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Graft Failure and Adaptation Period to Adult Healthcare Centers in Pediatric Renal Transplant Patients

Samuel, Susan M.1,2,11; Nettel-Aguirre, Alberto1,3; Hemmelgarn, Brenda R.4; Tonelli, Marcello A.5; Soo, Andrea6; Clark, Camillia1; Alexander, R. Todd7,8; Foster, Bethany J.9,10Pediatric Renal Outcomes Canada Group

doi: 10.1097/TP.0b013e31821b2f4b
Clinical and Translational Research

Background. Transfer from pediatric to adult care may require a period of adaptation to the new healthcare environment. We sought to determine whether this adaptation period was associated with an increased risk of graft failure.

Methods. Children (age, 0–18 years) recorded in the Canadian Organ Replacement Register who received a first kidney transplant in a pediatric health center between 1992 and 2007, and who had more than or equal to 3 months of graft function, were followed up until death, loss to follow-up, or December 31, 2007. Cox proportional hazards models were used to estimate the excess risk associated with a period of adaptation to adult-oriented care, defined as the interval 0.5 years before to 2.5 years after the first recorded adult care visit. Models were adjusted for age, gender, donor source, and ethnicity.

Results. Of the 413 patients evaluated, 149 were transferred to adult care during study period. In total, 78 (18.9%) patients experienced graft failure—23 during the adaptation period. Compared with the period before adaptation, the adjusted hazard ratio for graft loss within the adaptation period was 2.24 (95% confidence interval [CI]: 1.19–4.20). The adjusted graft failure rate was 2.26 (1.04–4.93) times higher after 18 years of age than between 0 and 13 years. Aboriginal ethnicity and deceased donor source were also associated with a significantly higher risk of graft failure.

Conclusions. The period of adaptation to adult-oriented care is associated with a high risk of graft failure in pediatric renal transplant patients.

1 Alberta Children's Hospital, Calgary, Alberta, Canada.

2 Division of Nephrology, Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada.

3 Departments of Pediatrics and Community Health Sciences, University of Calgary, Calgary, Alberta, Canada.

4 Division of Nephrology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada.

5 Division of Nephrology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.

6 Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada.

7 Stollery Children's Hospital, Edmonton, Alberta, Canada.

8 Division of Nephrology, Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.

9 Montreal Children's Hospital, Montreal, Quebec, Canada.

10 Division of Nephrology, Department of Pediatrics, McGill University, Montreal, Canada.

This study was supported by operating grants received from the Alberta Children's Hospital Foundation and Alberta Health Services, by New Investigator Awards from the Canadian Institutes of Health Research (M.A.T. and B.R.H.), by a Population Health Scholar Award (M.A.T.) and a Population Health Investigator Award (B.R.H.) from the Alberta Heritage Foundation for Medical Research (AHFMR), by Fonds de la recherche en santé du Québec Chercheur-Boursier Clinicien award (B.J.F.), by a Clinician Scientist Award from CIHR, a KRESCENT New Investigator Award and an AHFMR Clinical Investigator Award (R.T.A.), and by an AHFMR clinical fellowship award which facilitated the data acquisition period for this study (S.M.S.). The sponsors did not participate in analyses or influence the decision to submit for publication. The authors have no relevant competing financial interests to disclose.

Parts of this material are based on data and information provided by the Canadian Institute for Health Information. However, the analyses, conclusions, opinions, and statements expressed herein are those of the authors and not those of the Canadian Institute for Health Information.

Presented as a poster at the American Society of Nephrology 2010 meeting in Denver, CO.

11 Address correspondence to: Susan M. Samuel, M.D., M.Sc., Alberta Children's Hospital, 2888 Shaganappi Trail NW, Calgary, AB, Canada.


