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

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Maintenance Immunosuppression

(c) Calcineurin inhibitors
(i) Cyclosporine
The mechanism of inhibiting T-cell activation by calcineurin inhibitors (CNI) is well-understood [48]. After entering the cytoplasm, CNIs form complexes with their immunophilins. Cyclosporine binds to cyclophilin and Tacrolimus and Pimecrolimus bind to the 12 kDa FK 506-binding protein (FKBP-12). The CNI-immunophilin complexes inhibit calcineurin activity, and hence prevent nuclear translocation of NF-AT and cytokine gene transcription. The net result is that CNIs block the production of cytokines and as IL-2 and inhibit T cell activation and proliferation.

For induction purposes, cyclosporine is given intravenously in a dosage of 165mg/m2/kg/day in children over 6 years of age, and 145mg/kg/day should be given as a continuous infusion over a 24-hour period starting intraoperatively. Induction therapy should be continued only for 48 hours and then converted to oral cyclosporine. The recommended starting oral dose for children less than 6 years old is 500mg/m2/kg/day, administered in three divided doses. The doses given in children are much higher than in adults as the drug is metabolized more rapidly in children [5]. Calcium channel blockers are used concomitantly to reduce nephrotoxicity [49]. The irregular absorption and inherent nephrotoxicity of the drug makes drug monitoring and adjustment essential. In the first three months whole blood trough levels measured by high-pressure liquid chromatography should be maintained between 200-250mg/ml, then between 100-200mg/ml in patients after 3 months. More recent data suggest that measuring the level 2 hours after receiving the dose may lead to more accurate dosing, assessing the true area under the curve and avoiding toxicity [50,51,52].

Many of the side effects of CNIs are dose-dependent and relate to the sites where calcineurin concentrations are highest, notably the brain and kidney [53]. Nephrotoxicity is mainly due to severe vasoconstriction of the afferent arteriole, with concomitant reduction in renal blood flow and glomerular filtration rate [54,55,56]. Longterm use of CNIs leads to interstitial fibrosis and obliterative arteriolar changes due to fibrosis intimal thickening in the kidneys; changes that are non-reversible [57]. Because of its renal effects, hypertension is a common side effect of CNIs [58].

The neurotoxicity of CNIs are more common with tacrolimus than cyclosporine and are exacerbated by hypomagnesaemia [59]. Neurotoxic effects include headaches, tremors, agitation, convulsion, psychosis, hallucinations, encephalopathy, and impaired consciousness [60].

CNIs also have metabolic effects that include hyperglycemia, hyperkalemia, hyperuricemia, and hyperlipidemia. Hyperglycaemia is two to four times more common with Tacrolimus than cyclosporine, and may also reflect different sensitivity to the diabetogenic effects of corticosteroids [61,62]. Other side effects of CNIs include hyperplasia and hypertrichosis that are drug specific side effects of cyclosporin. Alopecia on the other hand may accompany Tacrolimus use [63].

Cyclosporin has been used in combination with all other immunosuppressive agents except tacrolimus. However, because of the potential increased risk of post transplant lymphoproliferative disease (PTLD), the use of a combination of a calcineurin inhibitor, rapamycin and corticosteroids should probably be avoided, particularly in high-risk children [64].

(ii) Tacrolimus
Tacrolimus is presently being increasingly used in paediatric renal transplant [65]. When compared to cyclosporin, patient and graft survival at 2 years using tacrolimus are equivalent [66]. Tacrolimus use is associated with a lower incidence of acute rejection and improved graft function. Children treated with tacrolimus had a lower incidence of rejection (9.7% vs. 18.3%) at 2 years.

Induction therapy is given as a continuous infusion using a dose of 0.1mg/kg/24 hours, with a switch to oral therapy within 2-3 days. Sometimes, the drug is commenced via nasogastric tube using the oral preparation because it has very good absorption. Initial oral doses should not exceed 0.15mg/kg twice daily and should not exceed 0.1mg/kg as maintenance dose. Monitoring trough blood levels is essential because of its nephrotoxicity. Recommended trough levels are between 10-20 mg/l in the first 3 months and therefore between 7-12mg/l up to 12 months and then maintained at 5-7mg/l.

In view of the similar mechanism of action with cyclosporin, the side-effect profile of tacrolimus is similar to that seen with cyclosporine [67]. Hypertrichosis and the dysmorphic features like gum hypertrophy seen with cyclosporin use are not seen with tacrolimus [68].

Nephrotoxicity is seen similar to cyclosporin use [69]. Neurological side effects are common and may be seen more frequently than with cyclosporine [59,70]. Tacrolimus treated patients have a higher incidence of post transplant lymphoproliferative disease and hyperglycaemia [71,72]. However, with lower doses the incidence of post transplant lymphoproliferative disease has significantly decreased [73].

Tacrolimus can be used in combination with all other immunosuppressants except cyclosporine. Combination with rapamycin and corticosteroids should be used with caution in children with a higher risk of developing post transplant lymphoproliferative disease [64].

(d) Mammalian target of rapamycin (mTOR) inhibitors
Sirolimus and everolimus are the newest immunosuppressive agents being used for kidney transplant. Both are macrocyclic lactones, with sirolimus being a naturally occurring fermentation product of the actinomycete streptomyces hygroscopicus, while everolimus represents a chemical modification of sirolimus to improve absorption.

TOR is a cytosolic enzyme that regulated differentiation and proliferation of lymphocytes. Inhibition of mTOR has a profound effect on the cell signaling pathway required for cell-cycle progression and cellular proliferation. The net effect is blockade of T-cell activation by preventing progression of the cell cycle from the GI to the S phase. The TOR inhibitors bind to the immunophillin

FKBPI2 inhibits the actions of TOR [74,75,76,77,78,79]. TOR inhibitors may be particular important in long-term immunosuppression since they stimulate T-cell apoptosis. They inhibit mesenchymal proliferation, an important factor in graft vascular disease [80,81]. mTOR also inhibits fibroblast growth factors required for tissue repair thus resulting in impaired wound healing.

Rapamycin is available as either a solid or a liquid oral preparation. Although in adults, a single dose may suffice to maintain therapeutic levels, in children it has a much shorter half-life and thus necessitates twice-daily dosaging [6]. Recommended therapeutic levels in children remain speculative and range from 12-25ng/ml in the early post-transplant period without calcineurin inhibitors and 4-12ng/ml with calcineurin inhibitors [6,82]. After the early post-transplant period (>3-6months), levels are maintained between 5-10ng/ml. Lower therapeutic levels are desired when used with calcineurin inhibitors because of enhanced nephrotoxicity.

Side effects of mTOR inhibitors include metabolic, haematological, dermatological effects and effects related to growth factor inhibition [83,84]. The most common side effects of rapamycin include hyperlipidaemia, thrombocytopenia, leucopenia and delayed wound healing [85]. Dermatological side effects include acne and mouth ulcers. Another side effect that is being increasingly seen is interstitial pneumonitis, which appear to be dose related and resolves with drug withdrawal [89]. Peripheral oedema, diarrhoea and lymphocele formation post renal transplant are also well recognized complications [87].

Rapamycin has been found to be effective in combination with calcineurin inhibitors [88,89,85,90,91] in a calcineurin-inhibitor sparing protocol [83] and in a steroid-free protocol [92].