, Volume 54, Issue 6, pp 925-975
Date: 24 Oct 2012

Tacrolimus

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Summary

Synopsis

Tacrolimus (FK 506) has been evaluated as immunosuppressive therapy in patients with a variety of solid organ and other transplants. Extensive data have now confirmed its efficacy as primary or rescue therapy in renal and hepatic transplantation. In prospective and historically controlled studies of primary therapy, tacrolimus generally demonstrated greater efficacy than the conventional formulation of cyclosporin for preventing episodes of acute rejection and allowed reduction of corticosteroid use. Chronic rejection rates were also significantly lower with tacrolimus in a large randomised liver transplantation trial. However, patient and graft survival rates were similar in both treatment groups (although numerically larger in adults with liver transplants). In children, rejection rates and corticosteroid requirements were usually lower with tacrolimus and patient and graft survival were generally similar with the 2 immunosuppressants. The finding of reduced corticosteroid requirements with tacrolimus may be of particular benefit in prepubertal children, who are still growing.

A small amount of evidence has also accumulated regarding the use of tacrolimus as primary therapy in patients who have undergone bone marrow or heart and/or lung transplantation. Data are not conclusive, particularly in children, but tacrolimus appears to be useful for treating patients who have undergone these organ transplantations and may be associated with a lower incidence of obliterative bronchiolitis than cyclosporin in the latter group. Potential efficacy has also been shown in a limited number of patients with pancreas or pancreas-kidney, pancreatic islet and intestinal or multivisceral transplants, and in children who have undergone heart or heart-lung transplantation. Tacrolimus also has a use as rescue therapy in bone marrow, heart, lung and pancreatic transplantation, but data are currently insufficient for conclusions to be made. However, these results support the need for further study in these populations.

Adverse effects occurring during tacrolimus therapy are generally of the type common to all immunosuppressive regimens. However, diabetes mellitus, neurotoxicity and nephrotoxicity are more common in tacrolimus than cyclosporin recipients. Hyperlipidaemia, hypertension, hirsutism and gingival hyperplasia are more common with cyclosporin. In 2 large multicentre clinical trials (US liver and European renal), tacrolimus was discontinued more frequently during the first year because of adverse events. However, the tolerability of tacrolimus appears related to dosage, improving as the dose is reduced.

Tacrolimus should be considered an effective primary immunosuppressant in renal and hepatic transplantation. The drug is also a useful agent for rescue therapy in patients experiencing rejection or poor tolerability to cyclosporin. Thus, tacrolimus provides the clinician with an effective option for patients requiring immunosuppression and, with a different tolerability and efficacy profile to cyclosporin, it will better allow the tailoring of therapy to meet the needs of individual patients.

Pharmacodynamic Properties

Although structurally unrelated, tacrolimus (FK 506) and cyclosporin have similar and well characterised cellular effects. Tacrolimus exerts potent inhibitory effects on T lymphocyte activation. It binds specifically to immunophilins termed FK 506 binding proteins (FKBP), and signal transduction pathways in T cells are interrupted by the tacrolimus-FKBP12 complex. At in vitro concentrations 10 to 100 times lower than that of cyclosporin, tacrolimus inhibits transcription of early T cell activation genes for interleukin (IL)-2 and other growth-promoting cytokines, tumour necrosis factor (TNF)-α and proto-oncogenes; it also suppresses the expression of IL-2 and IL-7 receptors. Tacrolimus also inhibits the mixed lymphocyte reaction, generation of cytotoxic T cells and T cell-dependent B cell activation. The secondary proliferation of activated T cells in response to IL-2 is not inhibited by tacrolimus, nor does the drug interfere with antigen presentation or modify mononuclear phagocyte or natural killer cell function.

Tacrolimus may differ from cyclosporin with regard to its effects on transforming growth factor (TGF)-β, high levels of which have been implicated in chronic renal allograft rejection. Whereas cyclosporin increases levels of TGF-β, tacrolimus does not seen to greatly alter these levels in patients with renal allografts.

Tacrolimus may also inhibit cellular activities such as nitric oxide synthetase activation, cell degranulation and apoptosis, and potentiate the action of glucocorticoids.

