Single centre experience with basiliximab in paediatric renal transplantation

Lars Pape1,, Juergen Strehlau1, Thomas Henne1, Kay Latta1, Bjoern Nashan2, Jochen H. H. Ehrich1, Juergen Klempnauer2 and Gisela Offner1

Departments of 1 Paediatric Nephrology and 2 Transplant Surgery, Hannover Medical School, Hannover, Germany



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Introduction of IL-2-receptor antagonists has led to significantly decreasing numbers of acute rejection episodes in renal transplantation in adults. No data are available in paediatric recipients.

Methods. Between 1997 and 2000, 78 renal transplantations were performed in 77 children aged 0.5–16 years. Basiliximab, cyclosporin A (CsA) and prednisolone were administered in 48 children (age 7.8±5.3 years) and compared with 29 children (age 7.3±5.2 years) receiving CsA and prednisolone only. The number of acute rejections, survival, glomerular filtration rate (GFR) and side effects were determined for 3 years after transplantation.

Results. All 77 patients survived the observation period. One year graft survival in the basiliximab group was 95%, which is similar to the comparison group (93%). Children receiving basiliximab showed a lower incidence of acute rejection than the comparison group (14% vs 34%). The calculated GFR was lower in the basiliximab group when discharging from hospital, with 51 compared with 66 ml/min/1.73 m2 in the non-basiliximab group. This was associated with higher CsA trough levels (214 vs 174 ng/ml) in the basiliximab patients. After 1 year the GFR was comparable in both groups (58 vs 52 ml/min/1.73 m2).

Conclusions. Basiliximab offers excellent allograft survival, a lower incidence of acute rejections and almost no side effects. Therefore it can be recommended for routine immunosuppressive therapy in paediatric renal transplantation.

Keywords: acute rejection; basiliximab; paediatric; renal transplantation; survival



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Renal transplantation leads to a high degree of rehabilitation in children with end-stage renal disease. However, transplant half-lives do not meet a child's anticipated life span. Thus, more effective immunosuppressive and better tolerated regimens are required to guarantee a long life with a functioning graft for a child [1].

Acute rejection of the transplanted kidney remains the most important complication in the immediate post-transplant period both because of its risk of immediate graft loss and its association with chronic rejection. The number of acute rejection episodes is the most important predictor of 5-year graft-survival in children [2] and adults [35].

Anti-lymphocyte antibody induction has been widely used to decrease acute rejection rates in paediatric recipients. OKT3, a drug with substantial side effects, was first thought to reach this goal successfully [5,6], but has failed to reduce acute and chronic rejection episodes in a large, double-blind, randomized paediatric trial [7].

A novel approach consists of targeting activated CD45R0 T-cells via the CD25 epitope [8]. Minimal cytokine release is assured by remodelling the molecule with human Fc chains. In adult renal transplantation such antibodies inhibit the IL-2 pathway effectively [9], and significantly reduce the incidence of acute rejections without a higher risk of infection or other adverse events [1012].

Because of these findings we used the chimerical human-murine anti-CD25 antibody, basiliximab, for induction treatment with prednisolone and cyclosporin A (CsA) in paediatric renal recipients [1315]. A pilot study of basiliximab in paediatric transplantation revealed a half-life of 9.4±4.5 days, compared with 5.8±2.0 days for adults, and the threshold to saturate CD 25 epitopes was limited to 31±12 days in children [16].

Up to now no data are available about the incidence of acute and chronic rejection, graft survival, renal function after transplantation, and safety and side effects of basiliximab in children undergoing renal transplantation, compared with conventional immunosuppression using CsA and prednisolone.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patients
From June 1997 to June 2000 77 children aged 0.5–16 years received 78 renal transplants at our centre (Table 1Go). A combined immunosuppression of basiliximab, CsA and prednisolone was administered to 48 children (38 male, 10 female, mean age 7.8±5.3 years) with 49 transplants from June 1997 to June 2000 in our centre. The numbers of first, second and third transplantations were 43, two and four. Sixteen organs came from living, related donors (LRD) and 33 from cadavaric donors (CAD). One child received a combined kidney and liver transplantation.


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Table 1. Demographic data of 77 patients included in the basiliximab study

 
During the same period 29 children (10 LRD, 19 CAD, mean age 7.3±5.2 years) were transplanted without basiliximab, either because they were not selected for the basiliximab trial, or because their parents did not agree to the immunosuppressive therapy with an unproven drug. These patients served as a comparison group, although they were not randomized.

