Eur J Cardiothorac Surg 2001;19:690-695
© 2001 Elsevier Science NL
Tacrolimus as a rescue immunosuppressant after heart transplantation
Michele De Bonis,
Lindsay Reynolds,
Junnet Barros,
Brendan P. Madden
Department of Cardiothoracic Surgery, St. George's Hospital, Blackshaw Road, London SW17 0QT, UK
Received 12 October 2000;
received in revised form 5 February 2001;
accepted 9 March 2001.
Corresponding author. Tel.: +44-208-725-1094; fax: +44-208-725-0360.
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Abstract
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Objective: The purpose of this retrospective study is to review our experience with tacrolimus as a rescue immunosuppressant for heart transplant recipients with refractory rejection or cyclosporine intolerance. Methods: From June 1995 to November 1998, 15 cardiac transplant recipients were converted from our standard cyclosporine-based immunosuppressive regimen to a tacrolimus-based treatment. Each patient had been treated with cyclosporine, azathioprine and steroids. Six were switched to tacrolimus for persistent rejection, four for recurrent acute rejection and five for severe debilitating side-effects attributed to cyclosporine. All ten patients converted to tacrolimus because of rejection had been treated with high-dose methylprednisolone intravenously and four had also received anti-lymphocyte globulin (ALG; one patient) or anti-thymocyte globulin (ATG; three patients) preparations. Results: The time between transplantation and conversion to tacrolimus ranged from 44 to 1866 (median, 380) days. The range of follow-up after conversion was 84–1379 (median, 806) days. Eleven patients are alive with a follow-up period of 764±435 (median, 820) days. Four patients died between 90 and 930 (median, 464) days after conversion. The average number of episodes of acute rejection/recipient decreased from 2.1±1.6 on the cyclosporine regimen to 0.2±0.4 on the tacrolimus regimen (P<0.001). When the incidence of acute rejection was normalized for follow-up times (episodes/100 patient-days), the results were 1.1±1.4 and 0.07±0.2, respectively (P<0.01). The persistent/recurrent rejection resolved in all ten patients who were converted to tacrolimus. None of the five cyclosporine intolerant patients converted to tacrolimus experienced rejection after the changeover. Conclusions: In our experience, conversion from a cyclosporine-based to a tacrolimus-based maintenance immunosuppression has been shown to be an effective and safe approach to the management of patients with persistent or recurrent cardiac allograft rejection or those with cyclosporine intolerance.
Key Words: Heart transplantation, Refractory rejection • Tacrolimus • Rescue immunosuppression
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1. Introduction
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Triple drug immunosuppression regimens, including cyclosporine, azathioprine and prednisone, have greatly improved survival after cardiac transplantation. However, despite the success of this treatment, 10–15% of patients on cyclosporine-based immunosuppression develop persistent or recurrent allograft rejection resistant to corticosteroids and/or antilymphocyte therapy [1,2]. In addition, some patients experience cyclosporine intolerance because of severe and debilitating adverse effects [3]. Tacrolimus may be an effective alternative for patients who develop problematic graft rejection or side-effects while on cyclosporin. It has been effective as a rescue therapy in renal [4], hepatic [5], lung [6] and heart [2,7,8] transplant recipients.
In this study, we retrospectively reviewed our experience with tacrolimus as a rescue immunosuppressant for heart transplant recipients with acute allograft rejection refractory to augmented conventional therapy or for those who had cyclosporine intolerance.
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2. Materials and methods
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2.1. Patients
Since 1986, 324 orthotopic heart transplantations were performed at St. George's Hospital, London. From June 1995 to November 1998, 15 patients were switched from our standard cyclosporine-based immunosuppressive regimen to a tacrolimus-based treatment because of recurrent (four patients) or persistent (six patients) steroid-resistant cellular rejection or significant morbidity (myalgia, arthralgia, nausea, vomiting, headache, dizziness) related to cyclosporine (five patients). A retrospective review of these patients was undertaken.
All patients had been receiving cyclosporine during the 30 days before conversion, all but one patient received azathioprine and seven patients received oral prednisolone. All ten patients converted to tacrolimus because of rejection had been treated with high-dose methylprednisolone intravenously and four of them had also received anti-lymphocyte globulin (ALG; one patient) or anti-thymocyte globulin (ATG; three patients) preparations (Table 1).
