Tacrolimus compared with cyclosporine microemulsion in primary simultaneous pancreas-kidney transplantation: the EURO-SPK 3-year results

This 3-year study compared tacrolimus versus cyclosporine (CsA) microemulsion (ME) in conjunction with rATG induction, mycophenolate mofetil (MMF) and short-term corticosteroids in primary simultaneous pancreas-kidney (SPK) transplantation. PATIENTS AND METHODS: This large, prospective, multicenter study was conducted in 10 European centers and one center in Israel. Of the 205 SPK transplants performed from 1998 to 2000, 103 patients were randomly assigned to tacrolimus and 102 to CsA ME. All patients received concomitant rATG induction therapy, MMF, and short-term corticosteroids. RESULTS: In total, 36.9% patients receiving tacrolimus and 57.8% receiving CsA ME discontinued treatment (P = .003). Although 3-year patient and kidney graft survival rates were similar in both groups, pancreas survival was superior with tacrolimus (89.2% versus 72.4%; P = .002). Thrombosis resulted in pancreatic allograft loss in 10 patients receiving CsA ME and in 2 treated with tacrolimus (P = .02). The first episode of biopsy-proven rejection was moderate or severe in 1 of 31 tacrolimus-treated patients and 11 of 39 patients receiving CsA ME (P = .009). Overall adverse event frequency was similar in both groups, but surgical events were lower in the tacrolimus treated group. CONCLUSION: Tacrolimus was more effective than CsA-ME to prevent moderate or severe kidney or pancreas rejection after SPK transplantation. It also provided superior pancreatic graft survival and reduced the risk of pancreas thrombosis.     

Efficacy and safety of tacrolimus compared with cyclosporin A microemulsion in renal transplantation: 2 year follow-up results.

BACKGROUND: Comparison studies of calcineurin inhibitors as cornerstone immunosuppressants in renal transplantation have demonstrated that tacrolimus consistently reduces acute rejection rates and, in some studies, also improves long-term renal outcome in comparison to cyclosporin A (CsA). The aim of the present 2 year follow-up of the European Tacrolimus vs Cyclosporin A Microemulsion Renal Transplantation Study was to investigate long-term clinical outcome in terms of rate of acute rejection, graft and patient survival and graft function. METHODS: The European Tacrolimus vs Cyclosporin A Microemulsion Renal Transplantation Study was a randomized, comparative 6 month trial of the calcineurin inhibitors tacrolimus and CsA in combination with both azathioprine and steroids. The intent-to-treat population (ITT) consisted of 286 patients in the tacrolimus arm and 271 in the CsA microemulsion (CsA-ME) arm. Whereas whole blood level targets were 10-20 and 5-15 ng/ml for tacrolimus and 100-400 and 100-200 ng/ml for CsA during months 0-3 and 4-6, respectively, during the investigator-driven follow-up after termination of the main study (months 7-24) no specific calcineurin inhibitor target levels were required. Follow-up data were collected at 2 years post-transplantation from 237 (82.9% of the ITT population) patients who received tacrolimus and 222 (81.9% of the ITT population) patients who received CsA-ME. RESULTS: Calculated on ITT populations, mortality (2.0% vs 3.3%; P<0.05 in Kaplan-Meier analysis) was lower, but rate of graft loss (9.3% vs 11.2%; P = 0.12 in Kaplan-Meier analysis) was not significantly different after 2 years with tacrolimus- vs CsA-ME-based immunosuppression. Biopsy-proven acute rejection was significantly lower (19.6%) with tacrolimus than with CsA-ME (37.3%) during months 0-6 (P<0.0001), but was not significantly different during months 7-12 and 13-24 of follow-up (1.7% and 0.8% with tacrolimus and 4.7% and 0.9% with CsA-ME, respectively). A composite endpoint consisting of graft loss, patient death and biopsy-proven acute rejection occurred significantly more frequently in CsA-ME patients than in tacrolimus patients (42.8% vs 25.9%; P<0.001) during 24 months follow-up. Renal function 2 years post-transplant, measured by serum creatinine concentrations, was significantly better in tacrolimus-based compared with CsA-ME-based immunosuppression (136.9 vs 161.6 micromol/l; P<0.01). Cornerstone immunosuppression remained unchanged in 82.5% and 66.2% of patients treated with tacrolimus and CsA-ME, respectively. At 2 years, more patients in the tacrolimus arm were off steroids and received calcineurin inhibitor monotherapy, and fewer tacrolimus patients remained on a triple immunosuppressive regimen. The cardiovascular risk profile was affected favourably in the tacrolimus arm, with lower cholesterol and triglyceride concentrations (despite less use of cholesterol-lowering drugs); no significant difference in requirement for antidiabetic medication was noted. CONCLUSIONS: The 2 year study results confirm that tacrolimus is a highly efficacious cornerstone immunosuppressant in kidney transplantation. Tacrolimus-based immunosuppression may induce long-term benefits with regard to graft function and graft survival. The overall side-effect profile is considered to be favourable.     

