de transplante foi de 92,5 por cento para a amostra completa do estudo. O grupo de normotensos apresentou sobrevida de 95,3 por cento e os hipertensos 90 por cento; a diferença não foi estatisticamente significante. CONCLUSÃO: Apesar do resultado estatístico não ser significante, a diferença observada entre os dois grupos após três anos de transplante, de 5 por cento maior sobrevida nos indivíduos que eram normotensos um ano após o transplante, nos parece clinicamente significativa e nos permite levantar a hipótese de que a hipertensão arterial pode ser um fator de risco para a sobrevida do enxerto pediátrico. Entretanto, não nos seria possível afirmar que a hipertensão é fator de risco independente para menor sobrevida do enxerto devido às limitações do estudo.
BACKGROUND: To evaluate the effect of 1 year systemic arterial hypertension on 3-year allograft survival in children with kidney transplantation. METHODS: A retrospective study was carried out of pediatric patients submitted to kidney transplantation at the Universidade Federal de São Paulo (UNIFESP) between January, 1998 and January, 2003. Patients were classified as normotensive or hypertensive according to presence of hypertension within the first year after transplantation. Survival analyses were performed with the Kaplan-Meier survival method, and survival curves were compared with the log-rank test. A p value of < 0.05 was considered statistically significant. RESULTS: Prior to transplantation there were 86 patients (64 percent) and after 1 year, 70 children (52 percent) were classified as hypertensive, respectively. Overall, the 3-year graft survival was of 92.5 percent. Survival of the normotensive group was 95.3 percent and 90.0 percent for the hypertensive group; the difference was not statistically significant. CONCLUSION: Although the difference between the two groups was not statistically significant the higher survival of the normotensive group seems to be clinically significant and allows hypothesizing that arterial hypertension could be a risk factor for pediatric graft survival. However, due to limitations of the study it is impossible to affirm that hypertension is an independent risk factor for lower graft survival.
Assuntos
Adolescente , Criança , Pré-Escolar , Humanos , Sobrevivência de Enxerto , Hipertensão/complicações , Transplante de Rim , Brasil/epidemiologia , Métodos Epidemiológicos , Hipertensão/diagnóstico , Hipertensão/epidemiologia , Hipertensão/etiologia , Fatores de Risco , Fatores de Tempo , Transplante HomólogoRESUMO
UNLABELLED: Mycophenolate mofetil (MMF) and sirolimus (SRL) are effective immunosuppressive drugs with distinct safety profile. METHODS: Kidney transplant recipients receiving tacrolimus (TAC)-based immunosuppressive regimen were randomized to receive fixed daily doses of MMF (2 g/d, n = 50) or SRL (one loading dose of 15 mg, 5 mg/d till day 7 and 2 mg/d thereafter, n = 50) without induction therapy. RESULTS: No differences were observed in the incidence of the composite (biopsy-confirmed acute rejection, graft loss or death) end-point (18% vs. 16%, p = 1.000), biopsy confirmed acute rejection (12% vs. 14%, p = 1.000), one-yr patient (94% vs. 98%, p = 0.308), graft (92% vs. 98%, p = 0.168), and death-censored graft survival (98% vs. 100%, p = 0.317) comparing patients receiving MMF or SRL respectively. Patients receiving SRL showed worse safety outcomes, higher mean creatinine (1.6 +/- 0.5 mg/dL vs. 1.4 +/- 0.3 mg/dL, p = 0.007), higher proportion of patients with proteinuria (52.0% vs. 10.7%, p = 0.041), higher mean urinary protein concentrations (0.3 +/- 0.5 g/L vs. 0.1 +/- 0.2 g/L, p = 0.012), higher mean cholesterol concentration (217 mg/dL vs. 190 mg/dL, p = 0.030), and higher proportion of patients prematurely discontinued from randomized therapy (26% vs. 8%, p = 0.031). CONCLUSION: In patients receiving TAC, MMF produced similar efficacy but superior safety profile compared with SRL.
