Efficacy of Prolonged- and Immediate-release Tacrolimus in Kidney Transplantation: A Pooled Analysis of Two Large, Randomized, Controlled Trials.

BACKGROUND: Two large, prospective studies (12-03; OSAKA) compared the efficacy and tolerability of prolonged-release versus immediate-release tacrolimus in kidney transplant patients also receiving mycophenolate mofetil and low-dose corticosteroids (without induction therapy). METHODS: Data were combined into one database to compare results over 24 weeks using 3 alternative endpoints: biopsy-confirmed acute rejection (BCAR); the Food and Drug Administration composite endpoint (graft loss, BCAR, and loss to follow-up), and the European Medicines Agency composite endpoint (graft loss, BCAR, and graft dysfunction). The 95% confidence intervals were calculated (10% noninferiority margin). RESULTS: Overall, 633 patients received prolonged-release tacrolimus (12-03, n = 331; OSAKA, n = 302) and 645 received immediate-release tacrolimus (n = 336; n = 309). Baseline characteristics were comparable. Proportionately more patients receiving prolonged-release tacrolimus had trough levels of 5-15 ng/mL on day 1 (60.8%) and 2 (56.6%) versus immediate-release tacrolimus (42.5% and 43.9%, respectively, both P < .001). Efficacy of prolonged-release and immediate-release tacrolimus were similar as assessed by BCAR (13.9% vs 14.1%, respectively), European Medicines Agency composite endpoint (40.3% vs 38.3%) and US Food and Drug Administration composite endpoint (21.5% vs 19.8%). CONCLUSIONS: Novel efficacy endpoints as required by the European Medicines Agency and US Food and Drug Administration demonstrate noninferiority of prolonged-release versus immediate-release tacrolimus. Significantly more patients treated with prolonged-release tacrolimus versus immediate-release tacrolimus achieved trough levels of 5 to 15 ng/mL early after transplantation. ClinicalTrials.govNCT00189839; NCT00717470.

Three-year follow-up of malignancies in tacrolimus-treated renal recipients--an analysis of European multicentre studies.

Five prospective, multicentre adult renal studies of three yr duration conducted in Europe for which tacrolimus was used as the primary immunosuppressant in at least one treatment arm was identified. This was confirmed by literature review as the only source fulfilling these criteria. Our goal was to identify absolute (reported) incidences of malignancies in patients exposed to tacrolimus and relative rates as a proportion of the total malignancies recorded for three yr after transplant. The five studies provided 2435 patients in nine different treatment regimens. All regimens combined tacrolimus with azathioprine or mycophenolate mofetil and corticosteroids except for one regimen which also employed daclizumab without corticosteroids. There were 83 patients with malignancies or 3.4% of the total population. No patient experienced more than I malignancy type. Malignancy incidences relative to those patients experiencing a malignancy were: total skin 37.3%, lymphoma 15.7%, and non-skin-non-lymphoma 47.0%. Annual occurrence of all malignancies reflected a progressive increase with time. While the larger proportion of lymphoma and non-skin-non-lymphoma malignancies occurred during the first year after transplant, malignancies affecting the skin increased more linearly with time. These findings are consistent with reports in the literature, reflect the current established experience with tacrolimus to date, and should provide a robust basis for future comparisons with tacrolimus-based immunosuppression.

Dose optimization of mycophenolate mofetil when administered with a low dose of tacrolimus in cadaveric renal transplant recipients.

