A randomized long-term trial of tacrolimus/sirolimus versus tacrolimus/mycophenolate mofetil versus cyclosporine (NEORAL)/sirolimus in renal transplantation. Ii. Survival, function, and protocol compliance at 1 year

Ciancio, Gaetano; Burke, George W.; Gaynor, Jeffrey J.; Mattiazzi, Adela; Roth, David; Kupin, Warren; Nicolas, Maud; Ruiz, Phillip; Rosén, Anne; Miller, Joshua

doi:10.1097/01.tp.0000101495.22734.07

Cited by 143 publications

(125 citation statements)

References 16 publications

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“…15 Numerous single-center reports describe sirolimus/tacrolimus-based immunosuppression in organ transplant recipients. [17][18][19][20][21][22][23][24][25] Consistent with the findings of our study, a retrospective analysis by El-Sabrout et al 19 emphasized the use of sirolimus loading doses to increase rejection-free survival. In a pilot study of early tacrolimus withdrawal, Grinyo et al reported improved renal function and blood pressure in patients randomly assigned to a regimen of tacrolimus withdrawal versus those who remained on standard-dose tacrolimus and sirolimus.…”

Section: Discussionsupporting

confidence: 88%

“…16 There is an expanding body of literature on the successful clinical application of the combination of sirolimus-and tacrolimusbased immunosuppression in renal and nonerenal allograft recipients. [17][18][19][20][21][22][23][24][25] In an attempt to minimize the toxicity of tacrolimus, this study was designed to investigate the clinical safety and efficacy of a regimen of sirolimus plus reduced-dose tacrolimus (rTAC) in renal allograft recipients.…”

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confidence: 99%

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A Comparative, Randomized Trial of Concentration-Controlled Sirolimus Combined With Reduced-Dose Tacrolimus or Standard-Dose Tacrolimus in Renal Allograft Recipients

Bechstein

Pączek

Wramner

et al. 2013

Transplantation Proceedings

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Background. The clinical safety and efficacy of sirolimus plus reduced-dose tacrolimus was evaluated in de novo renal allograft recipients enrolled in a comparative, open-label study. Methods. One hundred twenty-eight renal allograft recipients were randomly assigned (1:1) to receive reduced-dose tacrolimus plus sirolimus (rTAC) or standard-dose tacrolimus and sirolimus (sTAC) for 6 months. The primary efficacy endpoint was calculated creatinine clearance values at 6 months. Results. Demographic variables were similar between groups. At 6 months, mean (AE standard deviation) calculated creatinine clearance was significantly improved in the rTAC group (63.8 vs 52.7 mL/min, P ¼ .005), although mean serum creatinine values were not significantly different. Patient survival (95.2% and 96.9%) and graft survival (93.7% and 98.5%) were similar between the rTAC and sTAC groups, respectively. Acute rejection rates were 17.5% with rTAC and 7.7% with sTAC (P ¼ .095). Conclusions. The rTAC regimen provided effective immunosuppression and was associated with improved creatinine clearance. Adequate immunosuppressant exposure must be achieved in the early postoperative period to minimize the risk of acute rejection.

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Section: Discussionsupporting

confidence: 88%

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confidence: 99%

A Comparative, Randomized Trial of Concentration-Controlled Sirolimus Combined With Reduced-Dose Tacrolimus or Standard-Dose Tacrolimus in Renal Allograft Recipients

Bechstein

Pączek

Wramner

et al. 2013

Transplantation Proceedings

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“…Large clinical trials did not reveal any increase in the incidence of posttransplantation diabetes among patients who were treated with sirolimus (13-16), either alone or in combination with CNI, although recent investigations have challenged this conclusion (38,39). In the above studies, however, posttransplantation diabetes has been defined and recognized only by the patient's requirement for insulin.…”

