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1.
Transplantation ; 104(1): 154-164, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30893292

RESUMO

BACKGROUND: A calcineurin inhibitor (CNI)-free immunosuppressive regimen has been demonstrated to improve renal function early after heart transplantation, but long-term outcome of such a strategy has not been well described. METHODS: In the randomized SCHEDULE trial, de novo heart transplant recipients received (1) everolimus with reduced-exposure CNI (cyclosporine) followed by CNI withdrawal at week 7-11 posttransplant or (2) standard-exposure cyclosporine, both with mycophenolate mofetil and corticosteroids; 95/115 randomized patients were followed up at 5-7 years posttransplant. RESULTS: Mean measured glomerular filtration rate was 74.7 mL/min and 62.4 mL/min with everolimus and CNI, respectively. The mean difference was in favor of everolimus by 11.8 mL/min in the intent-to-treat population (P = 0.004) and 17.2 mL/min in the per protocol population (n = 75; P < 0.001). From transplantation to last follow-up, the incidence of biopsy-proven acute rejection (BPAR) was 77% (37/48) and 66% (31/47) (P = 0.23) with treated BPAR in 50% and 23% (P < 0.01) in the everolimus and CNI groups, respectively; no episode led to hemodynamic compromise. Coronary allograft vasculopathy (CAV) assessed by coronary intravascular ultrasound was present in 53% (19/36) and 74% (26/35) of everolimus- and CNI-treated patients, respectively (P = 0.037). Graft dimensions and function were similar between the groups. Late adverse events were comparable. CONCLUSIONS: These results suggest that de novo heart transplant patients randomized to everolimus and low-dose CNI followed by CNI-free therapy maintain significantly better long-term renal function as well as significantly reduced CAV than patients randomized to standard CNI treatment. Increased BPAR in the everolimus group during year 1 did not impair long-term graft function.


Assuntos
Inibidores de Calcineurina/administração & dosagem , Doença da Artéria Coronariana/epidemiologia , Everolimo/administração & dosagem , Rejeição de Enxerto/epidemiologia , Transplante de Coração/efeitos adversos , Imunossupressores/administração & dosagem , Adulto , Inibidores de Calcineurina/efeitos adversos , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/etiologia , Vasos Coronários/diagnóstico por imagem , Ciclosporina/administração & dosagem , Ciclosporina/efeitos adversos , Relação Dose-Resposta a Droga , Everolimo/efeitos adversos , Feminino , Seguimentos , Taxa de Filtração Glomerular/efeitos dos fármacos , Taxa de Filtração Glomerular/fisiologia , Glucocorticoides/administração & dosagem , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/fisiopatologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Sobrevivência de Enxerto/imunologia , Humanos , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/efeitos adversos , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Ultrassonografia de Intervenção
2.
Am J Transplant ; 19(4): 1050-1060, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30312541

RESUMO

Cardiac allograft vasculopathy (CAV) causes heart failure after heart transplantation (HTx), but its pathogenesis is incompletely understood. Notch signaling, possibly modulated by everolimus (EVR), is essential for processes involved in CAV. We hypothesized that circulating Notch ligands would be dysregulated after HTx. We studied circulating delta-like Notch ligand 1 (DLL1) and periostin (POSTN) and CAV in de novo HTx recipients (n = 70) randomized to standard or EVR-based, calcineurin inhibitor-free immunosuppression and in maintenance HTx recipients (n = 41). Compared to healthy controls, plasma DLL1 and POSTN were elevated in de novo (P < .01; P < .001) and maintenance HTx recipients (P < .001; P < .01). Use of EVR was associated with a treatment effect for DLL1. For de novo HTx recipients, a change in DLL1 correlated with a change in CAV at 1 (P = .021) and 3 years (P = .005). In vitro, activation of T cells increased DLL1 secretion, attenuated by EVR. In vitro data suggest that also endothelial cells and vascular smooth muscle cells (VSMCs) could contribute to circulating DLL1. Immunostaining of myocardial specimens showed colocalization of DLL1 with T cells, endothelial cells, and VSMCs. Our findings suggest a role of DLL1 in CAV progression, and that the beneficial effect of EVR on CAV could reflect a suppressive effect on DLL1. Trial registration numbers-SCHEDULE trial: ClinicalTrials.gov NCT01266148; NOCTET trial: ClinicalTrials.gov NCT00377962.


