Optimizing outcomes for pediatric recipients†
Potential conflict of interest: Nothing to report.
1. After liver transplantation (LT), the majority of children now grow into adulthood, with 10-year patient survival rates of 74% to 84% and graft survival rates of 62% to 72% according to United Network for Organ Sharing data.
2. Graft and patient survival rates decrease for patients undergoing transplantation between the ages of 12 and 17 years, and this raises the importance of dedicated adolescent care and appropriate transitioning to adult services.
3. Complications associated with long-term immunosuppression, including renal complications, infections, malignancies, and cardiovascular complications, are well described, and the risk factors are defined.
4. Biomarkers for measuring clinical immunosuppression and the concept of tolerance-inducing regimens are exciting, but further assessment is needed in large, prospective, multicenter studies.
5. As long-term medical complications are better managed, we need to focus on understanding the challenges for pediatric LT patients with respect to quality of life and health status. Liver Transpl, 2012. © 2012 AASLD.
Since the start of pediatric liver transplantation (LT), improved surgical techniques and newer immunosuppressive agents have improved patient and graft survival, with the majority of patients now moving into adolescence and adulthood; this success has brought its own challenges. United Network for Organ Sharing data from 2010 show rates of 10-year patient survival after deceased donor LT varying from 74% (12–17 years) to 84% (1–5 years) and rates of graft survival varying from 62% (12–17 years) to 72% (1–5 years).1 Another factor affecting long-term survival is the type of graft, with a slightly higher 5-year survival rate reported for living donor grafts (82%) versus deceased donor grafts (73%).1
A 1-day clinical research workshop on improving long-term outcomes for pediatric LT recipients was held on February 12, 2007 in Washington, DC. The speakers' topics were germane to research priorities delineated in the chapters on pediatric liver diseases and LT in the Trans-NIH Action Plan for Liver Disease Research,2 and the following were identified:
- 1Identification of risk factors associated with complications of long-term immunosuppression.
- 2Development of tolerance-inducing regimens.
- 3Definition of biomarkers that reflect the level of clinical immunosuppression.
- 4Development of instruments for the measurement of health wellness.
- 5Identification of risk factors that impede growth and intellectual development before and after LT.
- 6Identification of barriers and facilitators that affect nonadherence and the transition of care for adolescents.
Where are we 5 years later?
IDENTIFICATION OF RISK FACTORS ASSOCIATED WITH COMPLICATIONS OF LONG-TERM IMMUNOSUPPRESSION
The complications associated with the long-term use of immunosuppressive agents and more specifically calcineurin inhibitors and steroids are well known and well described for both pediatric and adult transplant patients. The most common complications are renal impairment, Epstein-Barr virus (EBV) infections and posttransplant lymphoproliferative disorder (PTLD), and cardiovascular complications (including diabetes and hypertension). Large multicenter databases such as the Studies of Pediatric Liver Transplantation (SPLIT) database and recent publications concerning long-term outcomes after pediatric LT have reported on this.
The reported incidence of chronic renal impairment after LT in children varies from 17% to 25%. Calcineurin inhibitors cause nephrotoxicity (either acute or chronic). Tacrolimus is thought to be less nephrotoxic than cyclosporine because it causes less renal vasoconstriction. Risk factors identified before transplantation include renal impairment, hepatorenal syndrome, and an older age at transplantation, whereas a decreased glomerular filtration rate 1 year after LT, hypertension, and liver disease with known renal involvement (Alagille syndrome, metabolic conditions, or congenital hepatic fibrosis) are posttransplant risk factors.3 The effects of the introduction of interleukin-2–blocking agents and other induction agents in the perioperative period and the proactive use of a more renal-sparing immunosuppressive regimen using agents other than calcineurin inhibitors (eg, mycophenolate mofetil and sirolimus) in patients with impaired renal function or identified risk factors have been reported; however, large multicenter studies are not available. Also, the monitoring of renal function in children with liver disease has become more accurate through the use of other methods such as cystatin C because serum creatinine levels and calculated glomerular filtration rates are not reliable in this population.
