Research Article: Efficacy and Safety of Everolimus for Maintenance Immunosuppression of Kidney Transplantation: A Meta-Analysis of Randomized Controlled Trials

Date Published: January 20, 2017

Publisher: Public Library of Science

Author(s): Jinyu Liu, Dong Liu, Juan Li, Lan Zhu, Chengliang Zhang, Kai Lei, Qiling Xu, Ruxu You, Stanislaw Stepkowski.

http://doi.org/10.1371/journal.pone.0170246

Abstract

Conversion to everolimus is often used in kidney transplantation to overcome calcineurin inhibitor (CNI) nephrotoxicity but there is conflicting evidence for this approach.

To investigate the benefits and harm from randomized clinical trials (RCTs) involving the conversion from CNI to everolimus after kidney transplantation.

Databases were searched up to March 2016. Two reviewers independently assessed trials for eligibility and quality, and extracted data. Results are expressed as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI).

Eleven RCTs, with a total of 1,633 patients, met the final inclusion criteria. Patients converted to everolimus had improved renal function at 1 year posttransplant with an estimated glomerular filtration rate (eGFR) of 5.36 mL/min per 1.73 m2 greater than patients remaining on CNI (p = 0.0005) and the longer-term results (> 1 year) of renal function was identical to that of 1 year. There was not a substantial difference in graft loss, mortality, and the occurrence of adverse events (AEs) or serious AEs. However, the risks of acute rejection and trial termination due to AEs with everolimus are respectively 1.82 and 2.63 times greater than patients staying on CNI at 1 year posttransplant (p = 0.02, p = 0.03, respectively). Further, those patients who converted to everolimus had a substantially greater risk of anemia, hyperlipidemia, hypercholesterolemia, hypokalemia, proteinuria, stomatitis, mouth ulceration, and acne.

Conversion from CNI to everolimus after kidney transplantation is associated with improved renal function in the first 5 years posttransplant but increases the risk of acute rejection at 1 year posttransplant and may not be well endured.

Partial Text

Kidney transplantation is the treatment of choice for most patients with end-stage renal disease. Strategies to increase donor organ availability and to prolong the transplanted kidney’s survival have become priorities in kidney transplantation. Immunosuppressive therapy is essential and significant in this respect, nevertheless, but choosing the best suitable immunosuppressive therapy is still fairly complex. The calcineurin inhibitors (CNIs) are the principal components of immunosuppressive therapy after kidney transplantation and have made a major contribution to current long-term transplant outcomes[1, 2]. Meanwhile, tacrolimus has been recommended as a first-line agent for kidney transplantation recipients in kidney disease improving global outcomes (KDIGO) in 2009 [3]. However, CNIs are associated with a number of potentially serious side effects, including nephrotoxicity, diabetes, hypertension, and neurotoxicity that contribute to morbidity and mortality after transplantation [4–8]. Upon the fifth year, 90% of grafts revealed evidence of CNI-related lesions, and whereas early acute nephrotoxicity is typically reversible with CNI minimization; chronic lesions cannot be altered once initiated [5]. Furthermore, combined therapy with tacrolimus and mycophenolic acid may be associated with a particularly higher risk of BK infection [9], which is the significant and dangerous factor in the failure of the transplanted kidney. Therefore, diminishing or even eliminating CNI has become the focus of further optimization of immunosuppressive therapy in renal transplantation.

The findings from this meta-analysis establish that conversion from CNI to EVR-based maintenance immunosuppression after kidney transplantation is associated with an increased eGFR (about 10%, p < 0.01) up to 5 years after transplantation. There were no substantial differences in efficacy results between the 2 groups except that recipients who converted to EVR had a higher risk of acute graft rejection up to 1 year after transplantation. In terms of safety and tolerability, results were subordinate in the EVR group in contrast to the CNI group. The currently available randomized evidence indicates that conversion from CNI to EVR after kidney transplantation is associated with short and long-term improvements in GFR in a number of studies, but these findings must be balanced against the greater rates of proteinuria, discontinuation due to AEs, and higher incidences of acute rejection up to 1 year posttransplant with the use of EVR as compared with CNI. Moreover, late conversion to EVR might be associated with a trend toward better renal function and a lower risk of acute rejection up to 1 year posttransplantion than early conversion. Additionally, in deciding the optimal immunosuppression strategy for their patients, clinicians should be alert to the increased risk of bone marrow suppression, dyslipidemia, mouth ulceration, and stomatitis after conversion to EVR which, however, has no effect on graft and patient survival.   Source: http://doi.org/10.1371/journal.pone.0170246