RESUMO
UNLABELLED: The aim was to study the influence of sirolimus (SRL) on body weight in a rat model and in kidney transplant patients. Wistar rats (15 weeks old) were either treated with vehicle (VEH; n = 8) or SRL (n = 7) 1.0 mg/kg three times per week for 12 weeks. Body mass and food intake were measured weekly. Adipocyte diameter was determined in hematoxylin-eosin stains. The body mass index (BMI) obtained from clinical kidney transplant trials comparing SRL-based with cyclosporine-based therapy was analyzed. ANIMALS: SRL produced a decrease of the weight gain curve. At the end of the study, mean body weight in the SRL group was lower than in the VEH group (356 vs. 507 g, P < 0.01) in spite of comparable food intake normalized for body weight was not different. Mean adipocyte diameter was 36 mum in VEH and 25 mum in SRL rats (P = 0.009). Mean SRL blood trough concentration was 38 ng/ml. Kidney transplant patients: Two years after transplantation, BMI was significantly lower in the SRL-based treatment arm compared to cyclosporine (24.17 +/- 2.99 vs. 25.97 +/- 5.01 kg/m(2), P = 0.031). SRL treatment leads to less body mass. Adipocyte cell diameter was reduced in SRL-treated animals. A possible explanation may be the effects of SRL on metabolic regulation and cell growth.
Assuntos
Peso Corporal/efeitos dos fármacos , Rejeição de Enxerto/prevenção & controle , Imunossupressores/uso terapêutico , Transplante de Rim/métodos , Proteínas Quinases/efeitos dos fármacos , Sirolimo/uso terapêutico , Adipócitos/efeitos dos fármacos , Adipócitos/patologia , Animais , Índice de Massa Corporal , Ciclosporina/uso terapêutico , Modelos Animais de Doenças , Rejeição de Enxerto/metabolismo , Rejeição de Enxerto/patologia , Humanos , Imunossupressores/farmacocinética , Masculino , Radioimunoensaio , Ratos , Ratos Wistar , Sirolimo/farmacocinética , Serina-Treonina Quinases TOR , Resultado do TratamentoRESUMO
Measured glomerular filtration rates (mGFRs) were obtained by (99)mTc-DPTA, (125)I-iothalamate, iohexol, (51)Cr-EDTA, non-radiolabeled iothalamate, or inulin clearance from centers agreeing to perform mGFR in six completed and one ongoing Wyeth Research multicenter trials evaluating sirolimus (SRL) in regimens with or without a calcineurin inhibitor (CNI). Estimated GFRs (eGFRs) were calculated by the Cockcroft-Gault (eGFR(CG)), Nankivell (eGFR(NK)), and simplified Modification of Diet in Renal Disease (eGFR(MDRD)) equations. Bias, precision, and accuracy for each of these equations were estimated by tertiles and by regimen. For the Rapamune Maintenance Regimen (RMR) trial, eGFR outcomes were also compared between treatments {[SRL-cyclosporine (CsA) versus SRL]} using the three eGFR formulas. In the lowest mGFR tertile (6-40 ml/min), eGFR(MDRD) gave the best accuracy with the least bias whereas eGFR(NK) and eGFR(CG) performed better in the highest mGFR tertile (58-139 ml/min). At 24 months in the RMR study, mean differences in eGFR between treatments were 13.6, 14.2, and 13.5 ml/min/1.73 m(2) for eGFR(CG), eGFR(NK), and eGFR(MDRD), respectively, favoring CsA withdrawal (P-values for all <0.001). The accuracy of the three eGFR equations was affected by mGFR range but not by immunosuppressive regimens utilizing SRL, SRL-CNI or CNI-based therapy.
