Reduced-exposure Cyclosporine Research Articles

SP732Introduction of everolimus with reduced exposure cyclosporine is associated with graft function improvement in kidney transplant recipients with BKV associated nephropathy

SP732Introduction of everolimus with reduced exposure cyclosporine is associated with graft function improvement in kidney transplant recipients with BKV associated nephropathy

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.

Efficacy of everolimus with reduced-exposure cyclosporine in de novo kidney transplant patients at increased risk for efficacy events: analysis of a randomized trial.

The efficacy of de novo everolimus with reduced-exposure calcineurin inhibitor (CNI) was examined in kidney transplant subpopulations from the A2309 study that were identified to be at increased risk for efficacy events. A2309 was a 24-month, multicenter, open-label trial in which 833 de novo kidney transplant recipients were randomized to everolimus targeting 3-8 or 6-12 ng/ml with reduced-exposure cyclosporine (CsA), or mycophenolic acid (MPA) with standard-exposure CsA, all with basiliximab induction. The composite efficacy endpoint was treated biopsy-proven acute rejection (BPAR), graft loss, death, or loss to follow-up. Cox proportional hazard modeling showed male gender, younger recipient age, black race, delayed graft function, human leukocyte antigen (HLA) mismatch ≥3 and increasing donor age to be significantly predictive for the composite efficacy endpoint at months 12 or 24 post-transplant. CsA exposure was 53-75 % lower, and 46-75 % lower, in patients receiving everolimus 3-8 ng/ml or receiving everolimus 6-12 ng/ml, respectively, versus MPA-treated patients. The incidence of the composite endpoint was similar in all three treatment groups within each subpopulation analyzed. The incidence of treated BPAR was similar with everolimus 3-8 ng/ml or MPA in all subpopulations, but less frequent with everolimus 6-12 ng/ml versus MPA in patients with HLA mismatch ≥3 (p = 0.049). This post hoc analysis of a large, randomized trial suggests that a de novo regimen of everolimus with reduced-exposure CsA maintains immunosuppressive efficacy even in kidney transplant patients at increased risk for efficacy events despite substantial reductions in CsA exposure.

Фармакоэкономическое исследование применения эверолимуса для иммуносупрессивной терапии после пересадки почки

Objective: to calculate cost difference between two approaches for immunosuppressive therapy after renal transplantation: everolimus plus reducedexposure cyclosporine and mycophenolic acid plus standard-exposure cyclosporine. Methods. We calculated the two-year difference in costs that resulted from effectiveness and safety differences of alternatives employing the probability-statistical model. Data on safety and efficiency were taken from D. Cibrik et al. (2013) randomized control trial. We also estimated the budget impact for everolimus inclusion into 7 expensive diseases program (7EDP). 7 EDP is the special federal program of drug provision for patients suffering from 7 certain diseases and health states including organ posttransplantation period. Results. Everolimus plus reduced-exposure cyclosporine leads to cost reduction by 161 RUB thousands (17%) per patient in a two-year period. The reduction mainly results from cheaper medication in everolimus plus reduced-exposure cyclosporine approach compared to mycophenolic acid plus standard-exposure cyclosporine. Everolimus inclusion into 7 expensive diseases program leads to reduction in federal budget spending starting from the first year; the total five-year budget savings are 275 RUB millions.

Safety and efficacy of the early introduction of everolimus with reduced-exposure cyclosporine a in de novo kidney recipients.

Everolimus and cyclosporine A (CsA) exhibit synergistic immunosuppressive activity when used in combination. We examined the safety and efficacy of the use of everolimus with a cyclosporine-sparing strategy in de novo renal transplant recipients. A comparative, parallel, randomized, open-label 1-year study has been performed in 148 patients from five transplant centers to compare the efficacy and tolerability of everolimus and reduced exposure CsA (the investigational group) or enteric-coated mycophenolate sodium and standard-exposure CsA (the control group) in combination with basiliximab and steroids. The eligible subjects were randomly assigned at 1 month after transplantation. Efficacy failure (biopsy-proven acute rejection, death, graft loss, or loss to follow-up), safety, and renal function were evaluated. One graft loss has been reported in the control group and no patient death were reported in either group. The incidence of biopsy-proven acute rejection until 12 months after transplantation of the investigational group was 7.5%, compared to 11.1% of the control group (P=0.565). The mean estimated glomerular filtration rates of the investigational group at 12 months after transplantation was significantly higher (68.1 ± 16.8 ml/min/1.73 m(2)) than that of the control group (60.6 ± 15.8 ml/min/1.73 m(2); P=0.016). There was no significant difference (P>0.05) in the incidence of discontinuations and serious adverse events between the groups. The results of this study provide the evidences that (1) the calcineurin inhibitor (CNI) minimization by the introduction of everolimus after 1-month posttransplantation keeps the incidences of acute rejection and additional risks as low as the conventional immunosuppression; (2) it allows minimizing CNI exposure, consequently reducing CNI nephrotoxicity and preserving renal function.

