primary outcome:
Target of rapamycin inhibitors (TOR‐I; sirolimus and everolimus) for primary immunosuppression in kidney transplant recipients
Death (all causes)All‐cause graft loss (death with functioning allograft or dependence on dialysis)Graft loss censored for death with functioning allograftAll acute rejection and biopsy‐proven acute rejectionIncidence of cytomegalovirus (CMV) infections (all definitions), with diagnosis by culture, serology, antigen or antibody testing, or as specified by authors.All adverse wound outcomes and lymphocoeleAll malignanciesNumber needing to change treatment.Probably makes little or no difference to death (Analysis 1.1 (19 studies, 3618 participants): RR 1.31, 95% CI 0.87 to 1.98; I2 = 0%) (moderate certainty evidence).Probably increases graft loss uncensored for death (Analysis 1.2 (20 studies, 3619 participants): RR 1.41, 95% CI 1.11 to 1.80; I2 = 0%) and censored for death (Analysis 1.3 (15 studies, 3277 participants): RR 1.32, 95% CI 0.96 to 1.81; I2 = 0%) (moderate certainty of evidence). When graft loss was reported for subgroups according to CNI administered, TOR‐I compared with tacrolimus probably slightly increases graft loss while TOR‐I compared with cyclosporin probably makes little or no difference to graft loss uncensored for death (Analysis 1.2.1; Analysis 1.2.2) or censored for death (Analysis 1.3.1; Analysis 1.3.2).Probably increases all acute rejection (Analysis 1.4 (19 studies, 3019 participants): RR 1.58, 95% CI 1.30 to 1.91; I2 = 21%) and biopsy‐proven rejection (Analysis 1.5 (15 studies, 2708 participants): RR 1.60, 95% CI 1.25 to 2.04; I2 = 35%) (moderate certainty evidence).Reduces the risk of CMV infection (Analysis 1.6 (13 studies, 2026 participants): RR 0.43, 95% CI 0.29 to 0.63; I2 = 27%) (high certainty evidence).Probably increases the risk of all wound complications (Analysis 1.7.1 (12 studies, 1679 participants): RR 2.56, 95% CI 1.94 to 3.36; pI2 = 0%) and of lymphocoele (Analysis 1.7.2 (8 studies, 2538): RR 2.29, 95% CI 1.73 to 3.02; I2 = 0%) (moderate certainty evidence).Probably increases the need to change immunosuppressive therapy‐related to adverse events (Analysis 1.9 (14 studies, 3148 participants): RR 2.42, 95% CI 1.88 to 3.11; I2 = 52%) (moderate certainty evidence).Probably makes little or no difference to all malignancies (Analysis 1.8 (10 studies, 2584 participants): RR 0.86, 95% CI 0.50 to 1.48; I2 = 0%) (moderate certainty evidence).A small substudy of SYMPHONY 2007 involving 156 participants found no difference in health‐related quality of life between participants receiving TOR‐I and those receiving CNI.Probably makes little or no difference to death (Analysis 4.1 (31 studies, 10,482 participants): RR 1.06, 95% CI 0.84 to 1.33; I2 = 0%) (moderate certainty evidence).Probably makes little or no difference to graft loss (uncensored) (Analysis 4.2 (27 studies, 7626 participants): RR 1.14, 95% CI 0.93 to 1.40; I2 = 8%) or graft loss (censored for death) (Analysis 4.3 (26 studies, 8966 participants): RR 1.09, 95% CI 0.82 to 1.45; I2 = 25%) (moderate certainty evidence).Probably makes little or no difference to all acute rejection (Analysis 4.4 (31 studies, 10,075 participants): RR 0.90, 95% CI 0.79 to 1.02; I2 = 35%) or to biopsy‐proven acute rejection (Analysis 4.5 (24 studies, 10,101 participants): RR 0.95, 95% CI 0.81 to 1.12; I2 = 51%) (moderate certainty evidence). In sensitivity analyses for both outcomes, heterogeneity was reduced below 30% by exclusion of ATHENA 2016 and Qazi 2017. These studies showed reduced biopsy‐proven acute rejection with TOR‐I in contrast to other studies, which showed no differences. Subgroup analysis demonstrated that TOR‐I with reduced dose CNI, compared with antimetabolite and CNI, probably makes little or no difference to the number with biopsy‐proven acute rejection (Analysis 4.5)Probably reduces the risk of CMV infection (Analysis 4.6 (26 studies, 10,049 participants): RR 0.44, 95% CI 0.34 to 0.58; I2 = 68%) (moderate certainty evidence). Heterogeneity of the results may have been due to different reporting of CMV infection and/or disease in different