Daclizumab induction therapy associated with tacrolimus-MMF has better outcome compared with tacrolimus-MMF alone in pediatric living donor liver transplantation

AIMS: Immunosuppression therapy for the control of immunologic rejection is a key aspect in liver transplantation. The objective of this study was to evaluate induction therapy with daclizumab (DAC) in living donor liver transplantation (LDLT) in children. METHODS: We compared 2 different immunosuppression protocols in 30 children undergoing LDLT. The patients were divided into 2 groups: 12 patients received tacrolimus with mycophenolate mofetil (TAC-MMF), and 18 patients received tacrolimus with MMF and DAC induction therapy at days 0 and 14 after LDLT (DAC-TAC-MMF). Both groups were similar with regard to age, sex, weight, and indication for liver transplantation. The incidence of biopsy-proved rejection episodes, posttransplantation lymphoproliferative disease (PTLD), and renal dysfunction were evaluated. Tacrolimus levels at posttransplantation day 14 and at 2 months after transplantation were compared in the 2 groups. RESULTS: Acute rejection episodes were observed in 8 patients in the TAC-MMF group (66%), and none in the DAC-TAC-MMF group (0%; P < .05). Neither PTLD nor renal dysfunction was seen in any patient. Mean Tacrolimus level on posttransplantation day 14 was 10.67 +/- 5.4 ng/mL in the TAC-MMF group and 5.65 +/- 3.6 ng/mL in the DAC-TAC-MMF group (P < .05). After the second month the mean tacrolimus levels were 7.2 +/- 2.9 ng/mL and 6.8 +/- 3.5 ng/mL in the TAC-MMF and DAC-TAC-MMF groups, respectively. (P = NS). CONCLUSION: Induction therapy with DAC is safe and associated with a lower incidence of rejection episodes among children undergoing LDLT.     

Randomized trial of immunosuppressive regimens in renal transplantation

The optimal long-term regimen for immunosuppression for kidney transplant recipients is unknown. We conducted a randomized trial involving 150 kidney transplant recipients to compare tacrolimus/sirolimus, tacrolimus/mycophenolate mofetil (MMF), and cyclosporine/sirolimus. All patients received daclizumab induction and maintenance corticosteroids. Median follow-up was 8 yr post-transplant. Acute rejection (AR) occurred significantly less often among those treated with tacrolimus/MMF (12%) than among those treated with tacrolimus/sirolimus (30%) or cyclosporine/sirolimus (28%). Mean estimated GFR was consistently higher in the tacrolimus/MMF arm, especially after controlling for donor age in a multivariable model during the first 36 mo (P ≤ 0.008). The rate of dying with a functioning graft was significantly higher among those treated with tacrolimus/sirolimus (26%) than among those treated with tacrolimus/MMF (12%) or cyclosporine/sirolimus (4%). We did not observe significant differences in actuarial graft survival at 8 yr post-transplant between the groups. Patient noncompliance seemed responsible for 45% (13/29) of observed graft failures, with 11 of these occurring after 36 mo. Significantly more viral infections, protocol violations, and need for antilipid therapy occurred among patients receiving sirolimus, but we did not observe differences between the groups with regard to infections requiring hospitalization or new-onset diabetes. Taken together, these results suggest that maintenance therapy with tacrolimus/MMF is more favorable than either tacrolimus/sirolimus or cyclosporine/sirolimus.     

