Everolimus plus early tacrolimus minimization: a phase III, randomized, open-label, multicentre trial in renal transplantation.

There is increasing interest in tacrolimus-minimization regimens. ASSET was an open-label, randomized, 12-month study of everolimus plus tacrolimus in de-novo renal-transplant recipients. Everolimus trough targets were 3-8 ng/ml throughout the study. Tacrolimus trough targets were 4-7 ng/ml during the first 3 months and 1.5-3 ng/ml (n = 107) or 4-7 ng/ml (n = 117) from Month 4. All patients received basiliximab induction and corticosteroids. The primary objective was to demonstrate superior estimated glomerular filtration rate (eGFR; MDRD-4) at Month 12 in the tacrolimus 1.5-3 ng/ml versus the 4-7 ng/ml group. Secondary endpoints included incidence of biopsy-proven acute rejection (BPAR; Months 4-12) and serious adverse events (SAEs; Months 0-12). Statistical significance was not achieved for the primary endpoint (mean eGFR: 57.1 vs. 51.7 ml/min/1.73 m(2)), potentially due to overlapping of achieved tacrolimus exposure levels (Month 12 mean ± SD, tacrolimus 1.5-3 ng/ml: 3.4 ± 1.4; tacrolimus 4-7 ng/ml: 5.5 ± 2.0 ng/ml). BPAR (months 4-12) and SAE rates were comparable between groups (2.7% vs. 1.1% and 58.7% vs. 51.3%; respectively). Everolimus-facilitated tacrolimus minimization, to levels lower than previously investigated, achieved good renal function, low BPAR and graft-loss rates, and an acceptable safety profile in renal transplantation over 12 months although statistically superior renal function of the 1.5-3 ng/ml tacrolimus group was not achieved.

Conversion of long-term kidney transplant recipients from calcineurin inhibitor therapy to everolimus: a randomized, multicenter, 24-month study.

BACKGROUND: Benefits of conversion from calcineurin inhibitor (CNI) to mammalian target of rapamycin inhibitor-based immunosuppression in long-term kidney transplant patients remain uncertain. METHODS: ASCERTAIN was a 24-month, open-label, multicenter study. Kidney transplant patients more than 6 months posttransplant receiving CNI (baseline glomerular filtration rate [GFR] 30-70 mL/min/1.73 m) were randomized to everolimus with CNI elimination (n=127) or CNI minimization (n=144), or continued CNI unchanged (controls, n=123) to assess the effect on measured GFR at month 24 after randomization. RESULTS: Renal function was stable in all groups to month 24. Mean measured GFR at month 24, the primary endpoint, was 48.0±22.0 mL/min/1.73 m, 46.6±21.1 mL/min/1.73 m, and 46.0±20.4 mL/min/1.73 m in the CNI elimination, CNI minimization, and control groups, respectively. Differences between CNI elimination (1.12 mL/min/1.73 m, 95% confidence interval [CI] -3.51 to 5.76, P=0.63) and CNI minimization (0.59 mL/min/1.73 m, 95% CI -3.88 to 5.07, P=0.79) versus controls at month 24 were nonsignificant that is, the primary endpoint was not met. No efficacy endpoint differed significantly between groups. Post hoc analyses showed that patients with baseline creatinine clearance (CrCl) more than 50 mL/min had a significantly greater increase in measured GFR after CNI elimination versus controls (difference 11.4 mL/min/1.73 m, 95% CI 2.1 to 20.8 mL/min/1.73 m, P=0.017). Adverse events resulted in discontinuation in 36 (28.3%) CNI elimination patients, 24 (16.7%) CNI minimization patients, and 5 (4.1%) controls (P<0.001 vs. CNI elimination; P=0.020 vs. CNI minimization). CONCLUSION: Conversion to everolimus with CNI elimination or minimization a mean of 5.6 years after kidney transplantation had no overall renal benefit and was associated with more frequent adverse events and discontinuations. Patients with CrCl more than 50 mL/min may benefit from a change in therapy more than 6 months after renal transplantation.

Multicenter, randomized study of the use of everolimus with tacrolimus after renal transplantation demonstrates its effectiveness.

