Randomized trial of tacrolimus in combination with sirolimus or mycophenolate mofetil in kidney transplantation: results at 6 months

BACKGROUND: This is the first report of a randomized, multicenter, clinical trial comparing the combination of sirolimus or mycophenolate mofetil (MMF) with tacrolimus-based immunosuppression in kidney transplantation. Results at 6 months of follow-up are presented. METHODS: Before transplantation, patients were randomized to receive tacrolimus plus corticosteroids with sirolimus (n=185) or MMF (n=176). The primary endpoint of the study was the incidence of biopsy-confirmed acute rejection. Patient and graft survival, renal function, and composite endpoints also were evaluated. Safety was assessed by monitoring laboratory parameters and adverse events. RESULTS: By 6 months of follow-up, the incidence of biopsy-confirmed acute rejection was similar in both treatment groups (13.0% tacrolimus+sirolimus vs. 11.4% tacrolimus+MMF; P=0.64 log-rank). Patient survival (97.3% tacrolimus+sirolimus vs. 97.7% tacrolimus+MMF) and graft survival (93.0% tacrolimus+sirolimus vs. 95.5% tacrolimus+MMF) were equivalent (P=0.53, overall survival log-rank). There was a significantly higher incidence of study drug discontinuation in patients receiving sirolimus (21.1% vs. 10.8%; P=0.008). Renal function was significantly better in the MMF-treatment group (serum creatinine 1.44+/-0.45 mg/dL vs. 1.77+/-1.42 mg/dL; P=0.018). Hyperlipidemia was significantly more prevalent in the sirolimus-treatment group. Diastolic blood pressure was significantly higher in sirolimus-treated patients. There were significantly more leukopenia and gastrointestinal adverse events in the MMF-treatment group. The incidence of posttransplant diabetes mellitus was 7.6% in the sirolimus group and 7.7% in the MMF group. CONCLUSION: Tacrolimus is equally effective in renal transplantation when combined with sirolimus or MMF. The tacrolimus-MMF combination may be superior in terms of improved renal function and improved cardiovascular risk factors including hyperlipidemia and hypertension.     

Improved renal function after conversion from tacrolimus/sirolimus to tacrolimus/mycophenolate mofetil in kidney transplant recipients

BACKGROUND: There is limited data on the potential nephrotoxicity of sirolimus (SRL) and tacrolimus (TAC) in combination. METHODS: We reviewed the course of 97 kidney transplant patients treated with SRL and reduced-dose TAC. Conversion from SRL to mycophenolate mofetil (MMF) was prescribed in a minority (n = 19) for various nonrenal side effects. We compared outcomes of converted patients to those remaining on TAC/SRL (n = 78). RESULTS: TAC levels were increased in converters (P = 0.009). Rejection rates were similar between groups over 18 months (21% vs. 16%, p = ns). Serum creatinine (Cr) and MDRD glomerular filtration rate (GFR) were similar between groups at nadir and six-months, but at 18 months the percent change from six-month Cr was +17% in non-converters vs. -10% in converters (P = 0.004 for the difference). The difference in GFR between groups at 18 months was also significant (P = 0.01). By multivariate analysis, only conversion to MMF was associated with a greater percent change in Cr from 6 to 18 months (P = 0.015). Conversion to MMF also correlated with higher GFR at 18 months independent of rejection, delayed graft function, and ethnicity. CONCLUSIONS: Conversion from TAC/SRL to TAC/MMF led to improved renal function despite increased TAC exposure after conversion.     