Treatment
Basiliximab was administered by i.v. bolus 2 h before and 4 days after transplantation. We used a paediatric dose of 10 mg for children under 35 kg and 20 mg for children above 35 kg in accordance with the international trial with basiliximab in de novo paediatric renal transplantation. All patients received baseline dual immunosuppression consisting of CsA-microemulsion (Neoral, Novartis, Basel, Switzerland) and prednisolone. CsA doses were adjusted to the target range of 200–300 ng/ml trough levels in the first week and 200–250 ng/ml in the following 3 months. A dose of 300 mg/m2 prednisolone was given intravenously during the transplantation and the oral prednisolone was tapered weekly after transplantation in steps of 60, 30, 15, 12, 9, 6, 4 mg/m2.

Creatinine, the glomerular filtration rate (GFR) according to the Schwartz formula, CsA doses and whole blood trough levels (EMIT assay) were registered daily for the first 14 days and twice weekly, thereafter.

Acute rejection
An acute rejection was defined as a sudden increase of serum creatinine of more than 30% from the baseline, with ultrasonographic signs of increasing volume and an increase of vascular resistance index of 10% from the baseline after exclusion of toxic or infectious causes. Acute rejection episodes were treated with prednisolone 300 mg/m2 i.v. (maximum 500 mg) for 6 days. A renal biopsy was performed in all patients with acute rejection. In case of steroid-resistant rejection patients were switched to tacrolimus.

Statistics
Patient and graft survival were analysed according to the Kaplan–Meier method. Subgroups were compared by a log-rank test. The GFRs and CsA trough levels were compared by Mann–Whitney U-tests. P<0.05 was regarded as significant. As the two groups with or without basiliximab were not randomized, statistical differences may be related to factors other than basiliximab.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patient and graft survival
All 48 children survived the whole observation period of 1.7±0.8 years. The first year graft survival was 95% in patients who received basiliximab (LRD 100%, CAD 92%) compared with 93% (LRD 92%, CAD 93%) in patients who were not treated with basiliximab (Figure 1Go and Table 2Go).



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Fig. 1. Survival rate (%) of grafts of LRD (n=16) and CAD (n=33) in 49 transplanted children under immunosuppression with basiliximab, cyclosporin A and prednisolone. The numbers indicate the number of grafts included at each point of follow-up.

 

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Table 2. Graft survival and cumulative percentage of grafts with acute rejection episodes in the comparison group (no basiliximab administered)

 
Three grafts were lost in patients with organs from cadaveric donors (91% graft survival). One child with a first transplant developed severe bleeding from the renal vein leading to graft loss within 24 h. The child was successfully re-transplanted 4 months later, again with basiliximab. One transplant was lost due to recurrent atypical haemolytic uraemic syndrome in a boy who had already lost two previous grafts for the same reason. One child with combined kidney and liver transplantation had a kidney failure due to repeated rejection episodes. In the comparison group, two grafts were lost, one due to pseudomonas sepsis and the other one after recurrence of focal segmental sclerosis.

Rejections
In the first year seven acute rejection episodes (15%) were observed in the basiliximab group, without statistical significant differences between CADs (16%) and LRDs (13%) (Figure 2Go). Renal biopsy confirmed the diagnosis of rejection in all patients. All seven episodes occurred in a time period of 3–14 weeks post-transplantation and two out of seven were steroid resistant.



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Fig. 2. Cumulative percentage of acute rejection episodes in grafts from LRD (n=16) and CAD (n=33) donors in 49 transplanted children under immunosuppression with basiliximab, cyclosporin A and prednisolone. The numbers indicate the number of grafts included at each point of follow-up.

 
In contrast, 10 children in the comparison group experienced acute rejection episodes (34%) over a wider time-frame, from day 7 to 2 years after transplantation (Table 2Go). Five out of 10 rejections were steroid resistant and these children were switched to tacrolimus. The differences of rejection rates in both groups are significant in a {chi}2 test (P<0.05).

Glomerular filtration rate
The mean GFR in the basiliximab group was 51±14 ml/min/1.73 m2 at discharge from the hospital (4–6 weeks after transplantation) and was stable in the first year after transplantation (58±21 ml/min/1.73 m2). Patients not treated with basiliximab presented with a significantly higher GFR at discharge (66±35 ml/min/1.73 m2, P<0.05 in Mann–Whitney U-test), which slightly decreased within the first year after transplantation to 52±19 ml/min/1.73 m2 (no significant differences).