S.M.S., M.A.T., B.R.H., and A.N.-A. conceived the study design, applied for grant funding, and obtained the dataset used in this study; S.M.S., B.J.F., and A.N.-A. directed the study design, data analysis, and interpreted the results; S.M.S. wrote the manuscript and all co-authors performed critical review of the manuscript; A.S. participated in the study design and performed the data analysis; and C.C. and R.T.A. critically reviewed the manuscript.

Received 28 December 2010. Revision requested 25 January 2011.

Accepted 17 March 2011.

Children with end-stage renal disease (ESRD) now live well into adulthood and must adapt from receiving medical care in pediatric health centers to receiving care in adult health centers in which there may be reduced availability of care providers for questions and support, and greater emphasis placed on the patient's responsibility for self-care (1). Transfer to an adult health center is currently mandated at the of age 18 years in many pediatric institutions. Timing of this transfer generally coincides with the potentially vulnerable adolescent developmental period, during which issues such as nonadherence with medications and risk-taking behavior may increase (1–3). It is well known that adolescent and young adult age at the time of renal transplant is associated with a higher risk of graft failure compared with younger and older age at transplant (4–7). Graft failure risk may be higher during adolescence and young adulthood irrespective of age at transplant (8). This may be due in part to behavioral and developmental characteristics of this age interval (9–13); transfer of care to adult care centers may also play a role in the unacceptably high rates of graft failure in adolescents and young adults (14, 15).

Among the few studies that addressed the effect of transfer of care on graft outcomes, results were conflicting. A small case series from the United Kingdom reported unexpected graft failure within 36 months of transfer in 40% of kidney transplant patients (14). In contrast, the risk of acute rejection episodes decreased after transfer to an adult care center in a Dutch study (16). However, these studies did not provide information regarding the independent effects of age versus transfer of care on graft failure risk. Because transfer typically coincides with adolescence, it is difficult to separate potential risks associated with the adaptation period after transfer from those associated with age.

The objectives of this study were to estimate age- specific graft failure rates among pediatric renal transplant recipients in Canada and to determine the influence of exposure to the adaptation period after transfer to an adult-oriented care environment on graft failure risk, independent of age. We hypothesized that age-specific graft failure rates would be highest during the adolescent years and that the graft failure risk would be higher during the adaptation period compared with periods before and after adaptation.

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We studied the experience of 413 individuals with childhood-onset ESRD (younger than 18 years) recorded in the Canadian Organ Replacement Register (CORR), who had received a first kidney transplant in a pediatric health facility between January 1, 1992, and December 31, 2007, and for whom the sequence of healthcare facility type (adult vs. pediatric) was clear. Figure 1 details the construction of the cohort. All patients were initially followed up in a pediatric center. The median age at transplant was 12.1 (range 1.1–21.2) years. Median follow-up from first transplant to graft failure, death, or study end was 5.2 (interquartile ranges [IQRs] 2.5–8.7) years, with a total of 2409 person-years of observation. During the interval of observation, 149 patients were transferred to an adult health facility for continued care; the median age at first visit to an adult center was 18.1 (IQR 18.0–19.4) years. Of those not transferred to adult care during the observation interval, 77.3% were aged 18 years or younger at the end of the observation.



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Patient Characteristics

Characteristics of the study cohort are outlined in Table 1. The gender and primary renal disease distributions, and proportion with living donors (47.7%) were consistent with what is generally observed for the pediatric kidney transplant population (17). Most patients were white (62.0%); 2.2% were black and 8.5% were Aboriginal in ethnicity.



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Age-Specific Graft Failure Rates

During the period of observation, 78 patients (18.9%) experienced graft failure. Median time to graft loss was 5.3 (IQR 2.9–8.1) years. Figure 2 illustrates age-specific graft failure rates for ages 0 to less than 22 years.



