This multicenter, 1:1‐randomized, parallel‐group, noninferiority study compared the efficacy and safety of twice‐daily tacrolimus (Tacrolimus BID; Prograf) and once‐daily tacrolimus prolonged release (Tacrolimus QD; Advagraf), combined with steroids and low‐dose mycophenolate mofetil without antibody induction, in 667 de novo kidney transplant recipients. A double‐blind, double‐dummy 24‐week period was followed by an open extension of up to 12 months posttransplant. Biopsy‐proven acute rejection rate at 24 weeks (primary endpoint, per‐protocol analysis) was 15.8% for Tacrolimus BID versus 20.4% for Tacrolimus QD (p = 0.182; treatment difference 4.5%, 95% confidence interval—1.8%, 10.9%, just outside the prespecified 10% noninferiority margin). Kaplan–Meier 12‐month patient and graft survival rates were 97.5% and 92.8% for Tacrolimus BID and 96.9% and 91.5% for QD. Both treatment groups showed equally well‐maintained renal function at 12 months (mean creatinine clearance approximately 67 mL/min) and similar adverse event profiles. Overall results obtained with either Tacrolimus QD or BID, without antibody induction, were good, supporting use of the once‐daily formulation as an effective alternative to the established twice‐daily formulation.

Background. Comparison studies of calcineurin inhibitors as cornerstone immunosuppressants in renal transplantation have demonstrated that tacrolimus consistently reduces acute rejection rates and, in some studies, also improves long-term renal outcome in comparison to cyclosporin A (CsA). The aim of the present 2 year follow-up of the European Tacrolimus vs Cyclosporin A Microemulsion Renal Transplantation Study was to investigate long-term clinical outcome in terms of rate of acute rejection, graft and patient survival and graft function. Methods. The European Tacrolimus vs Cyclosporin A Microemulsion Renal Transplantation Study was a randomized, comparative 6 month trial of the calcineurin inhibitors tacrolimus and CsA in combination with both azathioprine and steroids. The intent-to-treat population (ITT) consisted of 286 patients in the tacrolimus arm and 271 in the CsA microemulsion (CsA-ME) arm. Whereas whole blood level targets were 10–20 and 5–15 ng/ml for tacrolimus and 100–400 and 100–200 ng/ml for CsA during months 0–3 and 4–6, respectively, during the investigator-driven follow-up after termination of the main study (months 7–24) no specific calcineurin inhibitor target levels were required. Follow-up data were collected at 2 years post-transplantation from 237 (82.9% of the ITT population) patients who received tacrolimus and 222 (81.9% of the ITT population) patients who received CsA-ME. Results. Calculated on ITT populations, mortality (2.0% vs 3.3%; P<0.05 in Kaplan–Meier analysis) was lower, but rate of graft loss (9.3% vs 11.2%; P = 0.12 in Kaplan–Meier analysis) was not significantly different after 2 years with tacrolimus- vs CsA-ME-based immunosuppression. Biopsy-proven acute rejection was significantly lower (19.6%) with tacrolimus than with CsA-ME (37.3%) during months 0–6 (P<0.0001), but was not significantly different during months 7–12 and 13–24 of follow-up (1.7% and 0.8% with tacrolimus and 4.7% and 0.9% with CsA-ME, respectively). A composite endpoint consisting of graft loss, patient death and biopsy-proven acute rejection occurred significantly more frequently in CsA-ME patients than in tacrolimus patients (42.8% vs 25.9%; P<0.001) during 24 months follow-up. Renal function 2 years post-transplant, measured by serum creatinine concentrations, was significantly better in tacrolimus-based compared with CsA-ME-based immunosuppression (136.9 vs 161.6 µmol/l; P<0.01). Cornerstone immunosuppression remained unchanged in 82.5% and 66.2% of patients treated with tacrolimus and CsA-ME, respectively. At 2 years, more patients in the tacrolimus arm were off steroids and received calcineurin inhibitor monotherapy, and fewer tacrolimus patients remained on a triple immunosuppressive regimen. The cardiovascular risk profile was affected favourably in the tacrolimus arm, with lower cholesterol and triglyceride concentrations (despite less use of cholesterol-lowering drugs); no significant difference in requirement for antidiabetic medication was noted. Conclusions. The 2 year study results confirm that tacrolimus is a highly efficacious cornerstone immunosuppressant in kidney transplantation. Tacrolimus-based immunosuppression may induce long-term benefits with regard to graft function and graft survival. The overall side-effect profile is considered to be favourable.

