Triple Immunosuppression With or Without Basiliximab in Pediatric Renal Transplantation: Acute Rejection Rates at One Year A. Duzova, N. Buyan, M. Bakkaloglu, A. Dalgic, O. Soylemezoglu, N. Besbas, and A. Bakkaloglu ABSTRACT Acute rejection (AR) is a major determinant of chronic allograft dysfunction and graft survival. This study evaluated the effect of basiliximab on AR in pediatric renal transplantation on triple immunosuppression. Forty-three transplantations (25 males and 18 females; mean age 14.9 ⫾ 3.6 years) were performed between 1996 and 2002. Thirteen of the grafts came from cadaveric donors and 30 from living-related donors. All patients were placed on immunosuppression with prednisolone ⫹ (azathioprine or mycophenolate mofetil) ⫹ (cyclosporine [CYA] or tacrolimus). Basiliximab was also administered in 20 cases. The respective rates of biopsy-proven AR in the basiliximab group (BG) and the standard-regimen group (N-BG) were 0% vs 17.4% (P ⬎ .05) at 1 month posttransplantation; 0% vs 26.1% (P ⬍ .05) at 3 months; 0% vs 26.1% (P ⬍ .05) at 6 months, and 7.1% vs 26.1% (P ⬎ .05) at 12 months. In the N-BG group the 1- and 3-year graft survival rates were 91.3% (21/23) and 83.3% (15/18), respectively. The mean glomerular filtration rate (GFR) in the first year after the transplantation was 75 ⫾ 33 mL/min/1.73 m2 in the N-BG and 98 ⫾ 21 mL/min/1.73 m2 in the BG patients (P ⬍ .05). Basiliximab significantly reduced the rates of acute rejection at 3 and 6 months after pediatric renal transplantation. The GFR in the first year was significantly higher among the patients treated with basiliximab, which was well tolerated by all patients and caused no significant adverse effects. The effect of basiliximab on long-term graft survival and chronic allograft dysfunction deserves further investigation.
CUTE REJECTION (AR) remains the most important determinant of chronic allograft dysfunction and graft survival in renal transplantation. The rate of this complication at most renal transplantation centers varies from 40% to 60%.1,2 In a previous study, we reported that the AR rate with triple immunosuppression at the Hacettepe University Pediatric Renal Transplantation Center was 42%, with 78% of all AR episodes occurring within the first 4 weeks’ posttransplantation.3 Basiliximab is a 156-kDa chimeric monoclonal antibody (human and murine) directed against the alpha chain of the interleukin (IL)-2 receptor of human lymphocytes. Blockade of these receptors prevents the clonal expansion of lymphocytes involved in the immune response.4 A few studies have focused on the effects and safety of basiliximab in pediatric renal transplantation.5,6 In this report we present the experience of two Turkish centers that have added basiliximab to the primary tripledrug immunosuppression regimen for children and adolescents undergoing renal transplantation. Findings in the
group that received basiliximab were compared to those in patients that did not receive this agent. PATIENTS AND METHODS Patients From January 1996 to September 2002, a total of 43 renal transplantations were performed in 43 children (25 boys and 18 girls) (Table 1) at two pediatric renal transplantation centers. The mean recipient age was 14.9 ⫾ 3.6 years (range 7–21 years). Twenty-six patients were on hemodialysis, 15 on peritoneal dialysis, From the Hacettepe University Faculty of Medicine, Pediatric Nephrology Unit, Ankara, Turkey; Hacettepe University Faculty of Medicine, Department of Urology, Ankara, Turkey; Gazi University Faculty of Medicine, Pediatric Nephrology Unit, Ankara, Turkey; and Gazi University Faculty of Medicine, Department of Surgery, Ankara, Turkey. Address reprint requests to Ali Duzova, Hacettepe University Faculty of Medicine, Pediatric Nephrology Unit, Ankara 06100, Turkey.
0041-1345/03/$–see front matter doi:10.1016/j.transproceed.2003.10.087
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Transplantation Proceedings, 35, 2878 –2880 (2003)
PEDIATRIC RENAL TRANSPLANT
Table 1. Patient Demographic Characteristics and Causes of End-Stage Renal Disease (ESRD) Immunosuppression Group Characteristics
Recipient age (y, mean ⫾ SD) Gender (male/female) LRD/CAD Cause of ESRD Reflux nephropathy Nephrolithiasis Focal segmental glomerulosclerosis Membranoproliferative glomerulonephritis Membranous glomerulonephritis Polyarteritis nodosa Henoch-Scho¨nlein purpura Systemic lupus erythematosus Chronic glomerulonephritis Alport’s syndrome Juvenile nephronophytisis Laurence-Moon-Biedl syndrome Oxalosis Undetermined
Nonbasiliximab (n ⫽ 23)
Basiliximab (n ⫽ 20)
15.3 ⫾ 4.2 13/10 14/9
14.5 ⫾ 2.7 12/8 16/4
9 1 1 1
6 1 1 1
1 2 1 1 1 2 2 1 2 6
biopsy was used to confirm suspected AR. The glomerular filtration rate (GFR) was calculated according to the Schwartz formula. Statistical Analysis: The chi-square and Fisher exact tests were used to analyze differences between categorized patient characteristics. A P value ⬍.05 was considered to indicate statistical significance.
