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Natasha E Whitaker
BM BS MRCP
Lung Transplant Service
Gregory I Snell
MB BS FRACP
Lung Transplant Service
Department of Allergy, Immunology and Respiratory Medicine
Alfred Hospital and Monash University
Lung transplantation was first performed in 1983, and since then approximately 20,000 patients with end-stage lung disease have been transplanted. The diseases most commonly requiring transplantation are cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Thus, lung transplant patients have a broad age spectrum and varying tolerance to immunosuppression drugs and their side-effects. The current five-year actuarial survival is 60%, with most patients dying from either infections or bronchiolitis obliterans syndrome (BOS) – a form of chronic rejection. Immunosuppression is therefore a balance between undertreatment leading to rejection and overtreatment leading to infection and other side-effects. Currently, long-term immunosuppression regimens usually consist of three agents: calcineurin inhibitor, cell cycle inhibitor and steroids. In this review, we will discuss each of the commonly used immunosuppressants in lung transplantation.
Ciclosporin A (CsA) is a fungal polypeptide that forms complexes with intracytoplasmic proteins to inhibit calcineurin. Calcineurin is important for T-cell activation and production of cytokines, especially IL-2.(1) Immediately post-transplant, CsA is given in an intravenous form, which is three times more potent than oral CsA. Thus, the dose must be increased when the patient starts oral therapy. CsA is insoluble and thus is given as a microemulsion to improve gastrointestinal absorption.(2) Of note, cystic fibrosis (CF) patients absorb and metabolise CsA differently from non-CF patients and therefore require different dosing regimens and an oral dose corresponding to five times the intravenous dose. CsA is now off-patent, so generic forms are available. While these are similar, they are not identical to the original preparation, and therefore brand changes should be undertaken cautiously.
CsA dosing is monitored with blood levels. The targeted level varies according to time from transplantation, episodes of rejection and side-effects experienced. Trough (C(0)) levels correlate poorly with actual systemic exposure, thus levels measured two hours after ingestion (C(2)) may also be used, as these better reflect the pharmacokinetic profile.(3) C(2) levels are particularly useful in CF patients and in patients for whom toxicity is suspected, but the C(0) level appears acceptable.
There are limited data to support a role for inhaled CsA in the treatment of refractory acute rejection. However, Iacono et al recently demonstrated that patients receiving nebulised CsA, in conjunction with a standard three-drug immunosuppression regimen, had less BOS and prolonged survival, despite there being no significant effect on acute rejection.(4)
The main side-effects of systemic CsA are hypertension and dose-dependent renal impairment, which may lead on to irreversible chronic renal failure (see Table 1).(5)
Tacrolimus is a macrolide lactone that binds to the cytosolic protein FK-binding protein to inhibit calcineurin. Its effects are similar to CsA; however, tacrolimus is 50–100 times more potent than CsA.(2) Tacrolimus absorption is unaffected by fat, so CF patients have the same dosing regimen as non-CF patients.
However, tacrolimus should be taken before eating, as food reduces its absorption. Tacrolimus has highly variable oral bioavailability, requiring monitoring by measuring trough levels.(1) Tacrolimus and CsA cause similar dose-dependent and usually reversible side-effects (see Table 1). However, tacrolimus is associated with post-transplant diabetes mellitus.(5) There is currently no convincing evidence that tacrolimus is superior to CsA as first-line immunosuppression in lung transplantation.(6)
Cell cycle inhibitors
Azathioprine is converted to 6-mercaptopurine, which inhibits both nucleic acid bio‑synthesis and de-novo purine synthesis. Consequently, it prevents proliferation of B- and T-lymphocytes.(1)
There is no role for measuring azathioprine levels, as these do not correlate with efficacy or toxicity. However, the full blood count and liver function should be monitored, as azathioprine may cause haematological suppression and impaired hepatic function (see Table 2).(1)
Mycophenolate mofetil (MMF) is a prodrug of mycophenolic acid (MPA) – an inhibitor of inosine monophosphate dehydrogenase (IMPDH), which is essential for de-novo purine synthesis. Proliferating lymphocytes are selectively affected as, unlike other cells, they cannot use the salvage pathway for purine synthesis instead.(2)
MMF is absorbed by the gut, then metabolised to MPA in the liver. Enterohepatic recirculation leads to secondary peaks in the concentration of MPA approximately 6–12 hours after ingestion.(2) The main side-effects (see Table 2) are gastrointestinal, which may limit dose escalation. Mycophenolate sodium is an alternative formulation that was hoped to be associated with less gastrointestinal toxicity, but clinical studies have not supported this. MMF has not been shown to be superior to azathioprine in preventing acute rejection in lung transplantation.(7)
Steroids form part of maintenance immuno‑suppression and are used in high dose to treat acute rejection. Inhaled steroids are not useful for treating either acute rejection or BOS.(8)
New agents, used on a case-by-case basis
Sirolimus is a macrolide lactone that combines with the intracellular protein FKBP-12 to inhibit the activation of the cell cycle kinase mammalian target of rapamycin (mTOR). This leads to interruption of numerous signal transduction pathways, and thus prevents proliferation of various cells, including lymphocytes, fibroblasts and also potentially virus-infected cells and tumour cells. As a result of its general antiproliferative effect, sirolimus is avoided in the immediate post-transplant period, as it may cause delayed wound healing, particularly of the airway anastomosis.(9) The other notable side-effect of sirolimus is “sirolimus lung”, a form of interstitial lung disease, which may develop in the graft (see Table 3).(10)
Everolimus is structurally very close to sirolimus and thus acts similarly; however, it has a slightly different side-effect profile and does not appear to cause a “sirolimus lung” equivalent. Both drugs require significant dose reduction when used with calcineurin inhibitors, as they act in synergy to enhance the immunosuppressive effects of the latter.(11)
Induction therapy using IL-2 receptor-blocking monoclonal antibodies (basiliximab or dicluzimab) are not uncommonly used; however, their benefits remain controversial in lung transplantation.
In summary, there has been an explosion of different combinations of immunosuppressants over the last 10 years, which has allowed greater individualisation of patient regimens. However, the complexities of patient management have meant that current practice is driven by local experience and not evidence-based medicine from randomised controlled trials. The recent trial of inhaled CsA raises the possibility of even further novel combinations in the future.