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Right arrow Transplantation - heart

Ann Thorac Surg 2004;77:363-371
© 2004 The Society of Thoracic Surgeons

Review

Drug immunosuppression therapy for adult heart transplantation. Part 2: clinical applications and results

Xavier M. Mueller, MDa*

a Department of Cardiovascular Surgery, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada

* Address reprint requests to Dr Mueller, Department of Cardiovascular Surgery, Centre Hospitalier Universitaire de Sherbrooke, 3001, 12e Avenue Nord, Sherbrooke, Quebec J1H 5N4, Canada
e-mail: xavier.mueller{at}usherbrooke.ca


   Abstract
Top
 Abstract
Induction therapy
 Maintenance therapy
 Acute rejection therapy
 Conclusions
 References
 
This review describes the clinical application of classical immunosuppressive drugs as well as that of more recent drugs. All current immunosuppressive drugs target T-cell activation, and cytokine production and clonal expansion, or both. Immunosuppressive protocols can be broadly divided into induction therapy, maintenance immunosuppression, and treatment of acute rejection episodes.


   Induction therapy
Top
 Abstract
 Induction therapy
Maintenance therapy
 Acute rejection therapy
 Conclusions
 References
 
Induction therapy is a heterogeneous application of perioperative antibody therapy used in combination with a base immunosuppressive regimen in solid-organ transplantation. The use of antibody therapy began as "sequential therapy" with the use of antilymphocyte globulin in the early postransplant course to allow for potent immunosuppression, while the renal graft was allowed to reach baseline function prior to initiating the cyclosporine, which is nephrotoxic [1]. As this concept gained acceptance, longer-term administration (10 to 14 days) of various antilymphocyte antibodies were used and the term "induction therapy" was adopted. Nowadays this concept refers more broadly to the higher dose immunosuppression in the early posttransplantation period, which could confer a state of hyporesponsiveness on the part of the recipient against the transplanted organ and prevent early and late posttransplantation rejection.

Polyclonal antibodies and murine monoclonal CD-3
The ultimate aim would be to inhibit only those T cells that respond to donor antigen, thus achieving immunologic unresponsiveness to the transplant in the face of a fully functional immune system (donor-specific tolerance). The initial effort to achieve this goal was through the use of polyclonal antibody preparations or polyclonal antilymphocyte globulin [2, 3]. The next step toward the goal of selective immunosuppresion occurred when cell hybridization techniques were developed that could yield monoclonal antibodies (mAb) to single-cell membrane determinants [4]; currently murine monoclonal CD-3 (OKT3) is the only mAb that has widespread use in clinical transplantation. Many controversies exist when one considers antibody induction therapy. Its practice is institutional as well as country dependent [5]. Remarkably, no prospective clinical study in unselected heart transplant recipients have compared the prophylactic use of polyclonal or monoclonal preparations with controls using no prophylaxis.

Copeland and colleagues [6] reported their 10-year experience with RATG. In their group of 98 patients, treated with a 3-day course of RATG and maintenance therapy with cylcosporine, steroids and azathioprine, the actuarial survival at 3 years was 88%, and freedom from rejection at 1 year was 30%, from infection was 50%, and from death from rejection was 99%. The number of rejections that occurred in the first 90 days totaled less than one episode per patient. The chance of having a rejection after the first 90 days was 8%. Therefore RATG provided immunosuppressive coverage along with azathioprine and steroids until therapeutic cyclosporine levels were achieved. However, RATG was responsible for the following complications: thigh pain, rash, and weakness (28%); serum sickness as manifested by a fever with polyarthralgias and muscular ache (21%); leukopenia defined as a white blood cell count below 4000/mm3 (3%); and fever of unknown origin during the 2 weeks after RATG administration (18%). RATG was responsible for T-cell counts falling from the normal range (72%–92%) to a mean of 20% at 3 days postoperatively. It remained in that range for the next 3 weeks. More recently, another large retrospective study analyzed the clinical effect of induction of immunosuppression with RATG [7]. Over a 10-year period, 163 patients received a 3-day course of RATG immediately after heart transplantation, and they were compared with a historical group of 48 patients who received oral or intravenous cyclosporine immediately after the transplantation. All the patients were treated with a cyclosporine-based maintenance immunosuppression. At 1 year, the freedom rate from an episode of acute rejection averaged 43% ± 4% in the RATG versus 30% ± 7% in the control group (p = 0.03). Moreover, the risk of infection at 1 year and that of developing cancer at 10 years were not increased. No significant side-effect related to the intravenous injection of RATG was reported in this study.

