Circadian and time-dependent variability in tacrolimus pharmacokinetics.

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.

[Alemtuzumab induction in kidney transplant recipients].

INTRODUCTION: Induction therapy has been used in sensitized patients, re-transplants, and in patients who have high risk to delayed graft function (DGF) after renal transplantation. METHODS: Retrospective study with aim to compare transplant endpoints between recipients of deceased donors which have received induction with alemtuzumab (n = 9) versus thymoglobulin (n = 18). Patients were matched for age, duration of dialysis treatment and cold ischemia time. RESULTS: There were no differences at demographic characteristics. All patients received kidney grafts from deceased donors and 67% of these donors met the expanded criteria. The incidence of DFG was similar in alemtuzumab and thymoglobulin groups, 55% and 56%. At 12 months, rates of rejection free survival (67% versus 89%, p = 0,13), graft survival (62,5% versus 76,6%; p = 0,73), graft with death censored (62,5% versus 76,6%; p = 0,82) and patient survival (83,3% versus 81,2%; p = 0,63) were similar between the two groups. Viral infections and renal function were similar between groups. At the end of the first month, alemtuzumab patients displayed a fewer lymphocyte number (135 ± 78 versus 263 ± 112 N/mm³, p < 0,05) followed by a more rapid recovery after 3 months (day 90: 683 ± 367 versus 282 ± 72 N/mm³; p < 0,05). Cost associated with alemtuzumab and thymoglobulin inductions therapies were R$ 1,388.00 and R$ 7,398.00. CONCLUSION: In this cohort of patients, alemtuzumab induction showed efficacy and safety comparable to thymoglobulin but with significant cost reduction.

Tacrolimus pharmacokinetic drug interactions: effect of prednisone, mycophenolic acid or sirolimus.

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.

Cyclosporine and sirolimus pharmacokinetics and drug-to-drug interactions in kidney transplant recipients.

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.

Terapia de indução com alentuzumabe em receptores de transplante renal / Alemtuzumab induction in kidney transplant recipients

Introdução: Terapias de indução são usualmente utilizadas em receptores sensibilizados contra antígenos HLA, retransplantes e pacientes com risco de apresentar função tardia do enxerto (FTE). Método: Estudo retrospectivo com objetivo de avaliar os desfechos do transplante renal com doador falecido em pacientes que receberam indução com alentuzumabe (n=9). os pacientes do grupo controle, pareados conforme idade do receptor, tempo em diálise e tempo de isquemia fria, receberam timoglubina (n= 18). Resultados: Não houve diferença nas características demográficas entre os grupos. A idade média dos receptores foi de 47 anos e dos doadores, de 59 anos. Entre os doadores, 67 % apresentavam critério expandido. A incidência de FTE foi de 55% e 56%, respectivamente. Ao final do primeiro ano, não houve diferença nas sobrevidas livre de rejeição aguda comprovada por biópsia (67,0% e 84,6%, p=0,26), do paciente (83,3% e 81,2%; p=0,63), do enxerto (62,5% e 66,7%; p=0,82), do enxerto com óbito censorado (62,5% e 76,6%; p= 0,73) e na função renal 9depuração de creatinina: 61,6 +- 18,2 versus 52,7 +- 26,1 mL/min, p= 0,503). Houve maior redução na contagem de linfócitos no sangue periférico no grupo alentuzumabe (dia 14:172 +- 129 versus 390 +- 195 N/mm³, p< 0,05; dia 30: 135 +- 78 versus 263 +- 112 N/mm³, p< 0,05), porém com retorno mais rápido a valores normais após o transplante (dia 90: 683 +- 367 versus 282 +- 72 N/mm³, p < 0,05; dia 360: 1269 +- 806 versus 690 +- 444 N/mm³, p < 0,05). O custo do tratamento com alentuzumade foi de R$ 1.388,00, enquanto que o custo médio com timoglobulina foi de R$ 7.398,00. Conclusão: Essa experiência com alentuzumabe não demonstrou eficácia e/ou segurança superiores aos regimes com timoglobulina, apesar do custo ser em média cinco vezes menor.

