Interleukin 2 receptor antagonists for kidney transplant recipients

Angela C Webster; Lorenn P Ruster; Richard G McGee; Sandra L Matheson; Gail Y Higgins; Narelle S Willis; Jeremy R Chapman; Jonathan C Craig

doi:10.1002/14651858.CD003897.pub3

. 2010 Jan 20;2010(1):CD003897. doi: 10.1002/14651858.CD003897.pub3

Interleukin 2 receptor antagonists for kidney transplant recipients

Angela C Webster ^1,^✉, Lorenn P Ruster ², Richard G McGee ³, Sandra L Matheson ², Gail Y Higgins ⁴, Narelle S Willis ⁴, Jeremy R Chapman ⁵, Jonathan C Craig ³

Editor: Cochrane Kidney and Transplant Group

PMCID: PMC7154335 PMID: 20091551

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 methods

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, 10,520 participants). Where IL2Ra were compared with placebo (32 studies; 5,854 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 µmol/L 95% CI ‐14.28 to ‐2.09) but these differences were not sustained.

When IL2Ra were compared to ATG (18 studies, 1,844 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 µmol/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.

Plain language summary

Interleukin 2 receptor antagonists (IL2Ra) reduce the risk of acute rejection episodes at six and twelve months after kidney transplantation

Acute rejection is a major problem in the early period following kidney transplantation. Immunosuppressive drugs are used to prevent this. IL2Ra, a newer antibody therapy, can be added to a patient's existing immunosuppression to further reduce the risk of rejection. This review found that adding IL2Ra reduced the risk of graft loss or death with a functioning transplant, acute rejection, and early malignancy, but did not improve patient survival. Compared to ATG, another possible antibody option, IL2Ra treatment caused less CMV disease and malignancy and had fewer side effects, but although there was no difference in clinically diagnosed acute rejection, IL2Ra treatment resulted in more biopsy proven rejection at 1 year.

Background

Kidney transplantation is the treatment of choice for patients with end‐stage kidney disease (ESKD). In the developed world there are approximately 280 patients per million population (pmp) with a functioning kidney transplant. The transplant rate is around 30 pmp and between 30‐50% of transplanted organs come from living donors. Graft survival beyond five years has remained unchanged since the 1970s, with an average annual decline of approximately 5%. Waiting lists for transplantation continue to grow, demand exceeding organ availability. Strategies to increase donor organ availability and to prolong kidney allograft survival have become priorities in kidney transplantation (ANZDATA 2008; OPTN/SRTR 2008; UK National Transplant Database 2009; UK Renal Registry report 2007).

Transplant outcome is influenced by many factors. In the absence of immunosuppression, transplanted organs undergo progressive immune mediated injury (rejection). Standard immunosuppressive therapy consists of initial induction and then maintenance regimens to prevent rejection, with short courses of more intensive immunosuppressive therapy to treat episodes of acute rejection. Standard protocols in use typically involve three drug groups each directed to a site in the T‐cell activation and proliferation cascade which is central to the rejection process: calcineurin inhibitors (e.g. cyclosporin, tacrolimus), anti‐proliferative agents (e.g. azathioprine, mycophenolate mofetil) and steroids (prednisolone) (Hong 2000).

Short‐term graft survival is related to control of the acute rejection process. The risk of graft rejection is greatest in the immediate post‐transplant period, and immunosuppression is therefore initiated at high levels. This is either by using higher doses of the agents used in maintenance therapy, or by adding an additional immunosuppressive induction agent. The potential induction agents are an anti‐T cell antibody preparation, either a polyclonal anti‐lymphocyte antibody (e.g. anti‐thymocyte globulin (ATG)) or a monoclonal antibody (e.g. muromonab‐CD3), or an interleukin 2 receptor antibody (IL2Ra, also sometimes called anti‐CD25 antibodies).

IL2Ra are humanised or chimeric (murine/human) IgG monoclonal antibodies to the alpha subunit of the IL2 receptor present only on activated T lymphocytes. The binding of IL2 to its receptor induces second messenger signals to stimulate the T cell to enter the cell cycle and proliferate, resulting in clonal expansion and differentiation. IL2Ra inhibit this IL2 mediated activation. The rationale for use of IL2Ra has been as induction agents in combination with standard agents to try to prevent acute rejection, or to minimise exposure to the calcineurin inhibitors (particularly in recipients deemed at high risk of delayed initial graft function) thereby ameliorating their short and long‐term nephrotoxic side effects (so called calcineurin inhibitor sparing regimes) (Cibrik 2001; Goebel 2000)

Current opinion favours minimising early graft injury by using induction therapy (including IL2Ra) to prevent acute rejection, particularly in patients at high risk of early acute rejection . High‐risk groups include young adults and children, recipients of kidney with pancreas transplant, African‐Americans, and immunologically 'sensitised' patients. Sensitised patients are those with high titres of preformed circulating anti‐HLA antibodies, which can be estimated by testing Panel Reactive Antibodies (PRA) and other related tests. These circulating anti‐HLA antibodies may come about as a result of underlying illness, previous transplantation, previous pregnancy or blood transfusion. However there is no evidence that a decrease in early rejection rates translates into a uniform increase in long‐term graft survival for all. There is concern that newer drugs or combinations of drugs, whilst apparently improving early graft outcome by reducing early acute rejection episodes, may in fact increase the risk of malignant or cardiovascular disease in the medium and longer term, thereby curtailing patient survival (i.e. increasing death with a functioning allograft). (Pascual 2001; Vanrenterghem 2001)

There is considerable variability in the use of immunosuppressive agents both geographically and within patient groups. There is also variation in terms of the combinations of agents chosen and the dosage regimens employed. This variation is partly, but not completely, explained by different perceptions of the relative potency and specificity of different immunosuppressive regimens. In the Unites States in 2007, 27% of new kidney recipients received an IL2Ra as induction therapy, and 45% received an ATG preparation, whereas in Australia 70% received an IL2Ra and only 5% an ATG preparation (ANZDATA 2008; OPTN/SRTR 2008).

We originally reviewed the randomised control trial (RCT) evidence of benefits and harms of IL2Ra, compared with no treatment, or compared with another immunosuppressive strategy, in 2004 (Webster 2004). The aim of this review was to update the short and longer‐term benefits and harms of IL2Ra in kidney transplant recipients with new evidence from RCTs.

Objectives

To update the evidence and evaluate the benefits and harms of IL2Ra in kidney transplant recipients, when they are added to a standard dual or triple therapy regimen or when compared to another induction agent or immunosuppressive strategy.

To determine whether the benefits and harms vary in absolute or relative terms dependant on the type of IL2Ra (basiliximab or daclizumab), the co‐interventions used, or the population sub group of transplant recipients.

Methods

Criteria for considering studies for this review

Types of studies

All RCTs and quasi‐RCTs, whether published or unpublished, in which IL2Ra were used to treat kidney transplant recipients.

Types of participants

Adults and children with ESKD that are the recipient of a first or subsequent cadaveric or living donor kidney transplant. Recipients who received another solid organ in addition to a kidney transplant (e.g. kidney and pancreas) were excluded.

Types of interventions

IL2Ra given in the intra operative period or at any time post‐transplantation, in combination with any other immunosuppressive agents for any declared rationale (e.g. induction therapy, or prophylaxis against rejection, or calcineurin sparing etc). All dosage regimens were included.
Control patients receive no IL2Ra, placebo, a different IL2Ra or a different dosage of IL2Ra, or another agent that the IL2Ra arm did not receive.

Types of outcome measures

The outcome measures relate to those used by transplant registries to assess patient and graft survival. Outcome events were assessed at one, three and six months, one year, and two to five years post‐transplant.

Primary outcomes

Patient mortality (all‐cause)
Graft loss or death with a functioning allograft
Graft loss censored for death with a functioning graft (loss of graft function resulting in dependence on dialysis)
Incidence of acute rejection (classified as clinically suspected and treated, or biopsy proven, or steroid resistant)

Secondary outcomes

Incidence of malignancy (all‐site)
Incidence of post‐transplant lymphoproliferative disease (PTLD) and lymphoma
Incidence of Cytomegalovirus (CMV) disease, diagnosed by culture, serology, antigen or antibody testing, or as specified by authors.
Incidence of new onset post‐transplant diabetes mellitus (PTDM)
Incidence of treatment related adverse reactions (including reactions to drug administration, and also haematological adverse reactions)

NEW OUTCOMES added for the review update, but not present in the original review

Transplant function, measured by
- serum creatinine
- directly measured or estimated glomerular filtration rate (GFR)

Search methods for identification of studies

Initial review

The literature search from the original review used search strategies detailed in Appendix 1, and consisted of;

Cochrane Renal Group specialised register of RCTs (June 2003). Cochrane Central Register of Controlled Trials (CENTRAL ‐ issue 3, 2003 in The Cochrane Library) for any "New" records not yet incorporated in the specialised register,
MEDLINE and Pre MEDLINE (1966 to November 2002) were searched using the above terms, combined with the optimally sensitive strategy for the identification of RCTs Dickersin 1994.
EMBASE (1980 to November 2003) was searched using terms similar to those used for MEDLINE and combined with a search strategy for the identification of RCTs Lefebvre 1996.
Reference lists of nephrology textbooks, review articles and relevant studies.
Conference proceeding's abstracts from nephrology scientific meetings.
Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies.

Review update

For the update of this review, the following sources were used.

Cochrane Renal Group specialised register of RCTs.
Cochrane Central Register of Controlled Trials (CENTRAL ‐ issue 4, 2009) in The Cochrane Library) for any "New" records not yet incorporated in the specialised register.
MEDLINE (2009) were searched using the above terms, combined with the optimally sensitive strategy for the identification of RCTs (Glanville 2006).
EMBASE (2009) was searched using terms similar to those used for MEDLINE and combined with a search strategy for the identification of RCTs (Lefebvre 2008)

Note: The Cochrane Renal Group's specialised register contains studies identified from:

Quarterly searched of CENTRAL
Weekly searches of MEDLINE
Handsearched results of journals and the proceedings of major conferences (Renal Group 2009).

The electronic search strategies used are in Appendix 1.

Data collection and analysis

The review update was undertaken by seven authors (ACW, LPR, RMG, SLM, GYH, NSW, JCC).

Selection of studies

The search strategy described was performed to identify eligible studies (GYH). The titles and abstracts were independently screened by two authors (of ACW, LPR, SLM, RMG). Where necessary, the full text was independently assessed by two authors. Disagreement about inclusion was resolved by discussion (ACW, NSW).

Where duplicate reports of the same study were suspected, where necessary authors were contacted for clarification. If duplication was confirmed, the initial first complete publication was selected (the 'index' publication) and was the primary data source, but any other additional prior or subsequent reports were also included. These additional prior or subsequent reports containing additional outcome data (such as longer‐term follow‐up, or different outcomes) also contributed to the meta‐analysis. Studies were named using the family name of the first author of the earliest full report of the study to appear in a peer‐reviewed journal, together with the year of publication. Where no peer‐reviewed journal article was identified, the study was named using the family name of the first author of the earliest report, and the calendar year of that report.

Data extraction and management

Data extraction was performed independently by two authors (of ACW, LPR, SLM, RMG, NSW) using a standardised form. Authors of published work were contacted for clarification of unclear data, and any data they provided was incorporated (see acknowledgements). Data was entered into RevMan (AW, SLM, RMG).

