Well over 50% of pediatric renal transplants are performed in adolescents (1). Numerous studies have demonstrated that, although those transplanted as adolescents have the best 3-month and 1-year graft survival among all age groups (including all adult age groups), the 5-year graft outcome is among the worst of all age groups (2, 3).
Although helpful in a general way, studies that classify pediatric patients according to age groupings at the time of transplant have obvious methodologic shortcomings. When, for example, a group of patients 13 to 18 years old are considered, it is impossible to know at what specific age individual patients run into trouble with their graft function. For in pediatrics, it is not the age at which a patient is transplanted that is relevant so much as it is the age at which the patient begins to experience medical complications.
In this issue of Transplantation, Foster et al. (4) have written a seminal article which more precisely identifies the ages at which adolescents experience graft loss. This article uses the huge United States Renal Data System database and control for time posttransplant in their analysis. The authors demonstrate that beginning at approximately 9 years of age, adolescent patients experience year to year graft loss at an ever increasing rate until it peaks at an age of 19 to 20 years. They also demonstrate that in children younger than 12 years old, the rate of graft loss increases dramatically over the late posttransplant period. The greatest incidence of graft failure occurs in patients aged 17 to 24 years. Foster et al. found that, in young children at the time of transplant, the highest rate of graft failure occurred some 13 to 17 years posttransplant, whereas higher failure rates were found in the years immediately following transplant among those transplanted during adolescence (4).
The reasons underlining these findings are by no means obvious because the process of graft loss in pediatric transplantation is not a straightforward process. The most obvious explanation of the findings of Foster et al. is medication nonadherence. The undeniable characteristic of pediatric transplant medicine is that patients go though a stepwise progression of physical, psychologic, and immunobiologic changes. The developmental tasks that the adolescent must accomplish are well documented. Adolescents are navigating the difficult task of establishing individuality, while still being somewhat dependant on their family. The importance of peer pressure to not appear different, the difficulty of thinking abstractly rather than concretely, and the emerging issues of sexuality, all of these help contribute to the adolescent's vulnerability when it comes to medication administration. This is certainly not helped by the omnipresent ambivalence of the family when it comes to deciding how much and when to give increased levels of freedom to the adolescent.
Unfortunately, the level of research dealing with adolescent medication nonadherence (and truth to tell, all of nonadherence) leaves the clinician wanting as to how to confront it. There is ambiguity as to the definition (how much nonadherence is enough to eventuate in graft damage), the best method(s) to detect nonadherence, and the approach(es) to ameliorate it (5). A discussion of adolescent nonadherence is beyond the scope of this short commentary. But it is important to remember that nonadherent behavior is a pattern established over a long period of time and often doesn't manifest itself clinically until pathologic processes (acute and chronic rejection) are far along in their evolution.
The process of graft loss in the adolescent and the young adult may be accentuated by other immunobiologic processes. Human immune responses vary considerably from individual to individual, and it is increasingly clear that this variability is dynamic and continually influenced by one's response to environmental pathogens, particularly viruses (6–10). It is hypothesized that exposure to viruses, particularly herpes viruses, expands an individual's alloreactivity repertoire. Because most young children are naïve to the herpes viruses, they experience these viruses over time, frequently during adolescence. In short, adolescents may become more immune reactive at different times as they mature and experience vial infection. Thus, while it is tempting to ascribe graft failure in adolescence to nonadherence, it is important to recognize that the results of Foster et al. may relate as much to an unfortuitous intersection of immune maturation with the developmental variability of the adolescent. Thus, there are two potential sides to consider: less consistent adherence to drug regimens, and heightened vulnerability, varying from recipient to recipient, resulting from mounting heterogeneous T-cell memory. As such, understanding pediatric transplant outcomes may require simultaneous consideration of behavioral and immunologic factors. It is reasonable to postulate that, to the extent that nonadherence results in allograft rejection, it will have detectible immunobiologic correlates.
The finding of Foster et al. (4) that the ages of maximum graft loss extend from 17 to 24 years brings into stark relief the concerns about transitioning patients from pediatric to adult care. The authors' database could not formally address this issue. Nonetheless, there is ample data suggesting that this is a time of peril for recipients who move from pediatric to internal medicine care (11, 12). The precise reasons for this phenomenon are beyond the scope of this discussion, but it is safe to say that there are a number of factors that can be implicated. Although it has been demonstrated that medication nonadherence is the key reason for graft loss (11, 13), there is information that this may not be the total answer, at least as judged by acute rejection rates. A recent study from centers in Amsterdam and Nijmegen found that the incidence of acute rejection episodes did not differ between the times before and after the patients were transitioned from Pediatric to Internal Medicine care (14). Nevertheless, it is likely that the failure to continue with an appropriate immunosuppressive regimen for whatever reason (e.g., loss of insurance status and failure to connect with appropriate health care providers) can hasten the progression of chronic kidney injury in the kidney absent overt acute rejection episodes.