Efficacy and safety of tacrolimus versus cyclosporine microemulsion in primary cardiac transplant recipients: 6-month results in Taiwan

INTRODUCTION: This study compared the efficacy and safety of a tacrolimus (TAC)-based with a cyclosporine (CsA)microemulsion-based immunosuppressive regimen in primary cardiac transplantation. METHODS: Heart recipients were randomly assigned to receive either TAC or CsA regimen after sequential induction with rabbit anti-thymoglobulin. Endomyocardial biopsies were performed at weeks 1, 2, 3, and 4 and months 2, 3, and 6. RESULTS: Among 21 adult patients (TAC, 11; CsA, 10) in this study, patient survival rates were 100% in both groups at the end of 6 months. One patient (9%) in the TAC group experienced acute rejection (ISHLT > or = 1B) versus 6 patients (60%) in the CsA group (P = .02). The effects on hematology, biochemistry, cytomegalovirus infection, and hemodynamics were similar in both groups except for better lipid profiles in the TAC group. There were no significant differences in severe adverse events. CONCLUSION: The TAC-based regimen had a lower risk of acute rejection compared with CsA in heart transplant recipients. The safety profiles were similar in both groups. Therefore, TAC is an alternative to CsA as a primary maintenance immunosuppressant in heart transplantation.     

Pharmacokinetic profiling of cyclosporine microemulsion during the first 3 weeks after simultaneous pancreas-kidney transplantation

The optimal effect of therapy with cyclosporine (CsA) seeks to minimize undesirable side effects while maximizing immunosuppression. This balance, depends on CsA exposure, which may be characterized by the area under the concentration-time-curve (AUC). Therefore, we tested the pharmacokinetic profile of microemulsion CsA as a superior approach to guide clinical immunosuppression after de novo simultaneous pancreas-kidney transplantations. We examined 10 consecutive pancreas-kidney recipients with type 1 diabetes and end-stage renal disease. All patients were treated with a regimen consisting of CsA, mycophenolate mofetil (MMF), and prednisone. Full (9-point) pharmacokinetic studies (C0, C1, C2, C3, C4, C6, C8, C10, C12) were performed on week 1 and during week 3 to examine CsA pharmacokinetic profiles. Mean AUC0-12 of 4431 +/- 2400 microg x h/L at week 1 remained stable at week 3 (5119 +/- 1190 microg x h/L). The C6 sampling time displayed the best correlation with AUC0-12 (r2 = 0.881), followed by C3 (r2 = 0.758). Our preliminary data after simultaneous pancreas-kidney transplantation support the hypothesis that C3 or C6 sampling is a more accurate predictor of the AUC0-12 than C0. The combination of two samplings, namely C3 + C6 (r2 = 0.938) or C2 + C6 (r2 = 0.955) proved excellent prediction of exposure after simultaneous pancreas-kidney transplantation.     

Efficacy and safety of tacrolimus compared with ciclosporin A in renal transplantation: three-year observational results.

