Calcineurin Inhibitor-sparing Regimens Research Articles

1438-P: Diabetes after Cardiac Transplant with Low-Dose Everolimus and Tacrolimus

Background: Although modern immunosuppressants improve survival post-transplant, they are associated with long-term metabolic complications, such as post-transplant diabetes mellitus (PTDM). Calcineurin inhibitor-sparing regimens using everolimus attenuate some complications such as left ventricular hypertrophy. However, the metabolic effects of everolimus following transplant are less clear. Aims: To compare incidence of diabetes in heart transplant recipients exposed to low-dose everolimus and tacrolimus versus standard-dose tacrolimus. Methods: Post-hoc analysis in participants of a randomised open-label clinical trial of low-dose everolimus and tacrolimus versus standard-dose tacrolimus in heart transplant recipients. Results: There were 39 participants in the trial, mean follow up was 6.4 ± 1.5 years. There was a high rate of pre-existing diabetes (26%) and newly-diagnosed PTDM (36%) during follow-up (Figure 1). Half the patients who developed PTDM in the everolimus-tacrolimus group (n=4/8) ceased diabetes medications during follow-up, which was not observed in patients on standard tacrolimus (n=0/6). Conclusion: This study suggests that treatment with everolimus may improve PTDM outcomes relative to treatment with standard doses of calcineurin inhibitor. These findings should be further studied in prospective randomised trials. Disclosure L.M.Raven: None. C.A.Muir: None. J.Pouliopoulos: None. P.S.Macdonald: Advisory Panel; AstraZeneca, Boehringer Ingelheim Inc., Other Relationship; Novartis. A.Jabbour: None. J.Greenfield: None.

MO981OUTCOMES OF INTERLEUKIN-2 RECEPTOR ANTAGONIST INDUCTION THERAPY IN STANDARD-RISK RENAL TRANSPLANT RECIPIENTS MAINTAINED ON TACROLIMUS - A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract Background and Aims Interleukin-2 (IL-2) antagonist has been used as an induction therapy in many centres in calcineurin inhibitor-sparing regimens. Tacrolimus has overwhelmingly replaced cyclosporine in the maintenance immunosuppressive protocols in many transplant centres. The aim of our study and meta-analysis is to explore the effect of IL-2 induction therapy on the rate of rejection and patient and graft survival in standard-risk renal transplant patients with tacrolimus-based maintenance immunotherapy. Secondary aims included assessment of the effect of IL-2 induction therapy on the risk of delayed graft function, cytomegalovirus (CMV) infection, and malignancy. Method We conducted a systematic review in different databases to identify studies and research work that assessed the effect of IL-2 antibody induction therapy on renal transplant outcomes. Inclusion criteria for our meta-analysis were all studies that compared IL-2 induction therapy with placebo or no induction therapy in standard-risk renal transplant recipients on tacrolimus-based maintenance immunosuppressive therapy. Data collected were the name of the first author, journal title, year of publication, country where the study was conducted, number of patients in the IL-2 induction therapy arm and in the placebo arm, number of patients who had biopsy-proven rejection and graft survival in each arm. A random effects model was used for the meta-analysis. We divided the studies included in this meta-analysis into two groups: Group A (included studies that used same dose of tacrolimus in both arms of each study) and Group B (included studies that compared patients who received induction therapy and low dose tacrolimus versus those who received no induction therapy and high dose of tacrolimus). Standard-risk renal transplant was defined as HLA mismatch <5 and PRA<50%. Results In group A, 11 studies were included (n=2886). IL2-RA induction therapy was not associated with significant differences in comparison to no induction therapy in terms of acute rejection rates (Risk Ratio=1.03, 95% Confidence Interval [CI] range: 0.84 - 1.26, I squared=0%, P=0.79), graft survival (Risk Ratio=1.15, 95% CI range: 0.82 to 1.62), delayed graft function (Risk Ratio=1.01, 95% CI range: 0.82 to 1.24), CMV infection (Risk Ratio =1.37, 95% CI range: 0.53 to 3.51) or malignancy (Risk Ratio=1.29, 95% CI range: 0.61 to 2.75). In group B, two studies were included (n=669). There was no difference between both arms in terms of acute rejection rates (Risk Ratio=0.62, with 95% CI range: 0.33 to 1.14) or graft survival (Risk Ratio=1, 95% CI range: 0.57 to 1.74) or delayed graft function (Risk Ratio=0.88, 95% CI range: 0.45 to 1.71). Conclusion IL2-RA induction therapy does not improve outcomes in patients maintained on tacrolimus-based immunotherapy in standard risk population. our results strengthen the argument for individualized medical therapy and the potential tailoring the immunosuppression regimes according to the actual patients, needs.