Everolimus Initiation and Early Calcineurin Inhibitor Withdrawal in Heart Transplant Recipients: A Randomized Trial

In a randomized, open-label trial, everolimus was compared to cyclosporine in 115 de novo heart transplant recipients. Patients were assigned within 5 days posttransplant to low-exposure everolimus (3–6 ng/mL) with reduced-exposure cyclosporine (n = 56), or standard-exposure cyclosporine (n = 59), with both mycophenolate mofetil and corticosteroids. In the everolimus group, cyclosporine was withdrawn after 7–11 weeks and everolimus exposure increased (6–10 ng/mL). The primary efficacy end point, measured GFR at 12 months posttransplant, was significantly higher with everolimus versus cyclosporine (mean ± SD: 79.8 ± 17.7 mL/min/1.73 m2 vs. 61.5 ± 19.6 mL/min/1.73 m2; p < 0.001). Coronary intravascular ultrasound showed that the mean increase in maximal intimal thickness was smaller (0.03 mm [95% CI 0.01, 0.05 mm] vs. 0.08 mm [95% CI 0.05, 0.12 mm], p = 0.03), and the incidence of cardiac allograft vasculopathy (CAV) was lower (50.0% vs. 64.6%, p = 0.003), with everolimus versus cyclosporine at month 12. Biopsy-proven acute rejection after weeks 7–11 was more frequent with everolimus (p = 0.03). Left ventricular function was not inferior with everolimus versus cyclosporine. Cytomegalovirus infection was less common with everolimus (5.4% vs. 30.5%, p < 0.001); the incidence of bacterial infection was similar. In conclusion, everolimus-based immunosuppression with early elimination of cyclosporine markedly improved renal function after heart transplantation. Since postoperative safety was not jeopardized and development of CAV was attenuated, this strategy may benefit long-term outcome.

Proteinuria and Histopathological Change of Everolimus Based Immunosuppression On De Novo Kidney Transplantation With 5 Years Follow-Up in Protocol Biopsies.

Purpose: The impact of everolimus (EVR) based immunosuppression in De Novo Kidney Transplantation was evaluated in safety profile, focusing proteinuria and histopathological change through the protocol biopsy findings compared with mycophenolate mofetile (MMF) based immunosuppression. Method: During March 2008 and August 2009, we enrolled 24 living donor kidney transplant patients in a 2-year, multicenter, randomized phase 3 study (RAD001A1202 study) to compare the safety and efficacy with protocol biopsy data between EVR based and MMF based immunosuppression. We extended further 3 years and evaluated clinical outcome in a single center. EVR group received reduced-exposure cyclosporine (target C0 25-50ng/ml after 6 months), and EVR-C0 were adjusted 3-8ng/ml. MMF group received standard-exposure cyclosporine (target C0 100-250ng/ml). Both group received basiliximab induction. We evaluated in safety profile, focusing proteinuria and histopathological change through the protocol biopsy findings. Protocol biopsies were performed at 1hour, 3 weeks, 6 months and 12 months after transplantation. Result: All patients continued in each regimen. With a mean observation period of 60.1 months, current patient and graft survival is 100% in both groups (EVR; n=13, MMF; n=11). eGFR (ml/min/1.73m2) was similar 40.7 in EVR group and 37.4 in MMF group. None of both groups was treated for clinical acute rejection, similar incidence of Banff borderline change on protocol biopsies were observed in 7.7% of EVR group and 18.2% of MMF group. Calcineurin inhibitor nephrotoxicity was observed less in EVR group (7.7%) than in MMF group (27.3%) in biopsies over 12 months. Proteinuria were observed more in EVR group (76.9%) than in MMF group (54.5%) respectively. There were two patients whose proteinuria developed over 2g/day at 12 months or later in EVR group. We could not find any particular glomerular lesion in the biopsies, however neovascular hyalinosis at glomerular vascular pole was noticeable. The proteinuria in EVR group was successfully treated with angiotensin-II receptor blockade. Conclusion: EVR based immunosuppression does not provide particular histological change at the glomerular level even though proteinuria was observed.

