Introduction

Liver transplantation (LT) is a highly successful treatment for fulminant liver failure, end-stage chronic liver disease and hepatocellular carcinoma. Alongside improved surgical techniques, medical advances including the implementation of potent immunosuppression have helped achieve high one-year survival rates by reducing the risk of immune-mediated allograft rejection. One-year LT survival rates in the United States was up to 92% in 2015 and death due to rejection and graft failure in one-year survivors was as low as 1.7% [1].

Despite significant improvements in short-term survival, long-term survival post-LT has remained largely unchanged over the last three decades [1]. Currently, Australia and New Zealand LT recipients have a survival rate of up to 70% at 10 years post-LT and an overall median survival of approximately 20 years [2]. The minimal improvements in long-term survival are a consequence of the long-term sequelae of immunosuppression, with elevated rates of obesity, type 2 diabetes mellitus, cardiovascular disease and cancer incidence compared to the general population. Malignancy, infection and cardiovascular disease are notably the leading causes of death amongst one-year LT survivors [1, 3,4,5]. There is therefore now a strong rationale to optimise immunosuppression management to mitigate these risks while maintaining long-term graft function.

Systemic corticosteroids have a central role in LT induction immunosuppression, treatment of T cell-mediated allograft rejection and in a small proportion of patients, long-term maintenance immunosuppression. LT recipients are vulnerable to the multitude of off-target side effects associated with short- and long-term systemic corticosteroid use. While corticosteroid-free protocols have been suggested as a means to minimise corticosteroid-related side effects, the increased risk of acute cellular rejection (ACR), corticosteroid-resistant rejection and renal impairment limits their use [6].

Budesonide is a second generation oral corticosteroid that undergoes significant first pass hepatic metabolism with minimal systemic concentration and toxicity [7, 8]. The metabolism of oral budesonide in the gastrointestinal tract and liver enables its use in the management of luminal gastrointestinal disease (microscopic colitis [9], inflammatory bowel disease [10]) and autoimmune hepatitis (AIH) [11, 12], respectively. The efficacy of budesonide in AIH is particularly relevant to the LT population given the shared intended target of immune suppression in the non-cirrhotic AIH and the post-LT populations. Furthermore, oral budesonide is well-tolerated with literature supporting a more favourable adverse effect profile compared to prednisolone [13,14,15].

The long-term side effects associated with current drugs have become a major challenge in the modern era of LT immunosuppression. This review will explore the rationale for considering budesonide as a potential alternative immunosuppressant to conventional corticosteroids following LT.

Budesonide

Budesonide is a second generation synthetic corticosteroid with an oral formulation first approved in 2001 by the United States Food and Drug Administration for the management of Crohn’s Disease [16]. Enteric-coated budesonide is rapidly absorbed into the portal venous circulation, following a pH- and time-dependent release into the terminal ileum and proximal colon (Fig. 1) [17]. Budesonide has high intrinsic potency with a 15-fold stronger affinity for the glucocorticoid receptor than prednisolone, enabling a local immunosuppressant effect in the liver prior to undergoing greater than 90% first pass hepatic metabolism by cytochrome P450 3A4 [7, 8]. The extensive first pass hepatic clearance results in a systemic availability as low as 10% [17]. Furthermore, the principle metabolites of budesonide, 6b-hydroxy-budesonide and 16a-hydroxy-prednisolone, lack glucocorticoid activity, thus further minimising systemic toxicities prior to excretion by the kidneys [8, 17]. The pharmacokinetic profile of oral budesonide suggests at least comparable efficacy to systemic corticosteroids but with less systemic toxicity.

