Address for Correspondence:
Rajendra Bhimma,
Department Of Maternal & Child Health, Nelson R Mandela School Of Medicine, University Of Kwazulu-Natal, Private Bag 7, Congella, 4013, Durban, South Africa.
E-MAIL: bhimma@ukzn.ac.za

Keywords:
immunosuppression, children, kidney, transplantation

Introduction

Renal transplantation is now the optimal treatment for many children with end-stage kidney disease. Effective immunosuppression is quintessential to successful kidney transplantation. Both national and international registries report 1-year graft survival rates of over 85% and this improvement in outcome has largely been dependent on developments in immunosuppressive therapy [1].

Although protocols for kidney transplantation are similar in both adults and children, there are nonetheless distinct differences. Children develop end-stage kidney failure at a much lower frequency than adults do and the diseases that result in kidney failure are substantially different [2]. Infants and young children cannot swallow pills and they metabolize at substantially different rates from adults. As a result, they frequently require special formulations and schedules [3,4,5,6]. Children also have unique medical and surgical requirements, both before and following transplantation.

Current all available immunosuppressive agents cause non-specific immunosuppression and hence increase the risk of infection and certain types of malignancy (skin cancer and post-transplant-lymphoproliferative disease). The latter has a much higher incidence in children compared to adults [7]. If these issues are specifically and carefully addressed, the outcome of kidney transplantation in children can parallel or even surpass that in adults [2]


An increasing number of immunosuppressive agents are available for use in both adult and paediatric kidney transplants and these target different steps of the immunological response to an allograft. Table 1 lists the most common immunosuppressive agents used in kidney transplantation.

Table 1. Immunosuppressive agents used in solid organ transplantation

Class of agent	Agent
Corticosteroid	Prednisolone Prednisone Methyl-prednisone
Antiproliferative	Azathioprine Mycophenolate mofetil Mycophenolate sodium
Calcineurin Inhibitor	Cyclosporine Tacrolimus
TOR inhibitor	Sirolimus Everolimus
Polyclonal anti-lymphocyte antibodies	ALG ATG ALS
Monoclonal antibodies	Muromonab-CD3 Basiliximab Daclizumab
Adapted from: Taylor AL, et al. Immunosuppressive agents in solid organ transplantation: Mechanisms of action and therapeutic efficacy. Critical Reviews in Oncology/Hematology 2005; 03: 012

Currently, the majority of paediatric transplant recipients are treated with some form of induction antibody [8]. Although presently no 'universal' protocol for immunosuppression in paediatric kidney transplant exists, current trends are towards early steroid withdrawal or directed at eliminating either steroids or calcineurin inhibitors, or both [9,10]. Another approach is to use robust induction therapy with alemtuzumab (Campath®), followed by eventual monotherapy with Tacrolimus [11,12].

Thus, although presently there is no clearly defined approach to immunosuppression in kidney transplantation for children, the eventual goal is to permit long-term graft survival and minimize side effects by the use of the fewest possible chronic medications.

A. Induction Therapy
(a) Polyclonal lymphocyte depleting antibodies.
The 2 polyclonal antibodies currently in use are Equine gamma globulin and anti thymocyte globulin.
Equine gamma globulin has to be given through a central catheter because of the sclerosing nature of the preparation. Calcineurin inhibitors are generally withheld during administration. The dose used is 15mg/kg per day. Thymoglobulin may be given through a peripheral line at a dose of 1.5-2mg/kg per day. A single centre study has shown that recipients of thymoglobulin have decreased incidence of acute rejections [13]. However, this result may be the reflection of the overall improved outcomes of kidney transplants in more recent cohorts of patients [8]. Anti-lymphocyte antibody preparations are still widely used to treat steroid resistant acute rejection episodes and are effective in 70-96% of patients [14,5,16,17].If a second course of polyclonal antibody therapy is required in a patient, it is advisable to ;use a preparation obtained from a different species because of reduced efficacy resulting from the development of xenospecific neutralizing antibodies.

(b) Monoclonal antibodies
(i) Monoclonal lymphocyte depleting antibodies
In comparison to polyclonal antibody preparations, monoclonal antibodies do not contain irrelevant proteins, are more standardised and have a single well-defined specificity. The two most widely used monoclonal lymphocyte-depleting antibodies are OKT3 and Alemtuzumab.

OKT3 is administered as a bolus injection into a peripheral vein daily for 10-14 days at a dose of 5mg per day for children >30kg and 2.5mg per day for children <30kg. Calcineurin inhibitors are withheld during the use of OKT3. Adverse effects include neurological problems [18] reactivation of viral infections such as cytomegalovirus and Epstein-Barr virus as well as 'first-dose reaction' [19,20].Campath has been used in multiple uncontrolled pilot trials mainly in adult renal transplant recipients. Alemtuzumab was well tolerated, but some children had acute rejection episodes.This agent has been used more extensively in paediatric small bowel transplants [21]. Presently there is no recommended paediatric dosing for children undergoing kidney transplantation.

(ii) Monoclonal nondepleting antibodies
IL2-receptor antibodies

The two IL2-receptor antibodies presently used are basiliximab and daclizumab. These two high-affinity chimeric or humanized antibodies act on the inducible a chain of the interleukin-2 receptor (IL-2r) on the surface of the activated lymphocyte.

Basiliximab is given on day 0 and 4 post-transplant (generally 10mg for children <40kg and 20mg for those >40mg) [22]. One study showed that paediatric patients receiving basiliximab as induction therapy may have elevated cyclosporine levels and therefore would require reduced doses to avoid toxicity [23]. Induction with basiliximab in adult kidney transplant recipients has been induced to allow the successful early withdrawal of steroids [24] and even steroid avoidance albeit with a high incidence of rejection [25].

Daclizumab is generally given in a regimen of 1mg/kg intravenously on the day of transplantation and every 14 days thereafter for 5 doses [26]. Higher doses may be required for saturation of IL-2r in younger children [9].

Unlike OKT3, these antibodies do not produce a first-dose-reaction and have few side effects.