BACKGROUND: Clinical data are lacking concerning concomitant administration of everolimus and tacrolimus in renal transplant recipients. METHODS: In a prospective, multicenter, open-label, exploratory, randomized, 6-month study, 92 de novo renal transplant patients received everolimus, steroids, and basiliximab with low or standard tacrolimus exposure. The primary objective was to compare renal function at 6 months after transplant. RESULTS: Mean 6-month serum creatinine (primary safety variable) was 112+/-31 micromol/L (1.26+/-0.35 mg/dL) and 127+/-50 micromol/L (1.44+/-0.57 mg/dL) in the low and standard tacrolimus groups, respectively, (n.s.); mean estimated GFR (Nankivell) was 75.3+/-16.6 mL/min and 72.5+/-15.2 mL/min (n.s.). Biopsy-proven acute rejection occurred in 13 patients: seven (14%) in the low tacrolimus group and six (14%) in the standard tacrolimus group, n.s. One graft was lost in the standard tacrolimus group. No patients died. CONCLUSIONS: Tacrolimus exposure reduction in the presence of everolimus, steroids and basiliximab induction results in good efficacy in de novo renal transplant recipients with very well-preserved renal function. Additional studies are warranted because between-group comparisons were limited by the relatively small differences in tacrolimus exposure in the 2 arms; trough levels were toward the upper end of the low-exposure ranges and toward the bottom of the standard-exposure ranges.

Renal function with cyclosporine C2 monitoring, enteric-coated mycophenolate sodium and basiliximab: a 12-month randomized trial in renal transplant recipients.

BACKGROUND: Cyclosporine exposure, as estimated by the area under the curve (AUC), predicts outcomes in renal transplantation. Cyclosporine concentration at two h post-dose (C(2)) has been shown to be the most reliable, single-point surrogate marker for AUC. The objective of this study was to measure renal function beyond month 2 post-transplant using two different C(2) maintenance targets in combination with enteric-coated mycophenolate sodium (EC-MPS), corticosteroids, and basiliximab induction. METHODS: In this open-label, multicenter trial, renal transplant recipients entered one of two randomized groups at day 61 post-transplant: group A (higher-C(2) range) or group B (lower-C(2) range). RESULTS: Patients (164) were recruited, and 141 patients were entered the randomized groups (group A, n = 66; group B, n = 75). At 12 months, the mean calculated creatinine clearance was significantly greater in group B than in group A (79.2 vs. 71.0 mL/min, p < 0.05). Biopsy-proven acute rejection occurred in 14.7% patients in group B and in 24.2% patients in group A (n.s.). During the 12-month trial, 17.7% patients discontinued EC-MPS because of adverse events. Group B (44.0%) had fewer serious adverse events when compared with group A (62.1%; p = 0.04). Overall patient and graft survival were 99.4% and 95.7% respectively. Among 99 high-risk patients (i.e., African-American race, previous transplant, PRA >35% or >4 HLA mismatches), mean creatinine clearance at 12 months was 65.6 mL/min and biopsy-proven rejection occurred in 20.2% patients. CONCLUSIONS: Low cyclosporine C(2) levels are associated with improved renal function compared with higher C(2) levels when used in conjunction with EC-MPS, steroids and basiliximab induction. EC-MPS with low cyclosporine C(2) levels, corticosteroids and basiliximab provides excellent renal function with good efficacy even in high-risk patients.

Everolimus treatment downregulates renocortical cyclooxygenase-2 expression in the rat kidney.

Based on recent evidence that renal cyclooxygenase-2 (COX-2) gene expression is suppressed by immunosuppressive agents such as cyclosporin A (CsA), tacrolimus and dexamethasone, this study aimed to characterize the effect of the new immunosuppressant everolimus on COX-2 expression in the rat kidney. Oral application of everolimus (3 mg kg(-1) day(-1)) to male Sprague-Dawley rats (175-200 g; n=8) for 7 days lowered COX-2 expression in the rat renal cortex and outer medulla, while COX-2 expression in the inner medulla as well as COX-1 expression remained unaltered. Furthermore, everolimus decreased renocortical prostaglandin (PG) E(2) concentration. Everolimus also attenuated the stimulation of renocortical COX-2 expression by furosemide (12 mg day(-1) for 7 days; s.c. via osmotic minipumps), by low salt intake (0.02% NaCl, wt wt(-1)) or by a combination of low salt intake with the AT(1)-receptor antagonist valsartan (30 mg kg(-1) day(-1); oral). In line with these findings, everolimus decreased renocortical PGE(2) concentration during these treatment maneuvers. Everolimus moderately increased natriuresis and diuresis, while the urinary excretion of PGE(2), 6-keto PGF(1alpha) and thromboxane B(2) was decreased. These findings suggest that everolimus inhibits basal and also stimulated expression of renocortical COX-2 and of tissue prostanoid formation. Since inhibition of renal prostanoid formation by everolimus was associated by an increased rather than decreased natriuresis and diuresis, it appears as if everolimus also inhibits tubular salt and water resorption.