The use of daclizumab as induction therapy in combination with tacrolimus and mycophenolate mofetil in recipients with previous transplants

Clinical trials using daclizumab as induction therapy in combination with tacrolimus (TAC) and mycophenolate mofetil (MMF) have been shown to reduce the incidence of acute rejection episodes in solid organ transplantation. In an attempt to obtain a low rejection rate we proceeded with the use of daclizumab as induction therapy, in combination with TAC and MMF for recipients with previous transplants. In this study, we analyzed patients who received previous transplants, treated with the above immunosuppressive regimen. Group A consisted of four patients with previous liver transplants, group B consisted of 16 recipients with previous kidney transplants and group C consisted of three patients with previous simultaneous pancreas-kidney transplants. All patients underwent cadaveric kidney transplants except one patient in group B, who underwent a pancreas transplant. At 12 months, patient and graft survival for all groups was 100 and 100%, respectively. Acute rejection rate was 0% for group A, 12.5% for group B, and 0% for group C. Daclizumab induction therapy is effective for patients with previous transplants and does not appear to increase the risk of acute rejection.     

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transplant and then every two weeks), MMF (1 g b.i.d.), tacrolimus (0.2 mg/kg/d), and low-dose prednisolone, which was withdrawn at day 150 after transplant.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 Corticosteroids were withdrawn completely in 91% of patients at 12 months.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.     

Randomized trial of early corticosteroid reduction vs. regular‐dose corticosteroid maintenance in combination with tacrolimus and mycophenolate mofetil in living donor kidney transplant recipients: the Brazilian CORRETA trial

Garcia VD, Carvalho DBM, Gonçalves RT, Cavalcanti RL, Campos HH, Abbud‐Filho M, Lobao‐Neto AA. Randomized trial of early corticosteroid reduction vs. regular‐dose corticosteroid maintenance in combination with tacrolimus and mycophenolate mofetil in living donor kidney transplant recipients: the Brazilian CORRETA trial.
Clin Transplant 2010: 24: E109–E115.
© 2009 John Wiley & Sons A/S. Abstract: This multicenter, randomized trial aimed to compare the safety and efficacy of an early reduction in corticosteroid dose vs. long‐term maintenance in Brazilian patients on an immunosuppressive regimen based on tacrolimus and mycophenolate mofetil (MMF). In the control arm, prednisone was progressively reduced from days 8 to 90 and then kept for 12 months. In the experimental arm, prednisone was given for 12 months at the dose of 5 mg every other day. Endpoints were the composite occurrence of death, graft loss, or Banff III acute rejection, and safety. A total of 83 patients were enrolled, and 77 were analyzed for efficacy safety. One death occurred in each group. There were no cases of graft loss and one case of grade 3 acute rejection in the early reduction arm. There was no difference in the rate of the composite primary endpoint between both arms (p = 0.215), and there were no significant differences between both arms in terms of adverse events. Except for higher incidence of hypertriglyceridemia levels among patients in the regular‐dose arm, there were no significant differences between both arms in terms of adverse events. The results of this trial suggest that early reduction of corticosteroid can be feasible and safe within a timeframe of 12 months in patients receiving tacrolimus and MMF.     

Combination therapy with tacrolimus and mycophenolate mofetil: effects of early and late minimization of mycophenolate mofetil after renal transplant

The objectives of the study were: (i) to compare the efficacy and safety of minimizing mycophenolate mofetil (MMF) early (30 d) or late (90 d) after renal transplantation, when used in combination with tacrolimus; (ii) to retrospectively investigate factors associated with early, acute rejections and (iii) to investigate the pharmacokinetic interaction between tacrolimus and diltiazem. A prospective, randomized, multicenter, open-label study was conducted in 124 de novo kidney transplant recipients. Efficacy and safety outcomes were assessed for 180 d after transplantation and subjects were followed-up for a mean duration of 5.1 yr. The efficacy and safety outcomes were comparable whether the dose of MMF was minimized early or late. The incidence of early, acute rejection episodes was higher for recipients who were younger, received a graft from an unrelated donor or failed to achieve adequate tacrolimus concentrations (trough > 10 ng/mL) in the first seven d after transplant. Concomitant use of diltiazem had a tacrolimus-sparing effect in some subjects. Based on these results, we support the achievement of a high target tacrolimus concentration within the first week after renal transplant and suggest that early minimization of MMF can be achieved when used in combination with tacrolimus.     