Efficacy and Safety of Everolimus Based Immunosuppression On De Novo Kidney Transplantation With 5 Years Follow-Up Especially in Protocol Biopsy Findings and Donor Specific Antibody Production.

Purpose: The impact of everolimus (EVR) based immunosuppression in De Novo Kidney Transplantation was evaluated in clinical outcomes, protocol biopsies findings and donor specific antibody (DSA) production.Methods: During 2008 and August 2009, we enrolled twenty-four living donor kidney transplant patients in a 2-year, multicenter, randomized phase 3 study (RAD001A1202 study) to compare the safety and efficacy between EVR based and mycophenolate mofetile (MMF) based immunosuppression. We extended further three years and evaluated clinical outcome in a single center.EVR group received reduced-exposure cyclosporine (target C0 25-50ng/ml after 6 months) + steroid, and EVR-C0 were adjusted 3-8ng/ml. MMF group received standard-exposure cyclosporine (target C0 100-250ng/ml after 6 months) + steroid. Both group received basiliximab induction.Results: All patients continued in each regimen. With a mean observation period of 60.1 (43.8-69.4) months, current patient and graft survival is 100% in both groups (EVR; n=13, MMF; n=11). Renal function expressed as eGFR (ml/min/1.73m2) was similar 40.7±14.6 in EVR group and 37.4±8.6 in MMF group. Significant proteinuria, more than 300mg/day, were observed more in EVR group (76.9%) than in MMF group (54.5%), however the proteinuria in EVR group was successfully treated with angiotensin-II receptor blockade. None of EVR and MMF group was treated for clinical T cell mediated rejection, similar incidence of Banff borderline change on 6 or 12 months protocol biopsies were observed in 7.7% of EVR group and 18.2% of MMF group, but none of both groups revealed peritubular capillaritis. Luminex solid phase assay revealed the similar incidence of class II DSA production in both groups, 7.7% of EVR group at 2 years after transplant and 15.4% of MMF group at 3 years. Protocol oral glucose tolerance test at 6 and 12 months revealed more, but no significantly, worsen profile in 46.1% of EVR group to 18.2% in MMF group.Conclusions: EVR based immunosuppression provides equivalent clinical outcomes as well as the incidence of De Novo DSA production with MMF based immunosuppression with 5 years follow-up.

Efficacy and safety of concentration-controlled everolimus with reduced-dose cyclosporine in Japanese de novo renal transplant patients: 12-month results

BackgroundNo study to date has evaluated the efficacy and safety of everolimus with reduced-exposure cyclosporine in Japanese de-novo renal transplant (RTx) patients.MethodsThis 12-month, multicenter, open-label study randomized (1:1) 122 Japanese de-novo RTx patients to either an everolimus regimen (1.5 mg/day starting dose (target trough: 3 to 8 ng/ml) + reduced-dose cyclosporine) or a mycophenolate mofetil (MMF) regimen (2 g/day + standard dose cyclosporine). All patients received basiliximab and corticosteroids. Key endpoints at month 12 were composite efficacy failure (treated biopsy-proven acute rejection, graft loss, death, or loss to follow-up) and renal function (estimated glomerular filtration rate; Modification of Diet in Renal Disease-4).ResultsClear cyclosporine exposure reduction was achieved in the everolimus group throughout the study (52% reduction at month 12). Month 12 efficacy failure rates showed everolimus 1.5 mg to be non-inferior to MMF (11.5% vs. 11.5%). The median estimated glomerular filtration rate at month 12 was 58.00 ml/minute/1.73 m2 in the everolimus group versus 55.25 ml/minute/1.73 m2 in the MMF group (P = 0.063). Overall, the incidence of adverse events was comparable between the groups with some differences in line with the known safety profile of the treatments. The everolimus group had a higher incidence of wound healing events and edema, whereas a higher rate of cytomegalovirus infections was reported in the MMF group.ConclusionsThis study confirmed the efficacy of everolimus 1.5 mg/day (target trough: 3 to 8 ng/ml) in Japanese RTx patients for preventing acute rejection, while allowing for substantial cyclosporine sparing. Renal function and safety findings were comparable with previous reports from other RTx populations.Trial registrationClinicalTrials.gov number: NCT00658320

