Objectives: To examine the clinical effectiveness and cost-effectiveness of the newer immunosuppressive drugs for renal transplantation: basiliximab, daclizumab, tacrolimus, mycophenolate (mofetil and sodium) and sirolimus. Data sources: Electronic databases. Industry submissions. Current Clinical Trials register. Cochrane Collaboration Renal Disease Group. Review methods: The review followed the InterTASC standards. Each of the five company submissions to the National Institute for Clinical Excellence (NICE) contained cost-effectiveness models, which were evaluated by using a critique covering (1) model checking, (2) a detailed model description and (3) model rerunning. Results: For induction therapy, three randomised controlled trials (RCTs) found that daclizumab significantly reduced the incidence of biopsy-confirmed acute rejection and patient survival at 6 months/1 year compared with placebo, but not compared with the monoclonal antibody OKT3. There was no significant gain in patient survival or graft loss at 3 years. The incidence of side-effects with daclizumab reduced compared to OKT3. Eight RCTs found that basiliximab significantly improved 6-month/1-year biopsy-confirmed acute rejection compared to placebo, but not compared to either ATG or OKT3. There was no significant gain in either 1-year patient survival or graft loss. The incidence of side-effects with basiliximab was not significantly different compared to OKT3/ATG. For initial/maintenance therapy, 13 RCTs found that tacrolimus reduced the 6-month/1-year incidence of biopsy-proven acute rejection compared to ciclosporin. There was no significant improvement in either 1-year or long-term (up to 5 years) graft loss or patient survival. The acute rejection benefit of tacrolimus over ciclosporin appeared to be equivalent for Sandimmun and Neoral. There were important differences in the side-effect profile of tacrolimus and ciclosporin. Seven RCTs found that mycophenolate mofetil (MMF) reduced the incidence of acute rejection. There was no significant difference in patient survival or graft loss at 1-year or 3-year follow-up. There appeared to be differences in the side-effect profiles of MMF and azathioprine (AZA). No RCTs comparing MMF with AZA were identified. One RCT compared mycophenolate sodium (MPS) to MMF and reported no difference between the two drugs in 1-year acute rejection rate, graft survival, patient survival or side-effect profile. Two RCTs suggest that addition of sirolimus to a ciclosporin-based initial/maintenance therapy reduces 1-year acute rejections in comparison to a ciclosporin (Neoral) dual therapy alone and substituting azathioprine with sirolimus in initial/maintenance therapy reduces the incidence of acute rejection. Graft and patient survival were not significantly different with either sirolimus regimen. Adding sirolimus increases the incidence of side-effects. The side-effect profiles of azathioprine and sirolimus appear to be different. For the treatment of acute rejection, three RCTs suggested that both tacrolimus and MMF reduce the incidence of subsequent acute rejection and the need for additional drug therapy. Only one RCT and one subgroup analysis in children (< 18 years) were identified comparing ciclosporin to tacrolimus and sirolimus, respectively. Conclusions: The newer immunosuppressant drugs (basiliximab, daclizumab, tacrolimus and MMF) consistently reduced the incidence of short-term (1-year) acute rejection compared with conventional immunosuppressive therapy. The independent use of basiliximab, daclizumab, tacrolimus and MMF was associated with a similar absolute reduction in 1-year acute rejection rate (approximately 15%). However, the effects of these drugs did not appear to be additive (e.g. benefit of tacrolimus with adjuvant MMF was 5% reduction in acute rejection rate compared with 15% reduction with adjuvant AZA). Thus, the addition of one of these drugs to a baseline immunosuppressant regimen was likely to affect adversely the incremental cost-effectiveness of the addition of another. The trials did not assess how the improvement in short-term outcomes (e.g. acute rejection rate or measures of graft function), together with the side-effect profile associated with each drug, translated into changes in patient-related quality of life. Moreover, given the relatively short duration of trials, the impact of the newer immunosuppressants on long-term graft loss and patient survival remains uncertain. The absence of both long-term outcome and quality of life from trial data makes assessment of the clinical and cost-effectiveness on the newer immunosuppressants contingent on modelling based on extrapolations from short-term trial outcomes. The choice of the most appropriate short-term outcome (e.g. acute rejection rate or measures of graft function) for such modelling remains a matter of clinical and scientific debate. The decision to use acute rejection in the meta-model in this report was based on the findings of a systematic review of the literature of predictors of long-term graft outcome. Only a very small proportion of the RCTs identified in this review assessed patient-focused outcomes such as quality of life. Since immunosuppressive drugs have both clinical benefits and specific side-effects, the balance of these harms and benefits could best be quantified through future trials using quality of life measures. The design of future trials should be considered with a view to the impact of drugs on particular renal transplant groups, particularly higher risk individuals and children. Finally there is a need for improved reporting of methodological details of future trials, such as the method of randomisation and allocation concealment. A number of issues exist around registry data, for example the use of multiple drug regimens and the need to assess the long-term outcomes. An option is the use of observational registry data including, if possible, prospective data on all consecutive UK renal transplant patients. Data capture for each patient should include immunosuppressant regimens, clinical and patient-related outcomes and patient demographics. © Queen's Printer and Controller of HMSO 2005. All rights reserved.