Assuntos
Everolimo/uso terapêutico , Transplante de Coração/efeitos adversos , Imunossupressores/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/sangue , Proteínas de Membrana/sangue , Doenças Vasculares/etiologia , Adulto , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
3.
Circ Heart Fail ; 11(9): e004050, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30354362

RESUMO

Background Cardiac allograft vasculopathy (CAV) limits survival after heart transplantation, and the effect of different immunosuppressive regimens on CAV is not fully understood. The randomized SCHEDULE trial (Scandinavian Heart Transplant Everolimus De Novo Study With Early Calcineurin Inhibitors Avoidance) evaluated whether initiation of the proliferation signal inhibitor everolimus and early cyclosporine elimination can reduce CAV development. Methods and Results The SCHEDULE trial was a multicenter Scandinavian trial, where 115 de novo heart transplantation recipients were randomized to everolimus with complete cyclosporine withdrawal 7 to 11 weeks after heart transplantation or standard cyclosporine-based immunosuppression. Seventy-six (66%) patients had matched intravascular ultrasound examinations at baseline and 12 and 36 months. Intravascular ultrasound analysis evaluated maximal intimal thickness, percent atheroma volume, and total atheroma volume. Qualitative plaque analysis using virtual histology assessed fibrous, fibrofatty, and calcified tissue as well as necrotic core. Serum inflammatory markers were measured in parallel. The everolimus group (n=37) demonstrated significantly reduced CAV progression as compared with the cyclosporine group (n=39) at 36 months (Δ maximal intimal thickness, 0.09±0.05 versus 0.15±0.16 mm [ P=0.03]; Δ percent atheroma volume, 5.3±2.8% versus 7.6±5.9% [ P=0.03]; and Δ total atheroma volume, 33.9±71.2 versus 54.2±96.0 mm3 [ P=0.34], respectively]. At 36 months the number of everolimus patients with rejection graded ≥2R was 15 (41%) as compared with 5 (13%) in the cyclosporine group ( P=0.01). Everolimus did not affect CAV morphology or immune marker activity during the follow-up period. Conclusions The SCHEDULE trial demonstrates that everolimus initiation and early cyclosporine elimination significantly reduces CAV progression at 12 months, and this beneficial effect is clearly sustained at 36 months. Clinical trial registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT01266148.


Assuntos
Inibidores de Calcineurina/administração & dosagem , Doença da Artéria Coronariana/prevenção & controle , Ciclosporina/administração & dosagem , Everolimo/administração & dosagem , Transplante de Coração/efeitos adversos , Imunossupressores/administração & dosagem , Adulto , Aloenxertos , Inibidores de Calcineurina/efeitos adversos , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/etiologia , Ciclosporina/efeitos adversos , Esquema de Medicação , Everolimo/efeitos adversos , Feminino , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Imunossupressores/efeitos adversos , Mediadores da Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Placa Aterosclerótica , Estudos Prospectivos , Países Escandinavos e Nórdicos , Fatores de Tempo , Resultado do Tratamento , Ultrassonografia de Intervenção
4.
Clin Transplant ; 31(9)2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28640529

RESUMO

The Scandinavian heart transplant everolimus de novo study with early calcineurin inhibitors avoidance (SCHEDULE) trial was a 12 month, randomized, open-label, parallel-group trial that compared everolimus (EVR; n=56) to conventional CsA (n=59) immunosuppression. Previously, we reported that EVR outperformed CsA in improving renal function and coronary artery vasculopathy, despite a higher rejection rate with EVR. This study aimed to compare the effects of these treatments on quality of life (QoL). Within five post-operative days, patients (mean age 50±13 years, 27% women) were randomized to EVR or a standard CsA dosage (CsA group). This study assessed quality of life (QoL), based on the Short Form-36, EuroQol-5D, and Beck Depression Inventory (BDI). Assessments were performed pre-HTx and 12 and 36 months post-HTx. At 12 and 36 months, the groups showed similar improvements in Short Form-36 measures (at pre-HTx, 12 and 36 months the values were as follows: Physical component summary: EVR: 31.5±110.9, 49.1±9.7, and 47.9±10.6; P<.01; CsA: 32.5±8.2, 48.4±8.5, and 46.5±11.5; P<.01; mental component summary: EVR: 46.0±12.0, 51.7±11.9, and 52.1±13.0; P<.01; CsA: 38.2±12.5, 53.4±7.1, and 54.3±13.0; P<.01); similar decrease in mean BDI (EVR: 10.9±10.2, 5.4±4.7, and 8.1±9.0; P<.01; CsA: 11.8±7.1, 6.3±5.4, and 6.2±6.5; P<.01); and similar Euro Qol-improvements. Thus, in this small-sized study, EVR-based and conventional CsA immunosuppressive strategies produced similar QoL improvements.


