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2.
Transplant Proc ; 51(9): 3181-3185, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31711586

RESUMO

Small intestinal transplantation is performed for patients with intestinal failure who failed other surgical and medical treatment. It carries notable risks, including, but not limited to, acute and chronic cellular rejection and graft malfunction. Late severe acute intestinal allograft rejection is associated with increased risk of morbidity and mortality and, in the majority of cases, ends with total enterectomy. It usually results from subtherapeutic immunosuppression or nonadherence to medical treatment. We present the case of a 20-year-old patient who underwent isolated small bowel transplant for total intestinal Hirschsprung disease at age 7. Due to medication nonadherence, she developed severe late-onset acute cellular rejection manifested by high, bloody ostomy output and weight loss. Ileoscopy showed complete loss of normal intestinal anatomic landmarks and ulcerated mucosa. Graft biopsies showed ulceration and granulation tissue with severe architectural distortion consistent with severe intestinal graft rejection. She initially received intravenous corticosteroids and increased tacrolimus dose without significant improvement. Her immunosuppression was escalated to include infliximab and finally antithymocyte globulin. Graft enterectomy was considered repeatedly; however, clinical improvement was noted eventually with evidence of histologic improvement and salvage of the graft. The aggressive antirejection treatment was complicated by development of post-transplant lymphoproliferative disorder that resolved with reducing immunosuppression. Her graft function is currently maintained on tacrolimus, oral prednisone, and a periodic infliximab infusion. We conclude that a prompt and aggressive immunosuppressive approach significantly increases the chance of rescuing small bowel transplant rejection.


Assuntos
Rejeição de Enxerto/tratamento farmacológico , Imunossupressão/métodos , Imunossupressores/uso terapêutico , Intestinos/transplante , Feminino , Doença de Hirschsprung/cirurgia , Humanos , Complicações Pós-Operatórias/tratamento farmacológico , Gravidez , Adulto Jovem
3.
Transplant Proc ; 51(7): 2308-2311, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400977

RESUMO

BACKGROUND: This study aimed to determine whether de novo, prolonged-release tacrolimus- (PR-tacro) based immunosuppressive regimen affected graft and patient survival when compared to an immediate-release, twice-daily, tacrolimus- (IR-tacro) based regimen in kidney transplant recipients. We also aimed to determine the difference between the frequency of side effects, including diabetes control, in study groups. METHODS: A total of 115 standard risk kidney transplant recipients were enrolled in this single center, retrospective study. Fifty-two patients received PR-tacro and 63 patients received IR-tacro as a calcineurin inhibitor. The primary outcome measures included incidence of graft loss and delayed graft function (DGF), biopsy-proven acute rejection , graft and patient survival, and creatinine clearance. Secondary outcome measures included the incidence of non-adherence, drug-induced tremor; post-transplant diabetes mellitus diagnosis rate; and control of diabetes in pre-transplant diabetic patients. RESULTS: Baseline characteristics and mean tacrolimus trough levels were comparable between groups. Incidence of graft loss, DGF, and graft and patient survival were similar between groups (P > .05). Mean creatinine clearance level was also similar (P > .05). Mean serum levels of fasting glucose (P < .05) and A1C (P < .05) were lower in PR-tacro group when compared to IR-tacro group. Post-transplant diabetes mellitus diagnosis rate was also lower in PR-tacro group when compared to IR-tacro group (P = .040). CONCLUSION: This study suggests that there is no statistically significant difference between PR-tacro and IR-tacro in terms of patient and graft survival, DGF, and biopsy-proven acute rejection rates in kidney transplant recipients. Post-transplant diabetes mellitus frequency is lower in non-diabetic patients, and glucose metabolism control is better in diabetic patients.


Assuntos
Inibidores de Calcineurina/administração & dosagem , Rejeição de Enxerto/mortalidade , Imunossupressores/administração & dosagem , Transplante de Rim/mortalidade , Tacrolimo/administração & dosagem , Adulto , Função Retardada do Enxerto/etiologia , Feminino , Rejeição de Enxerto/tratamento farmacológico , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida
4.
Biomater Sci ; 7(9): 3729-3740, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31403142