2.2. Immunosuppression regimen
All patients initially received standard therapy with cyclosporine, azathioprine and prednisolone. Cyclosporine A was commenced when haemodynamics were stable, without evidence of hepatic or renal failure (serum creatinine of <180 µmol/l) to achieve target blood levels of 300–500 ng/ml for the first 4 weeks, 200–250 ng/ml from 4 weeks to 6 months, 150–200 ng/ml from 6 months to 1 year, and 100–150 ng/ml after 1 year.
Azathioprine was administered at anaesthetic induction (2 mg/kg IV) and post-operatively at a dose of 2 mg/kg per day. If the leucocyte count fell below 4000x109/l or the patient developed thrombocytopenia, cholestatic jaundice or pancreatitis, azathioprine was stopped.
Methylprednisolone (1000 mg intravenously) was administered intra-operatively at the release of aortic cross-clamp and continued with three subsequent doses of 125 mg IV at 12-h intervals. Thereafter, oral prednisolone (60 mg/day) was given, decreasing by 5 mg each day until a cyclosporine level of 300 ng/ml was attained. Maintenance oral prednisolone was continued for the first 3 post-operative months and weaned afterwards whenever possible.
2.3. Diagnosis and treatment of acute rejection
Acute rejection was definitively diagnosed by endomyocardial biopsy (EMB) or by a combination of clinical examination, electrocardiography, echocardiography and radiography. The policy of our centre was to treat International Society for Heart and Lung Transplantation (ISHLT) biopsy grade 3a or above. Grade 2 biopsies or lower were treated if this correlated with symptoms or investigations suggestive of rejection, or evidence of haemodynamic deterioration. Acute rejection episodes were treated with intravenous methylprednisolone 1000 mg daily on three consecutive days and optimization of cyclosporine and azathioprine doses. If acute rejection occurred more than 6 months after transplantation, intravenous steroids were followed by oral prednisolone at a dose of 60 mg/day, reducing this by 5 mg/day to 10 mg/day maintenance. Subsequent episodes of acute rejection were treated with antilymphocyte therapy in some patients. Ten heart transplant recipients with biopsy-proven persistent or recurrent acute rejection grade 3a or higher were converted from a cyclosporine- to a tacrolimus-based immunosuppressive regimen. Persistent steroid-resistant rejection was defined as a rejection in which a biopsy grade of 3a or greater was present on two or more successive biopsies 7–10 days apart, after at least two courses of pulsed intravenous steroids. An increase in the histological grade of rejection or a clinical deterioration after the first steroid pulse was also considered to be representative of persistent steroid-resistant rejection.
Recurrent steroid-resistant rejection was defined as two or more acute rejection episodes treated with augmented immunosuppression occurring within a 3 month period.
2.4. Statistics
Descriptive statistics were used to present the data. The Student's t-test for paired observations was used to compare differences between cyclosporine regimen immunosuppression and tacrolimus mean values. Each patient served as his or her own control after the switch in immunosuppressive agents. The incidence of rejection was measured per 100 patient-days to normalize for the different follow-up times among the recipients. The results are reported as mean values±SD, and P<0.05 was considered significant.
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3. Results
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All patients underwent a simple switch (‘clean conversion’) from cyclosporine to tacrolimus. The time between transplantation and switch to tacrolimus immunosuppression ranged from 44 to 1866 (median, 380) days. Three patients were converted to tacrolimus during the first 3 post-operative months, one between 3 and 6 months, three between 9 and 12 months, five between 12 and 18 months, one at 24 months, one at 48 months and one at 60 months. All previous immunosuppressants, except cyclosporine, were maintained after conversion to tacrolimus. To reduce the risk of drug interactions and combined toxicity, cyclosporine was stopped at least 12 h before the first dose of tacrolimus. No intravenous loading dose of tacrolimus was administered. An oral dose of 0.075 mg/kg per day was given in two divided doses at either 1 h before or 2–3 h after meals. Dose adjustments were made on the basis of trough blood levels. During the first post-operative year, the target levels were 10–20 ng/ml, and for patients 1 year or more post-transplantation, these were 5–15 ng/ml. The mean oral dose of tacrolimus and the corresponding whole blood through levels are shown in Table 2. After conversion, the maintenance therapy was with tacrolimus. The average azathioprine dose was not significantly different after the changeover to tacrolimus, although in three patients, this agent had to be temporarily suspended because of leucopenia. Oral prednisolone was discontinued in four of the seven patients previously treated with maintenance prednisolone. The duration of follow-up after conversion to tacrolimus varied widely: with a mean of 691.8±442.1 days and a median of 806 days (range, 84–1379 days). Two patients were followed up for 2–6 months, three for 6–12 months, two for 16 months, five for 30 months, and three for more than 40 months.