Assuntos
Rejeição de Enxerto/prevenção & controle , Imunossupressores/uso terapêutico , Transplante de Rim/imunologia , Ácido Micofenólico/análogos & derivados , Sirolimo/uso terapêutico , Corticosteroides/uso terapêutico , Adulto , Quimioterapia Combinada , Feminino , Rejeição de Enxerto/imunologia , Humanos , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/efeitos adversos , Ácido Micofenólico/uso terapêutico , Estudos Prospectivos , Sirolimo/efeitos adversos , Tacrolimo/uso terapêutico , Resultado do TratamentoRESUMO
We performed a case-control study in renal transplant patients between 1998 and 2003 to identify risk factors for arterial hypertension over the medium term in pediatric patients undergoing renal transplantation. Three years after transplant, patients were classified into hypertensive or control groups. The following risk factors were analyzed: hypertension before transplant, glomerular filtration rate at sixth posttransplant month, acute rejection episodes, renal artery stenosis, accumulated prednisone and calcineurin inhibitor doses, presence of native kidneys, donor type (living or cadaver), body mass index at 1 year posttransplant, and glomerular disease as renal insufficiency etiology. Of 161 transplants, 124 fulfilled the inclusion criteria; 63 were hypertensive, and 61 were controls. Univariate analysis showed hypertension before transplant (52/63 vs. 27/61, p < 0.001), glomerulopathies (23/63 vs. 12/61, p = 0.001), glomerular filtration rate at 6 months (71 +/- 18 vs, 80 +/- 18 ml/min per 1.73 m(2), p = 0.003) as risk factors. A tendency to statistical significance was observed with regard to body mass index (SDS) in the first year (0.40 +/- 1.10 vs, 0.04 +/- 1.10, p = 0.072). Multivariate analysis showed statistical significance concerning previous hypertension and glomerular filtration rate at 6 months. Hypertension before transplant and early graft function are the major risk factors for hypertension in the medium term following renal transplant.
Assuntos
Hipertensão/etiologia , Transplante de Rim/efeitos adversos , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Fatores de Risco , Fatores de TempoRESUMO
Tacrolimus (TAC) is considered a critical dose drug. The purpose of our study was to investigate circadian and time-dependent changes in TAC pharmacokinetics over the first year after kidney transplantation. Pharmacokinetic (PK) studies were performed in 26 recipients of first living donor kidney transplants at day 7 after morning (a.m.) and evening (p.m.) doses of TAC. Additional serial PK studies were carried out in nine patients at month 6 (M6) and month 12 (M12). Blood samples were collected before 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 h after TAC administration. Demographics, TAC and adjunctive immunosuppressive doses, hematology, and biochemistry were recorded in each PK study. Mean age was 37 years, body mass index 23 kg/m(2), 58% males, and 85% Caucasian. Higher AUC (231.4 vs. 220 ng.h/mL, P = 0.06) and C(max) (34.1 +/- 12.6 vs. 24.4 +/- 9.8 ng/mL, P < 0.001), and lower T(max) (1.6 +/- 0.8 vs. 2.7 +/- 2.0 h, P = 0.05) values were observed comparing a.m. and p.m. administrations. Comparing D7, M6 and M12, there was a significant increase in dose-normalized AUC (31.4 +/- 22.2 vs. 50.1 +/- 33 vs. 39.2 +/- 24.4 ng.h/mL/mg, P = 0.005), C(max) (4.4 +/- 2.4 vs. 7.8 +/- 3.5 vs. 6.0 +/- 3.3 ng/mL/mg, P < 0.001) and T(max) (1.6 +/- 1.1 vs. 1.7 +/- 0.4 vs. 1.8 +/- 0.8 h, P = 0.006), respectively. Over the first year the intraindividual variability of dose-normalized AUC, C(max) and C(0) were 82%, 72%, and 90%, respectively. No significant changes were observed comparing inter-individual variability of dose-normalized AUC (21%, 24%, 33%), C(max) (46%, 45%, 55%), C(0) (49%, 83%, 81%) at D7, M6 and M12, respectively. We observed a good correlation between a.m. and p.m. TAC AUC (r(2) = 0.90) and C(0) (r(2) = 0.88). Tacrolimus pharmacokinetics display circadian variation suggesting a slower and delayed absorption phase at nighttime. Tacrolimus also showed time-dependent PK changes, suggesting an improvement in absorption during the first 6 months. Despite circadian variation we observed good correlations between a.m. and p.m. TAC AUC (r(2) = 0.90) and C(0) (r(2) = 0.88) and between C(0) and total daily TAC exposure (a.m. + p.m. AUC) suggesting that trough-guided therapeutic monitoring is still a reliable and simple strategy to optimize the clinical use of TAC.