Assuntos
Inibidores de Calcineurina/uso terapêutico , Everolimo/uso terapêutico , Rejeição de Enxerto/prevenção & controle , Transplante de Coração , Imunossupressores/uso terapêutico , Qualidade de Vida , Adulto , Feminino , Seguimentos , Indicadores Básicos de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
5.
Transpl Int ; 29(7): 819-29, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27067532

RESUMO

The NOCTET study randomized 282 patients ≥1 year after heart or lung transplantation to continue conventional calcineurin inhibitor (CNI) therapy or to start everolimus with reduced-exposure CNI. Last follow-up, at ≥5 years postrandomization (mean: 5.6 years) was attended by 72/140 everolimus patients (51.4%) and 91/142 controls (64.1%). Mean measured GFR remained stable in the everolimus group from randomization (51.3 ml/min) to last visit (51.4 ml/min) but decreased in controls (from 50.5 ml/min to 45.3 ml/min) and was significantly higher with everolimus at last follow-up (P = 0.004). The least squares mean (SE) change from randomization was -1.5 (1.7)ml/min with everolimus versus -7.2 (1.7)ml/min for controls (difference: 5.7 [95% CI 1.7; 9.6]ml/min; P = 0.006). The difference was accounted for by heart transplant patients (difference: 6.9 [95% 2.3; 11.5]ml/min; P = 0.004). Lung transplant patients showed no between-group difference at last follow-up. Rates of rejection, death, and major cardiac events were similar between groups, as was graft function. Pneumonia was more frequent with everolimus (18.3% vs. 6.4%). In conclusion, introducing everolimus in maintenance heart transplant patients, with reduced CNI, achieves a significant improvement in renal function which is maintained for at least 5 years, but an early renal benefit in lung transplant patients was lost. Long-term immunosuppressive efficacy was maintained.


Assuntos
Inibidores de Calcineurina/uso terapêutico , Everolimo/uso terapêutico , Transplante de Coração/métodos , Transplante de Pulmão/métodos , Adulto , Idoso , Dinamarca , Feminino , Seguimentos , Taxa de Filtração Glomerular , Rejeição de Enxerto , Sobrevivência de Enxerto , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Noruega , Pneumonia/etiologia , Suécia , Transplantados , Resultado do Tratamento
6.
Transpl Int ; 28(1): 42-51, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25176389

RESUMO

In a 36-month, open-label, multicenter trial, 202 kidney transplant recipients were randomized at week 7 post-transplant to convert to everolimus or remain on cyclosporine: 182 were analyzed to month 36 (92 everolimus, 90 controls). Mean (SD) change in measured GFR (mGFR) from randomization to month 36 was 1.3 (14.0) ml/min with everolimus versus -1.7 (15.4) ml/min in controls (P = 0.210). In patients who remained on treatment, mean mGFR improved from randomization to month 36 by 7.9 (11.5) ml/min with everolimus (n = 37) but decreased by 1.4 (14.7) ml/min in controls (n = 62) (P = 0.001). During months 12-36, death-censored graft survival was 100%, patient survival was 98.9% and 96.7% in the everolimus and control groups, respectively, and 13.0% and 11.1% of everolimus and control patients, respectively, experienced mild biopsy-proven acute rejection (BPAR). Protocol biopsies in a limited number of on-treatment patients showed similar interstitial fibrosis progression. Donor-specific antibodies were present at month 36 in 6.3% (2/32) and 18.0% (9/50) of on-treatment everolimus and control patients with available data (P = 0.281). During months 12-36, adverse events were comparable, but discontinuation was more frequent with everolimus (33.7% vs. 10.0%). Conversion from cyclosporine to everolimus at 7 weeks post-transplant was associated with a significant benefit in renal function at 3 years when everolimus was continued.


