Reduced Kidney Transplant Survival in Adolescence and Young Adulthood: Is it Due to Age, Transfer of Care, or Both?

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Poor kidney allograft survival was first reported in 1997 by Cecka and colleagues (1). Using the United Network Organ Sharing database, they demonstrated that the 5-year graft survival rate among 13- to 21-year-old kidney transplant recipients was worse than the rates observed in other age groups. Subsequently in 2002, Smith and colleagues (2) showed an increased risk of graft failure in 13- to 17- year-old transplant patients registered in the North American Pediatric Renal Trials and Collaborative Studies database. They also observed that there was a significantly higher number of late acute rejection episodes among those receiving transplants between 6 and 17 years of age compared with younger age groups.

These two studies identified adolescent age at the time of transplant as a determinant of poor graft survival, but did not consider the possibility that it is adolescence itself (a developmental period) that determines graft failure risk. Almost all pediatric transplant patients will eventually enter adolescence—a period of major physical, cognitive, emotional, and social development, and of increasing independence. Adolescence can be a volatile and turbulent time in some patients, which makes this period ripe for complications. It is during this vulnerable developmental stage that almost all adolescents are transferred to adult care—around 18 to 21 years of age in most pediatric institutions across North America. Behavioral changes associated with adolescence and upheaval related to transfer of care may combine to increase the risk of graft failure during this period.

Recently, our group estimated age-specific graft failure rates using the United States Renal Data System (USRDS) database (3), and showed a gradual increase in graft failure rates starting at 11 to 12 years of age, peaking at 19 to 21 years of age, and declining thereafter. Compared with 25 to 29 year-olds with the same time elapsed since transplant, graft failure rates were 20 percent higher among 17 to 24 year-olds, regardless of the age they received the transplant. This study provided strong evidence that graft failure risk is age dependent, and that late adolescence and early young adulthood is a high-risk period. This study did not refute the earlier studies’ conclusions that adolescent age at transplant is a risk factor. Rather, it indicated that individuals transplanted as adolescents enter immediately into a high-risk period. We were unable to account for the effect of transfer of care because transfers are not captured well within USRDS datasets.

In 2007, the U.S. Government Accountability Office commissioned a report to investigate whether pediatric transplant recipients are more likely than their adult counterparts to lose access to immunosuppressive medications once Medicare coverage for end stage renal disease (ESRD) ends 3 years after receiving a transplant (4). They used USRDS databases to study this problem. Although the investigators of the report did not find that graft failure was necessarily associated with loss of Medicare, they found that graft failure risk was higher at 3, 5, and 7 years after transplant for patients who had an 18th birthday during observation period compared to older and younger patients. This high-risk group of patients was defined as “transitional” patients as some of them would have been transferred to adult care during the observation interval. This study also could not ascertain the effect of transfer of care due to the limitations of USRDS data. We could postulate that poor transfer of care may have had a role in determining high graft-failure rates in transitional patients. The association between graft failure and age, therefore, has been clearly characterized in these two studies, but further studies are needed to identify the factors mediating the relationship between age and graft failure and, in particular, the role of transfer of care.

The higher graft-failure risk during adolescence and young adulthood has been postulated to be due to a state of net under-immunosuppression related to some or all of the following factors: puberty-related changes in immune reactivity, de novo exposure to viruses, and under-dosing of immunosuppression medication during a period of rapid growth and nonadherence.

Nonadherence with immunosuppressive medications is probably the most widely cited explanation for poor graft outcomes during adolescence. The prevalence of nonadherence among adolescents can be as high as 43 percent. Several studies have shown a greater degree of nonadherence in adolescents compared with older and younger patients. Failing to take immunosuppressants can be a cause for late acute transplant rejection. Therefore, Smith’s finding of increased late rejection and incomplete rejection reversal in the adolescent age group supports nonadherence as a potential mechanism of graft failure in this age group (2).

There are many reasons for nonadherence. Some have suggested that nonadherence may increase immediately following transfer from pediatric to adult care leading to graft failure. This idea was first put forward over a decade ago by Alan Watson, who observed unanticipated kidney transplant failures in seven of 20 patients in the 3 years following transfer of care. Although studies using large USRDS datasets were unable to account for the effect of transfer of care when examining the relationship between age and graft failure rates, a study of Canadian pediatric transplant recipients found a 2- to 5-fold increased risk in graft failure during the period immediately following transfer from pediatric to adult care (5). Nonadherence after transfer of care could not be quantified in this study.

Poorer graft survival after transfer of care suggests that sudden changes in health care system and provider characteristics may create an environment that exacerbates nonadherence and other behaviors that can accelerate graft failure. Medical care for pediatric patients with ESRD generally tends to be intense and multidisciplinary. Staff-to-patient ratios are high and a large amount of time is usually spent on each clinical encounter. Detailed attention is paid to patient compliance with medical appointments and medication. Although such intense support may not be medically necessary for most adult patients, a sudden change in type of care after transfer to adult-oriented care may be disorienting to pediatric patients, who have been accustomed to receiving intense care and attention all their lives. The shift of focus from family to the individual—with emphasis being placed on the patient’s responsibility for his/her own care—has been identified as a factor which may contribute to impaired adherence to therapy following transfer to adult care.

For individuals with ESRD, adapting to transfer of care may be particularly challenging. On the surface, most adolescent and young adult kidney transplant recipients look like their healthy peers. It is easy to forget that they may have severe cognitive deficits related to childhood exposure to renal failure or other medical problems. It is even easier to forget that even healthy adolescents—while physically fully mature—do not complete frontal lobe development until their mid-to-late 20s. Given these challenges, it may be difficult for the adolescent ESRD patient to cope with expectations of increased self-management and independence in the adult care system. Therefore, the high-risk period of adaptation to adult care may be a critical window during which intense support is warranted.

We can conclude that the relationships and interactions between age, graft-failure risk, and transfer of care are complex. In reviewing the current evidence it is difficult to distinguish graft-failure risk attributable to age from that conferred by transfer of care. Patient and health care system factors may all contribute to age-related graft-failure risk. Perhaps, the most important question is how to improve graft outcomes in this vulnerable age interval. This is most likely to be achieved by providing care that is well matched with the developmental needs of this age group. The first step will be to identify patient-, provider-, and system-level factors associated with better outcomes. Then trials need to test multicomponent interventions at the patient, provider, and system levels to optimize care for this group of patients.

Notes

[1] Drs. Samuel and Foster are affiliated with McGill University, Montréal, Quebec, Canada.

References

1. Cecka JM, et al. Pediatric renal transplantation: a review of the UNOS data. United Network for Organ Sharing. Pediatr Transplant 1997; 1:55–64.

2. Smith JM, et al. Renal transplant outcomes in adolescents: a report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Transplant 2002; 6:493–499.

3. U.S. Government Accountability Office. Report to Congressional Requesters: End-Stage Renal Disease: Characteristics of Kidney Transplant Recipients, Frequency of Transplant Failures, and Cost to Medicare. Washington, DC, Government Accountability Office, 2007

4. Foster BJ, et al. Association between age and graft failure rates in young kidney transplant recipients. Transplantation 2011; 92:1237–1243.

5. Samuel SM, et al. Graft failure and adaptation period to adult healthcare centers in pediatric renal transplant patients. Transplantation 2011; 91:1380–1385.

September 2012 (Vol. 4, Number 9)