SEARCH

SEARCH BY CITATION

Keywords:

  • Basiliximab;
  • efficacy;
  • kidney transplant;
  • tacrolimus

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

In a 6-month, multicenter, randomized, controlled, open-label, parallel-group trial, we investigated the efficacy and safety of adding basiliximab to a standard tacrolimus-based regimen in pediatric renal transplant recipients. Patients <18 years received tacrolimus/azathioprine/steroids (TAS, n = 93) or tacrolimus/azathioprine/steroids/basiliximab (TAS + B, n = 99). Target tacrolimus levels were 10–20 ng/mL between days 0–21 and 5–15 ng/mL thereafter. Steroid dosing was identical in both groups. Basiliximab was administered at 10 mg (patients <40 kg) or 20 mg (patients ≥40 kg) within 4 h of reperfusion; the same dose was repeated on day 4. Biopsy-proven acute rejection rates were 20.4% (TAS) and 19.2% (TAS + B); steroid-resistant acute rejection rates were 3.2% and 3.0%, respectively. Patient survival was 100%; graft survival rates were 95% in both arms. The nature and incidence of adverse events were similar in both arms except toxic nephropathy and abdominal pain, which were significantly higher in the TAS + B arm (14.1% vs. 4.3%; p = 0.03 and 11.1% vs. 2.2%; p = 0.02; respectively). Median serum creatinine concentrations at 6 months were 86 μmol/L in the TAS and 91 μmol/L in the TAS + B arm; glomerular filtration rate was 79.4 and 77.6 (mL/min/1.73 m2), respectively. Adding basiliximab to a tacrolimus-based regimen is safe in pediatric patients, but does not improve clinical efficacy.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Research in organ transplantation has found that reducing acute rejection in the early phase post-transplantation improves long-term graft and patient survival (1). Tacrolimus-based immunosuppression has proven efficacy in reducing graft rejection and minimizing adverse events in pediatric patients undergoing renal transplantation (2–6). In an effort to expand the options for effective and safe prophylaxis against early rejection, there has been investigation into new adjunctive immunosuppressants such as the interleukin-2 receptor antagonists (IL-2 Ra). The IL-2 Ra, basiliximab, is a high-affinity chimeric monoclonal antibody that acts on the inducible alpha-chain of the interleukin-2 receptor. It selectively targets activated T-lymphocytes and inhibits rejection-promoting pathways, especially when used in combination with calcineurin inhibitors.

Several randomized clinical trials conducted in adult renal transplant recipients have reported a statistically significant reduction in the incidence of acute rejection by combining interleukin-2 receptor antagonists with cyclosporin (7–9). In pediatric renal transplantation, isolated reports have demonstrated that induction therapy with basiliximab combined with calcineurin inhibitors is safe and efficacious (10–13). However, so far there have been no randomized, controlled, prospective trials in pediatric patients. Here we report the results of the first large multicenter, randomized trial in pediatric renal transplantation to evaluate the efficacy and safety of a tacrolimus-based immunosuppressive regimen with and without induction therapy using basiliximab.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Study design

This was a 6-month, randomized, open-label, parallel-group, comparative, phase III trial conducted in 15 centers in six European countries. The trial was conducted in accordance with the Declaration of Helsinki. Ethics committee approval was obtained at each center prior to study commencement, and each patient or legal guardian provided written consent to participate in the study. The first patient was enrolled in March 2001, the last patient was enrolled in September 2003, and the study was completed in March 2004.

Patients

Male and female patients, aged 18 years or younger, with end-stage renal disease and suitable candidates for primary renal transplantation or retransplantation from a deceased donor or living donor with compatible ABO blood type were eligible for study enrolment.

Random assignment

The randomization was stratified by center using the method of permuted blocks. Allocation to treatment was performed locally using sealed randomization envelopes supplied by the study sponsor. In addition, patients were stratified according to age: patients <12 years (children) and those ≥12 years (adolescents).