Once-daily tacrolimus extended-release formulation (Prograf XL, formerly referred to as MR or MR4) was compared with the twice-a-day tacrolimus formulation (TAC) and cyclosporine microemulsion (CsA), all administered in combination with mycophenolate mofetil (MMF), corticosteroids and basiliximab induction, in a phase 3, randomized (1:1:1), open-label trial in 638 de novo kidney transplant recipients. In combination with MMF and corticosteroids, XL had an efficacy profile comparable to TAC and CsA. XL/MMF and TAC/MMF were statistically noninferior at 1-year posttransplantation to CsA/MMF for the primary efficacy endpoint, efficacy failure (death, graft loss, biopsy-confirmed acute rejection (BCAR) or lost to follow-up). One-year patient and graft survival were 98.6% and 96.7% in the XL/MMF group, 95.7% and 92.9% in TAC/MMF group and 97.6% and 95.7% in CsA/MMF group. The safety profile of XL in comparison with CsA was similar to that observed with TAC in this study and consistent with previously published reports of TAC in comparison with CsA. The results support the safety and efficacy of tacrolimus in combination with MMF, corticosteroids and basiliximab induction, as well as XL as a safe and effective once-daily dosing alternative.

We studied the role of endogenous activated protein C (APC), the major physiological anti-coagulant with concomitant anti-inflammatory properties, on ischemia/reperfusion (I/R) in 45 patients participating in a larger trial comparing three immunosuppressive protocols in cadaveric renal transplantation: perioperative anti-thymocyte globulin (ATG, Fresenius AG, Bad Homburg, Germany), perioperative basiliximab and conventional triple therapy. Blood samples for assessing plasma APC, protein C, and lactoferrin concentrations, neutrophil CD11b and L-selectin expressions and blood leukocyte differential counts were obtained preoperatively and before reperfusion from central venous cannula, complemented with simultaneous samples from iliac artery and graft vein for calculation of transrenal differences (Delta) of study parameters at 1 and 5 min after reperfusion. Unlike basiliximab or conventional therapy groups, ATG infusion induced a substantial increase in plasma APC concentration (119 [88-144]% before infusion vs. 232 [85-1246]% after infusion, p<0.001), resulting in renal graft sequestration of APC at 1 min after reperfusion (Delta=-72 [-567 to 12]%, p<0.001). Graft APC consumption was associated with transrenal reduction of neutrophil activation markers (L-selectin r=0.7, p=0.01; lactoferrin r=-0.6, p=0.02; CD11b r=-0.8, p=0.001), and with both warm (r=0.6, p=0.01) and cold ischemia time (r=0.6, p=0.02) and donor age (r=0.6, p=0.01). These findings suggest that APC has an anti-inflammatory role in I/R injury in clinical renal transplantation.

Steroid-induced adverse effects after transplantation include cosmetic, metabolic, and cardiovascular complications. Steroid withdrawal or avoidance with cyclosporine-based regimens have been hampered by an unacceptably high rate of acute rejections and increased rates of graft loss. Recently the results of several large, randomized trials of steroid withdrawal/avoidance with tacrolimus-based immunosuppression in renal transplant recipients became available. A review of these trials appeared to be of clinical interest. Data from the THOMAS trial clearly indicate that steroid withdrawal from a regimen of tacrolimus, mycophenolate mofetil (MMF), steroids after 3 months after transplantation is safe with regard to acute rejection rate and graft survival. If an induction therapy with daclizumab is used in combination with tacrolimus and MMF (CARMEN trial), even steroid avoidance is safe with regard to acute rejection rate and graft survival. Finally, in the ATLAS trial, steroid avoidance with basiliximab in combination with tacrolimus (resulting in tacrolimus monotherapy) or alternatively with tacrolimus and MMF both resulted in similar graft survival, but higher rates of acute rejection. In conclusion, steroid withdrawal is safe from a triple-drug regimen of tacrolimus, MMF, and steroids after 3 months after transplantation, and steroid use may completely be avoided with tacrolimus, and MMF combined with daclizumab induction. Tacrolimus monotherapy may be achieved using basiliximab induction at the price of higher rates of acute rejection, but with unaffected graft survival. Thus tacrolimus-based immunosuppression with or without interleukin-2 receptor antagonist induction has made steroid withdrawal or avoidance a realistic option in renal transplantation.

