Randomized trial of tacrolimus in combination with sirolimus or mycophenolate mofetil in kidney transplantation: results at 6 months1

Gonwa, Thomas A.; Mendez, Robert; Yang, Harold C.; Weinstein, Stefanie; Jensik, Stephen C.; Steinberg, Steven M.

doi:10.1097/01.tp.0000062837.99400.60

Cited by 158 publications

(82 citation statements)

References 18 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: 89%

“…Gonwa et al reported that the combination of sirolimus and standarddose tacrolimus may exacerbate nephrotoxicity and result in inferior renal function and higher blood pressure compared with MMF and standard-dose tacrolimus. 22 Lo et al also reported a high incidence of biopsy-proven tacrolimus nephrotoxicity with the combined use of full doses of tacrolimus and sirolimus. 17 Furthermore, tacrolimus generally has a less significant impact on lipids, a known adverse effect of sirolimus compared with cyclosporine.…”

Section: Discussionmentioning

confidence: 98%

“…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: 89%

Section: Discussionmentioning

confidence: 98%

mentioning

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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“…Plasma HDL cholesterol has been shown to be unchanged or slightly increased in clinical trials (43,44,45,46,47). Thus, the detrimental effect of sirolimus on lipids is obvious and also confirmed by the fact that sirolimus-treated patients more frequently require adjunctive treatment with lipid lowering drugs (49).…”

Section: Effects Of Mtor Inhibitors On Lipids "mentioning

confidence: 90%

“…Sirolimus (rapamycin) " A significant increase in total cholesterol ranging from 25 to 55% has been observed with sirolimus (40,41,43,44,45,46,47,48). In most clinical studies, sirolimus treatment is associated with a significant increase in LDL cholesterol (40,43,47).…”

Section: Effects Of Mtor Inhibitors On Lipids "mentioning

confidence: 99%

ENDOCRINE SIDE EFFECTS OF ANTI-CANCER DRUGS: Effects of anti-cancer targeted therapies on lipid and glucose metabolism

Vergès

Walter

Cariou

2014

European Journal of Endocrinology

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During the past years, targeted therapies for cancer have been developed using drugs that have significant metabolic consequences. Among them, the mammalian target of rapamycin (mTOR) inhibitors and, to a much lesser extent, the tyrosine kinase inhibitors (TKIs) are involved. mTOR plays a key role in the regulation of cell growth as well as lipid and glucose metabolism. Treatment with mTOR inhibitors is associated with a significant increase in plasma triglycerides and LDL cholesterol. mTOR inhibitors seem to increase plasma triglycerides by reducing the activity of the lipoprotein lipase which is in charge of the catabolism of triglyceride-rich lipoproteins. The increase in LDL cholesterol observed with mTOR inhibitors seems to be due to a decrease in LDL catabolism secondary to a reduction of LDL receptor expression. In addition, treatment with mTOR inhibitors is associated with a high incidence of hyperglycemia, ranging from 13 to 50% in the clinical trials. The mechanisms responsible for hyperglycemia with new onset diabetes are not clear, but are likely due to the combination of impaired insulin secretion and insulin resistance. TKIs do not induce hyperlipidemia but alter glucose homeostasis. Treatment with TKIs may be associated either with hyperglycemia or hypoglycemia. The molecular mechanism by which TKIs control glucose homeostasis remains unknown. Owing to the metabolic consequences of these agents used as targeted anti-cancer therapies, a specific and personalized follow-up of blood glucose and lipids is recommended when using mTOR inhibitors and of blood glucose when using TKIs.

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Target of rapamycin inhibitors (TOR-I; sirolimus and everolimus) for primary immunosuppression in kidney transplant recipients

Webster

Lee

Chapman

et al. 2006

Cochrane Database of Systematic Reviews

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TOR-I have been evaluated in four different primary immunosuppressive algorithms; as replacement for CNI and for antimetabolites, in combination with CNI at low and high dose and with variable dose of CNI. Generally, surrogate endpoints for graft survival favour TOR-I (lower risk of acute rejection and higher GFR) and surrogate endpoints for patient outcomes are worsened by TOR-I (bone marrow suppression, lipid disturbance). Long-term hard-endpoint data from methodologically robust RCTs are still needed.

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Randomized trial of tacrolimus in combination with sirolimus or mycophenolate mofetil in kidney transplantation: results at 6 months1

Abstract: Tacrolimus is equally effective in renal transplantation when combined with sirolimus or MMF. The tacrolimus-MMF combination may be superior in terms of improved renal function and improved cardiovascular risk factors including hyperlipidemia and hypertension.

Cited by 158 publications

References 18 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

ENDOCRINE SIDE EFFECTS OF ANTI-CANCER DRUGS: Effects of anti-cancer targeted therapies on lipid and glucose metabolism

Target of rapamycin inhibitors (TOR-I; sirolimus and everolimus) for primary immunosuppression in kidney transplant recipients

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