Assessment of risk of bias in included studies

Quality of studies was assessed independently by two authors (of ACW, LPR, SLM, RMG) without blinding to journal or authorship. Discrepancies were resolved by discussion (ACW, JCC, NSW). The quality items were assessed using the risk of bias assessment tool (Higgins 2008) (seeAppendix 2), with each of the six risk of bias domain assessed as yes, no or unclear.

Was there adequate sequence generation?
Was allocation adequately concealed?
Was knowledge of the allocated interventions adequately prevented during the study (objective and subjective outcomes)?
Were incomplete outcome data adequately addressed (intention‐to‐treat analysis)?
Are reports of the study free of suggestion of selective outcome reporting?
Was the study apparently free of other problems that could put it at a risk of bias?

Measures of treatment effect

For dichotomous outcomes (e.g. malignancy or no malignancy) results were expressed as risk ratio (RR), and continuous outcomes were expressed as mean difference (MD), both with 95% confidence intervals (CI).

Dealing with missing data

Where a study reported outcome data after excluding some randomised participants from the denominator, if sufficient information was reported elsewhere, or was supplied by the study authors, we re‐included missing data in the analyses.

In studies where the standard deviation was not reported, it was calculated where possible (e.g. from the standard error) or inferred from available data by imputation (Higgins 2008).

Assessment of heterogeneity

Heterogeneity amongst study results was analysed using a Cochran Q test (n ‐1 degrees of freedom), with P < 0.05 used to denote statistical significance, and with I² calculated to measure the proportion of total variation in the estimates of treatment effect that was due to heterogeneity beyond chance (Higgins 2003).

Assessment of reporting biases

Potential for publication bias was assessed for the primary outcomes and for CMV disease and malignancy, using funnel plots of the log odds ratio (OR) (Egger 1997).

Data synthesis

Data was extracted first from individual studies and then pooled for summary estimates using a random effects model. The random effects model was chosen as it provides a more conservative estimate of effect in the presence of known or unknown potential heterogeneity (Deeks 2001).

Meta‐regression was performed for the following outcomes: all‐cause mortality, graft loss (death censored), acute rejection, CMV disease and malignancy, using data from all studies reporting these outcomes at any time within the first year post‐transplantation, with a priori subgroups listed above as explanatory variables (see below). Meta‐regression was undertaken on the log RR scale using STATA software (Stata11, StataCorp LP, Texas, USA), each study weighting equal to the inverse of the variance of the estimate for that study, with between study variance estimated using the restricted maximum‐likelihood method.

Subgroup analysis and investigation of heterogeneity

Stratified meta‐analysis and meta‐regression were used to explore important clinical differences among the studies that might potentially be expected to alter the magnitude of treatment effect, using restricted maximum‐likelihood to estimate the between study variance. Subgroups were defined a priori and included.

Baseline immunological risk for acute rejection of study population (low, mixed, or high)
Type of calcineurin inhibitor used (cyclosporin or tacrolimus)
Type of antimetabolite used (azathioprine or mycophenolate)
Intervention IL2Ra used (basiliximab or daclizumab)
Whether the calcineurin inhibitor was given from the time of transplantation at standard dose or used differently (e.g. delayed introduction or given in different dosages across the IL2Ra and control arms)

Sensitivity analysis

Sensitivity analyses based on publication type (conference abstract or peer reviewed journal) and study methodological quality (whether the study was conducted using an intention to treat analysis judged as adequate versus inadequate/unclear) were undertaken, aiming to establish whether the estimated treatment effects were robust to reasonable assumptions of the influence of these potential biases.

Results

Description of studies

The process of identifying reports of RCT for inclusion in the original review and in the review update are outlined in Figure 1. The review update contributed 189 reports from 33 studies. 41 were new reports of studies already included in the original review, 148 were reports of new studies.

A total of 306 reports (publications and abstracts) of 71 studies qualified for inclusion in the review (Figure 1). The 71 combined studies represented a total of 10,520 randomised participants. Sixteen of these studies (Bernarde 2004; Cerrillos 2006; Chen 2003; de Boccardo 2002; Fangmann 2004; Flechner 2000; Garcia 2002; Hanaway 2008; Khan 2000; Locke 2008; Philosophe 2002; Pourfarziani 2003; Sandrini 2002; Shidban 2000; Shidban 2003; Yussim 2004) were available in abstract form only (1,705 participants), whilst the remaining 55 (8,815 participants) were published in 15 different journals. Basiliximab was used in 36 studies, daclizumab in 31, and other IL2Ra were used in six studies (either Anti‐tac, BT563, 33B3.1 or Lo‐tac‐1)

IL2Ra versus placebo/ no treatment

Thirty‐two studies (5,854 participants) compared an IL2Ra with placebo or no treatment in a calcineurin inhibitor based treatment regimen (Ahsan 2002; Baczkowska 2002; Bernarde 2004; Bingyi 2003; Cerrillos 2006; Chen 2003; Daclizumab double 1999; Daclizumab triple 1998; de Boccardo 2002; CAESAR (Ekberg) 2007; Fangmann 2004; Folkmane 2001; Grenda 2006; Ji 2007; Kahan 1999; Kirkman 1989; Kirkman 1991; Kyllonen 2007; Lawen 2003; Martin Garcia 2003; Nashan 1997; Offner 2008; Parrott 2005; Pescovitz 2003; Pisani 2001; Ponticelli 2001; Sandrini 2002; Sheashaa 2003; SYMPHONY (Ekberg) 2007; Tan 2004; van Gelder 1995; Yussim 2004).

IL2Ra versus ATG

Eighteen studies (1,844 participants) compared IL2Ra to an ATG preparation. Of these 12 studies (1,286 participants) used rabbit ATG ("thymoglobulin") (Abou‐Ayache 2008; Brennan 2006; Ciancio 2005; Kim 2008a; Lebranchu 2002; Locke 2008; Mourad 2004; Noel 2009; Pourfarziani 2003; Soulillou/Cant 1990; Hernandez 2007) and 7 (558 participants) used equine ATG (e.g. "ATGam") (Hourmant 1994; Kriaa 1993; Ruggenenti 2006; Shidban 2003; Sollinger 2001; Tullius 2003; Kyllonen 2007).

IL2Ra versus other antibody

Four studies (165 participants) compared IL2Ra with muromonab‐CD3 (OKT3) and one study (13 participants) compared IL2Ra with rituximab (Clatworthy 2009). Two studies (395 participants) compared IL2Ra with alemtuzumab (Ciancio 2005; Hanaway 2008).

IL2Ra versus other immunosuppressive strategy

Five studies (293 participants) (Grego 2007; Khan 2000; Lin 2006; Nair 2001; Perrea 2006) compared basiliximab with daclizumab. Four studies (345 participants) (Bernarde 2004; Kumar 2005; Matl 2001; Vincenti 2003) compared different doses of IL2Ra. Four studies (208 participants) (Asberg 2006; Garcia 2002; Gelens 2006; Wilson 2004) compared an IL2Ra with a calcineurin inhibitor, although study design for these four studies was heterogeneous, with co‐interventions varying across study arms (Characteristics of included studies). Three studies (1,372 participants) (ATLAS 2003; CARMEN (Rostaing) 2005; ter Meulen 2002) compared IL2Ra with steroids. One study (31 participants) compared IL2Ra with MMF (Kaplan 2003).

Two studies which had more than two arms were able to contribute data to more than one of the above comparisons (Bernarde 2004; Kyllonen 2007).

Baseline immunosuppression

Baseline immunosuppression varied both within studies (where three arms were investigated) and amongst studies. Cyclosporin was used in 55 studies (including 29 studies in the IL2Ra with placebo/ no treatment comparison and 14 studies in the IL2Ra with ATG comparison). In 20 of these studies the cyclosporin was stated to be the microemulsion (Neoral) formulation (Abou‐Ayache 2008; Asberg 2006; de Boccardo 2002; Grego 2007; Kahan 1999; Kaplan 2003; Lawen 2003; Lebranchu 2002; Lin 2006; Mourad 2004; Nashan 1997; Offner 2008; Parrott 2005; Ponticelli 2001; Sandrini 2002; Shidban 2000; Shidban 2003; Sollinger 2001; SYMPHONY (Ekberg) 2007; Tan 2004). In the remaining studies the cyclosporin formulation was not stated or was in solution (sandimune). Tacrolimus was used in 22 studies (Ahsan 2002; ATLAS 2003; CARMEN (Rostaing) 2005; Cerrillos 2006; Ciancio 2005; Clatworthy 2009; Garcia 2002; Gelens 2006; Grenda 2006; Hanaway 2008; Hernandez 2007; Khan 2000; Martin Garcia 2003; Noel 2009; Perrea 2006; Philosophe 2002; SYMPHONY (Ekberg) 2007; ter Meulen 2002; Tullius 2003; Vincenti 2003; Wilson 2004; Yussim 2004).

Reported outcome measures

The reporting of outcome measures was variable across studies (56/71 studies reported patient mortality, 30/71 reported CMV disease, see Figure 1). Reporting of harms was more limited and inconsistent among studies and frequently studies reported incomplete data for harm outcomes. Participants with any serious infection were reported in 32 (45%) studies, however a further 15 (21%) studies also assessed infection, but expressed their results as 'infectious episodes', and so this data could not be easily meaningfully combined.

Risk of bias in included studies

Reporting of details of study methodology was incomplete for the majority of studies, and are summarised in Figure 2.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

Sequence generation and allocation concealment

Sixteen studies reported adequate sequence generation, and 15 studies reported adequate allocation concealment. One study (Nair 2001) used inadequate methods of sequence generation and allocation concealment. The remainder (54 studies for sequence generation and 55 for allocation concealment) used unclear methodology.

Blinding of objective and subjective outcomes

One study (Abou‐Ayache 2008) adequately reported blinding of objective outcomes, and two studies (Parrott 2005; Ponticelli 2001) adequately reported blinding of subjective outcomes. Twenty four had inadequate blinding of objective and 25 inadequate blinding of subjective outcomes. The remainder had unclear methods.

Incomplete outcome data and selective reporting

Incomplete outcome data was adequately addressed in 36 studies, and inadequately in 13 (the remainder were unclear). Forty one studies were free of selective reporting, but 12 were inadequate, the remainder unclear.

Other biases

Eight studies (Kirkman 1989; Kirkman 1991; Hernandez 2007; Ciancio 2005; Kumar 2005; Kyllonen 2007; Noel 2009; Soulillou/Cant 1990) declared their funding source to be an independent or academic funding body, and so were judged free of potential other bias. The remainder either declared sponsorship by a pharmaceutical industry company, or included an author who declared a pharmaceutical company as an affiliation, and so were judged as not free of potential bias. Others did not disclose the funding source of the study (judged unclear).

Effects of interventions

IL2Ra versus placebo/no treatment

Results can be found in comparison 1, Analyses 1.1 to 1.21. In general, all effects were homogeneous across all outcomes.

