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Mammalian Target of Rapamycin Inhibitors Combined With Calcineurin Inhibitors as Initial Immunosuppression in Renal Transplantation

A Meta-analysis

Montero, Nuria MD, PhD1; Quero, Maria MD1; Melilli, Edoardo MD, PhD1; Pérez-Sáez, María José MD, PhD2; Redondo-Pachón, Dolores MD, PhD2; Bestard, Oriol MD, PhD1; Crespo, Marta MD, PhD2; Cruzado, Josep M. MD, PhD1; Pascual, Julio MD, PhD2

doi: 10.1097/TP.0000000000002769

Background. The current standard of care immunosuppressive regimen in kidney transplantation (KT) includes a combination of mycophenolates (MMF/MPA) with a calcineurin inhibitor (CNI).

Methods. We designed a systematic review including all randomized clinical trials (RCTs) assessing the outcomes in KT recipients receiving mTORi + CNI compared with regimens containing MMF/MPA or azathioprine with CNI.

Results. A total of 24 studies with 7356 participants were included. The comparison between mTORi-CNI and MMF/MPA-CNI did not show differences in acute rejection, mortality, or graft loss rates. Better graft function was observed using MMF/MPA-CNI than using mTORi + CNI, but this difference was not evident when the mTORi was associated with reduced dose CNI in more recent studies with everolimus. Dyslipidemia, lymphoceles, and impaired wound healing were more frequent with mTORi-CNI and diarrhea and leukopenia were more frequent with MMF/MPA-CNI. Viral infections at any time and malignant neoplasia beyond 2 years were less frequent with mTORi-CNI. Rates of discontinuation because of adverse effects in the mTORi groups varied between 17% and 46% compared to 0%–26.6% in MMF/MPA groups. The current use of lower mTORi dosage has decreased the discontinuation rates.

Conclusions. Efficacy is similar with mTORi + CNI and MMF/MPA-CNI. The safety profile is the predominant difference between the 2 regimens.

1 Department of Nephrology, Hospital Universitari de Bellvitge, Barcelona, Spain.

2 Department of Nephrology, Hospital del Mar, Barcelona, Spain.

Received 25 September 2018. Revision received 1 April 2019.

Accepted 4 April 2019.

Disclosure: The authors declare no conflicts of interest.

This study was performed with funding from projects PI13/00598 and PI16/00619 (Spanish Ministry of Health ISCIII FIS-FEDER), RD16/0009/0013 and RD16/0009/0003 (ISCIII FEDER RedinRen). N.M. did this work as part of her doctoral thesis at the Universitat de Barcelona.

N.M. drafted the protocol, planned the study, selected and assessed the studies, extracted data, performed the analysis, and prepared the article. M.Q. assessed studies and extracted data. E.M. selected the studies. M.Q., E.M., M.P., D.R., O.B.M.C., and J.C. assisted in article review. J.P. planned the study and assisted in the data analysis, article preparation, and review. All authors read and approved the final article.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (

Correspondence: Julio Pascual, MD, PhD, Department of Nephrology, Hospital del Mar, Passeig Marítim 25–29, Barcelona 08003, Spain. (

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