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 micromol/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.