Effective immunosuppression is the key to successful organ transplantation, with success being defined as minimal rejection risk with concomitant minimal drug toxicities. Despite the general recognition of this fact, a paucity of appropriate clinical trials in children has contributed to lack of standardization of clinical management regimens, resulting in an extensive diversity of favored approaches. Nonetheless, although consensus has not been reached on the ideal approach to immunosuppression in pediatric transplantation, new drug therapies have contributed to a continuing improvement in graft and patient survival. Future clinical research must focus on diminishing the extensive burden of toxicities of these therapeutic agents in children.
Effective immunosuppression is the key to successful organ transplantation, with success being defined as minimal rejection risk with concomitant minimal drug toxicities. Despite the general recognition of this fact, there is a lack of standardization of clinical management regimens, with an extensive diversity of favored approaches, particularly in pediatric transplantation. Although differences associated with the transplanted organ are obvious, even single organ transplant groups are far from consensus on the ideal approach to immunosuppression.
Current strategies in pediatric solid-organ transplantation are different amongst the organs. Induction treatment as an early first strike on the immune system during the perioperative period has become more common, but is not universally accepted as a mandatory part of organ transplantation. With improved pretransplant identification of high-risk patients such as patients with preformed anti-HLA antibodies, different desensitization protocols have been proposed, which require further evaluation.
Strategies used for maintenance immunosuppression also vary amongst the organ transplant groups, illustrated in the various registry reports. In kidney transplantation the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) annual report 2008 showed that more than 50% of patients now receive a combination of calcineurin inhibitors (CNI), cell cycle inhibitors and steroids, with tacrolimus (TAC) being used more commonly than cyclosporine A (CSA). The International Society of Heart and Lung Transplantation (ISHLT) 2009 Registry Pediatric Report showed that heart transplant immunosuppression is mainly based on a combination of CNI with cell cycle inhibitors. TAC/mycophenolate (mycophenolic acid; MPA) is the most common combination in current use followed by CSA/MPA. Steroids are continued beyond the first year in nearly half of the patients and mTOR (mammalian target of rapamycin) inhibitors are used in 8% of patients. For pediatric lung transplant recipients, the maintenance immunosuppression used is usually a combination of CNI and cell cycle inhibitors. The most commonly used CNI is TAC, which is used almost twice as often as CSA, with the most frequent combination regimen being TAC/MPA. Nearly all patients remain on steroids at 5 years after transplant.
A study from the Studies of Pediatric Liver Transplantation (SPLIT) database registry examining 5-year liver transplant survivors showed that 64% are on CNI-based monotherapy immunosuppression. Of those patients, 74% are receiving TAC. Steroids are still used at 5 years after transplant in 24%.
Fig. 1 illustrates the options for immunosuppression in a time line. Most transplant patients require some kind of indefinite maintenance immunosuppression, with the exception of weaning from immunosuppression late after transplantation, which has been successful in up to 20% of pediatric liver transplant recipients. Single cases of pediatric patients weaned from immunosuppression have also been reported after kidney transplantation, and, although anecdotal cases exist, there have not been published reports of successful weaning from immunosuppression in pediatric recipients of thoracic organ transplants. Perioperative high-dose steroid treatment is also accepted as a general approach amongst all organs, although the role of steroids in maintenance treatment is currently under vigorous discussion.
Fig. 2 illustrates the cellular targets of immunosuppressive drugs. The drugs in most common current usage, including dosage and specific side effects, are shown in Table 1 and discussed in the following sections. The later sections provide a future outlook and discussion of current investigative approaches.