RESUMO

Targeted delivery of immunosuppressants to allografts can increase the concentrations of drugs in pathological tissues, improve therapeutic effects and reduce unfavorable side effects. Therefore, we synthesized FK506-loaded microbubbles (FK506-MBs) for site-specific release of FK506 into transplanted hearts by the ultrasound-targeted microbubble destruction (UTMD) technique. The average particle size of FK506-MBs was 1.65 ± 0.32 µm and they had high drug loading and encapsulation efficiency. The in vivo drug concentration in transplanted hearts that were treated with FK506-MBs plus UTMD was about 1.64-fold higher than that in grafts that received free FK506 at the same dosage. The degree of graft rejection in the FK506-MB plus UTMD group was lower than those of other groups. Both infiltration of T cells and secretion of inflammatory cytokines were significantly reduced in the FK506-MB plus UTMD group. More importantly, the mean survival time of the grafts was significantly longer (16.00 ± 0.89 day) than those of the PBS group (6.66 ± 1.36 day) and the FK506 group (12.83 ± 1.17 day). In addition, we also found that the concentration of FK506 in whole blood was lower in the FK506-MB plus UTMD group than that in the FK506 group, which would be beneficial for reducing the side effects. Hence, our results showed that combining FK506-MBs with UTMD was an effective strategy to deliver FK506 to transplanted hearts, which can increase the local drug concentration and enhance its efficacy on rejection. Ultrasound-targeted drug release is safe and radiation-free, with great potential for clinical transformation, and could also be extended to the treatment of other graft rejection cases, such as liver transplantation, kidney transplantation and so on.


Assuntos
Portadores de Fármacos/química , Rejeição de Enxerto/tratamento farmacológico , Transplante de Coração , Imunossupressores/farmacocinética , Miocárdio/metabolismo , Tacrolimo/farmacocinética , Animais , Liberação Controlada de Fármacos , Estudos de Viabilidade , Imunossupressores/administração & dosagem , Masculino , Microbolhas , Fosfatidilcolinas/química , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Ratos , Tacrolimo/administração & dosagem , Ultrassonografia
5.
Transfus Apher Sci ; 58(4): 515-524, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31383541

RESUMO

Background - Extracorporeal photopheresis (ECP) has shown encouraging results in the prevention of allograft rejection in heart transplantation. However, the role of ECP in kidney transplant (KT) rejection needs to be determined. Methods - This multicentre retrospective study included 33 KT recipients who were treated with ECP for allograft rejection (23 acute antibody-mediated rejections (AMRs), 2 chronic AMRs and 8 acute cellular rejections (ACRs)). The ECP indications were KT rejection in patients who were resistant to standard therapies (n = 18) or in patients for whom standard therapies were contraindicated because of concomitant infections or cancers (n = 15). Results - At 12 months (M12) post-ECP, 11 patients (33%) had a stabilization of kidney function with a graft survival rate of 61%. The Banff AMR score (g + ptc + v) was a risk factor for graft loss at M12 (HR 1.44 [1.01-2.05], p < 0.05). The factorial mixed data analysis identified 2 clusters. Patients with a functional graft at M12 tended to have cellular and/or chronic rejections. Patients with graft loss at M12 tended to have acute rejections and/or AMR; higher serum creatinine levels; DSA levels and histologic scores of AMR; and a longer delay between the rejection and ECP start than those of patients with functional grafts. Conclusions - ECP may be helpful to control ACR or moderate AMR in KT recipients presenting concomitant opportunistic infections or malignancies when it is initiated early.


Assuntos
Rejeição de Enxerto/tratamento farmacológico , Transplante de Rim , Fotoferese , Adolescente , Adulto , Idoso , Feminino , Rejeição de Enxerto/fisiopatologia , Humanos , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
6.
Int Immunopharmacol ; 75: 105758, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31377589

RESUMO

OBJECTIVE: The present study aimed to investigate the functional role of bortezomib in the development of acute allograft rejection (AR) after renal transplant. METHODS: The mouse model of AR was established by allograft kidney transplant followed by the treatment of bortezomib. The serum cytokines, renal function, and the percentage of T follicular helper (Tfh) cells in CD4+ T cells were measured. The effect of miR-15b and interferon-regulatory factor 4 (IRF4) on Tfh cell proliferation and differentiation was assessed by cell transfection technology and CCK-8 assay. The interaction between miR-15b and IRF4 was assessed by luciferase reporter assay. RESULTS: Bortezomib relieved acute AR after renal transplant by suppressing Tfh cell proliferation and differentiation. Meanwhile, bortezomib treatment markedly increased miR-15b expression in AR renal tissues. The upregulation of miR-15b inhibited Tfh cell proliferation and differentiation by reducing IRF4. In addition, bortezomib ameliorated AR by suppressing Tfh cell proliferation and differentiation through miR-15b/IRF4 axis in vitro and in vivo. CONCLUSION: Our findings indicated the mechanism underlying the bortezomib in treating acute AR after renal transplant, and suggested the critical role of miR-15b in Tfh cell proliferation and differentiation, which provided a therapeutic target in attenuating acute AR.


