Interleukin 2 receptor antagonists for kidney transplant recipients

Abstract

BACKGROUND: Interleukin 2 receptor antagonists (IL2Ra) are used as induction therapy for prophylaxis against acute rejection in kidney transplant recipients. Use of IL2Ra has increased steadily since their introduction, but the proportion of new transplant recipients receiving IL2Ra differs around the globe, with 27% of new kidney transplant recipients in the United States, and 70% in Australasia receiving IL2Ra in 2007. OBJECTIVES: To systematically identify and summarise the effects of using an IL2Ra, as an addition to standard therapy, or as an alternative to another immunosuppressive induction strategy. SEARCH STRATEGY: We searched the Cochrane Renal Group's specialised register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE to identify new records, and authors of included reports were contacted for clarification where necessary. SELECTION CRITERIA: Randomised controlled trials (RCTs) in all languages comparing IL2Ra to placebo, no treatment, other IL2Ra or other antibody therapy. DATA COLLECTION AND ANALYSIS: Data was extracted and assessed independently by two authors, with differences resolved by discussion. Dichotomous outcomes are reported as relative risk (RR) and continuous outcomes as mean difference (MD) with 95% confidence intervals (CI). MAIN RESULTS: We included 71 studies (306 reports, 10,537 participants). Where IL2Ra were compared with placebo (32 studies; 5,784 patients) graft loss including death with a functioning graft was reduced by 25% at six months (16 studies: RR 0.75, 95% CI 0.58 to 0.98) and one year (24 studies: RR 0.75, 95% CI 0.62 to 0.90), but not beyond this. At one year biopsy-proven acute rejection was reduced by 28% (14 studies: RR 0.72, 95% CI 0.64 to 0.81), and there was a 19% reduction in CMV disease (13 studies: RR 0.81, 95% CI 0.68 to 0.97). There was a 64% reduction in early malignancy within six months (8 studies: RR 0.36, 95% CI 0.15 to 0.86), and creatinine was lower (7 studies: MD -8.18 micromol/L 95% CI -14.28 to -2.09) but these differences were not sustained.When IL2Ra were compared to ATG (16 studies, 2211 participants), there was no difference in graft loss at any time point, or for acute rejection diagnosed clinically, but the was benefit of ATG therapy over IL2Ra for biopsy-proven acute rejection at one year (8 studies:, RR 1.30 95% CI 1.01 to 1.67), but at the cost of a 75% increase in malignancy (7 studies: RR 0.25 95% CI 0.07 to 0.87) and a 32% increase in CMV disease (13 studies: RR 0.68 95% CI 0.50 to 0.93). Serum creatinine was significantly lower for IL2Ra treated patients at six months (4 studies: MD -11.20 micromol/L 95% CI -19.94 to -2.09). ATG patients experienced significantly more fever, cytokine release syndrome and other adverse reactions to drug administration and more leucopenia but not thrombocytopenia. There were no significant differences in outcomes according to cyclosporine or tacrolimus use, azathioprine or mycophenolate, or to the study populations baseline risk for acute rejection. There was no evidence that effects were different according to whether equine or rabbit ATG was used. AUTHORS' CONCLUSIONS: Given a 38% risk of rejection, per 100 recipients compared with no treatment, nine recipients would need treatment with IL2Ra to prevent one recipient having rejection, 42 to prevent one graft loss, and 38 to prevent one having CMV disease over the first year post-transplantation. Compared with ATG treatment, ATG may prevent some experiencing acute rejection, but 16 recipients would need IL2Ra to prevent one having CMV, but 58 would need IL2Ra to prevent one having malignancy. There are no apparent differences between basiliximab and daclizumab. IL2Ra are as effective as other antibody therapies and with significantly fewer side effects.