Nephrotoxicity is a serious adverse effect of both tacrolimus and cyclosporin. These agents produce virtually indistinguishable clinical and histological changes. Most patients treated with tacrolimus develop elevated serum creatinine levels, and although dosage adjustment may reduce nephrotoxicity, whole-blood drug concentrations do not correlate well with renal function. In patients with renal allografts, early morphological markers of tacrolimus-induced nephrotoxicity include tubular and myocyte vacuolation whereas long term changes include interstitial fibrosis and arteriolar hyalinosis. Increased endothelin levels have been implicated in post-transplant renal vasoconstriction.

Marked reductions in biliary acid secretion and bile flow in T-tube bile were seen in the immediate post—liver transplantation period in patients receiving either tacrolimus or the conventional formulation of cyclosporin. However, biliary secretion rates increased to normal levels with time and, in 1 report, improvement was faster with tacrolimus than with cyclosporin.

In animals, tacrolimus stimulated hepatic regeneration after partial hepatectomy. This effect was organ specific and was not seen in animals after partial nephrectomy or intestinal resection.

Immunosuppressive therapy is associated with diabetogenic effects. Although tacrolimus has also been shown to produce these effects (see tolerability summary), the exact mechanism(s) of action remains to be elucidated. In animals, tacrolimus inhibited insulin gene transcription in vitro, possibly via interruption of a calcium-mediated signalling pathway.

In renal or hepatic transplant recipients, tacrolimus generally caused significantly smaller changes in total and low density lipoprotein cholesterol than cyclosporin.

Pharmacokinetic Properties

Assessment of the pharmacokinetics of tacrolimus is greatly affected by the biological fluid analysed, the analytical method used and the duration of study. Whole blood appears to be the most appropriate medium for assessing the pharmacokinetics of tacrolimus.

Absorption of tacrolimus is variable after oral administration and oral bioavailability is poor. In most patients, maximum plasma or blood concentrations are reached after about 0.5 to 1 hour, although some patients have a flat absorption profile (overall mean time to maximum concentrations of about 2 hours). Complete biliary diversion or addition of bile salts does not appear to have a significant effect on the oral bioavailability of tacrolimus. Therefore, oral therapy does not need to be overlapped with intravenous therapy in adults, as is the case for the conventional formulation of cyclosporin.

Tacrolimus is highly bound to plasma proteins, primarily α1-acid glycoprotein and albumin. It also binds to erythrocytes and lymphocytes. High concentrations of tacrolimus are detected in organs such as the lungs, spleen, heart, kidney, pancreas, brain, muscle and liver in animals, but the drug has not been detected in the CSF.

Tacrolimus is mainly metabolised in the liver (and to a lesser extent, the gut), by the cytochrome P450 CYP3A4 isoenzyme, to at least 15 metabolites. Less than 1% of an intravenous dose of tacrolimus undergoes urinary excretion as unchanged drug, with renal clearance accounting for <1 % of total body clearance. The main excretory pathway of tacrolimus metabolites is biliary.

Clearance of tacrolimus appears to be higher in children than adults; therefore children require higher mg/kg doses of the drug. Clearance of the drug is reduced in patients with marked hepatic impairment compared with those with normal hepatic function.

Clinical Efficacy

Tacrolimus is an established immunosuppressant agent for primary and rescue therapy in patients with liver and kidney transplants. It has also been investigated in transplantation of many other types of organ, including heart, lung or heart-lung, pancreas with or without kidney, pancreatic islet and intestine with or without other organs, and in preventing graft versus host disease (GVHD) after bone marrow transplantation (BMT). Protocols for tacrolimus as primary immunosuppression or as rescue therapy varied depending on the type of graft and many included corticosteroids with or without azathioprine and, less frequently, an antilymphocyte agent. The conventional formulation of cyclosporin was used in all the comparisons of this drug and tacrolimus that are discussed.

Hepatic Transplantation: Tacrolimus produces graft survival (>70%) and patient survival (>80%) rates at 1 year and retransplantation rates that do not differ significantly from those with cyclosporin. Likewise, after 3 and 5 years graft and patient survival rates do not differ significantly between tacrolimus and cyclosporin (although rates are numerically higher with tacrolimus). However, a large randomised study demonstrated a trend toward improved 3-year patient survival with tacrolimus. Individual studies of tacrolimus have reported graft and patient survival rates of 64.5 and 71.1%, respectively, at a mean follow-up of 78 months and, in US veterans (a high-risk group), 77 and 84% at 4 years.