The use of intravenous tacrolimus and mycophenolate mofetil as induction and maintenance immunosuppression in simultaneous pancreas--kidney recipients with previous transplants

Clinical trials using quadruple immunosuppression that include the combination of tacrolimus (TAC) and mycophenolate mofetil (MMF) have been shown to reduce the incidence of acute rejection episodes in simultaneous pancreas-kidney (SPK) transplantation. In attempting to obtain a low rejection rate without antibody induction therapy, we proceeded with the combination of TAC intravenous (i.v.), MMF, and steroids as induction therapy and as primary immunosuppression for recipients with previous transplants. In this study, we analyzed 10 patients who received previous transplants, treated with low-dose TAC i.v. as induction therapy. Group A consisted of 6 patients with previous transplants that underwent SPK and group B consisted of four recipients with previous SPK that underwent cadaveric kidney transplants. For group A, the previous transplants were: living related kidney (LRK) followed by islet cell (IC) transplant (n=2), LRK transplant (n=1), cadaver kidney (CAD) and IC transplant (n=1), SPK (n=1), and three previous CAD kidney transplants (n=1). In group A, all six kidneys were lost due to recurrent diabetic nephropathy, IC possibly to rejection, and the pancreas due to thrombosis. In group B with previous SPK transplants, three recipients lost their kidney to chronic rejection and one to long-term use of a nephrotoxic antibiotic. Currently, in all group A and B patients, the kidney and the pancreas are functioning, although 1 patient in group A developed type 2 diabetes (normal fasting C-peptide). Two patients in group A developed three rejection episodes that responded to steroid treatment. The results indicate the TAC i.v. in combination with oral TAC, MMF, and steroids offer effective induction therapy in patients with previous transplants.     

Impact of tacrolimus and mycophenolate mofetil regimen vs. a conventional therapy with steroids on cardiovascular risk in liver transplant patients

The aim of this study was to evaluate the impact of a steroid‐free regimen with tacrolimus and mycophenolate mofetil (modified therapy) vs. a standard regimen of tacrolimus and steroids on the cardiovascular risk score of liver transplant recipients. Patients who received a liver transplant were randomized to a modified therapy (n = 58) or a standard regimen (n = 59). Both groups were balanced at baseline, except for a higher prevalence of diabetes mellitus (DM) (p < 0.01) and a higher serum creatinine concentration (p < 0.05) in the modified therapy group. After 12 months, the prevalence of new‐onset DM, arterial hypertension, hypercholesterolemia, hypertriglyceridemia, and changes in cardiovascular risk factors was similar in both groups. The increase in serum creatinine (mg/dL) compared to baseline at one yr post‐transplantation was numerically lower in the modified therapy group (0.22 ± 0.42) than in the standard regimen group (0.41 ± 0.67) (p = 0.068). Although estimated cardiovascular risk score did not vary significantly compared to baseline in either group, there was a slight reduction in the modified regimen (?0.27 ± 2.87) vs. a mild increase (0.17 ± 2.94) in the standard regimen (p = 0.566). In conclusion, a steroid‐free regimen with tacrolimus and mycophenolate mofetil was associated with a trend toward better preservation of kidney function and reduction of cardiovascular risk score.     

Mycophenolate mofetil, with cyclosporine and prednisone, reduces early rejection while allowing the use of less antilymphocytic agent induction and cyclosporine in renal recipients with delayed graft function

Antilymphocytic agent induction (ALAI), with antithymocyte globulin or monoclonal antibody, is generally used in renal transplantation (TX) to spare renal allografts with poor initial function from the toxic effects of cyclosporine (CsA) and/or to augment immunosuppression (IS) in the patient at a high risk for early rejection. ALAI, unfortunately, increases the cost of TX and the risk to the patient, having been associated with many adverse side effects. An IS protocol, which results in a low incidence of early rejection while using less CsA and ALAI, is a worthwhile goal.
We compare our experience with mycophenolate mofetil (MMF), CsA, and prednisone (MMFCP; n=62) to our azathioprine (AZA), CsA, and prednisone (AZACP; n=50) triple‐drug IS, with and without ALAI. The patient characteristics for age, race, first TX, cadaveric donor, pediatric recipient, and dialysis in the first post‐op week (DGF) were not different for the MMFCP versus AZACP groups. There were more females in the MMFCP group (51.6% versus 30.0%, p=0.022).
We report that rejection‐free survival at 6 months (RF6) was better in the MMFCP versus AZACP group (83.9% versus 60.0%, p=0.005). Less ALAI and CsA were used in the MMFCP patients. At 1 year, actuarial graft survival was 91.9% in the MMFCP group and 81.9% in the AZACP group (p=0.116). Actuarial 1‐year patient survivals were not different in the two patient groups. In the sub‐population of patients with DGF, the RF6 in the MMFCP (n=13) group was 92.3% versus 57.1% in the AZACP (n=14) group (p=0.041). The reduction in early rejection episodes in the patients on MMFCP with DGF was accomplished while using half as much ALAI and lower CsA doses and levels. The African‐American recipient sub‐population on MMFCP also demonstrated an improvement in RF6 while using less ALAI and CsA (78.6% versus 48.0%, p=0.022).
We conclude that the use of MMF‐based triple‐drug IS results in fewer rejection episodes while allowing for lower CsA levels and less ALAI, even in patients with delayed graft function.     