Introduction: Induction Therapies are usually used in recipients sensitized against HLA antigens, retransplantation and patients at risk for delayed graft function (FTE). Method: A retrospective study to evaluate the outcomes of cadaveric renal transplant in patients who received induction alentuzumabe (n = 9). patients in the control group, matched by recipient age, time on dialysis and cold ischemia time, received timoglubina (n = 18). Results: No differences in demographic characteristics between groups. The average age of recipients was 47 years and from donors in 59 years. Among donors, 67% had expanded criteria. The incidence of FTE was 55% and 56% respectively. At the end of the first year, there was no difference in survival free of acute rejection proven by biopsy (67.0% and 84.6%, p = 0.26), the patient (83.3% and 81.2%, p = 0.63), graft (62.5% and 66.7%, p = 0.82) and death censored graft (62.5% and 76.6%, p = 0.73) and 9depuração renal creatinine: 61.6 + - 18.2 vs. 52.7 + - 26.1 mL / min, p = 0.503). Higher reduction in lymphocyte count in peripheral blood in group alentuzumabe (day 14:172 + - 129 versus 390 + - 195 N / mm ³, p <0.05; 30 days: 135 + - 78 versus 263 + - 112 N / mm ³, p <0.05), but with a faster return to normal after transplantation (day 90: 683 + - 367 versus 282 + - 72 N / mm ³, p <0.05, day 360: 1269 + - 806 versus 690 + - 444 N / mm ³, p <0.05). The cost of treatment with alentuzumade was R $ 1,388.00, while the average cost timoglobulina was R $ 7,398.00. Conclusion: This experience with alentuzumabe not demonstrated efficacy and / or security schemes with higher timoglobulina, despite the cost be on average five times lower.

Eficácia, tolerabilidade e segurança do uso do sirolimo após o transplante renal / Sirolimus efficacy, tolerability, and safety for treatment after kidney transplantation

Introdução: Sirolino (SRL) é um imunossupressor com conhecida eficácia e perfil de segurança na profilaxia da rejeição aguda após o transplante renal. Objetivos:Avaliar eficácia, tolerabilidade e segurança do uso do SRL e de prednisona em associação a ciclosporina (CSA) ou tarcolino (TAC) após o transplante renal. Metodologia: Estudo retrospectivo de 332 receptores de transplantes renais realizados entre 1999 e 2006. O desfecho primário foi a falha de tratamento, definida como a incidência cumulativa de rejeição aguda confirmada por biópsia (RACB), perda do enxerto, óbito ou descontinuação do SRL. Resultados: Dos 332 transplantes, 92% foram com doador vivo. A média de idade dos receptores foi de 37 anos, sendo 65% homens, 46% brancos e 6% diabéticos. SRL foi associado a CSA ou TAC em 70,8% e 29,2% dos pacientes. A incidência de falha de tratamento foi de 22,2% e de 47,8% no final do primeiro e do quinto ano de transplante, sem diferença entre pacientes recebendo CSA ou TAC. Ao final do quinto ano, as sobrevidas do paciente, do enxerto, do enxerto censorando o óbito e livre de RACB foram de 92,8%, 86,1%, 92,7% e 82,2%, respectivamente. O tratamento com SRL foi interrompido em 27,1% dos pacientes: 22,9% em razão de reações adversas e 3,3% devido à ineficácia. os principais motivos de suspensão do SRL foram dislipidemia (6,0%), disfunção do enxerto (5,2%), proteinúria (4,5%), infecções (1,5%), dificuldade de cicatrização (1,2%) e anemia (0,9%). Conclusão: Na população estudada, a eficácia e a segurança do SRL foram semelhantes quando combinado com CSA ou TAC. A tolerabilidade oral foi adequada considerando-se a relativa baixa taxa de interrupção do uso de SRL.

