CHAPTER IV
Immunosuppression: Evolution in Practice and Trends,
1993-2003
Introduction
This chapter focuses on trends that have evolved over the past 10 years in the immunosuppression of recipients of vascularized solid organ transplants. This period is of particular interest because it was during this decade that the variety of immunosuppressant medications approved by the Food and Drug Administration (FDA) expanded sufficiently to allow for clinically meaningful alternatives in immunosuppressive management. The mid-1980s and early 1990s offered few choices; patients could receive corticosteroids in combination with the calcineurin inhibitor cyclosporine and the antimetabolite azathioprine. The important clinical questions of that era revolved around the use of antibody induction and the proper dosing of these medications.
The first of the newer immunosuppressive agents, tacrolimus, and of the improved formulations of cyclosporine, cyclosporine for micro-emulsion, were approved in 1994. Over the next several years, the FDA licensed several important new maintenance immunosuppressants -- mycophenolate mofetil (1995), sirolimus (1999), and mycophenolate sodium (2004) -- as well as the new antibody preparations rabbit antithymocyte globulin (1999), daclizumab (1999), and basiliximab (2000). The introduction of these agents substantially increased the number of options available for immunosuppression. While the OPTN/SRTR data do not capture all of the nuances of these newer combinations, they provide important information about trends in immunosuppressive practice.
Despite some strategic
dissimilarity specific to the transplantation of different types of organs,
there exist broad therapeutic patterns. Antibody induction continues to be
prescribed for the majority of kidney, pancreas, and intestine recipients, and
for just under half of thoracic organ recipients; but its use remains uncommon
in liver transplantation Figure IV-1
. However, there is an ongoing shift in the choice of antibody
preparations being utilized from muromonab-CD3 (OKT3B., Orthobiotech,
Bridgewater, NJ) and horse antithymocyte globulin (ATGAMB., Pharmacia &
Upjohn, Kalamazoo, MI) to rabbit antithymocyte globulin (ThymoglobulinB.,
SangStat Medical Corp., Fremont, CA) and the monoclonal anti-IL-2 receptor
antagonists daclizumab (ZenapaxB., Roche, Nutley, NJ) and basiliximab
(SimulectB., Novartis, East Hanover, NJ). More recently, there has been growing
interest in induction with the anti-CD52 monoclonal antibody alemtuzumab
(Campath-1HB., ILEX Pharmaceuticals, San Antonio, TX). In 2003, 4% of kidney, 7%
of simultaneous pancreas-kidney (SPK), 13% of pancreas after kidney (PAK), 35%
of pancreas transplant alone (PTA), 9% of intestine, and <1% of other
organ recipients were treated with this agent [Tables 5.6a-12.6a]. To
avoid misinterpretation of various antibody preparations, we indicate both
generic and brand names in Table IV-1, but we use those brand names that are commonly employed in clinical
practice in the text and figures.
Table IV-1. Drug Names Used in This Chapter
| General Names | Generic Names | Brand Names |
|---|---|---|
| Corticosteroids | prednisone |
|
| Calcineurin inhibitors | tacrolimus (or FK-506) cyclosporine |
Prograf Sandimmune, Neoral, Gengraf, Eon, SangCya, generic cyclosporine |
| Antimetabolites | azathioprine cyclophosphamide mycophenolate mofetil mycophenolate sodium |
Imuran Cytoxan, Neosar CellCept Myfortic |
| Polyclonal antibodies | antithymocyte globulin (rabbit) antithymocyte globulin (equine) NRATG, NRATS, ALG |
Thymoglobulin ATGAM |
| Anti-CD3 monoclonal antibodies | muromonab-CD3 | Orthoclone OKT3 |
| Anti-CD52 monoclonal antibodies | alemtuzumab | Campath |
| Anti- IL-2 receptor monoclonal antibodies | basiliximab daclizumab |
Simulect Zenapax |
| TOR Inhibitors (or rapamycin) | sirolimus | Rapamune |
Maintenance immunosuppression is also undergoing gradual evolution. Although corticosteroids are prescribed for the overwhelming majority of patients, there is increasing interest across all solid-organ transplant disciplines in the implementation of steroid avoidance and minimization protocols. Calcineurin inhibitors continue to be administered to most patients, but with the exception of cardiac transplantation and reflecting a progressive trend over the past 10 years, the majority of recipients treated with calcineurin inhibition now receive tacrolimus Figure IV-2 . Similarly, the use of azathioprine has been almost completely replaced by mycophenolate mofetil which has become the most widely employed adjunctive immunosuppressive agent in solid organ transplantation Figure IV-3. In addition, the roles and indications for immunosuppression with sirolimus in combination with other medications continue to evolve.
Importantly, the incidence of acute rejection has declined over the last decade. Treatments for acute rejection continue to include high-dose corticosteroid and antibody therapies. Practices of conversion of maintenance immunosuppressive regimens, principally between cyclosporine, tacrolimus and sirolimus, in association with antirejection therapy or in response to medication-related toxicities, are not fully reflected in the SRTR database.
The remainder of this chapter is devoted to organ-specific discussions, focusing on antibody induction, maintenance immunosuppression, the use of corticosteroids, and the treatment of rejection. It provides a window into the dramatic changes that have occurred over the past 10 years on the part of practitioners within the transplant community.