Assuntos
Inibidores de Calcineurina/uso terapêutico , Transplante de Rim , Insuficiência Renal/cirurgia , Adulto , Idoso , Biópsia , Ciclosporina/uso terapêutico , Everolimo , Feminino , Fibrose/fisiopatologia , Taxa de Filtração Glomerular , Rejeição de Enxerto , Sobrevivência de Enxerto , Humanos , Terapia de Imunossupressão , Imunossupressores/uso terapêutico , Rim/fisiologia , Masculino , Pessoa de Meia-Idade , Insuficiência Renal/terapia , Sirolimo/análogos & derivados , Sirolimo/uso terapêutico , Resultado do Tratamento
7.
Biomark Med ; 8(2): 239-45, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24521021

RESUMO

AIM: Predictors of renal recovery following conversion from calcineurin inhibitor- to proliferation signal inhibitor-based therapy are lacking. We hypothesized that plasma NGAL (P-NGAL) could predict improvement in glomerular filtration rate (GFR) after conversion to everolimus. PATIENTS & METHODS: P-NGAL was measured in 88 cardiac transplantation patients (median 5 years post-transplant) with renal dysfunction randomized to continuation of conventional calcineurin inhibitor-based immunosuppression or switching to an everolimus-based regimen. RESULTS: P-NGAL correlated with measured GFR (mGFR) at baseline (R(2) = 0.21; p < 0.001). Randomization to everolimus improved mGFR after 1 year (median [25-75 % percentiles]: ΔmGFR 5.5 [-0.5-11.5] vs -1 [-7-4] ml/min/1.73 m(2); p = 0.006). Baseline P-NGAL predicted mGFR after 1 year (R(2) = 0.18; p < 0.001), but this association disappeared after controlling for baseline mGFR. CONCLUSION: P-NGAL and GFR correlate with renal dysfunction in long-term heart transplantation recipients. P-NGAL did not predict improvement of renal function after conversion to everolimus-based immunosuppression.


Assuntos
Inibidores de Calcineurina , Rejeição de Enxerto/tratamento farmacológico , Insuficiência Cardíaca/cirurgia , Transplante de Coração , Imunossupressores/uso terapêutico , Lipocalinas/sangue , Proteínas Proto-Oncogênicas/sangue , Proteínas de Fase Aguda , Idoso , Calcineurina/metabolismo , Creatinina/sangue , Everolimo , Feminino , Seguimentos , Taxa de Filtração Glomerular , Rejeição de Enxerto/prevenção & controle , Humanos , Lipocalina-2 , Masculino , Pessoa de Meia-Idade , Sirolimo/análogos & derivados , Sirolimo/uso terapêutico
8.
J Heart Lung Transplant ; 31(3): 259-65, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22333403