There was no difference in mortality, but graft loss including death with a functioning graft (Analysis 1.2) was reduced by 25% at six months (16 studies, 3017 participants: RR 0.75, 95% CI 0.58 to 0.98) and at one year after transplantation (24 studies, 4672 participants: RR 0.75, 95% CI 0.62 to 0.90). Graft loss censored for death with function showed similar significant reduction favouring IL2Ra (Analysis 1.3) at 6 months and 1 year. Beyond one year, there were fewer studies reporting graft loss outcomes, and so there was uncertainty whether the reduction was sustained beyond the first post‐transplant year (Analysis 1.2; Analysis 1.3). Incidence of biopsy‐proven acute rejection was reduced by 69% at three months, 32% at six months, and 28% at one year post‐transplantation for those treated with an IL2Ra (Analysis 1.5: at 3 months (2 studies): RR 0.31, 95% CI 0.14 to 0.68; at 6 months (15 studies): RR 0.68, 95% CI 0.62 to 0.76; at one year (14 studies): RR 0.72, 95% CI 0.64 to 0.81). This advantage was similar for clinically suspected acute rejection (Analysis 1.4). Treatment with an IL2Ra showed a pronounced effect in preventing early steroid‐resistant rejection, reducing incidence at six months by 48% (Analysis 1.6 (9 studies, 1928 participants): RR 0.52, 95% CI 0.39 to 0.68).

1.2 — Comparison 1 IL2Ra versus placebo or no treatment, Outcome 2 Graft loss or death with functioning allograft.

1.3 — Comparison 1 IL2Ra versus placebo or no treatment, Outcome 3 Graft loss censored for death with functioning graft.

1.5 — Comparison 1 IL2Ra versus placebo or no treatment, Outcome 5 Acute rejection: biopsy‐proven.

1.4 — Comparison 1 IL2Ra versus placebo or no treatment, Outcome 4 Acute rejection: clinically suspected or biopsy proven.

1.6 — Comparison 1 IL2Ra versus placebo or no treatment, Outcome 6 Acute rejection: steroid resistant.

Use of IL2Ra resulted in a 64% reduction in early malignancy within six months of transplantation (Analysis 1.7 (8 studies, 1878 participants): RR 0.36, 95% CI 0.15 to 0.86), but the effect was not sustained beyond six months. CMV infection was reduced in IL2Ra treated patients at three and six months, but not significantly so (Analysis 1.10). At one year, when more studies reported CMV outcomes, there was a 19% reduction in CMV disease for IL2Ra treated recipients (Analysis 1.9 (13 studies, 3169 participants): RR 0.81, 95% CI 0.68 to 0.97).

1.7 — Comparison 1 IL2Ra versus placebo or no treatment, Outcome 7 Malignancy: total.

1.10 — Comparison 1 IL2Ra versus placebo or no treatment, Outcome 10 Infection: CMV invasive.

1.9 — Comparison 1 IL2Ra versus placebo or no treatment, Outcome 9 Infection: CMV all.

Serum creatinine was significantly lower for IL2Ra treated patients at one, three and six months post‐transplantation (Analysis 1.15: at 1 month (4 studies, 646 participants) MD ‐21.45 µmol/L 95% CI ‐33.03 to ‐9.38; at 3 months, (7 studies, 820 participants) MD ‐7.33 µmol/L 95% CI ‐13.58 to ‐1.08; and at 6 months (7 studies, 1231 participants) MD ‐8.18 µmol/L 95% CI ‐14.28 to ‐2.09), but this effect was not sustained at one year (Analysis 1.15 (8 studies, 1135 participants): MD ‐5.31 µmol/L 95% CI ‐13.90 to 3.28) or beyond, where there was no difference in creatinine. Few studies reported GFR, and there was no evidence of difference for IL2Ra or placebo (Analysis 1.16). Data was sparse for other outcomes, and there was no difference demonstrated for PTDM (Analysis 1.12), total serious infections (Analysis 1.11) or for adverse reaction to drug administration (Analysis 1.13).

1.15 — Comparison 1 IL2Ra versus placebo or no treatment, Outcome 15 Creatinine µmol/L.

1.16 — Comparison 1 IL2Ra versus placebo or no treatment, Outcome 16 Glomerular filtration rate (GFR) mL/min/1.73 m².

1.12 — Comparison 1 IL2Ra versus placebo or no treatment, Outcome 12 Post‐transplant diabetes mellitus (PTDM).

1.11 — Comparison 1 IL2Ra versus placebo or no treatment, Outcome 11 Infection: serious all‐cause total.

1.13 — Comparison 1 IL2Ra versus placebo or no treatment, Outcome 13 Adverse reaction.

There was no significant heterogeneity of effects for any outcomes when IL2Ra was compared with placebo/no treatment. We performed sensitivity analysis to examine the effect of studies methodology (whether intention‐to‐treat analysis was used, or not) and publication status (whether the study results were published in a peer‐reviewed journal, or not) on the outcomes death, graft loss censored for death, acute rejection (diagnosed clinically or by biopsy), CMV and malignancy, using data from studies reporting these outcomes at any time within the first post‐transplant year. Results are summarised in Table 1 and Table 2. There was no evidence to suggest difference in estimates of effect for studies that did not use intention‐to‐treat analysis or were unclear in how they analysed data. For studies published in non‐peer reviewed journals or as conference abstracts, there was a greater benefit in reduction of graft loss using IL2Ra (10 studies, RR 0.36 95% CI 0.18 to 0.71) than for those studies published in peer reviewed journals (19 studies, RR 0.81 95%CI 0.66 to 1.01 (P for difference 0.02), but no significant difference for other outcomes. Figure 3 shows the funnel plot for graft loss within the first year post‐transplantation.

1. IL2Ra compared with placebo/no treatment: stratified meta‐analysis (death, graft loss, acute rejection).

	Death			Graft loss			Acute rejection
	N	RR (95% CI)	P	N	RR (95% CI)	P	N	RR (95% CI)	P
Publication status
Abstract	8	0.70 (0.22, 2.20)	0.81	10	0.36 (0.18, 0.71)	0.02	10	0.61 (0.48, 0.77)	0.20
Journal	16	0.81 (0.54, 1.21)		19	0.81 (0.66, 1.01)		20	0.72 (0.66, 0.79)
ITT analysis
ITT used	13	0.80 (0.46, 1.32)	0.90	15	0.87 (0.65, 1.15)	0.17	15	0.69 (0.59, 0.80)	0.80
No/ unclear	11	0.81 (0.48, 1.40)		14	0.65 (0.48, 0.88)		15	0.69 (0.62, 0.78)
Risk for AR
Low	10	0.80 (0.42, 1.50)	0.74	10	0.84 (0.59, 1.20)	0.39	11	0.68 (0.60, 0.76)	0.02^†
Mixed	7	0.83 (0.52, 1.35)		9	0.73 (0.55, 0.97)		9	0.75 (0.64, 0.88)
High	2	0.08 (0.01, 7.20)		2	0.61 (0.14, 2.63)		2	0.25 (0.11, 0.56)
Unclear	5	0.42 (0.03, 7.31)		8	0.57 (0.26, 1.23)		8	0.66 (0.50, 0.88)
CNI
Cyclosporine	21	0.90 (0.57, 1.42)	0.37	25	0.82 (0.64, 1.03)	0.17	26	0.69 (0.63, 0.77)	0.69
Tacrolimus	2	0.10 (0.01, 9.76)		3	0.77 (0.24, 2.48)		3	0.66 (0.28, 1.57)
Unclear/mixed	1	0.63 (0.32, 1.25)		10	0.56 (0.36, 0.89)		1	0.71 (0.59, 0.86)
Antimetabolite
Azathioprine	8	0.97 (0.44, 2.14)	0.80	10	0.78 (0.52, 1.16)	0.38	10	0.66 (0.57, 0.76)	0.69
Mycophenolate	12	0.71 (0.42, 1.21)		14	0.59 (0.42, 0.83)		15	0.69 (0.55, 0.88)
Unclear/mixed	4	0.61 (0.18, 2.12)		5	0.95 (0.67, 1.35)		5	0.69 (0.60. 0.79)
IL2Ra
Basiliximab	12	0.93 (0.51, 1.71)	0.95	16	0.77 (0.57, 1.03)	0.67	16	0.68 (0.61, 0.76)	0.88
Daclizumab	9	0.65 (0.39, 1.08)		10	0.68 (0.92, 0.93)		11	0.70 (0.57, 0.87)
Other	3	1.88 (0.42, 8.48)		3	1.26 (0.59, 2.72)		3	0.60 (0.43, 0.84)

	Cytomegalovirus disease			Malignancy
	N	RR (95% CI)	P	N	RR (95% CI)	P
Publication status
Abstract	5	0.97 (0.65, 1.44)	0.47	4	1.18 (0.15, 9.62)	0.70
Journal	12	0.82 (0.69, 0.98)		15	0.76 (0.41, 1.42)
ITT analysis
ITT used	11	0.93 (0.73, 1.18)	0.30	11	0.71 (0.31, 1.61)	0.72
No/ unclear	6	0.78 (0.63, 0.97)		8	0.89 (0.37, 2.10)
Risk of AR
Low	8	0.82 (0.65, 1.05)	0.47	9	0.70 (0.28, 1.81)	0.82
Mixed	5	0.83 (0.66, 1.06)		6	0.93 (0.41, 2.11)
High	0	No data		0	No data
Unclear	4	1.02 (0.63, 1.65)		4	0.22 (0.01, 5.99)
CNI
Cyclosporine	15	0.88 (0.73, 1.06)	0.34	16	0.73 (0.38, 1.40)	0.43
Tacrolimus	1	5.00 (0.61, 41.3)		2	0.06 (0.01, 5.84)
Unclear/mixed	1	0.72 (0.53,0.99)		1	1.66 (0.35, 7.94)
Antimetabolite
Azathioprine	5	1.18 (0.84, 1.65)	0.05	8	0.58 (0.20,1.72)	0.81
Mycophenolate	7	0.78 (0.60, 1.02)		7	1.10 (0.42, 2.87)
Unclear/mixed	5	0.75 (0.58, 0.97)		4	0.70 (0.18, 2.74)
IL2Ra
Basiliximab	9	0.88 (0.71, 1.10)	0.74	11	0.51 (0.25, 1.05)	0.05
Daclizumab	6	0.81 (0.61, 1.08)		7	1.81 (0.63, 5.20)
Other	2	0.81 (0.10, 6.32)		1	7.00 (0.38, 129.9)

Date	Event	Description
18 February 2010	Amended	New data available, no change to conclusions
31 October 2009	New citation required and conclusions have changed	Complete update of review, 33 new studies added