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Impact of the Adaptation to Adult Care

We defined the 3-year period from 6 months before to 2.5 years after the first-recorded visit at an adult health facility as the “adaptation period.” We compared the graft failure risk in the adaptation period with the risk in the intervals before and after adaptation. Table 2 compares the composition of the experience in the three intervals of interest (before, during, and after adaptation). Thirty-eight graft failures occurred before the adaptation period, for a crude failure rate of 2.2 per 100 person-years. During the adaptation period, 23 grafts failed, for a crude failure rate of 6.6 per 100 person-years, and after the adaptation period, 17 grafts failed, for a crude failure rate of 5.1 per 100 person-years. The results of adjusted models are presented in Table 3. Compared with experience before the adaptation period, the adjusted hazard ratio (HR) for graft loss within the adaptation period was 2.24 (95% confidence interval [CI]: 1.19–4.20). The period after adaptation was also associated with increased risk of graft failure compared with the period before adaptation (adjusted HR 1.44 [95% CI: 0.71–2.91]); however, this difference was not statistically significant. When we examined alternate definitions of the adaptation period, we found a gradient of risk suggesting that the highest risk for graft failure is in the early posttransfer period. Compared with experience before the adaptation interval, the adjusted HR for graft failure within a 1-year adaptation interval (0.5 years before to 0.5 years after) was 5.42 (95% CI: 2.83–10.39) and within a 2-year adaptation interval (0.5 years before to 1.5 years after) was 3.14 (95% CI: 1.67–5.90). Results of adjusted models with varying definitions of the adaptation period are shown in Table 3.





Individuals of Aboriginal ethnicity had a 3.26 times higher risk of graft failure (95% CI: 1.51–7.04) compared with whites. Deceased donor transplant was associated with worse graft survival compared with living donor transplant (adjusted HR 2.25 [95% CI: 1.32–3.83]). The risk of graft failure did not differ significantly by gender. Compared with observed experience at the age of younger than 13 years, the graft failure rate was 2.26 [95% CI: 1.04–4.93] times higher during experience at the age of 18 years or more, after adjustment for all other covariates, including time since transplant (which was the timescale of the model).

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Transfer to adult care occurs during adolescence or young adulthood—a potentially turbulent time in which nonadherence to medications and decreased attendance at clinic visits may be more likely (13, 15, 18–20). Patients undergoing transfer must adapt to a new reality in adult- oriented care; adaptation during the vulnerable adolescent period may be particularly challenging. We demonstrate a progressively higher risk of graft failure with increasing age in the interval between birth and young adulthood, with a significantly higher risk associated with age older than 18 years compared with 0 to 13 years.

Even after accounting for age-related failure risk, we found that the adaptation period, defined as a 3-year interval beginning 6 months before the first-recorded visit to an adult center, was associated with a twofold increase in the risk of graft failure, compared with the period before adaptation for pediatric renal transplant patients in Canada. The magnitude of the relative hazard of graft failure associated with adaptation was even higher when we considered shorter adaptation intervals, suggesting that the risk is concentrated in the early posttransfer period. These observations call for implementation of additional support during the transition from pediatric to adult care, with most intense support immediately after transfer. Alternate models of care should also be considered; these include flexible age of transfer (to accommodate individual patient needs), a clinic devoted to transitional care with participation of both pediatric and adult care providers, and an interval during which care is shared between pediatric and adult care providers.

No prior studies considered the effects of both transfer of care and age on the risk of graft failure. A retrospective study from Ontario, Canada, found little difference in graft failure rates by age during adolescence (graft loss rates per 100 person-years were 5.06 between 14.1 and 17.9 years, 5.63 between 18.1 and 19.9 years, and 5.80 between 20.1 and 23.9 years) and concluded that there was no evidence for higher failure rates during transition from pediatric to adult-oriented care (21). In contrast, a U.S. Government Accountability Office report found that a higher percentage of transplant recipients who were younger than 18 years at the time of transplant and 18 years or older at the time of study experienced graft failure at 3, 5, and 7 years posttransplant than those who had not yet reached 18 years or who had received a transplant at the age of more than 18 years (22). However, neither this nor the Ontario study identified a transfer date; therefore, neither can make specific conclusions about the effect of transfer. Nonetheless, our results are consistent with the findings of the Government Accountability Office report suggesting that patients negotiating the transition from childhood to adulthood—and all that it entails, including transfer of care—are at high risk for graft failure.