Albuminuria after renal transplantation: maintenance with sirolimus/low-dose tacrolimus vs. mycophenolate mofetil/high-dose tacrolimus

Maintenance immunosuppression with sirolimus (SRL) in renal transplantation has been associated with proteinuria. We report long-term outcomes of kidney transplant recipients maintained on steroid-free regimens, either SRL with low-dose tacrolimus (SRL/L-Tac) or mycophenolate mofetil (MMF) with high-dose tacrolimus (MMF/H-Tac). We conducted a case-matched study of 50 patients receiving MMF/H-Tac, matched 1:2 with 100 patients maintained on SRL/L-Tac. All patients were induced with rabbit antithymocyte globulin followed by early steroid withdrawal. Comparisons were made of patient and graft survival, graft function, acute rejection, and albuminuria. There were no significant differences between the SRL/L-Tac and MMF/H-Tac groups for patient survival, graft survival, occurrence of acute rejection, or graft function. There was no difference in the proportion of patients with albumin/creatinine ratio (ACR) ≥300 μg/mg (19% vs. 20%), but more patients in the SRL group were receiving renin-angiotensin system blocking agents (72% vs. 53%, p = 0.04). Only flushing the donor kidney with histidine-tryptophan-ketoglutarate solution (vs. UW solution) was predictive of albuminuria. Long-term outcomes are similar at our center for kidney transplant patients receiving either SRL/L-Tac or MMF/H-Tac. Although the occurrence of albuminuria was not different, significantly more SRL-treated patients were receiving antiproteinuric medications.     

A prospective, randomized trial of tacrolimus in combination with sirolimus or mycophenolate mofetil in kidney transplantation: results at 1 year

BACKGROUND: This is the 1-year report of a randomized, multicenter, clinical trial comparing the combination of sirolimus or mycophenolate mofetil (MMF) with tacrolimus-based immunosuppression in kidney transplantation. METHODS: Prior to transplantation, recipients were randomized to receive tacrolimus plus corticosteroids with either sirolimus (n=185) or MMF (n=176). The incidence of biopsy-confirmed acute rejection at 6 months was the primary endpoint of the study. Patient and graft survival, renal function, study drug dosing and discontinuations were evaluated at 1 year. RESULTS: At 1 year, there was no difference in patient survival (95.7% sirolimus vs. 97.2% MMF; P=0.45) or graft survival (90.8% sirolimus vs. 94.3% MMF; P=0.22). Patients without delayed graft function (DGF) receiving MMF had significantly better graft survival (99% vs. 93%; P=0.01). Patients receiving a transplant from a live donor had a trend towards better graft survival with MMF as compared to sirolimus (98% vs. 91%; P=0.07). Patients receiving sirolimus had a significantly higher incidence of study drug discontinuation (26.5% vs. 14.8% MMF; P=0.006). Patients receiving MMF had significantly better renal function as shown by median serum creatinine levels (1.3 mg/dL vs. 1.5 mg/dL; P=0.03) and a trend towards higher calculated creatinine clearance (CrCl), (58.4 ml/min vs. 54.3 ml/min; P=0.06). More patients in the sirolimus group had a serum creatinine >2.0 mg/dL, (20.4% vs. 11.0%; P=0.02). CONCLUSIONS: Tacrolimus is safe and effective in live and deceased donor kidney transplantation when given in combination with sirolimus or MMF. Patient and graft survival were excellent in both arms. Renal function is superior for patients treated with tacrolimus + MMF combination.     

Five years of steroid sparing in renal transplantation with tacrolimus and mycophenolate mofetil

Steroid sparing with tacrolimus and mycophenolate mofetil (MMF) is associated with good short-term renal transplant outcomes. However, late allograft dysfunction and failure remain concerns. In this study, 101 consecutive patients underwent renal transplantation with tacrolimus, MMF, and 7 days of corticosteroids only. After a median follow-up of 51 months (range 36-62), overall patient survival is 97%, and overall survival with graft function is 91%. The acute rejection rate at 12 months was 19%. Late rejection was uncommon, with only three further episodes beyond 12 months. Graft function was stable during the study, with a mean creatinine of 140 micromol/L and mean estimated creatinine clearance of 57 ml/min at the end of follow-up. Six patients developed posttransplant diabetes mellitus (three cases beyond 12 months). This steroid avoidance regimen is associated with excellent medium-term patient and graft outcomes, and a low incidence of side effects.     