3.1. Survival
Eleven patients are alive with a follow-up period of 764–435 (median, 820) days. Eight of these patients have been weaned off steroids. Four patients died a mean of 493±464 days after conversion (median, 464; range, 90–930 days; Table 3).
3.2. Allograft rejection
Before conversion to tacrolimus, there were 33 episodes of grade 3A rejection in 14 patients. Twenty-five episodes (75.7%) occurred in the first 6 months after transplantation. The results of switching from cyclosporine to tacrolimus on acute rejection in all of the 15 patients of the study group are shown in Table 4. The average number of episodes of acute rejection/recipient decreased from 2.1±1.6 on the cyclosporine regimen to 0.2±0.4 on the tacrolimus regimen (P<0.001). When the incidence of acute rejection was normalized for follow-up times (episodes/100 patient-days), the results were 1.1±1.4 and 0.07±0.2, respectively (P<0.01). None of the five cyclosporine intolerant patients converted to tacrolimus experienced rejection after the changeover. The persistent/recurrent rejection resolved in all ten patients who were converted to tacrolimus. Seven of them experienced a continuous remission from rejection with no further episodes after conversion (Table 5). Three new acute rejection episodes of grade 3a subsequently occurred in three of these patients after conversion. One was in the first week after commencing tacrolimus treatment in a patient with persistent rejection and this was successfully treated with intravenous methylprednisolone followed by oral prednisolone at 60 mg/day, reducing this by 5 mg/day to 10 mg/day maintenance. The second episode occurred 14 days after conversion in a patient with recurrent rejection and this resolved with intravenous ATG administration (1000 mg/day for 3 days). The third patient had a history of recurrent acute rejection and he developed a further acute rejection episode 26 months after conversion. This patient developed a lymphoproliferative disorder and immunosuppression was reduced. He eventually died from acute rejection in spite of intravenous methylprednisolone.
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Table 4. The impact of conversion from cyclosporine to tacrolimus on acute rejection in all 15 patients of the study
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Table 5. The impact of conversion from cyclosporine to tacrolimus on acute rejection in the ten patients converted to tacrolimus because of refractory rejection
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3.3. Allograft function
Allograft function was assessed by history, examination, electrocardiography and echocardiography. Right heart catheterization was performed when clinically indicated. One month before conversion to tacrolimus, the average echocardiographic left ventricular shortening fraction was 27.8±9.7% and the mean ejection fraction was 53.3±18.1%. At the time of longest follow-up after conversion to tacrolimus, the corresponding values were 35±6.2 and 66.5±11,.5%. Although these differences are not statistically significant (P=0.058 and P=0.06, respectively), they show that all recipients experienced stable or improved allograft function after conversion to tacrolimus. No documented coronary artery disease occurred in our study patients.
3.4. Complications of immunosuppression
3.4.1. Infections
The type and nature of the infectious episodes during cyclosporine treatment and tacrolimus ‘rescue’ therapy are presented in Table 6. After switching to tacrolimus, there was no significant difference in the incidence of bacterial, fungal or viral infections.
3.4.2. Hypertension
Eight patients required one or more antihypertensive medications to control blood pressure while receiving triple drug immunosuppression. Since switching to tacrolimus, antihypertensive medications have been discontinued in three patients. The other five patients are well controlled on the pre-conversion agent. No patient developed hypertension following conversion to tacrolimus.
3.4.3. Hyperlipidemia
The total cholesterol values during cyclosporine treatment ranged from 148 to 220 mg/dl (mean, 177.2±23.2) and remained stable after 1 year of tacrolimus therapy (mean, 182.2±31.6; range, 152–240 mg/dl; P=NS).
3.4.4. Renal function
Three patients had moderate to severe renal dysfunction after cyclosporine-based immunosuppression and two required continuous ambulatory peritoneal dialysis (CAPD) before conversion to tacrolimus. Both patients on CAPD subsequently died. Their renal indices before and after conversion were excluded from the comparative analysis. Laboratory values for the remaining 13 patients are presented in Table 7.
3.4.5. Diabetes mellitus
During cyclosporine-based immunosuppression, three recipients developed diabetes mellitus and required insulin therapy. One was a diet controlled diabetic prior to transplantation, two developed new onset diabetes mellitus, but were also on prednisolone (5 mg/day). Diabetes resolved in one patient after weaning off prednisolone. One patient was maintained on oral hypoglycaemic agents and one on insulin therapy before tacrolimus ‘rescue’ treatment began. They were stable following conversion. Two patients developed insulin-dependent diabetes mellitus after conversion to tacrolimus.
