CMV and BKPyV Infections in Renal Transplant Recipients Receiving an mTOR Inhibitor-Based Regimen Versus a CNI-Based Regimen: A Systematic Review and Meta-Analysis of Randomized, Controlled Trials

Abstract

Background and objectives: The objective of this meta-analysis is to compare the incidences of cytomegalovirus and BK polyoma virus infections in renal transplant recipients receiving a mammalian target of rapamycin inhibitor (mTOR)-based regimen compared with a calcineurin inhibitor-based regimen.

Design, setting, participants, & measurements: We conducted a comprehensive search for randomized, controlled trials up to January of 2016 addressing our objective. Other outcomes included acute rejection, graft loss, serious adverse events, proteinuria, wound-healing complications, and eGFR. Two review authors selected eligible studies, abstracted data, and assessed risk of bias. We assessed quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation methodology.

Results: We included 28 randomized, controlled trials with 6211 participants classified into comparison 1: mTOR inhibitor versus calcineurin inhibitor and comparison 2: mTOR inhibitor plus reduced dose of calcineurin inhibitor versus regular dose of calcineurin inhibitor. Results showed decreased incidence of cytomegalovirus infection in mTOR inhibitor-based group in both comparison 1 (risk ratio, 0.54; 95% confidence interval, 0.41 to 0.72), with high quality of evidence, and comparison 2 (risk ratio, 0.43; 95% confidence interval, 0.24 to 0.80), with moderate quality of evidence. The available evidence neither confirmed nor ruled out a reduction of BK polyoma virus infection in mTOR inhibitor-based group in both comparisons. Secondary outcomes revealed more serious adverse events and acute rejections in mTOR inhibitor-based group in comparison 1 and no difference in comparison 2. There was no difference in graft loss in both comparisons. eGFR was higher in the mTOR inhibitor-based group in comparison 1 (mean difference =4.07 ml/min per 1.73 m²; 95% confidence interval, 1.34 to 6.80) and similar to the calcineurin inhibitor-based group in comparison 2. More proteinuria and wound-healing complications occurred in the mTOR inhibitor-based groups.

Conclusions: We found moderate- to high-quality evidence of reduced risk of cytomegalovirus infection in renal transplant recipients in the mTOR inhibitor-based compared with the calcineurin inhibitor-based regimen. Our review also suggested that a combination of a mTOR inhibitor and a reduced dose of calcineurin inhibitor may be associated with similar eGFR and rates of acute rejections and serious adverse events compared with a standard calcineurin inhibitor-based regimen at the expense of higher incidence of proteinuria and wound-healing complications.

Keywords: Assessment; BK virus; Calcineurin; Calcineurin Inhibitors; Calcineurin inhibitor; Confidence Intervals; Cytomegalovirus Infections; Incidence; Meta-analysis; Odds Ratio; Polyomavirus; Randomized Controlled Trials as Topic; Risk; Sirolimus; Wound Healing; cyclosporine; cytomegalovirus; everolimus; glomerular filtration rate; immunosuppression; kidney transplantation; proteinuria; sirolimus; tacrolimus.

Graphical abstract

Figure 1.

Preferred reporting items for systematic reviews and meta-analyses study flow chart. Of 5880 screened citations, we included 28 studies with a total of 6211 participants. CNI, calcineurin inhibitor; mTORi, mammalian target of rapamycin inhibitor; RCT, randomized, controlled trial.

Figure 2.

Forest plots, comparison 1. Results showed a significant 46% decreased risk of Cytomegalovirus infections in mTORi-based group and no significant difference between the two groups with regards to BK polyoma virus infection. (A) Cytomegalovirus infection. (B) BK polyoma virus infection. 95% CI, 95% confidence interval; CNI, calcineurin inhibitor; M-H, Mantel-Haenszel method; mTORi, mammalian target of rapamycin inhibitor.

Figure 3.

Forest plots, comparison 2. Results showed a significant 57% decreased risk of Cytomegalovirus infections in mTORi-based group and no significant difference between the two groups with regards to BK polyoma virus infection. (A) Cytomegalovirus infection. (B) BK polyoma virus infection. 95% CI, 95% confidence interval; CNI, calcineurin inhibitor; M-H, Mantel-Haenszel method; mTORi, mammalian target of rapamycin inhibitor.