Immunosuppression

The initial daily dose of tacrolimus was 0.3 mg/kg administered in two equal oral doses. The first dose was administered within 24 h post-transplantation. Subsequent doses were adjusted to attain target whole blood trough levels from 10–20 ng/mL for days 0–21 and 5–15 ng/mL for days 22–183. Whole blood trough levels of tacrolimus were determined using the Abbott IMX or a similar assay. Azathioprine was administered at 1–2 mg/kg/day to all of the patients. In addition, all patients received methylprednisolone or equivalent at 300–600 mg/m2 i.v. on day 0. Daily oral doses were tapered from 60 mg/m2 on day 1 to ≤10 mg/m2 from day 43 onwards. Basiliximab was administered at 10 mg in patients <40 kg or 20 mg in patients ≥40 kg. The first dose was administered on day 0 within 4 h of reperfusion; patients received the same dose repeated on day 4.

Outcome variables

The primary efficacy endpoint was the incidence of and time to first biopsy proven acute rejection (BPAR) over the first 6 months post-transplantation. Histological classification of graft biopsies was performed using the Banff 97 (14) classification (IA—III). Secondary efficacy endpoints included: clinically diagnosed frequency of acute rejection (AR), incidence of and time to first corticosteroid-resistant AR, severity of BPAR, graft and patient survival, incidence of adverse events, and renal function measured by serum creatinine concentration and estimated by glomerular filtration rate (GFR) [Schwartz formula (15)]. Acute rejection was evaluated in terms of the frequency of episodes at 6 months post-transplant including suspected rejection without biopsy confirmation, incidence of and time to first corticosteroid-resistant AR during the first 6 months, and severity of BPAR using the Banff classification schema. In this trial, increased creatinine was defined as an increase of plasma creatinine concentration at least 10% above the considered baseline post-transplantation. Toxic nephropathy, for purposes of this trial, was defined as an increase of plasma creatinine concentration of at least 10% above baseline post-transplantation accompanied by an undesired increase in tacrolimus whole blood trough levels and resolving after reduction of the tacrolimus dose. Adverse events were coded using a modified COSTART dictionary [Coding Symbols for Thesaurus of Adverse Reaction Terms (16)].

Statistical analysis

It was assumed that the expected incidence of BPAR in the tacrolimus/azathioprine/steroid (TAS) arm would be 25%. A clinically meaningful difference between the two treatment arms was assumed to be 18%. At the significance level α= 5% and power 1 −β= 80%, for the 2-tailed Wilcoxon-Gehan test, 124 patients per treatment arm would be necessary assuming a 10% dropout rate. However, as recruitment for the trial was slower than anticipated, the study could not be completed with the originally planned number of patients. Therefore, during the course of the study the protocol was amended (December 2002) aiming for 85 patients in each treatment arm. Power was recalculated maintaining all other assumptions (type I error, expected incidence of BPAR, clinical meaningful difference, dropout rate). Power to show superiority remained at 80% and to show noninferiority the recalculated power decreased to 63%.

The full analysis set was used for all the statistical analyses, i.e. all randomized patients who were transplanted and received at least one dose of study drug. The primary endpoint was analyzed using the Wilcoxon-Gehan test. The two treatment groups were compared using the chi-square, Mann-Whitney, or Student's t-test as applicable. Survival estimates were calculated using Kaplan-Meier analyses for time to first BPAR, time to first corticosteroid-resistant AR, and for patient and graft survival; the Wilcoxon-Gehan test was used to calculate differences in survival. In addition to the overall analysis, the key endpoints were also analyzed according to age group. Investigators recorded any untoward clinical event experienced by a patient irrespective of causality in relation to study drug. Fisher's exact test was used to analyze the incidence of adverse events. p values are only quoted where the difference was statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Patient demographics and baseline characteristics

The full analysis set included 192 patients: 93 patients received tacrolimus/steroid/azathioprine (TAS arm) and 99 patients received tacrolimus/azathioprine/steroid + basiliximab (TAS + B arm). In the TAS arm there were 42 children and 51 adolescents. In the TAS + B arm there were 46 children and 53 adolescents. The treatment groups were comparable with respect to demographic and baseline characteristics (Table 1).