Assuntos
Bortezomib/uso terapêutico , Rejeição de Enxerto/tratamento farmacológico , Imunossupressores/uso terapêutico , Fatores Reguladores de Interferon/imunologia , Transplante de Rim , MicroRNAs/imunologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Aloenxertos , Animais , Bortezomib/farmacologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citocinas/sangue , Feminino , Rejeição de Enxerto/imunologia , Imunossupressores/farmacologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Linfócitos T Auxiliares-Indutores/imunologia
7.
Transplant Proc ; 51(7): 2302-2307, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31358448

RESUMO

PURPOSE: HLA antibodies have been shown to be associated with late graft loss. In this study, we defined the incidence and profiles of anti-HLA antibodies and their impact on graft outcome in long-term kidney recipients. METHODS: The sera of 118 kidney transplant recipients were screened for anti-HLA antibody presence. The antigen specificity of the detected HLA class I and class II antibodies was identified using a Luminex assay (Luminex Corp, Austin, TX, United States). Presence of donor specific antibodies (DSA) was examined in individuals with anti-HLA antibodies using the Luminex method. RESULTS: Anti-HLA class I and/or class II antibodies were detected in serum of 16.1% of the kidney transplant patients. The antibodies were directed against HLA class I antigens in 4 patients (21.1%), HLA class II antigens in 9 patients (47.4%), and both class I and class II antigens in 6 patients (31.6%). The overall prevalence of DSA was 10.2%. Anti-HLA antibodies were significantly associated with higher rate of cyclosporine use. Presence of DSA was associated with a lower rate of tacrolimus use, a higher rate of cyclosporine use, and lower donor age. Presence of anti-HLA antibodies was associated with higher acute cellular rejection and higher chronic active humoral rejection rates. Presence of DSA was associated with chronic active humoral rejection. CONCLUSION: The presence of either HLA antibodies or DSA significantly correlated with lower graft survival, poor transplant function, and proteinuria.


Assuntos
Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/imunologia , Antígenos HLA/imunologia , Isoanticorpos/sangue , Transplante de Rim/efeitos adversos , Adulto , Especificidade de Anticorpos , Feminino , Sobrevivência de Enxerto/imunologia , Humanos , Imunossupressores/uso terapêutico , Isoanticorpos/imunologia , Rim/imunologia , Transplante de Rim/métodos , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Proteinúria/imunologia , Tacrolimo/uso terapêutico , Transplantes/imunologia , Resultado do Tratamento
8.
Transplant Proc ; 51(7): 2268-2273, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31358450

RESUMO

AIM: Sensitization to HLA antigens creates an immunologic barrier, linked to an increased risk of antibody-mediated rejection and poorer graft survival, that remains a persistent and often impenetrable deterrent to transplantation. Desensitization can improve transplantation rates in broadly sensitized kidney transplant recipients. We aimed to compare the clinical outcomes of immunologic high-risk kidney recipients who had desensitization treatment with the outcomes of those who did not. MATERIALS AND METHODS: We retrospectively evaluated patients who underwent desensitization protocol due to immunologic risk between 2010 and 2018. Living-donor transplantation patients with panel reactive antibody positivity, retransplantation, donor specific antibody, and/or single antigen bead positivity were included in the study. We excluded deceased-donor transplantation recipients. Demographic data (age, sex, etiology of end-stage renal disease, blood transfusions, pregnancy, etc), immunologic status (HLA-mismatch [HLA-MM], panel reactive antibody, donor specific antibody, etc), induction and maintenance of immunosuppressive medications, and complications (all-cause hospitalizations, episodes of acute rejections, etc) were noted. We compared data and clinical outcomes of patients who had desensitization (Group 1) with data and clinical outcomes of patients who had not had desensitization (Group 2). FINDINGS: There were 124 living-kidney donors (49 female, mean age 43.7 ± 12.2 years, mean body mass index [BMI] 25.8 ± 5.8 kg/m2, mean follow-up time 20.9 ± 14.6 months). Thirty-four of these patients (25 female, mean age 43.7 ± 12.5 years, mean follow-up time 26.1 ± 17.7 months, mean BMI 27 ± 6.5 kg/m2) had desensitization treatment (rituximab+plasmapheresis for 19 patients, rituximab for 11 patients, rituximab+plasmapheresis+intravenous immunoglobulin for 4 patients). Ninety patients (24 female, mean age 43.7 ± 12.2 years, mean follow-up time 18.9 ± 12.9 months, mean BMI 25.3 ± 5.4 kg/m2) had not had desensitization. There was no statistical difference between groups for age, sex, hepatitis serology, history of blood transfusion, history of pregnancy, or history of dialysis (P < .05 for all parameters). While scores for HLA-MM and HLA-relative intensity scale (RIS) were 2.7 ± 1.6 and 7.86 ± 6.2, respectively, in Group 1, in Group 2 the same scores were 2.1 ± 1.1 and 3.6 ± 2.5, respectively (P: .053 and .03). Delayed graft function, acute rejection episodes, and hospitalizations were similar between groups (P: .47, .29, and .34, respectively). Follow-up time and length of hospitalization were longer in Group 1 (P: .013 and .001, respectively). Total doses of ATG were higher in Group 1 patients (P: .007). CONCLUSION: Despite the higher HLA-MM and RIS scores, clinical outcomes in desensitized patients were found to be similar to those in nondesensitized patients for acute rejection episodes and hospitalizations. Desensitization with rituximab in patients with high HLA-RIS scores can prevent acute rejection and hospitalization.