3.4.6. Other adverse events
Adverse effects before and after conversion are shown in Table 8. Most were dose related and were successfully managed by reducing the tacrolimus dose. None were significantly severe to warrant stopping tacrolimus.
3.4.7. Malignancy
One patient developed a B cell post-transplant lymphoproliferative disease 2 years after being switched to tacrolimus, and this patient died in spite of a reduction in immunosuppression and high-dose acyclovir.
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4. Discussion
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Cardiac transplant recipients who develop persistent or recurrent allograft rejection or cyclosporine intolerance, present a difficult management problem. Conversion from cyclosporine to tacrolimus is a potential therapy for these patients, which appears to be efficacious and well tolerated [2,7–9]. The immunosuppressive properties of both cyclosporine and tacrolimus result primarily from a selective inhibition of the same enzyme, calcineurin. However, the molecular structure and the cytosolic binding sites of the drugs are different. This may explain why tacrolimus may control ongoing refractory rejection when cyclosporine cannot, or why it may be well tolerated in patients who suffer from cyclosporine morbidity. In our study, both patient and graft survivals were 73.3%. Only one death (6.6%), due to post-transplant lymphoproliferative disease, may have been related to the immunosuppressive effect of tacrolimus. The ten patients of our study with recurrent or persistent rejection had experienced an average of almost three episodes of acute rejection each, refractory to a mean of two courses of intravenous methylprednisolone. After the changeover from cyclosporine to tacrolimus, the frequency and severity of acute rejection decreased significantly. Acute rejection was reversed in all cases. Three patients subsequently experienced a new episode of acute rejection that made further treatment necessary. In the remaining seven patients, remission from rejection was sustained. This is in contrast with the 19% freedom from further rejection episodes, after conversion to tacrolimus, reported by Mentzer [9]. This difference may be due to our concomitant use of other immunosuppressive agents like azathioprine, which was discontinued before conversion to tacrolimus in the other study. It is well known that the incidence of acute rejection is highest early after transplantation and decreases later. Since cyclosporine was prescribed initially and tacrolimus was introduced subsequently, the apparent treatment effect, in this series, could be influenced by the naturally declining risk of rejection over time. However, this tendency is unlikely to be the sole explanation for the observed results. The drug exchanges were made at various times throughout the first 18 months, and the treatment effect was always temporally associated with the conversion to tacrolimus. Furthermore, we have a population of patients who have developed persistent or recurrent acute rejection episodes after transplantation prior to the availability of tacrolimus. Like other centres, we have employed ATG, OKT3 or total lymphoid irradiation with varying success. We have not observed a similar efficacy in terms of control of rejection as that in the present study, and have been concerned about the increased incidence of infection and lymphoproliferative disorders in these patients.
Debilitating side-effects resolved after the discontinuation of cyclosporine. All patients tolerated the introduction of the new agent without significant complications.
After the administration of tacrolimus, allograft function improved or remained stable in most cases. The incidence of infection did not increase in spite of significant immunosuppression before commencing treatment. Hypertension improved when cyclosporine and, in most cases, corticosteroids could be eliminated from the immune suppression regimen. Creatinine and blood urea nitrogen levels (at the longest follow-up time) remained stable or slightly decreased compared with baseline pre-conversion values. This finding of low renal toxicity differs from what has previously been reported by others [7]: in our study, however, the drug was administered at a relatively lower dose compared with other groups, which may account for the difference in the renal toxicity reported. Two patients developed insulin-dependent diabetes following conversion to tacrolimus, but the control of blood glucose was not difficult. The other adverse effects of tacrolimus in our patients were mild and manageable by reducing its dose; notably absent were complaints of gingival hyperplasia or hirsutism. One case of post-transplant lymphoproliferative disease occurred during tacrolimus therapy, although this can also occur in patients taking cyclosporine-based immunosuppression.
We appreciate that this, like most rescue studies, is not a randomized prospective trial and contains small numbers, therefore, definitive conclusions cannot be firmly made. Nevertheless, our experience suggests that conversion from a cyclosporine-based to a tacrolimus-based maintenance immunosuppression regimen is an effective and well tolerated approach to the management of patients with persistent or recurrent cardiac allograft rejection or cyclosporine intolerance.
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Abstract
1. Introduction