BACKGROUND: The European tacrolimus versus ciclosporin A microemulsion (CsA-ME) renal transplantation study showed that tacrolimus was significantly more effective in preventing acute rejection and had a superior cardiovascular risk profile at 6 months. METHODS: The endpoints of this investigator-initiated, observational, 36-month follow-up were acute rejection incidence rates, rates of patient and graft survival and renal function. An additional analysis was performed using the combined endpoints BPAR, graft loss and patient death. Data available from the original ITT population (557 patients; 286 tacrolimus and 271 CsA-ME) were analysed. RESULTS: A total of 231 tacrolimus and 217 CsA-ME patients participated. At 36 months, Kaplan-Meier-estimated BPAR-free survival rates were 78.8% in the tacrolimus group and 60.6% in the CsA-ME group, graft survival rates were 88.0% and 86.9% and patient survival rates were 96.6% and 96.7%, respectively. The estimated combined endpoint-free survival rate was 71.4% with tacrolimus and 55.4% with CsA-ME (P 6 mmol/L (26.3% versus 12.6%, P 相似文献   

Corticosteroid withdrawal in simultaneous pancreas-kidney transplantation: a 3-year report

Corticosteroids are an important element of immunosuppressive protocols, but their long-term use has detrimental effects on patient health, requiring eventual discontinuation. Herein, we present an evaluation of the safety and feasibility of corticosteroid withdrawal based on the findings of the Euro-SPK001 study. PATIENTS AND METHODS: In this prospective, multicenter study, 205 simultaneous pancreas-kidney (SPK) transplant recipients were randomized to immunosuppressive treatment with either tacrolimus and mycophenolate mofetil (MMF) (n = 103) or cyclosporine microemulsion (CsA-ME) and MMF (n = 102). All patients received concomitant rATG induction therapy, MMF, and short-term corticosteroids. RESULTS: Corticosteroid withdrawal was successful in the majority of in-study patients: 66% tacrolimus and 73% cyclosporin-ME. In-study patients selected for corticosteroid withdrawal experienced fewer pancreatic or kidney graft losses and fewer episodes of acute rejection compared with out-of-study patients or those continuing corticosteroid therapy. Acute rejection episodes occurred after corticosteroid withdrawal in two patients who had a previous rejection and in five patients who were rejection free before corticosteroid withdrawal. No rejection episodes were associated with graft loss or immediate serious consequences. Overall, corticosteroid withdrawal was achieved with an increase in both MMF and tacrolimus dosage. CONCLUSION: Corticosteroid withdrawal was successful in the majority of in-study patients. A long-term survey of corticosteroid withdrawal in SPK transplantation with multifactorial analyses is necessary to confirm these early results and to evaluate possible positive effects on glucose metabolism and hypertension.     

他克莫司在胰、肾同期联合移植中的应用体会

目的回顾性总结他克莫司（FK506）在胰、肾同期联合移植（SPK）中的应用经验。方法37例SPK受者，术后早期采用抗淋巴细胞球蛋白（最初3例）或抗白细胞介素2受体单克隆抗体（34例）诱导治疗，采用FK506、霉酚酸酯（MMF）和皮质激素维持治疗。FK506于术后第3～4天开始口服，起始剂量为0．05～0．08mg·kg^-1·d^-1，3～5d后根据血药浓度调整用量，血FK506的浓度谷值，术后1个月内维持在10～12μg／L，2～3个月为6～10μg／L，3个月后为4～8μg／L。结果37例术后均停用胰岛素，仅1例（2．7％，1／37）术后6个月死于急性心肌梗死，受者、移植胰和移植肾1年存活率均为97％。空腹血糖恢复正常的时间为（13．4±8．9）d。28例1型糖尿病患者术后空腹血糖恢复正常的时间为（9．7±3．2）d，9例2型糖尿病患者术后空腹血糖恢复正常的时间显著延长，为（23．0±11．7）d。1年内急性排斥反应发生率为13．5％（5／37），其中4例为单纯移植肾排斥反应，1例同时累及移植胰腺和肾脏；2例经激素冲击治疗后逆转，1例经激素和抗淋巴细胞球蛋白治疗逆转，另2例经激素冲击治疗后，血肌酐一度下降，但2～3个月后因再次发生排斥反应，血肌酐逐渐上升，恢复血液透析，但移植胰功能良好，其后行再次肾移植。结论以FK506为基础的免疫抑制能安全、有效地预防SPK后的排斥反应。     