Assuntos
Dessensibilização Imunológica/métodos , Rejeição de Enxerto/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Transplante de Rim/efeitos adversos , Rituximab/uso terapêutico , Adulto , Anticorpos/efeitos dos fármacos , Anticorpos/imunologia , Feminino , Seguimentos , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Antígenos HLA/imunologia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Rim/imunologia , Falência Renal Crônica/etiologia , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Plasmaferese , Período Pós-Operatório , Estudos Retrospectivos , Resultado do Tratamento
9.
Transplant Proc ; 51(6): 1732-1738, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31301858

RESUMO

Plasma cell-rich acute rejection (PCAR) and antibody-mediated rejection (ABMR), for which a standard treatment has not yet been established, are associated with poor graft survival after kidney transplantation. Here, we report a case series of 3 Japanese patients diagnosed with PCAR accompanied by ABMR. Steroid pulse therapy and rabbit antithymocyte globulin, plasma exchange, intravenous immunoglobulin, and rituximab therapies were sequentially performed in the first case. A graft biopsy after each treatment showed that plasma cell infiltration persisted. Five months after the initiation of rejection therapy, the patient was subjected to bortezomib therapy, which led to the partial elimination of plasma cells from the graft. However, the graft function gradually deteriorated, and hemodialysis treatment was warranted. In the other 2 cases, the patients received the same combination of therapy including bortezomib within a short period. Graft biopsies performed subsequently showed a marked decrease in the number of infiltrated plasma cells, and stabilization of renal graft function was achieved in both cases. Bortezomib, which targets plasma cells, is a potent drug that eliminates infiltrated plasma cells from the graft in PCAR. Thus, in addition to conventional therapy comprising plasma exchange, intravenous immunoglobulin, and rituximab against ABMR, bortezomib may be necessary to administer without any delay to control PCAR.


Assuntos
Bortezomib/uso terapêutico , Terapia Combinada/métodos , Rejeição de Enxerto/tratamento farmacológico , Plasmócitos/efeitos dos fármacos , Inibidores de Proteassoma/uso terapêutico , Adolescente , Corticosteroides/administração & dosagem , Pré-Escolar , Feminino , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Transplante de Rim/efeitos adversos , Masculino , Plasmócitos/patologia , Plasmaferese , Estudos Retrospectivos , Rituximab/administração & dosagem , Adulto Jovem
10.
Drug Des Devel Ther ; 13: 2187-2193, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31308630

RESUMO

Background: Tablet and capsule forms have advantages and disadvantages in the market. Generally, the tablet form (500 mg) of mycophenolate mofetil (MMF) is more convenient for drug ingestion and more cost-effective than the capsule form (250 mg). We examined the efficacy and safety of MMF in its different forms combined with tacrolimus in liver transplant recipients. Methods: A randomized controlled trial was performed to compare the efficacy and safety between the tablet form of MMF (tablet group) and the capsule form of MMF (capsule group) in liver transplant patients. One hundred sixteen patients were enrolled in the present study from 2014 to 2017. Fifty-six patients in the full-analysis set (FAS) population were in the capsule group and 60 were in the tablet group. The primary endpoint was incidence of biopsy-proven acute rejection (BPAR) by 24 weeks after liver transplantation (LT). Secondary endpoints were patient survival, serum creatinine level, and adverse events (AEs). Results: In the per-protocol population, 45 patients were in the tablet group and 49 were in the capsule group. There were no statistically significant differences in MMF dose, mycophenolic acid trough level, and tacrolimus trough level between the two groups. The incidence of BPAR at 24 weeks after randomization was 6.7% in the tablet group and 6.1% in the capsule group (P=0.627). All patients with BPAR responded well to steroid pulse therapy and increased tacrolimus. Serum creatine level and eGFR were not different between the two groups. The incidence of serious AEs was 7.2% in the tablet group and 7.6% in the capsule group, and none were related to formulation. There was no significant difference in incidence of discontinuations or serious AEs between the two groups. Conclusion: The present study suggests that the new tablet formulation can be a useful treatment option to maintain a consistent systemic exposure level of MMF, which may help reduce graft failure in liver transplant patients.