Tacrolimus offers several advantages over cyclosporin, such as significantly lower acute and refractory rejection rates, a steroid-sparing effect and earlier conversion to oral therapy. Indeed, refractory rejection occurred about 5 times more often with cyclosporin. Additionally, fewer patients receiving tacrolimus are switched to the alternative therapy because of rejection. Chronic rejection rates were also significantly lower during tacrolimus therapy than during cyclosporin therapy in 1 large multicentre trial.

Chronic hepatitis C virus (HCV) infection with cirrhosis is a major indication for liver transplantation and its recurrence, which occurs in up to half of graft recipients after transplantation, may be associated with a poor prognosis. Patient and graft survival rates in a randomised US multicentre study did not differ between patients with HCV given tacrolimus and those given cyclosporin at 3 years. However, at 5 years, the patient survival rate was significantly higher in patients with HCV receiving tacrolimus than in those receiving cyclosporin. A small randomised trial and 2 nonrandomised comparisons have demonstrated higher rates of acute and steroid-resistant rejection in patients with HCV receiving tacrolimus, and in 1 trial cumulative 1 — to 7-year survival was higher with cyclosporin.

Chronic hepatitis B virus (HBV) infection recurs in almost all patients after transplantation and indicates a very poor outcome. Survival was 73% at a median of 24 months (31 of the 57 survivors had HBV recurrence) in 78 patients with HBV liver disease who received tacrolimus plus corticosteroids as primary immunosuppression in 1 retrospective analysis. When tacrolimus was compared with cyclosporin in small trials, somewhat higher rates of acute rejection (52 vs 36.5%) and decreased survival rates were seen with tacrolimus. Analysis of a subgroup of patients with fulminant hepatic failure from the randomised prospective European trial revealed similar graft and patient survival rates in tacrolimus (n = 32) and cyclosporin (n = 23) recipients but lower rates of acute and chronic rejection with tacrolimus.

Tacrolimus has an established role as rescue therapy in hepatic allograft recipients with steroid-resistant acute or chronic rejection or drug toxicity. Graft survival is ≥65% and patient survival is >75% at 1 year in patients with acute or chronic rejection who receive tacrolimus rescue therapy. Graft and patient survival rates in patients with chronic rejection appear to be close to those seen overall in patients receiving tacrolimus rescue for any reason. Long term (6 years) graft and patient survival rates were about 50% in 1 study. The rate of graft survival in patients with chronic rejection is halved if total bilirubin levels are high (≥60 mg/L).

Similar results to those found in adults have been reported in children, although evidence is less substantial in this population. In children receiving tacrolimus, 1-year graft survival rates of ≥70% are achieved and patient survival rates are ≥80%. 78% of children receiving tacrolimus did not need steroids at 5 years at the University of Pittsburgh. Patient and graft survival rates in children receiving tacrolimus rescue therapy are similar to those seen in adults, with 1-year graft and patient survival rates of >70 and about 80%, respectively. The longest follow-up information available (5 years) shows a graft survival rate of 66.5%, with steroids withdrawn in 84% of children. In smaller studies, the response to rescue therapy with tacrolimus was generally good in children with acute rejection but poor in those with chronic rejection.

Renal Transplantation: Tacrolimus is an effective immunosuppressant for patients who have undergone renal transplantation. In 395 patients, the addition of azathioprine to a tacrolimus plus prednisone regimen did not increase 1- and 2-year survival rates (actuarial patient survival rates were ≥90% and graft survival rates were ≥79% for both regimens). Three-year graft survival rates were higher in patients given tacrolimus and prednisone than in those who received all 3 agents (84 vs 76%). Graft and patient survival is greater in individuals maintained on steroid-free immunosuppressive regimens than in those requiring steroids. 49% of tacrolimus recipients with successful transplants were weaned from corticosteroids at 20 months and 69% at 33 months in 1 trial. Graft origin (from living related donors or cadavers) does not appear to significantly alter 3-year patient or graft survival; however, 2-year results of another trial showed a cadaveric donor to be a risk factor for rejection.

Graft and patient survival rates at 1 year were similar with cyclosporin- and tacrolimus-based regimens, but acute or corticosteroid-resistant rejection occurred less frequently with tacrolimus. Chronic rejection rates did not differ significantly between tacrolimus and cyclosporin recipients, and about 12.5% of grafts failed in each treatment group.

