Papers

Interleukin-2 receptor monoclonal antibodies in renal transplantation: meta-analysis of randomised trials

Dwomoa Adu, consultant nephrologist ^a, Paul Cockwell, consultant nephrologist ^a, Natalie J Ives, statistician ^b, Jonathan Shaw, house physician ^a, Keith Wheatley, professor ^b. 

^a Department of Nephrology, Queen Elizabeth Hospital, Birmingham, B15 2TH, ^b Birmingham Clinical Trials Unit, Park Grange, Birmingham B15 2RR

Correspondence to: D Adu dwomoa.adu{at}uhb.nhs.uk

	Abstract

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Objective: To study the effect of interleukin-2 receptor monoclonal antibodies on acute rejection episodes, graft loss, deaths, and rate of infection and malignancy in patients with renal transplants.
Design: Meta-analysis of published data.
Data sources: Medline, Embase, and Cochrane library for years 1996-2003 plus search of medical editors' trial amnesty and contact with manufacturers of the antibodies.
Selection of studies: Randomised controlled trials comparing interleukin-2 receptor antibodies with placebo or no additional treatment in patients with renal transplants receiving ciclosporin based immunosuppression.
Results: Eight randomised controlled trials involving 1871 patients met the selection criteria (although only 1858 patients were analysed). Interleukin-2 receptor antibodies significantly reduced the risk of acute rejection (odds ratio 0.51, 95% confidence interval 0.42 to 0.63). There were no significant differences in the rate of graft loss (0.78, 0.58 to 1.04), mortality (0.75, 0.46 to 1.23), overall incidence of infections (0.97, 0.77 to 1.24), incidence of cytomegalovirus infections (0.81, 0.62 to 1.04), or risk of malignancies at one year (0.82, 0.39 to 1.70). The different antibodies had a similar sized effect on acute rejection (test for heterogeneity P=0.7): anti-Tac (0.37, 0.16 to 0.89), BT563 (0.37, 0.1 to 1.38), basiliximab (0.56, 0.44 to 0.72), and daclizumab (0.46, 0.32 to 0.67). The reduction in acute rejections was similar for all ciclosporin based immunosuppression regimens (test for heterogeneity P=1.0).
Conclusions: Adding interleukin-2 receptor antibodies to ciclosporin based immunosuppression reduces episodes of acute rejection at six months by 49%. There is no evidence of an increased risk of infective complications. Longer follow up studies are needed to confirm whether interleukin-2 receptor antibodies improve long term graft and patient survival.

What is already known on this topic Episodes of acute rejection reduce graft survival in patients with renal transplants Increasing immunosuppression to reduce rejection can increase infection and malignancy What this study adds Addition of interleukin-2 receptor antibodies to ciclosporin based immunosuppression regimens halves the risk of acute rejection Patients receiving antibodies did not have an increased risk of infection The effects on graft loss and mortality at one year were not significant

	Introduction

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Over 15 000 people in the United Kingdom have functioning renal transplants, almost half of all patients with end stage renal failure.¹ Episodes of acute rejection reduce the chance of long term survival of the graft. ^{2 3} However, increasing immunosuppression to lower the risk of acute rejection or to treat episodes of acute rejection increases the incidence of infections and malignancies. ^{4 5}

Acute rejection arises when alloreactive T cells infiltrate the graft. A critical step in the activation of these cells is the expression of the high affinity interleukin-2 receptor, which induces rapid proliferation of T cells when interleukin-2 binds to it.⁶ The interleukin-2 receptor consists of three transmembrane protein chains:  (CD25),  (CD122), and  (CD132). CD25 does not transduce a signal but associates with CD122 and CD132 to form the receptor that triggers signalling.⁷

Initial human studies with mouse monoclonal antibodies to CD25 showed a significant reduction in acute rejection, but patients developed anti-mouse antibodies. ^{8 9} Chimeric and humanised antibodies to CD25 have been developed to overcome the problem of immunogenicity, but individual trials are not large enough to be clear about the effectiveness of these antibodies. We did a systematic review and quantitative meta-analysis of randomised trials of interleukin-2 receptor antibodies versus placebo in patients receiving ciclosporin based immunosuppression after renal transplantation.

	Methods

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Literature search
We searched Medline, Embase, and Cochrane Library databases for studies published between 1966 and 2003, and located unpublished studies by searching the medical editors' trial amnesty and by contacting the manufacturers of the interleukin-2 receptor antibodies basiliximab and daclizumab. See bmj.com for details.

Selection of trials
Studies had to meet the following criteria: treatment assigned by randomisation; all patients received standard immunosuppression; the experimental group received interleukin-2 receptor antibody; the control group received placebo or no other drug.

Outcome measures and statistics
The main outcome measures were biopsy proved acute rejection at six months after transplantation, graft loss and death at 12 months, and incidence of infections, cytomegalovirus infections, and malignancy at 3, 6, or 12 months.

We determined the number of patients with each outcome measure in the antibody and control groups for each trial from the published papers. For each trial we calculated the expected number of events in the interleukin-2 group and then the difference between the observed and expected numbers and its variance. The sum of the statistics for each trial provided the overall statistics, which we used to calculate odd ratios with 95% confidence intervals.

	Results

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Eight trials fulfilled the inclusion criteria (see bmj.com). Four studies used cadaveric donors, and four both cadaveric and living donors. Two of the studies included patients receiving second transplants. All but one of the studies used a double blind method of randomisation. Four studies described the method of randomisation in detail. In one study, the patients in the control arm did not receive placebo.