Assuntos
Inibidores de Calcineurina , Taxa de Filtração Glomerular , Imunossupressores/uso terapêutico , Transplante de Rim , Sirolimo/uso terapêutico , Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-IdadeRESUMO
Sirolimus (SRL) has a concentration-related effect on hematopoiesis. In this study, 430 renal transplant recipients were randomized (1:1) 3 months post-transplantation to continue SRL-cyclosporine (CsA)-steroids (ST) or to have CsA withdrawn (SRL-ST). Over 5 years, on therapy calculated glomerular filtration rate (GFR), hematological indices, erythropoietin (EPO) use, and rates of mild, moderate, and severe anemia were determined. Longitudinal analyses using linear mixed models examined covariates predicting hemoglobin (Hgb) levels. Mean Hgb was significantly lower with SRL-ST at 6 months; but subsequently became significantly higher (at 2 years, 129 vs. 135 g/l, SRL-CsA-ST vs. SRL-ST, P<0.001). Mean corpuscular volume was low with both therapies, and significantly lower with SRL-ST. EPO use was similar in the two groups, approximately 30% during the first year and 10% thereafter. The incidence of anemia was significantly higher with SRL-CsA-ST>or=2 years. At year 5, only 39.1% of SRL-CsA-ST patients had normal Hgb vs. 68.5% of SRL-ST patients. GFR and recipient age as well as the interaction term x treatment time were significant covariates predicting Hgb. CsA withdrawal followed by SRL immunotherapy resulted in significantly less anemia than SRL-CsA-ST, despite twofold higher SRL exposure. This suggests that the improvement in GFR accompanying CsA withdrawal may mitigate the effect of SRL on hematopoiesis. (ClinicalTrials.gov number: NCT00428064).
Assuntos
Anemia/induzido quimicamente , Anemia/epidemiologia , Imunossupressores/efeitos adversos , Transplante de Rim , Rim/fisiopatologia , Sirolimo/efeitos adversos , Adolescente , Adulto , Idoso , Envelhecimento/sangue , Criança , Pré-Escolar , Ciclosporina/administração & dosagem , Ciclosporina/uso terapêutico , Esquema de Medicação , Quimioterapia Combinada , Eritropoetina/uso terapêutico , Feminino , Taxa de Filtração Glomerular , Hemoglobinas/metabolismo , Humanos , Imunossupressores/uso terapêutico , Incidência , Rim/efeitos dos fármacos , Modelos Lineares , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Sirolimo/uso terapêuticoRESUMO
Changes in calculated glomerular filtration rate (GFR) from baseline to five yr were analyzed in relation to risk factors among renal transplant recipients. At three months after transplantation (baseline), 430 eligible patients receiving sirolimus (SRL), cyclosporine (CsA), and steroids (ST) were randomly assigned (1:1) to continue SRL-CsA-ST or have CsA withdrawn and SRL trough levels increased (SRL-ST group). For each risk factor, changes from baseline were compared within each treatment using a t-test and between treatments using ANCOVA. Univariate then multivariate robust linear regression analyses were also performed. In the SRL-ST group, changes from baseline were not significantly different for any risk factor. With the exception of cold ischemia time >24 h, GFR values declined significantly for all risk factors in SRL-CsA-ST patients. For all risk factors, except second transplant or cold ischemia time >24 h, renal function was significantly different between groups. By order of significance in the multivariate analysis, treatment (p < 0.001), donor age (p < 0.001), proteinuria (p < 0.001), and biopsy-confirmed rejection (p = 0.010) were significant predictors of GFR change from baseline. In conclusion, patients with risk factors for reduced renal function benefit from SRL maintenance therapy without CsA vs. those remaining on CsA.
Assuntos
Ciclosporina/uso terapêutico , Imunossupressores/uso terapêutico , Transplante de Rim/fisiologia , Sirolimo/uso terapêutico , Adolescente , Adulto , Fatores Etários , Idoso , Creatinina/sangue , Feminino , Taxa de Filtração Glomerular , Humanos , Transplante de Rim/imunologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fatores de RiscoRESUMO
Sirolimus (SRL) is a mammalian target of rapamycin inhibitor that, in contrast to cyclosporine (CsA), has been shown to inhibit rather than promote cancers in experimental models. At 3 mo +/- 2 wk after renal transplantation, 430 of 525 enrolled patients were randomly assigned to remain on SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold (SRL-ST). Median times to first skin and nonskin malignancies were compared between treatments using a survival analysis. Mean annualized rates of skin malignancy were calculated, and the relative risk was determined using a Poisson model. Malignancy-free survival rates for nonskin malignancies were compared using Kaplan-Meier estimates and the log-rank test. At 5 yr, the median time to a first skin carcinoma was delayed (491 versus 1126 d; log-rank test, P = 0.007), and the risk for an event was significantly lower with SRL-ST therapy (relative risk SRL-ST to SRL-CsA-ST 0.346; 95% confidence interval 0.227 to 0.526; P < 0.001, intention-to-treat analysis). The relative risks for both basal and squamous cell carcinomas were significantly reduced. Kaplan-Meier estimates of nonskin cancer were 9.6 versus 4.0% (SRL-CsA-ST versus SRL-ST; P = 0.032, intention-to-treat analysis). Nonskin cancers included those of the lung, larynx, oropharynx, kidney, gastrointestinal tract, prostate, breast, thyroid, and cervix as well as glioma, liposarcoma, astrocytoma, leukemia, lymphoma, and Kaposi's sarcoma. Patients who received SRL-based, calcineurin inhibitor-free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and nonskin malignancies at 5 yr after renal transplantation compared with those who received SRL therapy combined with CsA. Longer follow-up and additional trials are needed to confirm these promising results.