Introduction: Sirolino (SRL) is an immunosuppressive agent with known efficacy and safety profile for prophylaxis of acute rejection after renal transplantation. Objectives: To evaluate efficacy, tolerability and safety of the SRL and prednisone in combination with cyclosporine (CSA) or tarcolino (TAC) after renal transplantation. Methodology: A retrospective study of 332 recipients of kidney transplants performed between 1999 and 2006. The primary outcome was treatment failure, defined as the cumulative incidence of acute rejection confirmed by biopsy (RACB), graft loss, death or discontinuation of SRL. Results: Of 332 transplants, 92% were with living donors. The mean age of recipients was 37 years, 65% men, 46% white and 6% were diabetic. SRL was combined with CSA or TAC in 70.8% and 29.2% of patients. The incidence of treatment failure was 22.2% and 47.8% at the end of the first and fifth year of transplantation, with no difference between patients receiving CSA or TAC. At the end of the fifth year, the survival of the patient, graft, death censored graft and free of RACB were 92.8%, 86.1%, 92.7% and 82.2% respectively. Treatment with SRL was discontinued in 27.1% of patients: 22.9% because of adverse reactions and 3.3% due to inefficiency. The main reasons for discontinuation of SRL were dyslipidemia (6.0%), graft dysfunction (5.2%), proteinuria (4.5%), infections (1.5%), poor wound healing (1.2% ) and anemia (0.9%). Conclusion: In this population, the efficacy and safety of SRL were similar when combined with CSA or TAC. The oral tolerance was adequate considering the relatively low rate of discontinuation of SRL.

Fatores de risco para deiscência de ferida cirúrgica em receptores de transplante renal / Risk factors for wound dehiscence in kidney transplant recipients

Introdução: As complicações cirúrgicas após o transplante renal são a principal causa de morbidade no período pós-operatório. A deiscência da ferida cirúrgica (FC) aumenta o tempo e o número de internações hospitalares e determina pior evolução a longo prazo do transplante renal. Método: Estudo prospectivo de 582 transplantes renais consecutivos realizados no período de 20/JAN/2005 a 20/DEZ/2005, no Hospital do Rim e Hipertensão. Os pacientes foram acompanhados por 16 a 24 dias no período pós-operatório, para determinar a incidência de deiscência da ferida cirúrgica e o risco atribuído aos seguintes fatores de risco para sua ocorrência: idade do receptor, índice de massa corporal, circunferência abdominal, tipo de doador, tempo de utilização de cateter vesical, diabetes mellitus pré-transplante, tempo de cirurgia, tipo de anastomose ureterovesical e tipo de imunossupressão (análise de regressão logística). Resultados. A incidência de deiscência da FC no período de internação hosar após o transplante foi de 11,6%. O modelo de regressão logística múltipla mostrou que os fatores de risco independentes para o desenvolvimento de deiscência da FC foram a idade do receptor superior a 42 anos (OR 2,7, p<0,05), a presença de diabetes mellitus pré-transplante (OR 2,3, p<0,05), a utilização de rins de doadores falecidos 9OR 2,2, p<0,05) e a utilização de sirolimo nos protocolos imunossupressores (OR 2,9, p<0,05). Conclusões. A incidência de deiscência da FC é elevada após o transplante renal e decorre da presença de fatores de risco prevalentes entre os receptores de transplante renal, sendo o uso de sirolimo o que apresenta o maior risco relativo (OR 2,9, p<0,05).

Introduction: Surgical complications after kidney transplantation are the major cause of morbidity in the postoperative period. The surgical wound dehiscence (HR) increases the time and number of hospitalizations and a poorer long-term outcome of renal transplantation. Method: Prospective study of 582 consecutive kidney transplants performed between the 20/JAN/2005 20/DEZ/2005 in Kidney and Hypertension Hospital. Patients were followed for 16 to 24 days post-operatively to determine the incidence of wound dehiscence and surgical risk attributed to the following risk factors for its occurrence: recipient age, body mass index, waist circumference, type of donor, time of use of bladder catheter, pre-transplant diabetes mellitus, duration of surgery, type of ureterovesical anastomosis and type of immunosuppression (logistic regression analysis). Results. The incidence of FC dehiscence hosar during hospitalization after transplantation was 11.6%. The multiple logistic regression model showed that independent risk factors for the development of FC dehiscence were recipient age above 42 years (OR 2.7, p <0.05), presence of diabetes mellitus pre-transplant (OR 2.3, p <0.05), the use of kidneys from deceased donors 9OR 2.2, p <0.05) and the use of sirolimus in immunosuppressive protocols (OR 2.9, p <0.05) . Conclusions. The incidence of FC dehiscence is high after renal transplantation and results from the presence of risk factors prevalent among renal transplant recipients, and the use of sirolimus that has the highest relative risk (OR 2.9, p <0, 05).