Long-term use of corticosteroids is associated with considerable morbidity, including cardiovascular and metabolic adverse effects. This study evaluated the long-term efficacy and safety of two steroid-free regimens compared with a triple immunosuppressive therapy in renal transplant recipients. This was a 3-year follow-up to a 6-month, open-label, randomized, multicenter study. Data from 3 years were available for 421 (93.3%) of 451 patients in the original intent-to-treat population (143 tacrolimus/basiliximab [Tac/Bas], 139 tacrolimus/mycophenolate mofetil [Tac/MMF], and 139 tacrolimus/MMF/steroids [triple therapy]). In the time interval from 6 months to 3 years after transplantation, the incidence of biopsy-proven acute rejection was low and similar (Tac/Bas, 2.1%; Tac/MMF, 2.2%; triple therapy, 2.2%); Most rejection episodes occurred during the first 6 months of the study. Graft survival was high (Kaplan-Meier estimates: 92.7%, 92.5%, and 92.5%), as was patient survival (93.1%, 96.4%, and 97.0%). There were 10 graft losses (n=2, 4, and 4) and 12 patient deaths (n=5, 2, and 5). Renal function was well preserved throughout the study and similar between groups. There was a trend toward improved cardiovascular risk factors in the Tac/Bas group, including reduced total and low-density lipoprotein cholesterol and lower new-onset insulin use. There were no between-group differences in the incidence or type of adverse events. Higher rates of acute rejection early in treatment were seen with the steroid-free regimens, but this did not translate into poorer long-term outcomes, such as graft and patient survival and renal function. A trend for a more favorable cardiovascular risk profile was observed for steroid-free immunosuppression with Tac/Bas.

Background. The incidence of acute renal failure (ARF) after cardiac surgery remains high, despite improvements in surgical techniques and perioperative care, and is associated with an inacceptably high mortality. The adenosine receptor antagonist theophylline has been shown to confer some benefit in experimental and clinical ARF due to ischaemia, contrast media and various nephrotoxic agents. Methods. In a double‐blind, randomized, placebo‐controlled trial, the effectiveness of theophylline for prevention of renal impairment after elective coronary artery bypass grafting (CABG) was evaluated. Fifty‐six patients with normal renal function received a bolus of 4 mg/kg and a subsequent continuous infusion of 0.25 mg/kg/h theophylline (n=28) or isotonic saline (n=28) for up to 96 h. Serum creatinine concentrations were measured preoperatively and daily until day 5 after surgery, and the glomerular filtration rate (GFR) ([⁵¹Cr]EDTA‐clearance) was determined preoperatively, and at days 1, 3 and 5 after surgery. Results. Serum creatinine and GFR were the same in both groups. The number of patients with increases of serum creatinine ≥0.4 mg/dl were five in the theophylline group and four in the placebo group. Volumes of infused fluid and urine volumes were not different between groups, both ranging from ∼7.5 to 8 l during the first 24 h after surgery. The number of patients with termination of study medication due to presumed side effects was not different between placebo and theophylline groups. Conclusions. Theophylline administration for renal protection after CABG appears to be ineffective in a pilot study in well‐hydrated patients. However, the statistical power of our study was not sufficient to exclude a possible protective effect of theophylline. The present study demonstrated the feasability of a larger trial with theophylline or one of the new specific adenosine A1 receptor antagonists in the setting of ARF after cardiac surgery.

Background. The European tacrolimus versus ciclosporin A microemulsion (CsA-ME) renal transplantation study showed that tacrolimus was significantly more effective in preventing acute rejection and had a superior cardiovascular risk profile at 6 months. Methods. The endpoints of this investigator-initiated, observational, 36-month follow-up were acute rejection incidence rates, rates of patient and graft survival and renal function. An additional analysis was performed using the combined endpoints BPAR, graft loss and patient death. Data available from the original ITT population (557 patients; 286 tacrolimus and 271 CsA-ME) were analysed. Results. A total of 231 tacrolimus and 217 CsA-ME patients participated. At 36 months, Kaplan–Meier-estimated BPAR-free survival rates were 78.8% in the tacrolimus group and 60.6% in the CsA-ME group, graft survival rates were 88.0% and 86.9% and patient survival rates were 96.6% and 96.7%, respectively. The estimated combined endpoint-free survival rate was 71.4% with tacrolimus and 55.4% with CsA-ME (P ≤ 0.001, chi-square test). Significantly more CsA-ME patients crossed over to tacrolimus during the 3-year follow-up: 21.2% versus 2.6%, P ≤ 0.0001, chi-square test. Most patients in the tacrolimus arm discontinued steroids and received monotherapy and fewer tacrolimus patients remained on a triple regimen. Mean serum creatinine concentration was 145.4 ± 90.9 μmol/L with tacrolimus and 149.0 ± 92.1 μmol/L with CsA-ME. Significantly more CsA-ME patients had a classified cholesterol value >6 mmol/L (26.3% versus 12.6%, P ≤ 0.0003, chi-square test). Conclusions. Patients treated with tacrolimus had significantly higher combined endpoint-free survival rates and lower acute rejection rates with less immunosuppressive medication at 36 months.