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Matthew J Koch
Department of Medicine
Washington University School of Medicine at Barnes-Jewish Hospital
St Louis, MO
The use of induction and the administration of adjunctive immunosuppressive agents during the early transplant period have significantly decreased the incidence of acute rejection. Before the routine use of induction, acute rejection rates of 40–50% were common, whereas many centres are currently reporting acute rejection rates of less than 10%. Induction agents can be broadly classified as polyclonal antibodies (PAbs) or monoclonal antibodies (MAbs) (see Table 1). PAbs comprise antithymocyte globulins (ATGs) and antilymphocyte globulins (ALGs). MAbs include muromonab- CD3 (mb-CD3), alemtuzumab and interleukin- 2-receptor blockers (IL-2RBs).
In the USA, the use of induction in renal transplantation has increased from approximately 11% to 68% over the last 10 years.(1) In a recent US database report, rabbit-derived ATG (Thymoglobulin) was used in 26% of recipients, while one of the IL-2RBs (basiliximab [27%] or daclizumab [13%]) was used in almost all other induction recipients.(1)
Controversy exists regarding the appropriate clinical situations in which a specific induction agent should be administered. Decisions tend to be centre-specific, based on experience, chronic immunosuppression protocol and gestalt. Unfortunately, few randomised studies comparing the available induction agents have been published.
Use of induction to decrease rates of acute rejection or minimise maintenance immunosuppression, particularly in protocols designed to minimise or avoid calcineurin inhibitor (CNI) or steroid exposure, must be balanced against the potential for an increased risk of infection and malignancy. It must also be noted that, despite the impressive decrease in acute rejection and the resultant improvement in early outcomes, evidence for improved long-term graft survival is lacking.
Polyclonal antibody preparations
PAb preparations are produced by immunising animals with human thymocytes or lymphocytes. Commercially available preparations in the USA are Thymoglobulin and equine- derived ATG (Atgam). In Europe, two additional products are available: rabbit-immortalised cell-derived (F-ATG) and equine thymocyte-derived (Lymphoglobulin).
In addition to a profound and prolonged lymphopenia, the broad specificity of PAb affects multiple costimulatory and adhesion molecules important in cellular and antibody- mediated processes. These properties are most likely responsible for the reduced incidence of delayed graft function associated with intraoperative administration of Thymoglobulin.(2)
Although xenogenic antibodies may develop after PAb exposure, they are rarely associated with significant inhibitory effect with repeat administration. Administration of PAb may cause mild-to-moderate cytokine release syndrome, which can be minimised with pretreatment corticosteroids.
Thymoglobulin has commonly been given as a dose of 1.5mg/kg/day for 7–10 days. A three-day induction regimen (3mg/kg intraoperatively and 1.5mg/kg for two additional doses) using triple therapy immunosuppression (TTI) has also been effective, with a one-year acute rejection rate of 5%.(3) Adjustments in dosage or interval dependent on cell counts may be required.
Alemtuzumab is a humanised anti-CD52 MAb that is selectively lytic for T- and B-cells and monocytes and has been used for induction.(4–6) Current dosing regimens are usually a single dose of 30–40mg or two doses of 20–30mg. This agent produces a prolonged lymphopenia and has most commonly been used in CNI or steroid minimisation/ avoidance trials.
Available IL-2RBs are daclizumab, a primarily humanised immunoglobulin, and basiliximab, a more chimeric immunoglobulin. Basiliximab is administered as 20mg on day 0 and day 4. The recommended dose of daclizumab is 1mg/kg every 14 days for a total of five doses. Anti-IL-2RBs target the alpha subunit of the IL-2 receptor, present on activated T-cells, and limit the proliferative response.
Three basiliximab trials demonstrated a statistically significant decrease in acute rejection compared with placebo, but no improvement in graft survival at one year. Two of these studies, in which dual therapy immunosuppression (DTI) was used, showed a decrease in acute rejection from 44% to 29.8% at six months, and from 49.1% to 35.3% at one year.(7,8) A third trial using TTI showed a decrease in acute rejection from 34.9% to 20.8% at six months.(9) Another basiliximab versus placebo trial using TTI showed a nonstatistically significant trend toward reduced acute rejection (15.3% versus 26.6%) at one year.(10)
Two daclizumab versus placebo induction trials also demonstrated a statistically significant reduction in the incidence of acute rejection at six months. A DTI trial demonstrated 28% versus 47%, and a TTI trial demonstrated a 22% versus 35% rate.(11,12) Pooled analysis showed no statistically significant difference at three years in patient or graft survival.
Muromonab-CD3 is a murine MAb against the T-cell CD3 receptor that depletes CD3+ cells, inhibits activation of CD4+ cells and inhibits CD8+ cell targeting. Risk of a severe cytokine release syndrome, combined with favourable results using alternative agents, has made mb-CD3 for induction obsolete. Humanised anti-CD3 antibodies have been used successfully in induction trials and will likely revitalise interest in this class, as they have a propensity for limited cytokine release and display an absence of neutralising antibody formation.(13)
Unfortunately, there is a lack of relevant published trials comparing induction agents by class. An induction trial comparing Thymoglobulin with Atgam using TTI demonstrated one-year acute rejection rates of 4% and 25%, respectively,(14) and improved outcomes in the Thymoglobulin arm through five years of follow-up.(15) Thymoglobulin and basiliximab were compared in an induction trial using TTI in recipients considered at low risk for acute rejection. Basiliximab (with early initiation of CNI) and Thymoglobulin (with delayed CNI initiation) produced a similar incidence of acute rejection (19% versus 20%, respectively) and similar patient and graft survival at one year.(16) Other small analyses comparing IL-2RB with PAbs have been published, but often differ in the timing of CNI initiation, use of antiviral prophylaxis and recipient risk for rejection, making interpretation difficult.
The increased utilisation of induction has been driven by two factors: evidence for a significant decrease in acute rejection, and use in steroid or CNI minimisation/avoidance protocols. Despite the decrease in acute rejection, it has yet to be demonstrated that long-term results are improved, and the question of appropriate utilisation of these costly agents remains. The use of induction in low-risk recipients may unnecessarily increase the risk of infection and malignancy, while avoidance in other recipients may result in exposure to an increased total intensity of immunosuppression in an effort to treat rejection as well as in premature graft loss.
With acute rejection now a fairly rare event at most centres, attention has been directed toward improvement in long-term outcomes. Thus, long-term results from randomised induction trials including high- and low-risk recipients using standard TTI and antiviral prophylaxis are needed. Randomised trials using induction agents in minimisation/avoidance protocols will also be necessary. Given the opinion of many transplant clinicians that agents such as Thymoglobulin or alemtuzumab are necessary for successful outcomes in high-risk recipients and in minimisation/ avoidance protocols, the ability to perform randomised trials comparing these agents with IL-2RB or placebo is limited. Trials attempting to define the optimal induction regimens for the various agents are more likely to transpire and will help to answer many important questions, but they are unlikely to resolve fully the induction debate.