Acute rejection rates were substantially and significantly lower after transfer than before (HR 0.10 [95% CI: 0.04–0.28] for Dutch born and 0.69 [95% CI: 0.33–1.40] for immigrant patients) in a recent study of pediatric renal transplant recipients (16). It is difficult to reconcile this large protective effect of transfer with the substantially increased risk of graft loss found in our study. It is possible that the lower posttransfer acute rejection rates were due to less-intense surveillance for rejection during the adaptation period. Adjustment for age as a continuous and non-time-dependent variable in the Dutch study may not have permitted complete control for the effects of age (16).

Although age at transfer of care may vary between centers, the median age at first adult visit in our study was 18 years, with a tight IQR, indicating that transfer occurs within a narrow age range in Canada. We are unable to account for differing transitional care practices across the country in this is registry-based study. Care patterns may vary across centers depending on regional health service delivery, pediatric and adult clinic staff availability, and patient volume. Furthermore, transitional care practices have likely changed over time. We acknowledge that there may be overlapping pediatric and adult care in some centers for part of the adaptation period.

An important strength of this study is the use of a longitudinal population-based cohort from the sole prospective Canadian organ failure registry within a universal access healthcare system. The cohort represents almost all pediatric renal transplants in Canada during the study interval, and as such it has greater generalizability. However, caution should be used in generalizing our results to other countries with different healthcare delivery systems.

This study has some limitations. First, because of the narrow age range at first visit to adult care, there was relatively little representation of the younger age intervals within the adaptation period and after adaptation. Similarly, there was little representation of the older age intervals before adaptation. As a result, it is possible that adjustment for age in the association between adaptation and graft failure risk was incomplete. Regardless of whether the age and adaptation effects are independent of each other, we can conclude that the interval around transition to adult-oriented care is a high-risk period. Second, as was performed by van den Heuvel et al. (16), we used the first visit to adult center to define the adaptation period. However, the first visit to adult center recorded in the registry may not have accurately reflected the first actual visit, that is some patients may have had visits to adult centers and had went unreported before a visit was recorded. This would result in a shift of the defined adaptation period to a later time in some individuals. Given that the adaptation period was quite broad—a 3-year time interval beginning 6 months before first adult ESRD center visit—the impact of small errors in transfer date is likely minimal. Because discrete rejection episodes are not captured within CORR, we could not evaluate the effect of transfer of care on rejection rates. Finally, we were unable to assess potential mechanisms for higher graft loss rates during the adaptation period, such as adherence to medications and clinic visits, because this information is not captured by CORR. Future retrospective studies with examination of primary medical charts, or prospective studies enrolling patients before the transition period, will be necessary to determine the reasons for graft loss during the transition period.

This study demonstrates a significantly higher risk of renal graft loss during the adaptation period between pediatric and adult care in pediatric renal transplant patients in a universal access healthcare system. The findings presented here support the development and implementation of programs to support young transplant recipients after transfer from pediatric to adult care. Future studies will identify determinants of risk during the adaptation period, permitting the development of targeted interventions with the goal of improving long-term graft survival among pediatric renal transplant recipients.

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Study Design and Population

After obtaining institutional ethics approval from the University of Calgary, we performed a retrospective cohort study of all patients in 9 of the 10 Canadian provinces and three territories who initiated renal replacement therapy (dialysis or transplant) at younger than 18 years of age between January 1, 1992, and December 31, 2007, who received their first transplant in a pediatric center, and who had at least 3 months of graft function (Fig. 1). Patients from the province of Quebec were not included as their data were not available for release to investigators. Patients were followed up from date of transplant until outcome (graft failure), death, loss to follow-up, or end of observation (December 31, 2007).