Assuntos
Ciclosporina/administração & dosagem , Imunossupressores/administração & dosagem , Transplante de Rim , Neoplasias/epidemiologia , Sirolimo/administração & dosagem , Adulto , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada , Seguimentos , Humanos , Incidência , Medição de RiscoRESUMO
BACKGROUND: It has become increasingly important to refine therapeutic strategies according to individual patient characteristics. We evaluated the long-term impact of renal function at the time of withdrawing cyclosporine (CsA) in renal allograft recipients receiving sirolimus (SRL), CsA, and steroids (ST). METHODS: At 3 months+/-2 weeks, 430 of 525 patients were eligible to be randomized to remain on triple-therapy (SRL-CsA-ST, n=215) or to have CsA withdrawn (SRL-ST, n=215). Patients were divided into quartiles according to their baseline (last value before randomization) calculated GFR: Assuntos
Ciclosporina/administração & dosagem
, Imunossupressores/administração & dosagem
, Transplante de Rim/imunologia
, Rim/fisiopatologia
, Sirolimo/administração & dosagem
, Doença Aguda
, Adolescente
, Adulto
, Idoso
, Ciclosporina/efeitos adversos
, Ciclosporina/uso terapêutico
, Esquema de Medicação
, Quimioterapia Combinada
, Feminino
, Taxa de Filtração Glomerular
, Rejeição de Enxerto/epidemiologia
, Humanos
, Imunossupressores/efeitos adversos
, Imunossupressores/uso terapêutico
, Incidência
, Transplante de Rim/mortalidade
, Masculino
, Pessoa de Meia-Idade
, Sirolimo/efeitos adversos
, Sirolimo/uso terapêutico
, Esteroides/uso terapêutico
, Resultado do Tratamento
RESUMO
AIMS: The influence of the trimethoprim-sulphamethoxazole combination on the steady-state pharmacokinetics of sirolimus, a potent macrocyclic immunosuppressant, was studied in renal transplant recipients. METHODS: Fifteen kidney transplant recipients were treated with sirolimus 8-23 mg m(-2) in combination with azathioprine and prednisolone from the day of transplantation. Whole blood sirolimus AUC and C(max) were determined on days 6 and 7 after transplantation. On day 7, sirolimus was coadministered with the first dose of trimethoprim (80 mg) and sulphamethoxazole (400 mg). RESULTS: On day 6, the mean (95% confidence interval) whole blood sirolimus AUC((0-24 h)) was 1040 (846, 1234) ng ml(-1) and mean C(max) was 109 (88, 129) ng ml(-1). Corresponding values on day 7 were AUC((0-24 h)) 1060 (826, 1293) ng ml(-1) and C(max) mean 107 (87, 127) ng ml(-1). The mean difference in the dose-corrected AUC((0-24 h)) was 0.40% (-9.4, +10). CONCLUSIONS: A single dose of trimethoprim-sulphamethoxazole does not affect the pharmacokinetics of sirolimus in renal transplant patients.