Assuntos
Ritmo Circadiano , Imunossupressores/farmacocinética , Transplante de Rim , Tacrolimo/farmacocinética , Adulto , Área Sob a Curva , Relação Dose-Resposta a Droga , Esquema de Medicação , Monitoramento de Medicamentos , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de TempoRESUMO
The purpose of this study was to prospectively analyze the relationship between posttransplant IgG anti-HLA class I and/or class II antibodies and graft failure due to chronic allograft nephropathy (CAN). We studied 512 first kidney graft recipients transplanted at a single center, with a graft functioning for at least 3 years. A single blood sample was collected from each patient, and the presence of antibodies was evaluated by PRA-ELISA. The median post-transplant time after blood collection was 4.4 years and did not differ between patients with or without anti-HLA antibodies. Among the 512 recipients, 55 (10.7%)were positive for anti-HLA class II, 20 (3.9%) for anti-HLAclass I, and 16 (3.1%) for anti-HLA class I and class II antibodies. After antibody evaluation, the patients were followed for at least 34 months. Anti-HLA class II antibodies and serum creatinine levels > or = 2 mg/dl at the time of antibody testing were independently associated with graft loss due to CAN, with relative risks (RR) of 3.29 and 13.82, respectively. When both factors were present, the RR rose to 36.07. In graft biopsies with CAN, the lesions believed to be mediated by antibodies (chronic glomerulopathy, arteriosclerosis, and lamination of the peritubular capillaries basement membrane) were more prevalent in biopsies with CAN from patients with anti-HLA class II antibodies. In conclusion, our data support not only an association but also a pathogenic role of anti-HLA class II antibodies in approximately 40% of chronic allograft cases.
Assuntos
Antígenos HLA-D/imunologia , Isoanticorpos/sangue , Transplante de Rim/imunologia , Creatinina/sangue , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Imunoglobulina G/sangue , Imunossupressores/uso terapêutico , Fatores de Risco , Transplante Homólogo/imunologia , Falha de TratamentoRESUMO
AIM: This study was designed to identify optimal therapeutic sirolimus (SRL) concentrations in black kidney transplant recipients on reduced cyclosporine (CsA) exposure and prednisone. METHODS: Seventy patients (64 living/six deceased) received CsA (8-10 mg/kg/d), prednisone, and 15 mg loading dose followed by 5-mg fixed doses of SRL till day 7 when they were randomized to maintain SRL trough concentrations (high-performance liquid chromatography) of 8-12 (GI = 34) or 15-20 (GII = 36) ng/mL. RESULTS: Mean CsA concentrations were 109 +/- 53 vs. 89 +/- 41 ng/mL and 75 +/- 54 vs. 60 +/- 35 ng/mL (ns) at 2 and 6 months. Accordingly, mean SRL trough concentrations were 12.4 +/- 6.1 vs. 20.0 +/- 9.5 ng/mL (p < 0.001) and 10.8 +/- 5.8 vs. 18.0 +/- 6.1 ng/mL (p < 0.001). The incidence of biopsy-proven acute rejection [13% (GI: 18% vs. GII: 8%, ns)], graft loss or death was 16% (GI: 21% vs. GII: 11%, ns]. There were no deaths and three graft losses (GI = 1; GII = 2). Creatinine clearance was higher in GI (64.5 +/- 17 vs. 54.4 +/- 14.7 mL/min, p = 0.011). The incidence of post-transplant diabetes mellitus was 13% and no CMV disease was observed. CONCLUSION: In black recipients of primarily living renal allograft donors reduced CsA exposure and SRL concentration-controlled regimens produced low incidences of acute rejection, post-transplant diabetes mellitus and CMV disease, with no significant impairment in graft function.