Several reports compared the efficacy of prophylactic protocols using polyclonal antibody versus OKT3 [8–13]. These studies must be interpreted cautiously because specific polyclonal agents vary, duration of treatment and concurrent immunosuppressive protocols differ, numbers of patients are small, duration of follow-up is limited, criteria for rejection vary, and prophylactic application of OKT3 may induce modified histologic features of rejection [14]. Therefore, it is not surprising that the results have been conflicting. Whereas Renlund and coworkers [8], and Starnes and colleagues [9] reported superiority for OKT3 in time to first rejection episode, overall number of rejection episodes, and linearized rejection rates, the other studies [10–13] found the two preparations essentially equivalent in rejection prevention over extended follow-up.

Routine adjuvant use of OKT3 for induction in all heart transplant recipients has been reported to provide no clear immunologic advantage compared with classical triple-drug immunosuppression alone in retrospective studies [15, 16]. Although some centers have chosen to routinely apply induction therapy and some have avoided it entirely, it is becoming more clear that its least controversial use is in the high-risk recipients. Risk patients can be divided into two groups. Patients with hepatic and kidney dysfunction were demonstrated to be at increased risk of early death after transplantation [17]. In particular, prerenal kidney dysfunction leads to a high rate of dialysis postoperatively with increased incidence of death. Similar to the rationale of development of induction therapy in the early days of kidney transplantation, cytolytic induction therapy has been advocated in such patients in order to allow renal recovery without the burden of nephrotoxic cyclosporine level [18]. Similar findings have been reported with hepatic dysfunction [19, 20]. Second, some patients are at increased risk of rejection, such as in a mismatch situation with retransplantation, and peripartum cadiomyopathy. Polyclonal induction therapy has been reported to counteract this risk in such patients [21].

Further contributing to the controversy of the usefulness of induction therapy with OKT3, some studies have suggested an effect on rejection that is maintained only while antibody therapy is ongoing [22]. Without repeated administration, these agents only delay the time to a first rejection episode without decreasing the overall frequency or severity of rejection [22]. Therefore, this agent appears to induce T-cell anergy and not clonal deletion. Moreover, because of the development of human antimurine antibody (HAMA) response, prolonged or repeated courses are generally not possible.

The downside to the use of induction therapy has been the fear of excessive immunosuppression resulting in infections, and lymphoproliferative disorders, as well as side effects of the antibody preparation including the cytokine release syndrome of OKT3. Available data, all based on retrospective studies, suggest that only OKT3 has a negative impact on the occurrence of infection during the first 6-months after transplantation. However, a reduction in the dose regimen of OKT3 has been demonstrated to reduce the number of infections without affecting the incidence of rejection [23]. Cytomegalovirus is the single most common infectious agent seen early after transplantation. Its increased incidence after induction therapy has been controversial [24, 25]. This controversy has settled with the introduction of gancyclovir in clinical transplantation, which markedly decreased its incidence. An increase incidence of Epstein-Barr virus associated posttransplant lymphoproliferative disorder (PTLD) has been reported following treatment with OKT3 [25]. However, as mentioned in the first part, the progression to lymphoma appears to be related to the intensity of the immunosuppression rather than specifically to any particular agent.