Kidney Transplantation
Trends in Induction Therapy in Kidney Transplantation
Induction therapy refers to the temporary use of high doses of immunosuppressive medications in the early post-transplant period. Recipients treated with induction immunosuppression typically receive a brief course of antibody therapy that is intended to reduce or modify early immune system activity against the transplanted organ. During induction, some maintenance immunosuppressive medications, in particular the nephrotoxic calcineurin inhibitors, may be withheld for a variable number of days, usually until renal function stabilizes.
The trend for the increasing use
of induction therapy in the perioperative period continues, from 25% in 1994 to
70% in 2003. Rabbit antithymocyte globulin (Thymoglobulin) was the most
commonly used agent in 2003, and its use increased from 26% in 2002 to 34% in
2003 [Table 5.6a]. In 2003, the two
anti-IL-2 receptor preparations, basiliximab and daclizumab, accounted for 22%
and 13% of induction therapy, respectively. Administration of ATGAM and OKT3
for induction therapy continued to decline to only 1.1% and 0.4% of kidney
transplant recipients, respectively Figure IV-4.
Trends in Maintenance Immunosuppression Therapy Prior to Discharge in Kidney Transplantation
Since 1999, the use of steroids
as maintenance therapy has gradually decreased. Compared to only 3% in 1999, in
2003, 15% of kidney transplant recipients were discharged on a steroid-free
protocol. [Table 5.6b]. Among the
calcineurin inhibitors, the use of tacrolimus continues to increase (from 64%
in 2002 to 67% in 2003), while the number of recipients treated with
cyclosporine preparations declined over the same period, from 30% to 26%. In
2003, the purine synthesis inhibitor mycophenolate mofetil was used in over 81%
of renal transplant recipients at discharge, while the substituted purine
precursor azathioprine was given to fewer than 2% of patients. The use of
sirolimus for pre-discharge immunosuppression peaked at 17% in 2001 and has
stabilized at 15% in 2002 and 16% in 2003 Figure IV-5.
Trends in Maintenance Immunosuppression Therapy for the First Year in Kidney Transplantation
Because a substantial number of renal transplant recipients have received induction therapy with an anti-T cell antibody in the perioperative period, some of the maintenance immunosuppressive medications, in particular nephrotoxic calcineurin inhibitors, are frequently withheld for a variable number of days post transplant, usually until renal function stabilizes. The OPTN/SRTR data reflects this practice, since the percentage of patients receiving these agents increases during the first year posttransplant from that reported at discharge. The yearly trends in the administration of individual immunosuppressive agents seen following discharge are similar to those seen in the pre-discharge period. Within the category of calcineurin inhibitors, the trend towards more tacrolimus use and less cyclosporine maintenance continues. Among the antimetabolites, there is a notable preference for mycophenolate mofetil over azathioprine, the former accounting for 82% while the latter only 4% of recipients in 2002 [Table 5.6c]. After a rapid increase in the use of sirolimus from 3% in 1998 to 17% in 2000, the number of kidney transplant recipients on this drug has reached a plateau at 22% and 21% in 2001 and 2002, respectively. In 2002, 9% of patients were on steroid-free immunosuppressive regimens in the post-discharge period, reflecting the increased practice of attempting to spare recipients ongoing exposure to corticosteroid treatments.
Trends in Antirejection Treatment in Kidney Transplantation
In 2002, only 2,185 out of
14,774 kidney transplant recipients (15%) required treatment for an acute
rejection episode within one year of transplantation Figure IV-6. This represents a decline from 17% in 2001 and 18% in 2000 [Table
5.6d].B Corticosteroids are still the mainstay
of treatment for acute rejection, used alone or with antibodies in 78%-80% of
cases since 1998. The use of antilymphocyte antibodies for treatment of
rejection has also remained relatively stable at 36% to 39% since 1998. Within
the antibody category, however, rabbit antithymocyte globulin has largely
replaced the monoclonal anti-T cell receptor antibody muromonab-CD3 as the
principal antirejection treatment Figure IV-7.
Pancreas Transplantation
Induction, maintenance, and antirejection immunosuppressive therapies for recipients of pancreas transplantation are rapidly evolving. The majority of pancreas transplant recipients in the early 1990s received muromonab-CD3 induction; corticosteroids, azathioprine, and cyclosporine for maintenance immunosuppression; and corticosteroids or muromonab-CD3 as treatment for rejection. Reliance on these agents has decreased over the past 10 years. The use of muromonab-CD3 for induction has been supplanted by rabbit antithymocyte globulin, daclizumab, and basiliximab. Similarly, while corticosteroids are still commonly employed in maintenance immunosuppression protocols, tacrolimus, mycophenolate mofetil and sirolimus have largely replaced cyclosporine and azathioprine. Finally, when antibodies have been employed within the last several years to treat rejection, the utilization of rabbit antithymocyte globulin (begun in 1998) has become similar to or surpassed that of muromonab-CD3.
Trends in Induction Therapy in Pancreas Transplantation
SPK recipients are more likely
to receive induction immunosuppression (79%) than are PAK (74%) or PTA (79%)
recipients [Tables 6.6a, 7.6a and 8.6a]. In
1994, muromonab-CD3 was the most common induction agent utilized in pancreas
transplantation. However, with FDA approval in the late 1990s of rabbit
antithymocyte globulin and the anti-IL-2 monoclonal antibodies daclizumab and
basiliximab, the use of muromonab-CD3 for pancreas transplantation induction
began to decrease. By 2003, the administration of muromonab-CD3 for induction
in SPK, PAK, and PTA transplantation had fallen to less than 1%. In 2003,
rabbit antithymocyte globulin was the most frequently utilized induction agent
in SPK (49%), PAK (51%), and PTA (35%) recipients. However, daclizumab and
basiliximab were received by a sizeable minority of SPK (8% and 16%), PAK (9%
and 8%), and PTA (10% and 8%) recipients for induction therapy Figure IV-8.