Cyclosporin A toxicity
Four patients developed rapidly increasing ALT/AST levels >50 U/l within the first week associated with CsA trough levels >300 ng/ml, which all normalized after reduction of the dose of CsA. Three patients developed a de novo haemolytic uraemic syndrome, one was confirmed by biopsy.

At the time of discharge, CsA trough levels were in a high range with 215±59 ng/ml and decreased to 139±56 ng/ml 1 year after transplantation.

At time of discharge, CsA trough levels in the basiliximab group were significantly higher (215±59 ng/ml) than in the comparison group (174±78 ng/ml, P<0.05 in Mann–Whitney U-test), whereas 1 year after transplantation no significant differences between the two groups could be found (CsA trough level of 139±56 ng/ml in the basiliximab group compared with 157±48 ng/ml in the comparison group).

Infections
Before transplantation 29% of the basiliximab patients had a positive IgG for CMV and 24% for EBV in contrast to 48 and 65% in the comparison group.

During the first year after transplantation three patients (6%) developed a positive IgM for CMV (two sero-conversions, one reactivation), 10 (20%) for EBV (seven sero-conversions, three reactivations) in the basiliximab group. In contrast, six patients (21%) of the comparison group became IgM positive for CMV (four sero-conversions, two reactivations) and two (7%, both sero-conversions) for EBV. One of three children with sero-conversion in the basiliximab group was at high risk because of the constellation CMV-positive donor and -negative recipient. Concerning EBV, no donor information was available.

Hospital admissions after transplantation because of infections (bacterial and viral) were necessary in 24% of the patients treated with basiliximab compared with 34% in the comparison group. None of the patients developed post-transplant lymphoproliferative disease (PTLD).



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Acute rejections and graft survival rates
The introduction of basiliximab to conventional immunosuppression has led to a significant decrease in the number of acute rejections (14 vs 34% in the comparison group) in the first 2 years after transplantation. These numbers were lower than NAPRCTS [2] data (40–50%) or results published for adults receiving basiliximab (25%) [12,17]. Moreover, five of seven rejections in the basiliximab patients were steroid responsive. Regarding the impact of acute rejection and loss of function, especially in steroid-refractory episodes, a better long-term prognosis is likely in children initially treated with basiliximab. All patients with steroid-resistant rejection were switched to an immunosuppression with prednisolone and tacrolimus.

Graft survival within the first year after transplantation did not differ between the basiliximab group and the comparison group. Graft survival is improved compared with historical data from our own and other centres [1,18], and comparable with UNOS data of children transplanted between 1989 and 1997 [19], which demonstrated 1 year graft survival 94.3 and 90.4% in LRD and CAD, respectively. Furthermore, it should be noted that only one graft loss was due to an acute rejection. It has to be noted that increasing experience with immunosuppressive regimens seems to play a more important role in first year graft survival than additional effects of a single drug, such as basiliximab. Therefore a controlled paediatric study with and without basiliximab is necessary in order to prove its effectiveness.

Glomerular filtration rate
GFR was stable during the first year after transplantation. In the early period after transplantation we recognized suddenly decreasing CsA trough levels combined with increasing serum creatinine levels and discussed an interaction between basiliximab and ciclosporin [20]. This might be responsible for an initially reduced GFR correlated with high CsA trough levels.

Infections
Increasing immunosuppression carries the risk of more opportunistic infections and lymphoproliferative disorders. Neither viral nor bacterial infections that led to hospital admissions were frequent in the children treated with basiliximab. EBV-related PTLD is a severe complication after transplantation [21,22]. Although we observed sero-conversion in six patients with basiliximab, no child has developed PTLD so far. However the long-term risk remains to be evaluated in larger numbers of patients.

Conclusions
Basiliximab combines excellent 1 year graft survival rates (CAD 91%, LRD 100%) with a low incidence (14%) and severity of acute rejections without increased infectious complications. Therefore, long-term benefits of basiliximab can be expected.



