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Evidence summaries

Sirolimus and Everolimus for Primary Immunosuppression in Kidney Transplant Recipients

Target of rapamycin inhibitors (TOR-i) sirolimus and everolimus appear to be as effective as calcineurin inhibitors and antimetabolites for mortality and graft survival in kidney transplant recipients. They appear to cause more wound healing complications and needs to change treatment, but less cytomegalovirus infections. Level of evidence: "B"

A Cochrane review [Abstract] 1 included 70 studies with a total of 17 462 subjects. No differences in the hard-end points of patient and graft survival were demonstrated for or against TOR inhibitor (TORi; sirolimus and everolimus) in comparison with calcineurin inhibitors (CNI; ciclosporin or tacrolimus) and antimetabolites (azathioprine, mycophenolate) (table T1, T2). Need to change treatment and wound complications were higher with TOR-i, but there were less cytomegalovirus (CMV) infections (table T1, T2).

TOR-i versus CNI: outcomes up to 2 years (main outcomes) for primary immunosuppression

Outcomes (up to 2 years for primary outcomes)Relative effect(95% CI)Risk with CNIRisk with TOR-I (95% CI)No. of participants(studies)Certainty of the evidence
Death (all causes)RR 1.31(0.87 to 1.98)25 per 100033 per 1000(22 to 50)3618 (19) Moderate
Graft loss censored for deathRR 1.32(0.96 to 1.81)51 per 100068 per 1000(49 to 93)3277 (14) Moderate
CMV infectionRR 0.43(0.29 to 0.63)157 per 100068 per 1000(46 to 99)2026 (13) High
Adverse wound outcomes: all complicationsRR 2.56(1.94 to 3.36)77 per 1000198 per 1000(150 to 260)1679 (12) Moderate
Number needing to change treatmentRR 2.42(1.88 to 3.11)132 per 1000320 per 1000(249 to 412)3148 (14) Moderate

TOR-i versus antimetabolites: outcomes up to 2 years (main outcomes) for primary immunosuppression

Outcomes (up to 2 years for primary outcomes)Relative effect(95% CI)Risk with antimetabolitesRisk with TOR-I (95% CI)No. of participants(studies)Certainty of the evidence
Death (all causes)RR 1.06 (0.84 to 1.33)29 per 100031 per 1000(24 to 38)10 482 (31) Moderate
Graft loss censored for deathRR 1.09(0.82 to 1.45)35 per 100038 per 1000(29 to 51)8 966 (26) Moderate
CMV infectionRR 0.44(0.34 to 0.58)136 per 100059 per 1000(46 to 78)10 049 (26) Moderate
Adverse wound outcomes: all complicationsRR 1.56(1.28 to 1.90)155 per 1000241 per 1000 (199 to 297)6 913 (17) Moderate
Number needing to change treatmentRR 1.56 (1.28 to 1.90)174 per 1000248 per 1000(203 to 302)9747 (25) Moderate

A meta-analysis 2 included 28 RCTs with 6211 participants. There were less cytomegalovirus infections (RR 0.54, 95% CI 0.41 to 0.72; 19 trials, n=3914) and better creatinine clearance with mTORi compared with calcineurin inhibitor. There were no difference in graft loss (RR 1.10, 95% CI 0.74 to 1.65; 17 trials, n=3589), but more serious adverse events (RR 1.26, 95% CI 1.02 to 1.56; 7 trials, n=2173), proteinuria (RR 2.35, 95% CI 1.52 to 3.64; 12 trials, n=2844), and wound healing complications (RR 1.62, 95% CI 1.22 to 2.15; 7 trials, n=1826) with mTORi.

Comment: Data were limited beyond two years post-transplantation. The quality of evidence is downgraded by study quality (unclear allocation concealment in half of the studies).

    References

    • Hahn D, Hodson EM, Hamiwka LA et al. Target of rapamycin inhibitors (TOR-I; sirolimus and everolimus) for primary immunosuppression in kidney transplant recipients. Cochrane Database Syst Rev 2019;(12):CD004290.[PubMed]
    • Mallat SG, Tanios BY, Itani HS et al. 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. Clin J Am Soc Nephrol 2017;12(8):1321-1336. [PubMed]

Primary/Secondary Keywords