Early steroid withdrawal after liver transplantation: The canadian tacrolimus versus microemulsion cyclosporin a trial: 1-year follow-up

Corticosteroid therapy contributes significant toxicity to liver transplantation. The safety and efficacy of early steroid withdrawal were determined in patients treated with either tacrolimus or microemulsion cyclosporin A (micro-CsA). The primary outcome was the proportion of patients who were steroid-free 1 year posttransplantation. From the seven Canadian adult liver transplant centers, 143 patients were randomly allocated oral treatment with either tacrolimus (n = 71) or micro-CsA (n = 72), together with corticosteroids and azathioprine. Eligibility criteria for steroid withdrawal included freedom from acute rejection for a minimum of 3 months, and prednisone ≤0.15 mg/kg/d. In eligible patients, the daily steroid dose was reduced by 2.5 mg each month until complete discontinuation was achieved. At 1 year after transplantation, 75% of the tacrolimus patients and 63% of the micro-CsA patients were steroid-free (P = .20). Of all of the patients who became eligible for steroid withdrawal, steroid discontinuation was achieved in over 80%. One-year patient survival was 97% with tacrolimus and 89% with micro-CsA (P = .052) . Graft survival was 97% and 86%, respectively (P = .017). The overall incidence of acute rejection during the first year was 35% with tacrolimus and 43% with micro-CsA (P = .26). There was no difference in survival, acute rejection, or rate of steroid withdrawal when adjusting for hepatitis C. All acute rejection episodes experienced during steroid withdrawal were steroid-responsive. Steroid-resistant rejection occurred in 5.6% of the tacrolimus and 9.7% of the micro-CsA patients. One patient, in the micro-CsA group, experienced refractory rejection. Chronic rejection was not observed in either group. The toxicity profiles were similar. Postoperative serum creatinine levels were similar, and dialysis was required in less than 10% of patients in each group. Infectious complications were similar in both groups. Neurotoxicity was a serious adverse event in 13% and 10% of patients receiving tacrolimus and micro-CsA, respectively. Early steroid withdrawal is safe and effective after liver transplantation using either tacrolimus plus azathioprine or micro-CsA plus azathioprine immunoprophylaxis. (Liver Transpl 2003;9:587-595.)     

Single-center, open, prospective, randomized pilot study comparing cyclosporine versus tacrolimus in simultaneous pancreas-kidney transplantation

BACKGROUND: Although tacrolimus (Prograf) is the calcineurin inhibitor usually employed in simultaneous pancreas-kidney transplantation (SPKTx), no prospective randomized studies have compared its efficacy to cyclosporine (Neoral), when either drug is used in combination with mycophenolate mofetil (MMF) and the pancreas is drained into the portal vein. METHODS: Between May 2001 and June 2003, 16 SPKTx recipients were randomized to be prescribed Neoral and 17 Prograf in addition to basiliximab, steroids, and MMF. All pancreata were drained into the portal vein. RESULTS: After a median follow-up of 15.6 months, six kidney acute rejection episodes were observed with Prograf (36.5%; one steroid-resistant) and one Neoral (n = 1, 6.2%; P =.04). No pancreas rejection episode was recorded. Two infections occurred in two recipients from each group. No major adverse events were noted other than a severe hematological toxicity (Prograf). Metabolic parameters were equivalent in the two groups, save for higher total cholesterol (212 +/- 39 mg/dL vs 173 +/- 23 mg/dL; P =.008), LDL (129 +/- 33 mg/dL vs 101 +/- 21 mg/dL; P =.029), and triglyceride (191 +/- 86 mg/dL vs 126 +/- 40 mg/dL; P =.028), values with Neoral, although the same differences were already present at baseline. One recipient (Neoral) died with functioning grafts. Patient, pancreas, and kidney survival rates were all 94% for Neoral versus 100% for Prograf. CONCLUSIONS: Although a larger series and a longer follow-up are needed, Neoral and Prograf used in combination with MMF seem to achieve equivalent success rates among primary SPKTx when the pancreas is drained into the portal vein.     