Randomized Trial of Everolimus-Facilitated Calcineurin Inhibitor Minimization Over 24 Months in Renal Transplantation

Strategies allowing calcineurin inhibitor minimization while maintaining efficacy may improve renal transplant outcomes. A2309 was a 24-month, phase IIIb, open-label trial of 833 de novo renal transplant recipients randomized to everolimus, targeting trough concentrations of 3-8 or 6-12 ng/mL plus reduced-exposure cyclosporine A (CsA) or to mycophenolic acid (MPA) 1.44 g per day plus standard-exposure CsA. All patients received basiliximab ± corticosteroids. The incidence of the primary composite efficacy endpoint and its components (treated biopsy-proven acute rejection, graft loss, death, or loss to follow-up), renal function (serum creatinine and estimated glomerular filtration rate), and adverse events (AEs) were compared at 24 months; as per the protocol, these analyses were not noninferiority. Composite efficacy failure rates (95% confidence interval for difference vs. MPA) were 32.9% (-2.2%, 13.0%), 26.9% (-7.9%, 6.8%), and 27.4% at month 24 in the everolimus 3-8 and 6-12 ng/mL and MPA groups, respectively. Mean estimated glomerular filtration rate (Modification of Diet in Renal Disease) at month 24 was 52.2 (-2.1, 5.5 mL/min/1.73 m(2)), 49.4 (-4.8, 2.7 mL/min/1.73 m(2)), and 50.5 mL/min/1.73 m(2), respectively. AEs were generally mild to moderate in severity and comparable between the groups. AEs leading to discontinuation were reported in 28.5% (P = 0.03 vs. MPA), 30.6% (P = 0.007 vs. MPA), and 20.5% of patients receiving everolimus 3-8 and 6-12 ng/mL and MPA, respectively. Everolimus trough concentrations targeted to 3-8 ng/mL, along with a greater than 60% reduction in CsA exposure, was associated with comparable efficacy and renal function versus MPA plus standard-exposure CsA over the 2-year period. A significantly higher incidence of AEs led to discontinuation in the everolimus groups compared with the MPA group.

Association of clinical events with everolimus exposure in kidney transplant patients receiving reduced cyclosporine

The association between clinical events and everolimus exposure in patients receiving reduced-exposure calcineurin inhibitor therapy is poorly explored. In a pre-planned, descriptive analysis of data from a randomized controlled trial, events were correlated with everolimus trough concentrations in 556 newly transplanted kidney transplant patients receiving everolimus with reduced-exposure cyclosporine (CsA) and steroids. Influence of everolimus exposure on clinical events was stratified according to predefined time-normalized concentrations. The incidence of treated biopsy-proven acute rejection and graft loss at month 12 was highest in patients with everolimus <3 ng/mL (36.4% and 28.6%, respectively, vs. 9.1-15.3% and 0.9-5.0% with higher concentration ranges). A higher mortality rate was observed in patients with an everolimus trough concentration ≥ 12 ng/mL (10.0% vs. 1.7-5.6% with lower concentration ranges). The lowest rates of renal dysfunction (defined as poor renal function [estimated GFR, serum creatinine] or proteinuria), wound healing events, peripheral edema, new-onset diabetes mellitus, hypercholesterolemia and hypertriglyceridemia were generally observed with everolimus trough concentration in the range 3-8 ng/mL and CsA <100 ng/mL. Proteinuria occurred most frequently in patients with very low or very high everolimus trough concentrations. These results support an exposure-response relationship between clinical events and everolimus trough concentrations in kidney transplant patients receiving reduced-exposure CsA.