Daclizumab
The most recent attempt to improve efficacy and decrease side effects of antibody therapy has been to use humanized mAb. A lot of antibodies directed at different antigens have been investigated experimentally with promising results. So far, in the field of cardiac transplantation, only daclizumab has been studied in a randomized trial comparing induction therapy with daclizumab versus generalized immunosuppressive therapy [26]. Fifty-patients were assigned to receive either daclizumab within 24-hours after transplantation and every 2 weeks thereafter (for a total of five doses), in addition to standard immunosuppressive therapy including cyclosporine, mycophenolate mofetil, and prednisone, or standard immunosuppresive therapy alone. During induction therapy, the mean frequency of acute rejection episodes was significantly reduced: 0.64/patient in the control group and 0.19/patient in the daclizumab group (p = 0.02). No adverse reaction to daclizumab was reported. However, although treatment with daclizumab decreased significantly the frequency and severity of rejection during the treatment period, after the cessation of the therapy, the frequency of rejection increased to a level similar to that of the control group. This suggests that daclizumab induces T-cell anergy and not clonal deletion, similarly to other mAb-based therapy. However, humanized interleukin-2R (IL-2R) antibody has definite advantages over previous mAb. First it is not functionally immunogenic; on the one hand this improves drug tolerance especially avoiding the "first dose effect" or "cytokine release syndrome," and on the other hand this makes a prolonged course possible, and may permit repeated use of this agent. Secondly, its prolonged half-life of 21 days provides saturation for at least 3 months [27], thereby covering the period at highest risk for cardiac acute rejection [28].

In conclusion, the first clinical trial with heart transplant recipients confirms most of the potential advantages of IL-2R antibodies, which are especially linked to their lack of immunogenicity and their specificity. However, they do not suppress completely the occurrence of acute rejections, probably because of the presence of other cytokines that may act as alternatives for IL-2 in allogeneic response. Studies with larger cohorts are awaited to address the short-term and long-term survival benefits, the incidence of cardiac allograft vasculopathy, and to determine the optimal combination of associated immunosuppressive drugs as well as the optimal dosing schedule with possible repeated use.


   Maintenance therapy
Top
 Abstract
 Induction therapy
 Maintenance therapy
Acute rejection therapy
 Conclusions
 References
 
In the absence of the ideal immunosuppressive drug, maintenance immunosuppression is achieved with combinations of immunosuppressive agents. Combination therapy is intended to minimize the side effects of a single drug while maintaining adequate overall immunosuppresion by targeting multiple steps in T-cell activation. Usually corticosteroids are combined with a calcineurine inhibitor (cyclosporine or tacrolimus), and an antiproliferative agent such as azathioprine or mycophenolate mofetil. The limitation of the current strategies to balance the risks of over-immunosuppression and under-immunosuppression is illustrated by the prediction of 30% to 40% incidence of neoplasia in transplant patients over a period of 30 years [29].

Corticosteroids
Adrenal corticosteroids are global in their assault on the immune system. They were fist used in clinical renal transplantation in 1963 [30], and have been part of the immunosuppression since the early days of cardiac transplantation.

However, concern remains about steroid treatment due to their numerous side effects. The review from the combined ISHLT/UNOS thoracic registry [31] reported the morbidity within the first year of transplantation. Many of them are recognized side effects of prednisone: hypertension (61%), diabetes mellitus (16%), hyperlipidemia (26%), symptomatic bone disease (5%), and cataract (2%). Moreover hypertension, diabetes, and hyperlipidemia may all contribute to the development of graft vasculopathy.

The initial report suggesting that immunosuppression after cardiac transplantation could be achieved without steroids dates back to the mid-1980s [32]. Since then many transplant teams have reported their experience with steroid withdrawal. Despite these excellent reports, nearly 90% of patients continue to receive prednisone at 1-year posttransplant and 70% at 3 years [33].