Fig. 1
figure 1

Pharmacokinetics of oral budesonide. Ingested oral budesonide is absorbed through the terminal ileum and proximal colon into the portal venous circulation, before undergoing extensive first pass hepatic metabolism

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Budesonide is well-tolerated with similar rates of reported side effects compared to placebo [18,19,20,21]. Patient-reported side effects from pooled safety data are mostly mild to moderate in severity and include gastrointestinal symptoms (6–35%) [20, 21], headache (9–12%) [13, 20, 21], insomnia (18%) [22], mood alterations (9–18%) [13, 22] and corticosteroid-related cutaneous changes (11–15%) [21, 22]. Gastrointestinal side effects described in the literature including abdominal pain, nausea and diarrhoea occurred in patients with inflammatory bowel disease and was likely associated with underlying disease activity [21, 22]. Two causally-related serious adverse events have been reported with treatment of budesonide 6 mg a day for up to one year. One patient developed melaena [21]. Another patient developed avascular osteonecrosis but had been treated with long-term high dose conventional corticosteroids prior to inclusion in the study [21].

The majority of safety data on short- and long-term budesonide use is derived from pooled analyses of large inflammatory bowel disease RCTs. Short- and long-term budesonide use is associated with fewer corticosteroid-related adverse effects and less adrenal suppression, in comparison to prednisolone [18, 20, 22]. Furthermore, corticosteroid-naïve patients treated with long-term budesonide have greater preservation of bone mineral density compared to patients treated with prednisolone [22]. Prospective safety data in the AIH population is lacking, however a multi-centre RCT demonstrated a lower proportion of corticosteroid-related adverse effects with budesonide induction therapy compared to prednisolone, and a 40% reduction in incidence of corticosteroid-related adverse effects when patients were converted from prednisolone to budesonide [13].

Thus, budesonide may address the unmet need for a medical therapy that has efficacy but with a better safety profile compared to current immunosuppression with conventional corticosteroids.

Corticosteroids in Liver Transplant Immunosuppression

Seventy-two percent of LT recipients in the United States receive corticosteroid-containing immunosuppression regimens [23]. Contrary to budesonide, oral corticosteroids have a high systemic bioavailability ranging from 80 to 95%, and a moderate apparent volume of distribution with rapid penetration into multiple organs [17, 24]. Consequently, corticosteroid use is associated with well-documented short- and long-term adverse effects across multiple body systems including immune, metabolic, endocrine, musculoskeletal and neuropsychological (Fig. 2) [25,26,27]. Corticosteroid-associated adverse effects increase with dose and duration of therapy. Safety data on chronic low-dose prednisolone is scarce and predominantly derived from rheumatic disease cohorts. However, a retrospective analysis of patients with autoimmune hepatitis on maintenance prednisolone has demonstrated an increased odds of new fractures at prednisolone doses less than 5 mg a day, and increased odds of new diabetes and cataracts at doses greater than 5 mg a day [28]. Furthermore, each additional milligram of daily prednisolone increases the odds of new-onset fracture, diabetes or cataracts in the same year by 8% [28].

Fig. 2
figure 2

Systemic adverse effects associated with oral corticosteroid use

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The LT population is particularly vulnerable to corticosteroid-related adverse effects, including infection, reduced bone density and metabolic complications. Cumulative immunosuppression exposure is associated with increased infection risk, a leading cause of post-LT morbidity and mortality [29]. In particular, corticosteroids are a risk factor for Pneumocystis jiroveci fungal infection, with prophylaxis recommended for higher doses of prednisolone (≥ 20 mg daily prednisolone for ≥ 2 weeks) and for at least 6 to 12 months post-transplant [30]. Transplant recipients have a fourfold increased risk of fractures compared to the general population [27]. Cumulative corticosteroid dose has been negatively correlated with bone mineral density post-LT, however the impact on fracture risk is yet to be established [31, 32]. Corticosteroids can induce de novo or worsen pre-existing metabolic risk factors post-LT. Metabolic dysfunction-associated fatty liver disease is the second leading cause and fastest growing indication for LT [33]. Internationally, post-LT hypertension is present in 70% of recipients, post-transplantation diabetes mellitus (PTDM) in 26% of recipients, dyslipidaemia in 40–66% of recipients and 30–70% of recipients become overweight or develop obesity, particularly within the first 6 to 12 months following LT [34, 35]. Furthermore, cardiovascular disease is progressively becoming a leading cause of post-LT mortality [36]. The causative effect of corticosteroids on metabolic risk is difficult to distinguish from confounding factors, however the early withdrawal or complete avoidance of corticosteroid in post-LT immunosuppression regimens has been demonstrated to reduce the risk of hypertension and diabetes mellitus, and lower serum cholesterol levels [6].