Database searched	Search terms
Cochrane Renal Group Specialised Register	The following terms were used: Kidney transplant, kidney allograft, graft rejection, interleukin 2 receptor antagonists, basiliximab, daclizumab, simulect, zenapax together with register codes used to identify studies relevant to this review.
CENTRAL	MeSH descriptor Kidney Transplantation "interleukin 2" near (antagonist* or antibod* or inhibit* or block) in Clinical Trials interleukin‐2 near (antagonist or antibod* or inhibit* or block) in Clinical Trials "interleukin 2 receptor" in All Fields, in Clinical Trials "interleukin‐2 receptor" in All Fields, in Clinical Trials il2 or il2r in All Fields, in Clinical Trials il‐2 or il‐2r* or il‐2‐r* in All Fields, in Clinical Trials basiliximab in All Fields in Clinical Trials daclizumab in All Fields in Clinical Trials cd25 or cd‐25 or "cd 25" in All Fields in Clinical Trials bt563 or bt‐563 or "bt 563" in All Fields in Clinical Trials simulect in All Fields in Clinical Trials zenapax in All Fields in Clinical Trials (2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13) (1 and 4)
MEDLINE	1. Kidney Transplantation/  2. basiliximab.tw.  3. daclizumab.tw.  4. zenapax.tw.  5. cd25.tw.  6. cd 25.tw.  7. bt563.tw.  8. simulect.tw.  9. exp Receptors, Interleukin‐2/  10. exp Antibodies, Monoclonal/  11. interleukin‐2 receptor$.tw.  12. (interleukin 2 adj10 antagoni$).tw.  13. il2.tw.  14. il 2.tw.  15. il2R.tw.  16. il 2R.tw.  17. il 2 R.tw.  18. monoclonal antibod$.tw.  19. or/2‐18  20. 1 and 19
EMBASE	1. exp Interleukin 2 Receptor Antibody/  2. basiliximab.tw.  3. daclizumab.tw.  4. dacliximab.tw.  5. cd25.tw.  6. cd 25.tw.  7. bt563.tw.  8. simulect.tw.  9. zenapax.tw.  10. interleukin‐2 receptor$.tw.  11. (interleukin 2 adj10 antagonist$).tw.  12. (interleukin‐2 adj10 antibod$).tw.  13. il2.tw.  14. il‐2.tw.  15. il2r.tw.  16. il‐2r.tw.  17. il‐2‐r.tw.  18. or/1‐17  19. exp Kidney Transplantation/  20. 18 and 19

Potential source of bias	Assessment criteria
Was there adequate sequence generation?	Yes (low risk of bias): Random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimization (minimization may be implemented without a random element, and this is considered to be equivalent to being random).
	No (high risk of bias): Sequence generated by odd or even date of birth; date (or day) of admission; sequence generated by hospital or clinic record number; allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention.
	Unclear: Insufficient information about the sequence generation process to permit judgement.
Was allocation adequately concealed?	Yes (low risk of bias): Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study (e.g. central allocation, including telephone, web‐based, and pharmacy‐controlled, randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes).
	No (high risk of bias): Using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non‐opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.
	Unclear: Randomisation stated but no information on method used is available.
Was knowledge of the allocated interventions adequately prevented during the study?	Yes (low risk of bias): No blinding, but the review authors judge that the outcome and the outcome measurement are not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken; either participants or some key study personnel were not blinded, but outcome assessment was blinded and the non‐blinding of others unlikely to introduce bias.
	No (high risk of bias): No blinding or incomplete blinding, and the outcome or outcome measurement is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken; either participants or some key study personnel were not blinded, and the non‐blinding of others likely to introduce bias.
	Unclear: Insufficient information to permit judgement of ‘Yes’ or ‘No'
Were incomplete outcome data adequately addressed?	Yes (low risk of bias): No missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods.
	No (high risk of bias): Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; ‘as‐treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.
	Unclear: Insufficient information to permit judgement of ‘Yes’ or ‘No'.
Are reports of the study free of suggestion of selective outcome reporting?	Yes (low risk of bias): The study protocol is available and all of the study’s pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified (convincing text of this nature may be uncommon).
	No (high risk of bias): Not all of the study’s pre‐specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre‐specified; one or more reported primary outcomes were not pre‐specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.
	Unclear: Insufficient information to permit judgement of ‘Yes’ or ‘No'.
Was the study apparently free of other problems that could put it at a risk of bias?	Yes (low risk of bias): The study appears to be free of other sources of bias.
	No (high risk of bias): Had a potential source of bias related to the specific study design used; stopped early due to some data‐dependent process (including a formal‐stopping rule); had extreme baseline imbalance; has been claimed to have been fraudulent; had some other problem.
	Unclear: Insufficient information to permit judgement of ‘Yes’ or ‘No'.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality	28		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
1.1 at 3 months	2	197	Risk Ratio (M‐H, Random, 95% CI)	3.15 [0.13, 75.82]
1.2 at 6 months	15	2919	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.45, 1.40]
1.3 at 1 year	24	4647	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.54, 1.10]
1.4 at 3 years	4	695	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.30, 1.29]
1.5 at ≥ 5 years	3	261	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.34, 1.33]
2 Graft loss or death with functioning allograft	29		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
2.1 at 3 months	2	177	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.11, 1.06]
2.2 at 6 months	16	3017	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.58, 0.98]
2.3 at 1 year	24	4672	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.62, 0.90]
2.4 at 3‐5 years	4	695	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.64, 1.22]
2.5 ≥ 5 years	3	261	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.39, 2.05]
3 Graft loss censored for death with functioning graft	30		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
3.1 at 3 months	2	177	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.09, 1.48]
3.2 at 6 months	17	3048	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.55, 0.99]
3.3 at 1 year	24	4672	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.60, 0.93]
3.4 at 3‐5 years	4	695	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.71, 1.59]
3.5 ≥ 5 years	3	261	Risk Ratio (M‐H, Random, 95% CI)	1.51 [0.52, 4.37]
3.6 Any time within the first year	29	5527	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.61, 0.92]
4 Acute rejection: clinically suspected or biopsy proven	30		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
4.1 at 3 months	6	364	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.21, 0.59]
4.2 at 6 months	19	4751	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.63, 0.76]
4.3 at 1 year	20	4300	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.66, 0.78]
4.4 Any time within the first year	30	5577	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.64, 0.76]
5 Acute rejection: biopsy‐proven	21		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
5.1 at 3 months	2	197	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.14, 0.68]
5.2 at 6 months	15	4451	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.62, 0.76]
5.3 at 1 year	14	3898	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.64, 0.81]
6 Acute rejection: steroid resistant	16		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
6.1 at 3 months	1	55	Risk Ratio (M‐H, Random, 95% CI)	0.15 [0.01, 2.74]
6.2 at 6 months	9	1928	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.39, 0.68]
6.3 at 1 year	6	1834	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.54, 0.92]
7 Malignancy: total	19		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
7.1 at 6 months	8	1878	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.15, 0.86]
7.2 at 1 year	15	3898	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.46, 1.67]
7.3 at 3‐5 years	3	635	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.45, 1.53]
7.4 ≥ 5 years	2	159	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.17, 6.80]
7.5 Any time within the first year	19	4860	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.42, 1.28]
8 PTLD/lymphoma	14		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
8.1 at 3 months	1	76	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
8.2 at 6 months	6	1241	Risk Ratio (M‐H, Random, 95% CI)	0.32 [0.09, 1.17]
8.3 at 1 year	8	2481	Risk Ratio (M‐H, Random, 95% CI)	0.46 [0.10, 2.12]
8.4 at 3 years	1	275	Risk Ratio (M‐H, Random, 95% CI)	0.32 [0.01, 7.71]
8.5 ≥ 5 years	1	59	Risk Ratio (M‐H, Random, 95% CI)	2.90 [0.12, 68.50]
8.6 Any time within the first year	13	3864	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.18, 1.29]
9 Infection: CMV all	18		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
9.1 at 3 months	2	131	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.09, 5.09]
9.2 at 6 months	9	1735	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.74, 1.21]
9.3 at 1 year	13	3169	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.68, 0.97]
9.4 at 3 years	1	100	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.21, 4.72]
9.5 ≥ 5 years	1	100	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.26, 3.78]
9.6 Any time within the first year	17	3767	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.72, 0.99]
10 Infection: CMV invasive	6		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
10.1 at 6 months	3	613	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.38, 2.78]
10.2 at 1 year	5	1070	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.61, 1.41]
11 Infection: serious all‐cause total	17		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
11.1 at 3 months	2	136	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.63, 1.50]
11.2 at 6 months	8	1375	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.85, 1.10]
11.3 at 1 year	9	2333	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.92, 1.05]
12 Post‐transplant diabetes mellitus (PTDM)	4	1372	Risk Ratio (M‐H, Random, 95% CI)	1.04 [0.51, 2.12]
12.1 at 1 year	3	1272	Risk Ratio (M‐H, Random, 95% CI)	1.52 [0.43, 5.33]
12.2 at 5 years	1	100	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.18, 1.83]
13 Adverse reaction	2	610	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.70, 1.24]
13.1 All adverse reactions at 6 months	2	610	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.70, 1.24]
14 Creatinine mg/dL	13		Mean Difference (IV, Random, 95% CI)	Subtotals only
14.1 at 1 month	4	654	Mean Difference (IV, Random, 95% CI)	‐0.24 [‐0.37, ‐0.11]
14.2 at 3 months	7	831	Mean Difference (IV, Random, 95% CI)	‐0.11 [‐0.18, ‐0.03]
14.3 at 6 months	7	1231	Mean Difference (IV, Random, 95% CI)	‐0.09 [‐0.16, ‐0.02]
14.4 at 1 year	8	1135	Mean Difference (IV, Random, 95% CI)	‐0.06 [‐0.15, 0.04]
14.5 at 2 years	1	38	Mean Difference (IV, Random, 95% CI)	‐0.40 [‐0.74, ‐0.06]
14.6 at 3 years	1	94	Mean Difference (IV, Random, 95% CI)	‐0.05 [‐0.23, 0.13]
15 Creatinine µmol/L	13		Mean Difference (IV, Random, 95% CI)	Subtotals only
15.1 at 1 month	4	646	Mean Difference (IV, Random, 95% CI)	‐21.45 [‐33.03, ‐9.86]
15.2 at 3 months	7	820	Mean Difference (IV, Random, 95% CI)	‐7.33 [‐13.58, ‐1.08]
15.3 at 6 months	7	1231	Mean Difference (IV, Random, 95% CI)	‐8.18 [‐14.28, ‐2.09]
15.4 at 1 year	8	1135	Mean Difference (IV, Random, 95% CI)	‐5.31 [‐13.90, 3.28]
15.5 at 2 years	1	38	Mean Difference (IV, Random, 95% CI)	‐35.0 [‐65.21, ‐4.79]
15.6 at 3 years	1	94	Mean Difference (IV, Random, 95% CI)	‐4.42 [‐20.51, 11.67]
16 Glomerular filtration rate (GFR) mL/min/1.73 m²	6		Mean Difference (IV, Random, 95% CI)	Subtotals only
16.1 at 1 month	1	340	Mean Difference (IV, Random, 95% CI)	4.03 [‐1.14, 9.20]
16.2 at 3 months	2	359	Mean Difference (IV, Random, 95% CI)	0.24 [‐3.97, 4.45]
16.3 at 6 months	2	571	Mean Difference (IV, Random, 95% CI)	1.81 [‐2.27, 5.89]
16.4 at 1 year	5	2247	Mean Difference (IV, Random, 95% CI)	2.61 [0.45, 4.78]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality	2	395	Risk Ratio (M‐H, Random, 95% CI)	1.93 [0.29, 12.87]
2 Graft loss or death with functioning allograft	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
3 Graft loss censored for death with a functioning graft	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
4 Acute rejection: biopsy‐proven	2	395	Risk Ratio (M‐H, Random, 95% CI)	2.90 [0.35, 24.29]
5 Infection: CMV all	2		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Methods	Design: Open‐label parallel group RCT Duration: 12 months
Participants	Setting: National multi centre study Country: France First cadaveric kidney transplant Mean age (± SD): 44 ± 12 years Number (group 1/group 2): 115 (58/57) Sex (% M/F): 70/30 Exclusions: CMV status (D‐/R‐); multi‐organ transplantation; second transplant or living‐related donor; steroids in previous 30 days for autoimmune or kidney disease; significant liver disease; malignancy; potential non‐compliance
Interventions	Treatment group 1 Daclizumab (2mg/kg day 0, 1 mg/kg day 14) Treatment group 2 ATG (1‐1.5 mg/kg thymoglobulin) Baseline immunosuppression CSA: initial dose 2‐4 mg/kg, trough target level ‐ 150‐250 ng/mL from day 7 to 2 months, then 125‐150 ng/mL (3‐6 months), 125‐ 175 ng/mL (7‐12 months) MMF: 2 g/d Steroids: Tapered in stages and ceased at 5‐6 months post‐transplant CMV prophylaxis
Outcomes	Mortality Acute rejection Graft loss CMV infection Delayed graft function
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Stated "centrally randomised", no further information provided
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding (performance bias and detection bias)   Objective outcomes	Low risk	Open‐label, however for acute rejection "a blinded centralized analysis was carried out by two pathologists".
Blinding (performance bias and detection bias)   Subjective outcomes	High risk	Open‐label, blinding of outcome assessors not stated
Incomplete outcome data (attrition bias)   All outcomes	High risk	ITT analysis reported, however (1) 3 patients excluded post‐randomisation due to no transplant and or treatment, (2) 2 patients excluded after one dose of intervention but no transplant, (3) 1 excluded due to receipt of poor quality graft due to ecstasy abuse, and (4) 8 excluded form "on therapy population" due to protocol violation
Selective reporting (reporting bias)	Low risk	Primary outcomes for this review (death, graft loss and acute rejection) have been reported. No study protocol available to assess secondary outcomes of study
Other bias	High risk	"...supported by a grant from ROCHE ‐ France *Trial name: ECTAZ; protocol identification: 010624; date of registration: 16 July 2001, without restrictions on publication."