Table 1.  Demographics and baseline characteristics
 Tacrolimus
+ azathioprine + steroids n = 93+ azathioprine + steroids + basiliximab n = 99
  1. Full analysis set.

  2. Number of patients (%).

  3. 1Variable not recorded for all patients.

Age (years)
 2–511 (11.8)11 (11.1)
 6–1131 (33.3)35 (35.4)
 ≥1251 (54.8)53 (53.5)
 Mean (±SD)11.3 (±4.0)11.5 (±4.1)
 Median (range)12 (2–17)12 (2–17)
Male:female %61.3:38.762.6:37.4
Primary diagnosis
 Uropathy24 (25.8)34 (34.3)
 Congenital nephropathy21 (22.6)24 (24.2)
 Glomerulonephritis16 (17.2)12 (12.1)
 Other hereditary nephropathy10 (10.8)13 (13.1)
 All other diagnoses22 (23.6)16 (16.2)
First transplant87 (93.5)95 (96.0)
ABO
 Identical match83 (89.2)82 (85.4)
 Compatible match10 (10.8)14 (14.6)
PRA1
 0–<25%86 (92.5)94 (100)
 ≥25–100%3 (3.2)0 (0)
Mean total HLA mismatch2.32.5
CMV
 D+/R−28 (30.1)35 (35.4)
Viral status at baseline1
 CMV positive24 (26.4)32 (32.3)
 EBV positive48 (53.9)58 (62.4)
 HBV positive4 (4.6)7 (7.4)
 HCV positive7 (8.3)5 (5.2)
Donor age (years)
 Mean (±SD)24.5 (±13.6)27.2 (±13.9)
 Range5–602–53
Donor type
 Deceased77 (82.8)79 (79.8)
 Living16 (17.2)20 (20.2)
Cold ischemia time (h)18.0 ± 8.516.5 ± 8.5

Patient disposition

More patients in the TAS treatment arm discontinued the study compared with the TAS + B arm (Table 2). Adverse events were the main reason for study discontinuation and accounted for the withdrawal of 8 patients in the TAS and 4 patients in the TAS + B arm. The adverse events leading to study discontinuation in the TAS arm were: toxic nephropathy (1), post-transplant lymphoproliferative disease (1), diabetes (1), neurotoxicity (2), primary graft nonfunction (1), recurrence of primary disease (1) and neutropenia (1). In the TAS + B arm, the adverse events leading to study discontinuation were: toxic nephropathy (1), diabetes (1), recurrence of primary disease (1) and acute tubular necrosis (1). Graft failure was the second most common reason for study withdrawal and accounted for the withdrawal of 4 patients in each treatment arm. Thrombosis was the cause of graft failure in all 4 TAS patients and 2 of the TAS + B patients. Nine patients in the TAS and 5 patients in the TAS + B group were withdrawn from the trial during the first week.

Table 2.  Disposition of study population
 Tacrolimus
+ azathioprine + steroids n = 93+ azathioprine + steroids + basiliximab n = 99
  1. Full analysis set.

  2. Number of patients (%).

Total number of discontinuations17 (18.3)11 (11.1)
 Adverse event8 (8.6)4 (4.0)
 Graft failure4 (4.3)4 (4.0)
 Protocol violation5 (5.4)3 (3.0)

Immunosuppression

Tacrolimus therapy was initiated orally in all TAS patients and in 96 of 99 TAS + B patients. One patient in the TAS group and 5 patients in the TAS + B group had one episode of intravenous therapy. Median oral dose at day 1 was 0.29 mg/kg/day in both treatment groups. Median tacrolimus maintenance doses ranged from 0.20–0.30 mg/kg/day during the first 2 months of treatment in both groups, and decreased by month 6 to a median dose of 0.13 mg/kg/day in the TAS arm and 0.16 mg/kg/day in the TAS + B arm.