The impact of corticosteroid-related adverse effects is becoming even more damaging, due to the increased rate of pre-existing and de novo metabolic comorbidities in liver transplant recipients. Current guidelines suggest minimisation of corticosteroid use following LT to reduce the risk of corticosteroid-related adverse effects [34, 37, 38]. The International Liver Transplantation Society consensus is for recipients to be weaned off corticosteroids by 3 months post-LT [39]. However, there are currently no other consensus recommendations regarding corticosteroid minimisation strategies following LT.

Corticosteroid-Free Immunosuppression Regimens

Corticosteroid-free immunosuppression protocols post-LT attempt to reduce the burden of corticosteroid-related morbidity. A 2018 Cochrane review summarised 16 randomised-controlled trials (RCTs) consisting of 1,347 patients: 10 RCTs compared corticosteroid avoidance (excluding use intra-operatively or for treatment of acute rejection) to short-term corticosteroid use, and 6 RCTs compared short-term to long-term corticosteroid use [6]. Corticosteroid withdrawal or avoidance was associated with reduced hypertension (RR 0.76, 95% CI 0.65–0.90), de novo and pre-existing diabetes mellitus (RR 0.81, 95% CI 0.66–0.99) and total cholesterol levels (mean difference -18.49 mg/dL, 95% CI -22.02- -14.96), compared to standard corticosteroid-containing regimens [6]. However, ACR (RR 1.33, 95% CI 1.08–1.64), corticosteroid-resistant rejection (RR 2.14, 95% CI 1.13–4.02) and serum creatinine levels (mean difference 0.11 mg/dL, 95% CI 0.07–0.16) were significantly higher when corticosteroid withdrawal or avoidance was compared to corticosteroid-containing regimens [6]. Changes associated with graft loss, mortality, chronic rejection and infection rates did not reach statistical significance [6]. No trials reported on the total number of adverse events. This Cochrane review indicates a trade-off between improvement of some cardiovascular risk factors with increased rates of acute rejection and corticosteroid-resistant rejection, in corticosteroid-free immunosuppression regimens.

The findings of the 2018 Cochrane review mirror that of earlier meta-analyses on corticosteroid avoidance in post-LT recipients [40,41,42,43,44]. Corticosteroid-free protocols were similarly associated with a significant reduction in rates of diabetes [41,42,43] and total cholesterol levels [40, 41], and a significant increase in rates of ACR [40, 41], when analysed with conventional meta-analyses. The risk of ACR was reduced in corticosteroid-free regimens when corticosteroids were replaced with alternative induction immunosuppressants such as interleukin-2 receptor monoclonal antibodies or polyclonal anti-T cell antibodies [40, 41]. Again, no statistically significant changes were found with graft loss, infection, chronic rejection and mortality outcomes [40,41,42,43,44].

The low-quality evidence of current studies further limits the applicability of corticosteroid-free regimens. All the included trials in the 2018 Cochrane analysis were of small number, at high risk of bias and had limited evidence for long-term outcomes [6]. Furthermore, there was substantial heterogeneity across all trials in dose and duration of corticosteroids, as well as type and combinations of concomitant immunosuppression used [6, 45]. Although corticosteroid-free immunosuppression regimens may benefit select patients at high risk of corticosteroid-specific adverse effects, the increased risk of ACR requires careful consideration. Thus, corticosteroid-free immunosuppression regimens are not widely utilised in clinical practice and alternative agents need to be explored.