Several strategies to decrease, or even to avoid, the steroid load have been developed. Some centers have reported their results with immunosuppressive regimen excluding oral steroids completely from the time of transplantation. Katz and associates [34] treated 61% of their patients without any steroids with similar survival, infection and rejections rates, but a much lower incidence of diabetes mellitus, compared with standard triple-drug treated patients. Keogh and coworkers [35] followed-up 112 patients who were randomized to triple-drug therapy or double-drug therapy with cyclosporine and azathioprine. Of the last group, 47% of patients had to be converted to triple-drug immunosuppression because of renal dysfunction or repeated rejection episodes. Survival was excellent in both groups. Rejection was lower with triple-drug therapy in the first 3 months, but did not differ beyond 3 months. Patients with triple-drug therapy had higher serum cholesterol and required more antihypertensive agents. Livi and colleagues [36] reported similar results in another group of 112 patients planned for double-drug therapy. Overall, these studies show that steroid-free immunosuppression is possible in at least half of the patients, is as safe as triple-drug therapy, and has the potential to reduce some of the long-term complications of steroids.

Other investigators used steroids in all patients in the early posttransplant period, and began to wean selected patients after several weeks or months. Taylor and coworkers [37] applied a policy of early steroid withdrawal within 2 months after transplantation, using center-specific indications for steroid withdrawal. They could wean successfully 30% of 374 patients. The group of patients without steroids had lower short-term and long-term mortality, a lower prevalence of late acute rejection, and a lower (but not significant) prevalence of graft vasculopathy. The authors concluded that successful early steroid withdrawal indentifies a subgroup of "immunologically privileged" patients with a low risk for long-term mortality, and is not associated with an increased prevalence of late rejection or clinically significant coronary artery disease.

In order to maintain steroids during the time of greatest risk of rejection, several transplant teams have chosen to wean steroids 6 months or more after transplantation. Olivari and associates [38] indicated a lower incidence of cataract and compression fracture, as well as a lower degree of bone loss in patients weaned from steroids by 6 months, whereas the degree of weight gain, lipid abnormalities, and incidence of hypertension were not modified. Miller and colleagues [39] could wean successfully 82% of 48 patients at an average of 11 months after the transplantation. Seydoux and coworkers [40] changed their standard triple immunosuppressive therapy for steroid dose tapering at the end of the hospital stay until total discontinuation between 6 and 12 months. Since the introduction of this policy, steroid administration could be stopped within the first year in 83% of their patients, without increased incidence of rejection and without effect on weight gain. However, it should be emphasized that weight gain may be explained by the amelioration of global well-being and cannot be attributed to the unique role of steroid administration. Oaks and associates [33] could wean almost 70% of 63 patients by 24 months postransplant with an excellent overall survival at 5 years of 88.3% ± 6%, an actuarial freedom from a first rejection episode of 60.7% ± 6.5% at 6 months, 58.5% ± 6.7% at 24 months, and a low freedom from infection of 76.5% ± 5.7% at 12 months.

Baran and coworkers [41] reported their experience of steroid weaning with a protocol of immunosuppression involving tacrolimus instead of cyclosporine. Among 77 patients receiving tacrolimus and prednisone as primary immunosuppression, 43 patients could be weaned from steroids at a mean time of 246 ± 127 days. Here too, the incidence of rejection was low with a freedom of rejection of 69% at 90 days, and 52% at 1 year.