Living related kidney transplantation without calcineurin inhibitors: initial experience in a Mexican center

We performed a prospective randomized trial comparing sirolimus/mycophenolate mofetil (MMF)/prednisone to cyclosporine/MMF/prednisone and selected induction therapy with basiliximab. Twenty patients received sirolimus (10 mg loading dose followed by 3 mg/m body surface area/day, keeping 24-hr trough levels at 10-15 ng/mL for six months and 5-10 ng/mL thereafter. Twenty-one patients began cyclosporine (4 to 8 mg/kg/day, keeping 12-hour trough levels at 150-300 ng/mL for 6 months and 100-200 ng/mL afterwards). Mean follow up was 15.8 months. One-year patient and graft survival was similar in both groups (>90%). Acute rejection rate was 16.6% in the sirolimus group and 5.2% in the cyclosporine group (P=NS). There were no differences in mean serum creatinine between groups. No patients who received basiliximab and had sirolimus target levels suffered acute rejection at one year. The sirolimus group had significantly higher cholesterol and triglycerides. A calcineurin inhibitor-free regimen using sirolimus produces comparable one-year transplant outcomes in living related kidney transplants compared to a calcineurin inhibitor regimen.     

Lipid metabolism in renal transplant patients receiving tacrolimus/sirolimus combination therapy

INTRODUCTION: The administration of sirolimus has been reported to be associated with high serum cholesterol and high triglyceride values. In a large prospective, multicenter 6-month study in renal transplantation, basic parameters of lipid metabolism (total serum cholesterol and triglycerides) were systematically assessed in patients who received tacrolimus/mycophenolate mofetil/steroids (Tac/MMF), tacrolimus/0.5 mg sirolimus (SIR)/steroids (Tac/0.5SIR) on tacrolimus/2 mg sirolimus/steroids (Tac/2SIR). METHODS: For purposes of analysis, lipid parameters were classified using the National Kidney Foundation Dyslipidemia Classification definitions. RESULTS: Complete sets of data at all visits (baseline, months 1, 3, and 6) were available for 211 Tac/MMF, 210 Tac/0.5SIR, and 203 Tac/2SIR patients. Total serum cholesterol in the Tac/MMF group was 193.4 at baseline and 202.9 mg/dL at month 6. Values increased from 196 mg/dL to 212.5 mg/dL in Tac/0.5SIR and from 200 mg/dL to 230.5 mg/dL in Tac/2SIR. Differences in parameters between treatment groups were statistically significant (P < .05). Serum triglycerides decreased from baseline to 6 months in Tac/MMF, increased from 176.3 mg/dL (baseline) to 191.4 mg/dL (6 months) in Tac/0.5SIR and from 203 mg/dL to 255.3 mg/dL in Tac/2SIR. Parameters differed significantly between Tac/0.5SIR versus Tac/2SIR at P = .0069, and between Tac/MMF versus Tac/2SIR at P = .0013. In the Tac/2SIR group 36.5% had "high" serum cholesterol and 8.3% had "very high" triglyceride levels at 6 months. CONCLUSION: Total serum cholesterol levels were relatively stable and serum triglycerides decreased between baseline and month 6 using a Tac/MMF regimen. Contrastingly, the Tac/SIR combinations led to increased total cholesterol values (at both sirolimus dose levels) and Tac/2SIR also led to increased triglyceride levels.     

Calcineurin Inhibitor Minimization in the Symphony Study: Observational Results 3 Years after Transplantation

The Symphony study showed that at 1 year posttransplant, a regimen based on daclizumab induction, 2 g mycophenolate mofetil (MMF), low-dose tacrolimus and steroids resulted in better renal function and lower acute rejection and graft loss rates compared with three other regimens: two with low-doses of cyclosporine or sirolimus instead of tacrolimus and one with no induction and standard cyclosporine dosage. This is an observational follow-up for 2 additional years with the same endpoints as the core study. Overall, 958 patients participated in the follow-up. During the study, many patients changed their immunosuppressive regimen (e.g. switched from sirolimus to tacrolimus), but the vast majority (95%) remained on MMF. During the follow-up, renal function remained stable (mean change: −0.6 ml/min), and rates of death, graft loss and acute rejection were low (all about 1% per year). The MMF and low-dose tacrolimus arm continued to have the highest GFR (68.6 ± 23.8 ml/min vs. 65.9 ± 26.2 ml/min in the standard-dose cyclosporine, 64.0 ± 23.1 ml/min in the low-dose cyclosporine and 65.3 ± 26.2 ml/min in the low-dose sirolimus arm), but the difference with the other arms was not significant (p = 0.17 in an overall test and 0.077, 0.039 and 0.11, respectively, in pair-wise tests). The MMF and low-dose tacrolimus arm also had the highest graft survival rate, but with reduced differences between groups over time, and the least acute rejection rate. In the Symphony study, the largest ever prospective study in de novo kidney transplantation, over 3 years, daclizumab induction, MMF, steroids and low-dose tacrolimus proved highly efficacious, without the negative effects on renal function commonly reported for standard CNI regimens.     