EBV Viremia and PTLD
EBV-related PTLD is a result of unrestrained lymphoproliferation secondary to inadequate surveillance against EBV-immortalized B cells, and its spectrum ranges from self-limited polyclonal proliferation to malignant monoclonal lymphoma. It is more common after intestinal transplantation and constitutes 50% of posttransplant malignancies. Risk factors associated with EBV infections and PTLD are the age at transplantation and a naive EBV status before transplantation. Increased awareness, regular and more accurate monitoring with molecular testing (EBV DNA), and alterations of the blood levels of immunosuppression in patients who become EBV-positive or EBV-reactive after LT, together with improved therapeutic options such as the use of rituximab, may contribute to a milder phenotype of the disease and improved clinical outcomes.4
Cardiovascular disease–related risk factors have increased significantly among children and adults after solid organ transplantation and include hypertension, dyslipidemia, and diabetes mellitus as well as an increased body mass index. Induced by calcineurin inhibitors and steroids, hypertension has been reported to occur in 15% to 28% of LT recipients. Risk factors for the development of post-LT diabetes mellitus include the age at transplantation, treatment with tacrolimus (versus cyclosporine), steroid use, hyperglycemia in the peritransplant period, obesity, a sedentary lifestyle, and a family history of diabetes mellitus, and these factors are similar across all types of organ transplantation.3
DEVELOPMENT OF TOLERANCE-INDUCING REGIMENS
This is a very exciting area of posttransplant medicine. The definition of tolerance is the “condition whereby a transplanted organ has normal function and lacks histological signs of rejection in the absence of immunosuppression.” A state of clinical operational tolerance has been described after LT in 6% to 38% of patients. In a recent study of 369 pediatric LT patients, Talisetti et al.5 found that 4.9% were labeled as tolerant, and 7.3% required minimal immunosuppression with drug levels lower than the detectable range. The age at transplantation was found to be a predictive factor for tolerance, and this is supported by studies reporting T helper cell cytokine profiles that immunologically predispose infants to graft acceptance.5 Large, prospective, multicenter studies will be required to define tolerance-inducing regimens and validate their use.
DEFINITION OF BIOMARKERS THAT REFLECT THE LEVEL OF CLINICAL IMMUNOSUPPRESSION6
In recent years, a variety of biomarkers have been developed with the aim of assessing the individual patient's risk of allograft damage or accommodation. These transplantation biomarkers are aimed at monitoring immunosuppression, reducing patient morbidity, and improving long-term graft function and life expectancy. In the LT setting, a variety of biomarkers for predicting tolerance or operational tolerance have been described. For example, Li et al. found that a set of 13 unique genes highly expressed in natural killer cells was significantly expressed in tolerant children and adults, regardless of different clinical and demographic confounders, and they suggested its use as a monitoring tool for the diagnosis of operational tolerance. Increased levels of human leukocyte antigen G were found by Zarkhin et al. to be associated with operational tolerance in pediatric and young adult liver recipients, and it was hypothesized to be an immunomodulatory molecule. Biomarker development studies now need to be more uniform and standardized, and prospective validation in a large patient population is required.
IDENTIFICATION OF RISK FACTORS THAT IMPEDE GROWTH AND INTELLECTUAL DEVELOPMENT BEFORE AND AFTER LT
An analysis of post-LT data from the SPLIT registry of children showed a mean height standard deviation score of −1.55 for children at the time of transplantation. Accelerated catch-up growth was seen initially after LT and reached a plateau 3 years after LT. Height and weight at the time of transplantation were positively associated with catch-up growth, and the presence of metabolic and nonbiliary atresia as an underlying condition was negatively associated. Prolonged steroid exposure was also linked to less catch-up growth.7 Growth has become more important because of its potential psychosocial effects on the long-term outcomes and quality of life of children after LT, and treatment with recombinant human growth hormone has been shown to improve intelligence and psychosocial functioning in parallel with improved growth.
Most available reports have focused on cognitive development after transplantation, and approximately 15% of children after LT have been found to have an intelligence quotient in the borderline range of 70 to 79 (in contrast to 2% in the general population). Stewart et al. reported that 3 to 9 years after LT, 18% of 50 school-age children had an intelligence quotient less than 70, which is within the intellectual deficit range. An analysis of the SPLIT registry found learning disabilities in 17.7% of 636 LT recipients who were older than 6 years, and Gilmour et al.8 found that 27% of children who underwent transplantation before the age of 6 years performed more than 2 standard deviations below test norms when they were tested. Pretransplant growth retardation and increased calcineurin inhibitor exposure were associated with a lower intelligence quotient.
Limited information is available on cognitive development in children before LT. At the time of the LT assessment, infants with biliary atresia between the ages of 3 and 20 months were noted to have deficits affecting expressive language and gross motor skills, with girls being weaker in visual receptor skills, having higher conjugated serum bilirubin levels, and being shorter.9
IDENTIFICATION OF BARRIERS AND FACILITATORS THAT AFFECT NONADHERENCE AND THE TRANSITION OF CARE FOR ADOLESCENTS
What is the difference between adolescents and young adults? Because many pediatric LT recipients are surviving into adolescence and adulthood, the challenges facing the health professionals looking after them are evolving.
The World Health Organization defines adolescents as individuals between the ages of 10 and 19 years and youth as individuals between the ages of 15 and 24 years. These 2 overlapping age groups are combined as young people, a term that covers the age range of 10 to 24 years. Adolescence is “the period of physical and psychological development from the onset of puberty to compete growth and maturity” and is divided into 3 psychosocial developmental phases: early adolescence (10–13 years), middle adolescence (14–16 years), and late adolescence (17–19 years). Young people currently constitute 1.8 billion of the world's population.
