Side Effects Of Immunosuppressive Agents
Immunosuppressants are necessary to prevent allograft rejection, but these agents have a number of unwanted side effects. These include generic side effects associated with all immunosuppressive agents, such an increased susceptibility to infection and malignancy, and drug-specific side effects.
High-dose, intravenous corticosteroids (usually methyl prednisolone) are used at induction and to treat acute cellular rejection. Oral corticosteroids, typically prednisolone, are used for maintenance therapy. Prolonged exposure to corticosteroids results in a number of side effects:
· thinning of the skin and easy bruising
· weight gain with central adiposity and abdominal striae
· proximal myopathy
· avascular necrosis
· glucose intolerance/new onset diabetes mellitus
· peptic ulceration.
These adverse effects may be minimised by rapidly tapering steroid dose post-transplant and by using gastric (an H2 blocker or a proton pump inhibitor) and bone protection (vitamin D3 or calcium) in high-risk individuals. Some transplant centres avoid using maintenance corticosteroids because of these side effects.
Calcineurin inhibitors (CNIs)
Although CNIs significantly reduce the risk of acute rejection, and thus revolutionised early graft survival, it was rapidly appreciated that these agents were nephrotoxic. Serial renal biopsies show that CNI toxicity may affect the graft within weeks of transplantation. Typical acute changes include vacuolation of tubular cells. Following chronic exposure there is intimal thickening of arterioles, tubular atrophy and interstitial fibrosis. CNIs are also associated with tremor, which is dose-dependent, and at very high levels or in susceptible patients, may cause fitting.
Specific side effects associated with ciclosporin include hirsuitism and gingival hypertrophy. Tacrolimus is associated with glucose intolerance and a three times increased risk of developing new onset diabetes after transplant (NODAT) compared with ciclosporin.
Azathioprine inhibits purine production and hence DNA synthesis, thus preventing cell division. Associated side effects include bone marrow suppression, resulting in pancytopaenia or isolated leukopaenias. The risk of marrow suppression is increased if high doses are used or if patients have a low-activity polymorphism in the enzyme that breaks down azathioprine (thiopurine methyl- transferase [TPMT]).
Mycophenolate specifically inhibits inosine monophosphate dehydrogenase (IMPDH), which is the rate-limiting enzyme in guanine nucleotide synthesis. Its effects are said to be lymphocyte- specific (given that other cells have an alternative salvage pathway for nucleotide synthesis). However, pancytopaenia is frequently observed particularly if prescribed in combination with ganciclovir. Gastrointestinal upset, particularly diarrhoea, is also a common problem.
The effects of mTOR inhibitors (sirolimus and everolimus) are not limited to immune cells, as mTORC1 is a critical signalling complex in most cells. Associated side effects include dyslipidaemia, skin rashes, mouth ulceration, inhibition of wound healing and an increased risk of lymphocoeles. Interstitial pneumonitis is an uncommon but serious side effect of sirolimus, occurring in around 1% of patients, and requires immediate cessation of the drug. Sirolimus can exacerbate CNI-mediated nephrotoxicity and may cause proteinuria.
Biological agents are usually administered via the intravenous route, and agents that cause cytolysis (e.g. ATG, alemtuzumab) are associated with first-dose reactions (also known as cytokine release syndrome) of varying severity, which may be reduced by pre-medicating with intravenous corticosteroids and an antihistamine, such as chlorpheniramine.
These agents are variably xenogeneic and may incite an immune response, characterised by the development of neutralising antibodies. This may prevent recurrent use and even predispose to anaphylactic reactions during re-challenge.
Lymphocyte-depleting agents such as ATG lead to profound immunosuppression and their use has been associated with an increased risk of cytomegalovirus (CMV) infection and post-transplant lymphoproliferative disease (PTLD).
The anti-CD25 agents basiliximab and daclizumab are not T cell depleting, and therefore appear to have a very good safety profile. The anti-CD52 agent alemtuzumab causes lymphocyte depletion but does not appear to be associated with an increased risk of CMV infection. Its use has been linked with the subsequent development of antibody-mediated autoimmune diseases, for example, immune thrombocytopaenia and haemolytic anaemia.