Methods	Design: Parallel RCT Duration: 12 months follow‐up
Participants	Setting: Single centre Country: USA First cadaveric or living‐related kidney transplant Number (treatment/control): 100 (50/50) Age: > 18 years Treatment group (years ± SEM): 47.0 ± 2.0 Control group: 47.0 ± 2.15 Sex (males) Treatment group: 66% Control group: 64% Exclusions: Already received an organ or multiorgan transplant
Interventions	Treatment group Daclizumab: 2 mg/kg IV administered after induction of anaesthesia Control group No treatment Baseline immunosuppression Tacrolimus (0.16‐0.2 mg/kg/d (trough levels 10‐15 ng/mL) MMF (500 mg orally twice a day) Steroids ((descending dose from 2 to 0.15 mg/kg/d at the end of 180 days) Co‐interventions Trimethoprim‐sulfamethoxazole was administered to both groups Oral ganciclovir (500 mg twice daily for 3months to all patients
Outcomes	Mortality Graft loss Acute rejection Infection/CMV Delayed graft function Malignancy
Notes	Significantly younger donors in control group
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Patients were randomly selected" no further information provided
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding (performance bias and detection bias)   Objective outcomes	Unclear risk	For acute rejection "All biopsies were reviewed by a pathologist unaware of the protocol"
Blinding (performance bias and detection bias)   Subjective outcomes	Unclear risk	Not stated who assessed the outcomes
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All patients followed up or accounted for at 6 months (acute rejection) and 12 months (death and graft loss)
Selective reporting (reporting bias)	Low risk	Primary outcomes for this review (death, graft loss and acute rejection) have been reported. No study protocol available to assess secondary outcomes of study
Other bias	Unclear risk	Funding source not stated

Methods	Design: Parallel RCT Duration: Commenced February 2002 and was to run for 2 years
Participants	Setting: Single centre Country: Norway First cadaveric kidney transplant, all low immunogenic risk Mean age (± SD) Treatment group: 57.7 ± 14.6 Control group: 58.2 ± 13.6 Number (treatment/control): 54 (27/27) Sex (M/F) Treatment group: 18/9 Control group: 20/7 Exclusions: multiorgan transplant; HLA‐identical transplant; PRA > 20%; active peptic ulcer disease; active infection; reabsorption disorders; ongoing malignancies; pregnancy; nursing mothers; WCC < 2.5 x 10⁹/L; platelet count < 100 x 10¹²/L; Hb < 6 g/dL
Interventions	Treatment group Daclizumab: 2 mg/kg on day 0, then 1 mg/kg every 2 weeks for a total of 5 doses Control group Nothing Baseline immunosuppression CSA Treatment group: No CSA Control group: 10 mg/kg day 0, then C₂ target level of 1500‐2000 µg/L for first month; 1400‐1600 g/L [sic] for second month; 1000‐1200 µg/L third month; followed by C_o monitoring tapering initially from 100‐200 µg/L to 75‐125 µg/L MMF Treatment group: 3g day 0, trough levels of 2‐6 mg/L with dose restrictions between 1‐4 g/d Steroids: IV day 0 and 1 then tapered from 80 to 20 mg/d (first months), 10 mg/d after 2 months and to 5 mg/g within the following months
Outcomes	Mortality Graft loss Acute rejection Delayed graft function Infection Adverse reaction
Notes	1 year follow‐up Stopped by data safety monitoring board when 54/70 (27/27) patients randomised due to unacceptable high rejection rates in DAC‐group.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Stated "randomized in a 1:1 ratio", no further information provided
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding (performance bias and detection bias)   Objective outcomes	High risk	Open‐label, blinding of outcome assessors not stated
Blinding (performance bias and detection bias)   Subjective outcomes	High risk	Open‐label, blinding of outcome assessors not stated
Incomplete outcome data (attrition bias)   All outcomes	Low risk	ITT analysis reported, all patients followed up or accounted for
Selective reporting (reporting bias)	Low risk	Primary outcomes for this review (death, graft loss and acute rejection) have been reported
Other bias	High risk	Supported by a grant from Roche Norway AS

Methods	Multicentre (21) parallel‐RCT Duration: NS Stratified by centre
Participants	Countries: Poland, Czech Republic, Finland, Sweden First cadaveric (87%) or living donor kidney transplant Mean age (± SD) Treatment group: 43.2 ± 11.4 Control group 1: 43.2 ± 12.8 Control group 2: 43.9 ± 12.1 Number (treatment/control 1/control 2): 457 randomised, 451 analysed (153/151/147) Sex (% male) Treatment group: 62.1% Control group 1: 61.2% Control group 2: 65.6% Exclusions: PRA ≥ 50% in previous 6 months; any organ transplant or kidney re transplant; ongoing immunosuppressive therapy; pregnancy or breast feeding; allergy or intolerance to study medication; HIV infection; significant liver disease; current or history of malignancy; significant uncontrolled infection; severe diarrhoea, vomiting or active peptic ulcer; NHBD
Interventions	Treatment group Basiliximab: 2 mg days 0 and 4 Control group 1 MMF: 2 g/d for up to 14 days then 1 g/d Control group 2 MMF: 2 g/d for up to 14 days then 1 g/d Steroids: 125 mg IV day 1 then orally 20 mg/d (days 2‐14), 15 mg/d (days 15‐28) 10 mg/d (days 29‐42) and 5 mg/d thereafter Baseline immunosuppression TAC: Initial dose 0.2 mg/kg/d then adjusted for trough levels of 10‐20 ng/mL (days 0‐28) then 5‐15 ng/mL thereafter Steroids: all patients received 500 mg IV on day 0
Outcomes	Mortality Graft loss Acute rejection CMV
Notes	6 month follow‐up
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“the randomisation list was generated by the Data Operations department” "stratified by centre”
Allocation concealment (selection bias)	Low risk	“each centre received a unique sequence of patient numbers and a set of sealed envelopes” ”the corresponding envelopes were opened providing the information for the allocated treatment”
Blinding (performance bias and detection bias)   Objective outcomes	High risk	Open‐label, blinding of outcome assessors not stated
Blinding (performance bias and detection bias)   Subjective outcomes	High risk	Open‐label, blinding of outcome assessors not stated
Incomplete outcome data (attrition bias)   All outcomes	Low risk	ITT analysis reported, all patients followed up or accounted for. 6/457 excluded ‐ never received transplant or study drug ‐ unlikely to affect results
Selective reporting (reporting bias)	Low risk	Primary outcomes for this review (death, graft loss and acute rejection) have been reported
Other bias	High risk	Sponsored by a grant from Fujisawa GmbH

	Death			Graft loss			Acute rejection
	N	RR (95% CI)	P	N	RR (95% CI)	P	N	RR (95% CI	P
Publication status
Abstract	2	21.64 (0.24, 930.90)	0.21	2	2.64 (0.72, 9.65)	0.17	4	0.92 (0.66, 1.27)	0.16
Journal	10	1.19 (0.68, 2.07)		10	1.01 (0.66. 1.55)		11	1.21 (0.98, 1.50)
ITT analysis
ITT used	8	1.33 (0.68, 2.62)	0.56	8	1.18 (0.69, 2.00)	0.62	10	1.10 (0.87, 1.39)	0.42
No/ unclear	4	1.08 (0.42, 2.79)		4	1.03 (0.54, 1.94)		4	0.96 (0.68, 1.37)
Risk for AR
Low	5	1.53 (0.62, 3.78)	0.56	4	0.99 (0.44, 2.23)	0.82	6	1.10 (0.78, 1.55)	0.96^†
Mixed	3	1.20 (0.44, 3.28)		4	1.15 (0.61, 2.18)		4	1.12 (0.84, 1.49)
High	2	1.03 (0.37, 2.85)		2	1.13 (0.51, 2.50)		3	1.04 (0.60, 1.80)
Unclear	2	1.01 (0.07, 13.86)		2	1.29 (0.29, 5.72)		2	1.05 (0.48, 2.27)
CNI
Cyclosporine	10	1.33 (0.72, 2.45)	0.62	10	1.10 (0.65, 1.84)	0.93	11	1.12 (0.90, 1.41)	0.76
Tacrolimus	2	1.65 (0.08, 33.44)		2	1.35 (0.45, 4.01)		3	1.19 (0.84, 1.70)
Unclear/mixed	0	No data		0	No data		1	0.73 (0.36, 1.50)
Antimetabolite
Azathioprine	4	1.14 (0.25, 5.08)	0.41	4	0.97 (0.41, 2.30)	0.42	4	1.02 (0.71, 1.45)	0.57
Mycophenolate	6	1.05 (0.54, 2.07)		6	1.07 (0.66, 1.74)		8	1.30 (1.02, 1.66)
Unclear/mixed	2	2.24 (0.67, 7.53)		0	No data		3	0.83 (0.56, 1.24)
IL2Ra
Basiliximab	7	1.45 (0.73, 2.88)	0.58	7	1.41 (0.77, 2.58)	0.34	8	1.12 (0.87, 1.44)	0.76
Daclizumab	2	0.83 (0.26, 2.66)		2	0.93 (0.47, 1.85)		4	1.21 (0.86, 1.70)
Other	3	1.14 (0.25, 5.23)		3	0.88 (0.35, 2.23)		3	1.01 (0.69, 1.47)
ATG formulation
Equine	5	1.95 (0.51, 7.42)	0.47	6	1.69 (0.67, 4.27)	0.33	7	0.96 (0.73, 1.24)	0.12
Rabbit ‐thymoglobulin	7	1.13 (0.62, 2.07)		6	1.00 (0.64, 1.58)		8	1.27 (1.00, 1.62)