Excellent outcome of ABO-incompatible living kidney transplantation under pretransplantation immunosuppression with tacrolimus, mycophenolate mofetil, and steroid

INTRODUCTION: ABO-incompatible living kidney transplantation (LKT) has been performed to widen the indications for kidney transplantation. Since 2001, using a 7-day period of pretransplantation immunosuppression with tacrolimus (FK) plus mycophenolate mofetil (MMF) plus methylprednisolone (MP), we have observed a marked reduction in acute humoral/vascular rejection without any serious complications. PATIENTS AND METHODS: Forty-five adult patients underwent ABO-incompatible LKT at our institute between January 2000 and September 2002. There were 20 men and 25 women of mean age 33 years. Plasmapheresis was performed to remove anti-AB antibodies prior to kidney transplantation. In 2000, 13 patients were treated with FK plus MMF plus MP without 7-day pretransplantation immunosuppression (group 1). Since January 2001, we have administered FK (0.1 mg/kg/d) plus MMF (1-2 g/d) plus MP (125 mg/d) concomitantly with plasmapheresis starting from 7 days before transplantation in 32 patients (group 2). Splenectomy was performed at the time of kidney transplantation in all patients. RESULTS: Patient survival rate was 100% in both treatment groups. Graft survival rate was 92% and 97% in groups 1 and 2, respectively. One patient in group 1 lost the graft due to severe pancreatitis and 1 patient in group 2, due to severe humoral rejection. The incidence of acute rejection was 56% and 19% in group 1 and group 2, respectively. No patient experienced any lethal infectious complication. CONCLUSION: Pretransplantation immunosuppression for 7 days using FK, MMF, and MP in ABO-incompatible LKT provides an excellent outcome without severe infectious complications.     

Age-dependency of mycophenolate mofetil dosing in combination with tacrolimus after pediatric renal transplantation

BACKGROUND: Dosing of mycophenolate mofetil (MMF) must be lower in combination therapy with Tacrolimus (Tac) than with Cyclosporine. One study with mostly adolescent recipients recommended an MMF dose of 250 mg/m2 BID. Because this dose resulted in low area-under-the-curve (AUC) in our infant population, we retrospectively analyzed all available pharmacokinetic (PK) profiles in pediatric renal transplant patients on MMF plus Tac therapy to propose appropriate MMF dosing in pediatric patients of all ages. PATIENTS AND METHODS: Forty-four PK profiles were performed in 27 patients (median age, 11.6 years; range, 1.8-20.7 years). The investigations were performed at a median of 299 days (range, 24-3424) after transplantation. Ten patients were converted to Tac plus MMF, all others received this as primary therapy. For patients with repeated measurements, we calculated the average AUC and doses. We used first-order PK modeling to calculate the doses for a mycophenolic acid (MPA) AUC of 60 ug*h/mL and a Tac AUC of 150 ng*h/mL. RESULTS: The mean Tac dose was 2.6 +/- 1.2 mg/m2/d or 0.086 +/- 0.038 mg/kg/d, resulting in an average AUC of 120.6 +/- 30.4 ng*h/mL. The MMF dose was not normally distributed; the median dose was 549 mg/m2/d (range, 146-1413) and the median MPA AUC was 49.8 ug*h/mL (range, 26.7-156.0). The mean dose for a Tac AUC of 150 ng*h/mL was 3.50 +/- 1.77 mg/m2/d (0.117 +/- 0.058 mg/kg) and was independent of age or time after transplantation. By contrast, we found a negative relationship between the dose per m2 (r2 = 0.29; P = 0.0038) or per kg (r2 = 0.58; P < .0001) required for an MPA AUC of 60 ug*h/mL and patient age. Converted and primary patients behaved identically. The dosing requirement decreased from 500 mg/m2 BID in 2-year-old patients to 250 mg/m2 in adolescents. There was substantial interpatient variability of 44%. CONCLUSIONS: Higher MMF doses are required for young children. Our data suggest a starting dose for infants of 500 mg/m2 BID, with PK monitoring of MPA due to substantial interpatient variability.     