Assuntos
Rejeição de Enxerto/tratamento farmacológico , Imunossupressores/administração & dosagem , Imunossupressores/uso terapêutico , Transplante de Fígado , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/uso terapêutico , Adulto , Idoso , Cápsulas , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Comprimidos , Adulto Jovem
12.
Transplant Proc ; 51(8): 2655-2659, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31345597

RESUMO

BACKGROUND: Rejection is still a barrier to long-term allograft survival, but there are not many reports of clinical outcomes according to rejection types. The purpose of this study was to investigate differences in pathologic features and graft outcomes of rejection on kidney transplant (KT). MATERIALS AND METHODS: We retrospectively analyzed 139 kidney transplant recipients diagnosed to rejection by allograft biopsy results between 2006 and 2018. We divided kidney transplant recipients into 3 groups as follows: T cell-mediated rejection (TCMR), antibody-mediated rejection, and mixed rejection. We investigated clinical characteristics, pathologic findings, death-censored graft survival rates, and patient survival rates among the 3 groups. RESULTS: Mean follow-up duration was 113.5 (SD, 80.6) months. The mixed rejection group was the youngest significantly. There were no significant differences of the proportion of sex, KT type, KT number, number of HLA mismatches, induction immunosuppressant, and maintenance immunosuppressant among the 3 groups. In pathologic findings, microvascular inflammation and C4d were significantly different among the 3 groups. Death-censored graft survival of mixed rejection was the least. In multivariate analysis, recipient age, TCMR, and positive C4d were the risk factors associated with graft failure. However, patient survival rates showed no significant differences among the 3 groups. CONCLUSIONS: Our study showed that mixed rejection had poor prognosis in comparison with TCMR and antibody-mediated rejection groups, and TCMR and positive C4d were the most important risk factors for graft survival. Therefore, constant monitoring through allograft biopsy and early treatment for rejection are very important in post-transplant clinical outcomes.


Assuntos
Aloenxertos/patologia , Rejeição de Enxerto/patologia , Imunossupressores/uso terapêutico , Transplante de Rim/efeitos adversos , Rim/patologia , Adulto , Aloenxertos/imunologia , Anticorpos/imunologia , Biópsia , Feminino , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto , Humanos , Rim/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Linfócitos T , Transplante Homólogo
13.
Transplant Proc ; 51(8): 2602-2605, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31324482

RESUMO

BACKGROUND: Rabbit antithymocyte globulin (rATG) induction is associated with reduction in the occurrence of de novo donor-specific antibody (DSA) and antibody-mediated rejection (AMR). Therefore, rATG administration is considered as a treatment for AMR. However, only a few studies have investigated the treatment of AMR with rATG after kidney transplantation. METHODS: Between April 2013 and March 2018, 162 consecutive de novo kidney transplantations were performed with induction immunosuppressive therapy comprising tacrolimus, mycophenolate mofetil, methylprednisolone, and basiliximab. AMR was diagnosed on the basis of the presence of DSA and episode biopsy findings. For DSA-positive recipients, plasmapheresis was performed to remove DSA before rATG administration (1.5 mg/kg for 5 days). Patients treated with rATG against active AMR were retrospectively analyzed for graft function. RESULTS: A total of 13 kidney transplant recipients developed active AMR within 302 days after transplantation. After rATG administration, the mean serum creatinine and urine protein levels significantly declined from 3.03 mg/dL to 1.68 mg/dL (P = .002) within 46 days and from 3.01 g/gCr to 0.54 g/gCr (P = .006) within 106 days, respectively. The peripheral blood lymphocyte count rapidly decreased after rATG administration and remained low for 12 months. With regard to adverse events, fever (84.6%), cytomegaloviremia (84.6%), thrombocytopenia (61.5%), anemia (30.8%), and neutropenia (15.4%) occurred within 3 months after rATG administration. CONCLUSIONS: rATG improved graft function by suppressing peripheral blood lymphocytes in kidney transplant recipients with active AMR. The rATG administration as a treatment for active AMR may contribute to positive graft outcomes after kidney transplantation.


Assuntos
Soro Antilinfocitário/uso terapêutico , Rejeição de Enxerto/tratamento farmacológico , Imunossupressores/uso terapêutico , Transplante de Rim , Adulto , Basiliximab/uso terapêutico , Feminino , Rejeição de Enxerto/imunologia , Humanos , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/uso terapêutico , Plasmaferese/métodos , Estudos Retrospectivos , Tacrolimo/uso terapêutico , Resultado do Tratamento
14.
Ann Transplant ; 24: 319-327, 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31160549