Tacrolimus plus mycophenolate mofetil vs. cyclosporine plus everolimus in deceased donor kidney transplant recipients: three‐yr results of a single‐center prospective clinical trial

We compared in kidney transplantation two immunosuppressive regimens: tacrolimus plus mycophenolate mofetil (MMF) (TAC) and everolimus plus low‐dose cyclosporine (EVE). Sixty consecutive patients received TAC (30 patients) or EVE (30 patients) as immunosuppressive regimen; all subjects also received induction with basiliximab and corticosteroids. After three‐yr follow‐up, no difference was found in patient and graft survival (PTS: TAC: 97% vs. EVE: 100%; GS: TAC: 93% vs. EVE: 93%). The incidence of acute rejection was higher in the EVE group but the difference was not statistically significant (17% vs. 23%, p = ns). Patients in EVE showed higher serum cholesterol (205 ± 41 vs. 235 ± 41 mg/dL, p = 0.0012) and lower hemoglobin concentration (13.6 ± 1.4 vs. 12.4 ± 1.9, p = 0.01). Renal function was not significantly different in the two groups (3 Y creatinine: TAC 1.4 ± 0.8 vs. EVE 1.6 ± 0.8 mg/dL, p = ns). Treatment discontinuation was higher in the EVE group (TAC 17 vs. EVE 36%, p = ns). Our data show that in the middle‐term follow‐up, an immunosuppressive regimen with tacrolimus plus MMF has a similar efficacy and safety profile in comparison with the combination of low‐exposure cyclosporine plus everolimus. Further follow up could evidence the benefits related to the anti‐proliferative effects of everolimus.     

Corticosteroid avoidance in adult kidney transplant recipients under rabbit anti‐T‐lymphocyte globulin,mycophenolate mofetil and delayed cyclosporine microemulsion introduction

We conducted the first prospective, randomized, open‐label multicenter study in low‐immunologic risk adult recipients of primary cadaver kidney transplants receiving rabbit anti‐T‐lymphocyte globulin, mycophenolate mofetil, cyclosporine microemulsion introduced on day 5, with and without corticosteroids. Patients were randomly assigned according to age and cold ischemia time to receive corticosteroids for at least 6 months or no corticosteroids at all. The main efficacy evaluation criterion was acute rejection (including all treated episodes and those biopsy‐confirmed) during the first year following transplantation. For this purpose, this report includes the actual results of the whole 12‐month follow‐up of all randomized patients. For efficacy analysis, 98 patients were evaluated in the Steroid avoidance group and 99 in the Steroid maintenance group. Taken as a whole, 81% of the patients (n = 159) never received anti‐rejection treatment. From the 38 patients who received anti‐rejection treatment, 25 (25.5%) were in the Steroid avoidance group and 13 (13.1%) in the Steroid maintenance group (P < 0.031), experiencing respectively 17 (17.3%) and 7 (7.1%) biopsy‐proven first episodes of acute rejection (P < 0.031). Borderline changes (6 vs. 3) were not considered as biopsy‐proven acute rejections. Onset of first rejection was significantly shorter in the Steroid avoidance group (P < 0.027). First‐line anti‐rejection treatment response, need for any rescue therapy, as well as histologic severity of rejection episodes did not statistically differ between the groups. One‐year post‐transplantation analysis showed no differences in delayed graft function, serum creatinine, creatinine clearance, 24‐h proteinuria, as well as serious adverse events between the groups. De novo diabetes (P < 0.07) or dyslipidemia (P < 0.01) as well as newly diagnosed malignancies (P < 0.059) were however more frequently observed in the Steroid maintenance group. At the end of the first post‐transplant year, 99% of patients in the Steroid avoidance group and 97% of patients in the Steroid maintenance group were respectively alive (P = 0.34), with respectively 95% and 93.2% of functioning kidney grafts (P = 0.62). Our results showed that total avoidance of corticosteroids from the day of transplantation was associated with a significantly increased number of clinically diagnosed and treated, and biopsy‐proven acute rejections during the first year of transplantation. Nevertheless, overall outcome, 1‐year patient and graft survival as well as renal function were similar, and the patients in the Steroid avoidance group exhibited a lower incidence of de novo dyslipidemia, diabetes mellitus and malignancies often associated with steroid treatment (Clinical Trials.gov NCT00200551).