| Drug Name | Mechanism | Pediatric Dose | Side Effects | Comments |
|---|---|---|---|---|
| Induction Therapy | ||||
| Polyclonal Antibodies | ||||
| •Rabbit ATG (thymoglobulin) | Antibodies against thymus-derived human epitopes | 1.5 mg/kg/d | Anaphylaxis and increased risk of (opportunistic) infections | Aim for lymphocyte count of 0.1–0.3 lymphocytes/mL |
| •Equine ATG | 10–25 mg/kg/d | |||
| Monoclonal Antibodies | ||||
| •Basiliximab | IL-2 receptor (CD25) blocking antibodies | 2 doses 12 mg/m 2 day 0 and 4 | Hypersensitivity | Start before transplant |
| •Daclizumab | Inhibit T-cell activation | 5 doses 1 mg/kg every 14 days | Hypersensitivity | Start before transplant |
| Induction and Maintenance Therapy | ||||
| Steroids | ||||
| •Methylprednisolone | Inhibition of activator protein-1 and nuclear factor κ-B | Induction 5–10 mg IV pre-/intraoperative IV or oral steroids are weaned to maintenance dose 0.1–0.3 mg/kg/d | Hypertension, diabetes, salt/water, retention, osteopenia, hyperlipidemia, Cushingoid habitus, hirsutism, acne, growth retardation | Can be discontinued in liver, heart and kidney |
| •Prednisone | Usually continues in lung | |||
| Maintenance Therapy | ||||
| Calcineurin Inhibitors | ||||
| •Cyclosporin | Inhibit expansion and differentiation of T cells | IV starting dose 1–3 μg/kg/d Oral maintenance 3–8 mg/kg/d in 2 divided doses | CSA: Hypertrichosis, gingival hyperplasia and hypertension | Choice and aimed level of CSA or TAC depend on type of organ, time after transplant and individual variables eg, renal impairment |
| •TAC | Inhibit expansion and differentiation of T cells | IV starting dose 0.01–0.05 mg/kg/d Oral maintenance 0.15–0.2 mg/kg/d divided in 2 doses | TAC: Hyperglycemia, tremor, alopecia, dose-dependent neurotoxicity All CNI: Nephrotoxicity and hypertention | |
| Antiproliferative Drugs | ||||
| •MMF •ecMPA | Inhibit de novo DNA synthesis | 25–50 mg/kg/d divided in 2 doses | Myelosuppression, leucopenia, gastrointestinal symptoms | Doses for MMF and ecMPA equal Change from one to the other formulation may relieve gastrointestinal problems. Avoid MMF/ecMPA use in pregnancy. Limit sun exposure on AZA |
| •AZA | 1–2 mg/kg/d divided in 2 doses | Myelosuppression, leucopenia, UV-dependent increase in skin cancer | ||
| mTOR Inhibitors | ||||
| •Sirolimus | Arrest in cell cycle and differentiation | 1 mg/m 2 daily | Delayed wound healing, aphthous ulcers, hyperlipidemia, edema, bone marrow suppression, pneumonitis | May be protective against coronary allograft vasculopathy |
| •Everolimus | 0.8–1.5 mg/m 2 daily | |||
Induction therapy
The use of induction immunotherapy is defined as intense immunosuppression in the immediate perioperative phase of organ implantation and has become more common in the last decade in all areas of solid-organ transplantation. The initial rationale for the use of induction treatment was the expected lower incidence of acute rejection in the early posttransplant phase. This finding was proven for several different agents for 1-year posttransplant outcomes of several organs. As chronic graft failure and decreased long-term survival correlate with the frequency of acute rejection, induction treatment will likely bring advantages in these aspects as well. However, it is recognized that associated adverse events such as higher incidence of (opportunistic) infections, lymphoproliferative disorders, and hypersensitivity reactions may outweigh the benefits. A more recent approach uses the immunosuppressive potential of induction treatment to facilitate a delayed and more careful initiation of maintenance therapy. The avoidance of nephrotoxic effects of high doses of CNI, TAC, and CSA is especially beneficial to avoid early graft failure in kidney transplant patients and prolonged kidney dysfunction following heart transplantation.