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.     

Is the malononitrilamide FK778 better for the prevention of acute or chronic rejection?

OBJECTIVE: The aim of this study was to assess the efficacy of FK778 to prevent acute and chronic allograft rejection compared with other immunosuppressive agents. MATERIALS AND METHODS: Heterotopic Brown-Norway (BN)-to-Lewis rat cardiac transplantations and heterotopic BN-to-Lewis tracheal transplantations were performed to study acute heart rejection and the development of chronic obliterative airway disease (OAD), respectively. Recipients were treated with FK778, tacrolimus, MMF, or sirolimus for 10 days (acute rejection study) or 28 days (chronic OAD study) at varying doses. RESULTS: In untreated recipients, cardiac allograft survival was 6.2 +/- 0.4 days. FK778 (20 mg/kg), tacrolimus (2 or 8 mg/kg), mycophenolate mofetil (MMF; 40 mg/kg), or sirolimus (0.5 or 2 mg/kg) significantly prolonged graft survival to 17.0 +/- 2.8, 18.5 +/- 2.7, 25.0 +/- 2.5, 20.7 +/- 3.8, 14.5 +/- 2.2, and 23.2 +/- 1.5 days, respectively (P < .05). Tracheal grafts in untreated recipients showed intense infiltration and complete luminal obliteration by day 28. FK778 (20 mg/kg), tacrolimus (1 or 4 mg/kg), MMF (10 or 40 mg/kg), or sirolimus (0.5 or 2 mg/kg) significantly inhibited tracheal luminal obliteration (19.5% +/- 16.4%, 44.2% +/- 33.6%, 12.3% +/- 3.3%, 61.7% +/- 18.6%, 18.3% +/- 11.3%, 55.0% +/- 30.9%, and 8.5% +/- 3.5% (P < .05). All 4 high-dose groups showed similar efficacy. CONCLUSIONS: When used in therapeutic doses, tacrolimus and sirolimus were more effective than FK778 to prolong cardiac allograft survival. However, with its antiproliferative effects on smooth muscle cells, its good tolerability, and its blockade of cytomegalovirus replication, FK778 proved effective to prevent chronic OAD development. Thus, FK778 may acquire an important role in maintenance therapy for the prevention of long-term fibroproliferative complications.     

Sirolimus: A Switch Option for Mycophenolate Mofetil–Induced Leukopenia in Renal Transplant Recipients

Mycophenolate mofetil (MMF) is a potent immunosuppressive agent used to prevent acute and chronic rejection in kidney transplantation or for rescue therapy. One side effect of MMF is bone marrow toxicity, including leukopenia, which may necessitate drug withdrawal. We report 2 patients who underwent kidney transplantation and developed leukopenia while receiving MMF and safely switched to sirolimus. A 35-year-old woman underwent deceased donor kidney transplantation. She received basiliximab, tacrolimus, MMF, and a corticosteroid. On postoperative day (POD) 75, her white blood cell (WBC) count was 1800/μL. A 44-year-old women underwent deceased donor kidney transplantation and received basiliximab, tacrolimus, MMF, valganciclovir, and a corticosteroid. On POD 88, her WBC count was 1320/μL. MMF was switched to sirolimus, resulting in recovery of WBC count without rejection. Switch from MMF to sirolimus is safe and favorable in MMF-induced leukopenia in renal transplant recipient.     

