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Webster AC, Lee VW, Chapman JR, Craig JC.
Transplantation. 2006 May 15;81(9):1234-48.
Target of rapamycin inhibitors (sirolimus and everolimus) for
primary immunosuppression of kidney transplant recipients: a systematic review
and meta-analysis of randomized trials.
Cochrane Renal Group, Children's Hospital at Westmead, Westmead,
and School of Public Health, University of Sydney, Sydney, Australia.
angela.webster@gmail.com
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: T
OR-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.
PMID: 16699448
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