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Citation
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Bechstein WO, Malaise J, Saudek F, Land W, Fernandez-Cruz L, Margreiter R, Nakache R, Secchi A, Vanrenterghem Y, Tydén G, Van Ophem D, Berney T, Boucek P, Landgraf R, Kahl A, Squifflet JP. Transplantation 2004; 77(8): 1221-1228. |
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Abstract
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Background. Simultaneous pancreas-kidney transplantation (SPK) transplantation has become an accepted therapy for type 1 diabetic patients with end-stage renal disease. This open-label, multicenter study compared the efficacy and safety of tacrolimus with the microemulsion (ME) formulation of cyclosporine in a clinical setting. The 1-year results are reported here.
METHODS. The study was conducted in 10 European centers and one center in Israel. One hundred three patients were randomly assigned to tacrolimus and 102 to cyclosporine-ME. All patients received concomitant rabbit anti-T-cell globulin induction therapy, mycophenolate mofetil (MMF), and short-term corticosteroids. The initial daily oral doses were 0.2 mg/kg for tacrolimus, 7 mg/kg for cyclosporine-ME, and 2 to 3 g for MMF.
RESULTS. The 1-year incidence of biopsy-proven kidney or pancreas acute rejection was lower with tacrolimus (27.2%) than with cyclosporine-ME (38.2%; P=0.09). Pancreas graft survival at 1 year was 91.3% with tacrolimus and 74.5% with cyclosporine-ME (P<0.0005). Renal graft survival was similar in the two study groups. There were no significant treatment-related differences in pancreatic or renal graft function. In total, 34 patients switched treatment from cyclosporine-ME to tacrolimus, but only 6 patients receiving tacrolimus required alternative therapy. Mean doses of MMF at 1 year were also lower in the tacrolimus group (1.36 vs. 1.67 g/day; P=0.007).
CONCLUSION. These findings support the use of tacrolimus therapy for uremic patients with type 1 diabetes who are undergoing SPK transplantation.; AuthorsConclusions:The findings reported in the present study support the use of tacrolimus-based immunotherapy for uremic patients with type 1 diabetes who undergo SPK transplantation. Not only was tacrolimus associated with a reduced risk of moderate or severe renal- or pancreas-allograft rejection compared with cyclosporine-microemulsion, but it also improved pancreas graft survival and a reduced the need to change immunosuppressive therapy.; FreeText:All patients received oral mycophenolate mofetil (MMF) 2 to 3 gms daily in two divided doses, with subsequent dosage adjustments based on tolerability and adverse effects. The choice of the rabbit anti-T-cell globulin (rATG) and the corticosteroid regimens were made according to standard practices at each study center. All patients received the dose of rATG perioperatively, starting before unclamping, followed by three daily postoperative doses (4 mg/kg daily or thymoglobulin 1.25 mg/kg daily). Corticosteroid therapy was tapered during the first 3 months posttransplant and was intended to be withdrawn completely by month 6. Rejection episodes were treated according to local practice. The choice and modalities of prophylactic antibiotic treatment and anti-cytomegalovirus (CMV) preemptive treatment, as well as treatment of CMV disease, were also undertaken according to the routine procedures at each center. The primary study endpoints were the incidence of biopsy-proven acute rejection of either the pancreas or kidney at 1 year posttransplantation and the incidence of treatment failure for any reason. A percutaneous renal biopsy was mandated before initiation of antirejection therapy. Renal biopsies were graded as borderline, mild, moderate, or severe in accordance with the Banff classification. Pancreas biopsies were rated according to Drachenberg scale. Treatment failure was defined according to the following guidelines: switch to another immunosuppressive drug, permanent discontinuation of a drug (except steroids), withdrawal for adverse effects, withdrawal for noncompliance, failure of steroid withdrawal at 6 months, graft loss (pancreatic or renal transplantectomy), delayed kidney-graft function requiring dialysis for more than 1 month, functional graft loss of kidney or pancreas, and death of patient. Functional kidney-graft loss was defined as return to dialysis and functional pancreas graft loss as need for exogenous insulin. Secondary efficacy endpoints included patient and graft survival rates at 1 year, the time to the first rejection episode, the histologic grade of rejection, incidence of rejection leading to graft loss, the cumulative dose of corticostereids administered, and the number and length of hospitalizations. Other assessments included kidney graft function, as measured by serum creatinine, calculated glomerular filtration rate (Cockcroft-U Gault formula), and pancreas graft function; fasting blood glucose levels; fasting C-peptide; and glycosylated hemoglobin (HbA1C).