Long-term efficacy and safety of a calcineurin inhibitor-free regimen in live-donor renal transplant recipients

Calcineurin inhibitor (CNI) nephrotoxicity is a major concern after renal transplantation. To investigate the safety and efficacy of a CNI-free immunosuppressive regimen, 132 live-donor renal transplant recipients were included in a prospective, randomized controlled trial. All patients received induction therapy with basiliximab and steroids. The patients were randomized to a maintenance immunosuppression regimen that included steroids, sirolimus, and either low-dose tacrolimus or mycophenolate mofetil (MMF). Over a mean follow-up period of approximately 5 yr, patient and graft survival did not significantly differ between the two maintenance regimens. Patient survival was 93.8% and 98.5% in the tacrolimus/sirolimus and MMF/sirolimus groups, respectively, and graft survival was 83% and 88%, respectively. However, the MMF/sirolimus group had significantly better renal function, calculated by Cockcroft-Gault, from the second year post-transplant until the last follow-up. In addition, this group was less likely to require a change in their primary immunosuppression regimen than the tacrolimus/sirolimus group (20.8% versus 53.8%, P = 0.001). The safety profile was similar between groups. In summary, after long-term follow-up, a CNI-free maintenance regimen consisting of sirolimus, MMF, and steroids was both safe and efficacious among low to moderate immunologic risk renal transplant recipients.     

Discontinuation of mycophenolate mofetil from a tacrolimus-based triple regimen 2 months after renal transplantation: a comparative randomized multicentre study

Previous clinical data suggested that with a tacrolimus-based regimen adjunctive immunosuppressives may be withdrawn after an initial treatment period. This study investigated the early discontinuation of mycophenolate mofetil (MMF) from a standard triple regimen. Patients were randomized either to receive a continued tacrolimus/MMF/steroids triple regimen (control group) or to reduce and then stop the MMF dose (MMF stop group). Both groups received identical daily tacrolimus and corticosteroid doses. The initial MMF dose was 1 g/day in both arms, but in the MMF stop group the dose was reduced to 0.5 g/day from week 7 to week 12 and then stopped. The intent-to-treat population consisted of 74 (control) and 78 (MMF stop) patients. MMF was tapered off as planned in 82.9% of the patients in the MMF stop arm. The 6-month incidence of biopsy-proven acute rejection was similar in both arms (21.6% control, 16.7% MMF stop). Graft loss occurred in 5.4% (control) and 3.8% (MMF stop) of the patients. MMF could be safely discontinued from a tacrolimus-based triple therapy early after transplantation without any rebound in efficacy during the 6-month follow-up period. (Name of registry: ClinicalStudyResults.org, number: FG-02-CEE-01, date: 9 June 2006).     

A "steroid-free" tacrolimus and low-dose mycophenolate mofetil primary immunosuppression does not prevent early acute rejection after liver transplantation

To assess the efficacy and safety of a primary immunosuppressive regimen with tacrolimus (Tac) and low-dose mycophenolate mofetil (MMF) without steroids and to determine the exposure to mycophenolic acid (MPA) in the early postoperative period, we performed a single-center, randomized 1:1, open-label, controlled study planned to be 60 liver transplantation patients randomized into 2 groups: group A, tacrolimus + MMF (750 mg orally twice a day); and group B, tacrolimus + MMF (750 mg orally twice a day) + steroids. After an interim analysis by the ethical committee patient enrollment was stopped. Data from 30 patients (12 in group A and 18 in group B with a mean follow-up period of 31 +/- 7 months) showed a patient survival rate of 91.7% in group A and 100% in group B and a graft survival rate of 91.7% and 88.9%, respectively. Nine patients (75%) in group A suffered an acute rejection episode, whereas in group B only 3 patients (16.7%) showed acute rejection (P = .002). All rejection episodes occurred in both groups at 1 week after transplantation. The difference in histological grading was statistically significant (P = .021). The toxicity profiles were similar in both groups. A primary immunosuppressive regimen based on Tac and low-dose MMF without steroids is safe but unable to prevent acute rejection at 1 week after transplantation even if early acute rejection does not affect the outcome in terms of morbidity and graft or patient survival.     

