State-of-the-art immunosuppression protocols for pediatric renal transplant recipients
Immunosuppressive protocols used in pediatric kidney transplantation have changed substantially within the last decade. Many transplant centers now focus on the use of tacrolimus and mycophenolate mofetil in combination with early steroid withdrawal, frequently combined with antibody induction therapy. However, this approach is mainly based on treatment efficacy and—compared to other immunosuppressive regimens used in this context—leads to higher rates of viral infections in patients. In this review I assess data from prospective, interventional trials of immunosuppressive therapy in pediatric kidney transplantation. However, since there is a paucity of randomized controlled trials, I also describe the results of studies with weaker designs. The advantages and disadvantages of different immunosuppressive strategies are discussed. Within this framework I suggest ideas for individualized immunosuppressive regimens based on different stratificators that could effect a change from a ‘one size fits all’ to a tailored approach for initial and maintenance immunosuppressive therapy after renal transplantation in the pediatric setting.
KeywordsPediatric transplantation Immunosuppressive therapy Viral infections Rejections Evidence Graft survival
There have been tremendous developments in transplant immunology and immunosuppression from the first transplant in 1954 to the present era of transplantation. The most common immunosuppressive regimens use a combination of agents with differing modes of action to maximize efficacy and minimize the toxicities associated with each class of agent. Immunosuppressive medications can be categorized into the following categories: glucocorticoids, antimetabolites, calcineurin inhibitors (CNI), antilymphocyte antibody therapies (monoclonal and polyclonal), costimulation blockers, and mammalian target of rapamycin (mTOR) inhibitors. Azathioprine was the first non-steroid immunosuppressant used in organ transplantation and has been used for more than 50 years. In the 1980s cyclosporine A (CsA) was the first CNI to be developed, followed by tacrolimus some years later. The newer antimetabolites mycophenolate mofetil (MMF) and mycophenolic acid are inosine-5′-monophosphate dehydrogenase inhibitors and have mainly replaced azathioprine as the drug of choice. The mTOR inhibitors everolimus and sirolimus have been developed as alternative antiproliferative drugs with antiviral potency. Belatacept was the first costimulation inhibitor to replace CNIs in therapeutic regimens and has been in use now for nearly 10 years. Current induction therapy consists of basiliximab, a monoclonal interleukin 2 (IL-2) antibody, or alemtuzumab, a monoclonal-depleting CD52 antibody, in addition to an antithymocyte globulin (ATG), a polyclonal depleting antibody.
The trend over the last few years towards tacrolimus-based protocols in combination with an antiproliferative drug raises the question as to whether there is any evidence base for these changes in immunosuppressive therapy. In addition, an explanation should be sought for why around half of transplantations are performed with antibody induction therapy and why the use of steroids varies so widely.
Trials in pediatric renal transplantation
Taking the evidence pyramid into account, initial decisions about how to choose the right immunosuppressive regimen should focus primarily on the results of RCTs. Brooks et al. published a survey of RCTs of kidney transplantation in children and adolescents up to 2010 . Unfortunately, many of these trials were on topics other than immunosuppression, such as the use of growth hormones [7, 8], the treatment of osteopenia and osteoporosis , or even the impact of sonic tooth brushing on gingival growth . In 2007, Ferraris et al. tested two different steroids, deflazacort versus methylprednisone , and found that neither therapy had an advantage over the other. Thus, methylprednisone has remained the primary steroid of choice.
In 2002, Trompeter and colleagues published the first ‘landmark immunosuppression trial’ comparing different immunosuppressive regimens (CsA/steroids vs. tacrolimus/steroids) after pediatric kidney transplantation . These authors found that the patients treated with tacrolimus had better graft survival and experienced fewer acute rejections in the first year after transplantation. In this trial CsA dosing was quite low, and transferability to real-life practice is quite difficult because triple immunosuppression with an antiproliferative drug was not used and there was no induction therapy.
The next prospective trial of maintenance immunosuppression in pediatric transplantation was performed by Cransberg and colleagues and published in 2007 . They compared CsA withdrawal versus MMF withdrawal at 1 year after transplantation in two small groups of patients who were previously on CsA/MMF/prednisone therapy. Although the glomerular filtration rate (GFR) improved in the CsA withdrawal group, two patients in this group experienced severe antibody-mediated rejection, leading the authors to conclude that while CsA withdrawal had short-term benefits for kidney function compared with CsA treatment, it was not without risk of complications. It is currently known that CNI-free regimens lead to a higher number of patients with acute  and chronic humoral rejection, and so this study cannot contribute to the debate on modern immunosuppressive protocols.