RESULTS Patient and Graft Survival
Forty-two patients survived the observation period (median 27 months, range 3– 80 months). One N-BG patient with systemic lupus erythematosus died at 21 months after transplantation with a creatinine level % 0.9 mg/dL. Thirtyseven and 19 patients respectively, had completed 1 and 3 years of follow-up with graft survival rates of 91.3% (21/23) and 83.3% (15/18), in the N-BG group. The three grafts lost in the N-BG group were due to AR in the first month, recurrent renal disease (10th month) and chronic rejection (23rd month). In the BG group, the median observation time was 14 months (range 3–38 months). Seventeen of the 20 BG patients were observed for longer than 6 months, and 14 for longer than 12 months. No graft was lost in the BG group.
Abbreviations: LRD, living-related donor; CAD, cadaveric donor.
Acute Rejection and two cases were preemptive transplantations. The median time from diagnosis of end-stage renal disease to transplantation was 13 months (range 0 –108 months). Combined immunosuppression with basiliximab, a calcineurin inhibitor (cyclosporine [CyA] or tacrolimus), and azathioprine or mycophenolate mofetil was administered to 20 patients (basiliximab group, BG). In this group, 16 organs came from living-related donors (LRD) and 4 from cadaveric donors (CAD). The other 23 recipients received the same drug regimen minus basiliximab (nonbasiliximab group, N-BG). In this group, 14 organs came from LRD and 9 from CAD. Although the patients were not randomized, the groups were compared.
Immunosuppression Basiliximab (Simulect) 12 mg/m2 (20 mg maximum) was administered intravenously (IV) over 20 to 30 minutes. The first dose was given within the 2 hours prior to transplantation surgery, and the second was given on day 4 posttransplantation. All patients received baseline immunosuppression consisting of prednisolone, CyA or tacrolimus, and azathioprine (AZA, 2 mg/kg) or mycophenolate mofetil (MMF, 1200 mg/m2). Methylprednisolone 10 mg/kg IV (maximum dose 500 mg) was administered in the operating room. Prednisolone was started at 60 mg/m2/d divided every 12 hours (maximum daily dose 60 mg), and was tapered to 5 to 10 mg/d over 6 months. Blood CyA levels were maintained at 150 to 300 ng/mL for weeks 1 and 2 postsurgery, and at 100 to 200 ng/mL for the remainder of the study. The starting dose of tacrolimus was 0.2 to 0.3 mg/kg divided every 12 hours. The target blood tacrolimus levels were 15 to 20 ng/mL in the first month, 10 to 12 ng/mL for the second and third months, 5 to 10 ng/mL from the fourth to the sixth month, and ⬍5 ng/mL after 6 months. No prophylaxis for Pneumocystis carinii pneumonia, cytomegalovirus, or herpes simplex virus was used. An episode of AR was defined as a requirement for antirejection therapy. Renal
The AR rates at 1,3,6, and 12 months in the N-BG group were 17.4% (4/23), 26.1% (6/23), 26.1% (6/23), and 26.1% (6/23), respectively. The corresponding rates for each time in the BG was 0% (0/20), 0% (0/20), 0% (0/17), and 7.1% (1/14), respectively. The differences between the AR rates for BG and N-BG at 3 and 6 months were statistically significant (P ⬍ .05). Glomerular Filtration Rate
The mean GFR in the first year after the transplantation was 98 ⫾ 21 mL/min/1.73 m2 in the BG group and 75 ⫾ 33 mL/min/1.73 m2 in the N-BG (P ⬍ .05). Side Effects
No adverse effects were attributable to basiliximab. None of the children developed opportunistic infections with cytomegalovirus, Epstein-Barr virus, or P. carinii. Twenty-seven of the 43 patients started on CyA. Thirteen (48%) were switched to tacrolimus owing to severe gingival hypertrophy (n ⫽ 4), tubulopathy (n ⫽ 4), hypertrichosis (n ⫽ 3), and chronic rejection (n ⫽ 2). Another patient developed facial paralysis on the 9th day of treatment. Although CyA was stopped, the patient could not tolerate tacrolimus either and continued on prednisolone and MMF. Of the 16 patients who started with tacrolimus, 3 developed hyperglycemia by the end of the 3rd month. This resolved in two patients after a switch to CyA; the other patient required insulin therapy. Mycophenolate mofetil was used in 22 patients. The observed side effects included elevated liver enzymes (n ⫽ 1) and diarrhea (n ⫽ 2). Azathioprine was used in 21
patients; the adverse effects were elevated liver enzymes (n ⫽ 1) and neutropenia (n ⫽ 2). DISCUSSION
