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.
Corticosteroids
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
· osteoporosis
· avascular
necrosis
· glucose
intolerance/new onset diabetes mellitus
· hypertension
· 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.
Anti-metabolites
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.
mTOR inhibitors
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
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.
Polyclonal antibodies
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).
Monoclonal antibodies
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.