In 2005, Benfield et al. compared two induction regimens, muromonab-CD3 (OKT3) and intravenous CsA, and found no difference in terms of efficacy or side effects between the arms of the trial . However, newer therapies, such as ATGs and IL-2 antibodies, have now replaced such induction regimens, so that the results of this trial cannot be applied today. In 2008, Offner et al. published another prospective, randomized trial on induction therapy in which they compared induction therapy with basiliximab in a prednisone/CsA/MMF regimen to no induction  in an immunologically low-risk population. The study showed a numerical but not significant decrease in the number of acute rejection episodes in the basiliximab group, and the authors therefore concluded that no significant differences could be shown between the groups. Interestingly, this trial led to a significant reduction in the use of basiliximab, mainly in Europe, and as similar trials have been carried out in adult transplant medicine, there is currently a discussion as to whether there really is a role for IL-2 induction in present-day kidney transplantation . As there is also a scarcity of RCTs on induction therapy in adult transplantation, opinions continue to differ on the value of basiliximab. The IL-2 receptor antagonist daclizumab has been used in several trials, but this agent is unfortunately no longer available.
Höcker and team proved that discontinuing steroids late (12–24 months after transplantation) in a stable, post-transplant population is safe and leads to improved growth and cardiovascular risk . The TWIST study, published in 2010 , was the first study to have a completely different primary endpoint, which was to prove that steroid-free immunosuppression, based on IL-2 receptor antagonist induction followed by tacrolimus/MMF, leads to better growth and has similar efficacy as steroid based immunosuppressive regimens. Interestingly, patients in the control arm received markedly higher doses of prednisone than reported in other multicenter studies (e.g., the study of Sarwal and colleagues ). As a result, it was easier to show a difference in growth patterns in the steroid-free versus on-steroid patients. It is also interesting to note that, although the hypothesis was proven, the intervention group protocol was not adopted as standard in most centers. Sarwal et al. demonstrated in 2012 that steroid-free immunosuppression is feasible in a low-risk pediatric transplantation population using unconventional long-term monoclonal induction with daclizumab . As this agent is no longer available in renal transplant recipients, the results of this study are of limited usefulness today. Two meta-analyses on steroids in immunosuppression have been published. Haller et al. focused on adults in their Cochrane analysis , but came to the conclusion that the effect of steroid withdrawal in children is unclear. Zhang et al.  evaluated the effect of steroid avoidance or withdrawal in a meta-analysis of five RCTs. They demonstrated that (1) an increase in the delta height standard deviation score (SDS) was present at the first year but that there was no significant difference thereafter, (2) the benefit was seen only in pre-pubertal patients, and (3) there were no significant differences in delta height SDS when complete avoidance was compared with early or late withdrawal. They also concluded that there was no significant difference in the risk of acute rejection between steroid avoidance or withdrawal. Late withdrawal was associated with a lower risk of rejection than early withdrawal or steroid avoidance. There was no difference in graft function between the groups, but steroid withdrawal was associated with a lower incidence of post-transplant diabetes mellitus and arterial hypertension. The primary limitation of these trials was that the cohort consisted mainly of immunologically low-risk Caucasian patients.
Many transplant physicians still do not use steroid-free or steroid-withdrawal protocols, even in low-risk, pre-pubertal, Caucasian patients. This may, in part, be due to the study published by Benfield and colleagues  which found an unacceptably high number of patients with post-transplant lymphoproliferative disease (PTLD) following treatment with a steroid-free immunosuppressive regimen comprising full-dose CNI and sirolimus . PTLD was mainly seen in Epstein–Barr (EBV)-naïve young children. At the time when this trial was conducted, the routine regular surveillance of EBV was not in practice. This immunosuppressive combination was therefore rated as overimmunosuppression.
Sirolimus was used as the mTOR inhibitor in the trial conducted by Benfield and colleagues in 2010 . In the last few years, however, everolimus has been the most widely used mTOR inhibitor in studies on pediatric kidney transplantation. Consequently, it is very difficult to draw any conclusions on the use of sirolimus or to establish whether sirolimus could replace the newer agent should everolimus not be available. A second RCT, the CRADLE study, using mTOR inhibitor-based immunosuppressive therapy with steroid withdrawal 9 months after transplantation has recently been conducted . In this study patients were randomized to a group receiving standard treatment with steroids and a group receiving full-dose tacrolimus and MMF, versus an intervention group treated with low-dose tacrolimus and everolimus with steroid cessation planned 5–6 months after transplantation. The authors found that in fact 22% of patients were still on steroids at 9 months after treatment initiation and the majority (>90%) were only off steroids at month 12. One-year data showed no differences in efficacy parameters between the group receiving the standard treatment and the one receiving tacrolimus and MMF, but there were some differences in side effects between these groups and the intervention group, as well as a higher discontinuation rate in the latter group . However, the final 3-year data are still awaited. The IVIST study, an RCT in pediatric kidney transplantation, is currently under way. In this trial both arms receive similar immunosuppression therapy (low-dose CsA and everolimus) and in the intervention group the dose of immunosuppression is additionally steered by the level of virus-specific T cells . As this study is still ongoing, there are no published results to inform clinical decisions about the use of everolimus. It has to be taken into account that everolimus has not yet been approved by the U.S. Food and Drug Administration (FDA) and other national authorities for use in pediatric renal transplantation.