Although various transplant registries generally show an increasing use of induction therapy in adult and pediatric transplantation in the last 5 to 10 years, the frequency of induction treatment and the agents used vary widely amongst centers and transplanted organs. Some protocols generally include induction in any immunosuppressive regimen, whereas others choose an individualized approach using induction only for special indications (eg, accompanying renal failure or presensitization), or modify the agents and doses according to the individual indication. The use of high initial doses of steroids, which could be classified as induction, is discussed together with maintenance steroids in a later section.
Polyclonal Cytolytic Sera and Antithymocyte Globulin
This group contains the initially custom-made polyclonal antibody sera (often referred to as antilymphocyte globulin) as well as the currently commercially available drugs, equine antithymocyte globulin (ATG) and rabbit ATG. Polyclonal sera are prepared by injection of human thymocytes into animals that subsequently produce antibodies against a variety of human antigens including HLA and surface receptors of immune cells (eg, CD3, CD4). As thymocytes are used for sensitization of the animals, the main targets of the antibodies are T lymphocytes, but other lymphocytes and antigen-presenting cells are also targeted. After processing and purification these sera can be administered intravenously to patients. The antibodies coat the recipient’s immune cells, inducing a variety of mechanisms to deplete them via complement activation, opsonization to optimize phagocytosis, and activation of natural killer cells. Sufficient dosage leads to a rapid drop in the circulating lymphocyte count, especially T cells, resulting in profound suppression of the adaptive immune system. Most centers define a target threshold of 0.1 to 0.3 lymphocytes (×10 3 /mm 3 ) as a safe range of sufficient immunosuppression and maintain these values for the first 5 to 7 days after transplant. This approach allows renal function to recover, with introduction of CNI therapy by either intravenous (IV) or enteral administration later after the operative procedure. In the setting of cardiac transplantation, this process allows smoother recovery of hemodynamic stability before initiation of agents that impair renal function. Comparative studies have shown that the rabbit-derived preparation Thymoglobulin provides a more profound and more easily adjustable lymphocyte reduction than the equine-derived ATG without increasing side effects.
Side effects of polyclonal lymphocyte depleting sera may be severe, including fever, rash, weakness, hypotension, and allergic-type reactions such as anaphylactic shock. The reduction in immune cell numbers may exceed the duration of therapy for weeks and in some cases even months, associated with an increased risk of infectious complications. The available literature analyzing this is not unanimous, however. Opportunistic infections have been reported, and most studies have attributed a higher probability of cytomegalovirus (CMV) infection or reactivation and Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disorder (PTLD) to the use of ATG, when compared with no induction or to use of monoclonal CD25-directed antibodies. Increased incidence of opportunistic infections was mainly found when ATG was used as a rejection treatment, most likely because of lower surveillance and absence of prophylaxis later after transplant.
Monoclonal Antibodies
Muronomab
The first available commonly used monoclonal antibody used for transplant induction therapy was muronomab, a murine antibody that targets CD3, a cell-surface molecule present on all T cells, and reduces their number. Because of severe systemic side effects including rapid sensitization and a cytokine release syndrome as well as absence of proven long-term benefits, this substance has almost disappeared from clinical use and therefore is not discussed further.
Anti-interleukin 2 receptor (CD25) antibodies (daclizumab, basiliximab)
CD25, the interleukin 2 (IL-2) receptor α chain, is expressed on activated and regulatory CD4+ T cells and provides transduction of the most powerful signal for T-cell proliferation. Therefore, monoclonal antibodies to CD25 specifically target these T-cell subsets. In contrast to polyclonal antibodies, the monoclonal anti-CD25 antibodies do not necessarily cause depletion of target cells but mainly inactivate the function of the IL-2 receptor (IL-2R). This prevents T lymphocytes from becoming activated and actively engaging in the immune response toward the donor organ. Despite expression of CD25, regulatory T cells seem to be less targeted by anti-CD25 antibodies than activated T cells and are more likely to persist beyond resolution of the receptor blockade. This finding explains why it is crucial to administer the antibodies before the implantation of the graft (typically infusion starts about 2 hours before transplant operation). Thus the blockade of massive early T-cell activation outweighs the theoretic disadvantages of inactivation of immune-suppressing regulatory T cells. Administration of IL-2R blockade after transplant has been found to be clinically less beneficial.