Effect of Everolimus on Left Ventricular Hypertrophy of De Novo Kidney Transplant Recipients

Although conversion from calcineurin inhibitors to mammalian target of rapamycin inhibitors proved to be effective in regressing left ventricular hypertrophy (LVH) in renal transplant recipients (RTRs) with chronic allograft dysfunction, there are currently no reports of randomized trials on this issue involving de novo RTRs administered everolimus (EVL). This randomized, open-label, controlled trial evaluated the effect of EVL on the left ventricular mass index (LVMi) of 30 nondiabetic RTRs (21 men; age 28-65 years). Ten were allocated to EVL plus reduced-exposure cyclosporine A (CsA), and 20 to standard dose CsA. LVMi was assessed by echocardiography both at baseline and 1 year later. Blood pressure (BP), hemoglobin, serum creatinine, lipids, trough levels of immunosuppressive drugs, and daily proteinuria were also evaluated twice monthly. Antihypertensive therapy that did not include renin-angiotensin system blockers was administered to achieve BP less than or equal to 130/80 mm Hg. Changes in BP were similar in the two groups (between group difference 1.2 ± 5.7 mm Hg, P=0.84 for systolic, and -1.5 ± 3.7, P=0.69, for diastolic BP), whereas LVMi significantly decreased in the EVL group alone (between group difference 9.2 ± 3.1 g/m(2.7), P=0.005), due to a reduction in both the interventricular septum and the left ventricular posterior wall thickness. EVL therapy together with baseline LVMi were the only significant predictors of LVH regression according to a multivariate model that explained 49% of the total LVMi variance (P=0.0015). An immunosuppressive regimen consisting of EVL plus reduced exposure CsA proved to be effective in regressing LVH in RTRs regardless of BP, mainly by reducing left ventricular wall thickness.

Efficacy and Safety of Low-Dose Cyclosporine with Everolimus and Steroids inde novoHeart Transplant Patients: A Multicentre, Randomized Trial

A six-month, multicenter, randomized, open-label study was undertaken to determine whether renal function is improved using reduced-exposure cyclosporine (CsA) versus standard-exposure CsA in 199 de novo heart transplant patients receiving everolimus and steroids ± induction therapy. Mean C2 levels were at the low end of the target range in standard-exposure patients (n = 100) and exceeded target range in reduced-exposure patients (n = 99) throughout the study. Mean serum creatinine at Month 6 (the primary endpoint) was 141.0 ± 53.1 μmol/L in standard-exposure patients versus 130.1 ± 53.7 μmol/L in reduced-exposure patients (P = 0.093). The incidence of biopsy-proven acute rejection ≥3A at Month 6 was 21.0% (21/100) in the standard-exposure group and 16.2% (16/99) in the reduced-exposure group (n.s.). Adverse events and infections were similar between treatment groups. Thus, everolimus with reduced-exposure CsA resulted in comparable efficacy compared to standard-exposure CsA. No renal function benefits were demonstrated; that is possibly related to poor adherence to reduced CsA exposure.

15: Results of a 12-Month, Multicenter, Randomized Trial of Everolimus with Reduced-Exposure Cyclosporine Versus MMF and Standard-Exposure Cyclosporine in De Novo Cardiac Transplant Recipients

15: Results of a 12-Month, Multicenter, Randomized Trial of Everolimus with Reduced-Exposure Cyclosporine Versus MMF and Standard-Exposure Cyclosporine in De Novo Cardiac Transplant Recipients

Reduced-exposure cyclosporine is safe and efficacious in de novo renal transplant recipients treated with enteric-coated mycophenolic acid and basiliximab

The lower limit of exposure to calcineurin inhibitors has not yet been established in de novo renal transplant patients receiving mycophenolic acid therapy with basiliximab. A 12-month, multicenter, randomized, open-label trial was carried out in which de novo renal transplant patients received enteric-coated mycophenolate sodium, cyclosporine microemulsion, steroids and basiliximab. Patients were randomized to receive standard-exposure (n = 45) or reduced-exposure (n = 44) cyclosporine, based on differing C2 target ranges, after the first month post-transplant. Cyclosporine exposure gradually increased over the first month and was lower than previously recommended. Mean calculated creatinine clearance (primary end-point) was similar in the standard-exposure and reduced-exposure groups at month 6 (55.3+/-3.2 ml/min and 61.5+/-3.7 ml/min respectively, n.s.). There were 4 deaths but no death-censored graft losses, resulting in 95.5% patient and graft survival at one year in both groups. At 6 and 12 months, the incidence of biopsy-proven acute rejection was 17.8% and 17.8% in the standard-exposure group, and 13.6% and 15.9% in the reduced-exposure group. Adverse events were similar between treatment groups. Exploratory analyses could not identify a lower limit for the optimal CsA exposure range, but results suggested that high exposure at one year was associated with deteriorating renal function. These results indicate that enteric-coated mycophenolate sodium with reduced-exposure cyclosporine, steroids and basiliximab induction has an excellent therapeutic effect and is safe in de novo kidney transplant recipients. Lower C2 targets than previously recommended, particularly early post-transplant, do not appear to be associated with compromised efficacy.