Section: Discussionmentioning

confidence: 90%

Glucose Metabolism in Renal Transplant Recipients

Teutonico

Schena²,

Paolo³

2005

Journal of the American Society of Nephrology

227

151

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Cyclosporine A (CsA) and tacrolimus have been associated with an increased risk for diabetes after transplantation, whereas sirolimus is deemed to be devoid of any effect on glucose metabolism. This study was performed to investigate the effect of the withdrawal of calcineurin inhibitors and the switch to sirolimus on peripheral insulin resistance and pancreatic ␤ cell response. Twenty-six patients who received a kidney transplant and discontinued CsA and were converted to sirolimus and 15 recipients of suboptimal kidneys who were treated with tacrolimus plus sirolimus for the first 3 mo after grafting and thereafter with sirolimus alone were enrolled. All patients underwent an oral glucose tolerance test and intravenous insulin tolerance test before and 6 mo after the conversion to sirolimus-alone therapy. The withdrawal of CsA or tacrolimus was associated with a significant fall of insulin sensitivity (both P ‫؍‬ 0.01) and with a defect in the compensatory ␤ cell response, as measured by the disposition index (P ‫؍‬ 0.004 and P ‫؍‬ 0.02, respectively). The increase of insulin resistance and the decrease of disposition index significantly correlated with the change of serum triglyceride concentration after the conversion to sirolimus-based therapy (R 2 ‫؍‬ 0.30, P ‫؍‬ 0.0002; and R 2 ‫؍‬ 0.19, P ‫؍‬ 0.004, respectively). Clinically, the switch to sirolimus was associated with a 30% increase of incidence of impaired glucose tolerance and with four patients' developing new-onset diabetes. In conclusion, the discontinuation of calcineurin inhibitors and their replacement by sirolimus fail to ameliorate the glycometabolic profile of kidney transplant recipients. Rather, it is associated with a worsening of insulin resistance and an inappropriately low insulin response.

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“…As previously reported, [15][16] between May 2000 and December 2001, 150 recipients between 14 to 78 yr of age, of either deceased donor(DD) or non-HLA identical living donor (LD) first kidney transplants, were randomized immediately before transplantation into one of three study groups (the center institutional review board approved the protocol; patients gave written informed consent before enrollment): TAC/SRL, TAC/MMF, and CSA/SRL. In each arm, the CNI was not started until renal function had improved (serum creatinine concentration (Cr) Ͻ4 mg/dl absent dialysis).…”

Section: Concise Methodsmentioning

confidence: 99%

“…[15][16][17] In the present report, we compare, at a median follow-up of eight years post-transplant, the efficacy/ safety of TAC in decreasing maintenance dosage combined with SRL versus MMF (TAC/SRL versus TAC/MMF), and CSA in decreasing maintenance dosage combined with SRL (CSA/ SRL) in adult primary-kidney-transplant recipients.…”

mentioning

confidence: 99%

Randomized Trial of Immunosuppressive Regimens in Renal Transplantation

Guerra

Ciancio

Gaynor

et al. 2011

Journal of the American Society of Nephrology

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The optimal long-term regimen for immunosuppression for kidney transplant recipients is unknown. We conducted a randomized trial involving 150 kidney transplant recipients to compare tacrolimus/sirolimus, tacrolimus/mycophenolate mofetil (MMF), and cyclosporine/sirolimus. All patients received daclizumab induction and maintenance corticosteroids. Median follow-up was 8 yr post-transplant. Acute rejection (AR) occurred significantly less often among those treated with tacrolimus/MMF (12%) than among those treated with tacrolimus/sirolimus (30%) or cyclosporine/sirolimus (28%). Mean estimated GFR was consistently higher in the tacrolimus/MMF arm, especially after controlling for donor age in a multivariable model during the first 36 mo (P Յ 0.008). The rate of dying with a functioning graft was significantly higher among those treated with tacrolimus/sirolimus (26%) than among those treated with tacrolimus/ MMF (12%) or cyclosporine/sirolimus (4%). We did not observe significant differences in actuarial graft survival at 8 yr post-transplant between the groups. Patient noncompliance seemed responsible for 45% (13/29) of observed graft failures, with 11 of these occurring after 36 mo. Significantly more viral infections, protocol violations, and need for antilipid therapy occurred among patients receiving sirolimus, but we did not observe differences between the groups with regard to infections requiring hospitalization or new-onset diabetes. Taken together, these results suggest that maintenance therapy with tacrolimus/MMF is more favorable than either tacrolimus/sirolimus or cyclosporine/sirolimus.

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A randomized long-term trial of tacrolimus/sirolimus versus tacrolimus/mycophenolate mofetil versus cyclosporine (NEORAL)/sirolimus in renal transplantation. Ii. Survival, function, and protocol compliance at 1 year

Abstract: This 1-year interim analysis of a long-term, prospective, randomized renal-transplant study indicates that decreasing maintenance dosage of Tacro with adjunctive Siro or MMF appears to point to improved long-term function, with reasonably few adverse events.

Cited by 143 publications

References 16 publications

A Comparative, Randomized Trial of Concentration-Controlled Sirolimus Combined With Reduced-Dose Tacrolimus or Standard-Dose Tacrolimus in Renal Allograft Recipients

A Comparative, Randomized Trial of Concentration-Controlled Sirolimus Combined With Reduced-Dose Tacrolimus or Standard-Dose Tacrolimus in Renal Allograft Recipients

Glucose Metabolism in Renal Transplant Recipients

Randomized Trial of Immunosuppressive Regimens in Renal Transplantation

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