Basiliximab is a chimeric (mouse/human) antibody. It is generally administered in 2 doses of 12 mg/m 2 with the first infusion starting about 2 hours before transplant and the second on day 4 after transplant. With a half-life of approximately 7 days, this regimen in pediatric kidney transplant patients has been found to provide IL-2R saturation for 5 weeks when used without mycophenolate mofetil (MMF) and 10 weeks when used in combination with MMF. A shorter saturation interval has been found to be associated with higher rates of early acute rejection.
Daclizumab is a humanized antibody (<10% mouse and more than 90% human). Although the general aim of humanizing an antibody is a lower likelihood of sensitization in the recipient, this is not clinically proven for daclizumab. The recommended dosing of 5 doses of 1 mg/kg at intervals of 14 days starting shortly before transplant provides complete saturation of CD25 for at least 3 months, but regimens of only 2 doses have also been used and lead to saturation for 10 to 12 weeks. Daclizumab was withdrawn by the marketing authorization holder from the European market for commercial reasons in January 2009, but is still licensed and distributed in North America.
Several multicenter studies in adults have shown a significant reduction in the occurrence of acute rejection in the first year following kidney transplantation using basiliximab or daclizumab. Occurrence of side effects was comparable to the placebo groups, and long-term follow-up studies showed no increased incidence of infectious complications or PTLD. However, induction with either IL-2R antagonist failed to show long-term increased graft or patient survival in studies in kidney transplantation, confirmed by a Cochrane meta-analysis. The observations in adult heart transplantation are similar, showing low occurrence of side effects and reduction of early acute rejection but failing to prove long-term benefit for patient or graft. Few studies have been performed in pediatric patients.
Use of Induction: When and Which?
Currently available data do not allow a definitive recommendation as to whether the use of induction therapy in general is beneficial to pediatric transplant patients. Moreover, the question of which type of induction to use remains unresolved. Although the immediate benefits of induction treatment are undisputed in terms of reduction of acute rejection and improved early renal function, none of the available agents has shown a significant improvement in long-term outcomes in follow-up studies and registry reports. This finding, however, needs to be interpreted with caution as it is subject to confounding factors. With general improvement in the management of transplanted children, there has been a tendency to offer organ transplantation to more critically ill patients. Some centers use induction preferentially in the sickest patients and therefore generate a negative selection bias in registry data. Furthermore, actuarial survival analysis (eg, from the ISHLT Registry ) sometimes focuses on conditional survival of patients who were still alive at various time points after transplantation and therefore may not capture deaths associated with severe infections or overwhelming immune activation in the perioperative period immediately after induction therapy.
Across the different organ groups in pediatric transplantation, the use of induction therapy remains controversial and highly variable. Only about 20% of pediatric liver transplant patients receive any induction. In pediatric heart transplantation, the use of induction treatment has consistently increased in recent years except for a slight decline for the first time in 2008, with a reported use of CD25-directed antibodies in about 22% and polyclonal cytolytic agents in 38% of patients. In the last 10 years 10% to 15% of pediatric lung transplant recipients received polyclonal induction and 30% to 50% received CD25-directed antibodies. In pediatric kidney transplantation, the frequency of polyclonal induction declined until the beginning of the century, with a slight increase to 16% in deceased-donor and living-donor transplant recipients in the 2008 NAPRTC report. The use of monoclonal antibodies has consistently increased in the last 10 years to 50% in living-donor and 51% in deceased-donor pediatric kidney transplant recipients. Within this group muronomab has nearly disappeared and been replaced with basiliximab or daclizumab.
Overall it is appropriate that the use and type of induction treatment is tailored to the individual situation and the specific needs of a transplant candidate considering the benefits and risks. More recently developed drugs such as alemtuzumab (ATM) and costimulator targeting agents such as belatacept are discussed in the section about new developments.
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