Implication of interleukin-2 receptor antibody induction therapy in standard risk renal transplant in the tacrolimus era: a meta-analysis

BackgroundInterleukin-2 (IL-2) antagonist has been used as an induction therapy in many centres in calcineurin inhibitor-sparing regimens. Tacrolimus has overwhelmingly replaced cyclosporine in the maintenance immunosuppressive protocols in many transplant centres. The aim of our study and meta-analysis is to explore the effect of IL-2 induction therapy on the rate of rejection and patient and graft survival in standard-risk renal transplant patients with tacrolimus-based maintenance immunotherapy. Secondary aims included assessment of the effect of IL-2 induction therapy on creatinine change and the risk of cytomegalovirus (CMV) infection.MethodsWe conducted a systematic review in different databases to identify studies and research work that assessed the effect of IL-2 antibody induction therapy on renal transplant outcomes. Inclusion criteria for our meta-analysis were all studies that compared IL-2 induction therapy with placebo or no induction therapy in standard-risk renal transplant recipients on tacrolimus-based maintenance immunosuppressive therapy. Data collected were the name of the first author, journal title, year of publication, country where the study was conducted, number of patients in the IL-2 induction therapy arm and in the placebo arm, number of patients who had biopsy-proven rejection and graft survival in each arm. A random effects model was used for the meta-analysis.ResultsOf the 470 articles found in different databases, 7 were included in the meta-analysis. Forest plot analysis for rate of rejection during the follow-up period post-transplant showed no significant difference between the groups. There was no evidence of heterogenicity between included studies (I2 = 21.8%, P = 0.27). The overall risk difference was −0.02 [95% confidence interval (CI) −0.05–0.01]. A random effects meta-analysis for patient and graft survival was performed using forest plot analysis and showed no significant effect of IL-2 receptor (IL-2R) antibody induction on patient or graft survival compared with placebo. The overall risk difference was −0.01 (95% CI −0.04–0.01) and 0.00 (95% CI −0.00–0.01), respectively. Three of the included studies showed no effect of basiliximab on creatinine change, two showed no effect on risk of CMV infection and two showed less risk of post-transplant diabetes in the basiliximab group.ConclusionIL-2R antibody induction therapy has no significant effect on the rate of rejection or patient or graft survival in standard-risk renal transplant recipients on tacrolimus-based maintenance immunotherapy. More randomized controlled studies are needed.

Early conversion of pediatric kidney transplant patients to everolimus with reduced tacrolimus and steroid elimination: Results of a randomized trial.

In a 12-month, multicenter, open-label study, 106 children were randomized at 4 to 6 weeks after kidney transplantation to switch to everolimus with reduced TAC (EVR/rTAC) and steroid elimination from month 5 posttransplant or to continue standard tacrolimus with mycophenolate mofetil (sTAC/MMF) and steroids. The cumulative incidence of a co-primary efficacy end point (biopsy-proven acute rejection [BPAR], graft loss, or death from randomization to month 12) was 10.3% with EVR/rTAC and 5.8% with sTAC/MMF (difference 4.4%; P = .417). BPAR occurred in 9.6% and 5.6% of patients, respectively. Patient and renal allograft survival were 100%. The co-primary end point of mean estimated glomerular filtration rate at month 12 was 76.2 mL/min/1.73 m2 with EVR/rTAC and 72.5 mL/min/1.73 m2 for sTAC/MMF (difference 3.8 mL/min/1.73m2 ; P = .49). One EVR/rTAC patient developed posttransplant lymphoproliferative disease. Longitudinal growth and sexual maturation were equivalent between groups. The randomized drug regimen was discontinued in 34.6% and 13% of patients in the EVR/rTAC and sTAC/MMF groups, respectively (P = .024), and discontinued due to adverse events/infections in 25.0% and 11.1% of patients (P = .062). In conclusion, early conversion of pediatric kidney transplant patients from TAC, MMF, and steroids to EVR/rTAC and steroid withdrawal maintains immunosuppressive efficacy and preserves renal function.

