Effective immunosuppression is crucial for graft survival after renal transplantation. Acute rejection episodes occur in more than 50% of all pediatric transplant recipients (1) and are responsible for a significant proportion of all graft losses or may trigger chronic rejection (2). Acute rejection arises when alloreactive T cells infiltrate the graft. A critical step in the activation of these cells isthe expression of the high affinity interleukin-2 receptor, whichinduces rapid proliferation of T cells when interleukin-2 bindsto it (3). The interleukin-2 receptor consists of three transmembraneprotein chains:  (CD25),  (CD122), and  (CD132). CD25 doesnot transduce a signal but associates with CD122 and CD132 toform the receptor that triggers signalling (4).

Initial human studies with mouse monoclonal antibodies to CD25 showed a significant reduction in acute rejection, but patientsdeveloped anti-mouse antibodies (5,6). Chimeric and humanisedantibodies to CD25 have been developed to overcome the problemof immunogenicity. Traditional engineered monoclonal antibodies have been associated with severe cytokine release reactions and an increased risk of opportunistic infections. Basiliximab and daclizumab are monoclonal antibodies, interleukin-2 receptor antagonists which inhibit thymus-dependent lymphocyte proliferation. Interleukin-2 also affects the proliferation of natural killer cells, macrophages and monocytes, bursa-equivalent lymphocytes, epidermal dendritic cells, and lymphokine-activated killer cells. Interleukin-2 receptor antagonists have been shown to reduce the incidence of acute rejection without increasing the incidence of opportunistic infections or malignancy (7).

Basiliximab and daclizumab, IgG monoclonal antibody to the interleukin-2 (IL-2) receptor were approved to prevent acute rejection after renal transplantation. Basiliximab is a chimeric monoclonal antibody that was shown previously in a pediatric cohort to inhibit the -chain of the IL-2R for 29 ± 6 days (8). Basiliximab and daclizumab were studied in adult and pediatric renal allograft recipients, but the pediatric experience is still limited.

We review here the effects of basiliximab/daclizumab added to primary immunosuppression in children and adolescents with renal transplantation, on the incidence of acute rejection , as well as tolerability, costs and safety .

Introduction of IL-2-receptor antagonists has led to significantly decreasing numbers of acute rejection episodes in renal transplantation in adults. Few data are available in pediatric recipients.

A meta-analysis of publisheddata was done, to rewiew the effect of interleukin-2 receptormonoclonal antibodies on acute rejection episodes, graft loss,deaths, and rate of infection and malignancy in adult patients withrenaltransplants(9). 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). This meta-analysis showed that adding interleukin-2 receptor antibodies to cyclosporin 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.

There are a few studies in children, which are summarized in table 1. The incidence of acute rejection in children using IL-2-receptor antagonists ranges from 0 to 26%, and in these all series it was well tolerated (10-18).

The dose of basiliximab in children difers from the used in adults. In the beginning, two intravenous (IV) bolus injections of basiliximab (12 mg/m2) were administered (before and 4 days postsurgery). Later, two injections in patients less than 40 kg, 10 mg and in patients over 40 kg, 20 mg are administered at the same time points. (17, 19)

In phase III trials daclizumab was used in a five-dose regimen of 1 mg/kg at 2-weekly intervals, resulting in saturation of IL-2Ralpha on circulating lymphocytes for up to 120 days after renal transplantation. One study with the purpose to evaluate daclizumab blood concentrations and the saturation of the IL-2Ralpha on the circulating lymphocytes with a limited dosing regimen of daclizumab. Twelve patients undergoing primary cadaver or living donor transplantation were randomized to either receive one dose (2 mg/kg) or two doses (2^nd dose, 1 mg/kg) of daclizumab in addition to maintenance immunosuppression therapy. Pharmacokinetic and pharmacodynamic studies were performed up to 20 weeks after the transplantation. In patients treated with a single dose of daclizumab, the blood concentrations of daclizumab declined to 1 g/mL at 43± 7 days after the transplantation. In patients treated with two doses of daclizumab, the blood concentrations of daclizumab declined to 1 micro g/mL at 45 ± 13 days after the second dose for a total of 59 ± 13 days after the transplantation. Daclizumab levels of 1 g/mL or greater were associated with saturation of the IL-2Ralpha on the circulating lymphocytes. In the new era of effective maintenance immunosuppression, a limited dosing regimen of daclizumab may be desired, practical and economical (20).

Basiliximab and daclizumab are potent and relatively safe immunosuppressive induction agents used in transplantation. But there are some data showing cases with adverse effects. Leonard et al. report (21) a 42-year-old woman who received a dose of basiliximab without adverse reaction before a previous renal transplant that was canceled. Two weeks later, she received a second dose of basiliximab. Within 10 min of receiving the second dose, she developed chest tightness, shortness of breath, tongue swelling, diffuse pruritic rash, and skin flushing. The authors hypothesized that her anaphylaxis was mediated by IgE antibodies to basiliximab. Consistent with this hypothesis, intradermal administration of a 1:100 dilution of basiliximab induced a 10 x 10-mm flare. She mounted neither a prick nor an intradermal response to daclizumab. The patient was administered daclizumab without any adverse effects. The negative skin test and safe administration of daclizumab is surprising because the similarity of these hybrid antibodies would have predicted similar IgE responsiveness and clinical outcome. The authors propose that patients who develop anaphylaxis to basiliximab or other chimeric antibodies may be candidates for treatment with a humanized antibody preparation such as daclizumab in the presence of a negative skin test to the humanized agent. There are other reports of anaphylatic shock, including pediatric patients (22, 23, 24).

Costs in renal transplant recipients treated with basiliximab or placebo plus triple immunosuppressive therapy are similar. Considering the sum of costs regarding number of days spent in the hospital, steroid pulses, OKT3 treatment, graft biopsies, dialysis sessions in patients with acute rejection compared with a significant reduction in rejection episodes and a shorter length of stay in hospital achieved with basiliximab or daclizumab there was no statistically significant economical difference(25, 26).

Monoclonal antibody therapy (daclizumab and basiliximab) is an exciting new development, whereby T cell proliferation is inhibited by selective blockade of interleukin (IL)-2 receptors. Further clinical trials need to be carried out to establish efficacy, tolerability and pharmacokinetics in pediatric transplant recipients. Preliminary results, when used in combination with a standard immunosuppressive regimen, are good with respect to incidence of acute graft rejection, host immune response and adverse effects.

References

26. Nogueira PK, Feltran LS, Tabatabake E, Machado PP, Carvalhaes JTA, Pestana JOM. Basiliximab does not increase costs of kidney transplantation in children. Pediatr Nephrol 2001; 16:C176