Simultaneous pancreas-kidney transplantation in a large multicenter study: surgical complications

Simultaneous pancreas-kidney (SPK) transplantation has evolved as an effective treatment modality for patients with end-stage nephropathy owing to type 1 diabetes mellitus. This kidney-pancreas transplant procedure includes a number of risks, one of them being surgical complications, which were analyzed in this large prospective multicenter study. PATIENTS AND METHODS: The analysis included 205 patients randomly assigned to tacrolimus (n = 103) or cyclosporine ME (n = 102) in the Euro-SPK001 study. Surgical complications were defined as any intervention in the postoperative course related to the transplant procedure. RESULTS: The number of patients undergoing relaparotomy was significantly lower among the tacrolimus group (26.2%) as compared to the cyclosporine ME group (43.1%, P = .0109). Relaparotomy was performed earlier in the cyclosporine ME group (day 14 +/- 17) compared to patients in the tacrolimus group (day 26 +/- 26, P = .0506). Graft vessel thrombosis, intra-abdominal hemorrhage, and enteric or ureteral leakage within the first 3 months occurred significantly more frequently in cyclosporine ME-treated patients. Donor age above 45 years showed a negative impact on surgical complications. Relaparotomy had no impact on patient survival but significantly affected pancreas and kidney graft survival in both groups. CONCLUSION: This prospective, randomized, multicenter trial in patients undergoing primary SPK demonstrated a benefit of tacrolimus over cyclosporine ME with regard to the incidence of surgical complications and, consecutively, to kidney and pancreas graft survival.     

Four-year follow-up of a prospective randomized trial of mycophenolate mofetil with cyclosporine microemulsion or tacrolimus following liver transplantation

BACKGROUND: This is a 4-yr follow-up of a trial using mycophenolate mofetil (MMF) induction in orthotopic liver transplantation (OLT). The goal of this study was to evaluate a multidrug approach that would reduce both early and long-term morbidity related to immunosuppression while maintaining an acceptable freedom from rejection. METHODS: This was a prospective, randomized, intent to treat study designed to compare the primary endpoints of rejection and infection, and secondary endpoints of liver function, renal function, bone marrow function, cardiovascular risk factors, and the recurrence of hepatitis C. Ninety-nine consecutive patients with end stage liver disease who underwent OLT were randomized to receive either cyclosporine microemulsion (N) (50 patients) or tacrolimus (FK) (49 patients) starting on postoperative day 2, with MMF and an identical steroid taper begun preoperatively. RESULTS: Ninety of 99 patients (N 46, FK 44) completed the 4-yr follow-up. The overall 4-yr patient and graft survivals were 93 and 89%, respectively. There was no significant difference in 4-yr patient (N 96% vs. FK 90%, p = ns) or graft (N, 90% vs. FK, 88%, p = ns) survival between groups. The 4-yr rejection rate was not significantly different in either arm (N = 34%, FK = 24%; p = 0.28). There were no differences in infection rates in either arm. The patients with hepatitis C had no differences in the viral titers or Knodell biopsy scores between groups. However, in the hepatitis C subgroup (37 patients), the FK patients had a significantly lower rejection rate (p = 0.0097) and a significantly lower clinically recurrent hepatitis C rate (p = 0.05) than the N patients. No difference was seen in the percent of patients weaned off of steroids after 4 yr (N 51%, FK 49%). There were no differences in the incidences of diabetes mellitus and hypertension. When renal dysfunction was analyzed, a significant difference in the number of patients whose creatinine had increased twofold since transplant was seen (N 63%, FK 38%, p = 0.04). CONCLUSIONS: Use of MMF induction and maintenance following OLT in conjunction with either N or FK and an identical steroid taper, resulted in an acceptable long-term incidence of rejection and infection, without an increase in long-term graft or patient morbidity.     