Median daily doses of tacrolimus at 6 months in children <12 years were 0.17 mg/kg/day in the TAS arm and 0.20 mg/kg/day in the TAS + B arm. These median doses were somewhat higher than those documented at month 6 for children >12 years (0.12 mg/kg/day in both treatment arms).

Targeted median tacrolimus whole blood trough levels were achieved during the initial post-transplant period as well as at 6 months post-transplant (Figure 1). Median tacrolimus whole blood trough levels during the first 2 months were comparable between the two treatment arms. Median levels at month 6 were 6.65 ng/mL in the TAS and 7.05 ng/mL in the TAS + B arm. Tacrolimus trough levels were comparable in the age-defined treatment subgroups in both treatment arms for the duration of the study.

image

Figure 1. Median tacrolimus whole blood trough levels at day 21 were 10.70 ng/mL in the TAS arm and 10.85 ng/mL in the TAS + B treatment arm. Median levels at month 6 were 6.65 ng/mL in the TAS and 7.05 ng/mL in the TAS + B treatment arm.

Download figure to PowerPoint

Median daily corticosteroid maintenance dose decreased in the TAS arm from 1.53 mg/kg during week 1 to 0.15 mg/kg during months 4–6. In the TAS + B arm, median daily dose levels decreased from 1.51 mg/kg to 0.14 mg/kg during the same time periods.

Doses of azathioprine were comparable between treatment arms. A median dose of 1.86 mg/kg during week 1 and 1.48 mg/kg at months 4–6 was reported in the TAS arm. The respective median doses of azathioprine were 1.83 mg/kg and 1.49 mg/kg in the TAS + B arm. A total of 88% of patients received azathioprine at study end.

The first dose of basiliximab was administered perioperatively. Altogether, 12.1% of patients received the second dose on day 3 and 83.8% of patients received it on day 4 after perfusion.

Infection prophylaxis

Prophylactic antiviral medication was administered to 34 (36.6%) patients in the TAS arm and to 42 (42.4%) patients in the TAS + B arm for up to 3 months in the majority of centers.

Efficacy assessments

The overall incidence of BPAR was 20.4% in the TAS and 19.2% in the TAS + B arm (Table 3). The incidence of BPAR was lower in the patients <12 years in the TAS arm (9.5%) compared with the same patients in the TAS + B arm (13%; p = n.s.; Wilcoxon-Gehan test). In the patients aged >12 years, the incidence of BPAR was higher in the patients in the TAS arm (29.4%) compared with the TAS + B treatment arm (24.5%; p = n.s.; Wilcoxon-Gehan test). There was a low incidence of corticosteroid-resistant acute rejection: two adolescents and one child per arm. All corticosteroid-resistant rejection episodes were biopsy-proven and resolved with antibody treatment.

Table 3.  Incidence of biopsy proven acute rejection
 Tacrolimus
+ azathioprine + steroids+ steroids + azathioprine + basiliximab
  1. Full analysis set.

  2. Number of patients (%).

All patientsn = 93n = 99
19 (20.4)19 (19.2)
Children <12 yearsn = 42n = 46
4 (9.5)6 (13.0)
Adolescents ≥12 yearsn = 51n = 53
15 (29.4)13 (24.5)
Spontaneously resolving2 (2.2)1 (1.0)
Corticosteroid-sensitive14 (15.1)15 (15.2)
Corticosteroid-resistant3 (3.2)3 (3.0)

Banff grade I rejection was reported in 11 TAS and 15 TAS + B patients while biopsies in 7 TAS and 3 TAS + B patients were graded Banff II. One patient in each treatment arm had a Banff III biopsy result.