Calcineurine inhibitors
The calcineurine inhibitors cyclosporine and tacrolimus have become the cornerstone of immunosuppressive therapy in solid organ transplantation. The majority of experience in heart transplantation is with cyclosporine. To minimize its toxic effects, yet maintain adequate immunosuppression, dosage must be adapted to each patient. Monitoring of trough concentration is of primary importance. High doses of cyclosporine, trough levels between 250 and 350 µg/L [42], have been commonly recommended in the initial 6 to 12 months after transplantation. Hausen and colleagues [43] reported similar long-term survival and rejection rate when they compared a group of patients with high (250 to 350 µ/L) and low (150 to 250 µg/L) cyclosporine trough levels, suggesting that a policy of low cyclosporine dosage was safe. This dosage reduction is often associated with preservation or even improvement of renal function. Moreover, the same group [44] compared patients in whom cyclosporine was introduced during the first 2 days versus those in whom cyclosporine was started later, as well as those in whom cyclosporine blood level was less than 150 µg/L from day 0 to 14 versus those in whom the level was more than 150 µg/L. Neither comparison could demonstrate any difference in the rate of rejection and survival. Notably, there is still less agreement about the long-term dosage [45], and no comparative study with heart transplants is available. A recent prospective trial with kidney grafts could indicate that lower cyclosporine concentrations did not have any impact on 5-year graft survival, and was associated with a decrease in the incidence of neoplasia [46]. Better and more consistent bioaviability of Neoral (Novartis Pharmaceuticals, Canada, Dorval, Quebec, Canada) leads to a more reproducible daily exposure to cyclosporine with a significant rise of mean area under the time concentration curve, and of the whole blood trough level [47]. Some centers were reluctant to use this new form because of fear of its potential nephrotoxicity, which could not be substantiated by recent trials [48, 49].

Recent experience with tacrolimus suggests similar efficacy in cardiac transplant recipients. Following a randomized trial at the University of Pittsburgh [50], two other trials in Europe [51] and the United States [52] reported no major differences with cyclosporine in various measures of rejection. However, the side effects profile differ. Although both drugs are of roughly equivalent nephrotoxicity, hypertension, hirsutism, gingival hyperplasia, and hyperlipidemia are more frequent with cyclosporine, and diabetes and neuropathy are increased with tacrolimus. Moreover, alopecia has been documented with tacrolimus, which often regresses with dose reduction. These different side effects profiles may help in the choice of the calcineurine inhibitor: patients with difficult-to-control hyperlipidemia or hypertension may benefit from tacrolimus. In addition, female and pediatric patients may improve compliance and quality-of-life with tacrolimus. Recently, Baran and coworkers [53] could guarantee renal safety with a tailored protocol of tacrolimus administration without increased risk of allograft rejection.

In view of their efficacy, large experience, and identified toxicities, calcineurine inhibitors will likely remain the mainstay of immunosuppressive therapy in the future. One area of research is to try to reduce their toxicity by finding other synergistic agents in order to significantly lower their doses and levels.

Antiproliferatives
Before cyclosporine, conventional immunosuppression was provided by azathioprine and steroids. Despite the lack of randomized, controlled trials demonstrating the efficacy of azathioprine in solid organ transplantation, it has remained part of most immunosuppressive regimens since the beginning of transplantation. Following satisfactory results with steroid discontinuation during the first year after transplantation, Seydoux and associates [54] further simplified their immunosuppressive treatment and systematically withdrew azathioprine at the end of the second year to maintain long-term cyclosporine monotherapy. They compared the 3-year outcome of patients treated with triple-drug immunosuppression (n = 22), and those on a simplified immunosuppressive regimen (n = 25) with cyclosporine monotherapy from the end of the second year onwards. There was no influence of steroid tapering on the incidence of rejection episodes, which were even less frequent in the cyclosporine monotherapy patients. The incidence of infection was significantly decreased with a low immunosuppressive regimen, in particular during the first 12-months after intervention. Moreover, the same group [55, 56] reported that most surgical pathologies after heart transplantation are linked with either the immonusuppressive therapy or the transplantation procedure, further supporting a low-level immunosuppression policy. The overall complication rate after the surgery in this high-risk population was as low as 9%. The influence of this approach on graft coronary disease and oncologic complications deserves further study with larger groups of patients and longer follow-up.