studies.Probably increases the risk of all wound complications (Analysis 4.7.1 (17 studies, 6913 participants): RR 1.56, 95% CI 1.28 to 1.91; I2 = 59%) and the risk of lymphocoele (Analysis 4.7.2 (16 studies, 8415 participants): RR 1.55, 95% CI 1.32 to 1.81; I2 = 0%) (moderate certainty evidence). Heterogeneity in the risk of all wound complications was reduced by exclusion of ATHENA 2016.Probably makes little or no difference to the risk of malignancies (Analysis 4.8 (17 studies, 8799 participants): RR 0.83, 95% CI 0.64 to 1.07; I2 = 7%) (moderate certainty evidence).Probably increases the need to change immunosuppressive treatment because of adverse effects (Analysis 4.9 (25 studies, 9747 participants): RR 1.56, 95% CI 1.28 to 1.90; I2 = 71%) (moderate certainty evidence). Heterogeneity between studies was reduced by exclusion of Anil Kumar 2008, Kahan‐301 2000 and Tedesco‐Silva 2015,which found that TOR‐I were not associated with an increase in the need to change immunosuppressive therapy.Probably makes little or no difference to death (all causes) (Analysis 7.1 (9 studies, 1501 participants): RR 1.07, 95% CI 0.64 to 1.78; I2 = 0%) (moderate certainty evidence).Probably makes little of no difference to all graft loss (Analysis 7.2 (8 studies, 1385 participants): RR 1.09, 95% CI 0.68 to 1.75; I2 = 21%) and graft loss censored for death (Analysis 7.3 (8 studies, 1385 participants): RR 1.09, 95% CI 0.54 to 2.20; I2 = 25%) (moderate certainty evidence).Probably makes little or no difference to all acute rejection (Analysis 7.4 (9 studies, 1509 participants): RR 0.84, 95% CI 0.67 to 1.07; I2 = 0%) and biopsy‐proven acute rejection (Analysis 7.5 (8 studies, 1381 participants): RR 0.87, 95% CI 0.67 to 1.13; I2 = 0%) (moderate certainty evidence).May make little or no difference to CMV infection (Analysis 7.6 (5 studies, 865 participants): RR 1.42, 95% CI 0.78 to 2.60; I2 = 0%) (low certainty evidence).May make little or no difference to all wound complications (Analysis 7.7.1 (3 studies, 291 participants): RR 0.95, 95% CI 0.53 to 1.71; I2 = 0%) or lymphocoele Analysis 7.7.2 (3 studies, 702 participants): RR 0.86, 95% CI 0.45 to 1.63; I2 = 46%) (low certainty evidence).May make little or no difference to malignancies (Analysis 7.8 (7 studies, 1163 participants): RR 1.04, 95% CI 0.36 to 3.04; I2 = 0%) (low certainty evidence).May make little of no difference to the number of participants needing to change treatment (Analysis 7.9 (5 studies, 734 participants): RR 1.18, 95% CI 0.58 to 2.42; I2 = 76%) (low certainty evidence).Probably makes little or no difference to death (Analysis 9.1 (13 studies, 3894 participants): RR 0.89, 95% CI 0.63 to 1.25; I2 = 0%) (moderate certainty evidence).Probably makes little or no difference to overall graft loss (Analysis 9.2 (11 studies, 3476 participants): RR 0.84, 95% CI 0.67 to 1.06; I2 = 0%) and graft loss censored for death (Analysis 9.3 (12 studies, 3863 participants): RR 0.92, 95% CI 0.71 to 1.19; I2 = 0%) (moderate certainty evidence).Probably slightly increases the risk of acute rejection (Analysis 9.4 (13 studies, 3898 participants): RR 1.25, 95% CI 1.10 to 1.42; I2 = 0%) and biopsy‐proven acute rejection (Analysis 9.5 (11 studies, 3731 participants): RR 1.26, 95% CI 1.10 to 1.43; I2 = 0%) (moderate certainly evidence).Probably makes little or no difference to the risk of CMV infection (Analysis 9.6 (9 studies, 2099 participants): RR 0.87, 95% CI 0.63 to 1.21; I2 = 0%) (moderate certainty evidence).Probably makes little or no difference to the risk of malignancy (Analysis 9.7 (10 studies, 3175 participants): RR 0.84, 95% CI 0.54 to 1.32; I2 = 0%) (moderate certainty evidence).Probably makes little or no difference to the risk of all wound complications (Analysis 9.8.1 (7 studies, 2792 participants): RR 0.92, 95% CI 0.66 to 1.29; I2 = 61%) or lymphocoele (Analysis 9.8.2 (10 studies, 3302 participants): RR 0.81, 95% CI 0.63 to 1.04; I2 = 29%) (moderate certainty evidence).May make little or no difference to the need for treatment change (Analysis 9.9 (10 studies, 3652 participants): RR 0.91, 95% CI 0.78 to 1.05; I2 = 52%) (low certainty evidence).