Assuntos
Negro ou Afro-Americano , Ciclosporina/administração & dosagem , Rejeição de Enxerto/prevenção & controle , Imunossupressores/administração & dosagem , Transplante de Rim , Sirolimo/administração & dosagem , Adulto , Biópsia , Cromatografia Líquida de Alta Pressão , Ciclosporina/farmacocinética , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Seguimentos , Glucocorticoides/administração & dosagem , Glucocorticoides/farmacocinética , Rejeição de Enxerto/sangue , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto , Humanos , Imunossupressores/farmacocinética , Falência Renal Crônica/etnologia , Falência Renal Crônica/cirurgia , Masculino , Prednisona/administração & dosagem , Prednisona/farmacocinética , Estudos Prospectivos , Sirolimo/farmacocinética , Fatores de Tempo , Transplante Homólogo , Resultado do TratamentoRESUMO
Early kidney transplantation is crucial in order to accomplish both optimal mental development and the best adult height in children with end-stage renal disease. The aim was to evaluate the efficacy of the child priority policy for cadaveric kidney sharing adopted in the State of Sao Paulo (Brazil). We performed a retrospective study of data collected by the Government Transplant Department in São Paulo, involving all patients included in the waiting list from August 13, 1998 to December 31, 2001. During the study period, the child priority policy had been changed giving: period A--from the outset up to March 14, 2001, where the rule was to direct cadaveric kidneys obtained from children <12 yr, to recipients <12 yr; period B--from March 14, 2001 onwards, where the policy had been broadened to include cadaveric donors <18 yr, destined for recipients <18 yr. We performed the analysis of the data comprising 8940 patients, 8622 being adults (mean age = 48.6 +/- 14.1 yr, 3594 females) and 318 children (mean age = 11.9 +/- 5.1 yr, 156 females). Over the 3.5-yr follow-up there were 1964 deaths [1933 adults and 31 children, odds ratio (OR) 0.37; 95% CI 0.25-0.55], 1032 living donor kidney transplants (963 adults and 69 children, OR 2.20; 95% CI 1.66-2.93), and 556 cadaveric kidney transplants (444 adults and 112 children, OR 10.11; 95% CI 7.75-12.94). Three and a half years after being enrolled on the list, 24% of the children and 75% of the adults, respectively, were still awaiting a cadaveric kidney transplant (log rank test = 539, p < 0.00001). The analysis of period A vs. period B, suggests that the raising of the inclusion age upper limit to 18 yr, resulted in a twofold increase in the percentage of children being grafted within 6 months of enrollment. Overall, our data shows a slow rate of cadaveric kidney transplantation activity in Sao Paulo. Children's chances of receiving a living donor kidney almost doubled. Moreover, 19.5% of pediatric recipients had received their kidney within the first year of being enrolled on the waiting list. The scheme adopted in Sao Paulo is encouraging, but the results remain less favorable than those observed in other countries. The adoption of the priority policy did not result in an unacceptable increase of adult waiting time, given that the number of adults on our waiting list outweighs by far the number of children.
Assuntos
Transplante de Rim/legislação & jurisprudência , Adolescente , Adulto , Brasil , Cadáver , Criança , Pré-Escolar , Feminino , Humanos , Falência Renal Crônica/terapia , Masculino , Estudos Retrospectivos , Fatores de Tempo , Listas de EsperaRESUMO
BACKGROUND: The ability of sirolimus (SRL), in combination with reduced exposure of cyclosporine, was investigated to prevent acute rejection and associated side effects. METHODS: Between June 1999 and February 2000, 70 recipients of primary one-haplotype living-related donor renal allografts were randomized to receive SRL (2 mg/d) or azathioprine (AZA) (2 mg/kg/d) combined with cyclosporine and prednisone. The primary end-point was a composite of first occurrence of biopsy-confirmed acute rejection, graft loss, or death during the first 3 months after transplantation. RESULTS: From week 4 to month 12, SRL patients received lower cyclosporine (week 4: 364 mg/d vs. 455 mg/d, p = 0.004; month 12: 195 mg/d vs. 255 mg/d, p = 0.038) doses and showed lower cyclosporine concentrations (week 4: 247 ng/mL vs. 309 ng/mL, p = 0.04; month 12: 143 ng/mL vs. 188 ng/mL, p = 0.045). Compared with AZA, SRL patients showed reduced 3-month primary end point (0% vs. 17.1%, p = 0.025), and reduced incidence of biopsy-confirmed acute rejection at 3 months (0% vs. 14.3%, p = 0.01) but not at 12 months (11.4% vs. 14.3%, NS). Mean creatinine at 12 months were not different (1.8 +/- 0.6 vs. 1.6 +/- 0.6, p = 0.23). Hyperlipidemia was the only adverse event more frequent among SRL patients (49% vs. 17%, p = 0.01). There were no differences in infections and no malignancies in both groups. CONCLUSIONS: The combination of 2 mg fixed doses of SRL, reduced cyclosporine exposure and prednisone was associated with a low incidence of acute rejection and did not result in significantly impaired graft function compared with patients receiving AZA, standard doses of cyclosporine and prednisone.