RESUMO

BACKGROUND: The NOCTET (NOrdic Certican Trial in HEart and lung Transplantation) trial demonstrated that everolimus improves renal function in maintenance thoracic transplant (TTx) recipients. Nevertheless, introduction of everolimus is not recommended for patients with advanced renal failure. We evaluated NOCTET data to assess everolimus introduction amongst TTx recipients with advanced renal failure. METHODS: This 12-month multicenter Scandinavian study randomized 282 maintenance TTx recipients to everolimus introduction with calcineurin inhibitor (CNI) reduction or standard CNI therapy. The measured glomerular filtration rate (mGFR) was noted at baseline and after 1-year using Cr-ethylenediaminetetraacetic acid clearance. RESULTS: In 21 patients with a baseline mGFR of 20 to 29 ml/min/1.73 m(2), renal function improved in the everolimus group compared with the control group ((ΔmGFR 6.7 ± 9.0 vs -1.6 ± 5.1 ml/min/1.73 m(2); p = 0.03). Amongst 173 patients with moderate renal impairment (mGFR 30-59 ml/min/1.73 m(2)), renal function improvement was also greater amongst everolimus patients than in controls (ΔmGFR 5.1 ± 11.1 vs -0.5 ± 8.7 ml/min/1.73 m(2); p < 0.01). In 55 patients with mGFR 60 to 89 ml/min/1.73 m(2), mGFR did not change significantly in either group. Improvement in mGFR was limited to patients with a median time since TTx of less than 4.6 years and was also influenced by CNI reduction during the study period. CONCLUSIONS: Everolimus introduction and reduced CNI significantly improved renal function amongst maintenance TTx patients with pre-existing advanced renal failure. This beneficial effect was limited to patients undergoing conversion in less than 5 years after TTx, indicating a window of opportunity that is appropriate for pharmacologic intervention with everolimus.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Taxa de Filtração Glomerular/fisiologia , Transplante de Coração , Rim/fisiopatologia , Transplante de Pulmão , Insuficiência Renal/prevenção & controle , Sirolimo/análogos & derivados , Idoso , Ciclosporina/farmacologia , Ciclosporina/uso terapêutico , Everolimo , Feminino , Seguimentos , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Rim/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Insuficiência Renal/fisiopatologia , Países Escandinavos e Nórdicos , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Tacrolimo/farmacologia , Tacrolimo/uso terapêutico , Fatores de Tempo
9.
Transplantation ; 92(2): 235-43, 2011 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-21677600

RESUMO

BACKGROUND: Everolimus reduces the progression of cardiac allograft vasculopathy (CAV) in de novo heart transplant (HTx) recipients, but the influence on established CAV is unknown. METHODS: In this Nordic Certican Trial in Heart and lung Transplantation substudy, 111 maintenance HTx recipients (time post-HTx 5.8 ± 4.3 years) randomized to everolimus+reduced calcineurin inhibitor (CNI) or standard CNI had matching (intravascular ultrasound) examinations at baseline and 12 months allowing accurate assessment of CAV progression. RESULTS: No significant difference in CAV progression was evident between the treatment groups (P = 0.30). When considering patients receiving concomitant azathioprine (AZA) therapy (n = 39), CAV progression was attenuated with everolimus versus standard CNI (Δmaximal intimal thickness 0.00 ± 0.04 and 0.04 ± 0.04 mm, Δpercent atheroma volume 0.2% ± 3.0% and 2.6% ± 2.5%, and Δtotal atheroma volume 0.25 ± 14.1 and 19.8 ± 20.4 mm(3), respectively [P < 0.05]). When considering patients receiving mycophenolate mofetil (MMF), accelerated CAV progression occurred with everolimus versus standard CNI (Δmaximal intimal thickness 0.06 ± 0.12 vs. 0.02 ± 0.06 mm and Δpercent atheroma volume 4.0% ± 6.3% vs. 1.4% ± 3.1%, respectively; P < 0.05). The levels of C-reactive protein and vascular cell adhesion molecule-1 declined significantly with AZA+everolimus, whereas MMF+everolimus patients demonstrated a significant increase in levels of C-reactive protein, vascular cell adhesion molecule-1, and von Willebrand factor. CONCLUSIONS: Conversion to everolimus and reduced CNI does not influence CAV progression among maintenance HTx recipients. However, background immunosuppressive therapy is important as AZA+everolimus patients demonstrated attenuated CAV progression and a decline in inflammatory markers, whereas the opposite pattern was seen with everolimus+MMF. The different effect of everolimus when combined with AZA versus MMF could potentially reflect hitherto unknown interactions.


Assuntos
Progressão da Doença , Transplante de Coração/imunologia , Imunossupressores/uso terapêutico , Sirolimo/análogos & derivados , Doenças Vasculares/epidemiologia , Doenças Vasculares/prevenção & controle , Idoso , Azatioprina/uso terapêutico , Proteína C-Reativa/metabolismo , Inibidores de Calcineurina , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Everolimo , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/uso terapêutico , Fatores de Risco , Países Escandinavos e Nórdicos , Sirolimo/uso terapêutico , Ultrassonografia de Intervenção , Molécula 1 de Adesão de Célula Vascular/sangue , Doenças Vasculares/diagnóstico por imagem , Fator de von Willebrand/metabolismo
10.
Transplantation ; 90(12): 1581-9, 2010 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-21030905