Immunosuppression in pancreas transplantation: mycophenolate mofetil versus sirolimus

The use of mycophenolate mofetil (MMF) in pancreas transplantation has increased graft survival and decreased the incidence of acute rejections episodes (ARE), regardless of the choice of calcineurin inhibitor. The combination of MMF with tacrolimus (TAC) is the most common protocol, it is considered the gold standard for new protocols. In the last few years, there have been reports of a small number of patients treated with sirolimus (RAPA), usually combined with TAC. Patient and pancreas survival rates as well as the incidence of ARE were similar to protocols with TAC and MMF. Twenty simultaneous pancreas and kidney (SPK) transplantations were performed using an immunosuppressive protocol of TAC, RAPA, and steroids (STE) after 2000. The incidence of ARE was 25%; all episodes responded to STE. Only 2 patients (10%) displayed hypercholesterolemia requiring treatment with statins. The use of RAPA as an alternative to MMF is promising, although presently one with limited experience. The combination of MMF and RAPA with or without a calcineurin inhibitor is an option to be evaluated in the future.     

Randomized trial of tacrolimus (Prograf) in combination with azathioprine or mycophenolate mofetil versus cyclosporine (Neoral) with mycophenolate mofetil after cadaveric kidney transplantation

BACKGROUND: Our clinical trial was designed to investigate the optimal combination of immunosuppressants for renal transplantation. METHODS: A randomized three-arm, parallel group, open label, prospective study was performed at 15 North American centers to compare three immunosuppressive regimens: tacrolimus + azathioprine (AZA) versus cyclosporine (Neoral) + mycophenolate mofetil (MMF) versus tacrolimus + MMF. All patients were first cadaveric kidney transplants receiving the same maintenance corticosteroid regimen. Only patients with delayed graft function (32%) received antilymphocyte induction. A total of 223 patients were randomized, transplanted, and followed for 1 year. RESULTS: There were no significant differences in baseline demography between the three treatment groups. At 1 year the results are as follows: acute rejection 17% (95% confidence interval 9%, 26%) in tacrolimus + AZA; 20% (confidence interval 11%, 29%) in cyclosporine + MMF; and 15% (confidence interval 7%, 24%) in tacrolimus + MMF. The incidence of steroid resistant rejection requiring antilymphocyte therapy was 12% in the tacrolimus + AZA group, 11% in the cyclosporine + MMF group, and 4% in the tacrolimus + MMF group. There were no significant differences in overall patient or graft survival. Tacrolimus-treated patients had a lower incidence of hyperlipidemia through 6 months posttransplant. The incidence of posttransplant diabetes mellitus requiring insulin was 14% in the tacrolimus + AZA group, 7% in the cyclosporine + MMF and 7% in the tacrolimus + MMF groups. CONCLUSIONS: All regimens yielded similar acute rejection rates and graft survival, but the tacrolimus + MMF regimen was associated with the lowest rate of steroid resistant rejection requiring antilymphocyte therapy.     