The effects of a chronic illness or disability on adolescent development are multiple and include biological (eg, delayed puberty), psychological (eg, infantilization and impaired development of cognitive function and information processing), and social effects (eg, social isolation, educational failure, and reduced independence), and they can in turn contribute to poor adherence and disease control as well as risk-taking behaviors.10, 11
United Network for Organ Sharing data from 2010 on outcomes after LT and other types of organ transplantation suggest that the 10-year patient and graft survival rates for patients undergoing transplantation between the ages of 12 and 17 years or during adolescence are inferior to the rates for transplant patients who are 11 years old or younger.1 The survival rates are similar until 5 years after transplantation, but from 5 to 10 years after transplantation, patient survival declines in the 12- to 17-year-old group (73.7%) in comparison with the younger recipient population (82%–83.7%). Patients who are 11 to 25 years old constitute a unique and vulnerable transplant cohort facing major challenges such as adherence to treatment, the transition from pediatric services to adult services, and quality of life.
The posttransplant prevalence of nonadherence to medications in adolescents has been reported to exceed 50% (in contrast to 15%–25% for the entire pediatric population), and nonadherence can lead to graft loss and death. Although it has been estimated that 3% to 11% of patients are listed for retransplantation annually, no data are available on the number of cases in which nonadherence contributed to the graft loss.12
Adherence is difficult to measure, and health professionals, relying solely on immunosuppression levels and patient self-reporting, often fail to detect nonadherence. In adolescence, poor adherence should be regarded as relatively developmentally appropriate,10, 11 and it does not reflect distrust in health care professionals or equal rejection on the part of the adolescent. Nonadherence is often complex and can be related to a variety of factors, including the type of treatment, the side effects of medications, the health care providers' approach to the patient, and patient-related factors (eg, patient beliefs). Communication with the young person in a nonjudgmental way and the identification of barriers to adherence are crucial for identifying nonadherence and form the base for further management and intervention. Multidisciplinary teamwork contributes to the management of nonadherence because every patient is different and one approach does not fit all. The focus should be on the effective integration of adherence management into routine practice, with prevention being favored over a cure. Simplifying medication regimens and using slow-release preparations of calcineurin inhibitors can be helpful.
Transition of Care From Pediatric Services to Adult Services
The literature on the transition from pediatric services to adult services in the transplant population is limited. In 2000, an unexpected graft loss rate of 35% was reported for a group of 20 young adults who had undergone renal transplantation, with most graft losses occurring within 2 years of their transfer to adult services.13 A recent publication by the same group reported no episodes of late acute rejection or graft loss in 12 patients during a 4-year follow-up period after the introduction of an integrated pediatric/young adult joint transition clinic and care pathway in 2006.14 Kiberd et al.15 reported graft loss in 9 of 18 patients transferred to the adult service; however, all these patients had already shown a degree of graft dysfunction at the time of their transfer, and the authors commented that patient age (not graft function) determined the transfer to adult services. The transfer to adult services is determined by chronological age and not by maturity or readiness for the transition, and it comes at a challenging time in most adolescents' lives. The transition should be a “purposeful, planned process that addresses the medical, psychosocial and educational/vocational needs of adolescents and young adults with chronic physical and medical conditions from child-centered to adult-orientated healthcare systems.” This implies that pediatric teams should develop specific strategies for overcoming barriers to an adequate transition (eg, learning difficulties, foster care, and mental health problems) and aim for an integrative process. Different models can be applied, and they will depend on the setting of both pediatric and adult services and take into account local and cultural differences. The aim should be to manage young people with a chronic condition in a comprehensive and holistic way that includes parents/caregivers. A multidisciplinary approach is recommended, especially for more challenging patients, with an emphasis on improving self-management by improving a patient's knowledge of his or her condition and its management and by stimulating decision making and assertiveness. It is important to include general aspects of a young person's lifestyle, such as sexuality, drugs, alcohol, and relationships with peers, in the process. A variety of transition readiness scales are available, and they should be adapted to the individual requirements of the center and the patient and be used at the start of, during, and at the end of the transition process.
QUALITY OF LIFE
A recent study looking at the health status of 36 young adults 2 decades after LT concluded that pediatric transplant recipients who survive to adulthood have lower physical health-related quality of life, measurable transplant-related disabilities, and lower health utility, and although transplantation is lifesaving, physical and psychological sequelae continue to affect their health status up to 2 decades later. Unemployment, hospitalization, and less education were associated with lower health utility.16 At our center, we found that the self-reported health-related quality of life for 55 adolescents (12–18 years) after LT was on average 10 points lower than that of the general population, and this was comparable to the findings for other chronic illnesses. The factors associated with a lower health-related quality of life were the age at transplantation, secondary chronic illness, symptom distress, headaches, a history of emotional difficulties, self-esteem, and family conflict.17 LT should be considered a chronic condition requiring lifelong medical follow-up, including daily medications with a risk of comorbidities. Therefore, promoting a model of care that is adapted to the needs of the chronically ill, including the need for self-management support, should be considered, and this might improve outcomes (as reported for other populations with chronic illnesses). Socioeconomic factors affecting health cost burdens in certain health care settings cannot be ignored.
Identifying risk factors before LT and deciding on an appropriate multidisciplinary approach to manage them will become more important in order to optimize the long-term outcomes of pediatric recipients of LT.