No significant difference was found in Kaplan-Meier estimates for patients free from acute rejection at 6 months (Figure 2). The median (min-max) time to first BPAR was 43 days (1–150) in the TAS arm compared with 41 days (2–176) in the TAS + B arm.

image

Figure 2. Kaplan-Meier estimates for patients free from acute rejection at month 6 were 76.4% (TAS) vs. 78.8% (TAS + B) (p = 0.603; Wilcoxon-Gehan test). There was no significant difference between the age group subpopulations.

Download figure to PowerPoint

Patient survival was 100%. Graft survival at month 6 was comparable in both treatment arms: 94.6% in the TAS arm and 94.9% in the TAS + B arm. Causes of graft loss in the TAS arm were graft vessel thrombosis in 4 patients and transplantectomy due to post-transplant lymphoproliferative disease (PTLD) in 1 patient. The causes in the TAS + B arm were graft vessel thrombosis in 2 patients, a primary nonfunctioning graft in 1 patient and two cases of focal segmental glomerulosclerosis recurrence. In the age-defined subpopulations, graft vessel thrombosis occurred in two children and four adolescents.

Safety assessments

A total of 90.3% of patients in the TAS and 91.9% of patients in the TAS + B group experienced at least one adverse event. The incidences of the most frequently reported adverse events are listed in Table 4. There were no adverse events with a significantly higher incidence rate in the TAS arm compared with the TAS + B treatment arm. However, toxic nephropathy was reported significantly more in the patients in the TAS + B arm compared with the TAS arm (14.1% vs. 4.3%; p = 0.025; Fisher's exact test). Abdominal pain was also significantly higher in the TAS + B arm (11.1% vs. 2.2%; p = 0.019; Fisher's exact test). Following a reduction in tacrolimus dose, toxic nephropathy resolved in 3 of the 4 TAS patients and in 13 of the 14 TAS + B patients during the trial period. Most cases of toxic nephropathy in the patients in the TAS + B arm occurred during the initial phase post-transplant. Similarly, abdominal pain in the patients in the TAS + B arm was most prevalent in the first month of the study. The reported causes of abdominal pain were diverse and included graft site tenderness, epigastric pain and lower abdominal pain. Symptoms resolved in all patients and none of the patients required a change in study medication.

Table 4.  Incidence of the most frequently reported adverse events1
 Tacrolimusp values2
+ azathioprine + steroids n = 93+ azathioprine + steroids + basiliximab n = 99
  1. Full analysis set.

  2. Number of patients (%).

  3. 1Incidence ≥10% in either treatment arm, adverse events were coded using COSTART terms.

  4. 2Fisher's exact test; only values <0.05 quoted.

  5. 3An increase of plasma creatinine concentration ≥10% above baseline post-transplant.

  6. 4Diagnosis per biopsy.

  7. 5An increase of plasma creatinine concentration ≥10% above baseline post-transplant with an undesired increase in tacrolimus whole blood trough levels and resolving after tacrolimus dose reduction.

Hypertension36 (38.7)34 (34.3) 
Increased creatinine327 (29.0)30 (30.3) 
Urinary tract infection26 (28.0)19 (19.2) 
Diarrhea20 (21.5)19 (19.2) 
Hypophosphatemia17 (18.3)18 (18.2) 
Hypomagnesaemia15 (16.1)13 (13.1) 
Anemia12 (12.9)15 (15.2) 
Acute tubular necrosis411 (11.8)12 (12.1) 
Vomiting9 (9.7)10 (10.1) 
Toxic nephropathy54 (4.3)14 (14.1)0.03
Surgical complication6 (6.5)11 (11.1) 
Bronchitis4 (4.3)11 (11.1) 
Hyperglycemia5 (5.4)10 (10.1) 
Abdominal pain2 (2.2)11 (11.1)0.02

