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

Maintenance Immunosuppression


(a) Corticosteroids
Corticosteroids are still widely used as an important component of most immunosuppressive regimens and are almost universally used as first line treatment for acute rejection. The North American Pediatric Renal Transplant Collaborative Study (NAPRTCS) reports shows that until recently, up to 96% of children who underwent kidney transplantation and still have a functioning graft were maintained in prednisone [8,27]. In most steroid based regimens, the dosage is usually high in the immediate post-transplant period, approximately 2mg/kg//day (maximum 80mg), with a gradual reduction to approximately 0.2-0.3mg/kg/day within a 6-month to 1-year period.

Corticosteroids have a variety of anti-inflammatory and immunomodulatory effects [28]. These include stabilization of lysosomal membranes, suppression of prostaglandin synthesis, reduction of &histamine and bradykinin release and lowering of capillary permeability. Anti-inflammatory effects are mediated mainly through induced production of cytokines, including IL-1, IL-2, IL-6, ILN- and TNF- and TNF-a. Corticosteroids impair monocyte/macrophage function and decrease the number of circulating CD4+ T-cells.

The numerous mechanisms of action of corticosteroids lead to multiple side effects and toxicities. The major concern in children with respect to its long-term use in children is growth retardation. Studies have shown that doses in excess of 8.5mg/day will impair normal growth [29].

Other side effects include increased appetite with weight gain with Cushingoid facies, acne, glucose intolerance, hypertension, increased susceptibility to infection, impaired wound healing, aseptic necrosis of bone, cataracts, psychosis and peptic ulceration [30]. Sometimes there are consequences of the mineralocorticoid activity of these agents leading to fluid retention, hypokalemia and hypertension.

In view of these multiple side effects of maintenance steroid therapy, attempts are focused on early withdrawal or reduction of steroids or steroid avoidance [31]. Unfortunately, the majority of these attempts have failed because of the development of acute rejection episodes [32,33,34]. Alternate day steroid therapy reduces its impact on growth inhibition and should be encouraged. IL-2r antibody has been used in steroid avoidance protocols, with low acute rejection rates and striking reduction in post-transplant complications. The Cooperative Clinical Trial in Paediatric Transplantation aimed at corticosteroid withdrawal showed acute rejection rates at 6 months to be very low. However, the incidence of post-transplant lymphoproliferative disease was unacceptably high. In comparison, in the control group receiving chronic low-dose corticosteroids there was no higher rate of late rejection and long-term graft survival was similar in both groups [35]

(b) Anti-proliferative agents
(i) Azathioprine
This was the first immunosuppressive agent approved for organ transplantation use. Azathioprine is metabolized to 6-mercaptopurine (6-MP) through reduction by glutathiamine, and then converted to 6-thiouric acid, 6-methyl-MP, and 6 thioguanine (6 TG). These compounds are incorporated into replicating DNA, halt DNA replication, and block the de novo pathway of purine synthesis by duration of thio-iosinic acid. This latter effect confers specificity of action on lymphocytes that lack a salvage pathway for purine synthesis.

For pediatric patients, the dosage is 1-2mg/kg/day as a single dose. It can be used in combination with all other immunosuppressive agents except mycophenolate mofetil (MMF). The most serious side effects include skin cancers following chronic use, bone marrow suppression that is dose dependent and occasional liver impairment and cholestatic jaundice. Minor effects include hypersensitivity reactions manifesting as a rash [36].

(ii) Mycophenolate mofetil (MMF)
MMF and mycophenolate sodium (MPS) are rapidly converted in the liver to mycophenolic acid, which is the active compound. The target of mycophenolic acid is inosine monophosphate dehydrogenase (IMDPH). This is the rate-limiting enzyme in the de-novo synthesis of guanosine nucleotides, themselves essential for DNA synthesis. The majority of cells generate guanosine nucleotides by two pathways, the IMPDH pathway, and a salvage pathway; hence blockade of the IMPDH pathway results in relatively selective blockage of lymphocyte proliferation [37].

The recommended dose for paediatric patients is 1200/m2/day, divided in two, three, or four doses [38]. Although therapeutic monitoring is available, current standards in paediatric patients are not yet available to guide treatment [39,40,41,42,43,44]. MMF must not be used in combination with azathioprine.

The most common dose limiting adverse effects is diarrhoea. Other gastrointestinal side effects include nausea, vomiting and abdominal pain. Bone marrow suppression also occurs. Some clinical trials have shown an increased incidence of viral infections (CMV, herpes simplex) and candida [45].

Analysis of large databases of renal transplant recipients have shown decreased incidence of chronic allograft nephropathy with improved long-term renal graft function in patients on MMF [46,47].