Methods	Design: Parallel RCT Duration: 36 months follow‐up
Participants	Single centre Poland Primary kidney transplant recipients Age (mean): 42.6 ± 10.8 years Sex (M/F): NS Number (treatment/control): 42 (21/21)
Interventions	Treatment group Daclizumab: 1mg/kg before transplant and then days 14 and 28 CSA: Initial dose 5 mg/kg/d ([c2] 700‐900 ng/mL) then slowly tapered and withdrawn at 10 months Control group CSA: Initial dose 10 mg/kg/d. At 3 months [c2] 1500‐1700 ng/mL and at 4 months [c2] 900‐1200 ng/mL Baseline immunosuppression MMF: 2 g/d Steroids: standard dose
Outcomes	Acute rejection Delayed graft function Death (at 36 months)
Notes	Follow‐up: 3, 12, 36 and 60 months
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Stated "randomised, controlled study" no further information provided
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding (performance bias and detection bias)   Objective outcomes	High risk	Open label
Blinding (performance bias and detection bias)   Subjective outcomes	High risk	Open label
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	All patients followed or accounted for, however additional patients reported in 2008 abstract
Selective reporting (reporting bias)	Unclear risk	Primary outcomes for this review (death, graft loss and acute rejection) have been reported, however additional patients reported in 2008 abstract. No study protocol available to assess secondary outcomes of study
Other bias	Unclear risk	Funding source not stated

Methods	RCT
Participants	Setting: Single centre Country: Latvia First cadaveric kidney transplant. No significant differences between age, sex, type of donor, native kidney disease, comorbid conditions and HLA mismatches between the 3 groups Number (treatment/control):104 (69/35)
Interventions	Treatment groups Basiliximab Group 1: 20 mg day 0 and day 4 Group 2: 20 mg day 0 only Control group Nothing Baseline immunosuppression CSA: NS MMF: NS Steroids: NS
Outcomes	Mortality Graft loss Acute rejection CMV Delayed graft function
Notes	1 year follow‐up Abstract‐only data
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Stated "randomized", no further information provided
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding (performance bias and detection bias)   Objective outcomes	Unclear risk	Not stated
Blinding (performance bias and detection bias)   Subjective outcomes	Unclear risk	Not stated
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Data only available from conference proceedings abstract
Selective reporting (reporting bias)	Unclear risk	Primary outcomes for this review (death, graft loss and acute rejection) reported, however data only available from conference proceedings abstract
Other bias	Unclear risk	Funding source not stated, data only available from conference proceedings abstract

Methods	RCT
Participants	Setting: Single centre Country: China Primary cadaveric kidney transplant Age range Treatment group: 35‐59 years Control group: 36‐54 years Number (treatment/control): 12 (6/6) Sex (M/F) Treatment group: 4/2 Control group: 5/1
Interventions	Treatment group Basiliximab: 20 mg days 0 and 4 Control group Nothing Baseline immunosuppression CSA: 5‐8 mg/kg/d; trough levels NS AZA: 75‐100 mg/d Steroids: 50 mg/d on day 4 then tapers to 20 mg/d on day 28 and 10 mg/d on day 56
Outcomes	Acute rejection Infection Delayed graft function
Notes	1 year follow‐up
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Stated "randomly allocated", no further information provided
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding (performance bias and detection bias)   Objective outcomes	Unclear risk	Blinding of outcome assessors not stated
Blinding (performance bias and detection bias)   Subjective outcomes	Unclear risk	Blinding of outcome assessors not stated
Incomplete outcome data (attrition bias)   All outcomes	High risk	Numbers of patients at end of study not reported
Selective reporting (reporting bias)	High risk	For this review, only acute rejection was reported at 12 months, death and graft loss not stated and numbers at end of study not reported
Other bias	High risk	Supported by Novartis

Methods	Parallel RCT
Participants	Setting: International, Multicentre (28) Country: USA and Europe Cadaveric kidney transplant recipients (29/278 repeat transplant) Mean age (± SD) Group 1: 49.7 ± 13.0 Group 2: 51.3 ± 13.1 Number (group 1/group 2): 278 (137/141) Sex (M/F) Group 1: 82/55 Group 2: 79/62 Exclusions: Immunosuppression; investigation drugs within past 30 days; known contraindication to study drugs; know or suspected infection or seropositive for Hep B, HCV or HIV; cancer with previous 2 years; pregnancy; nursing mothers; women of child bearing age not using contraception
Interventions	Treatment 1 group 20 mg IV basiliximab administered before graft perfusion followed by second infusion on day 4 Treatment group 2 1.5 mg/kg ATG IV (days 0‐4), initiated before draft perfusion and then daily doses to day 4 for total dose of 7.5 mg/kg Acetaminophen and diphenhydramine given before receiving ATG Baseline immunosuppression CSA: 6‐8 mg/kg orally when graft function commenced MMF: 2 g/d orally, initiated intraoperatively and continued once patient tolerated oral medications Steroids: 7 mg/kg IV initiated intraoperatively and tapered to 5 mg by 6 months
Outcomes	Mortality Acute rejection Graft loss Delayed graft function Infection/CMV Adverse reactions Malignancy
Notes	1 year follow‐up Genzyme sponsor
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Stated "1:1 variable‐block randomization" used
Allocation concealment (selection bias)	Low risk	Stated "The treatment assignments were randomized at an independent centre"
Blinding (performance bias and detection bias)   Objective outcomes	High risk	Not stated
Blinding (performance bias and detection bias)   Subjective outcomes	High risk	Not stated
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All patients followed up or accounted for at 12 months
Selective reporting (reporting bias)	Low risk	Primary outcomes for this review (death, graft loss and acute rejection) have been reported. No study protocol available to assess secondary outcomes of study
Other bias	High risk	"The design, data collection, and analysis were performed by a sponsor, Genzyme, which hold the primary data"

Methods	Open‐label, parallel RCT Randomised 1:1:1 Duration: 12 months
Participants	International multicentre study, 32 centres Countries: Europe, Australia, Canada, Mexico, USA First cadaveric kidney transplant Mean age (range) Group 1: 47.2 (19‐78) Group 2: 47.6 (20‐77) Group 2: 48.7 (21‐73) Number (group 1/group 2/group 3): 536 (179/184/173) % males (group 1/group 2/group 3): 60/65/65
Interventions	Treatment groups (group 1 and 2) Daclizumab (2mg/kg first dose) Control group Nothing Baseline immunosuppression CSA Group 1: CSA withdrawal. Initial target trough level 50‐100 ng/mL. At 4 months dose decreased by 33% every month and withdrawn by 6 months Group 2: Low‐dose CSA. Target trough level 50‐100 ng/ML for 12 months Group 3: Standard‐dose CSA. Initial target trough level 150‐300 ng/mL. Reduced to 100‐200 ng/ml from 4 months to end of study. MMF: 2 mg/d Steroids: As per centre protocol
Outcomes	Mortality Graft loss Acute rejection Delayed graft function
Notes	1 year follow‐up 1 patient from group 2 was excluded post‐randomisation due to refusal to take all study medication.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Randomization code... generated in the Oracle Clinical randomization module"
Allocation concealment (selection bias)	Low risk	"Treatment assignment, corresponding to patient number, was provided on a sheet sealed inside a randomization envelope"
Blinding (performance bias and detection bias)   Objective outcomes	Unclear risk	Outcomes assessed locally, blinding of outcome assessors not stated
Blinding (performance bias and detection bias)   Subjective outcomes	Unclear risk	Outcomes assessed locally, blinding of outcome assessors not stated
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All patients followed up or accounted for. Excluded 1 randomised patient form group 2 because of refusal to take medications. Not likely to influence results
Selective reporting (reporting bias)	High risk	Primary outcomes for this review (death, graft loss and acute rejection) have been reported. No study protocol available to assess secondary outcomes of study and not all outcomes outlined in method are reported in results. There is no breakdown of numbers for 18 month data, and many outcomes reported as percentages
Other bias	High risk	Funded by Hoffmann‐LaRoche, 4/9 authors are employees of Roche

Methods	Multicentre (47) parallel‐RCT Duration: May 2000 to January 2002 Stratified by centre
Participants	Countries: France, Germany, Italy, Austria, Spain Cadaveric or living donor kidney transplant (93% first transplant) Mean age (± SD) Treatment group: 46.7 ± 12.1 Control group: 45.5 ± 12.3 Number (treatment/control) :551 enrolled, 538 analysed (260/278) Sex (M/F) Treatment group: 179/81 Control group: 177/101 Exclusions: PRA > 50%; previous graft loss with 12 months; historic positive cross‐match; NHBD; pregnancy or breast feeding; allergy/intolerance to study drugs; use of immunosuppression for reasons other than transplantation; HIV positive; significant liver disease; malignancy or history of; significant uncontrolled infection; severe diarrhoea, vomiting or active peptic ulcer; previous other organ transplant
Interventions	Treatment group Daclizumab: 1 mg/kg days 0 and 14 Control group Methyl prednisolone: 124 mg IV day 1, 20 mg oral dose (days 2‐15), 15 mg (days 15‐28), 10 mg (days 29‐42) and 5 mg (days 43‐183) Baseline immunosuppression TAC: 0.2 mg/kg then adjusted to maintain trough levels of 10‐20 ng/mL (days 0‐21), 10‐15 ng/mL (days 22‐41) and 5‐10 ng/mL (days 42‐183) MMF: 2 g/d (days 1‐14) then 1 g/d (days 15‐183) Steroids: Maximum of 500 mg on day 0
Outcomes	Mortality Graft loss Acute rejection Adverse reaction Malignancy Delayed graft function
Notes	6 month follow‐up
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“the randomisation schedule was generated by the Data Operations department, stratified by centre”
Allocation concealment (selection bias)	Low risk	“each patient number having a corresponding sealed envelope containing the randomisation details for that patient" "once assigned the envelope was opened”
Blinding (performance bias and detection bias)   Objective outcomes	High risk	Open‐label, blinding of outcome assessors not stated
Blinding (performance bias and detection bias)   Subjective outcomes	High risk	Open‐label, blinding or outcome assessors not stated
Incomplete outcome data (attrition bias)   All outcomes	Low risk	ITT analysis reported, all patients followed up or accounted for. 13/551 excluded as never transplanted and/or received study drug. Unlikely to influence results
Selective reporting (reporting bias)	Low risk	Primary outcomes for this review (death, graft loss and acute rejection) have been reported
Other bias	High risk	Supported by a grant from Fujisawa GmbH

Methods	RCT
Participants	Single centre Country: Mexico First kidney transplant, donor status unknown Age: NS Number (treatment/control): 52 (NS/NS) Sex (M/F): NS
Interventions	Treatment group Daclizumab: 2 unknown doses Control group None Baseline immunosuppression CSA or tacrolimus dose: NS MMF dose: NS Steroid dose: NS
Outcomes	Mortality Acute rejection Graft loss Delayed graft function
Notes	Abstract only No reportable data (numbers not broken down by group and email address not available)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Stated "randomly assigned", no further details provided
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding (performance bias and detection bias)   Objective outcomes	Unclear risk	Not stated
Blinding (performance bias and detection bias)   Subjective outcomes	Unclear risk	Not stated
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	52 patients randomised, however unclear how many per group and no numbers reported anywhere in the abstract
Selective reporting (reporting bias)	High risk	Primary outcomes for this review reported (death, graft loss and acute rejection), however only percentages given
Other bias	Unclear risk	No funding source provided Abstract only data

