Background.

Target of rapamycin inhibitors (TOR-I) have a novel mode of action but uncertain clinical role. We performed a systematic review of randomized trials where immunosuppressive regimens containing TOR-I were compared with other regimens as initial therapy for kidney transplant recipients.

Methods.

Databases (inception, June 2005) and conference proceedings (1996–2005) were searched. Two independent reviewers assessed trials for eligibility and quality. Results at 1 year, are expressed as relative risk (RR), where values< 1 favor TOR-I, or lower dose of TOR-I, and for continuous outcomes are expressed as weighted mean difference (WMD), both expressed with 95% confidence intervals (CI).

Results.

Thirty-three trials (142 reports) were included (27 trials of sirolimus, 5 of everolimus, and 1 of head-to-head comparison). When TOR-I replaced calcineurin inhibitors (CNI)(8 trials with 750 participants), there was no difference in acute rejection (RR, 1.03; 95% CI, 0.74–1.44), but serum creatinine was lower (WMD,− 18.31 μmol/L; 95% CI,− 30.96 to− 5.67) and bone marrow more suppressed (leukopenia: RR 2.02; 95% CI, 1.12–3.66; thrombocytopenia: RR, 6.97; 95% CI, 2.97–16.36; and anaemia: RR, 1.67; 95% CI, 1.27–2.20). When TOR-I replaced antimetabolites (11 trials with 3966 participants), acute rejection and cytomegalovirus infection (CMV) were reduced (RR, 0.84; 95% CI, 0.71–0.99; RR, 0.49; 95% CI, 0.37–0.65, respectively), but hypercholesterolemia was increased (RR, 1.65; 95% CI, 1.32–2.06). When low-was compared with high-dose TOR-I, with equal CNI dose (10 trials with 3,175 participants), rejection was increased (RR, 1.23; 95% CI, 1.06–1.43) but calculated glomerular filtration rate (GFR) higher (WMD, 4.27 mL/min; 95% CI, 1.12–7.41), and when lower-dose TOR-I and standard-dose CNI were compared with higher-dose TOR-I and reduced CNI, acute rejection was reduced (RR, 0.67; 95% CI, 0.52–0.88), but calculated GFR was also reduced (WMD,− 9.46 mL/min; 95% CI,− 12.16 to− 6.76). There was no significant difference in mortality, graft loss, or malignancy risk for TOR-I in any comparison.

Conclusions.

TOR-I have been evaluated in four different primary immunosuppressive algorithms: as replacement for CNI and antimetabolites, in combination with CNI at low and high doses, and with a variable dose of CNI. Generally, surrogate endpoints for graft survival favor TOR-I (lower risk of acute rejection and higher GFR), and surrogate endpoints for patient outcomes are worsened by TOR-I (bone marrow suppression and lipid disturbance). Long-term hard-endpoint data from methodologically robust randomized trials are still required.