Polyclonal and monoclonal antibodies for treating acute rejection episodes in kidney transplant recipients
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
-
To evaluate the short and long‐term benefits and harms of different antibody preparations over and above other immunosuppressive regimens:
-
To evaluate the relative and absolute effects of different of antibody preparations in preventing graft loss and resolving rejection episodes when used as a treatment for acute rejection in kidney transplant recipients.
-
To determine how the benefits and adverse events vary for each antibody preparation.
-
To determine how the benefits and harms vary for different formulations of antibody preparation.
-
To determine whether the benefits and harms vary in specific subgroups of recipients (children and sensitised recipients).
Background
Kidney transplantation is the treatment of choice for most patients with end‐stage renal failure (ESRF). Waiting lists for transplantation continue to grow because demand exceeds organ availability. Strategies to increase donor organ availability and to prolong kidney allograft survival have become priorities in kidney transplantation.
Standard immunosuppressive therapy consists of initial induction and maintenance regimes to prevent rejection. Maintenance protocols typically involve three drug groups each directed to a site in the T‐cell activation or proliferation cascade which are pivotal to the rejection process: calcineurin inhibitors (e.g. cyclosporin, tacrolimus), anti‐proliferative agents (e.g. azathioprine, mycophenolate mofetil) and a corticosteroid (prednisolone) (Hong 2000, Denton 1999). Additionally, antibody preparations may be added in the induction phase, particularly for those recipients deemed at high risk of rejection (children, subsequent transplants, certain racial groups such as African‐Americans, and other sensitised patients) as additional prophylaxis against acute rejection. Antibody preparations are also used for those at risk of delayed graft function, in order to delay the introduction of full dose calcineurin inhibitors, as their nephrotoxic effects may prolong acute tubular necrosis (Denton 1999).
Treatment of acute rejection requires intensified immunosuppressive therapy. Choice of agent is governed by the histological severity of the rejection episode, degree of allograft dysfunction and clinical history and condition of the patient. Commonly this involves pulsed high dose glucocorticoid therapy and/or an antibody preparation, although may also involve dose modification or substitution of maintenance drugs. For mild to moderate rejection episodes a step‐wise approach is favoured, starting with pulsed glucocorticoids, moving to an antibody preparation in the 10‐20% who fail to respond. Where a rejection episode is severe or recurrent, antibody preparations are commonly the first treatment of choice. (Suthanthiran 1997)
Horse and rabbit derived antilymphocyte polyclonal antibodies against the human lymphocyte (anti‐lymphocyte globulin ‐ ALG and anti‐thymocyte globulin ‐ ATG) have been used for the last 30 years. A murine monoclonal antibody against the CD3 receptor on activated T‐cells (muromonab‐CD3 ‐ OKT3) also became available in the late 1980s. These preparations remove the functional T‐cell population from circulation, producing immunosuppression useful for both induction therapy and the management of acute rejection. However, this profound immunosuppression is associated with immediate toxicity (cytokine release syndrome) and higher rates of infection and malignancy than standard triple therapy. (Soulillou 2001). Use of these preparations may also be limited by the development of neutralising antibodies to their xenogeneic components. (Kreis 1992)
More recently, the interleukin‐2‐receptor antagonists (IL2Ra) basiliximab and daclizumab have been used in the induction phase. IL2Ra are Ig G monoclonal antibodies to the interleukin‐2 receptor found only on activated T‐cells. IL2Ra are more specific immunosuppressants, with no immediate toxicity, and are increasingly used as induction agents, but not for treating acute rejection (Cibrik 2001). These agents are investigated in a separate Cochrane review and so will be considered here only in relation to other antibody classes. (Webster 2004a)
Favoured antibody preparations differ by country and amongst transplant units. Between 2000‐2002, in the USA, 60% of recipients received an antibody preparation as part of induction immunosuppression. Twenty per cent of kidney recipients received ATG, 1% OKT3 and 39% IL2Ra (UNOS 2003). In Australia, only 25% of patients received an antibody preparation over the same time period (ANZDATA 2003). This variation in practice in part reflects uncertainty over the relative value of antibody preparations over and above maintenance immunosuppression, and also because of their toxicity.
The aim of this systematic review is to identify and summarise the evidence available for the different antibody preparations in terms of short and long term benefits and adverse events (e.g. ATG, ALG and muromonab CD3), in patients receiving kidney transplants. This review will address the use of antibodies for the treatment of acute rejection episodes in kidney transplant recipients. A second review will look at the use of antibodies for induction therapy (Webster 2004b).
Objectives
-
To evaluate the short and long‐term benefits and harms of different antibody preparations over and above other immunosuppressive regimens:
-
To evaluate the relative and absolute effects of different of antibody preparations in preventing graft loss and resolving rejection episodes when used as a treatment for acute rejection in kidney transplant recipients.