12-month safety and efficacy of everolimus with reduced exposure cyclosporine in de novo renal transplant recipients

The proliferation signal inhibitor everolimus (Certican), has demonstrated efficacy with full-dose cyclosporine (CsA) (Neoral). Two multicenter randomized controlled studies were performed to compare 12-month efficacy and safety of everolimus 1.5 and 3.0 mg/day with reduced-dose CsA. Study 1 enrolled 237 de novo renal allograft recipients, randomizing 222 nonblack patients to either everolimus 1.5 or 3.0 mg/day, with the Neoral) dose guided by C(2) (monitoring of CsA concentration 2 h after dosing). Study 2 had a similar protocol, with basiliximab included, enrolling 256 recipients and randomizing 243 nonblack patients. In Study 1, there was a lower incidence of acute rejection in nonblack patients on 3 mg/day (16.4%) compared with 1.5 mg/day (25.9%), P = 0.08. In Study 2, the inclusion of basiliximab lowered the overall incidence of acute rejection; 14.3% of nonblack patients (3 mg/day) and 13.6% of nonblack patients (1.5 mg/day) had acute rejection by 12 months (P =0.891). Renal function was preserved throughout the study, with no differences observed between groups within studies. Everolimus was well tolerated with no significant differences between doses. Everolimus, in combination with reduced-dose Neoral), demonstrated efficacy and was well tolerated. Basiliximab allows for utilization of lower doses of everolimus with reduced dosing of Neoral).

Clinical Experience with Everolimus (Certican) in Elderly Recipients: The ???Old-for-Old??? Concept

With an increasing number of elderly patients now waiting for a kidney transplant, and the percentage of kidney donors over 55 years also rising, harvesting older kidneys specifically for use in older recipients is a way of extending the donor pool for renal transplantation. Two case studies from an everolimus (Certican) Phase III trial (A2306) are presented. They illustrate clinical experience of achieving stable graft function in the "old-for-old" kidney transplant program at the Ramon y Cajal Hospital in Madrid, Spain. The first case study demonstrates that stable graft function can be achieved in an "old-for-old" kidney transplant patient, who receives everolimus in combination with reduced-exposure cyclosporine (CsA). To optimize graft function in the long-term, CsA C(2) blood levels should be <400 ng/ml. The second case study highlights how "old-for-old" renal transplant recipients can be at risk of calcineurin-inhibitor (CNI)-induced nephrotoxicity. Here, graft function did not improve following CsA dose reduction; thus, CsA was withdrawn 1 year posttransplant. Stable graft function that is acceptable for an "old-for-old" kidney transplant was then achieved with everolimus trough blood levels of 10-15 ng/ml and low-dose prednisone. In these cases, everolimus was used safely and effectively in the "old-for-old" kidney transplant setting. Its combination with reduced-exposure CsA, or its facilitation of CsA withdrawal, minimized the risk of nephrotoxicity in the older renal graft. These findings need to be confirmed in larger studies specific to this population.