A Paradigm Shift
The study of Foster et al. (4) is the first to directly demonstrate evidence that pediatric patients continually undergo developmental changes that directly impact renal allograft outcome. It should cause us to reexamine our clinical and scientific practices to enhance allograft outcome in this challenging population. Perhaps the most important paradigm shift in our practice is to recognize that while successfully transplanted prepubertal children with good social situations could be followed as infrequently as once every 3 to 4 months, this is likely not so for patients who reach age 11 years or above, or who are transplanted in their teenage years. As they transit through adolescence, our patients should be followed much more closely, even if their medical course is uneventful. Our follow-up visits should target not only the patients' emerging medical needs but also their emerging psychologic requirements. In this area, skilled social worker and psychology support will prove to be as important as the physical examination and the laboratory determinations. It is important to recognize that this is not just an issue for patients transplanted in their adolescence but also for children who were transplanted in their prepubertal years, for they too will reach adolescence and experience the same developmental issues.
A Few Modest Suggestions
With our current technology, it is virtually impossible to detect with certainty when adolescent patients are nonadherent with immunosuppressive medications. There is no perfect self-reporting tool that can guarantee that patients will be telling the truth about their medication adherence practices. Drawing from the experience of Stuber et al. (15) in the pediatric liver transplant literature, our center has developed a new technique using the percent coefficient of variation over a period of time to determine by serial drug levels whether a patient is at higher risk for rejection from nonadherence (16).
But this technique, just as with current electronic monitoring, only gives us a picture of what has happened over a defined period of time. What is needed is some form of instantaneous reporting (using radio frequency identification chips or other electronic means), so that the team can react in a much more timely manner. But when dealing with adolescents, along with more sophisticated detection techniques, some manner of incentivization will be mandatory to get the adolescents to “buy into” the requirement for adherence, because, as outlined above, there are so many issues that emerging adolescents must negotiate.
Other technical, immunologic, and immunosuppressive strategies would possibly lend themselves to enhancing graft outcome in this population. Reliable immune monitoring, for example, might prove to be very advantageous to adolescent transplant recipients (17). Similarly, the use of markers of acute kidney injury could be studied as a means to monitor posttransplant adolescents (18). In fact, what is really required is a robust, reliable test of global immunosuppression so that maintenance medications can be tailored to the individual In addition, if the onset of viral infection does play a role in an enhanced immune responsiveness (see above) and graft loss (19), then increased monitoring for viral infections also will have a role in improving graft outcome in this age group.
The use of parenteral maintenance immunosuppressive agents would be useful here. Agents such as the new costimulatory blockade biologics (e.g., belatacept) could provide a means of long-term immunosuppression that may relieve the adolescent of taking oral agents in a rigidly prescribed manner (20). It goes without saying that the attainment of any form of clinical or operational tolerance would be of inestimable value (21). On a more mundane note, pediatric nephrologists will tend to continue with the same doses of maintenance immunosuppression and not make allowance for a child's often stunning growth. This is particularly true with drugs where levels cannot be measured, such as corticosteroids.
As noted above, the area of “Transition” has gained a good deal of traction in the pediatric and adult transplant medicine communities (22, 23). Many centers are setting up transition clinics, which have helped ameliorate the loss of allografts during late adolescence and young adulthood (24). However, as the data from the study by Foster et al. show, this still is a desperate time for these renal transplant recipients. Most centers have a “date certain” by which recipients must be transitioned to adult medicine care. This procedure, although common, may be ill advised. What is needed is a standardized, validated “transition tool” to identify when a patient is ready to assume adult responsibilities for his/her transplant care. There are attempts to create such a tool (25), but none are ready for “prime time.” As a medical community, we must seek to rely less on arbitrary age cutoffs and individualize the time of transition based on objective-validated criteria (23). Nephrologists trained in both pediatric and adult transplant nephrology may be vital in this effort. Where these individuals are not available, pediatric transplant nephrologists must have the active support of internal medicine nephrologists and surgeons (so-called “Transition Champions”) (23) to individualize the care necessary to avoid the disturbingly high incidence of graft failure in the 17 to 24 year olds. The recommendation, made above, that all children who reach the start of adolescence should be followed move closely would allow pediatric nephrologists to begin the transition training much earlier than it is in most centers (23). Because the training for transition requires such a long time period, the developmental issues of the adolescent require a long lead time if we are to effect change in the appalling rates of graft failure in the late-adolescent/young adult population.
In summary, the important contribution of Foster et al. should rouse the pediatric (and adult) transplant medicine communities to alter their practices so that the high tide of graft failure in adolescents can be stemmed. These few suggestions made here are certainly not the only ones that may be applicable. But they may be useful starting points in the dialogue as to how we may be better able to address the phenomena that have been described by Foster et al.
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