A randomized long-term trial of tacrolimus and sirolimus versus tacrolimus and mycophenolate mofetil versus cyclosporine (NEORAL) and sirolimus in renal transplantation. I. Drug interactions and rejection at one year

BACKGROUND: To reduce long-term nephrotoxic calcineurin inhibitor dosage, adjunctive sirolimus or mycophenolate mofetil (MMF) was used in a 150-patient, randomized, three-armed trial in cadaveric or human leukocyte antigen non-identical living-donor first renal transplant recipients (n=50/group). METHODS: Group A received tacrolimus and sirolimus. Target tacrolimus trough levels postoperatively were 10, 8, and 6 ng/mL at 1 month, 6 months, and 1 year, respectively. Group B received tacrolimus and MMF. Target tacrolimus trough levels were 10 and 8 ng/mL at 1 month and 1 year, with a targeted dose of MMF of 1 g twice daily. Group C received cyclosporine A (CsA) (Neoral, Novartis, Basel, Switzerland) and sirolimus with target CsA trough levels of 225 and 175 ng/mL at 1 month and 1 year. Maintenance sirolimus target trough levels were 8 ng/mL in groups A and C. Each group received daclizumab induction and methylprednisolone maintenance. This first of two companion 1-year reports details demographics, drug-dosing interactions, and rejection. RESULTS: There were no notable differences in group demographics, but a somewhat less favorable course occurred in group C, despite higher bioavailability of sirolimus in group C versus group A (P<0.001). Acute rejection rates were lower in groups A (4%) and B (4%) combined versus group C (14%) (P=0.03). Histopathologic findings were supported by comparing perioperative with 1-year postoperative protocol biopsies. CONCLUSIONS: This 1-year interim analysis indicates that a decreasing dosage of tacrolimus with either adjunctive sirolimus or MMF may optimize future graft survival versus a less favorable outcome using a similar algorithm with CsA and sirolimus.     

Comparison of Sirolimus vs. Mycophenolate Mofetil on Surgical Complications and Wound Healing in Adult Kidney Transplantation

Mycophenolate mofetil (MMF) and sirolimus impair wound healing. We compared sirolimus vs. MMF to determine the relative impact on surgical complications and wound healing in adult kidney transplant recipients. This retrospective, single center study of 235 adult kidney transplants performed between 1 January 2000 and 31 January 2002 identified 158 adult, kidney-only recipients treated with tacrolimus and prednisone, from which two groups were defined: group 1 (n = 84) received MMF, group 2 (n = 74) received sirolimus. The incidence of fluid collections, wound problems, dehiscence, and urine leak were compared. A multivariate stepwise logistical regression analysis was performed to identify risk factors. The overall incidence of complications was 21.5%, with rates significantly lower in group 1 (2.4%) vs. group 2 (43.2%, p < 0.0001). Regression analysis showed only sirolimus (p < 0.001) and hypo-albuminemia (p = 0.006) to independently correlate with complication occurrence. In subanalyses, lymphoceles correlated only with sirolimus (p = 0.003), while other wound problems also correlated with higher body mass index (p = 0.067). The use of sirolimus, tacrolimus and prednisone was associated with a greater incidence of lymphoceles, non-lymphocele perinephric fluid collections and other consequences of poor wound healing, as compared to contemporary patients treated with MMF, tacrolimus and prednisone.     