BACKGROUND:

Progressive nephrotoxicity caused by calcineurin inhibitor drugs contributes to the long-term decline in renal function in kidney transplant patients.

METHODS:

We conducted a randomized, prospective trial of calcineurin inhibitor drug avoidance in 61 adult primary kidney transplant recipients. Each patient received induction therapy with 20 mg basiliximab on days 0 and 4, and maintenance therapy with mycophenolate mofetil 1 g two times per day and steroids. Thirty-one patients received sirolimus, 5 mg daily after a 15-mg loading dose. Doses were then concentration-controlled to keep 24-hr trough levels at 10 to 12 ng/mL for 6 months and 5 to 10 ng/mL thereafter. Thirty patients began cyclosporine therapy at 6 to 8 mg/kg per day in divided doses and were then concentration-controlled to keep 12-hr troughs of 200 to 250 ng/mL.

RESULTS:

Mean follow-up is 18.1 months (range, 12-26 months). The percentages of 1-year patient survival, graft survival, and biopsy-confirmed acute rejection rates were not significantly different between the sirolimus-treated patients (96.7%, 96.7%, and 6.4%, respectively) and the cyclosporine-treated patients (100%, 95.4%, and 16.6%, respectively). At 6 and 12 months, respectively, the sirolimus-treated patients enjoyed significantly better (P=0.008 and P=0.004) mean serum creatinine levels (1.29 and 1.32 mg/dL) and calculated creatinine clearances (77.8 and 81.1 mL/min) than cyclosporine-treated patients (1.74 and 1.78 mg/dL, and 64.1 and 61.1 mL/min, respectively). Sirolimus-treated recipients have significantly (P=0.001) higher 1-year trough levels of mycophenolic acid (4.16 ng/mL) than cyclosporine-treated patients (1.93 ng/mL). Sirolimus also delays the repopulation of basiliximab-depleted CD25 T cells compared with cyclosporine.

CONCLUSIONS:

Calcineurin inhibitor drug avoidance with basiliximab induction and sirolimus provides comparable 1-year transplant outcomes, with significantly better renal function in primary renal allograft recipients.

BACKGROUND:

Immunosuppressive regimens based on low doses of cyclosporine A (CsA) or tacrolimus (TAC) may improve short-term outcome after kidney transplantation (KT), but the optimal immunosuppressive protocol is currently unknown.

METHODS:

This study compared the 24-month efficacy and safety of two immunosuppressive regimens using reduced calcineurin inhibitors (CNIs) exposure with standard dosage of CsA in 240 patients who were randomized into three groups: group A (n=80): Thymoglobulin, CsA (4 mg/kg twice daily) plus azathioprine (1.5 mg/kg once daily); group B (n=80): basiliximab, CsA (2 mg/kg/ twice daily) plus mycophenolate mofetil (MMF; 1 g twice daily); and group C (n=80): basiliximab, TAC (0.05 mg/kg/ twice daily) plus MMF (1 g twice daily). Steroid administration was identical for all groups.

RESULTS:

A significantly better creatinine clearance at 12 months, estimated by Cockcroft-Gault (57+/-12, 65.2+/-20, 73.5+/-27 ml/min, P=0.044), the Jelliffe-2 (51.5+/-16, 56+/-19, 59.4+/-19 ml/min/1.73 m2, P=0.041) and the Modification of Diet in Renal Disease equations (53+/-17, 58.5+/-20, 61.6+/-22 ml/min/1.73 m2, P=0.035), was observed in group C compared with group A. No significant differences were observed between groups B and C. The incidence of biopsy-proven acute rejection was similar between groups (15%, 13.8%, and 16.3%). In addition, patient and graft survival at 24 months were not different between groups. Adverse effects were similar among groups, but cytomegalovirus infections was significantly higher in group A (41% vs. 20% vs. 25%; P=0.008).

CONCLUSIONS:

Immunosuppressive regimens with reduced CNI exposure provide similar preservation of renal function compared with standard dose of CsA after KT and do not lead to underimmunosuppression.