Five-Year Outcomes in Kidney Transplant Patients Converted From Cyclosporine to Everolimus: The Randomized ZEUS Study

Budde, Klemens; Lehner, Frank; Sommerer, Claudia; Reinke, Petra; Arns, Wolfgang; Eisenberger, Ute; Wüthrich, Rudolf P.; Mühlfeld, Anja; Heller, Katharina; Porstner, Martina; Veit, Justyna; Paulus, Eva‐Maria; Witzke, Oliver

doi:10.1111/ajt.12952

Cited by 114 publications

(81 citation statements)

References 40 publications

(58 reference statements)

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“…Also combined reduced CNI + sirolimus or everolimus regimens have proven their efficacy and safety in a large number of studies. Besides improved preservation of renal function, reported rates of viral infections and malignancy are low compared with traditional CNI regimens [6][7][8][9][10][11]. However, the wider introduction of these agents has been limited by serious adverse effects and relatively high discontinuation rates [12].…”

Section: Introductionmentioning

confidence: 99%

Sirolimus and everolimus in kidney transplantation

Moes

Guchelaar

Fijter

2015

Drug Discovery Today

111

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Section: Introductionmentioning

confidence: 99%

Sirolimus and everolimus in kidney transplantation

Moes

Guchelaar

Fijter

2015

Drug Discovery Today

111

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“…A significant improvement in renal function with a mean estimated GFR difference of 5.3 mL/min/1.73 m 2 in favor of everolimus was reported at 5 years. 59 The increase in early mild acute rejection did not affect long-term graft function or survival. 59 Results of the second randomization in the 2014 3C Study are still awaited; patients were randomized at 6 months to continue with tacrolimus or switch to sirolimus.…”

Section: Conversion Early After Transplantmentioning

confidence: 90%

“…59 The increase in early mild acute rejection did not affect long-term graft function or survival. 59 Results of the second randomization in the 2014 3C Study are still awaited; patients were randomized at 6 months to continue with tacrolimus or switch to sirolimus. 42 Calcineurin inhibitor conversion to sirolimus due to adverse effects other than nephrotoxicity In a randomized controlled trial reported by Euvrard and associates, renal transplant recipients with a prior history of squamous cell carcinoma who had been receiving a CNI were randomized to continue with the CNI or to substitute sirolimus for the CNI.…”

Section: Conversion Early After Transplantmentioning

confidence: 90%

Untitled

Camilleri

Bridson

Halawa³

2016

Exp Clin Transplant

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The introduction of the calcineurin inhibitors cyclosporine and tacrolimus in the immuno suppressive regimens for kidney transplant has been associated with substantial reductions in the incidence of acute rejection, with a subsequent improvement in 1-year graft survival. However, this has not directly correlated with improvements in long-term allograft survival. Immunosuppressive medications are associated with toxicities related directly to immunosuppressive effects, and these are similar among different agents. In addition, there are other toxicities that are unique for each drug. Immunosuppressive minimization strategies have attempted to address both of these toxicities. Calcineurin inhibitors have been associated with chronic nephrotoxicity, and various calcineurin inhibitor-sparing strategies have been used to address this issue with the aim of improving long-term outcomes. However, there has been a paradigm shift over the past 10 to 15 years, with the appreciation that calcineurin inhibitor nephrotoxicity is not the major cause of late graft failure. Studies have now shown that chronic immune injury mediated by donorspecific antibodies may account for most late graft losses. Although some patients do benefit from calcineurin inhibitor-sparing approaches, others may have late allograft loss from chronic and subacute immune-mediated injury. Unfortunately, the vast majority of calcineurin inhibitor-sparing studies have short-term follow-up and have not explored the change in the donor-specific antibody profile. One of the biggest challenges that we face is being able to distinguish among patients who will benefit from this strategy and those who will not. In this study, we review the various strategies used to limit or avoid the use of calcineurin inhibitors and address the benefits and pitfalls associated in pursuing such strategies.

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“…Indeed, in these more recent studies, with follow-up ranging from 2 to 8 years, no differences were found in the incidence of graft loss or death, either with the combined use of imTOR/iCN 34,43,44 or with early conversion strategies from iCN to imTOR. 40,42,45,46 Similarly, in a single center retrospective analysis including 581 patients who participated in 10 clinical trials comparing SRL or EVR combinations or AZA or MMF in combination with iCN and antimetaboles, no difference was found in the incidence of acute rejection, graft loss, and patient death within 10 years of follow-up 47 ( The importance and central role of mTOR in various physiological and pathophysiological processes has become a pharmacological target for the treatment of a range of diseases, from neoplasms to immunosuppression after solid organ transplantation. 48 Despite this, the clinical use of imTOR has been complicated by the diversity of population heterogeneity, immunosuppression regimens, transplantation period, drug combinations, the doses/concentrations used and the potential for pharmacokinetic and pharmacodynamic interaction.…”

Section: Mortality and Graft Loss Outcomes In Studies Involving New Pmentioning

confidence: 99%