Budesonide in Liver Transplant Immunosuppression

With a greater therapeutic to toxicity ratio, there is a therapeutic opportunity for budesonide as an alternative to conventional corticosteroids in post-LT immunosuppression, particularly in recipients at high risk of corticosteroid-associated side effects or with concurrent infection. Due to differences in the metabolism and intrinsic potencies of oral budesonide and prednisolone, direct conversion into bioequivalent doses cannot be made. However, previous studies and current clinical practice guidelines have used budesonide 9 mg daily as an alternative first line induction therapy to prednisolone [11, 13, 14]. Thus, inferences can be made on the appropriate dosing of oral budesonide in LT recipients with a functioning allograft, due to the shared intended target of immunosuppression with patients with non-cirrhotic autoimmune hepatitis. Proposed uses of oral budesonide post-LT include in induction and maintenance immunosuppression, and the management of T cell-mediated ACR. However, the current literature on the use of budesonide in LT immunosuppression is scarce (Table 1).

Table 1 Existing studies on budesonide in liver transplantation immunosuppression
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Induction Immunosuppression

Budesonide may substitute prednisolone following initial induction immunosuppression with intravenous corticosteroids post-LT. This requires the recipient to be able to tolerate medications orally or via nasogastric tube and have a functioning gastrointestinal tract, in order to facilitate budesonide ingestion and absorption, respectively.

A limited case series reported on the use of budesonide monotherapy in three adult LT recipients with severe fungal and bacterial opportunistic infections within 2 weeks of LT [46]. Although no patients developed histological features of rejection with budesonide monotherapy, the presence of severe opportunistic infections reflects a significantly suppressed immune system that is less likely to generate a T cell-mediated allograft response. Nevertheless, budesonide was chosen as the most appropriate immunosuppressant in these cases of severe infection due to its intrinsic hepatic potency and low systemic toxicity.

A Phase 2a trial compared the efficacy and safety of budesonide to prednisolone in induction immunosuppression following adult LT [16]. At 6 months follow-up there was no significant difference in rates of ACR between budesonide and prednisolone groups (5% budesonide versus 5% prednisolone, p = 1.00) [16]. The budesonide group had significantly lower rates of infection (0% budesonide versus 30% prednisolone, p = 0.02) but no difference in rates of PTDM (0% budesonide versus 15% prednisolone, p = 0.23) [16]. Asymptomatic adrenal suppression occurred in 2 out of 15 (13%) patients treated with budesonide with no requirement for treatment [16]. There was no data describing adrenal suppression in the prednisolone arm. Limitations of this trial include small sample size, lack of randomisation, confounding from concomitant immunosuppressants and a short follow-up duration. Although the results of this pilot study is promising, larger randomised, controlled trials are required to consolidate these findings.

Acute Cellular Rejection

The majority of cases of ACR is treated with high dose oral and/or boluses of systemic corticosteroids, with escalation of background maintenance immunosuppression. Budesonide may be utilised in the treatment of ACR of mild to moderate severity, in place of prednisolone.

The efficacy of budesonide in the treatment of ACR was first explored in a rat model, whereby increasing doses of oral budesonide was associated with less rejection compared to no immunosuppression [48]. Three of five rats in the highest dosage group died of intestinal haemorrhage, likely secondary to incomplete dissolution of budesonide in water with subsequent high intestinal concentrations [48]. In a case series of paediatric LT recipients, mild to moderate cases of ACR was successfully treated with budesonide and optimisation of concomitant immunosuppression, at clinician-dependent doses [47]. The most common rationales for the selection of budesonide use included acute or recent infection and Epstein-Barr virus viraemia [47]. Eleven adverse events were reported; all infection-related with one severe case of viral pancreatitis but with no discontinuation of drug required [47].

Further large, prospective trials are required to examine the efficacy of budesonide in the treatment of ACR of different severities as well as the risk of corticosteroid-resistant ACR, compared to prednisolone.