Trends in Maintenance Immunosuppression Therapy Prior to Discharge in Pancreas Transplantation
Once among the key elements of
maintenance protocols for pancreas transplantation, the use of cyclosporine and
azathioprine have decreased dramatically over the past decade Figure IV-9. In 1994, 88% of SPK, 76% of PAK, and 57% of PTA recipients were
given cyclosporine during their initial transplant hospitalization [Tables 6.6b, 7.6b and 8.6b]. By 2003, the use of cyclosporine had
declined to 9%, 8%, and 3% for recipients of SPK, PAK, and PTA, respectively.
The diminished utilization of cyclosporine was accompanied by an increasing
reliance on tacrolimus for pancreas transplant immunosuppression. In 2003, 84%
of SPK, 81% of PAK, and 81% of PTA recipients received tacrolimus.
Even more striking changes have been seen in the use of azathioprine. In 1994, 99%, 91%, and 100% of SPK, PAK, and PTA recipients, respectively, received azathioprine following pancreas transplantation. In 2003, 1% or less of SPK, PAK, or PTA recipients were administered azathioprine during their initial transplant hospitalization. Mycophenolate mofetil and, to a lesser extent, sirolimus have supplanted azathioprine for the initial maintenance therapy of pancreas transplant recipients. In 2003, 82% of SPK, 85% of PAK, and 71% of PTA recipients received mycophenolate mofetil, and 20% of SPK, 15% of PAK, and 21% of PTA recipients received sirolimus.
The majority of pancreas transplant recipients continue to be treated with corticosteroids as part of their maintenance immunosuppression. However, over the past five years early maintenance corticosteroid use has declined for all three pancreas transplant procedures. In 2003, 84% of SPK, 81% of PAK, and 62% of PTA recipients were treated with corticosteroids prior to discharge from their initial transplant hospitalization [Tables 6.6b, 7.6b, 8.6b].
Trends in Maintenance Immunosuppression Therapy for the First Year in Pancreas Transplantation
Tacrolimus, mycophenolate mofetil, and corticosteroids are currently the bulwarks of pancreas transplant maintenance immunosuppression during the first posttransplant year. During 2002, tacrolimus was used for 89%, 88%, and 95%; mycophenolate mofetil for 80%, 77%, and 71%; and corticosteroids for 89%, 93%, and 90% of SPK, PAK, and PTA recipients, respectively [Tables 6.6c, 7.6c and 8.6c]. In addition, 28% of SPK, 32% of PAK, and 31% of PTA recipients received sirolimus.
In contrast to 1993, the use of cyclosporine and azathioprine has declined. In 2002, only 13% of SPK, 14% of PAK, and 8% of PTA recipients were given cyclosporine maintenance therapy during the first posttransplant year, and fewer than 2% were treated with azathioprine. In 1993, nearly all pancreas transplant recipients received cyclosporine and azathioprine.
Trends in Antirejection Treatment in Pancreas Transplantation
The incidence of rejection in
the first year after transplantation has declined in the past 10 years for SPK
recipients Figure IV-10. Corticosteroids remain the most commonly employed medications in
the treatment of pancreas transplant rejection. However, their use in SPK
recipients who have been treated for rejection has declined from 81% in 1993 to
76% in 2002. In contrast, corticosteroid treatment for rejection increased
between 1993 and 2002 from 40% to 91% for PAK recipients, and from 28% to 82%
for PTA recipients [Tables 6.6d, 7.6d and 8.6d].
During the same interval, the
use of antibody therapy has diminished. In 1993, 78% of SPK, 84% of PAK, and
72% of PTA recipients who were treated for rejection were given antibodies. In
2002, these percentages decreased to 51%, 49%, and 64%, respectively. The
biggest decline was in the use of muromonab-CD3 following SPK transplantation Figure IV-11. In 1993, 67% of SPK, 68% of PAK, and 56% of PTA recipients who were
treated for rejection were administered muromonab-CD3. In 2002, these
percentages declined to 11%, 26%, and 42%, respectively. Although rabbit
antithymocyte globulin was not available for pancreas transplantation in the United States until 1998, it is now the most commonly employed antibody for the treatment
of pancreas allograft rejection. In 2002, 34% of SPK, 30% of PAK, and 33% of
PTA recipients who were treated for rejection received rabbit antithymocyte
globulin. Of those pancreas transplant recipients who were treated for
rejection, 5% or less received daclizumab or basiliximab.
Liver Transplantation
Trends in Induction Therapy in Liver Transplantation
Induction therapy is not part of
the typical immunosuppressive regimen for most liver transplantation recipients
Figure IV-12. However, induction therapy is commonly employed in lieu of
calcineurin inhibitors immediately after transplantation for those patients
with marginal renal function to avoid the nephrotoxicity of tacrolimus and
cyclosporine. The fraction of patients receiving induction therapy has increased
incrementally since 1997 (when it was 7%), reaching 20% in 2003 [Table 9.6a]. The most important factor responsible for
this trend is the increasing prevalence of renal failure and renal
insufficiency in liver transplant recipients, due in large part to the
importance of serum creatinine in the determination of the priority for liver
transplantation using the Model for End-stage Liver Disease (MELD) score. Three
agents make up 93% of induction therapy for liver transplantation. The most
commonly administered agent is basiliximab (7% of all liver recipients),
followed by rabbit antithymocyte globulin and daclizumab (6% each) Figure IV-12). While the use of basiliximab and daclizumab has been relatively
stable from 2002 to 2003, the percentage of patients receiving rabbit
antithymocyte globulin increased by more than 50% from 2002 (4%) to 2003 (6%).