RESULTS were analyzed using statistical analysis.; Indications:Graft rejection prophylaxis in 107 patients undergoing primary simultaneous pancreas-kidney transplantation.; Patients:205 patients, 127 males and 78 females, aged 18-55 years. Neoral group: n=102, 61 males and 41 females, mean age was 38.5 ± 6.0 years. Tacrolimus group: n=103, 66 males and 37 females, mean age was 39.9 ± 7.8 years. Underlying diseases leading to transplantation were type 1 diabetes mellitus combined with end-stage renal disease. 6 patients in the tacrolimus group were switched to alternative immunosppression (5 were converted to Neoral and 1 to sirolimus), whereas 34 patients in the Neoral group were switched to tacrolimus therapy.; TypeofStudy:One-year results of a three-year study are reported comparing the efficacy and safety of Sandimmun Neoral versus tacrolimus in uremic patients with type I diabetes undergoing primary simultaneous pancreas-kidney transplantation (SPK). Open-label, multicenter, prospective, randomized, parallel-group study.; DosageDuration:Initial daily oral doses of 7 mg/kg in two divided doses, with subsequent dosage adjustments being undertaken to maintain whole-blood trough levels of 150-250 ng/mL by day 5, and continued throughout the first 6 months. After month 6, levels were reduced to 100-200 ng/mL. By the end of the first year, mean daily dose was 1.67 g daily. Mean doses were 6.8 ± 2.2 mg/kg daily (day 1-7, n=99), 4.8 ± 1.5 mg/kg daily (3 months, n=63), 4.5 ±1.0 mg/kg (6 months, n=52) and 4.2 ±1.1 mg/kg daily (1 year, n=46). Duration of treatment was for more than 1 year.; ComparativeDrug:Tacrolimus (Prograf) 0.1 mg/kg bid (= 0.2 mg/kg), orally, with subsequent dosage adjustments being undertaken to achieve whole-blood trough levels of 8 to 15 ng/mL by day 5, and continued throughout the first 6 months. After month 6, levels were reduced to 5 to 10 ng/mL. By the end of the first year, the mean dose was 1.36 g daily.; Results:The 1-year incidence of biopsy-proven kidney or pancreas acute rejection was lower in the tacrolimus group 28/103 (27.2%) than in the Neoral group (39/102) (38.2%). However, this difference did not reach statistical significance (P=0.09). The overall incidence of acute rejection episodes, including those confirmed by clinical signs and symptoms, was 43/103 (41.7%) with tacrolimus and 54/100 (52.9%) with Neoral (P=0.108). When looking only at moderate or severe rejection, this occurred significantly more often in the Neoral group (n = 12 [12%]) than in the tacrolimus group (n = 1 [1%], 1 patient with moderate kidney rejection) (P=0.0053, 95% confidence interval [CI] 4.4-17.7). In the Neoral group, 11 patients with a kidney rejection and 1 with a pancreas rejection had Banff grade II or III (moderate or severe) renal graft rejections or Drachenberg grade 4 pancreas graft rejection. There were a total of 66 acute clinical or biopsy-proven rejection episodes in 43 patients (1.53 per patient) in the tacrolimus group and 89 episodes in 54 patients (1.64 per patient) in the Neoral group. In the tacrolimus group, 33 patients had a biopsy-proven rejection. In the Neoral group, 44 patients had a biopsy-proven rejection. The difference between the two groups in terms of recurrent biopsy-proven rejection episodes is significant (P=0.0032). Treatment failure for any reason occurred in 24 patients receiving tacrolimus-based therapy and 54 patients in the Neoral treatment group. There was no difference between treatment groups with respect to patient survival at 1 year posttransplantation. Of the two deaths that occurred in the tacrolimus group, one was caused by brain edema and the other as a result of suicide. In the Neoral group, there were three deaths after study withdrawal: two were a result of peritonitis and the other caused by a cardiovascular event. Pancreas-graft survival at 1 year was significantly higher in the tacrolimus group 94/103 (91.3%) than in the Neoral group 76/102 (74.5%)(P=0.0014, 95% CI 6.7-26.8). There was no significant difference between the two treatment groups in terms of kidney-graft survival, with five graft losses in tacrolimus-treated patients and eight graft losses in the Neoral group. There was no significant difference between the two immunosuppressive regimens in terms of pancreas-graft function. Renal graft function at 1 year, as assessed by mean serum creatinine concentrations, was almost identical in patients treated with tacrolimus (124 ± 35 mcM/L) and Neoral based therapy (133 ± 44 mcM/L). Creatinine clearance was also comparable in both treatment groups. During the 12-months period, six (5.8%) patients in the tacrolimus group were switched to alternative immunosuppression (5 were converted to Neoral, and 1 was switched to sirolimus), whereas 34 (33.3%) patients in the Neoral group were switched to tacrolimus therapy. The number of patients switching treatment was significantly lower in the tacrolimus group than in the Neoral group (P<0.0001, 95% CI 17.3-37.7); AdverseEffects:40 developed urinary tract infection, 32 cytomegalovirus infection, 3 cytomegalovirus disease and 18 peritonitis (2 peritonitis patients died from their infection).
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