Assuntos
Azatioprina/uso terapêutico , Ciclosporina/uso terapêutico , Rejeição de Enxerto/prevenção & controle , Imunossupressores/uso terapêutico , Transplante de Rim/imunologia , Prednisona/uso terapêutico , Sirolimo/uso terapêutico , Adulto , Azatioprina/administração & dosagem , Azatioprina/efeitos adversos , Ciclosporina/administração & dosagem , Ciclosporina/efeitos adversos , Quimioterapia Combinada , Feminino , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Lipídeos/sangue , Masculino , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Estudos Prospectivos , Segurança , Sirolimo/administração & dosagem , Sirolimo/efeitos adversosRESUMO
UNLABELLED: The impact of ethnic miscegenation on tacrolimus clinical pharmacokinetics and therapeutic drug monitoring. We sought to determine the influence of ethnic miscegenation on tacrolimus pharmacokinetics and trough concentrations during the first 6 months after transplantation. METHODS: Tacrolimus concentrations were measured in blood samples obtained from 22 transplant recipients during the first week of transplant, within pharmacokinetic profiles, and throughout the first 6 months post-transplant, using the Pro Tac II ELISA method. Pharmacokinetic parameters and between- and within-subject blood concentration variability were compared stratifying the total population in two distinct ethnic groups of white (W) and non-white (NW) patients, according to a stringent criterion. RESULTS: Between-subject variability in dose-adjusted concentrations during dosing interval varied from 38.8 to 69.5%. Compared with W patients, NW patients showed higher variability in blood tacrolimus concentrations during dosing interval (37.40 +/- 5.64 vs. 56.95 +/- 11.49, p < 0.001) and lower drug exposures (AUC: 229.4 +/- 55.5 vs. 66.9 +/- 67.1 ng x h/mL, p=0.036). The correlation coefficients (r2) between C0, C12 or Cmax and AUC were 0.83, 0.91 and 0.5, respectively. An equation derived from early time concentrations (C0, C1.5 and C4) accounted for 94% of the variability observed in AUC. Compared with W patients, a higher proportion of tacrolimus blood determinations during the first week were below 10 nug/mL in NW patients (24% vs. 62%, p=0.028). Tacrolimus absorption increased from week 1-4 (1.1 +/- 0.53 vs. 1.73 +/- 0.97 nug/mL/mg, p < 0.0001) but was still showed high between- (41.6-70.4%) and within-subject (18.2-32.5%) variability, regardless of ethnicity, after stabilization. CONCLUSION: Non-white patients show higher tacrolimus variability and lower drug exposures after transplantation compared with W patients. Therefore, higher initial tacrolimus doses and intensive monitoring are recommended when administering tacrolimus-based immunosupressive therapy to NW patients of this transplant population.
Assuntos
Monitoramento de Medicamentos , Imunossupressores/farmacologia , Grupos Raciais , Tacrolimo/administração & dosagem , Tacrolimo/farmacocinética , Adulto , Feminino , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/sangue , Transplante de Rim , Masculino , Pessoa de Meia-Idade , Tacrolimo/sangue , Fatores de TempoRESUMO
Considerando que fatores dependentes de aloantígenos e näo-dependentes de aloantígenos associam-se ao desenvolvimento de nefropatia crônica do enxerto (NCE) e à reduzida sobrevida do enxerto renal, este trabalho objetivou analisar 1.544 transplantes renais quanto à incidência de rejeiçäo aguda (RA) de acordo com três protocolos imunossupressores: (1) azatioprina (AZA) mais prednisona (PRED); (2) AZA mais PRED mais ciclosporina (CSA); e (3) AZA mais PRED mais ciclosporina microemulsäo (CSAm). Além disso, fizeram-se análises uni e multivariadas dos fatores potencialmente associados à sobrevida funcional do enxerto. A incidência de RA foi menor entre pacientes que utilizaram protocolos com ciclosporina quando comparada a pacientes que receberam AZA mais PRED. Entre os pacientes com RA, a sobrevida de cinco anos do enxerto foi significativamente menor que aqueles sem RA. Receptores com RA apresentaram menor sobrevida livre de NCE em cinco anos que aqueles sem RA. As variáveis que apresentaram associaçäo significativa com o risco de perda do enxerto foram: compatibilidade HLA; número de episódios de RA; idade do doador e idade do receptor.Fatores relacionados à resposta imunológica representam maior risco para perda do enxerto renal.(au)