The augmented utilization of rabbit antithymocyte globulin is possibly a result
of recent data indicating successful liver transplantation with steroid-free
immunosuppressive regimens using rabbit antithymocyte globulin (1). The use of
induction therapy will likely continue to rise over the next few years because
of the increasing incidence of renal insufficiency in liver transplant
recipients.
Trends in Maintenance Immunosuppression Therapy Prior to Discharge in Liver Transplantation
Three important trends are noted
in immunosuppressive therapy employed prior to discharge in liver transplant
recipients since 2002. First, the percentage of patients receiving
corticosteroids prior to discharge decreased from 91% in 2002 to 82% in 2003 [Table
9.6b]. The continued trend of
corticosteroid-avoidance is due, in part, to the negative impact of this agent
on hepatitis C and the growing proportion of recipients infected with this
virus (2). In addition, a small but increasing proportion of transplant centers
have demonstrated that liver transplantation may be successfully performed in
the absence of (or with minimization of) corticosteroid exposure
(1,3-5). As a result, many liver transplant programs have reduced the dose and
duration of corticosteroid administration to their patients. Second, tacrolimus
remains the calcineurin inhibitor prescribed for most recipients (89%), with
cyclosporine recently given to less than 10% of liver transplant recipients Figure IV-13.
Third, mycophenolate mofetil is the most commonly prescribed
antimetabolite (administered to 54% of recipients), and the use of sirolimus
during the immediate postoperative phase is minimal and has decreased (from 7%
in 2002 to 4% in 2003). The decline in the administration of sirolimus (which
had been increasing yearly since introduction in 1998) may reflect the
influence on practice of the "black box" warning of an increased risk
of hepatic artery thrombosis that the FDA has issued for this agent (6).
Because of concerns related to hepatic artery thrombosis, the use of sirolimus
in the immediate perioperative period is likely to remain very small.
Trends in Maintenance Immunosuppression Therapy for the First Year in Liver Transplantation
The trends in immunosuppression administered during the first year after liver transplantation reflect the profile of immunosuppression at the time of discharge Figure IV-14. Corticosteroid use decreased from 89% in 2001 to 87% in 2002 [Table 9.6c]. However, 87% is still higher than the percentage of patients given corticosteroids prior to discharge (82%), indicating that some patients not receiving corticosteroids at discharge are initiated on them during the first year [Tables 9.6b and 9.6c]. Many of these patients will have autoimmune liver disease and require corticosteroid therapy to control recurrences. Cyclosporine use decreased by 22%, dropping from 18% in 2002 to 14% in 2003. A higher percentage of patients is administered cyclosporine following discharge (14%) than is administered cyclosporine between transplant and discharge (9%), which likely reflects conversion to cyclosporine in patients who were intolerant of tacrolimus. Mycophenolate mofetil was given to 50% of recipients and continued its upward trend since its introduction in 1994. The use of sirolimus decreased from 17% in 2002 to 14% in 2003. As noted above, the decreased use of sirolimus appears related to concerns associated with the "black box" warning issued by the FDA for this medication. However, the percentage of patients administered sirolimus following discharge (14%) is much higher than those administered sirolimus during the immediate perioperative period (4%). The increased use of sirolimus after discharge may reflect confidence in its safety as the posttransplant risk of hepatic artery thrombosis declines over time. The use of sirolimus during the first year following transplantation will likely continue to increase because of concerns regarding calcineurin inhibitor-related nephrotoxicity. In addition, transplant physicians are becoming more aggressive in weaning patients off calcineurin inhibitors during the chronic phase of immunosuppression to avoid the long-term nephrotoxic effects of these drugs (7).
Trends in Antirejection Treatment in Liver Transplantation
The rate of antirejection treatment
in 2002 (24%) is much lower than it was in 1993, when 50% of patients were
treated for rejection [Table 9.6d] Figure IV-14.
The two most important reasons for the decreased rate in the treatment of rejection were 1) the introduction of several new immunosuppressive agents that may reduce the incidence of acute cellular rejection and 2) a decreased likelihood of treating mild rejection in the growing number of hepatitis C patients because of recognition of the deleterious effects of antirejection treatment on the progression of hepatitis C. In 2002, corticosteroids were used to treat acute cellular rejection during the first year after liver transplantation in 90% of cases, and antibody therapy was given to 18% of recipients, as compared to 17% during 2001. The three most commonly administered antibody therapies were muromonab-CD3 (6%), rabbit antithymocyte globulin (6%), and basiliximab (4%), which collectively accounted for over 85% of all antirejection antibody therapies Figure IV-15.
Intestine Transplantation
The number of intestine transplants performed in the United States is relatively small compared with other organs. In 2003, only 116 cases with data on immunosuppression were registered with the SRTR [Table 10.6a]. Because of the small total number of cases, the significance of changes in the trends of immunosuppression may be difficult to assess.