Newer Immunosuppression and Strategies on the Horizon in Heart Transplantation

Balanced immunosuppressive therapy is the key to long-term survival after allograft transplantation. With a worldwide median recipient/graft survival of more than 11 years, heart transplantation is a highly successful treatment for selected patients with end-stage heart failure. However, current immunosuppressive regimens are associated with adverse effects. In the balance between acute rejection, cardiac allograft vasculopathy, infections and an increased risk of malignancy, there is room for improvement. The aim of this review article is to present an overview of immunosuppressive mechanisms and new immune therapy strategies in heart transplantation and to highlight emerging approaches in this field that may influence our immunosuppressive strategies in the future. Calcineurin inhibitors have been the central drug class in post-transplant immunosuppressive regimens. New trials have explored alternative drugs, such as inhibitors of mechanistic target of rapamycin and belatacept. There is ongoing research on the development of strategies to induce long-term allograft tolerance. This review briefly introduces allograft rejection immunology, and sums up contemporary immunosuppressive strategies with emphasis on the development of calcineurin inhibitor-sparing regimens and the prospect of achieving long-term tolerance.

Calcineurin inhibitor-sparing regimens based on mycophenolic acid after kidney transplantation

The use of calcineurin inhibitors (CNIs) has dramatically reduced the number of acute rejections and improved kidney allograft survival. However, CNIs can also cause kidney damage and several adverse events. This has prompted transplant physicians to use CNI-sparing regimens. CNI withdrawal, minimization, or avoidance protocols have been conducted using mycophenolic acid (MPA), and/or mammalian-target-of-rapamycin inhibitors, and/or belatacept. Herein, we review the outcomes of minimizing, withdrawing, or avoiding CNIs when giving mycophenolic acid to de novo and maintenance kidney transplant patients. Protocols on CNI withdrawal, when based on MPA without mammalian-target-of-rapamycin inhibitors (mTORi) or belatacept, in de novo and maintenance kidney transplant patients, are associated with an increased risk of acute rejection. Consequently, these strategies have been abandoned and are not recommended. Protocols on CNI minimization show a beneficial impact of kidney function and acceptable acute rejection rates mainly in patients who have been recipients of a graft for >3-5years. However, no significant improvement to graft survival has been observed.

Everolimus-based calcineurin-inhibitor sparing regimens for kidney transplant recipients: a systematic review and meta-analysis.

Calcineurin inhibitors (CNI) associated nephrotoxicity remains a risk factor for long-term graft dysfunction after renal transplantation. Everolimus is a mammalian target of rapamycin inhibitor and exhibits synergistic immunosuppressive activity with CNI to permit CNI-reduction. We conducted a systematic review to compare the efficacy of everolimus-based CNI sparing and standard CNI regimens in renal transplantation recipients. We searched PubMed and Web of Science databases to identify relevant randomized controlled trials. Glomerular filtration rate (GFR), biopsy-proven acute rejection (BPAR), death or graft loss and incidence of adverse events were the major estimates of renal function, efficacy, and tolerability of the two regimens. Seven studies providing data for 2,067 patients were included. Six of the seven studies used cyclosporine as the CNI. The patients were divided into two groups: everolimus-based CNI sparing (elimination and minimization) group and standard CNI group. Everolimus-based regimen was associated with increased GFR [P = 0.02; weighted mean difference (WMD) 4.83 mL/min], decreased serum creatinine (P = 0.004; WMD -9.94 μmol/L) and no more death or graft loss [P = 0.72; relative risk (RR) 1.07]. CNI-minimization was not associated with increased BPAR (P = 0.25; RR 0.85) while CNI-elimination was associated with more BPAR Grade 1 (P < 0.00001; RR 4.20). Use of everolimus reduced the risk of CMV infection (P = 0.0002; RR 0.47). There was a higher risk of discontinuation of everolimus (P < 0.00001; RR 1.69) and non-fatal adverse events (P < 0.00001; RR 1.73) in patients on the everolimus based CNI sparing regimens. Everolimus-based CNI sparing regimen could optimize long-term graft function without leading to more death or graft loss. Although CNI elimination was associated with higher risk of BPAR, everolimus use with CNI minimization did not increase the risk of acute rejections. Use of everolimus was associated with reduction in the incidence of CMV infection, but there was a higher risk of discontinuation of this drug and other non-fatal adverse events.