Assuntos
Anti-Infecciosos Urinários/farmacologia , Imunossupressores/farmacocinética , Transplante de Rim , Sirolimo/farmacocinética , Combinação Trimetoprima e Sulfametoxazol/farmacologia , Adulto , Idoso , Anti-Infecciosos Urinários/administração & dosagem , Área Sob a Curva , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cuidados Pós-Operatórios , Combinação Trimetoprima e Sulfametoxazol/administração & dosagemRESUMO
Sirolimus is a new immunosuppressive agent used as treatment to prevent acute renal allograft rejection. One of the complications of renal transplantation and subsequent long-term immunosuppression is bone loss associated with osteoporosis and consequent fracture. Two open-label, randomized, phase 2 studies comparing sirolimus versus cyclosporine (CsA) included indices of bone metabolism as secondary end-points. Markers of bone turnover, serum osteocalcin and urinary N-telopeptides, were measured over a 1-year period in 115 patients receiving either CsA or sirolimus as a primary therapy in combination with azathioprine and glucocorticoids (study A) or mycophenolate mofetil (MMF) and glucocorticoids (study B). Urinary excretion of N-telopeptides and the concentrations of serum osteocalcin were consistently higher in the CsA-treated patients and significantly different at week 24 for N-telopeptides and at weeks 12, 24, and 52 for osteocalcin. In conclusion, future trials are warranted to test whether a sirolimus-based regimen conserves bone mineral density compared with a CsA-based regimen.
Assuntos
Osso e Ossos/efeitos dos fármacos , Ciclosporina/efeitos adversos , Imunossupressores/efeitos adversos , Transplante de Rim , Sirolimo/efeitos adversos , Adulto , Idoso , Osso e Ossos/metabolismo , Cálcio/sangue , Colágeno/sangue , Colágeno Tipo I , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Osteocalcina/sangue , Peptídeos/sangueRESUMO
We report the 48-month results of a trial testing whether withdrawal of cyclosporine (CsA) from a sirolimus (SRL)-CsA-steroid (ST) regimen would impact renal allograft survival. Eligible patients receiving SRL-CsA-ST from transplantation were randomly assigned at 3 months to remain on triple therapy (SRL-CsA-ST, n = 215) or to have CsA withdrawn and SRL trough concentrations increased (SRL-ST, n = 215). SRL-ST therapy resulted in significantly better graft survival, either when including death with a functioning graft as an event (84.2% vs. 91.5%, P = 0.024) or when censoring it (90.6% vs. 96.1%, P = 0.026). Calculated glomerular filtration rate (43.8 vs. 58.3 ml/min, P < 0.001) and mean arterial blood pressure (101.3 vs. 97.1 mmHg, P = 0.047) were also improved with SRL-ST. Differences in the incidences of biopsy-proven acute rejection after randomization (6.5% vs. 10.2%, SRL-CsA-ST versus SRL-ST, respectively) and mortality (7.9% vs. 4.7%) were not significant. SRL-CsA-ST-treated patients had significantly higher incidences of adverse events generally associated with CsA, whereas those in the SRL-ST group experienced greater frequencies of events commonly related to higher trough levels of SRL. In conclusion, early withdrawal of CsA from a SRL-CsA-ST regimen rapidly improves renal function and ultimately results in better graft survival.
Assuntos
Sobrevivência de Enxerto/fisiologia , Imunossupressores/uso terapêutico , Transplante de Rim/fisiologia , Sirolimo/uso terapêutico , Corticosteroides/uso terapêutico , Ciclosporina/uso terapêutico , Quimioterapia Combinada , Seguimentos , Taxa de Filtração Glomerular , Sobrevivência de Enxerto/efeitos dos fármacos , Sobrevivência de Enxerto/imunologia , Humanos , Transplante de Rim/imunologia , Transplante de Rim/mortalidade , Cooperação do Paciente , Estomatite/induzido quimicamente , Estomatite/epidemiologia , Análise de Sobrevida , Fatores de TempoRESUMO
We performed a randomized prospective trial comparing calcineurin inhibitor (CNI)-free to CNI-based immunosuppression to determine the impact on renal function, structure and gene expression. Sixty-one kidney recipients treated with basiliximab mycophenolate mofetil (MMF) and prednisone (P) were randomly assigned to concentration-controlled sirolimus or cyclosporine. Two years post-transplant 55 patients underwent renal function studies, 48 (87%) underwent transplant biopsies; all classified by Banff scoring and 41 by DNA microarrays. Comparing sirolimus/MMF/P to cyclosporine/MMF/P there was a significantly lower serum creatinine (1.35 vs. 1.81 mg/dL; p = 0.008), higher Cockroft-Gault glomerular filtration rate (GFR) (80.4 vs. 63.4 mL/min; p = 0.008), iothalamate GFR (60.6 vs. 49.2 mL/min; p = 0.018) and Banff 0 (normal) biopsies (66.6 vs. 20.8%; p = 0.013). Regression analysis of calculated GFRs from 1 to 36 months yielded a positive slope for sirolimus of 3.36 mL/min/year, and a negative slope for cyclosporine of -1.58 mL/min/year (p = 0.008). Gene expression profiles from kidneys with higher Banff chronic allograft nephropathy (CAN) scores confirmed significant up-regulation of genes responsible for immune/inflammation and fibrosis/tissue remodeling. At 2 years the sirolimus-treated recipients have better renal function, a diminished prevalence of CAN and down-regulated expression of genes responsible for progression of CAN. All may provide for an alternative natural history with improved graft survival.