RESUMO

BACKGROUND The DIAMOND study of de novo liver transplant patients showed that prolonged-release tacrolimus exposure in the acute post-transplant period maintained renal function over 24 weeks of treatment. To assess these findings further, we performed a post-hoc analysis in patients according to baseline kidney function, Model for End-stage Liver Disease [MELD] scores, and donor age. MATERIAL AND METHODS Patients received prolonged-release tacrolimus (initial-dose, Arm 1: 0.2 mg/kg/day, Arm 2: 0.15-0.175 mg/kg/day, Arm 3: 0.2 mg/kg/day delayed until Day 5), mycophenolate mofetil and 1 steroid bolus. Arms 2 and 3 also received basiliximab. The recommended tacrolimus target trough levels to Day 42 post-transplantation were 5-15 ng/mL in all arms. In this post-hoc analysis, change in renal outcome, based on estimated glomerular filtration rate (eGFR), Modified Diet in Renal Disease-4 (MDRD4), values from baseline to Week 24 -post-transplantation, were assessed according to baseline patient factors: eGFR (≥60 and ˂60 mL/min/1.73 m²), MELD score (˂25 and ≥25) and donor age (˂50 and ≥50 years). RESULTS Baseline characteristics were comparable (Arms 1-3: n=283, n=287, n=274, respectively). Patients with baseline renal function, eGFR ≥60 mL/min/1.73 m², experienced a decrease in eGFR in all tacrolimus treatment arms. In patients with lower baseline renal function (eGFR ˂60 mL/min/1.73 m²), an advantage for renal function was observed with both the early lower-dose and delayed higher-dose tacrolimus regimens compared with the early introduction of higher-dose tacrolimus. At Week 24, renal function was higher in the early-lower tacrolimus arm with older donors, and the delayed higher-dose tacrolimus arm with younger donors, both compared with early higher-dose tacrolimus. CONCLUSIONS Pre-transplantation factors, such as renal function and donor age, could guide the choice of prolonged-release tacrolimus regimen following liver transplantation.


Assuntos
Imunossupressores/uso terapêutico , Falência Renal Crônica/cirurgia , Rim/efeitos dos fármacos , Transplante de Fígado/métodos , Tacrolimo/uso terapêutico , Doadores de Tecidos , Transplantados , Adulto , Fatores Etários , Idoso , Preparações de Ação Retardada , Feminino , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/administração & dosagem , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/uso terapêutico , Tacrolimo/administração & dosagem
15.
Int J Clin Pharm ; 41(4): 1047-1055, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31129889

RESUMO

Background The effects of mycophenolic acid exposure in the early period after transplantation on clinical outcomes have been reported; however, mycophenolic acid exposure in the early period after transplantation in Asian kidney transplant recipients who receive 1.5 g/d mycophenolate mofetil has never been investigated. Objective To determine mycophenolic acid exposure on day 3 post-transplantation in kidney transplant recipiens who receive 1.5 g/d mycophenolate mofetil. The effects of the reduced renal function on mycophenolic acid area under the concentration-time curve (AUC) and the achievement of the target AUC on the incidence of biopsy proven acute rejection during the first month post-transplantation were also evaluated. Setting A university hospital Method Blood samples and 24-h urine were collected on day 3 post-transplantation. Main outcome measures The mycophenolic acid AUC was calculated by linear trapezoidal rule and compared with the target of 45 mg*h/L. Results Of 42 Thai kidney transplant recipiens, the mean mycophenolic acid AUC of 45.1 mg*h/L (SD 14.7) was comparable to the AUC target (P = 0.962). Significant differences of the mycophenolic acid AUC were observed between patients with urine output of < 2400 mL and those with urine output ≥ 2400 mL (35.3 ± 6.6 and 47.4 ± 15.2, respectively; P = 0.002), and between patients with 24-h measured CrCl < 25 mL/min and those with CrCl ≥ 25 mL/min (38.0 (29.0, 42.2) and 49.2 ± 14.0, respectively; P = 0.017). Proportions of overall biopsy proven acute rejection among patients with mycophenolic acid AUC of < 45 and ≥ 45 mg*h/L were comparable (20.0% and 23.5%, respectively; P = 1.000). Conclusions After the starting dosage of 1.5 g/d mycophenolate mofetil, the mean mycophenolic acid AUC on day 3 post-kidney transplantation is comparable with the target of 45 mg*h/L. Severely reduced renal function significantly influences mycophenolic acid exposure.


Assuntos
Rejeição de Enxerto/epidemiologia , Transplante de Rim/estatística & dados numéricos , Ácido Micofenólico/farmacocinética , Transplantados/estatística & dados numéricos , Adolescente , Adulto , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Feminino , Rejeição de Enxerto/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/sangue , Tailândia/epidemiologia , Adulto Jovem
16.
Rev. neurol. (Ed. impr.) ; 68(10): 426-430, 16 mayo, 2019. tab, ilus
Artigo em Espanhol | IBECS | ID: ibc-180738