Trends in Induction Therapy in Intestine Transplantation
Induction therapy was utilized in 74% of intestine transplants in 2003. Two agents accounted for 82% of induction therapy. The most commonly administered induction agent was rabbit antithymocyte globulin (46%), followed by daclizumab (16%). The most notable changes in the type of induction therapy were the use of rabbit antithymocyte globulin, which increased from 31% in 2002 to 46% in 2003, and a drop in the use of basiliximab, from 13% in 2002 to less than 2% in 2003.
Trends in Maintenance Immunosuppression Therapy Prior to Discharge in Intestine Transplantation
Data on maintenance therapy prior to discharge were available on 103 intestine transplant recipients [Table 10.6b]. Corticosteroids were given to 67% of patients, which reflects a general downward trend in corticosteroid use in intestine transplantation. The percentage of intestine transplant recipients receiving corticosteroids decreased from 97% in 2000 to 80% in 2001 and 64% in 2002. Tacrolimus was administered to 93% of patients, while cyclosporine was used for only 1% of patients. Mycophenolate mofetil, the only antimetabolite used, was prescribed for only 9% of patients.
Trends in Maintenance Immunosuppression Therapy for the First Year in Intestine Transplantation
Only 80 intestine transplant recipients had evaluable immunosuppressive data between discharge and one year following transplantation. Corticosteroids were administered to 93% of patients [Table 10.6c]. Tacrolimus remained the calcineurin-inhibitor of choice, with 100% of patients receiving the drug and cyclosporine reported for only 1% of patients. Antimetabolites were rarely used (11% of patients). Mycophenolate mofetil was the most prescribed antimetabolite (10%), followed by azathioprine (1%). Sirolimus was given to 26% of recipients during this time.
Trends in Antirejection Treatment in Intestine Transplantation
Only 48 patients received antirejection therapy during the first year after intestine transplantation [Table 10.6d]. Corticosteroids were the most commonly used agent to treat rejection (96%), followed by antibodies (31%). The most commonly administered antibody therapy was muromonab-CD3 (29%), followed by rabbit antithymocyte globulin (6%), and ATG (2%).
Heart Transplantation
Trends in Induction Therapy in Heart Transplantation
The use of induction therapy in
heart transplantation has received a great deal of attention over the last
decade. Driven primarily by approaches to other solid organ transplant
patients, initial immunosuppression strategies often included an induction
protocol but not, generally, with the same frequency observed with other organ
transplants. Though few large-scale randomized clinical trials have been
performed to test the efficacy of induction regimens immediately after heart
transplant, some guidance has been developed, and these data are likely driving
the changes noted today. Figure IV-16 details the specific trends in immunosuppression used for induction
therapy from 1994 through 2003.
In the mid-1990s, there was a decrease in the percentage of recipients receiving induction therapy (from 36% in 1994 to 29% in 1998), but this trend has more recently been reversed, as 47% were given induction therapy in 2003 [Table 11.6a]. It has been speculated that recipient comorbidities often drive the decision to administer induction therapy to heart transplant recipients. Whereas induction therapy had primarily been employed as a strategy to decrease the incidence of early rejection following heart transplantation, induction therapy has more recently been used as a so-called "renal-sparing" regimen that delays exposure to calcineurin inhibitors and, more specifically, cyclosporine. In the setting of pretransplant renal insufficiency, some believe this approach will decrease the risk of developing renal failure early after heart transplant. With this observation in mind, several clear trends have emerged with respect to early posttransplant induction protocols for heart recipients. As Figure IV-16 demonstrates, muromonab-CD3 and equine ATG were the most commonly used induction agents in the latter half of the 1990s. Whereas 16% of patients receiving induction immunotherapy immediately posttransplant were treated with ATG in 1994, only 8% received this agent in 2003. Similarly, 20% receiving induction therapy in 1994 were given muromonab-CD3, but only 5% were prescribed this agent in 2003. As experience increased with the use of muromonab-CD3 for induction, concern was raised about acute pulmonary toxicity and about a seeming increase in posttransplant lymphoproliferative disease over the longer term. On the other hand, the administration of rabbit antithymocyte globulin increased substantially from 0% in 1998 to 13% in 2003. Similarly, the use of the anti-IL-2 receptor antibodies, daclizumab and basiliximab, has increased to 15% and 9%, respectively, both from 0% in 1997. These agents generally appear to be better tolerated. Clearly the use of rabbit antithymocyte globulin or an anti-IL-2 receptor antibody is the strategy most often chosen today when induction therapy is prescribed.
Trends in Maintenance Immunosuppression Therapy Prior to Discharge in Heart Transplantation
Although substantive changes in maintenance immunosuppression therapy prior to discharge from the hospital after heart transplantation can be seen between 1995 and 2000, no major changes in immunosuppressive schemes are noted from 2002 to 2003. Corticosteroids, an antimetabolite, and a calcineurin inhibitor remain the core therapies. In 2003, 93% of patients were on corticosteroids, 90% on an antimetabolite, and 100% on a calcineurin inhibitor, with more than 8% on other types of immunosuppression, such as sirolimus (8%) and cyclophosphamide (0.2%) [Table 11.6b]. However, there have been changes in immunosuppressive use within the major classifications.