   Notes
 
Correspondence and offprint requests to: Lars Pape, Department of Pediatric Nephrology, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30623 Hannover, Germany. Email: larspape{at}t\|[hyphen]\|online.de Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

  1. Offner G, Latta K, Hoyer PF et al. Kidney transplanted children come of age. Kidney Int1999; 55: 1509–1517[ISI][Medline]
  2. North American Pediatric Renal Transplant Cooperative Study (NAPRTCS), 1998 Annual Report: 4–3
  3. Rigg KM. Renal transplantation: Current status, complications and prevention. J Antimicrob Chemother1995; 36: 51–57[ISI][Medline]
  4. Cole E, Naimark D, Aprile M et al. An analysis of Prednisolone of long-term cadaveric renal allograft survival. Clin Transplant1995; 9: 282–288[ISI][Medline]
  5. Matas AJ, Gillingham KJ, Payne WD, Najarian JS. The impact of an acute rejection episode on long-term allograft survival (t1/2). Transplantation1994; 57: 857–859[ISI][Medline]
  6. Soulillou JP. Relevant targets for therapy with monoclonal antibodies in allograft transplantation. Kidney Int1994; 46: 540–553[ISI][Medline]
  7. Tejani A, Harmon W, Benfield M et al. A randomized, prospective multicentre trial of T-cell antibody induction therapy in pediatric renal transplantation. Transplantation2000; 69: S111[Medline]
  8. Morgan DA, Ruscetti FW, Gallo RC. Selective in vivo growth of T-lymphocytes from normal human bone marrow. Science1976; 193: 1007–1008[ISI][Medline]
  9. Amlot PL, Tahami F, Chinn D, Rawlings E. Activation antigen expression on human T cells. I. Analysis by two-colour flow cytometry of umbilical cord blood, adult blood and lymphoid tissue. Clin Exp Immunol1996; 105: 176–182[ISI][Medline]
  10. Kovarik JM, Kahan BD, Rajagopalan PR et al. Population pharmacokinetics and exposure-response relationships for Basiliximab in kidney transplantation. The U.S. Simulect Renal Transplant Study Group. Transplantation1999; 68: 1288–1294[ISI][Medline]
  11. Kahan RD, Rajagopalan PR, Hall M. Reduction of the occurrence of acute cellular rejection among renal allograft recipients treated with Basiliximab a chimeric anti-interleukin-2-receptor monoclonal antibody. United States Simulect Renal Study Group. Transplantation1999; 67: 276–284[ISI][Medline]
  12. Nashan B, Moore R, Amlot P, Schmidt AG, Abeywickrama K, Soulillou JP. Randomised trial of Basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients. Lancet1997; 250: 1993–1998
  13. Offner G, Hoyer PF, Brodehl J, Pichlmayr R. Cyclosprine A in paediatric kidney transplantation. Pediatr Nephrol1987; 1: 125–130[ISI][Medline]
  14. Amlot PL, Rawlings E, Fernando ON et al. Prolonged action of a chimeric interleukin-2 receptor (CD25) monoclonal antibody used in cadaveric renal transplantation. Transplantation1995; 60: 748–756[ISI][Medline]
  15. Onrust SV, Wiseman LR. Basiliximab. Drugs1999; 57: 207–213[ISI][Medline]
  16. Offner G, Broyer M, Loirat C et al. Disposition of Basiliximab in de novo Pediatric Renal Transplantation. Pediatr Nephrol1999; 13: C24 (abstract)
  17. Belitsky P. Neoral use in the renal transplant recipient. Transplant Proc2000; 32 [Suppl 3A]: 10–19[ISI][Medline]
  18. Offner G, Hoyer PF, Ehrich JHH, Pichelmayr R, Brodehl J. Paediatric aspects of renal transplantation: experience of a single centre. Eur J Pediatr1992; 151 [Suppl 1]: 16–22
  19. 1999 Annual report of the U.S. Scientific Registry of Transplant Recipients and the Organ Procurement and Transplantation Network: Transplant Data 1989–1998. (2000, February 21). Rockville MD and Richmond VA: HHS/HSRA/OSP/DOT and UNOS. Retrieved August 1, 2000 from the World Wide Web: http://www.unos.org/Data/anrpt_main.htm
  20. Strehlau J, Pape L, Offner G, Nashan B, Ehrich JHH. Interleukin-2 receptor antibody-induced alterations of ciclosporin dose requirements in paediatric transplant recipients. Lancet2000; 356: 1327–1328[ISI][Medline]
  21. Nalesnik MA, Makowa L, Starzl TE. The diagnosis and treatment of posttransplant lymphoproliferative disorders. Curr Probl Surg1988; 25: 367–472[ISI][Medline]
  22. Nalesnik MA. Lymphoproliferative disease in organ transplant recipients. Springer Semin Immunopathol1991; 13: 199–216[ISI][Medline]
Received for publication: 15. 5.01
Revision received 3.10.01.