Tacrolimus is effective as rescue therapy for patients who have refractory acute renal allograft rejection episodes during cyclosporin prophylaxis. Rates of graft survival are about 75% and patient survival was >90% at 1 and 2 years. The success of tacrolimus rescue therapy is likely to be influenced by the level of pre-conversion kidney function and the time to tacrolimus conversion. Although low serum creatinine levels are predictive of a better outcome, poor renal function does not prevent success. The steroid-sparing effect of tacrolimus is also demonstrated during rescue therapy.

Very good efficacy has been demonstrated for tacrolimus therapy in children, with 1-year patient and graft survival rates reported as 100% and >90%, respectively, during tacrolimus-based double or triple therapy. These rates were similar to those obtained in historical controls given cyclosporin. Although 1 trial showed acute rejection to be more common in tacrolimus recipients than in patients receiving cyclosporin, more recent data suggests that the acute rejection rate with tacrolimus has decreased as experience with the drug has increased. Graft origin does not influence efficacy. Steroid withdrawal was possible in >70% of children during tacrolimus prophylaxis.

Few data are available concerning use of tacrolimus as rescue therapy in paediatric patients with renal allografts, although they do suggest that the drug has efficacy in reversing rejecdon in these patients.

Thoracic Organ Transplantation: In patients with heart transplants enrolled in prospective trials, survival rates were similar with tacrolimus- and cyclosporin-based regimens, but tacrolimus was generally associated with a lower rate of acute rejection. Survival was about 90% at 1 year and about 75% at 5 years with both treatments. The percentage of patients free from coronary angiopathy was also similar with both treatments. When compared with patients who received a cyclosporin regimen that did not include antilymphocyte antibody agents, tacrolimus recipients had a lower rate of acute rejection, fewer associated steroid boluses and fewer episodes of acute rejection requiring lympholytic treatment per 100 patient-days in the largest trial in heart transplantation. In contrast, these differences were not detected when tacrolimus was compared with a cyclosporin regimen that did include induction with an antilymphocyte antibody agent in the same study.

Limited evidence suggests that tacrolimus is effective for treating episodes of acute rejection refractory to cyclosporin. Small numbers of patients with intractable episodes of acute rejection during cyclosporin therapy responded to conversion to tacrolimus treatment. The actuarial survival rate and number of individuals completely free of acute rejection in a retrospective analysis of patients with acute rejection refractory to cyclosporin was higher with tacrolimus than with muromonab CD3.

Data are scarce concerning use of tacrolimus in children undergoing heart transplantation. The most complete report available indicates an overall survival rate of 92% perioperatively and 82% at 1 and 3 years in 26 children (10 with cardiomyopathy, 16 with congenital heart disease) receiving primary immunosuppression with tacrolimus and low-dose corticosteroids. In a retrospective comparison with cyclosporin-based triple therapy and antithymocyte globulin induction, the actuarial rate of freedom from rejection (grade 3A or higher) was greater with tacrolimus therapy at 3 and 6 months. 85% of tacrolimus recipients and no cyclosporin recipients were weaned from steroids. Tacrolimus has also been successfully used as rescue therapy in small numbers of children with persistent grade 2, 3A or 3B rejection during cyclosporin therapy.

Tacrolimus may offer an advantage over cyclosporin in reducing the risk of obliterative bronchiolitis (chronic rejection) in patients undergoing lung transplantation. It may also be associated with a lower rate of acute rejection episodes. However, in a randomised trial, 1- and 2-year patient survival rates did not differ between tacrolimus and cyclosporin. Case reports also suggests that tacrolimus is effective as rescue therapy in patients with lung or heart-lung transplants who experience acute rejection during cyclosporin therapy. The drug may also be beneficial in children who have undergone lung or heart-lung transplantation, although experience is too limited for any conclusions to be drawn.

Pancreas or Pancreas-Kidney Transplantation: 18-month results from 250 patients suggest the drug is effective as primary therapy in pancreas transplantation. Rejection-associated graft loss was low in this series of patients who underwent pancreatic transplantation with or without kidney or BMT. Patient and pancreas graft survival rates were 95 and 85% at 18 months in 215 patients who did not undergo BMT (concurrent BMT reduced these rates).

Results of indirect comparisons suggest that rejection is less frequent and graft survival is higher with tacrolimus than with cyclosporin, particularly in patients who have undergone simultaneous kidney and pancreas transplantation.

As rescue therapy for rejection, tacrolimus produces a high rate of graft salvage: 18-month overall patient and pancreas graft survival rates of 92 and 80% have been reported. Patients experiencing cyclosporin nephrotoxicity have also benefited from tacrolimus therapy.