Corticosteroid and calcineurin inhibitor sparing regimens in kidney transplantation

Chronic kidney disease is a major public health problem that is associated with increased risks of kidney disease progression, cardiovascular disease and death. Kidney transplantation remains the renal replacement therapy of choice for patients with end-stage kidney disease. Despite impressive strides in short-term allograft survival, there has been little improvement in long-term kidney graft survival, and rates of death with a functioning allograft remain high. Long-term safety profiles of existing immunosuppressive regimens point to a need for continued search for alternative agents. This overview discusses emerging evidence on a few promising therapeutic approaches, juxtaposes conflicting findings and highlights remaining knowledge gaps.

Evidence for the Immunosuppressive Potential of Calcineurin Inhibitor-Sparing Regimens in Liver Transplant Recipients with Impaired Renal Function

Patients requiring liver transplantation (LT) frequently experience renal insufficiency (RI), which affects their survival. Although calcineurin inhibitor-sparing immunosuppressive regimens (CSRs) are well known to prevent RI, the immune state in recipients receiving CSR remains to be intensively investigated. In the present study, we investigated the immune state in liver transplant patients suffering from RI received a CSR comprising a reduced dose of calcineurin inhibitor (CNI), methylprednisolone, and mycophenolate mofetil (MMF). For monitoring the immune-state response to anti-donor allostimulation in these patients, we employed a mixed lymphocyte reaction (MLR) assay using an intracellular carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeling technique. Among 60 cases of living-donor LT at our institute, 68% of the patients had none to mild RI (non-RI group) and 32% of the patients had moderate to severe RI (RI group). The RI group received a CSR comprising reduced dose of tacrolimus, methylprednisolone, and MMF, while the non-RI group received a regimen comprising conventional dose of tacrolimus and methylprednisolone. One year after LT, the mean estimated glomerular filtration rate (eGFR) in the non-RI group had significantly deteriorated. In contrast, the mean eGFR in the RI group had significantly improved after LT, although it was still lower than that of the non-RI group. Notably, 53% of the patients in the RI group were completely cured of RI by 1 year after LT. None of the patients had severe RI at 1 year after LT nor required chronic hemodialysis during the observation period. Serial mixed lymphocyte reaction assays revealed that anti-donor T cell responses were adequately suppressed in both groups. To evaluate the immune status of these patients, we employed a serial MLR assay using a CFSE-labeling technique. In both groups, limited CD4+ and CD8+ T-cell proliferation was observed in the anti-donor responses as compared with the anti-third-party responses through the first year. At 1 month after LT, the average of stimulation index (SI) for CD4+ T cells in response to anti-third-party stimulation was >2 (the average value in healthy volunteers without any immunosuppressive treatment) i.e., there was a normal response in the anti-third-party. At 1 year after LT, the average of SIs for CD4+ and CD8+ T cells in response to both anti-donor and anti-third-party stimulation was < 2. There were no significant differences in acute rejection rates, bacterial, fungal, or cytomegalovirus infection rates and patient survival between the groups. In conclusion, patients with pre-transplant RI receiving CSR under immunological monitoring using an MLR assay were associated with less impairment of renal function without an increased frequency of rejection or patient survival. Anti-donor T cell responses were adequately suppressed in these patients as well as in patients who received the conventional immunosuppressive regimen comprising a standard dose of CNI.