Mycophenolate mofetil and tacrolimus as primary maintenance immunosuppression in simultaneous pancreas-kidney transplantation: initial experience in 50 consecutive cases

BACKGROUND: The current study examines the use of mycophenolate mofetil (MMF) and tacrolimus as primary immunosuppression in simultaneous pancreas-kidney (SPK) transplantation. In addition, analyses of the rates of conversion from one immunosuppressive agent to another, and its subsequent consequences with respect to outcomes were determined. Quality of graft function, infections, and effect on preexisting essential hypertension are also described. METHODS: Immunosuppression consisted of quadruple therapy with antithymocyte globulin induction, tacrolimus, MMF, and prednisone. Patient and graft survival and rejection rates in 50 consecutive SPK recipients, followed for a minimum of 3 months and a mean of 14 months (range: 3-34 months), are described. RESULTS: Thirty-nine of 50 (78%) patients tolerated the MMF/tacrolimus combination long-term (mean duration of follow-up: 14+/-7 months). Nine of 50 patients (18%) were converted to Neoral, and 4 patients were converted to azathioprine as a substitute for MMF. The 2-year actuarial patient, kidney, and pancreas survival rates were 97.7%, 93.3%, and 90.0%, respectively. At 6 months after transplant, the overall incidence of acute rejection was 16%. There was a statistically significant (P< or =0.04, Cox-Mantel test) difference in the rate of rejection associated with conversion to Neoral. The incidence of rejection 6 months after transplant in the group maintained on MMF/tacrolimus was 10.2% vs. 44.4% in the group converted to Neoral (P< or =0.04, Cox-Mantel test). Overall, the 1-year actuarial cumulative incidence of tissue-invasive cytomegalovirus disease was 6.6%. There were no cases of fungal infections or post-transplant lymphoproliferative disorders. One patient developed Kaposi's sarcoma 10 months after transplant. With respect to hypertensive disease, 60% (12/20) of the patients who required pharmacologic control of blood pressure before transplant were off all antihypertensive medications at 1 year after transplant. An additional 20% (4/20) of patients had a reduction in the number of medications required to control blood pressure at 1 year after transplant. CONCLUSIONS: We conclude that the combination of MMF and tacrolimus as primary immunosuppression for SPK transplantation results in excellent patient and graft survival rates, a very low rate of acute rejection, and low rates of infection and malignancy.     

Efficacy and safety of tacrolimus compared with ciclosporin‐A in renal transplantation: 7‐year observational results

The European Tacrolimus versus Ciclosporin‐A Microemulsion (CsA‐ME) Renal Transplantation Study demonstrated that tacrolimus decreased acute rejection rates at 6 months. Primary endpoints of this investigator‐initiated, observational 7‐year follow‐up study were acute rejection rates, patient and graft survival rates, and a composite endpoint (BPAR, graft loss, and patient death). We analyzed data from the original intent‐to‐treat population (n = 557; 286 tacrolimus, 271 CsA‐ME). A total of 237 tacrolimus and 208 CsA‐ME patients provided data. At 7 years, Kaplan–Meier estimated rates of patients free from BPAR were 77.1% in the tacrolimus arm and 59.9% in the CsA‐ME arm, graft survival rates amounted to 82.6% and 80.6%, and patient survival rates to 89.9% and 88.1%. Estimated combined endpoint‐free survival rates were 60.2% in the tacrolimus arm and 47.0% in the CsA‐ME arm (P = <0.0001). A higher number of patients from the CsA‐ME arm crossed over to tacrolimus during 7 year follow‐up: 19.7% vs. 7.9% (P = <0.002). More patients in the tacrolimus group stopped steroids and received immunosuppressive monotherapy. Significantly, more CsA‐ME patients received lipid‐lowering medication and experienced cosmetic and cardiovascular adverse events. Tacrolimus‐treated renal transplant recipients had significantly higher combined endpoint‐free survival rates mainly driven by lower acute rejection rates despite less immunosuppressive medication at 7 years.