RESUMO

BACKGROUND: Use of the mammalian target of rapamycin inhibitor everolimus with an accompanying reduction in calcineurin inhibitor (CNI) exposure has shown promise in preserving renal function in maintenance thoracic transplant patients, but robust, long-term data are required. METHODS: In a prospective, open-label, multicenter study, thoracic transplant recipients more than or equal to 1 year posttransplant with mild-to-moderate renal insufficiency were randomized to continue their current CNI-based immunosuppression or convert to everolimus with predefined CNI exposure reduction. After a 12-month core trial, patients were followed up to month 24 after randomization. RESULTS: Of 245 patients who completed the month 12 visit, 235 patients (108 everolimus and 127 controls) entered the 12-month extension phase. At month 24, mean measured glomerular filtration rate had increased by 3.2±12.3 mL/min from the point of randomization in everolimus-treated patients and decreased by 2.4±9.0 mL/min in controls (P<0.001), a difference that was significant within both the heart and lung transplant subpopulations. During months 12 to 24, 5.6% of everolimus patients and 3.1% of controls experienced biopsy-proven acute rejection (P=0.76). There were no significant differences in the rate of adverse events or serious adverse events (including pneumonia) between groups during months 12 to 24. CONCLUSIONS: Converting maintenance thoracic transplant recipients to everolimus with low-exposure CNI results in a renal benefit that is sustained to 2 years postconversion, with significantly improved measured glomerular filtration rate in both heart and lung transplant patients. Despite reductions of more than 50% in CNI exposure, there was no marked loss of efficacy. The safety profile of the everolimus-based regimen was acceptable.


Assuntos
Transplante de Coração/fisiologia , Transplante de Coração-Pulmão/fisiologia , Imunossupressores/uso terapêutico , Transplante de Rim/fisiologia , Transplante de Pulmão/fisiologia , Sirolimo/análogos & derivados , Proteínas Adaptadoras de Transdução de Sinal/efeitos adversos , Proteínas Adaptadoras de Transdução de Sinal/uso terapêutico , Relação Dose-Resposta a Droga , Everolimo , Taxa de Filtração Glomerular , Rejeição de Enxerto/epidemiologia , Transplante de Coração/imunologia , Transplante de Coração-Pulmão/imunologia , Humanos , Transplante de Rim/imunologia , Transplante de Pulmão/imunologia , Sirolimo/uso terapêutico
11.
Transplantation ; 89(7): 864-72, 2010 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-20061999

RESUMO

BACKGROUND: The proliferation signal inhibitor everolimus offers the potential to reduce calcineurin inhibitor (CNI) exposure and alleviate CNI-related nephrotoxicity. Randomized trials in maintenance thoracic transplant patients are lacking. METHODS: In a 12-month, open-labeled, multicenter study, maintenance thoracic transplant patients (glomerular filtration rate > or =20 mL/min/1.73m and <90 mL/min/1.73 m) >1 year posttransplant were randomized to continue their current CNI-based immunosuppression or start everolimus with predefined CNI exposure reduction. RESULTS: Two hundred eighty-two patients were randomized (140 everolimus, 142 controls; 190 heart, 92 lung transplants). From baseline to month 12, mean cyclosporine and tacrolimus trough levels in the everolimus cohort decreased by 57% and 56%, respectively. The primary endpoint, mean change in measured glomerular filtration rate from baseline to month 12, was 4.6 mL/min with everolimus and -0.5 mL/min in controls (P<0.0001). Everolimus-treated heart and lung transplant patients in the lowest tertile for time posttransplant exhibited mean increases of 7.8 mL/min and 4.9 mL/min, respectively. Biopsy-proven treated acute rejection occurred in six everolimus and four control heart transplant patients (P=0.54). In total, 138 everolimus patients (98.6%) and 127 control patients (89.4%) experienced one or more adverse event (P=0.002). Serious adverse events occurred in 66 everolimus patients (46.8%) and 44 controls (31.0%) (P=0.02). CONCLUSION: Introduction of everolimus with CNI reduction offers a significant improvement in renal function in maintenance heart and lung transplant recipients. The greatest benefit is observed in patients with a shorter time since transplantation.