Five patients (5.4%) in the TAS arm and 11 patients (11.1%) in the TAS + B arm experienced delayed graft function (DGF), which was defined as requiring dialysis for more than 1 day during the first study week (p = n.s.). One patient in the TAS arm had a never-functioning graft. Renal function at 6 months, as measured by serum creatinine concentration and GFR, was similar in both treatment arms. Median serum creatinine concentrations at month 6 were 86 μmol/L in the TAS and 91 μmol/L in the TAS + B arm. Median GFR was 79.4 in the TAS and 77.6 (mL/min/1.73 m2) in the TAS + B arm.

At baseline, none of the patients had glucose metabolism disorders (coded as glucose tolerance decreased, hyperglycemia or diabetes mellitus using the modified COSTART dictionary). During the study, 10 patients (10.8%) in the TAS and 13 patients (13.1%) in the TAS + B arm developed glucose metabolism disorders. Oral hypoglycemic medication for >30 days was required by 1 patient (1.1%) in the TAS arm. Insulin therapy use for >30 days was 2.2% in the TAS arm compared with 5.1% in the TAS + B arm (p = n.s.). At study completion, no patient in either arm was on oral hypoglycemic medication and 1 (1.1%) TAS and 4 (4.0%) TAS + B patients were on insulin therapy.

The incidence of bacterial and viral infections was similar in both groups (bacterial: 32% in both arms; viral: 16.1% and 15.2% in the TAS and TAS + B arms, respectively). The incidence of fungal infections was 6.5% in the TAS arm and 12.1% in the TAS + B arm.

A CMV infection was documented in 2.2% of patients in the TAS arm and in 7.1% in the TAS + B arm.

No solid tumor malignancies were reported. Two patients (2.2%) in the TAS group developed nonfatal PTLD. The dosage of study drug was reduced in 1 patient and discontinued in the other patient. PTLD was ongoing in both patients at study completion.

Systolic and diastolic blood pressure measurements, anti-hypertensive use and mean total cholesterol values were comparable between treatment arms. No acute hypersensitivity reactions were observed following the first or second dose of basiliximab in the patients in the TAS + B arm.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

This is the first large European multicenter randomized study to investigate the efficacy and safety of adding basiliximab to a standard tacrolimus-based regimen in pediatric kidney transplant patients. We observed a low incidence of biopsy-proven acute rejection in both treatment groups, and the rejection rates are comparable to those reported in other studies combining basiliximab with a cyclosporin-based regimen (10–11,13). However, in our study, adding basiliximab to a tacrolimus-based regimen did not result in a lower incidence of biopsy-proven acute rejection compared with the control treatment arm. There was also no difference between treatment arms in the incidence of biopsy-proven acute rejection when the patients were stratified by age.

Our pediatric study population was homogeneous with low numbers of HLA mismatched, retransplanted and pre-sensitized patients. Basiliximab induction may be beneficial in higher-risk immunologic patients. For example, data from NAPRTCS (17) showed an increased relative risk of first acute rejection in patients not given induction therapy in North America, a population considered to be more immunologically at risk than ours. In addition, the author of a literature review (18) on IL-2 receptor antagonist use in pediatrics concluded that a beneficial effect of IL-2 Ra in reducing early acute rejection would probably be optimal in immunologic high-risk patients. In our lower-risk population, basiliximab induction did not confer additional clinical efficacy as shown by the similar incidence of biopsy-proven acute rejection in both treatment arms.

We also found no difference in the incidence of corticosteroid-resistant biopsy-proven acute rejection between the two treatment groups. Interestingly, the incidence of corticosteroid-resistant BPAR in both treatment groups in our study was substantially lower than that reported with tacrolimus triple therapy (2), and with tacrolimus/steroid therapy with and without basiliximab induction (12).