Calcineurin inhibitors: Virtually
all patients are receiving a calcineurin inhibitor in the early posttransplant
period prior to hospital discharge Figure IV-17. There has been a steady rise in the use of tacrolimus from 16% in
2000 to 41% in 2003. Though the majority of patients on a calcineurin inhibitor
are still on cyclosporine, only 4% of the total population now receive the
original formulation Sandimmune, with 43% receiving Neoral and 14% Gengraf. It
is interesting to note the increase in proportion of patients on the generic
cyclosporine compound, Gengraf, since 2000 when it first became available (2%
in 2000 versus 14% in 2003).
Antimetabolites and sirolimus: Mycophenolate mofetil use has increased over the last decade and it is now the antimetabolite most frequently prescribed prior to hospital discharge after heart transplantation. As noted in Figure IV-17, in 2003, 82% of patients were treated with this agent versus 4% in 1994 [Table 11.6b]. This should be compared with the 94% administration of azathioprine in 1994 versus about 10% in 2003. Sirolimus has, over the last two years, seen a steady rise in utilization as well (from 0% in 1997 to about 10% in 2002 and 8% in 2003). Other immunosuppressive agents, such as cyclophosphamide, are now rarely used and have never been employed with significant frequency.
Corticosteroids: Data suggest that there is almost universal belief that corticosteroids are an essential component of the immunosuppressive protocol prior to hospital discharge after heart transplantation. Little change has been noted in prescriptive practice over the past decade, with 93% of patients transplanted in 2003 receiving steroids.
Trends in Maintenance Immunosuppression Therapy for the First Year in Heart Transplantation
In 2002, corticosteroids, calcineurin inhibitors, and the antimetabolite mycophenolate mofetil remained the most common maintenance agents within the first year after heart transplantation.
Calcineurin inhibitors: As with observations made earlier regarding practice at the time of the initial post heart transplant discharge, the trend over the last decade has been for an increasing role for tacrolimus as the calcineurin inhibitor of choice. In 2002, about 50% of patients were receiving this agent, compared with 43% in 2001 [Table 11.6c]. With regard to cyclosporine preparations, as noted with immunosuppression prior to hospital discharge, Gengraf use has increased to about 14%, with Neoral at approximately 43%, down from 68% in 2000.
Antimetabolites and sirolimus: The use of azathioprine continues to decrease substantially. Whereas in 1993 95% of patients were treated with this agent, only 12% received azathioprine in 2002. Indeed, 80% of patients on an antimetabolite in 2002 were receiving mycophenolate mofetil. Also important is the apparent decrease in antimetabolite use over the last decade. Whereas in 1993 96% of patients received an antimetabolite, in 2002 this fell to 87%. Some of this decline seems to be related to an increased use of sirolimus, which reached 14% in 2002, compared with 8% in 2001 and 5% in 2000.
Corticosteroids: Although the vast majority of heart transplant recipients are treated with corticosteroids as part of the maintenance immunosuppressive regimen during the first year posttransplant, this has declined over time, with 88% of patients receiving steroids in 2002 compared with 96% of patients in 1993. Some programs have focused on weaning heart transplant patients off steroids, but such patients represent a small minority.
Trends in Antirejection Treatment in Heart Transplantation
Over the past decade, the
occurrence of episodes of rejection requiring augmentation of immunosuppressive
therapy has shown only minor changes (41% in 1993 versus 37% in 2002) [Table
11.6d] Figure IV-18. However, a striking trend has occurred over the last decade
regarding therapeutic options for acute rejection. Corticosteroid utilization
remains high, with 88% of patients receiving these agents as treatment for
rejection in 1993 and 92% in 2002. However, as Figure IV-19 demonstrates, there is a continuing decrease in antibody
administration for acute rejection. In 1993, 27% of patients received
antibodies for acute rejection, versus 18% in 2002. Of the antibodies used in
2002, rabbit antithymocyte globulin (6%), muromonab-CD3 (7%), and equine antithymocyte
globulin (4%), made up the bulk of the treatments. Perhaps there has been a
slight decrease in the use of anti-IL-2 receptor antibodies for the treatment
of rejection, as only 2% of patients received these agents in 2002 versus
almost 3% in 2001.
Treatment of rejection within the first year of transplantation thus remains primarily based on corticosteroids, with the most notable changes being a gradual decline in the use of antibody therapy over time.
Lung Transplantation
Trends in Induction Therapy in Lung Transplantation
Overall, there has been a
continuing increase in the utilization of induction therapies for lung
transplant recipients. In 1994, 25% of patients received antibody induction
immediately after transplantation, compared with 44% in 2003 [Table 12.6a]. More specifically, the use of equine
antithymocyte globulin has declined from 23% in 1995 to about 5% in 2003, and
the use of muromonab-CD3 has declined from about 6% in 1994 to 1.1% in 2003.
There was some utilization of rabbit antithymocyte globulin, following its
approval by the FDA; however, its use was only 3% in 2003, compared with almost
8% in 2002. In contrast, significant increases have been noted in the
utilization of the anti-IL-2 receptor antibodies daclizumab and basiliximab Figure IV-20. Thus the overall increase since 1998 in utilization of lung
transplant induction protocols principally reflects the use of anti-IL-2
receptor antibodies
Trends in Maintenance Immunosuppression Therapy Prior to Discharge in Lung Transplantation
Paralleling heart transplantation over the last decade, major changes in maintenance immunosuppression immediately following lung transplantation were noted after the introduction of tacrolimus and mycophenolate mofetil in the latter 1990s. Over the last several years, however, less change has been seen.