Immunosuppression with Belatacept‐Based,Corticosteroid‐Avoiding Regimens in De Novo Kidney Transplant Recipients

Current immunosuppressive regimens in renal transplantation typically include calcineurin inhibitors (CNIs) and corticosteroids, both of which have toxicities that can impair recipient and allograft health. This 1‐year, randomized, controlled, open‐label, exploratory study assessed two belatacept‐based regimens compared to a tacrolimus (TAC)‐based, steroid‐avoiding regimen. Recipients of living and deceased donor renal allografts were randomized 1:1:1 to receive belatacept‐mycophenolate mofetil (MMF), belatacept‐sirolimus (SRL), or TAC‐MMF. All patients received induction with 4 doses of Thymoglobulin (6 mg/kg maximum) and an associated short course of corticosteroids. Eighty‐nine patients were randomized and transplanted. Acute rejection occurred in 4, 1 and 1 patient in the belatacept‐MMF, belatacept‐SRL and TAC‐MMF groups, respectively, by Month 6; most acute rejection occurred in the first 3 months. More than two‐thirds of patients in the belatacept groups remained on CNI‐ and steroid‐free regimens at 12 months and the calculated glomerular filtration rate was 8–10 mL/min higher with either belatacept regimen than with TAC‐MMF. Overall safety was comparable between groups. In conclusion, primary immunosuppression with belatacept may enable the simultaneous avoidance of both CNIs and corticosteroids in recipients of living and deceased standard criteria donor kidneys, with acceptable rates of acute rejection and improved renal function relative to a TAC‐based regimen.     

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.     

Complete Avoidance of Calcineurin Inhibitors in Renal Transplantation: A Randomized Trial Comparing Sirolimus and Tacrolimus

Calcineurin inhibitors have decreased acute rejection and improved early renal allograft survival, but their use has been implicated in the development of chronic nephrotoxicity. We performed a prospective, randomized trial in kidney transplantation comparing sirolimus-MMF-prednisone to tacrolimus-MMF-prednisone. Eighty-one patients in the sirolimus group and 84 patients in the tacrolimus group were enrolled (mean follow-up = 33 months; range 13-47 months). At 1 year, patient survival was similar in the groups (98% with sirolimus, 96% with tacrolimus; p = 0.42) as was graft survival (94% sirolimus vs. 92% tacrolimus, p = 0.95). The incidence of clinical acute rejection was 10% in the tacrolimus group and 13% in the sirolimus group (p = 0.58). There was no difference in mean GFR measured by iothalamate clearance between the tacrolimus and sirolimus groups at 1 year (61 +/- 19 mL/min vs. 63 +/- 18 mL/min, p = 0.57) or 2 years (61 +/- 17 mL/min vs. 61 +/- 19 mL/min, p = 0.84). At 1 year, chronicity using the Banff schema showed no difference in interstitial, tubular or glomerular changes, but fewer chronic vascular changes in the sirolimus group. This study shows that a CNI-free regimen using sirolimus-MMF-prednisone produces similar acute rejection rates, graft survival and renal function 1-2 years after transplantation compared to tacrolimus-MMF-prednisone.     

Efficacy and cardiovascular safety of daclizumab, mycophenolate mofetil, tacrolimus, and early steroid withdrawal in renal transplant recipients: a multicenter, prospective, pilot trial