RESUMO

Introducción. La relevancia del fármaco inmunosupresor tacrolimús en la prevención del rechazo y la enfermedad de injerto contra huésped en pacientes trasplantados es indiscutible. Sin embargo, con frecuencia, el tacrolimús presenta efectos neurotóxicos, incluyendo cuadros graves, como el síndrome de leucoencefalopatía posterior reversible. Caso clínico. Varón de 75 años, con antecedentes de trasplante renal hace cinco años, en tratamiento con tacrolimús y micofenolato, y de enfermedad de Parkinson avanzada, en tratamiento con varios agonistas dopaminérgicos. Acudió a urgencias por un cuadro de una semana de evolución consistente en alucinaciones visuales, delirios, ánimo expansivo, confusión y cefalea. La exploración psicogeriátrica por focos mostró como primera opción diagnóstica una psicosis secundaria a agonistas dopaminérgicos, sin excluir otras causas yatrógenas a pesar de encontrarse el tacrolimús en el rango terapéutico (8,3 ng/mL). Se realizaron una tomografía computarizada craneal, que no mostró hallazgos significativos, y una resonancia magnética, en la que se visualizó un edema parietooccipital bilateral, hallazgo compatible con un síndrome de leucoencefalopatía posterior reversible. Durante el ingreso se sustituyó el tacrolimús por everolimús y se ajustó la medicación dopaminérgica, con lo que se produjo de forma rápida una remisión completa del cuadro. Conclusiones. El diagnóstico de síndrome de leucoencefalopatía posterior reversible debe considerarse en los pacientes con antecedentes de trasplante de órgano en tratamiento con fármacos inmunosupresores que presentan un cuadro de instauración aguda con síntomas neurológicos o psiquiátricos


Introduction. The relevance of the immunosuppressive drug tacrolimus in the prevention of rejection and graft-versushost disease in transplanted patients is beyond all doubt. However, tacrolimus often has neurotoxic effects, including severe conditions such as posterior reversible leukoencephalopathy syndrome. Case report. A 75-year-old male who had undergone a kidney transplantation five years earlier, for which he was receiving treatment with tacrolimus and mycophenolate. He also had advanced Parkinson’s disease, treated with several dopamine agonists. The patient visited the emergency department after a week-long history of visual hallucinations, delirium, expansive mood, confusion and headache. The focal psychogeriatric examination revealed psychosis secondary to dopaminergic agonists as the first diagnostic option, without excluding other possible iatrogenic causes despite the tacrolimus being within the therapeutic range (8.3 ng/mL). Both cranial computed tomography, which did not show any significant findings, and a magnetic resonance scan, in which a bilateral parietooccipital oedema was observed, were performed, this latter finding being compatible with posterior reversible leukoencephalopathy syndrome. While the patient was in hospital, tacrolimus was replaced by everolimus, and the dopaminergic medication was adjusted, resulting in a swift and full remission of the clinical signs and symptoms. Conclusions. The diagnosis of posterior reversible leukoencephalopathy syndrome should be considered in patients with a history of organ transplantation treated with immunosuppressive drugs who have an acute onset condition with neurological or psychiatric symptoms


Assuntos
Humanos , Masculino , Idoso , Tacrolimo/efeitos adversos , Imunossupressores/efeitos adversos , Síndrome da Leucoencefalopatia Posterior/induzido quimicamente , Síndrome da Leucoencefalopatia Posterior/diagnóstico , Tacrolimo/uso terapêutico , Imunossupressores/uso terapêutico , Transplante de Rim , Rejeição de Enxerto/tratamento farmacológico
17.
Eur J Pharm Sci ; 133: 104-114, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30928512

RESUMO

This study aimed to develop a stable and biodegradable tacrolimus loaded nanocarrier that enhanced tacrolimus corneal penetration and delivered in a sustained manner, thus to create a promising treatment to prevent immune rejection after corneal allografts. Spherical tacrolimus loaded methoxy poly (ethylene glycol)-block-poly (D,L)-lactic-co-glycolic acid (mPEG-b-PLGA) micelles with a mean diameter of 81.3 ±â€¯1.3 nm were prepared by the solvent-evaporation-induced self-assembly. The physicochemical properties of tacrolimus loaded mPEG-b-PLGA micelles were evaluated, and the in vitro release behavior, degradation, cytotoxicity and bio-safety were all assessed. The ex vivo permeation of tacrolimus using rabbit corneas was also performed, and the cumulative permeation amount of tacrolimus from mPEG-b-PLGA micelles was significantly higher than 0.05% tacrolimus eye drops (p < 0.05). These results indicated that the formulations were feasible for intraocular drug delivery. Compared with 0.05% tacrolimus eye drops, the in vivo immunofluorescence analysis indicated the tacrolimus loaded mPEG-b-PLGA micelles remarkably inhibit the immune rejection after corneal allograft, with the lower expression levels of nuclear factor of activated T cells (NFAT), cluster of differentiation 4 (CD4) and cluster of differentiation 8 (CD8). In conclusion, we provided evidences that tacrolimus loaded mPEG-b-PLGA micelles would be a promising treatment for immune rejection after corneal transplantation.