The nature of adverse events seen in the patients in this study were as expected in pediatric renal transplantation and incidence rates were comparable between groups with the exception of toxic nephropathy and abdominal pain, both of which occurred significantly more often in the patients treated with basiliximab. The reason for the greater incidence of toxic nephropathy is unclear. Despite extensive analysis of the records of patients with toxic nephropathy, we could find no clear pattern of cause and effect. Furthermore, we could not identify any chronologic relationship between the onset of toxic nephropathy and the administration of basiliximab. Tacrolimus trough levels were within the normal target ranges at symptom onset in the majority of patients. We can only surmise that a center-effect may have influenced the results. With regard to abdominal pain, again there is no clear explanation for the higher incidence observed in the patients receiving basiliximab.

With the exception of patients with toxic nephropathy, renal function was good for most of the patients throughout the study and there was no difference in serum creatinine levels and glomerular filtration rates between the two groups. Our study results showed a higher incidence of delayed graft function in the basiliximab arm despite comparable tacrolimus trough levels. Elevated tacrolimus trough levels and early acute tubular necrosis in 50% of patients who received basiliximab were attributed to a possible drug interaction in one retrospective study (19). As cold ischemia time as well as donor source were comparable between treatment arms, there is no clear explanation for the disparity in incidences of delayed graft function in our study.

Between 4% and 5% of the patients in each treatment group required insulin for new-onset diabetes mellitus, but insulin use was discontinued with gradual decreases in tacrolimus and corticosteroid dosing. A positive aspect of this study was the fact that the corticosteroid dose could be rapidly reduced to 0.15 mg/kg/day by month 6 without compromising efficacy. In the European tacrolimus/cyclosporine comparative clinical trial, this dose level was only possible after 1 year (2).

The incidence of CMV infection in the patients receiving basiliximab was lower than that reported in other pediatric studies with basiliximab (11,20). There was also a low incidence of PTLD in the patients in our study, which corresponds well with reports of generally declining rates in this complication (21). In a multivariate analysis, performed in the United States, the actual incidence of PTLD associated with IL-2Ra treatment was essentially the same as that seen with no induction (22). We are, however, following up this study population to continue to assess the incidence of PTLD over time.

In conclusion, we found that adding basiliximab to a standard tacrolimus-based regimen did not result in lower rates of biopsy-proven acute rejection compared with a standard tacrolimus triple regimen. Furthermore, basiliximab induction did not confer additional benefit with regard to clinical efficacy and, with the exception of toxic nephropathy and abdominal pain, basiliximab was safe when combined with a tacrolimus-based immunosuppressive regimen in our immunologic lower-risk pediatric renal transplant recipients.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