Clinical Experience with Everolimus (Certican) in Young Renal Transplant Recipients

Young transplant recipients benefit most from graft longevity, but are at high risk of rejection. Thus, in young recipients, the challenge is provision of effective immunosuppression resulting in good renal function while minimizing the toxicities of immunosuppressant therapy. The following two case studies describe the clinical experience of achieving stable graft function in two young female transplant recipients of older living donor kidneys. As part of an ongoing clinical trial (A2307), immunosuppressant therapy consisted of everolimus (Certican) in combination with reduced-exposure cyclosporine (CsA) and prednisone. The two case studies demonstrate that rejection can be prevented and good, stable renal graft function achieved with everolimus 0.75-1.5 mg bid (long-term everolimus blood trough levels: 2.3-6.5 ng/ml in Case 1 and 3.8-9.3 ng/ml in Case 2) plus reduced-exposure CsA. CsA was reduced from an initial dose of 100 mg bid (C2 target levels of 500-700 ng/ml) to 75 mg and 35 mg bid in the two cases, respectively, in order to reach maintenance C2 target levels of 230-450 ng/ml. Maintenance prednisone dose was low in both cases (7-7.5 mg/day). Both patients tolerated the immunosuppressant regime well, and at 31-33 months follow-up they remained free of acute rejection episodes and toxicities associated with CsA. Everolimus plus reduced-dose CsA can provide safe, adequate immunosuppression resulting in prevention of acute rejection in young recipients. Reducing CsA exposure minimizes risk of nephrotoxicity and other adverse events that affect compliance in these patients for whom long-term graft survival is vital.

Clinical Experience with Everolimus (Certican): Optimizing Dose and Tolerability

Everolimus (Certican), a novel proliferation signal inhibitor, allows calcineurin inhibitor dose reduction in transplant patients, minimizing risk of nephrotoxicity without loss of immunosuppressive efficacy. As a result of its mode of action, this class of agent (i.e., everolimus and sirolimus) is associated with certain adverse events (e.g., lymphocele, arthralgia, edema and hyperlipidemia). Three case studies from within an everolimus Phase III trial (A2306) are presented with the aim of illustrating how treatment-related adverse events can be managed. The combination of everolimus with reduced-exposure cyclosporine was efficacious in these patients. One experienced mild acute rejection that was managed with steroid boluses. All have acceptable graft function during follow-up to date. Moderate lymphocele either resolved spontaneously or was easily managed by povidine-iodine instillations. One patient developed serious early lymphocele that, unusually, required surgical intervention. Everolimus dose reduction or withdrawal was not necessary to effectively manage lymphocele of any severity. A case of bilateral multiple arthralgia was effectively managed with everolimus dose reduction, but still maintained everolimus trough blood levels at approximately 3 ng/ml. Eyelid and ankle edemas were also easily managed with low dose furosemide, preferably coupled with cyclosporine and everolimus dose reduction. Hyperlipidemia responded to statin therapy. Everolimus-related adverse events can be effectively managed either with other treatments or, where necessary, by everolimus dose reduction, without loss of efficacy. Discontinuing everolimus therapy is generally not necessary.

Improving outcomes in heart transplantation: The potential of proliferation signal inhibitors

Graft failure and mortality among heart transplant recipients remains higher than in populations receiving renal transplants. A major cause of graft loss is cardiac allograft vasculopathy (CAV), a condition characterized by diffuse thickening of coronary blood vessels. CAV often progresses silently, with major cardiac events (eg, ventricular arrhythmia) being the first presentation. Better diagnosis and monitoring of CAV is now possible with intravascular ultrasonography, a sensitive technique for measuring intimal thickness. To date, immunosuppressants have shown little efficacy for preventing CAV. However, a new class of agents, proliferation signal inhibitors (sirolimus and everolimus), have shown considerable efficacy in this regard and for preventing rejection. In an open-label trial, sirolimus therapy was associated with less intimal and medial proliferation than azathioprine. More robust evidence is available from a larger-scale, double-blind trial involving everolimus. At 12-month follow-up the incidence of CAV was significantly lower in patients receiving everolimus (35.7% and 30.4% for everolimus 1.5 and 3.0 mg/d vs 52.8% for azathioprine; P < .05). Sirolimus and everolimus were also associated with a lower rate of cytomegalovirus infection. As with other immunosuppressants, these agents are associated with adverse events (eg, hyperlipidemia), but they can be managed. Coadministration with calcineurin inhibitors (CNIs) can exacerbate CNI-related nephrotoxicity, but evidence suggests that everolimus administered with reduced-exposure cyclosporine in the maintenance phase preserves renal function without loss of immunosuppressive efficacy. Reduced CNI dosing in de novo patients is also a potential future benefit. Proliferation signal inhibitors have considerable potential for improving outcomes in heart transplantation.