Uso combinado de inibidores da calcineurina e inibidores da mtor em receptores de transplante renal: eficácia, segurança e tolerabilidade em longo prazo

Introdução:Eficácia e segurança do uso de novo dos inibidores da mammalian target of rapamycin (imTOR) em longo prazo foram avaliadas principalmente baseadas em dados de registro. Métodos: Esta foi uma análise retrospectiva de 10 anos de dados obtidos de 10 estudos prospectivos randomizados em receptores de transplante renal de novo recebendo ICN em combinação com sirolimo (n=329), everolimo (n=128) ou antimetabólitos (n=124). Resultados: Não houve diferença ao longo de 10 anos nas sobrevidas do paciente (84,5 vs. 80,9 vs. 89,7,p=0,996), do enxerto (65,4 vs. 59,5 vs. 73,1% p=0,868) e livre de rejeição aguda comprovada por biópsia (78,1 vs. 77,3 vs. 79,0%, p=0,976). A incidência de infecção por CMV foi menor (6 vs. 3 vs. 11%, p=0,024) enquanto que descontinuação do tratamento foi maior (66 vs. 47,7 vs. 31,5%, p<0,001) entre pacientes recebendo imTOR, respectivamente. No quinto ano pós-transplante, a média da taxa de filtração glomerular estimada (49,8±18,5 vs. 47,6± 20,7 vs. 55,0±18,5 mL/min, p=0,023) e a proporção de pacientes com proteinúria (53 vs. 40 vs. 23%, p<0,001) foram maiores entre pacientes recebendo imTOR, respectivamente. Conclusão: A eficácia do uso de novo dos imTOR é comparável aos antimetabólitos em receptores de transplante renal recebendo ICN. Apesar da menor incidência de infecções por CMV, o perfil de segurança é desfavorável, mostrando maiores taxas de descontinuações do tratamento, função renal inferior e maior incidência de proteinúria.Dados abertos - Sucupira - Teses e dissertações (2013 a 2016

Avaliação da atividade antifúngica de extrato de Plinia cauliflora e Endopleura uchi

O uso indiscriminado dos medicamentos sintéticos e a própria evolução dos micro-organismos selecionou espécies extremamente resistentes aos agentes químicos utilizados. Para contornar tal situação e ampliar o arsenal de compostos ativos contra micro-organismos, o estudo de plantas tornou-se uma necessidade crescente. A utilização de fitoterápicos na prevenção e/ou cura de doenças são necessários estudos prévios relativos a aspectos botânicos, farmacognósticos, fitoquímicos, farmacológicos e toxicológicos. Neste trabalho, foram estudados extratos obtidos com as folhas de Plinia cauliflora (Mart.) Kausel e de cascas pulverizadas de Endopleura uchi (Huber) Cuatrec., quanto às propriedades antimicrobianas frente a diferentes linhagens de fungos: Aspergillus niger, Beauveria bassiana, Metarhizium anisopliae, Trichoderma reesei e Trichophyton rubrum. Foram avaliadas as atividades antifúngicas dos materiais vegetais determinando sua Concentração Inibitória Mínima (CIM). Com base nesses dados foi realizada a avaliação da atividade antifúngica observando o crescimento radial dos fungos em placas de Petri contendo meio de cultura incorporado com os materiais vegetais nas concentrações de CIM e 1%, sendo após realizada a mensuração dos diâmetros formados. Trichophyton rubrum foi o micro-organismo que apresentou maior sensibilidade frente ao extrato e as frações de P. cauliflora, com valores de CIM baixos, enquanto que a cepa industrial de Aspergillus niger mostrou-se totalmente resistente a todos os extratos testados. A determinação da atividade antifúngica em placas contendo meio sólido, mostrou uma confirmação dos resultados pois o extrato etanólico, a fração butanólica e a fração aquosa de P. cauliflora, tanto na concentração 1% quanto na obtida pelo CIM, inibiram o crescimento T. rubru

Pharmacokinetics and Long-TermSafety and Tolerability of Everolimus in Renal Transplant Recipients Converted From Cyclosporine