Because the anticipated life-span of pediatric patients is longer than the current renal graft half-life, the goal of the transplant team is optimal immunosuppression with minimum side effects. The incidence of AR in pediatric patients on dual- or triple-drug therapy ranges from 20% to 60%.1,2 Shapiro et al7 described reduction of the AR rate in children from 63% to 23% with the use of tacrolimus. Calcineurin inhibitors (CyA, tacrolimus) prevent the IL-2 gene from becoming activated. The T lymphocytes play a key role in rejection. When these cells receive the signal from IL-2, they enter mitosis and begin clonal expansion. Thus, blockade of IL-2 receptors by IL-2R monoclonal antibodies (MAbs) (basiliximab) represents a complementary mode of action to prevent AR.4 In a study by Swiatecka-Urban et al, 24 pediatric patients received basiliximab in addition to tacrolimus and steroids.5 The rates of AR in the basiliximab and nonbasiliximab groups were 26% and 43%, respectively (P ⬍ .05). After one year, GFR was 89.8 ⫾ 19.4 mL/min/1.73 m2 and 89.8 ⫾ 25.5 mL/min/1.73 m2. Pape et al6 compared 48 children receiving basiliximab, CyA, and prednisolone, with 29 children receiving CyA and prednisolone only. The AR rates in the basiliximab vs nonbasiliximab groups were 14% vs 34%, respectively (P ⬍ .05). After one year GFR was comparable in both groups (58 ⫾ 21 mL/min/1.73m2 vs 52 ⫾ 19 mL/min/1.73 m2). In our study, the BG group exhibited lower rates of AR than the N-BG group; 7.1% vs 26.1%. The differences between the AR rates for BG and N-BG at 3 and 6 months were statistically significant (P ⬍ .05). The mean GFR in the first year after the transplantation was 98 ⫾ 21 mL/min/ 1.73 m2 in the BG group and 75 ⫾ 33 mL/min/1.73 m2 in the N-BG cohort (P ⬍ .05). The previous studies did not exhibit a significant difference in GFR in the first year,5,6 although this was observed in the multicenter U.S. trial in adults. The lower rate of AR and the higher level of GFR could be attributed to the addition of AZA or MMF. Another interesting finding was that the AR rate in the
DUZOVA, BUYAN, BAKKALOGLU ET AL
N-BG group at 12 months was much lower than that noted in our earlier series (26% vs 42%, respectively).3 We believe that the higher rate of tacrolimus use in these more recently transplanted patients likely played a role in this reduction.7 The frequency of drug side effects in the present study is also noteworthy. Twenty children developed side effects severe enough to require treatment cessation or to be switched to another agent. Side effects may lead to noncompliance with drug use, resulting in insufficient immunosuppression and, ultimately, graft loss. Any approach that reduces side effects while maintaining adequate immunosuppression is sure to improve patient compliance, graft survival, and quality of life. Our results suggest that basiliximab combined with tripledrug immunosuppression is well tolerated and enhances immunosuppression in pediatric renal transplantation. The rates of AR at 1,3,6, and 12 months were lower when basiliximab was included in the regimen. It is hoped that future studies will clarify the role of basiliximab in graft and patient survival, and will provide information on how this agent may help to reduce the dosages of other immunosuppressants, resulting in fewer side effects and a better quality of life. REFERENCES 1. Tejani A, Stablein DM, Donaldson L, et al: Steady improvement in short-term graft survival of pediatric renal transplants: the NAPRTCS experience. Clin Transpl 95, 1999 2. Broyer M, Ehrich J, Jones E, et al: Five-year survival of kidney transplantation in children: data from the European (EDTA-ERA) Registry. Kidney Int 44:S22, 1993 3. Duzova A, Bakkaloglu M, Bakkaloglu A, et al: Pediatric renal transplantation: Experience from a center in Central Anatolia. Transplant Proc 33:3597, 2002 4. Bart D, Vanrenterghem YF: Anti-interleukin-2 receptor monoclonal antibodies in renal transplantation. Nephron Dial Transplant 14:2824, 1999 5. Swiatecka-Urban A, Garcia C, Feurstein D, et al: Basiliximab induction improves the outcome of renal transplants in children and adolescents. Pediatr Nephrol 16:693, 2001 6. Pape L, Strehlau J, Henne T, et al: Single centre experience with basiliximab in pediatric renal transplantation. Nephrol Dial Transplant 17:276, 2002 7. Shapiro R, Scantlebury VP, Jordan ML, et al: Pediatric renal transplantation under tacrolimus-based immunosuppression. Transplantation 67:299, 1999