BACKGROUND: Supplementation of immunosuppressive therapy with mycophenolate mofetil (MMF) has been found to reduce the rate of acute rejection in renal transplantation. We report a dose-finding study for MMF when administered in combination with low-dose tacrolimus and corticosteroid prophylaxis in cadaveric renal transplant recipients. METHODS: Two hundred thirty-two patients at 16 centers were enrolled in this randomized, parallel-group study. The three treatment groups were tacrolimus and corticosteroids (MMF-0 group, n=82); tacrolimus, corticosteroids, and 1 g of MMF daily (MMF-1 g group, n=79); and tacrolimus, corticosteroids, and 2 g of MMF daily (MMF-2 g group, n=71). Study duration was 6 months, and patients were followed up for patient and graft survival for 12 months. RESULTS: At 6 months posttransplantation, daily doses of 1 g and 2 g of MMF were associated with significantly lower rates of acute rejection compared with tacrolimus alone. The Kaplan-Meier rates were 48.5%, 24.9%, and 22.9%, respectively, for the three treatment groups when acute rejection was determined by clinical criteria (P=0.007). At month 12, patient survival rates were 100%, 97.5%, and 97.2% and graft survival rates were 90.2%, 92.4%, and 93.0% for the MMF-0 group, MMF-1 g group, and the MMF-2 g group, respectively. Gastrointestinal adverse events and leukopenia were higher in the MMF groups, especially in the MMF-2 g group (P<0.05). CONCLUSIONS: Low-dose tacrolimus combined with a MMF dose of 1 g daily and corticosteroids provided an optimized efficacy and safety profile. A higher dose of MMF (2 g) was associated with greater toxicity without a significant improvement in efficacy.

Multicenter randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of renal allograft rejection: a report of the European Tacrolimus Multicenter Renal Study Group.

BACKGROUND: To confirm the results of a number of studies conducted in Europe, the United States, and Japan, this multicenter, randomized trial compared the 12-month efficacy and safety of tacrolimus- and cyclosporine-based immunosuppressive regimens in the prevention of renal allograft rejection. METHODS: A total of 448 renal transplant recipients were recruited from 15 centers and assigned to receive triple-drug therapy consisting of tacrolimus (n=303) or cyclosporine (n=145) in conjunction with azathioprine and low-dose corticosteroids. RESULTS: At 12 months after transplantation, tacrolimus therapy was associated with a significant reduction in the frequency of both acute (tacrolimus 25.9% vs. cyclosporine 45.7%; P<0.001 [absolute difference: 19.8%, 95% confidence interval: 10.0-29.6%]) and corticosteroid-resistant rejection (11.3% vs. 21.6%; P=0.001 [absolute difference: 10.3%, 95% confidence interval: 2.5-18.2%]). Actuarial 1-year patient (tacrolimus 93.0% vs. cyclosporine 96.5%; P=0.140) and graft survival rates (82.5% vs. 86.2%; P=0.380) did not differ significantly between the two treatment groups. Overall, the safety profiles of the tacrolimus- and cyclosporine-based regimens were quite comparable. Infections, renal impairment, neurological complications, and gastrointestinal complaints were frequently reported but were mostly reversible in both groups. Higher incidences of elevated serum creatinine, tremor, diarrhea, hyperglycemia, diabetes mellitus, and angina pectoris were reported in the tacrolimus treatment group, whereas acne, arrhythmia, gingival hyperplasia, and hirsutism were more frequent with cyclosporine treatment. CONCLUSIONS: The significant reduction in the incidence of episodes of allograft rejection observed with tacrolimus therapy may have important long-term implications given the prognostic influence of rejection on graft survival.

Mycophenolate mofetil in patients with acute renal failure: evidence of metabolite (MPAG) accumulation and removal by dialysis.

Pharmacokinetics of mycophenolic acid (MPA) was analyzed in eight patients with post-transplant acute renal failure. Furthermore, the effect of hemodialysis upon blood levels of MPA and its major metabolite, MPA glucuronide (MPAG), was determined. The mean duration of the posttransplant renal failure was 18 days, but renal function resumed in all patients eventually. The patients were treated with 3 g/day of mycophenolate mofetil for 28 consecutive days combined with cyclosporine A, methylprednisolone, and ATG for induction therapy. In all patients, accumulation of MPAG but not of MPA was observed. MPA trough levels were in the range between 0.5 microgram/ml at day 2 and 2.3 micrograms/ml at the end of the study period. However, this concentration difference did not reach statistical significance. Trough levels of MPAG accumulated, reaching levels as high as 358 micrograms/ml. However, with increasing recovery of renal function, MPAG levels fell to a median trough concentration of 141 micrograms/ml. MPAG, but not MPA, could partially be removed from the circulation by hemodialysis treatment.