他克莫司联合霉酚酸酯应用于胰肾联合移植的初步经验

目的 总结他克莫司(FK506)联合霉酚酸酯(MMF)应用于胰液膀胱引流式胰肾联合移植受者的初步经验. 方法 胰肾联合移植患者14例,术后应用FK506 0.07～0.15mg·kg-1·d-1加MMF 1.0～1.5 g/d加泼尼松25 mg/d三联免疫抑制治疗方案.采用微粒子酶免疫分析法每周测定口服FK506后全血峰谷浓度,依此调整剂量维持最初3个月内FK506全血浓度峰值10～20 μg/L,谷值5～15μg/L.并观察排斥反应的发生及药物的肝肾毒性. 结果 9例患者术后胰肾功能恢复良好,早期无排斥反应发生,血糖及肌酐水平恢复正常.随访18～70个月,平均34个月.存活1～3年者3例,3年～者1例,4年～者1例,>5年者4例,胰肾功能良好,血糖正常,均未使用降糖药.1例因超急性排斥反应术后第2天切除移植胰腺,随访2年肾功能良好.4例死亡,死因分别为术后急性右心功能衰竭、呼吸骤停、急性排斥反应及十二指肠瘘.胰肾联合移植术后各时期FK506全血峰、谷浓度差异均有统计学意义(P<0.05).术后共发生肾脏急性排斥反应4例次,肾毒性2例次,肝毒性1例次. 结论 FK506与MMF在药效上有协同作用,联合应用于胰肾联合移植具有良好的免疫抑制效果,能有效降低排斥反应发生率和提高移植物长期存活率.     

Oral ulcers in kidney transplant recipients treated with sirolimus and mycophenolate mofetil

BACKGROUND: In an attempt to reduce calcineurin inhibitor toxicity, transplant patients treated with tacrolimus can be switched to maintenance treatment with sirolimus. METHODS: In a prospective, randomized, multicenter trial, 33 kidney transplant recipients on steroid-free maintenance treatment with tacrolimus and mycophenolate mofetil continued tacrolimus and mycophenolate mofetil (control group, n=18) or were converted from tacrolimus to sirolimus (study group, n=15) at 1 year after transplantation. RESULTS: The study was prematurely stopped as a result of a cluster of nine patients suffering from painful oral ulcerations in the study group. Oral ulcerations did not occur in the control group. The authors here report on the individual cases suffering from this side effect of the instituted immunosuppressive regimen. CONCLUSIONS: The authors review the literature with respect to the occurrence of oral ulcers associated with the use of sirolimus or mycophenolate mofetil and speculate on the causes of the high incidence of oral ulcers in their study group. Possible explanations are overimmunosuppression during the period of the conversion from tacrolimus to sirolimus without antiviral prophylaxis, the use of the oral emulsion instead of tablets, or the lack of corticosteroid co-administration.     

A prospective study of rapid corticosteroid elimination in simultaneous pancreas-kidney transplantation: comparison of two maintenance immunosuppression protocols: tacrolimus/mycophenolate mofetil versus tacrolimus/sirolimus

BACKGROUND: We examined the feasibility of rapid corticosteroid elimination in simultaneous pancreas kidney transplantation. METHODS: Forty consecutive simultaneous pancreas-kidney (SPK) transplant recipients were enrolled in a prospective study in which antithymocyte globulin induction and 6 days of corticosteroids were administered along with tacrolimus and MMF (n=20) or tacrolimus and sirolimus (n=20). Mean+/-SD follow-up for recipients receiving tacrolimus/MMF and tacrolimus/sirolimus were 12.7+/-3.9 and 13.4+/-2.9 months, respectively. Patient and graft survival, and rejection rates were compared to an historical control group (n=86; mean follow-up 41.5+/-15.4 months) of SPK recipients that received induction and tacrolimus, MMF, and corticosteroids. RESULTS: Demographic characteristics of recipient and donor variables were similar among all groups. The 1-year actuarial patient, kidney, and pancreas survival rates in the 40 SPK transplant recipients with rapid corticosteroid elimination were 100, 100, and 100%, respectively. In the historical control group the 1-year actual patient, kidney, and pancreas survival rates were 96.5, 93.0, and 91.9%, respectively. The 1-year rejection-free survival rate recipients in the rapid steroid elimination group collectively was 97.5 vs 80.2% in the historical control group (P=0.034). At 6 and 12 months posttransplant the serum creatinine values remained stable in all groups. CONCLUSIONS: We conclude that chronic corticosteroid exposure is not required in SPK transplant recipients receiving antithymocyte globulin induction and maintenance immuno-suppression consisting of either tacrolimus and mycophenolate mofetil or tacrolimus and sirolimus.