Four studies were restricted to patients with chronic hepatitis C virus (HCV) infection25, 29-30, 37 and in five studies patients

with moderate to severe renal dysfunction were excluded.24, 33-35, 40 In most studies daclizumab was used for induction.23-26, 28-30, 32, 34, 38, 40 Concomitant immunosuppressive medication (see Supporting Table 1 for details) included MMF in most studies,24-32, 34, 37-40 prednisolone in all studies, and calcineurin inhibitors, i.e., tacrolimus in 13 studies23-27, 29-32, 34, 36, 38, 40 and cyclosporine A in the remaining five studies.28, 33, 35, 37, 39 One study was divided into two cohorts because of different concomitant immunosuppression.29 Most trials had a follow-up of 12 months or longer, but four trials had a study duration of only 3-6 months.23, 31-32, 39 Table 2 shows the quality assessment of PI3K inhibitor the included studies. Buparlisib cell line The risk of bias is summarized in Supporting Fig. 1. Two studies35, 39 were randomized, double-blinded, and placebo-controlled. Of the remaining 16 studies, 11 were randomized,23-25, 29-30, 33-34, 36-38, 40 three were nonrandomized,27, 28, 31 and whether randomization was performed or not

could not be determined in two studies26, 32 (for the analysis, these studies were assumed to be nonrandomized). All studies were entirely prospective except for one trial27 in which a prospective experimental group was compared to historical controls. Of the randomized trials, allocation concealment was found to be adequate in four trials.24, 33-35 In seven study reports26-28, 32, 36, 37, 40 the patient population for the statistical analysis was not clearly defined. ITT analysis was stated and performed in two studies,30, 33 and we assumed ITT analysis in three studies25, 31, 39 because the authors report on all patients at the end of the study. Four authors23, 24, 35,

34 defined patient subsets (e.g., “modified ITT” or “full analysis set”) for the primary analysis and, for example, excluded patients that did not receive any study medication or patients that did not have any follow-up. One author did not perform ITT analysis and did not state the reasons for exclusions of patients from the analysis.29 Most authors23, 25-28, 31-32, 35-39 did also not state how missing values were handled. Available case analysis for continuous variables was MCE evident from three studies24, 40, 29 and imputation by last-observation-carried forward was reported in three other studies.30, 33, 34 Reduction of acute rejection favored the use of IL-2Ra (RR 0.84; CI 0.76-0.94; P = 0.002; 19 trials/cohorts) and the effect is seen in randomized and nonrandomized studies (Fig. 2). Stratifying trials by time of measurement showed a significant reduction of acute rejection with IL-2Ra at 12 months or later (RR 0.83; CI 0.74-0.94; P = 0.004; 14 trials/cohorts) but not at 3-6 months (Supporting Fig. 2), although this study-level covariate was not significant in the meta-regression (P = 0.76, Table 3).