Calcineurin inhibitors: Calcineurin inhibitor use prior to hospital discharge after lung transplantation is noted for practically every patient. However, in contrast with heart transplant recipients in both 2002 and 2003, tacrolimus was the most commonly used agent. Indeed in 2003, 66% of patients received tacrolimus compared with 34% receiving one formulation of cyclosporine or another [Table 12.6b] Figure IV-21. Of those lung transplant patients receiving cyclosporine compounds, the majority are on Neoral (24% of the total lung transplant population).
Antimetabolites and sirolimus: Over the past decade, the use of antimetabolites (azathioprine and mycophenolate mofetil) prior to discharge after lung transplantation has remained fairly constant at about 90%. The significant change that occurred was the decline in azathioprine use from 96% in 1994 to 46% in 2003, with mycophenolate mofetil now used for about 45% of patients Figure IV-21. Sirolimus is rarely prescribed early after lung transplantation. In 2001, 4% of patients received this agent, whereas in 2002 only 2% and in 2003 only 1% of patients were taking this compound as part of their immunosuppressive regimen. Cyclophosphamide continues to be used rarely for lung transplant recipients.
Corticosteroids: Corticosteroids are still a mainstay of immunosuppressive therapy following lung transplantation. In 2003, 95% of patients were on corticosteroids. This is similar to the heart transplant experience.
Trends in Maintenance Immunosuppression Therapy for the First Year in Lung Transplantation
In 2002, the most common maintenance regimens used within the first year following lung transplantation included corticosteroids (97%), tacrolimus (76%) or cyclosporine (35%), and an antimetabolite (89%), such as azathioprine (44%) or mycophenolate mofetil (54%) [Table 12.6c]. Sirolimus use increased to 14% in 2002, up from 11% in 2001.
Calcineurin inhibitors: Calcineurin inhibitors remain the basis of maintenance immunosuppression in patients during the first year following lung transplantation. In contrast to heart transplant recipients, however, there has been a more dramatic increase in the percentage of lung transplant patients receiving tacrolimus: from 47% in 1999 to 76% in 2002. For patients receiving cyclosporine, Neoral utilization has fallen from a high of 59% in 1998 to 27% in 2002; the utilization of alternative cyclosporine formulations in 2002 has not been common in these patients (3% Sandimmune and 7% Gengraf).
Antimetabolites and sirolimus: Though antimetabolite use overall is still frequent for lung transplant recipients during the first posttransplant year, the proportion of patients on mycophenolate mofetil versus azathioprine continues to change. In 2001, 49% of patients were on azathioprine, whereas in 2002, 44% of patients were on this agent and 54% on mycophenolate mofetil. Interestingly, the percentage of lung recipients on sirolimus within one year posttransplant (14%) was similar to that for heart transplant recipients (also 14%). However, the utilization of sirolimus at one year posttransplant (14%) should also be compared with its use prior to hospital discharge (1%) [Tables 12.6b and 12.6c]. In comparison, 8% of patients were on sirolimus prior to discharge after heart transplant [Table 11.6b]. The differences in early utilization of sirolimus are likely related to observations suggesting an increased risk of airway anastomotic dehiscence when sirolimus is employed as part of the protocol immediately after surgery.
Corticosteroids: As with heart transplant recipients, the vast majority of lung transplant recipients received corticosteroids as part of their immunosuppressive maintenance therapy during the first postoperative year. This has changed little over the last decade.
Trends in Antirejection Treatment in Lung Transplantation
There has been little change in the incidence of rejection within the first year following lung transplantation since 1996 Figure IV-22. In the treatment for rejection within the first year after lung transplantation, corticosteroids continued to be the agents primarily used. In 2002, 95% of recipients receiving antirejection treatments had steroids administered as part of the treatment protocol [Table 12.6d]. Overall, antibodies were used as the main class of agent for steroid-resistant rejection during the past decade. Since 1997, there has been a slight increase in the utilization of rabbit antithymocyte globulin (5% in 2002) and anti-IL-2 receptor antibodies, of which daclizumab was used for 5% of patients and basiliximab for 0.2% of patients in 2002 Figure IV-23.
Heart-Lung Transplantation
Trends in Induction Therapy in Heart-Lung Transplantation
It is difficult to comment definitively about immunosuppressive protocols in patients undergoing combined heart-lung transplantation because few such procedures are now performed. In 2003, only 29 en bloc heart-lung transplants were performed. With the success of single-lung, double-lung, and lung segment transplantation, sometimes combined with repair of primary cardiac lesions that obviate the need for heart transplantation, the demand for combined heart-lung transplant procedures has decreased. Thus over the last decade, no clear-cut trends in induction immunosuppressive therapy for these procedures can be identified. In 2003, about half of the patients received induction therapy, with a variety of approaches being used. Basiliximab was utilized for 19% of patients, daclizumab for about 7%, rabbit antithymocyte globulin in 11%, and muromonab-CD3 and equine antithymocyte globulin each in 4% of patients [Table 13.6a].
Trends in Maintenance Immunosuppression Therapy Prior to Discharge in Heart-Lung Transplantation
Utilization of immunosuppressive therapies in heart-lung transplant recipients parallels observations made in both isolated heart and lung transplant cases.
Calcineurin inhibitors: Virtually all patients after heart-lung transplantation received a calcineurin inhibitor. More like isolated heart recipients, the percentage receiving tacrolimus versus cyclosporine is closer to half. In 2003, 53% of heart-lung transplant recipients received tacrolimus [Table 13.6b]. Neoral and Gengraf were the most commonly used cyclosporine formulation, as they were both used in 21% of heart-lung transplants prior to discharge.