-
To determine how the benefits and adverse events vary for each antibody preparation.
-
To determine how the benefits and harms vary for different formulations of antibody preparation.
-
To determine whether the benefits and harms vary in specific subgroups of recipients (children and sensitised recipients).
Methods of the review
Selection Criteria
The review will be undertaken by seven reviewers (Angela Webster (AW), John Mahan (JM), Nick Webb (NW), Lois Orton (LO), Tanya Pankhurst (TP), Jeremy Chapman (JRC), Jonathan Craig (JCC)).
Eligible studies will be identified using the search strategy listed (AW, JM, TP, LO).
The titles and abstracts and, where necessary, the full text will be independently screened by two reviewers (from the group AW, JM, NW, TP, LO).
Studies not written in English will be translated.
Disagreement about inclusion will be resolved by discussion between co‐reviewers (AW, JRC, JCC).
Data extraction will be performed independently by reviewers, using a standardised form (AW, JM, NW, TP, LO). Discrepancies will be resolved by discussion (all).
Authors of published work will be contacted for clarification of unclear data.
Data will be entered into RevMan 4.2 twice (AW).
Quality of studies
Quality of included studies will be assessed independently by at least two reviewers (AW, JM, NW,TP, LO) without blinding to journal or authorship, using the checklist created by the Cochrane Renal Group.
Discrepancies will be resolved by discussion. The quality items to be assessed are allocation concealment, intention‐to‐treat analysis, completeness of follow‐up and blinding of investigators, subjects and outcomes assessment.
Each item will be assessed separately rather than combined in a scoring system.
Quality checklist
1. Allocation concealment
Adequate ‐ Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study
Unclear ‐ Randomisation stated but no information on method used is available
Inadequate ‐ Method of randomisation used such as alternate medical record numbers or unsealed envelopes.; Any information in the study that indicated that investigators or participants could influence intervention group
2. Blinding
Blinding of investigators: Yes/No/Not stated
Blinding of participants: Yes/No/Not stated
Blinding of outcome assessor: Yes/No/Not stated
Blinding of data analysis: Yes/No/Not stated
In trials where no placebo is used, or where the intervention and comparison arms use drugs with different dosing schedules then, unless otherwise clarified, both the investigators and the participants will be considered non‐blinded.
3. Intention‐to‐treat analysis
Yes: Specifically reported by authors that ITT was undertaken and this was confirmed on study assessment, or not stated but evident from study assessment that ITT was undertaken
Unclear: Reported but unable to confirm on study assessment, or not reported and unable to confirm by study assessment.
No: Lack of ITT confirmed on study assessment (Patients who were randomised were not included in the analysis because they did not receive the study intervention, they withdrew from the study or were not included because of protocol violation) regardless of whether ITT reported or not
Participants who are randomised but then subsequently do not receive a kidney transplant will be considered to be justifiable exclusions to the ITT population.
4. Completeness of follow‐up
Per cent of participants for whom data was complete at defined study end‐point
Where interim analyses are reported 'not stated' will be recorded
Statistical Assessment
For dichotomous outcomes (e.g. rejection or no rejection) results will be expressed as a relative risk (RR) with 95% confidence intervals (CI).
Where continuous scales of measurement are used to assess the effects of treatment (e.g. creatinine clearance), the weighted mean difference (WMD) will be used, or the standardised mean difference (SMD) if different scales have been used. For count data (such as total number of infections/person year of follow‐up) the rate ratio will be used. Where time‐to‐event data cannot be dichotomised, survival analysis methods will be used and the results expressed as hazard ratio (HR).
Data will be pooled using the random effects model. The fixed effect model will also be analysed to ensure robustness of the chosen model and the susceptibility to outliers (Egger 2001).
Clinical and methodological heterogeneity will be analysed using a Cochran Q test (χ² with N‐1 degrees of freedom and a P value of 0.05 used for statistical significance) and by I2 (with uncertainty intervals) (Higgins 2003).
Subgroup analysis will be used to explore possible clinical sources of heterogeneity:
1. Trial population (based on immunological risk)
2. Baseline maintenance immunosuppression.
3. Type of transplant i.e. cadaveric or living donor
4. Antibody formulation e.g. rabbit versus horse ATG.
5. Duration and dose of antibody treatment.
Where outcomes are not amenable to meta‐analysis, i.e. if reported idiosyncratically (eg. drug related specific adverse reactions), they will be tabulated and assessed with descriptive techniques, and the risk difference with 95% CI will be calculated. Quality of life and economic data will be analysed using descripitive techniques.
If sufficient RCTs are identified, publication bias will be addressed using a funnel plot as advocated by Egger 1997.