Methods	RCT
Participants	Single centre China Sensitised kidney transplant recipients ( PRA > 20%) Number (treatment/control):50 (17/33) Age and sex: NS
Interventions	Treatment group Daclizumab: 2 doses over 2 weeks Control group Nothing Baseline immunosuppression CSA dose: NS MMF dose: NS Steroid dose: NS
Outcomes	Mortality Graft loss Acute rejection
Notes	1 year follow‐up Abstract only data available
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Stated "randomised", no further information provided
Allocation concealment (selection bias)	Unclear risk	No stated
Blinding (performance bias and detection bias)   Objective outcomes	Unclear risk	Not stated
Blinding (performance bias and detection bias)   Subjective outcomes	Unclear risk	Not stated
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Unclear
Selective reporting (reporting bias)	Unclear risk	Primary outcomes for this review (death, graft loss and acute rejection) have been reported. Data only available from 2 conference proceedings abstracts
Other bias	Unclear risk	Funding source not stated. Data only available from 2 abstracts

Methods	Parallel, open label, RCT
Participants	Setting: Single centre Country: USA Primary cadaveric kidney transplant Mean age ± SE years Group 1: 49.9 ± 2.4 Group 2: 49.3 ± 2.5 Group 2: 50.2 ± 2.1 Number (group 1/group 2/group 3): 90 (30/30/30) Sex (M/F) Group 1: 18/12 Group 2: 19/11 Group 3: 19/11 Exclusions: Previous transplant; ABO incompatible donor kidney; seropositive for HIV, HCV, Hep B; malignancy in last 5 years; significant liver disease; uncontrolled concomitant infection and/or GI condition/s; will receive other immunosuppression, requiring warfarin, fluvastatin or herbal supplements; concurrent use of astemizole, pimozide, cisapride, terfenadine or ketoconazole; pregnancy or lactation; substance abuse or psychiatric disorder; low platelet count, WBC count or fasting HDL; high fasting triglycerides, fasting total cholesterol or fasting LDL
Interventions	Treatment group 1 1 mg/kg daclizumab at surgery and 4 additional doses once every 2 weeks Treatment group 2 1 mg/kg/d ATG during 1st week, total of 7 doses given Treatment group 3 0.3 mg/kg alemtuzumab day 0 and day 4 Baseline immunosuppression Daclizumab and ATG groups Tacrolimus: 0.1 mg/kg twice daily when kidney function had acceptably improved; trough level 8‐10 ng/mL MMF: 2 g/d (˜28.6 mg/kg/d) Steroids: 500 mg/d for 3 days tapered to 03 mg/kg at 1 month and 0.15 mg/kg at 3 months Alemtuzumab group Tacrolimus: 0.1 mg/kg twice daily when kidney function had acceptably improved; trough level 4‐7 ng/mL MMF: 1 g/d (˜14 mg/kg/d) Steroid avoidance after first week Co‐interventions CMV prophylaxis
Outcomes	Mortality Graft loss Acute rejection Infection Delayed graft function Adverse effects
Notes	1.25 and 2 year follow‐up Groups 2 and 3 combined for comparison group Funding ‐ University of Miami
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Standard randomised block design" was used
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding (performance bias and detection bias)   Objective outcomes	High risk	Open‐label, biopsy reading for acute rejection not stated
Blinding (performance bias and detection bias)   Subjective outcomes	High risk	Open‐label
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All patients followed up or accounted for at 2 years
Selective reporting (reporting bias)	Low risk	Primary outcomes for this review (death, graft loss and acute rejection) have been reported
Other bias	Low risk	Study supported by the University of Miami and registered at clinical.trials.gov. Unlikely to significantly influence on results

Methods	Open label randomised trial
Participants	Undergoing kidney transplant
Interventions	Daclizumab versus rituximab
Outcomes	Acute rejection Delayed graft function GFR Infections Malignancy Post‐transplant diabetes
Notes	Planned to recruit 120 patients. Stopped trial after first 13 recruitments Letter to editor only
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"randomised"
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding (performance bias and detection bias)   Objective outcomes	Unclear risk	"open‐label"
Blinding (performance bias and detection bias)   Subjective outcomes	Unclear risk	"open‐label"
Selective reporting (reporting bias)	Low risk	All outcomes reported
Other bias	High risk	Supported by Roche. Authors have received grants and fees from Roche, Wyeth, Astellas and GlaxoSmithKline

PERMALINK

Interleukin 2 receptor antagonists for kidney transplant recipients

Angela C Webster

Lorenn P Ruster

Richard G McGee

Sandra L Matheson

Gail Y Higgins

Narelle S Willis

Jeremy R Chapman

Jonathan C Craig

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Background

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Initial review

Review update

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Results

Description of studies

1.

IL2Ra versus placebo/ no treatment

IL2Ra versus ATG

IL2Ra versus other antibody

IL2Ra versus other immunosuppressive strategy

Baseline immunosuppression

Reported outcome measures

Risk of bias in included studies

2.

Sequence generation and allocation concealment

Blinding of objective and subjective outcomes

Incomplete outcome data and selective reporting

Other biases

Effects of interventions

IL2Ra versus placebo/no treatment

1.2. Analysis.

1.3. Analysis.

1.5. Analysis.

1.4. Analysis.

1.6. Analysis.

1.7. Analysis.

1.10. Analysis.

1.9. Analysis.

1.15. Analysis.

1.16. Analysis.

1.12. Analysis.

1.11. Analysis.

1.13. Analysis.

1. IL2Ra compared with placebo/no treatment: stratified meta‐analysis (death, graft loss, acute rejection).

2. IL2Ra compared with placebo/no treatment: stratified meta‐analysis (cytomegalovirus disease, malignancy).

3.

IL2Ra versus ATG

2.1. Analysis.

2.2. Analysis.

2.3. Analysis.

Methods	Placebo‐controlled RCT
Participants	Setting: International Multicentre (31) Countries: Argentina, Brazil, Costa Rica, Chile, Mexico Cadaveric (46%) or living donor kidney transplant Agee: 38.0 ± 12.4 years Number (treatment/control): 310 (NS/NS) Sex (% M/F): 58.6/40.4
Interventions	Treatment group Basiliximab: 20 mg days 0 and 4 Control group Placebo Baseline immunosuppression CSA: 10 mg/kg/d (day 0) and dose adjusted to predefine trough levels AZA: 1‐2 mg/kg/d Steroids: As per site standards, minimum daily dose of 5 mg at 6 months
Outcomes	Mortality Graft loss Acute rejection Malignancy
Notes	Number randomised in each group NS, calculated from given proportions 6 month follow‐up Trial on‐going Data from abstract only
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Stated "randomised", no further information provided
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding (performance bias and detection bias)   Objective outcomes	Unclear risk	"Double blind", blinding of outcome assessors not stated
Blinding (performance bias and detection bias)   Subjective outcomes	Unclear risk	"Double blind", blinding of outcome assessors not stated
Incomplete outcome data (attrition bias)   All outcomes	High risk	Stated ITT, but not all randomised patients were analysed. Data only available from conference proceedings abstract
Selective reporting (reporting bias)	Unclear risk	Primary outcomes for this review (death, graft loss and acute rejection) have been reported, however data only available as percentages from conference proceedings abstract
Other bias	Unclear risk	Funding source not stated, data only available from conference proceedings abstract

Methods	RCT
Participants	International Multicentre study, 14 centres from 3 countries (Germany, Switzerland, Austria) Number (daclizumab/control): 156 (NS/NS) Cadaveric donors: NS First transplant: NS
Interventions	Treatment group Daclizumab: 2mg/kg first dose, followed by 4 additional doses of 1 mg/kg every 2 weeks Control group Nothing Baseline immunosuppression CSA trough levels Daclizumab group: 75‐125 ng/mL Control group: 50‐250 ng/mL MMF: 2 g/d Steroid dose: NS (tapered identically in both groups)
Outcomes	Mortality Graft loss Acute rejection Delayed graft function
Notes	Ongoing study Data from abstracts presented for 121 (59/62) completing 3 months follow‐up (remainder not yet available)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Stated "randomised", no further information provided
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding (performance bias and detection bias)   Objective outcomes	Unclear risk	Not stated
Blinding (performance bias and detection bias)   Subjective outcomes	Unclear risk	Not stated
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Data only available from 3 conference proceedings abstracts
Selective reporting (reporting bias)	Unclear risk	Primary outcomes for this review (death, graft loss and acute rejection) have been reported. Data only available for 3 conference proceedings abstracts
Other bias	Unclear risk	Funding source not stated. Data only available from 3 abstracts

Methods	Single centre (USA)
Participants	Setting: Single centre Country: USA First or second, cadaveric (91%) or zero haplotype live donor (9%) kidney transplant recipients Age: NS Number (group 1/group 2): 45 (23/22) Sex (M/F): NS
Interventions	Treatment group 1 Basiliximab: 20 mg days 0 and 4 Treatment group 2 Muromonab‐CD3: 2.5 mg for 7‐14 days Baseline immunosuppression CSA: NS MMF: 2 g on day 1 Steroids: tapering
Outcomes	Mortality Graft loss Acute rejection
Notes	Follow‐up range 1‐12 months (median 6.4) Data contributes to 6 month outcome Trial on‐going, data from abstract.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Stated "randomised" no further information provided
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding (performance bias and detection bias)   Objective outcomes	Unclear risk	Not stated
Blinding (performance bias and detection bias)   Subjective outcomes	Unclear risk	Not stated
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Number randomised not reported
Selective reporting (reporting bias)	Unclear risk	Primary outcomes for this review (death, graft loss and acute rejection) have been reported, however data only available from abstract
Other bias	High risk	Funding source not stated; abstract only data available

Methods	RCT Duration: 1998 to 2000
Participants	Setting: Single centre Country: Latvia First (100%) or second cadaveric kidney transplant Age: NS Number (group 1/group 2/group 3): 71 (25/23/23) Sex (M/F): NS
Interventions	Treatment group (group 3) Basiliximab: 20 mg days 0 and 4 CSA, AZA, steroids Control groups (group 1 and group 2) Group 2 CSA, MMF, steroids Group 3 CSA, AZA, steroids Baseline immunosuppression CSA: Trough levels 150‐350 ng/mL (weeks 1‐4) and 150‐300 ng/mL thereafter AZA: 1‐2 mg/kg/d MMF: 2 g/d Steroids: 0.5 g/kg/d tapered to a minimum dose of 5 g/d at 12 months
Outcomes	Graft loss Acute rejection CMV
Notes	Group 2 and 3 combined for analysis
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Stated "randomised", no further information provided
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding (performance bias and detection bias)   Objective outcomes	Unclear risk	Not stated
Blinding (performance bias and detection bias)   Subjective outcomes	Unclear risk	Not stated
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Results presented as mixture of numbers and percentages, however all patients appear to be accounted for
Selective reporting (reporting bias)	Unclear risk	Primary outcomes, graft loss and acute rejection, were reported. Death not reported or mentioned
Other bias	Unclear risk	Funding source not stated