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Data Source

The CORR is the sole national organ failure registry in Canada and is maintained by the Canadian Institute for Health Information. All pediatric and adult dialysis and transplant centers in Canada submit data every 6 months to CORR using standardized forms. CORR data elements include demographics, ESRD treatment modalities, changes in treatment modalities, renal transplant details, comorbidities, and outcomes. The registry data have been used extensively in multiple studies in patients with kidney failure (23–27). Almost all renal transplants in Canada (98.5%) are captured by CORR; demographic data are coded with high reliability (28).

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Exclusion Criteria

We excluded pediatric patients for whom a clear pattern of care (i.e., consistent care at a pediatric center followed by consistent care at an adult center) could not be ascertained. Multiorgan transplant recipients were also excluded.

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Graft failure is reliably and consistently reported in the registry. The primary exposure of interest was the period of adaptation associated with transfer to an adult care environment. We defined adaptation as a 3-year time period beginning 6 months before the first visit to an adult healthcare center (adaptation period is 0.5 years before transfer date to 2.5 years after transfer date). The date of first visit to an adult center is recorded in CORR. This date will not capture missed appointments; therefore, we included a 6-month time interval before first adult clinic visit to allow capture of missed appointments and to minimize the impact of any delays in reporting first visit at an adult center. A 3-year adaptation period is consistent with what has been considered in prior studies and should be sufficiently long to allow adaptation to a new care environment (16). We also examined alternate definitions of the adaptation period (0.5 years before to 0.5 years after transfer and 0.5 years before to 1.5 years after transfer) and the results are presented. Potential confounders in the relationship between graft failure and the adaptation period include age, donor source (living or deceased), gender, ethnic origin (white, Aboriginal, black, Asian/Indian/other), primary renal disease, and socioeconomic status.

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The primary outcome was graft failure.

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Demographic and baseline clinical characteristics were described with medians (IQR) or proportions, as appropriate. A significance level α equal to 0.05 was used in all statistical tests.

Crude age-specific graft failure rates were calculated and plotted for each 3-year age interval from 0 to less than 22 years of age by adding all graft failures observed within a 3-year age interval and dividing by the total person-time observed within that age interval. Therefore, patients could contribute observation time to multiple age intervals. Patients were censored at death or loss to follow-up.

We used Cox proportional hazards models, with time from transplant as the timescale, to estimate the excess graft failure risk associated with being in the adaptation period, compared with the periods before and after adaptation; a three-level, time-dependent adaptation variable was included in the model. All patients started observation in “before adaptation.” Six months before the first adult care visit, they switched to “within adaptation,” where they remained until 2.5 years later (in the primary analysis), when they entered the “after adaptation” period. Additional models in which the adaptation period ended 0.5 years, and 1.5 years after the first adult care visit were also fitted. We adjusted all models for the potentially confounding effect of current age by entering age in the model as a time-dependent variable: younger than 13 years, 13 years to younger than 15 years, 15 years to younger than 18 years and 18 years or older. The models were also adjusted for gender, donor source, ethnicity, primary renal disease, and socioeconomic status. Socioeconomic status, estimated from median neighborhood income, was classified by quintile within the 2001 Statistics Canada census data by linking residence postal codes to census data. Retention of covariates in the final models was determined by statistical significance and minimizing of Akaike's (29) Information Criterion in nested models. Using this model-selection process, socioeconomic status and causes of primary renal disease were not included in the final models. The proportional hazards assumption in all models was tested based on the scaled Schoenfeld residuals (30). All analyses were performed using R (The R Foundation for Statistical Computing,

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The authors thank the director and personnel of the Canadian Organ Replacement Register at the Canadian Institute for Health Information (Dr. John Gill, Lilyanna Trpeski, Yingbo Na, Robert Williams) for their assistance in providing the dataset used in this study.

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Pediatric; Renal transplant; Transfer to adult care; Allograft failure

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