Background:Conversion from cyclosporine (CsA) to everolimus (EVR) in kidney transplant recipients receiving mycophenolate sodium (MPS) and corticosteroids has been used to reduce CsA associated toxicities. Nevertheless, exposures produced by the initial EVR dose, the steady state pharmacokinetic and long-term safety and tolerability have not been explored in detail.Methods:Twenty-four stable kidney transplant recipients receiving CSA, MPS, and corticosteroids were converted from CSA to EVR. The initial EVR dose was 3 mg BID. Weekly monitoring of EVR blood concentrations was followed by a full 12 hour pharmacokinetic profile 28 days after conversion. Therapeutic drug monitoring, safety, and tolerability were analyzed during 5 years of follow-up.Results:The study population was relatively young (mean of 42 years) with a predominance of males (62%) and White (67%) recipients of kidneys from living (54%) or deceased (46%) donors. Mean time of the conversion was 61 months after transplantation. In the first 7 patients, the initial EVR dose of 3 mg BID resulted in mean EVR trough blood concentration of 14.7 3.7 ng/mL at day 7. The initial EVR dose was then reduced to 2 mg BID for the following 17 patients. Four weeks after conversion, mean EVR dose was 1.7 +/- 0.5 mg BID (7 patients were receiving 1 mg BID and 17 were receiving 2 mg BID) resulting in mean EVR trough blood concentration of 4.0 +/- 1.4 ng/mL. Whereas mean maximum concentration (13.4 +/- 2.8 versus 22.9 +/- 7.4 ng/mL, P = 0.003) and mean apparent clearance (232 +/- 79 versus 366 +/- 173 mL/min, P = 0.016) were higher, mean area under the curve (78.2 +/- 22.1 versus 102.5 +/- 38.5 ng.h/mL, P = 0.067) and mean C-0 (3.7 +/- 1.3 versus 4.1 +/- 1.5 ng/mL, P = 0.852) were no different comparing patients receiving 1 mg and 2 mg EVR BID. Mean inter-subject variability of area under the curve, trough concentration, and maximum concentration was 38%, 36%, and 38%. EVR treatment was discontinued in 29% of patients due to proteinuria (N = 2), pneumonia (N = 2), dyslipidemia (N = 2), and anemia (N = 1) and MPS dose was reduced in 58% of patients.Conclusions:The initial 3 mg BID dose produced high EVR trough blood concentrations. The 2 mg BID dose appears to be the appropriate initial dose to provide therapeutic concentrations but still requires initial intensive therapeutic monitoring to achieve and maintain blood concentrations within the therapeutic target concentration. The combination of EVR and full dose MPS has limited long-term tolerability and safety.NovartisUniv Fed Sao Paulo, Div Nephrol, Hosp Rim, Rua Borges Lagoa,960 11 Andar, BR-04038002 Sao Paulo, BrazilUniv Fed Sao Paulo, Div Nephrol, Hosp Rim, Rua Borges Lagoa,960 11 Andar, BR-04038002 Sao Paulo, BrazilWeb of Scienc

The current burden of cytomegalovirus infection in kidney transplant recipients receiving no pharmacological prophylaxis

Abstract Cytomegalovirus (CMV) infection in kidney transplantation has changed its clinical spectrum, mostly due to the current and more effective immunosuppression. In the absence of preventive strategies it is associated with significant morbi-mortality. Objective: This study evaluated the incidence of CMV events and its effect on outcomes of kidney transplantation in recipients without pharmacological prophylaxis or targeted preemptive treatment. Results: The study cohort comprised 802 recipients of kidney transplants between 04/30/2014 and 04/30/2015. The majority received induction with anti-thymocyte globulin (81.5%), tacrolimus and prednisone in combination with either mycophenolate (46.3%) or azathioprine (53.7%). The overall incidence of CMV events was 42% (58.6% infection and 41.4% disease). Patients with CMV showed higher incidence of first treated acute rejection (19 vs. 11%, p = 0,001) compared with those without CMV but no differences in graft loss, death or loss to follow-up. The incidence of delayed graft function was higher (56% vs. 37%, p = 0.000) and the eGFR at 1 (41 ± 21 vs. 54 ± 28 ml/min, p = 0.000) and 12 months (50 ± 19 vs. 61 ± 29 ml/min, p = 0.000) were lower in patients with CMV. Recipients age (OR = 1.03), negative CMV serology (OR = 5.21) and use of mycophenolate (OR = 1.67) were associated with increased risk of CMV. Changes in immunosuppression was more often in patients with CMV (63% vs. 31%, p = 0.000). Conclusion: the incidence of CMV events was high and associated with higher incidence of acute rejection and changes in immunosuppression. Besides traditional risk factors, renal function at 1 month was independently associated with CMV infection