Summary of randomized trials in children
Summarizing the results of these randomized pediatric trials, it would appear that tacrolimus has some advantages over CsA in pediatric kidney transplantation, steroid-free protocols are feasible in low-(immunological) risk Caucasian patients if there is no overimmunosuppression, and induction therapy with IL-2 receptor antagonists might not be advantageous in a standard-risk population. Of note, there is no randomized, controlled, prospective trial to prove the advantages of combination therapy of tacrolimus or prednisolone and CsA or tacrolimus with MMF in pediatric patients in comparison to CsA/tacrolimus with steroids. Consequently, evidence from adult trials has to be relied upon. Concerning the use of mTOR inhibitors, only 1-year results from one randomized trial are currently available.
Non-randomized studies and different endpoints
As the results from the studies discussed in previous sections are not sufficient to base decision-making on the ‘right’ choice of immunosuppressive regimen, and as no other prospective, randomized trials have been carried out, cohort (registry data) and case–control studies must be considered in the decision-making process for selecting the best immunosuppressive regimen in children. In a retrospective analysis carried out in 2001, Stakewitz et al. showed that additional therapy with MMF can reduce the number of acute rejections , and in another retrospective study published in 2003, Henne and colleagues proved that the addition of MMF to an immunosuppressive regimen can reverse the loss of GFR . Concerning the use of the mTOR inhibitor everolimus, Brunkhorst et al. described a similar efficacy to that of a standard regimen but with different side effects . In the everolimus group, there were fewer viral infections [BK polyomovavirus (BKPyV)/cytomegalovirus (CMV)], whereas raised cholesterol levels and arterial hypertension were more frequent . A cohort analysis performed by Höcker and the CERTAIN group confirmed that mTOR inhibitor-based immunosuppression significantly reduces the risk of CMV viremia in patients with and without valganciclovir prophylaxis . The North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) results show fewer graft losses for children in whom no induction therapy was used , but these results are undoubtedly skewed by the more frequent use of induction therapy (such as rabbit ATG) in children with higher immunological risks. The results therefore demonstrate that registry data should be interpreted cautiously when used to develop clinical therapies. The depleting antibody alemtuzumab is mainly used in the USA for highly sensitized children, and in low-risk living donation kidney transplantation, reasonable long-term results can be achieved . For newer immunosuppressants, even cohort studies might not be available. For example, in a single-center study belatacept was administered to a small cohort of non-adherent adolescents as a switch from standard immunosuppression therapy only in the case of non-adherence-related increase . The results showed that GFR improved if the switch took place sufficiently early . However, it is very difficult to draw any conclusions from such a small retrospective study with the aim to develop recommendations for the use of immunosuppressive therapy. Additionally, it has to be taken into account that also belatacept has not yet been approved by the FDA and other national authorities for use in pediatric kidney recipients.
Studies in adults
Another option for obtaining evidence for correct practice in pediatric patients is to use data from studies carried out in adults. Although the physiology of children is clearly different to that of adults, adult studies frequently help to inform the direction of future research in children. Unfortunately, many of the trials carried out in adults are never repeated in children, so that pediatricians often have to extrapolate results from adult transplant medicine into their decision-making process. The limitations of this review does not permit a summary of the high number of immunosuppressive studies performed in adults. However, two examples from the New England Journal of Medicine illustrate how adult studies find their way into pediatric transplant medicine. In the ELITE-Symphony trial, Ekberg et al. showed the advantages of reduced-dose tacrolimus/MMF immunosuppression over CsA- and sirolimus-based regimens . This study forms the basis for why tacrolimus/MMF-based immunosuppression is the most frequently used immunosuppressive regimen in both adults and children. In another trial, 7-year data on the use of the co-stimulatory blocker belatacept in adults showed significantly better GFR than a CsA/MMF-based standard immunosuppression . Interestingly, these results have not yet led to a change in standard immunosuppressive therapy even in adults, probably because of the need for intravenous treatment and the higher cost. However, they may serve as a fundamental basis for the use of belatacept in adolescents, as described above.