Assuntos
Portadores de Fármacos/administração & dosagem , Rejeição de Enxerto/tratamento farmacológico , Imunossupressores/administração & dosagem , Ceratoplastia Penetrante , Micelas , Nanopartículas/administração & dosagem , Poliésteres/administração & dosagem , Polietilenoglicóis/administração & dosagem , Tacrolimo/administração & dosagem , Animais , Sobrevivência Celular/efeitos dos fármacos , Córnea/metabolismo , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Feminino , Imunossupressores/química , Masculino , Nanopartículas/química , Poliésteres/química , Polietilenoglicóis/química , Coelhos , Ratos Sprague-Dawley , Ratos Wistar , Tacrolimo/química
19.
Clin Exp Nephrol ; 23(7): 880-889, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30830549

RESUMO

BACKGROUND: Individuals who have kidney disease or kidney transplants need routine assessment of their kidney damage and function, which are largely measured based on histological examination of kidney biopsies, blood test, and urinalysis. These methods are practically difficult or inconvenient, and expensive. The objective of this study was to develop a model to estimate the kidney damage and function by surface-enhanced Raman spectroscopy (SERS). METHODS: Urine samples were collected from two previous studies: renal allograft recipient Lewis rats receiving anti-TGF-ß antibody or control antibody treatment and obese diabetic ZSF1 rats with kidney disease fed with whole grape powder-containing chow or control chow. Silver nanoparticle-based SERS spectra of urine were measured. SERS spectra were analyzed using principal component analysis (PCA) combined with linear discriminant analysis (LDA) and partial least squires (PLS) analysis. RESULTS: PCA/LDA separated anti-TGF-ß antibody-treated group from control group with 90% sensitivity and 70% specificity in kidney transplants, and grape-fed group from controls with 72.7% sensitivity and 60% specificity in diabetic kidneys. The receiver operating characteristic curves showed that the integration area under the curve was 0.850 ± 0.095 (p = 0.008) in kidney transplant groups and 0.800 ± 0.097 (p = 0.02) in diabetic kidney groups. PLS predicted the biochemical parameters of kidney function using the SERS spectra, resulting in R2 = 0.8246 (p < 0.001,urine protein), R2 = 0.8438 (p < 0.001, urine creatinine), R2 = 0.9265 (p < 0.001, urea), R2 = 0.8719 (p < 0.001, serum creatinine), and R2 = 0.6014 (p < 0.001, urine protein to creatinine ratio). CONCLUSION: Urine SERS spectral analysis suggesting that it may become a convenient method for rapid assessment of renal impairment.


Assuntos
Rejeição de Enxerto/diagnóstico , Nefropatias/diagnóstico , Testes de Função Renal , Transplante de Rim/efeitos adversos , Rim/metabolismo , Análise Espectral Raman , Animais , Anticorpos/farmacologia , Biomarcadores/urina , Suplementos Nutricionais , Modelos Animais de Doenças , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/urina , Rim/efeitos dos fármacos , Nefropatias/tratamento farmacológico , Nefropatias/etiologia , Nefropatias/urina , Extratos Vegetais/farmacologia , Valor Preditivo dos Testes , Ratos Endogâmicos Lew , Ratos Zucker , Reprodutibilidade dos Testes , Fator de Crescimento Transformador beta/antagonistas & inibidores , Fator de Crescimento Transformador beta/imunologia , Urinálise , Vitis
20.
Int Immunopharmacol ; 71: 32-39, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30877871

RESUMO

Chronic T cell mediated rejection (TCMR), which is characterized by infiltration of the interstitium by T cells and macrophages, still remains a major barrier to the long-term survival of kidney transplantation. Our recent report indicated that thalidomide can attenuate graft arteriosclerosis in an aortic transplant model. In this study, we investigated the effect of thalidomide on chronic TCMR in a rat model of kidney transplantation. Fischer or Lewis kidney allografts were transplanted into Lewis recipient rats. After kidney transplantation, recipient rats were divided into 3 groups: the isograft (Iso) group, allograft (Allo) group, and thalidomide (Tha) group. Rats were sacrificed at 8 weeks after kidney transplantation, and blood and kidney samples were collected. Serum concentrations of creatinine (SCr),interleukin (IL)-2, IL-6, IL-17, and TNF-α in recipients were determined, and flow cytometry was used to detect the percentages of CD4+CD25+, CD4+ Foxp3+and CD4+Th17+ cell subsets in the peripheral blood. Grafts were procured for histopathological examination, and the expressions of α-SMA, transforming growth-ß1 (TGF-ß1), and VEGF in kidney grafts were investigated using Western blot. Thalidomide treatment significantly ameliorated chronic rejection, reduced renal allograft tissue damage, and decreased serum creatinine levels. Attenuation of chronic TCMR was due to the prohibited production of inflammatory cytokines, altered distribution of the CD4+ CD25+ FoxP3+ regulatory T (Treg) and CD4+ Th17+ cells in the peripheral blood, and decreased expression of TGF-ß1, α-SMA, and VEGF in the kidney graft. These results demonstrated that thalidomide could effectively ameliorate chronic TCMR in a rat kidney transplant model.


Assuntos
Rejeição de Enxerto/tratamento farmacológico , Imunossupressores/uso terapêutico , Transplante de Rim , Rim/patologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Talidomida/uso terapêutico , Animais , Doença Crônica , Creatinina/sangue , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew , Transplante Homólogo
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