Evidence for the Immunosuppressive Potential of Calcineurin Inhibitor-Sparing Regimens in Liver Transplant Recipients with Impaired Renal Function

Patients requiring liver transplantation (LT) frequently experience renal insufficiency (RI), which affects their survival. Although calcineurin inhibitor-sparing immunosuppressive regimens (CSRs) are well known to prevent RI, the immune state in recipients receiving CSR remains to be intensively investigated. Among 60 cases of living-donor LT at our institute, 68% of the patients had none to mild RI (non-RI group) and 32% of the patients had moderate to severe RI (RI group). The RI group received a CSR comprising reduced dose of tacrolimus, methylprednisolone, and mycophenolate mofetil, while the non-RI group received a regimen comprising conventional dose of tacrolimus and methylprednisolone. One year after LT, the mean estimated glomerular filtration rate (eGFR) in the RI group had significantly improved, although it was still lower than that of the non-RI group. Serial mixed lymphocyte reaction assays revealed that antidonor T-cell responses were adequately suppressed in both groups. Thus, we provide evidence that CSR leads to improvement of eGFR after LT in patients with RI, while maintaining an appropriate immunosuppressive state.

Calcineurin inhibitor sparing regimens using m-target of rapamycin inhibitors: an opportunity to improve cardiovascular risk following kidney transplantation?

Maintenance therapy with calcineurin inhibitors (CNIs) increases cardiovascular risk. Use of the m-TOR inhibitors everolimus or sirolimus to minimize CNI exposure is usually undertaken to preserve renal function following kidney transplantation, but may also improve cardiovascular risk status. Recent studies of early conversion from CNI to m-TOR inhibitors have shown a numerical improvement in the incidence of hypertension, but results are not clear-cut. Dyslipidaemia, in contrast, is more frequent under m-TORs than with CNI-based immunosuppression. New-onset diabetes is rare (≤ 5%) using modern m-TOR regimens, for example, everolimus and reduced-exposure CNI. Renal function improvement with m-TOR inhibitor regimens versus CNIs would also be expected to improve cardiovascular risk. Moreover, m-TOR-based CNI-minimization regimens are not associated with proteinuria, a known cardiovascular risk factor, with the possible exception of late conversion in patients with poor renal function. Interestingly, m-TOR inhibitors may also exert cardioprotective effects. Animal data suggest that m-TORs may restrict the pathogenesis of atherosclerosis, consistent with preliminary clinical data that conversion from CNIs to everolimus can stabilize markers for arterial stiffness. In conclusion, use of m-TORs has the potential to lessen the toll of cardiovascular disease following kidney transplantation - an opportunity that merits further exploration.

Immunosuppressive Strategies to Improve Outcomes of Kidney Transplantation

The introduction of several immunosuppressive agents over the past decade has reduced the rate of acute rejection significantly and has improved short-term renal allograft survival. However, their impact on long-term outcomes remains unclear. Current immunosuppressive strategies are focused on improving long-term graft and patient survival along with maintaining allograft function. The approval of the new immunosuppressive agents: rabbit antithymocyte globulin, basiliximab, daclizumab, tacrolimus, mycophenolate, and sirolimus, also has facilitated the development of steroid- and calcineurin inhibitor-sparing regimens in kidney transplantation. We discuss the impact of various immunosuppressive regimens on the outcome measures of kidney transplantation: acute rejection episodes, allograft survival, and renal function.

Basiliximab: a review of its use as induction therapy in renal transplantation.