Fatores de risco associados à perda do enxerto e óbito após o transplante renal / Risk factors associated with graft loss and death after kidney transplantation

Objetivo: Avaliar os fatores de risco relacionados à mortalidade e à perda do enxerto nos primeiros dois anos após o transplante renal. Métodos: Análise retrospectiva de transplantes renais realizados entre 2003-2006, utilizando banco de dados informatizado. os desfechos analisados foram: sobrevidas do paciente, do enxerto e fatores de risco através de análise multivariada de Cox. Resultados: Dos 2.364 transplantes, 67% foram com doador vivo (DV), 6% com doadores falecidos (DF) com critério expandido (DCE). As sobrevidas do paciente e do enxero foram superiores entre receptores de DV do que entre os de DF (97% vs 91%; 96% vs 83%, p<0,001). Ao final de 24 meses, os receptores de etnia negra apresentaram sobrevida do enxerto (84% vs 89%, p<0,05) inferior devido à maior mortalidade (sobrevida do paciente: 87% vs 93%, p<0,01). Na data do transplante, os fatores de risco relacionados à mortalidade do receptor foram o tipo de doador (DF, RR=2,4, IC 1,6-3,6) e a etnia negra (RR=1,8, IC 1,2-2,9). Os fatores de risco relacionados à perda do enxerto foram o tipo de doador (DF,RR=2,1, IC 1-3,2), DCE (RR=2,0 IC:1,2-3,3), presença de função retardada do enxerto (RR=1,8, IC 1,2-2,7) e ocorrência de rejeição aguda (RA, RR=3,5, IC2,5-4,8) no primeiro ano após o transplante. Aos seis meses de transplante, os fatores de risco relacionados à mortalidade do receptor foram o tipo de doador (DF, RR=2,5, IC 1,5-4,3) e a ocorrência de RA (RA, RR=2,4, IC 1,6-3,8). Os fatores de risco para a perda do enxerto foram o tipo de doador (DF, RR=2,0, IC 1,1-3,7), rins de DCE (DCE, RR=2,6, IC 1,1-6,2), a ocorrência de RA (RA, RR=9,5, IC 5,4-16,4) e a função renal no 6º mês (creatinina> 1,5 md/dL) (RR=2,1, IC 1,3-3,4). Conclusão: Os fatores de risco tradicionais continuam a exercer influência negativa nos desfechos do transplante.

Objective: To evaluate the risk factors related to mortality and graft loss in the first two years after renal transplantation. Methods: Retrospective analysis of renal transplants performed between 2003-2006, using computerized database. outcomes analyzed were patient survival, graft and risk factors by multivariate Cox Results: Of the 2364 transplants, 67% were living donor (DV), 6% with deceased donors (DF) with expanded criteria ( DCE). The survival of patients and grafts were higher among recipients than among DV DF (97% vs 91%, 96% vs 83%, p <0.001). At the end of 24 months, recipients of black ethnicity had graft survival (84% vs 89%, p <0.05) lower due to higher mortality (patient survival: 87% vs 93%, p <0.01) . At the time of transplant, the risk factors related to mortality of the recipient were donor type (FD, RR = 2.4, CI 1.6 to 3.6) and black race (RR = 1.8, CI 1, 2 to 2.9). Risk factors related to graft loss were donor type (FD, RR = 2.1, CI 1 to 3.2), DCE (RR = 2.0 CI :1,2-3, 3), presence delayed graft function (RR = 1.8, CI 1.2 to 2.7) and the occurrence of acute rejection (AR, RR = 3.5, IC2 0.5 to 4, 8) in the first year after transplantation. At six months after the transplant, the risk factors related to mortality of the recipient were donor type (FD, RR = 2.5, CI 1.5 to 4.3) and the occurrence of RA (RA, RR = 2.4 CI 1.6 to 3.8). Risk factors for graft loss were donor type (FD, RR = 2.0, CI 1.1 to 3.7), kidney DCE (DCE, RR = 2.6, CI 1.1 - 6.2), the occurrence of RA (RA, RR = 9.5, CI 5.4 to 16.4) and renal function at 6 months (creatinine> 1.5 md / dL) (RR = 2.1, CI 1.3 to 3.4). Conclusion: The traditional risk factors continue to exert negative influence on the outcomes of transplantation.