Maintenance Immunosuppression

Long-term, low dose maintenance corticosteroids is not routinely used post-LT apart from select patients with recurrent allograft rejection or AIH as the underlying aetiology of their initial liver disease. Low dose oral budesonide could be proposed as an alternative to prednisolone, particularly in patients at high risk of long-term systemic corticosteroid side effects. However, there are currently no studies investigating budesonide as maintenance immunosuppression in this LT subpopulation.

Special Considerations Post-Liver Transplantation

Allograft Fibrosis or Cirrhosis

The metabolism and systemic bioavailability of oral budesonide is closely linked to hepatic function. Reduced first-pass hepatic metabolism secondary to liver fibrosis or cirrhosis has been associated with a 2.5-fold increase in budesonide bioavailability, reduced efficacy and increased adverse events [17, 49, 50]. Thus, hepatocellular damage may cause a functional loss of CYP 3A4 activity and higher systemic concentrations in LT patients with allograft dysfunction from advanced fibrosis or cirrhosis, and should be avoided in such scenarios.

Residual Spontaneous Portosystemic Shunts

Spontaneous portosystemic shunts (SPSS) are found in approximately 40% of patients with cirrhosis, and are expected to resolve following normalisation of portal pressures post-LT [51]. However, SPSS can persist post-LT if greater than 10 mm in diameter or with increased portal resistance (e.g. ischaemic-reperfusion injury, ACR, vascular complications) [52]. Residual SPSS can lead to a ‘portal steal’ phenomenon, whereby hepatofugal flow reduces portal perfusion leading to allograft dysfunction and portal vein complications [52]. Drugs such as budesonide bypass the liver and first-pass metabolism, resulting in reduced efficacy and higher systemic adverse effects. This phenomena is reflected in a case of budesonide-induced hyperosmolar hyperglycaemic state in a patient without pre-existing diabetes, following transjugular intrahepatic portosystemic shunt insertion for management of non-cirrhotic portal hypertension [53]. However, there is currently no consensus of a size threshold above which a SPSS is considered clinically significant. A recent retrospective analysis in living donor LT recipients found pre-LT portal vein thrombosis and a spleno-renal shunt diameter greater than 15 mm, to be independent predictors for post-LT portal complications [54]. In the absence of a clear definition of clinically significant SPSS, we suggest budesonide be used with caution in patients with large residual SPSS post-LT, particularly if greater than 15 mm in diameter.

Drug and Food Interactions

Although therapeutic drug monitoring is not required for budesonide, drug and food interactions may occur due to the dependence on CYP 3A4 for drug metabolism. Strong CYP 3A4 inhibitors such as protease inhibitors (e.g. ritonavir), azole anti-fungals (e.g. ketoconazole) and macrolide antibiotics (e.g. erythromycin) can prevent budesonide first-pass metabolism and thus increase its systemic exposure [17]. Cyclosporin, a CYP 3A4 inhibitor, can inhibit the formation of budesonide metabolites in vitro, however this yet to be demonstrated in vivo and thus the clinical relevance is unclear [55]. Interactions with other commonly used immunosuppressants post-LT have not been reported. Food items containing furanocoumarins (e.g. grapefruit juice) can also inhibit CYP 3A4 and increase systemic availability if taken in conjunction with budesonide [17]. Thus, patient counselling and careful review of concomitant medications is required prior to budesonide administration to avoid potential drug and food interactions.

Conclusion

There is a strong clinical rationale for corticosteroid-sparing immunosuppression following LT due to the increasing medical complexity and survival of LT recipients, with high rates of concomitant metabolic syndrome. Given the mixed results surrounding corticosteroid-free protocols, budesonide is an attractive alternative to conventional corticosteroids. Despite the pharmacokinetics of budesonide resulting in an improved therapeutic to toxicity ratio, and its use in other liver and gastrointestinal conditions, there have been surprisingly few studies investigating its application in the LT setting. The current LT literature is limited to small retrospective studies and case series which use variable doses of budesonide and lack direct comparison to conventional corticosteroids. Larger, randomised controlled trials investigating the potential use of budesonide as an alternative immunosuppressant post-LT are required.