Assuntos
Inibidores de Calcineurina , Ciclosporina/administração & dosagem , Transplante de Coração , Imunossupressores/administração & dosagem , Nefropatias/complicações , Transplante de Pulmão , Sirolimo/análogos & derivados , Tacrolimo/administração & dosagem , Idoso , Ciclosporina/efeitos adversos , Quimioterapia Combinada , Everolimo , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Imunossupressores/efeitos adversos , Nefropatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Países Escandinavos e Nórdicos , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Tacrolimo/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
12.
J Heart Lung Transplant ; 28(9): 919-26, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19716045

RESUMO

BACKGROUND: Cyclosporine (CsA) absorption varies early after transplantation and can be accurately assessed by the area under the absorption curve (AUC). The 2-hour post-dose (C2) level of CsA in whole blood is reported to be a useful surrogate marker of CsA AUC in kidney and liver transplant monitoring, but should be further explored in thoracic organ recipients. METHODS: In a 12-month study we included de novo lung (n = 95) and heart (n = 96) recipients. All participants received cyclosporine (Sandimmun Neoral) monitored by C0 and blood was collected for analysis of C2 retrospectively. Abbreviated AUC (AUC(0-4)) was measured at 7 days and 3 months. Primary outcome was C2 relation to the frequency of acute cellular rejection (ACR) needing treatment and possible decline in measured glomerular filtration rate (mGFR). Recipients were divided into lower, middle and upper third C2 groups based on 2-week post-operative values (tertiles T1 to T3). RESULTS: C2 was the most robust substitute for AUC(0-4) in the group of patients studied. For lung, but not heart, recipients there were differences in mean number of ACRs (p = 0.05), incidence of any rejections (p = 0.04), mean number of any rejections (p = 0.001) and time to first rejection (p = 0.03) between T1 and T3. C2 did not predict reduction in mGFR. CONCLUSIONS: C2 is a sensitive predictor for ACR in lung, but not heart, recipients, C2 was not predictive of a decline in mGFR. This study suggests that management of lung recipients by C2 may diminish the number of ACRs.


Assuntos
Ciclosporina/sangue , Ciclosporina/uso terapêutico , Rejeição de Enxerto/imunologia , Transplante de Coração/imunologia , Transplante de Pulmão/imunologia , Adulto , Área Sob a Curva , Pressão Sanguínea , Cardiomiopatias/cirurgia , Doença da Artéria Coronariana/cirurgia , Creatinina/sangue , Ciclosporina/farmacocinética , Fibrose Cística/cirurgia , Enfisema/cirurgia , Feminino , Taxa de Filtração Glomerular , Rejeição de Enxerto/epidemiologia , Transplante de Coração/mortalidade , Humanos , Imunossupressores/sangue , Imunossupressores/farmacocinética , Imunossupressores/uso terapêutico , Transplante de Pulmão/mortalidade , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica/métodos , Doença Pulmonar Obstrutiva Crônica/cirurgia
13.
Transplantation ; 84(8): 1052-4, 2007 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-17989612

RESUMO

Gastrointestinal (GI) symptoms are common in renal transplant recipients and are associated with impaired health-related quality of life (HRQoL). We investigated clinician attitudes to GI symptoms and HRQoL in these patients by surveying 145 nephrologists from Sweden, Denmark, Finland, and Norway. In total, 79 clinicians responded. They estimated that 20% of their patients experienced GI discomfort and that 36% had impaired HRQoL. We previously conducted a survey of the renal transplant recipients treated by these clinicians, in which 92% reported troublesome GI symptoms and 53% had impaired HRQoL compared with the general population. Nephrologists were more likely to manage GI symptoms by reducing immunosuppressant dose (87%) than by switching medication to one with fewer GI side effects (66%). We conclude that clinicians appear to underestimate the prevalence of GI symptoms and impaired HRQoL. Improving patient-clinician communication could lead to more informed management, resulting in better HRQoL and increased graft survival.