Randomized Trial of Machine Perfusion Versus Cold Storage in Recipients of Deceased Donor Kidney Transplants With High Incidence of Delayed Graft Function

Background. This study compared the use of static cold storage versus continuous hypothermic machine perfusion in a cohort of kidney transplant recipients at high risk for delayed graft function (DGF). Methods. In this national, multicenter, and controlled trial, 80 pairs of kidneys recovered from brain-dead deceased donors were randomized to cold storage or machine perfusion, transplanted, and followed up for 12 months. The primary endpoint was the incidence of DGF. Secondary endpoints included the duration of DGF, hospital stay, primary nonfunction, estimated glomerular filtration rate, acute rejection, and allograft and patient survivals. Results. Mean cold ischemia time was high but not different between the 2 groups (25.6 +/- 6.6 hours vs 25.05 +/- 6.3 hours, 0.937). The incidence of DGF was lower in the machine perfusion compared with cold storage group (61% vs. 45%, P = 0.031). Machine perfusion was independently associated with a reduced risk of DGF (odds ratio, 0.4995% confidence interval, 0.26-0.95). Mean estimated glomerular filtration rate tended to be higher at day 28 (40.6 +/- 19.9 mL/min per 1.73 m(2) vs 49.0 +/- 26.9 mL/min per 1.73 m(2)P = 0.262) and 1 year (48.3 +/- 19.8 mL/min per 1.73 m(2) vs 54.4 +/- 28.6 mL/min per 1.73 m(2)P = 0.201) in the machine perfusion group. No differences in the incidence of acute rejection, primary nonfunction (0% vs 2.5%), graft loss (7.5% vs 10%), or death (8.8% vs 6.3%) were observed. Conclusions. In this cohort of recipients of deceased donor kidneys with high mean cold ischemia time and high incidence of DGF, the use of continuous machine perfusion was associated with a reduced risk of DGF compared with the traditional cold storage preservation method.Univ Fed Sao Paulo, Hosp Rim, Sao Paulo, SP, BrazilEscola Paulista Med, Org Procura Orgaos, Sao Paulo, SP, BrazilUniv Sao Paulo, Fac Med, Hosp Clin, Sao Paulo, SP, BrazilHosp Israelita Albert Einstein, Kidney Transplant Unit, Sao Paulo, SP, BrazilHosp Samaritano, Sao Paulo, SP, BrazilSanta Casa Sao Paulo, Sao Paulo, SP, BrazilHosp Bandeirantes, Sao Paulo, SP, BrazilHosp Servidor Publ Estadual, Sao Paulo, SP, BrazilHosp Beneficencia Portuguesa, Sao Paulo, SP, BrazilHosp Dante Pazzanese, Sao Paulo, SP, BrazilHosp Base Sao Jose do Rio Preto, Sao Jose Do Rio Preto, SP, BrazilUniv Estadual Paulista, UNESP, Dept Internal Med, Rubiao Jr S-N, Sao Paulo, BrazilSanta Casa Ribeirao Preto, Ribeirao Preto, SP, BrazilHosp Alemao Oswaldo Cruz, Sao Paulo, SP, BrazilHosp Santa Marcelina, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Hosp Rim, Sao Paulo, SP, BrazilEscola Paulista Med, Org Procura Orgaos, Sao Paulo, SP, BrazilWeb of Scienc