Pancreatic Islet Transplantation: Grafting of pancreatic islet cells to replace the endocrine function of the pancreas is an alternative to whole pancreas transplantation. However, this procedure is still experimental in humans and, understandably, experience with tacrolimus is limited. Nonetheless, some success (e.g. stabilisation of diabetes or withdrawal of insulin) has been achieved in small numbers of patients with insulin-controlled diabetes mellitus who received intrahepatic islet allografts with tacrolimus immunosuppression.

Intestinal With or Without Other Organ Transplantation: Primary immunosuppression with a regimen of tacrolimus plus corticosteroids, and in some institutions prostaglandin E, is common in patients who undergo small bowel transplantation, although few results from clinical trials are available. Actuarial graft survival rates of 51 to 65% at 1 year and 29 to 38% at 3 years were obtained in patients enrolled in the intestinal transplant registry who received tacrolimus. Patient survival rates were 59 to 83% at 1 year and 40 to 47% at 3 years. Graft survival rates were lower in patients who received cyclosporin. These 170 patients underwent small bowel transplantation only, small bowel plus liver grafting or multivisceral transplantation and received either tacrolimus or cyclosporin. Rejection, the main complication of intestinal allograft transplantation, developed in 72% of a series of 43 patients given 45 intestinal transplants and immunosuppression with tacrolimus.

Graft versus Host Disease in Bone Marrow Transplantation: An increasing, though still limited, amount of data is accumulating to support the use of tacrolimus as prophylaxis against GVHD in patients who undergo BMT.

Acute GVHD developed in 41% of patients who received tacrolimus monotherapy after matched related donor BMT in a small trial (27 patients); combining methotrexate with tacrolimus results in increased efficacy of the regimen in other trials (11 and 14% rates of GVHD reported with this combination), although this requires confirmation. Chronic GVHD occurred in 20 to 33% of patients and relapse rates for leukaemia were about 7 to 18% in patients receiving any tacrolimus regimen. The event-free survival rate was 50% in the study with the longest follow-up (median of 14 months after transplantation).

Allogenic BMT from matched unrelated donors has a much higher risk of complications than transplantation using matched related donors. The incidence of acute GVHD in patients receiving tacrolimus and methotrexate after unrelated donor BMT ranged from 34 to 50% in small noncomparative or comparative trials. Chronic GVHD developed (in 2 studies) in 48 and 59% of these patients and disease relapse was reported in about 6 to 23%. The 2-year probability of disease-free survival (DFS) was 32% in patients receiving tacrolimus monotherapy, but was higher in patients with low-risk (65%) versus high-risk (4%) disease.

Limited evidence from short term pilot studies (usually conducted in patients who had received related donor BMT) suggests that tacrolimus can be used in the treatment of established acute or chronic GVHD resistant to other therapies. In 1 group of 17 patients with chronic GVHD, survival was 65% at a mean follow-up of 8.4 months.

Tolerability

Adverse events associated with tacrolimus have gready affected the optimal dosage regimen of the drug. The established dosage of the drug is now lower than that used in early clinical trials (as well as initially in some more recent trials) and, in general, this lower dosage is associated with a reduced incidence of adverse effects.

Most of the adverse effects of tacrolimus are common to other immunosuppressive therapies. These include neurotoxicity, nephrotoxicity, increased risk of infection and malignancy, diabetogenic effects and a lymphoproliferative disorder related to Epstein-Barr virus. The tolerability of tacrolimus is similar in adults and children, although children apparently tolerate higher dosages of the drug but are at increased risk of lymphoproliferative disorders. However, the incidence of lymphoproliferative disorders in paediatric patients receiving tacrolimus has decreased as experience with the drug has increased. Type of transplantation does not seem to greatly affect the tolerability profile of tacrolimus. After the first year of treatment (years 2 to 5), few new-onset adverse events were reported with tacrolimus or cyclosporin.

The most common adverse events associated with both oral and intravenous use of tacrolimus are tremor, headache, diarrhoea, hypertension, nausea and renal dysfunction. Hyperkalaemia, hypomagnesaemia and hyperuricaemia have also been reported. In the largest trial of patients with renal transplants receiving tacrolimus, the incidence of new-onset diabetes mellitus was 18%, although some patients could be weaned off insulin, leaving a final incidence of 10%. Although hypertension is commonly reported with tacrolimus, it is usually mild or moderate. However, some patients require antihypertensive therapy.