In many centers, mycophenolate mofetil is progressively replacing azathioprine in standard immunosuppression protocols. This policy is substantiated by a randomized, multicontinental trial [57] that demonstrated mycophenolate mofetil decreased both mortality and rejection within the first year after cardiac transplantation. In this study, 650 patients were randomized to receive in addition to cyclosporine and corticosteroids, 3000 mg/day of mycophenolate mofetil or 1.5 to 3 mg/kg per day of azathioprine. The use of mycophenolate mofetil resulted in a significant reduction in both mortality at 1 year (from 11% to 6%, p = 0.03) and the requirement for treatment of rejection within the first 6-months after transplantation (from 74% to 66%, p = 0.03). More patients in the mycophenolate mofetil were rejection free at 6 months (34% vs 26%, p = 0.04), and there was a trend toward lower high-grade rejection incidence (from 53% to 45%, p = 0.06). However, despite reduced antithymocyte antibody use (from 21% to 15%, p = 0.06), patients receiving mycophenolate mofetil had a greater incidence of oportunistic infections, mostly herpes simplex (55% vs 42%, p = 0.02). Although significantly more mycophenolate mofetil-treated patients had diarrhea (45% vs 34%, p = 0.008), more azathioprine-treated patients had leukopenia (39% vs 30%, p = 0.04). These positive results in favor of mycophenolate mofetil were supported by an analysis of the joint UNOS/ISHLT thoracic registry with improved survival persisting at 3 years [58]. Meiser and coworkers [59] emphasized the importance of mycophenolate mofetil therapeutic drug monitoring. They assessed the efficacy of tacrolimus and mycophenolate mofetil as primary therapy following cardiac transplantation. Whereas no correlation was found between tacrolimus blood concentration and acute rejection, mean mycophenolate mofetil plasma levels greater than 3 µg/mL was not associated with rejection. Moreover, steroids could be withdrawn from all patients who completed a 6-month treatment. The authors concluded that the combination of tacrolimus and mycophenolate mofetil could suppress acute rejection with routine therapeutic drug monitoring. However, due to the limited number of patients, further confirmation is needed.

The place of sirolimus in the immunosuppressive regimen is still unclear. A phase III trial investigated the impact of the addition of sirolimus, compared with azathioprine, to a cyclosporine and prednisone regimen in kidney recipients [60]. Sirolimus reduced occurrence and severity of acute rejection episodes with no increase in complications. However, considering the mechanism of action of sirolimus (which is synergistic) with that of azathioprine, those drugs should rather be used in combination. The preliminary results of a large trial comparing SDZ-RAD, a derivative of sirolimus, with azathioprine in heart transplant recipients receiving cyclosporine and corticosteroids have been recently reported [61]. In this trial, involving 634 patients, SDZ-RAD demonstrated superior efficacy compared with azathioprine by decreasing the incidence of acute rejection. Interestingly, in a rat cardiac allograft model [62] sirolimus can prevent and even reverse established graft atherosclerosis, the sine qua non of chronic rejection.


   Acute rejection therapy
Top
 Abstract
 Induction therapy
 Maintenance therapy
 Acute rejection therapy
Conclusions
 References
 
A clear distinction between first-line treatment and rescue treatment of acute rejection should be pointed out here because these terms are sometimes mixed in the literature. The first-line, or primary, treatment is self-explanatory, whereas the rescue treatment involves any type of therapy introduced once the first-line treatment has failed.

Corticosteroids
For many years, high-dose steroid therapy was the sole option for the treatment of acute transplant rejection. This therapy has been demonstrated to be effective in up to 80% of rejection episodes in selected series [63], and today remains the first choice for the first-line treatment of most acute rejection episodes. A pulse of 1-g methylprednisolone intravenously every day for 3 days is generally administered [64]. However, because of the profound immunosuppression and the fear of serious infectious complications, lower doses of 500 mg/day [65] and even 250 mg/day [66] were applied with the same success. In keeping with these findings, low-dose oral prednisone (0.5–1 mg/kg) was demonstrated to be an adequate therapy for most acute rejection episodes with low morbidity [67] and no associated hemodynamic compromise [68]. Recurrent or steroid-resistant rejections demand more potent immunosuppressive intervention. Today a number of potent drugs are available for second-line or even third-line therapy for treating acute rejection.