Basiliximab (Simulect), a chimeric (human/murine) monoclonal antibody, is indicated for the prevention of acute organ rejection in adult and paediatric renal transplant recipients in combination with other immunosuppressive agents. Basiliximab significantly reduced acute rejection compared with placebo in renal transplant recipients receiving dual- (cyclosporin microemulsion and corticosteroids) or triple-immunotherapy (azathioprine- or mycophenolate mofetil-based); graft and patient survival rates at 12 months were similar. Significantly more basiliximab than placebo recipients were free from the combined endpoint of death, graft loss or acute rejection 3 years, but not 5 years, after transplantation. The incidence of adverse events was similar in basiliximab and placebo recipients, with no increase in the incidence of infection, including cytomegalovirus (CMV) infection. Malignancies or post-transplant lymphoproliferative disorders after treatment with basiliximab were rare, with a similar incidence to that seen with placebo at 12 months or 5 years post-transplantation. Rare cases of hypersensitivity reactions to basiliximab have been reported. The efficacy of basiliximab was similar to that of equine antithymocyte globulin (ATG) and daclizumab, and similar to or greater than that of muromonab CD3. Basiliximab was as effective as rabbit antithymocyte globulin (RATG) in patients at relatively low risk of acute rejection, but less effective in high-risk patients. Numerically or significantly fewer patients receiving basiliximab experienced adverse events considered to be related to the study drug than ATG or RATG recipients. The incidence of infection, including CMV infection, was similar with basiliximab and ATG or RATG. Basiliximab plus baseline immunosuppression resulted in no significant differences in acute rejection rates compared with baseline immunosuppression with or without ATG or antilymphocyte globulin in retrospective analyses conducted for small numbers of paediatric patients. Limited data from paediatric renal transplant recipients suggest a similar tolerability profile to that in adults. Basiliximab appears to allow the withdrawal of corticosteroids or the use of corticosteroid-free or calcineurin inhibitor-sparing regimens in renal transplant recipients. Basiliximab did not increase the overall costs of therapy in pharmacoeconomic studies. Basiliximab reduces acute rejection without increasing the incidence of adverse events, including infection and malignancy, in renal transplant recipients when combined with standard dual- or triple-immunotherapy. The overall incidence of death, graft loss or acute rejection was significantly reduced at 3 years; there was no significant difference for this endpoint 5 years after transplantation. Malignancy was not increased at 5 years. The overall efficacy, tolerability, ease of administration and cost effectiveness of basiliximab make it an attractive option for the prophylaxis of acute renal transplant rejection.

Safety and efficacy of TOR inhibitors in pediatric renal transplant recipients

Information about the pharmacokinetics, safety, and efficacy of target of rapamycin (TOR) inhibitors, such as sirolimus and everolimus, in pediatric renal transplant recipients is limited. In an ascending single-dose pharmacokinetic study of sirolimus in pediatric dialysis patients, no clinically significant association was observed between patient age and absorption of sirolimus from the gastrointestinal tract. However, young pediatric patients (5 to 11 years of age) exhibited significantly greater apparent oral clearances, suggesting that pediatric patients require slightly higher doses than do adults when adjusted for body weight or surface area. Similarly, in studies performed in pediatric renal transplant recipients, the half-life of sirolimus was shorter and the clearance was greater in younger patients. On the other hand, in single-dose pharmacokinetic studies of everolimus, the apparent clearance was reduced in pediatric renal transplant recipients compared with clearance in adults. This reduced clearance was attributed to a smaller apparent volume of distribution in pediatric patients, rather than to a difference in terminal half-life. This suggested that, although the adult 12-hour dosing interval was appropriate for pediatric patients, they would require reduced dosing based on body size compared with adults. In a large trial (N = 719) of sirolimus versus azathioprine in combination with cyclosporine microemulsion and prednisone, 6 pediatric patients (13 to 18 years of age) received sirolimus at 2 mg/d, 3 received sirolimus at 5 mg/d, and 3 received azathioprine. Seven of the nine patients who received sirolimus experienced no rejection episodes. Six infectious episodes occurred in the 6 patients receiving sirolimus at 2 mg/d, 10 episodes occurred in the 3 patients receiving sirolimus at 5 mg/d, and 8 episodes occurred in the 3 patients receiving azathioprine. At 6 months after transplantation, renal function was similar in all 3 groups, although there was a statistically nonsignificant increase in the group receiving sirolimus at 5 mg/d. The mean cholesterol and triglyceride levels were generally comparable in all 3 groups. TOR inhibitors are promising agents for the prevention of graft rejection in pediatric renal transplant recipients, but more pharmacokinetic data are required to assess the optimal dosing regimens in this population. In addition, further data are needed on the efficacy and safety of TOR inhibitors in combination with other agents in pediatric transplantation recipients to best assess the role of TOR inhibition in corticosteroid and/or calcineurin inhibitor-sparing regimens. © 2001 by the National Kidney Foundation, Inc.