So, what to do now? The easiest answer to the question of what is the best immunosuppressive regimen for children and adolescents would be that current data are insufficient to enable an informed response and that new prospective RCTs are needed. However, this answer does not help in the daily decision-making process of nephrologists on how transplanted children should be treated. It is also unlikely that any such trials will be carried out in the near future. We therefore have to rely on the data described in the preceding sections and our own personal experience; it is simply not possible to rely solely on evidence-based medicine.
The analyses that have been carried out on induction therapy do not really prove that in a standard, low-risk pediatric population with late-steroid withdrawal the use of such treatment is advantageous for patients. However, induction with IL2-receptor antagonists might have a role in steroid-free immunosuppression and early steroid withdrawal, or in those high-risk patients with contraindication for ATG therapy. In children who are sensitized, rabbit ATG seems to be an agent which leads to better outcome, and published studies do not demonstrate a higher risk for the development of malignancies among patients receiving this therapy . Alemtuzumab may also play a role in high-risk patients.
Unfortunately, the IL2-receptor antagonist daclizumab and now more recently alemtuzumab were or are being phased out of use for transplantation, and they are or will be only available for the treatment of multiple sclerosis. This is unfortunate since both have been useful drugs, particularly in pediatric renal transplantation, but commercial decisions have been made that are causing the withdrawal of these agents.
Even taking into account the fact that no randomized trials have been performed comparing CsA/MMF and tacrolimus/MMF in children, the mainstay of immunosuppression is still tacrolimus in combination with MMF, as proven by the ELITE-Symphony Study in adults . In addition, tacrolimus leads to fewer side effects, such as hirsutism and gingival hyperplasia, that represent a significant burden in pediatric kidney transplantation. However, it should also be borne in mind that data from the 3-year follow-up of this study are not as clear as the 1-year results. On the other hand, CsA may still play a role in patients at higher risk for BKPyV infection and post-transplant diabetes mellitus, as the risks for these are higher with tacrolimus than with CsA. Some of the studies described above have shown that a combination of an mTOR inhibitor and a low-dose CNI leads to similar results as standard immunosuppression, but with a different risk potential. While there are some disadvantages to mTOR inhibitor-based immunosuppression, such as higher cholesterol levels or its restricted use in proteinuric patients, but particularly for children who are BKpyV- and/or CMV-naïve, this immunosuppressive regimen might be, if not the first choice, a good alternative to tacrolimus/MMF.
Steroid-free immunosuppression, or an immunosuppressive regimen that eliminates steroids early or late, seems feasible, at least for Caucasian low-risk pediatric patients. This is especially true for pre-pubertal children as they profit from better growth and from a reduction in the lifelong negative effects on cardiovascular risk. There are as yet no studies in high-risk patients, and physicians must therefore make their own decisions about whether to continue using steroids.
As only preliminary data exist, the future role of belatacept cannot yet be determined, but in selected cases in adolescents with non-adherence this agent might be worth considering. For 16- to 18-year-old patients it may be possible to extrapolate results from adult patients, since patients falling in this age group are at high risk of organ loss due to non-adherence. However, the higher risk of EBV immunoglobulin G-negative patients developing PTLD should be taken into account and therapy restricted to EBV IgG-positive patients only, accompanied by strict EBV monitoring. Consequently, belatacept does not seem to be an option for children aged <10 years.
Fundamentals of individualized immunosuppressive selection as a possible basis for discussion of decisions made at individual centers
Possible individualized therapy
Low immunological risk + steroids
No induction therapy
Low immunological risk, steroid free or early steroid withdrawal
IL-2 receptor antagonist
High immunological risk
ATG or alemtuzumab
Standard immunologic risk (Caucasians)
Steroid-free immunosuppression or early/late steroid elimination
High immunologic risk
Continuous steroid therapy
Basic immunosuppressive therapy
Tacrolimus + MMF
Risk of post-transplant diabetes/BKPyV
CsA + MMF
CMV IgG negative patients
Low-dose tacrolimus/CsA + everolimus
BKPyV replication despite CNI reduction
Low-dose CsA + everolimus
Non-adherence in adolescents, 16–18 yrs
Belatacept + mTOR inhibitor or MMF (switch) as early rescue therapy
Compliance with ethical standards
Conflicts of interest
Lars Pape has received speaker’s honoraria and travel grants from Novartis Pharmaceuticals and travel grants from Astellas and Sanofi Aventis.
This article does not contain any studies with human participants performed by any of the authors.
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