Polyclonal and monoclonal antibodies
Polyclonal antilymphocyte globulin and, more recently, OKT3 have proven to be very effective in treating steroid-resistant rejection episodes [69]. Initially OKT3 was applied as a rescue therapy before being used as a prophylaxis against acute rejection. When used as a rescue therapy, a course of 10 to 14 days is usually applied. Kremer and colleagues [70] reported a multicentric study involving 35 patients with acute rejection resistant to high-dose steroids, ATG or their combination, who were treated with OKT3. Rejection was reversed in 94% (33/35) with a 6-month actuarial survival rate for patients and allografts of 91% and 82%, respectively. Costanzo-Nordin and associates [71] treated 9 patients in whom rejection was resistant to high-dose steroids plus ATG, and 1 patient with contraindication to this form of therapy. OKT3 led to resolution of rejection in 9 patients and a partial reversal in 1 patient with improvements in echocardiographic and hemodynamic parameters. In 7 patients resistant to high-dose steroids either with or without ATG, Gilbert and coworkers [72] reported 1 death related to the acute rejection episode, 4 patients with complete reversal, and 2 patients with partial reversal of the rejection episode. Havery and associates [73] could reverse acute heart rejection with OKT3 in 102 of 113 patients (90%). Complete reversal was achieved in 63 patients, and partial reversal in 39 patients. No significant differences were noted in reversal rate, and in 12-month graft and in patient survival rates between the patients with one rejection episode and those with two or more rejection episodes. Comparable reversal rates and graft and patient survival rates were achieved in patients whether OKT3 was administered as the primary rejection therapy or as rescue therapy. Overall, on the basis of these experiences, OKT3 appears highly effective in reversing acute cardiac allograft rejection.

However, the same drawbacks of antilymphocytic agents as with induction therapy are to be taken into account. While induction therapy appeared to only delay the time to first rejection episode without repeated administration, rebound of acute rejection episodes have been noted in a significant number of patients after a 10-day course of rescue therapy [74]. Moreover, the rate of infection and the incidence of lymphoproliferative disorders are noted to be even higher after repeated applications of these agents [25, 75]. Together with development of human antihorse or human antimurine antibodies against antilymphocyte globulin or OKT3 precluding repeated courses, these drawbacks have accelerated the demand for newer agents with similar potency and a less ominous side-effects profile, especially for high-risk (eg, older) recipients. The introduction of mycophenolate mofetil and tacrolimus in the treatment of acute rejection appears to have opened a new era in the treatment of acute rejection, especially in patients with resistance to high-dose steroids and antilymphocyte therapy.

Mycophenolate mofetil
Mycophenolate mofetil was reported to be successful in the treatment of mild rejection in heart allograft recipients [76]. Oral doses of 500 to 3000 mg/day of mycophenolate mofetil were substituted for azathioprine as the third agent in combination with cyclosporine and corticosteroids. In 20 of 30 patients with biopsy proven rejection, rejection resolved within 4 weeks. Resistance to mycophenolate mofetil therapy seemed to correlate with lower doses of mycophenolate mofetil; 2 of 6 patients receiving only 500 mg/day of mycophenolate mofetil experienced moderate rejection, compared with only 2 of 24 patients treated with 1000 to 3000 mg/day.

Another group also studied the use of mycophenolate mofetil to treat recurrent or persistent heart allograft rejection [77]. Seventeen patients with biopsy proven rejection at a mean of 5.4-months following transplantation were given 3000 to 3500 mg/day of mycophenolate mofetil instead of azathioprine in a standard triple-therapy regimen. Fourteen patients were doing well 5 to 10 months after the introduction of mycophenolate mofetil, with a decrease in the incidence of rejection from 0.67 to 0.27 rejection episodes per patient per month. Gastrointestinal intolerance was the only limiting factor to the use of mycophenolate mofetil in this group of patients.