Antimetabolites and sirolimus: Antimetabolite usage is still quite common among heart-lung transplant recipients (79% in 2003), with azathioprine used in 47% of cases and mycophenolate mofetil in 32% of cases in 2003. Clear-cut trends in prescription of these two agents cannot be identified, as the proportions have risen and fallen over the last several years. Interestingly, sirolimus use has been reported in 5% of combined heart-lung transplant recipients in 2003, compared to 0% from 1994 to 2002.
Corticosteroids: Corticosteroids remain an integral component of the immunosuppressive regimens for heart-lung transplant recipients at the time of discharge, with 90% of patients receiving these agents in 2003.
Trends in Maintenance Immunosuppression Therapy for the First Year in Heart-Lung Transplantation
Calcineurin inhibitors: Calcineurin inhibitors are the basis of immunosuppressive therapy in heart-lung transplant recipients, and this has been the case over the past decade. However, as with other organs, tacrolimus has been more frequently utilized during the last several years. Indeed, within the first posttransplant year, tacrolimus usage increased from 52% in 1999 to 65% in 2002 [Table 13.6c]. Among heart-lung transplant recipients, when cyclosporine was used, Neoral was the most common formulation prescribed and was used for 50% of the patients receiving cyclosporine.
Antimetabolites and sirolimus: Again, as with heart and lung transplantation, antimetabolites are frequently used as part of the immunosuppressive protocol and were used for 95% of heart-lung recipients in 2002. Azathioprine was used for 55% of recipients and mycophenolate mofetil for 55%. The use of sirolimus during the first operative year varied over the last few years from 0% in 2001to 5% in 2002, with a peak of 10% in 2000.
Corticosteroids: As with the other thoracic organ transplant recipients, corticosteroids play an extremely important role after heart-lung transplantation. Indeed, all patients in 2002 were receiving corticosteroids during the first posttransplant year.
In 2002, though the observations are few, as with heart and lung transplants, the most common maintenance therapy for heart-lung recipients within the first year included corticosteroids, tacrolimus, and mycophenolate mofetil.
Trends in Antirejection Treatment in Heart-Lung Transplantation
Only 8 of the 32 heart-lung transplant recipients received treatment for acute rejection in 2002 [Table 13.6d]. All of these patients received steroid therapy, with no antibody use, similar to what occurred in 2001.
Summary
There has been noticeable evolution in the selection of immunosuppressive agents in solid organ transplantation over the past 10 years. An ongoing shift is seen in the types of antibody preparation being utilized as induction therapy, from muromonab-CD3 and horse ATGAM to rabbit antithymocyte globulin and the monoclonal anti-IL-2 receptor antagonists daclizumab and basiliximab. Furthermore, while calcineurin inhibitors continue to be used for maintenance immunosuppression in most patients, there has been a movement in the preference of calcineurin inhibitor used from cyclosporine to tacrolimus. An even more noticeable transition is seen in the choice of antimetabolite from azathioprine to mycophenolate mofetil; the latter is currently the most commonly administered immunosuppressive agent in solid organ transplantation. Despite the impact of steroid avoidance and near-avoidance protocols, corticosteroids continue to be widely employed in discharge maintenance immunosuppression in most solid organ transplant recipients. The incidence of acute rejection is decreasing. Steroids and antibody therapies are employed for treatment of acute rejection. It is probable that future studies will continue to demonstrate a significant impact of the newer medications on immunosuppressive practices.
References
1. Eason JD, Nair S, Cohen AJ, Blazek JL, Loss GE Jr. Steroid-free liver transplantation using rabbit antithymocyte globulin and early tacrolimus monotherapy. Transplantation 2003;75:1396-1399.
2. Shiffman ML, Vargas HE, Everson GT. Controversies in the management of hepatitis C virus infection after liver transplantation. Liver Transpl 2003; 9:1129-1144.
3. Reding R, Gras J, Sokal E, Otte JB, Davies HF. Steroid-free liver transplantation in children. Lancet 2003; 362:2068-2070.
4. Greig P, Lilly L, Scudamore C, et al. Early steroid withdrawal after liver transplantation: the Canadian tacrolimus versus microemulsion cyclosporin A trial: 1-year follow-up. Liver Transpl 2003; 9:587-595.
5. Trotter JF, Wachs M, Bak T, Trouillot T, Stolpman N, Everson GT, Kam I. Liver transplantation using rapamycin and minimal corticosteroids (3-day taper). Liver Transpl 2001; 7:343-351.
6. Fung J, Marcos A. Rapamycin: friend, foe, or misunderstood? Liver Transpl 2003; 9:469-472.
7. Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med 2003; 349:931-940.
CONTRIBUTORS
The following individuals prepared this chapter: Ron Shapiro1, MD; James B. Young2, MD; Edgar L. Milford3, MD; James F. Trotter4, MD; Rami T. Bustami5, PhD; Alan B. Leichtman6, MD. 1Thomas E. Starzl Transplant / University of Pittsburgh; 2Cleveland Clinic Heart Center; 3Brigham and Women's Hospital; 4University of Colorado Health Sciences Center; 5Scientific Registry of Transplant Recipients / University Renal Research and Education Association; 6Scientific Registry of Transplant Recipients / University of Michigan.