Assuntos
Ciclosporina/uso terapêutico , Transplante de Rim/fisiologia , Sirolimo/uso terapêutico , Adulto , Idoso , Biópsia , Inibidores de Calcineurina , Sobrevivência de Enxerto/fisiologia , Humanos , Imunossupressores/uso terapêutico , Inflamação , Testes de Função Renal , Transplante de Rim/patologia , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Prednisona/uso terapêutico , Fatores de Tempo , Transplante Homólogo , Resultado do TratamentoRESUMO
Graft function and histology are predictive of renal transplant survival. The Rapamune Maintenance Regimen study demonstrated that early cyclosporine (CsA) withdrawal from a sirolimus (SRL)-CsA-steroid (ST) regimen improved renal function and blood pressure. We report the protocol-mandated biopsy findings from that study. Renal transplant patients (n = 430) receiving SRL-CsA-ST were randomized at 3 months after transplantation to remain on SRL-CsA-ST, or to have CsA withdrawn (SRL-ST group). Protocol-mandated biopsies were performed at engraftment and at 12 and 36 months. Two pathologists blindly evaluated 484 biopsies to obtain the Chronic Allograft Damage Index (CADI) scores. At 36 months among patients with serial biopsies (n = 63), the mean CADI score was significantly lower with SRL-ST(4.70 vs. 3.20, p = 0.003), as was the mean tubular atrophy score (0.77 vs. 0.32, p < 0.001). All six components of the CADI score were numerically lower in SRL-ST group; moreover, inflammation and the tubular atrophy scores decreased significantly in the SRL-ST group between 12 and 36 months. The calculated glomerular filtration rate at 36 months was significantly better in the CsA-withdrawal group (54.8 vs. 68.2 mL/min, p = 0.009). In conclusion, withdrawing CsA from the SRL-CsA-ST regimen resulted in improved renal histology and function.
Assuntos
Ciclosporina/uso terapêutico , Sobrevivência de Enxerto/efeitos dos fármacos , Imunossupressores/uso terapêutico , Transplante de Rim/fisiologia , Sirolimo/uso terapêutico , Adulto , Biópsia , Pressão Sanguínea , Feminino , Taxa de Filtração Glomerular , Rejeição de Enxerto/prevenção & controle , Humanos , Rim/efeitos dos fármacos , Rim/fisiologia , Masculino , Pessoa de Meia-Idade , Esteroides/uso terapêutico , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Graft function at 6 or 12 mo is positively correlated with renal transplant survival. The 36-mo results of a study that tested whether withdrawing cyclosporine (CsA) from a sirolimus (SRL)-CsA-steroid (ST) regimen would affect renal graft survival are reported. Eligible patients (n = 430) who were receiving SRL-CsA-ST were randomly assigned at 3 mo to remain on SRL-CsA-ST or to have CsA withdrawn (SRL-ST group). At 36 mo, the calculated GFR was significantly better with SRL-ST (47.3 versus 59.4 ml/min; P < 0.001) as was the slope of the GFR (-3.6 versus 0.8 ml/min; P < 0.001). This was accompanied by growing trend for improved graft survival in the SRL-ST group (85.1% versus 91.2%, P = 0.052 at 36 mo; 81.4% versus 91.2%, P = 0.015 in a cumulative data analysis up to 54 mo), despite numerically more biopsy-proven acute rejections after randomization (5.6% versus 10.2%; P = 0.107). Lipid parameters were similar between groups, whereas both systolic and diastolic BP were significantly lower in the SRL-ST group. Investigator-reported hypertension, abnormal kidney function, edema, hyperuricemia, hyperkalemia, gingival hyperplasia, and Herpes zoster occurred significantly more often in SRL-CsA-ST patients. Abnormal liver function test results, hypokalemia, thrombocytopenia, and abnormal healing were reported significantly more often with SRL-ST. The discontinuation rate was significantly higher for SRL-CsA-ST (48% versus 38%; P = 0.041). In conclusion, withdrawing CsA from a SRL-CsA-ST regimen at 3 mo after transplantation resulted in long-term benefits for renal transplant recipients.