We thank C. Krcmar for preparing the manuscript and S. Schleibner for his expert medical input. The study was supported by Astellas Pharma, Munich, Germany.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  • 1
    Tejani A, Ho PL, Emmett L, Stablein DM. Reduction in acute rejections decreases chronic rejection graft failure in children: A report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Am J Transplant 2002; 2: 142147.
  • 2
    Trompeter R, Filler G, Webb NJA et al. Randomized trial of tacrolimus versus cyclosporin microemulsion in renal transplantation. Pediatr Nephrol 2002; 17: 141149.
  • 3
    Shapiro R, Scantlebury VP, Jordan ML et al. Pediatric renal transplantation under tacrolimus-based immunosuppression. Transplantation 1999; 67: 299303.
  • 4
    Neu AM, Ho PL, Fine RN, Furth SL, Fivush BA. Tacrolimus vs. cyclosporine A as primary immunosuppression in pediatric renal transplantation: A NAPRTCS study. Pediatr Transplant 2003; 7: 217222.
  • 5
    Jensen S, Jackson EC, Riley L, Reddy S, Goebel J. Tacrolimus based immunosuppression with steroid withdrawal in pediatric kidney transplantation – 4-year experience at a moderate-volume center. Pediatr Transplant 2003; 7: 119124.
  • 6
    Filler G, Webb NJA, Milford DV et al. Four-year data after pediatric renal transplantation: A randomized trial of tacrolimus vs. cyclosporin microemulsion. Pediatr Transplant 2005; 9: 498503.
  • 7
    Nashan B, Moore R, Amlot P, Schmidt A-G, Abeywickrama K, Saulillou J-P. Randomized trial of basiliximab versus placebo for control of acute rejection in renal allograft recipients. Lancet 1997; 350: 11931198.
  • 8
    Kahan BD, Rajagopalan PR, Hall ML. Reduction in the occurrence of acute cellular rejection among renal allograft recipients treated with basiliximab, a chimeric anti-interleukin-2 receptor monoclonal antibody. Transplantation 1999; 67: 276284.
  • 9
    Vincenti F, Kirkman R, Light S et al. for the Daclizumab Triple Therapy Study Group. Interleukin-2 receptor blockade with daclizumab to prevent acute rejection in renal transplantation. N Engl J Med 1998; 338: 161165.
  • 10
    Vester U, Kranz B, Testa G. Efficacy and tolerability of interleukin-2 receptor blockage with basiliximab in pediatric renal transplant recipients. Pediatr Transplant 2001; 5: 297301.
  • 11
    Offner G, Broyer M, Niaudet P et al. A multicenter, open-label, pharmacokinetic/pharmacodynamic safety, and tolerability study of basiliximab (Simulect) in pediatric de novo renal transplant recipients. Transplantation 2002; 74: 961966.
  • 12
    Swiatecka-Urban A, Garcia C, Feuerstein D et al. Basiliximab induction improves the outcome of renal transplants in children and adolescents. Pediatr Nephrol 2001; 16: 693696.
  • 13
    Pape L, Strehlau J, Henne T et al. Single centre experience with basiliximab in paediatric renal transplantation. Nephrol Dialysis Transplant 2002; 17: 276280.
  • 14
    Racusen LC, Solez K, Colvin RB et al. The Banff 97 working classification of renal allograft pathology. Kidney Int 1999; 55: 713723.
  • 15
    Schwartz GJ, Haycock GB, Edelmann CM Jr, Spitzer A. A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics 1976; 58: 259263.
  • 16
    Food and Drug Administration. COSTART: Coding symbols for thesaurus of adverse reaction terms. 3rd ed. Rockville , MD : Department of Health and Human Services, Food and Drug Administration, Center for Durgs and Biologics, 1989.
  • 17
    Smith JM, Nemeth TL, McDonald RA. Current immunosuppressive agents: Efficacy, side effects, and utilization. Pediatr Clin North Am 2003; 50: 12831300.
  • 18
    Di Filippo S. Anti-IL-2 receptor antibody vs. polyclonal anti-lymphocyte antibody as induction therapy in pediatric transplantation. Pediatr Transplant 2005; 9: 373380.
  • 19
    Sifontis NM, Benedetti E, Vasquez EM. Clinically significant drug interaction between basiliximab and tacrolimus in renal transplant recipients. Transplant Proc 2002; 34: 17301732.
  • 20
    Ojogho O, Sahney S, Cutler D et al. Mycophenolate mofetil in pediatric renal transplantation: Non-induction vs. induction with basiliximab. Pediatr Transplant 2005; 9: 8083.
  • 21
    Shapiro R, Nalesnik M, McCauley J et al. Post-transplant lymphoproliferative disorders (PTLD) in adult and pediatric renal transplant patients receiving tacrolimus-based immunosuppression. Transplantation 1999; 68: 18511854.
  • 22
    Cherikh WS, Kauffman HM, McBride MA, Maghirang J, Swinnen LJ, Hanto DW. Association of the type of induction immunosuppression with posttransplant lymphoproliferative disorder, graft survival, and patient survival after primary kidney transplantation. Transplantation 2003; 76: 12891293.