Everolimus with cyclosporine withdrawal or low-exposure cyclosporine in kidney transplantation from Month 3: a multicentre, randomized trial

Budde, Klemens; Zeier, Martin; Witzke, Oliver; Arns, Wolfgang; Lehner, Frank; Guba, Markus; Jacobi, Johannes; Kliem, Volker; Reinke, Petra; Hauser, Ingeborg A.; Vogt, Bruno; Stahl, Rolf A.K.; Rath, Thomas; Duerr, Michael; Paulus, Eva‐Maria; May, Christoph; Porstner, Martina; Sommerer, Claudia

doi:10.1093/ndt/gfx075

Cited by 33 publications

(37 citation statements)

References 39 publications

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“…For the CNI-free group, reintroduction of CNI (CsA or tacrolimus) was widespread. 18 During the extension study, the incidence of BPAR remained low (<10% over 4 years) with no difference between groups. Conversely, 15% of patients in the standard-CNI group started mTOR inhibitor therapy.…”

Section: Discussionmentioning

confidence: 90%

“…HERAKLES was a multicenter, open-label, prospective, randomized, parallel-group, 12-month study, 18 after which patients could be followed in a 4-year extension study. Kidney transplant patients were randomized at month 3 posttransplant to continue a standardexposure CsA-based regimen, or convert to everolimus within a CNIfree regimen or everolimus with low-exposure CsA.…”

Section: Methodsmentioning

confidence: 99%

“…18 In the CNI-free group, everolimus was initiated and the dose adjusted to target C 0 5-10 ng/mL after CNI discontinuation. 18 In the CNI-free group, everolimus was initiated and the dose adjusted to target C 0 5-10 ng/mL after CNI discontinuation.…”

Section: Immunosuppression and Concomitant Medicationmentioning

confidence: 99%

“…18 After completing the 12-month study, patients were followed in a 4-year extension phase, ie, to year 5 posttransplant. 18 After completing the 12-month study, patients were followed in a 4-year extension phase, ie, to year 5 posttransplant.…”

mentioning

confidence: 99%

“…HERAKLES was a prospective, randomized, multicenter trial in which patients were randomized at 3 months after kidney transplantation to remain on standard cyclosporine (CsA)-based therapy or switch to everolimus with a CNI-free regimen, or everolimus with reduced-exposure CNI. 18 After completing the 12-month study, patients were followed in a 4-year extension phase, ie, to year 5 posttransplant. Results from this extension phase are described here.…”

mentioning

confidence: 99%

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Five-year outcomes in kidney transplant patients randomized to everolimus with cyclosporine withdrawal or low-exposure cyclosporine versus standard therapy

Sommerer

Duerr

Witzke

et al. 2018

American Journal of Transplantation

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HERAKLES was a 1-year randomized, multicenter trial. Patients were randomized at 3 months after kidney transplantation to remain on cyclosporine-based therapy, switch to everolimus without a calcineurin inhibitor (CNI), or switch to everolimus with low-exposure cyclosporine. Overall, 417 of 497 (83.9%) patients from the core study entered a 4-year extension study. The randomized regimen was continued to year 5 in 75.9%, 41.9% and 24.6% of patients in the standard-CNI, CNI-free and low-CNI groups, respectively. Adjusted estimated GFR at year 5 was significantly higher in the CNI-free group versus standard CNI (difference 7.2 mL/min/1.73 m , P < .001) or low CNI (difference 7.6 mL/min/1.73 m , P < .001). For patients who continued randomized therapy for 5 years, differences were 14.4 mL/min/1.73 m and 10.1 mL/min/1.73 m , respectively. Biopsy-proven acute rejection occurred during the 4-year extension study in 7.6%, 8.6%, and 9.0% of patients in the standard-CNI, CNI-free and low-CNI groups, respectively (P = .927). In conclusion, conversion to a CNI-free everolimus regimen 3 months after kidney transplantation improved long-term graft function, particularly in patients who continued the CNI-free regimen. Low CNI with everolimus did not improve renal function. Efficacy was comparable between groups but frequent immunosuppression changes should be taken into account.