Methods	Design: Single centre RCT
Participants	Country: Brazil Low risk first, living related kidney transplant Mean age: 36.3 ± 10.6 Number (treatment/control): 49 (23/26) Sex (M/F): 31/18 Race: Black (3)
Interventions	Treatment group Daclizumab: 1 mg/kg days 0 and 15 MMF: 3 g/d for 15 days, reduced to 2 g/d thereafter Steroids: Dose not stated Control group TAC: 0‐1‐1.5 mg/kg/d AZA: 2 mg/kg/d Steroids: Dose NS
Outcomes	Mortality Graft loss Acute rejection Infection
Notes	Follow‐up range 5‐10 months (mean 7.8). Data contributes to 6 month outcome. On‐going trial. Data from conference proceedings abstract only
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Stated "randomised" no further information provided
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding (performance bias and detection bias)   Objective outcomes	Unclear risk	Not stated
Blinding (performance bias and detection bias)   Subjective outcomes	Unclear risk	Not stated
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Data only available from conference proceedings abstract
Selective reporting (reporting bias)	Unclear risk	Primary outcomes for this review (death, graft loss and acute rejection) have been reported, however data only available from conference proceedings abstract
Other bias	High risk	No funding source stated, however 1 author is an employee of Produtos Roche Quimicos e Farmaceuticos

Methods	Single centre RCT
Participants	Country: Netherlands Cadaveric (46%) or living donor kidney transplant (91% first transplant) Median age: 53.2 years Number (treatment/control): 54 (18/36) Sex: 67% male Exclusions: Human leukocyte antigen‐identical sibling; high immunological risk (PRA > 85% in previous six months; previous graft survival < 1 year due to rejection).
Interventions	Treatment group Daclizumab: 1 mg/kg day 0 and 14 only MMF: 2 g/d to day 15, AUC then maintained at ≤ 30 µg.h/mL with dose adjustment to 1 g/d if required Sirolimus: 15 mg days 0 and 1, then 5 mg/d with doses adjusted to maintain target range 10‐15 µg/L to 6 months and 5‐10 µg/L thereafter Control group (groups 1 and 2) Group 1 TAC: 0.1 mg/kg with dose adjust for target range of 15‐20 µg/L (weeks 1‐2), 10‐15 µg/L (weeks 3‐4), then 5‐8 µg/L Group 2 TAC: 0.1 mg/kg with dose adjust for target range of 15‐20 µg/L (weeks 1‐2), 10‐15 µg/L (weeks 3‐4), then 5‐8 µg/L MMF: 2 g/d to day 15, AUC then maintained at ≤ 30 µg.h/mL with dose adjustment to 1 g/d if required Sirolimus: 3 mg days 0 and 1, then fixed dose of 1 mg/d All groups received 135 mg methylprednisolone on days 0 and 1 only
Outcomes	Mortality Graft loss Acute rejection
Notes	Group 3 Daclizumab group; Groups 1 and 2 combined for control group 9 month follow up coded as 6 months as only 4/18 were still on initial treatment by 6 months (all had daclizumab doses) Interim analysis at the request of the Ethics committee
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Stated "randomized (1‐1‐1)", no further information provided
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding (performance bias and detection bias)   Objective outcomes	High risk	Open‐label, blinding of outcome assessors not stated
Blinding (performance bias and detection bias)   Subjective outcomes	High risk	Open‐label, blinding of outcome assessors not stated
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	ITT analysis reported, however interim analysis at the request of the Ethical Committee
Selective reporting (reporting bias)	Unclear risk	Primary outcomes for this review (death, graft loss and acute rejection) have been reported, however results are from an interim analysis
Other bias	High risk	Supported by grants from Fujisawa Benelux and Roche Pharmaceuticals

Methods	Design: Single centre RCT Duration: June 2002 to May 2005
Participants	Country: Slovenia First (92%) or second, cadaveric kidney transplant Mean age (± SD) Group 1: 48 ± 10 Group 2: 48 ± 10 Number (group 1/group 2): 127 (62/65) Sex (M/F) Group 1: 42/20 Group 2: 32/33 Exclusions: NS
Interventions	Treatment group 1 Basiliximab: 20 mg days 0 and 4 Treatment group 2 Daclizumab: 1 mg/kg day 0 and weeks 2, 4, 6 and 8 Baseline immunosuppression CSA: 0.8 mg/kg/h day 0; 6 mg/kg/d day 2, then adjusted to maintain trough levels of 100‐300 ng/ML (to 3 months) then 70‐170 ng/mL MMF: 2.25 g/d Steroids: 0.4 mg/kg/d days 0‐3; 0.4 mg/kg/d from day 4 tapered by 4 mg/wk to achieve maintenance dose of 0.08 mg/kg/d Co‐interventions CMV prophylaxis: Ganciclovir for high risk patients for 100 days post‐transplant Trimethoprim‐sulfamethoxazole prophylaxis for 12 months for all patients
Outcomes	Mortality Graft loss Acute rejection Delayed graft function Infection/CMV Adverse events
Notes	1 year follow‐up
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Stated "randomized in a 1:1 ratio", no further information provided
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding (performance bias and detection bias)   Objective outcomes	High risk	Open‐label, blinding of outcome assessors not stated
Blinding (performance bias and detection bias)   Subjective outcomes	High risk	Open‐label, blinding of outcome assessors not stated
Incomplete outcome data (attrition bias)   All outcomes	Low risk	ITT analysis reported, all patients followed up or accounted for
Selective reporting (reporting bias)	Low risk	Primary outcomes for this review (death, graft loss and acute rejection) have been reported
Other bias	Unclear risk	Funding source not stated

Methods	Open‐label RCT Patients stratified by age: < 12 years (children) and ≥ 12 years (adolescents) Study duration: March 2001 to March 2004
Participants	Setting: International multicentre study Country: European study First (91%) or re transplant from cadaveric (81%) or living donor with compatible ABO blood type Mean age (± SD) Treatment group: 11.5 ± 4.1 Control group: 11.3 ± 4.0 Number (treatment/control): 92 (99/93) Sex (% M/F) Treatment group: 62.2/37.4 Control group: 61.3/38.7
Interventions	Treatment group Basiliximab:10‐20 mg days 0 and 4 (dose dependent on weight) Control group None Baseline immunosuppression TAC: initial dose daily 2 x 0.3 mg/kg, then adjusted for trough levels of 10‐20 ng/mL (0‐21 days), 5‐15 ng/mL (22‐183 days) AZA: 1‐2 mg/kg/d Steroids: 300‐600 mg/m² day 0 then tapered from 60 mg/m² on day 1 to ≤ 10 mg/m² from day 43 onwards
Outcomes	Mortality Graft loss Acute rejection Delayed graft function Infection/CMV Malignancy
Notes	All participants ≦ 18 years 2 year follow‐up data available in conference abstract
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	The "randomisation was stratified by centre using the method of permuted blocks"
Allocation concealment (selection bias)	Low risk	"Allocation to treatment was performed locally using sealed randomisation envelopes"
Blinding (performance bias and detection bias)   Objective outcomes	High risk	Open‐label, blinding of outcome assessors not stated
Blinding (performance bias and detection bias)   Subjective outcomes	High risk	Open‐label, blinding of outcome assessors not stated
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All patients were followed up or accounted for
Selective reporting (reporting bias)	Low risk	Yes: Primary outcomes for this review (death, graft loss and acute rejection) have been reported
Other bias	High risk	"study was supported by Astellas Pharma, Munich, Germany"

Methods	RCT
Participants	Setting: NS Country: USA Randomised and transplanted based on risk profile High risk (HR): African‐Americans; PRA ≥ 20%; re‐transplant Low risk (LR): non‐African‐Americans; PRA < 20%, primary transplant Age: Adults Number (Bas‐LR/CIH‐LR/CIH‐HR/Thymo‐HR): 474 (171/164/70/69)
Interventions	Treatment group Basiliximab: 2 doses (20 mg) days 0‐4 Control group (CIH‐LR/CIH‐HR/Thymo‐HR) Other antibodies (HR and LR patients given alemtuzumab) Alemtuzumab (CIH): 30 mg, day 0 Thymoglobulin: 15 mg/kg/d, days 0‐4 Baseline immunosuppression TAC: NS MMF: NS Steroids: 1 g prior to discharge
Outcomes	Mortality Graft loss Acute rejection Delayed graft function Infection/CMV Malignancy
Notes	Groups 2 and 3 and 4 combined for comparison IL2R versus other antibody 1 year follow‐up
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Stated "randomized" no further information provided
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding (performance bias and detection bias)   Objective outcomes	Unclear risk	Not stated
Blinding (performance bias and detection bias)   Subjective outcomes	Unclear risk	Not stated
Incomplete outcome data (attrition bias)   All outcomes	High risk	All patient numbers listed under parameters in results table, however dichotomous results presented as percentages and no SD for continuous outcomes
Selective reporting (reporting bias)	High risk	Primary outcomes only reported as percentages
Other bias	High risk	Funding source not stated, 1 author employee of the pharmaceutical company Astellas Pharma U.S. Abstract only data available

Methods	Open‐label, 3‐arm parallel RCT Duration: 24 months
Participants	Setting: Single centre Country: Spain First (91%) cadaveric (46%) kidney transplant; all low immunological risk Age: > 18 years Number (group A/group B+C): 240 (80/160) Exclusions: PRA > 30% in previous 6 months; significant liver disease; malignancy; HIV; active peptic ulcer disease; intolerance to study drugs; grafts form non‐heart beating donors; pregnancy
Interventions	Treatment group 1 (B+C) Basiliximab (20 mg IV days 0 and 4) Treatment group 2 (A) ATG (Thymoglobulin): 7‐day course (1 ‐1.5mg/kg/d) Baseline immunosuppression Group A CSA: 4 mg/kg twice daily, trough level 175‐300 ng/mL for 3 months and 150‐200 ng/mL thereafter AZA: 1.5 mg/kg/d Steroids Group B CSA: 2 mg/kg twice daily, trough level 125‐175 ng/ML throughout study MMF: 2 g/d Steroids Group C TAC: 0.05 mg/kg twice daily, trough level 7‐10 ng/mL throughout study MMF: 2 g/d Steroids
Outcomes	Mortality Graft loss Acute rejection Delayed graft function Infection CMV Malignancy
Notes	1 and 2 year follow‐up
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	A "computer generated random number sequence" was used
Allocation concealment (selection bias)	Low risk	"Sequentially numbered sealed envelopes...concealed from the members who were involved in the enrolment of patients"
Blinding (performance bias and detection bias)   Objective outcomes	High risk	"Neither patients nor clinicians were blinded to therapy". Blinding of outcome assessors not stated
Blinding (performance bias and detection bias)   Subjective outcomes	High risk	"Neither patients nor clinicians were blinded to therapy". Blinding of outcome assessors not stated
Incomplete outcome data (attrition bias)   All outcomes	Low risk	ITT analysis reported, 25% of randomised patients were excluded, however data for all patients has been reported
Selective reporting (reporting bias)	Low risk	Primary outcomes for this review (death, graft loss and acute rejection) have been reported. No study protocol available to assess secondary outcomes of study
Other bias	Low risk	Supported by grants FIS 02/1350 and FIS 04/0988 from Instituto de Salud Carlos III and RTIC (C03/03), Spanish Ministry of Health