Assuntos
Sobrevivência de Enxerto/efeitos dos fármacos , Imunossupressores/uso terapêutico , Transplante de Rim , Sirolimo/uso terapêutico , Doença Aguda , Ciclosporina/administração & dosagem , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/efeitos adversos , Transplante de Rim/mortalidade , Transplante de Rim/fisiologia , Sirolimo/efeitos adversos , Taxa de Sobrevida , Fatores de TempoRESUMO
INTRODUCTION: The purpose of this study was to evaluate early cyclosporine (CsA) withdrawal from a sirolimus (SRL)-CsA-steroid (ST) regimen. METHODS: Within 48 hr after transplantation, 525 primary (90%) or secondary (10%) renal allograft recipients with cadaveric (89%) or living (11%) donors received 2 mg of SRL (troughs >5 ng/mL; immunoassay), CsA, and ST. Those eligible (430) were randomly assigned (1:1) at 3 months +/- 2 weeks to remain on triple-drug therapy (SRL-CsA-ST group) or to have CsA withdrawn and SRL trough concentrations targeted to 20 to 30 ng/mL (SRL-ST group) until month 12, and 15 to 25 ng/mL thereafter. RESULTS: At 24 months, there were no statistically significant differences in patient survival (94.0% vs. 95.3%), graft survival (91.2% vs. 93.5%), acute rejection after randomization (5.1% vs. 9.8%) or discontinuations (34% vs. 33%) for SRL-CsA-ST versus SRL-ST, respectively. Serum creatinine level was significantly better in patients who had CsA withdrawn (167 vs. 128 micromol/L, P<0.001), as was the slope of 1/creatinine. Similarly, systolic blood pressure was lower in patients who had CsA withdrawn (141 vs. 134 mm Hg, P<0.001). High-density lipoprotein cholesterol was significantly higher in the SRL-ST group, whereas total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels were not significantly different. Hypertension, creatinine increase, abnormal kidney function, toxic nephropathy, edema, hyperuricemia, cataracts, Herpes zoster, and malignancy were reported significantly more often in patients continuing CsA. Thrombocytopenia, hypokalemia, abnormal liver function tests, abnormal wound healing, ileus, and pneumonia were reported significantly more frequently with SRL-ST. CONCLUSION: Data at 2 years confirm that early CsA withdrawal followed by an SRL-ST maintenance regimen results in long-term improvement in both renal function and blood pressure, without increased risk of graft loss or late acute rejection.
Assuntos
Ciclosporina/administração & dosagem , Imunossupressores/administração & dosagem , Transplante de Rim , Rim/fisiologia , Sirolimo/administração & dosagem , Pressão Sanguínea , Creatinina/sangue , Ciclosporina/efeitos adversos , Seguimentos , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/mortalidade , Sobrevivência de Enxerto/efeitos dos fármacos , Hemoglobinas , Humanos , Imunossupressores/efeitos adversos , Sirolimo/efeitos adversos , Resultado do TratamentoRESUMO
Sirolimus and cyclosporine (CsA) prevent acute rejection in man when used as primary therapies in triple drug regimens. Sirolimus does not act via the calcineurin pathway and therefore is not expected to produce the same renal side-effects. This paper presents the pooled 2-year data analysis of renal function parameters from two open-label, randomized, multicenter studies. Patients (18-68 years) receiving a primary renal allograft were randomized to receive concentration-controlled sirolimus (n = 81) or CsA (n = 80), in combination with azathioprine and steroids (n = 83), or mycophenolate mofetil (MMF) and steroids (n = 78). From week 10 through year 2, calculated glomerular filtration rate (GFR) was significantly higher in sirolimus--than in CsA-treated patients (69.3 vs. 56.8 mL/min, at 2 years, p = 0.004). Serum uric acid was significantly higher in the CsA-treated patients and magnesium was significantly lower; these parameters were more likely to be within normal limits in the sirolimus group. Mean serum potassium and phosphorus were lower in sirolimus-treated patients. In conclusion, sirolimus, when administered as primary therapy in combination with azathioprine or MMF, has a favorable safety profile compared to CsA with regards to renal function.