Target of rapamycin inhibitors (Sirolimus and Everolimus) for primary immunosuppression of kidney transplant recipients: A systematic review and meta-analysis of randomized trials

Background. Target of rapamycin inhibitors (TOR-1) have a novel mode of action but uncertain clinical role. We performed a systematic review of randomized trials where immunosuppressive regimens containing TOR-1 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 (0). Results. Thirty-three trials (142 reports) were included (27 trials of sirolimus, 5 of everolimus, and 1 of head-to-head comparison). When TOR-1 replaced calcineurin inhibitors (CNI) (8 trials with 750 participants), there was no difference in acute rejection (RR, 1.03;95% Cl, 0.74-1.44), but serum creatinine was lower (WMD, - 18.31 mu mol/L; 95% Cl, -30.96 to -5.67) and bone marrow more suppressed (leukopenia: RR 2.02; 95% Cl, 1.12-3.66; thrombocytopenia: RR, 6.97; 95% Cl, 2.97-16.36; and anaemia: RR, 1.67; 95% Cl, 1.27-2.20). When TOR-1 replaced antimetabolites (I I 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% Cl, 0.37-0.65, respectively), but hypercholesterolemia was increased (RR, 1.65; 95% Cl, 1.32-2.06). When low- was compared with high-dose TOR-1, with equal CNI dose (10 trials with 3,175 participants), rejection was increased (RR, 1.23; 95% Cl, 1.06-1.43) but calculated glomerular filtration rate (GFR) higher (WMD, 4.27 mL/min; 95% Cl, 1. 12-7.4 1), and when lower-dose TOR-I and standard-dose CNI were compared with higherdose TOR-1 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% Cl, - 12.16 to -6.76). There was no significant difference in mortality, graft loss, or malignancy risk for TOR-1 in any comparison. Conclusions. TOR-1 have been evaluated in four different primary immuncisuppressive 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-1 (lower risk of acute rejection and higher GFR), and surrogate endpoints for patient outcomes are worsened by TOR-1 (bone marrow suppression and lipid disturbance). Long-term hard-endpoint data from methodologically robust randomized trials are still required.