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Section: Discussionmentioning

confidence: 90%

Section: Methodsmentioning

confidence: 99%

Section: Immunosuppression and Concomitant Medicationmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Five-year outcomes in kidney transplant patients randomized to everolimus with cyclosporine withdrawal or low-exposure cyclosporine versus standard therapy

Sommerer

Duerr

Witzke

et al. 2018

American Journal of Transplantation

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The incidence of cytomegalovirus and BK polyomavirus infections in kidney transplant patients receiving mTOR inhibitors: A systematic review and meta‐analysis

Wang

Liu

et al. 2023

Pharmacotherapy

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Cytomegalovirus (CMV) and BK polyomavirus (BKPyV) infections after kidney transplant have become increasingly prevalent. Based on previous studies, the mammalian target of rapamycin (mTOR) inhibitors seem like attractive alternatives with antiviral activity. The objective of this systematic review and meta-analysis was to investigate the incidence of CMV and BKPyV infections in kidney transplantation recipients receiving mTOR inhibitors. This meta-analysis included three comparisons of immunosuppressant regimens commonly used after kidney transplantation: Comparison 1: mTOR inhibitors versus calcineurin inhibitors (CNI); Comparison 2: mTOR inhibitors versus antimetabolites (AM); and Comparison 3: mTOR inhibitors plus a reduced-dose of CNI versus AM plus a standard-dose of CNI. The group containing mTOR inhibitors was the study group and the remaining one was the control group. The incidence of CMV or BKPyV infection defined by positive culture, serology, or polymerase chain reaction testing was the primary outcome. A total of 61 studies involving 13,609 patients were included.As compared with the control group, a significantly decreased risk of CMV and BKPyV infections favoring the mTOR inhibitors-based group was shown in comparisons 1, 2, and 3 (p < 0.05). Compared with the control group in all three comparisons, mTOR inhibitors made no difference in regard to death and graft loss (p > 0.05). Compared with CNI, the incidence of biopsy-proven acute rejection (BPAR) and anemia was higher with mTOR inhibitors (p < 0.05). In comparisons 2 and 3, the risk of new-onset diabetes mellitus (NODM) was higher with mTOR inhibitors (p < 0.05). Early introduction of mTOR inhibitors reduced more CMV infections in comparisons 1 and 2 (p < 0.05). The mTOR inhibitor-based regimen is an attractive alternative with lower risk of CMV and BKPyV infections in kidney transplant recipients. The combination regimen is more appropriate and acceptable than the mTOR-inhibitor monotherapy-based regimen. Early introduction of mTOR inhibitors is recommended, although it is worth noting that attention should be paid to wound healing when mTOR inhibitors are introduced early.

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Immunosuppression and Solid Organ Transplantation

Silva

2022

Atlas of Dermatologic Diseases in Solid Organ Transplant Recipients

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Everolimus with cyclosporine withdrawal or low-exposure cyclosporine in kidney transplantation from Month 3: a multicentre, randomized trial

Abstract: Everolimus initiation with CNI withdrawal at Month 3 after kidney transplantation achieves a significant improvement in renal function at 12 months, with a similar rate of acute rejection.

Cited by 33 publications

References 39 publications

Five-year outcomes in kidney transplant patients randomized to everolimus with cyclosporine withdrawal or low-exposure cyclosporine versus standard therapy

Five-year outcomes in kidney transplant patients randomized to everolimus with cyclosporine withdrawal or low-exposure cyclosporine versus standard therapy

The incidence of cytomegalovirus and BK polyomavirus infections in kidney transplant patients receiving mTOR inhibitors: A systematic review and meta‐analysis

Immunosuppression and Solid Organ Transplantation

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