89; CI 0.80-0.98; P = 0.02). Six trials reported data on steroid-resistant rejection23-24, 27, 35-36, 39 measured at 3,23, 39 6,24 or 12 and more months.27, 35-36 Random effects analysis shows that the incidence of steroid-resistant rejection was

significantly lower in the experimental group (RR 0.66; CI 0.48-0.91; P = 0.011; six trials; Fig. 3, Table 3). Meta-regression and subgroup analysis showed that the effect is evident only in randomized trials (RR 0.65; CI 0.47-0.91; P = 0.011; five trials) and at three to six months (RR 0.44; CI 0.21-0.94; P = 0.03; three trials), but not at 12 months or later. Furthermore, we did not observe BGJ398 other significant covariates and there was no significant heterogeneity in any of the analyses (Table 4). Fifteen studies23-24,

27-38, 40 reported data on graft loss and all but one trial39 reported data on patient death. Random effects analysis showed insignificant Belnacasan supplier effects for both graft loss (Fig. 4) and patient death (Fig. 5). In the meta-regression (Table 3) we only found measurements of graft loss at 12 months or later to be significantly lower than measurements at 3-6 months (ratio of RR 0.60; CI 0.38-0.94; P = 0.03), but subgroup analysis did not show significant effects in either subgroup. There was only marginal heterogeneity in all analyses and funnel plot analysis suggested only missing studies at RR higher than one. In six trials,24, 26, 31, 34, 39-40 immunosuppression with IL-2Ra in combination with delayed or reduced CNI was compared to standard immunosuppression without IL-2Ra (comparison 2). The rationale of avoiding early and standard dose CNI is to

reduce the adverse effects of CNI, especially nephrotoxicity.43 In the subgroup of comparison 2 we therefore planned to analyze mid- to long-term renal function by comparing the appropriate surrogate markers, i.e., serum creatinine and/or eGFR. Of the six trials two reported only the incidence of renal dysfunction but not eGFR or creatinine,26, 39 another two reported only either eGFR or creatinine,31, 40 and two trials reported both.18, 34 GFR was either estimated by Cockcroft-Gault44 Fluorometholone Acetate or the MDRD formula.45 In studies included in comparison 2, both the analysis of eGFR and of serum creatinine favored the use of IL-2Ra (see Table 4). The analysis of serum creatinine in all comparisons revealed no difference in effect but significant heterogeneity (P = 0.008). Sources of heterogeneity were explored by meta-regression and we found that opposing effects in studies from comparison 2 and 3 caused considerable heterogeneity (P = 0.007). A limited number of trials reported data on complications, side effects, and (serious) adverse events (AE/SAE). We found no differences in the incidence of infection, malignancy, and overall AE/SAE (Table 4). Posttransplant diabetes mellitus (PTDM) was less common in patients treated with IL2-Ra (RR 0.56; CI 0.39-0.82; P = 0.