Assuntos
Atitude do Pessoal de Saúde , Gastroenteropatias/epidemiologia , Transplante de Rim/efeitos adversos , Médicos/psicologia , Coleta de Dados , Feminino , Finlândia/epidemiologia , Gastroenteropatias/diagnóstico , Gastroenteropatias/tratamento farmacológico , Humanos , Imunossupressores/uso terapêutico , Masculino , Pacientes , Prevalência , Qualidade de Vida , Países Escandinavos e Nórdicos/epidemiologia
14.
Transplantation ; 83(3): 282-9, 2007 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-17297402

RESUMO

BACKGROUND: Immunosuppressive therapies have been associated with gastrointestinal (GI) side effects, which may impair health-related quality of life (HRQoL). METHODS: In this survey, 4,232 renal transplant recipients from Denmark, Finland, Norway, and Sweden completed the Short-Form 36 (SF-36) questionnaire and the Gastrointestinal Symptom Rating Scale (GSRS). SF-36 scores were compared with country norm values. Multiple logistic regression analysis was used to identify immunosuppressants associated with GI symptoms. RESULTS: The prevalence of troublesome GI symptoms (GSRS>1) was 83% for indigestion, 69% for abdominal pain, 58% for constipation, 53% for diarrhea, 47% for reflux, and 92% for any GI symptom. Compared with the general population, HRQoL was most commonly meaningfully impaired in the general health dimension (53% of patients). The presence and severity of GI symptoms were associated with worse HRQoL. Tacrolimus showed a significant association with diarrhea (odds ratio [OR]: 1.7; 95% confidence interval [CI]: 1.4-2.0) and constipation (OR: 1.3; 95% CI: 1.1-1.6), and sirolimus with indigestion (OR: 2.9; 95% CI: 1.0-8.1) and abdominal pain (OR: 2.2; 95% CI: 1.1-4.4). CONCLUSIONS: GI symptoms are associated with impaired HRQoL in the renal transplant population. Managing GI symptoms by careful choice of immunosuppressants should be a focus for improving HRQoL in renal transplant recipients.


Assuntos
Gastroenteropatias/epidemiologia , Imunossupressores/efeitos adversos , Transplante de Rim , Qualidade de Vida , Adulto , Feminino , Humanos , Terapia de Imunossupressão/efeitos adversos , Masculino , Pessoa de Meia-Idade , Prevalência , Inquéritos e Questionários
15.
Lancet ; 361(9374): 2024-31, 2003 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-12814712

RESUMO

BACKGROUND: Renal transplant recipients are at increased risk of premature cardiovascular disease. Although statins reduce cardiovascular risk in the general population, their efficacy and safety in renal transplant recipients have not been established. We investigated the effects of fluvastatin on cardiac and renal endpoints in this population. METHODS: We did a multicentre, randomised, double-blind, placebo-controlled trial in 2102 renal transplant recipients with total cholesterol 4.0-9.0 mmol/L. We randomly assigned patients fluvastatin (n=1050) or placebo (n=1052) and follow up was for 5-6 years. The primary endpoint was the occurrence of a major adverse cardiac event, defined as cardiac death, non-fatal myocardial infarction (MI), or coronary intervention procedure. Secondary endpoints were individual cardiac events, combined cardiac death or non-fatal MI, cerebrovascular events, non-cardiovascular death, all-cause mortality, and graft loss or doubling of serum creatinine. Analysis was by intention to treat. FINDINGS: After a mean follow-up of 5.1 years, fluvastatin lowered LDL cholesterol concentrations by 32%. Risk reduction with fluvastatin for the primary endpoint (risk ratio 0.83 [95% CI 0.64-1.06], p=0.139) was not significant, although there were fewer cardiac deaths or non-fatal MI (70 vs 104, 0.65 [0.48-0.88] p=0.005) in the fluvastatin group than in the placebo group. Coronary intervention procedures and other secondary endpoints did not differ significantly between groups. INTERPRETATION: Although cardiac deaths and non-fatal MI seemed to be reduced, fluvastatin did not generally reduce rates of coronary intervention procedures or mortality. Overall effects of fluvastatin were similar to those of statins in other populations.


Assuntos
Anticolesterolemiantes/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Ácidos Graxos Monoinsaturados/uso terapêutico , Indóis/uso terapêutico , Transplante de Rim , Adulto , Idoso , LDL-Colesterol/sangue , LDL-Colesterol/efeitos dos fármacos , Método Duplo-Cego , Interações Medicamentosas , Feminino , Fluvastatina , Seguimentos , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Placebos , Fatores de Risco
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