Kobashigawa and colleagues [78] also treated 15 patients with mycophenolate mofetil for persistent or refractory rejection. Azathioprine was discontinued once rejection was diagnosed and mycophenolate mofetil was initiated at 2000 to 3000 mg/day. All patients with moderate rejection (n = 9) improved, confirmed by repeated biopsy. Complete resolution of rejection occurred in 6 of these 9 patients, at an average of 39 days after the start of mycophenolate mofetil treatment. All patients with documented mild rejection (n = 6) improved on repeat biopsy. Resolution was complete in 5 of 6 patients after an average of 47 days.

Therefore, mycophenolate mofetil is an effective first-line and rescue therapy in the management of biopsy proven rejection in patients on triple-drug immunosuppressive therapy. The substitution of mycophenolate mofetil for azathioprine is associated with a higher likelihood of resolution of the rejection episode and a significant lower rate of recurrent rejection episodes. However, patients should receive 1000 mg/day or more because lower doses tend to be associated with lower rates of resolution of the rejection episode.

Tacrolimus
Tacrolimus has been successfully used for rescue therapy in several small studies. The United States Multicenter FK506 Study Group reported their experience with 16 heart recipients who were converted to tacrolimus therapy because of cyclosporine intolerance, acute rejection, or humoral rejection [79]. Patient and graft survivals were 100% at a mean follow-up of 183 ± 65 days. Twenty percent of recipients experienced no rejection episode after conversion to tacrolimus and 60% experienced none or only one. In a 139 heart transplant cohort on cyclosporine-based immunosuppression, 15 patients (11%) experienced grade IIIa or greater rejection refractory to high-dose steroids and/or OKT3 therapy [80]. After tacrolimus rescue therapy, 93% (14 of 15 patients) converted to grade II or less rejection. The Montreal group switched 6 heart recipient patients under cyclosporine to tacrolimus therapy for refractory rejection [81]. Five patients underwent a successful rescue therapy and 1 patient died of refractory rejection despite the use of tacrolimus.

De Bonis and colleagues [82] reported on 10 recipients converted from a standard cyclosporine-based immunosuppressive regimen to a tacrolimus-based treatment for persistent rejection (n = 6) or recurrent acute rejection (n = 4). All these patients had been treated with high-dose methylprednisolone or polyclonal antibodies. The persistent/recurrent rejection resolved in all 10 patients. The average number of episodes of acute rejection or recipient decreased from 2.1 ± 1.6 on the cyclosporine regimen to 0.2 ± 0.4 on the tacrolimus regimen (p < 0.0001). In this study conversion from a cyclosporine-based to a tacrolimus-based maintenance immunosuppression has been demonstrated to be an effective approach to the management of patients with persistent or recurrent cardiac allograft rejection.


   Conclusions
Top
 Abstract
 Induction therapy
 Maintenance therapy
 Acute rejection therapy
 Conclusions
References
 
Although the advent of more potent orally active maintenance immunosuppressive agents has reduced the need for induction therapy with polyclonal antilymphocyte antibodies or monoclonal anti-CD3 antibodies, the recent introduction of humanized mAbs that are more specific and nonimmunogenic has reactivated the interest for induction therapy.

Maintenance therapy is traditionally based on a triple-drug regimen. There is increasing evidence that steroids can be weaned during the first year after transplantation in the majority of patients without any impact on long-term graft and patient outcome. Calcineurin inhibitors remain a mainstay of maintenance therapy and the choice between cyclosporin and tacrolimus appears to depend on their different side-effects profile. Azathioprine gives way progressively to mycophenolate mofetil, which has an increased efficiency on rejection. Sirolimus is still under investigation.

Most episodes of acute rejection respond to pulse dosage of steroids with lower dosage as efficient as the traditional high dosage. For those episodes refractory to steroids, polyclonal or monoclonal antibodies have been commonly used. However, because of their side effects and the formation of antibodies precluding their repeated administration, they are progressively replaced by tacrolimus and mycophenolate mofetil, which appear promising.


   References
Top
 Abstract
 Induction therapy
 Maintenance therapy
 Acute rejection therapy
 Conclusions
 References
 

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