FK 506 versus cyclosporin in the prevention of renal allograft rejection--European pilot study: six-week results.

FK 506 was compared with cyclosporin in a randomised trial in good-risk cadaveric renal transplant recipients. The objective was to evaluate whether oral FK 506 dosing was viable and whether blood concentrations in the range 10-20 ng/ml would prove to be practical. Thirty-one adult patients were randomised to FK 506 and 16 to cyclosporin. Both groups received an identical regimen of azathioprine and corticosteroids. Serum creatinine concentrations decreased rapidly in both groups with mean values below 200 mumol/l within 2 weeks. One graft in the cyclosporin group was lost due to renal vein thrombosis. During the 6-week study period, 19.4% of patients on FK 506 and 31.3% on cyclosporin experienced acute rejection. One patient in each group experienced corticosteroid-resistant rejection that responded to anti-lymphocyte therapy. Infections were reported in 51.6% of the FK 506 group compared with 37.5% of the cyclosporin group. The spectrum of adverse events was similar in both groups. However, minor neurological disorders were more common in the FK 506 group (54.8% versus 6.3%) whereas hypertension was less common (48.8% versus 75.0%). The results indicate that oral FK 506 rapidly achieves therapeutic blood concentrations and is an effective immunosuppressant for the initial treatment of renal allograft recipients.

Positive donor and negative recipient cytomegalovirus status is a detrimental factor for long-term renal allograft survival.

In 524 allogeneic cadaveric kidney transplants, the impact of cytomegalovirus (CMV) donor/recipient status on the incidence of CMV infection, CMV disease, early and long-term graft, and patient survival have been analyzed with respect to rejection episodes. Most CMV infections (59%) and diseases (17%) were found in CMV-negative recipients of CMV-positive kidneys. The 1-year function rate of CMV-positive kidneys (75%) dropped about 10% below that of CMV-negative organs (85%), and in the case of CMV-negative recipients an additional graft loss of more than 10% happened within the 4th and 5th years (5-year graft survival pos./neg.: 56%). This detrimental effect was exaggerated if it coincided with antibody-treated rejection episodes.

The beneficial effect of human recombinant superoxide dismutase on acute and chronic rejection events in recipients of cadaveric renal transplants.

In a prospective randomized double-blind placebo-controlled trial, the effect of rh-SOD, given in a dose of 200 mg intravenously during surgery to cyclosporine-treated recipients of cadaveric renal allografts, on both acute and chronic rejection events as well as patient and graft survival was investigated by analyzing the patients' charts retrospectively. The results obtained show that rh-SOD exerts a beneficial effect on acute rejection events as indicated by a significant reduction of (1) first acute rejection episodes from 33.3% in controls to 18.5%, as well as (2) early irreversible acute rejection from 12.5% in controls to 3.7%. With regard to long-term results, there was a significant improvement of the actual 4-year graft survival rate in rh-SOD-treated patients to 74% (with a projected half-life of 15 years) compared with 52% in controls (with an extrapolated half-life of 5 years). The beneficial effect of rh-SOD observed in this trial is not fully understood, although one can assume that the effect is related to its antioxidant action on ischemia/reperfusion injury of the renal allograft, thereby potentially reducing the immunogenicity of the graft. In addition and in accordance with the "response-to-injury hypothesis" in the pathogenesis of general atherosclerosis, rh-SOD has the potential to mitigate free radical-mediated reperfusion injury-induced acute endothelial cell damage that potentially may contribute to the process of chronic obliterative rejection arteriosclerosis.

The impact of free radical-mediated reperfusion injury on acute and chronic rejection events following cadaveric renal transplantation.