During the first year of treatment, more tacrolimus than cyclosporin recipients were withdrawn from both the US liver transplantation study and the European renal transplantation study because of adverse events, most commonly nephrotoxicity, neurotoxicity, cardiovascular complications, infection and diabetes mellitus. Alopecia, anaemia, anorexia, diarrhoea, hyperkalaemia, nausea, paraesthesia, pruritus, tremor and vomiting were all more common with tacrolimus than cyclosporin in the US trial. Tacrolimus was also associated with significantly more hyperglycaemia and new-onset diabetes mellitus than cyclosporin in a number of large studies. Diabetes mellitus was reversible in 40 to 50% of patients either with or without discontinuation of tacrolimus. Other events that were more common with tacrolimus than cyclosporin in these studies include nephrotoxicity, insomnia and headache.

Overall, cardiovascular disorders were reported with similar frequency in tacrolimus and cyclosporin recipients, but angina pectoris was more common with tacrolimus and arrhythmia was more common with cyclosporin.

Adverse events that occurred significantly more commonly with cyclosporin than with tacrolimus include hirsutism, gingival hyperplasia, constipation, hyperlipidaemia, hypercholesterolaemia and, in heart transplant recipients, new-onset hypertension.

Drug Interactions

As with cyclosporin, potential drug interactions are numerous with tacrolimus because the drug is metabolised mainly by the cytochrome P450 isoenzyme CYP3A enzyme system. Drugs that induce or inhibit this enzyme system may affect blood concentrations of tacrolimus, and so monitoring of whole blood tacrolimus concentrations and dosage adjustments are recommended when such drugs are administered with tacrolimus. However, very few drug interaction studies have been conducted with tacrolimus.

Care should be taken when coadministering tacrolimus with drugs that are known to be associated with renal impairment. As for other immunosuppressants, live vaccines should not be used in patients receiving tacrolimus.

Dosage and Administration

Dosage recommendations for use of tacrolimus in liver and kidney transplantation are available and those in other indications are likely to be similar. However, treatment regimens vary greatly between individual transplantation centres.

Intravenous administration of tacrolimus is usually unnecessary and should be avoided to minimise the risk of adverse events. If, for clinical reasons, this route is necessary, the starting intravenous dosage is 0.01 to 0.1 mg/kg/day in adults and 0.03 to 0.1 mg/kg/day in children, as a continuous infusion. As soon as possible (usually within 2 to 3 days), oral therapy should be started at a dosage of 0.1 to 0.3 mg/kg/day in adults and 0.15 to 0.3 mg/kg/day in children, as 2 divided doses taken every 12 hours. Black patients may require higher dosages of tacrolimus than White or Asian patients.

Tacrolimus should be started within 12 hours of liver and 24 hours of kidney transplantation, and concomitant use of corticosteroids is recommended early in the post-transplantation period. Dosage adjustments are made on the basis of clinical assessment of rejection and tolerability and on blood concentrations of tacrolimus.

Patients (adult and paediatric) with hepatic or renal dysfunction should be started on the lowest recommended dosages of the drug. Indeed, reductions in dosages below the recommended ranges may be required and patients should be closely monitored. In patients with post-operative oliguria, therapy with tacrolimus should be delayed for up to 48 hours.

Tacrolimus and cyclosporin should not be administered concomitantly, and 12 to 24 hours should elapse between doses if one of these agents is to replace the other.

Various sections of the manuscript reviewed by: L. Bäckman, Division of Transplantation and Liver Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden; H. Corey, Atlantic Health System’s Children’s Kidney Center, Morristown Memorial Hospital, Morristown, New Jersey, USA; R.D. Dowling, Department of Surgery, University of Louisville, Louisville, Kentucky, USA; C. Mignat, Institut für Pharmakologie, Klinikum der Christian-Albrechts-Universität zu Kiel, Kiel, Germany; P.J. Morris, Nuffield Department of Surgery, University of Oxford, Oxford, England; R.E. Morris, Falk Cardiovascular Research Center, Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California, USA; J.D. Pirsch, Department of Surgery, University of Wisconsin-Madison Medical School, Madison, Wisconsin, USA; K.-P. Platz, Department of Surgery, Virchow Clinic, Humboldt University Berlin, Berlin, Germany; R. Shapiro, School of Medicine, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; H.E. Wilczek, Department of Transplantation Surgery, Karolinska Institute, Huddinge Hospital, Huddinge, Sweden.