This single-arm, open-label, pilot study was designed to assess the efficacy and cardiovascular safety profile of daclizumab, a humanized monoclonal interleukin (IL)-2Ralpha antibody, in combination with mycophenolate mofetil (MMF), tacrolimus, and early corticosteroid withdrawal in renal transplant recipients. Seventy-nine renal allograft recipients were treated with daclizumab (1 mg/kg; five doses starting on the day before transplant and then every two weeks), MMF (1 g b.i.d.), tacrolimus (0.2 mg/kg/d), and low-dose prednisolone, which was withdrawn at day 150 after transplant. The rate of acute rejection was determined at 12 months. Lipid profile, oral glucose tolerance, and adverse events were monitored. Of the 76 patients eligible for analysis, eight (10.5%) developed biopsy-proven acute rejection (BPAR). Ten (13.2%) experienced clinical and/or BPAR. Corticosteroids were withdrawn completely in 91% of patients at 12 months. Graft and patient survival were 97.5% and 98.7% respectively. Mean total cholesterol and triglycerides were significantly lower at 12 months post-transplant than at baseline (201 +/- 47.5 vs. 190.8 +/- 43.6 mg/dL, p = 0.005 and 196.2 +/- 133.2 vs. 144.5 +/- 76.8 mg/dL, p < 0.001, respectively). Mean hemoglobin A1c levels did not differ between baseline (5.54%) and 12 months (5.48%). New-onset post-transplant diabetes mellitus occurred in 6.6% of the non-diabetic transplanted patients. The proportion of patients with abnormal oral glucose tolerance test (OGTT) was 47% at 3 months and 39% at 12 months (p = NS). Daclizumab induction in combination with MMF, tacrolimus, and low-dose (followed by withdrawal) prednisolone appears to be effective and safe in patients receiving renal allografts. The regimen appears to be associated with a favorable cardiovascular profile.     

Increased Risk of Thrombotic Microangiopathy in Patients Receiving a Cyclosporin–Sirolimus Combination

A single-center cohort study of kidney and kidney-pancreas recipients was conducted to evaluate the association between new immunosuppressive regimens and risk of thrombotic microangiopathy (TMA). From January 1st,1996 to December 31, 2002, 368 patients received a kidney or kidney-pancreas transplant at our center. Four immunosuppressive regimens were evaluated as potential risk factors of TMA: cyclosporin + mycophenolate mofetil (CsA + MMF), cyclosporin + sirolimus (CsA + SRL), tacrolimus + myophenolate mofetil (FK + MMF), and tacrolimus + sirolimus (FK + SRL). Thirteen patients developed biopsy-proven TMA in the absence of vascular rejection. The incidence of TMA was significantly different in the four immunosuppressive regimens studied (p < 0.001). The incidence of TMA was highest in the CsA + SRL group (20.7%). The relative risk of TMA was 16.1 [95% confidence interval (CI): 4.3-60.8] for patients in the CsA + SRL group as compared with those in the FK + MMF group. We also investigated in vitro the pathophysiological basis of this association. The CsA-SRL combination was found to be the only regimen that concomitantly displayed pro-necrotic and anti-angiogenic activities on arterial endothelial cells. We propose that this combination concurs to development of TMA through dual activities on endothelial cell death and repair.     

Steroid-Withdrawal at 3 Days After Renal Transplantation with Anti-IL-2 Receptor α Therapy: A Prospective, Randomized, Multicenter Study

Steroids have been included in most immunosuppressive regimens after renal transplantation, but are feared for their side-effects. We conducted a prospective multicenter study to investigate whether it is feasible to withdraw steroids early after transplantation with the use of anti-IL-2Ralpha induction, tacrolimus and mycophenolate mofetil (MMF). A total of 364 patients were randomized to receive either two doses of daclizumab (1 mg/kg) and, for the first 3 days, 100 mg of prednisolone (daclizumab group n = 186), or steroids (tapered to 0 mg at week 16; controls n = 178). All patients received tacrolimus and MMF. The incidence of biopsy-confirmed acute rejection at 12 months was not different between the daclizumab group (15%) and the controls (14%) (95% confidence interval of difference: -6 to + 8%, NS). Graft survival at 12 months was comparable in the two groups (daclizumab group: 91%; controls: 90%). Mean arterial blood pressure, serum lipids, and incidence of patients with hyperglycemia were temporary lower in the daclizumab group compared with controls. The immunosuppressive regimen of the daclizumab group was associated with increased costs. In conclusion, with the use of anti-IL-2Ra induction and daily therapy with tacrolimus and MMF it is feasible to withdraw steroids at 3 days after renal transplantation.