The baseline immunosuppression varied between studies. Four studies used ciclosporin and prednisolone, three studies used ciclosporin, azathioprine, and prednisolone, and one study used ciclosporin, mycophenolate mofetil, and prednisolone.

The overall proportion of patients with acute rejection at six months was 361/912 (39.6%) in the control group compared with 232/904 (25.7%) in the antibody group (figure). Treatment with interleukin-2 receptor antibodies was associated with a significant reduction in the risk of acute rejection at six months (odds ratio 0.51; 95% confidence interval 0.42 to 0.63; P<0.0001). Patients treated with antibodies had no significant reductions in graft loss at one year (0.78, 0.58 to 1.04; P=0.09) or in mortality at one year (0.75, 0.46 to 1.23; P=0.3).

View larger version (44K): [in this window] [in a new window]   Incidence of acute rejection by type of interleukin-2 receptor antibody. Note that only overall follow up data (six to 26 months) were available for anti-Tac and 12 week data for BT563

Treatment with interleukin-2 receptor antibodies had no significant effect on overall infection (0.97, 0.77 to 1.24; P=0.8) or cytomegalovirus infection (0.81, 0.62 to 1.04; P=0.1). There was no difference in the risk of lymphoma or other malignancies at one year (0.82, 0.39 to 1.70; P=0.6).

The effect on acute rejection was similar for all types of interleukin-2 receptor antibody (figure): anti-TAC (0.37, 0.16 to 0.89; P=0.03), BT563 (0.37, 0.1 to 1.38; P=0.1), basiliximab (0.56, 0.44 to 0.72; P<0.0001), and daclizumab (0.46, 0.32 to 0.67; P<0.0001). The test for heterogeneity between antibody groups was not significant (P=0.7).

The reduction in acute rejection was similar for all baseline immunosuppression regimens. The odds ratio was 0.52 (95% confidence interval 0.40 to 0.67; P<0.0001) for patients treated with ciclosporin and prednisolone; 0.5 (0.36 to 0.71; P<0.0001) with ciclosporin, prednisolone, and azathioprine; and 0.51 (0.22 to 1.21; P=0.1) with ciclosporin, prednisolone, and mycophenolate mofetil. There was no evidence of heterogeneity between the three immunosuppression treatment groups (P=1.0) or between the trials for any of the other outcomes.

	Discussion

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This meta-analysis confirms that adding interleukin-2 receptor antibodies to standard ciclosporin based immunosuppression greatly reduces the risk of rejection. Acute rejection proved by biopsy was reduced by 49% at six months. We also found non-significant reductions in graft loss and mortality, and there was no evidence of increased incidence of infections or risk of malignancy. The size of the reduction in acute rejections was similar for the different antibodies and immunosuppression regimens.

Reducing the rate of acute rejection is important in renal transplantation, as patients who have had one or more episodes of acute rejection have at least a 50% reduction in long term graft survival.² Because one year graft survival for renal transplantation is about 90%,² studies with follow up for more than one year are needed to determine the long term effect on graft loss.

A major concern with the addition of immunosuppression to standard regimens is the increased incidence of side effects. Although we found no increase in the incidence of malignancies in patients treated with interleukin-2 receptor antibodies compared with the control group at one year, the follow up was too short to draw useful conclusions. We found no evidence of an increase in the risk of infections. This is important because analyses of treatment with anti-lymphocyte antibodies in renal allograft recipients have shown an increased risk of infection. ^{4 5} Finally, we found some evidence of a reduction in the incidence of cytomegalovirus infections in patients treated with antibodies compared with the control group.

Some centres in the United Kingdom use tacrolimus based immunosuppression. A meta-analysis showed that this regimen reduced the risk of acute rejection but not graft loss compared with ciclosporin based immunosuppression.¹⁰ There are no randomised controlled studies of interleukin-2 receptor antibodies in patients with renal transplants treated with tacrolimus based immunosuppression.

Validity of results
The published results were presented as intention to treat, suggesting that all randomised patients were included in the analysis. However, one study excluded data from one centre as it did not collect biopsy samples according to the protocol. Furthermore, three studies defined the intention to treat analysis as including only patients who actually had renal transplantation. Two patients (one patient from each arm) in two of the studies, and four (three from the interleukin-2 group and one from the placebo group) in the other study were therefore excluded from analysis because they never had a renal transplant. Another study excluded three patients from the analysis because they lost their graft because of technical reasons or renal artery thrombosis. These exclusions mean that the results are not strictly intention to treat, but the number of patients excluded is small (11 in total) and therefore unlikely to bias the results.

As with all meta-analyses of published data, there is the potential problem of publication bias. We did a comprehensive literature search to identify published and unpublished data. It therefore seems unlikely that this would be a substantial source of bias.

	Acknowledgments

Contributors: See bmj.com

	Footnotes

Funding: No funding was sought for this study.

Competing interests: DA is an investigator in a trial of fluvastatin in renal transplant recipients that is funded by Novartis; PC and DA have a grant from Roche to study chronic allograft nephropathy; PC has an unrestricted educational grant from Novartis to support research into early immune events after renal transplantation, has received support from Roche and Novartis to attend transplant meetings, and has spoken at educational meetings sponsored by these companies.

This is an abridged version; the full version is on bmj.com

	References

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(Accepted 14 February 2003)