In a prospective, randomized, double-blind, placebo-controlled trial, rhSOD was given to cadaveric renal allograft recipients intravenously in a dose of 200 mg during surgery, and its effect on both acute and chronic rejection was investigated. The results showed that rhSOD exerts a beneficial effect on acute rejection episodes as indicated by a statistically significant reduction of first acute rejection episodes to 18.5% compared with 33.3% in controls, and a reduction in early irreversible acute rejection to 3.7% compared with 12.5% in controls. With regard to longterm results, there was a statistically significant improvement in the actual 5-year graft survival rate for rhSOD-treated patients to 68% (with a corresponding 13-year half-life) compared with 50% in controls (with a corresponding 6-year half-life). The incidence of acute rejection episodes did not prove to be a risk factor for long-term graft outcome. Rather only the combination of acute rejection episodes and the presence of uninfluenced reperfusion injury appeared to have a detrimental effect on long-term prognosis. The beneficial effect of rhSOD observed in this trial is not well understood, although one can assume that the effect is brought about by interference of rhSOD with ischemia or reperfusion injury to the allograft by oxygen-free radicals. In this sense, rhSOD may mitigate increased MHC expression and presentation, cytokine-adhesion molecule expression, and APC activation induced by reperfusion injury. In addition, in accordance with the "response-to-injury" hypothesis to explain the pathogenesis of arteriosclerosis, rhSOD may mitigate acceleration of chronic obliterative rejection or arterio-/arteriolosclerosis induced by reperfusion injury. In this sense, rhSOD may act indirectly by reducing acute rejection-mediated endothelial injury, or directly, by ablation of reperfusion-mediated acute endothelial injury.

[Status of treatment with free radical scavengers following kidney and pancreas transplantation]. / Stellenwert der Behandlung mit Radikalfängern nach Nieren- und Pankreastransplantation.

AIM OF THE STUDY: The frequency of acute renal failure (ARF) after preservation and kidney transplantation is rather high. The etiology of an ARF is an interaction of multiple mechanisms as donor conditions, explantation procedure, duration of ischemia and reperfusion injury. Different experiments demonstrated, that the damage produced by reperfusion can be prevented by the scavenger of free radicals, the enzyme superoxide dismutase (SOD). PATIENTS AND METHODS: After a double blind study, using consecutive intraarterial bovine SOD (n = 100) in kidney transplantation, showing a trend in favour to the SOD treated group, especially when long-time stored kidneys (> 30 h) had been grafted, a second study was designed to evaluate the efficiency of intravenous recombinant human SOD in the protection from ARF. This study (n = 180) was split into two different trials, double blind and randomized in itself: (A) grafts with cold ischemia time lower or equal 30 hrs., (B) cold ischemia more than 30 hrs. All grafts were preserved with Euro-collins. The study substances were either placebo or 200 mg rh-SOD (Grünenthal GmbH, FRG), given 10-2 minutes prior reperfusion intravenously. Parameters causing an ARF were equal and well comparable in both groups. RESULTS: Concerning early graft function there was no difference in study A between placebo and rh-SOD group. In study B the average and median of the day creatinine dropped the first time without interference of hemodialysis, showed a trend in favour to the rh-SOD group. If placebo was given only 19% of the grafts gained function within the first week, when rh-SOD was applied 47% functioned in the first week. The lack of significant benefit from SOD treatment could be explained by the dependency of the proportion of the total injury caused by reperfusion compared with the proportion resulting from ischemic injury per se. The rh-SOD group showed a better 3 years graft survival rate (+16%). CONCLUSIONS: It seems rh-SOD is able to augment the early graft function and is helpful to reduce the ARF frequency when long-time stored cadaveric kidneys have to be transplanted. These promising results encourage us to continue the study in protocol B to get greater numbers and definitive results.

Outcome of renal grafts after simultaneous kidney/pancreas transplantation.

Nineteen patients with endstage renal failure due to Type 1 (insulin-dependent) diabetes mellitus received simultaneous pancreas/kidney transplants using bladder drainage technique. Another group of 25 Type 1 diabetic patients received pancreas/kidney transplants by the duct occlusion technique. We observed a higher incidence of rejection episodes in the patients of the bladder drainage group than those in the duct occlusion group, 14 of 19 patients (74%) vs 7 of 25 (28%) respectively. Anti CD3 antibodies (OrthocloneR, OKT3) as a part of induction treatment was used more often in the bladder drainage group (58%) than in the control group (20%).