More than 250,000 solid organ transplantations have been performed since 1986, approximately 8% of these have occurred in children under 18 years of age. Traditionally, the success of liver transplantation has been measured by 1-, 3- and 5-year survival rates. Over the past 20 years, advances in medical and surgical therapy have dramatically improved these survival rates. Specifically, the introduction of the calcineurin inhibitors (CNI), cyclosporine and tacrolimus, revolutionized solid organ transplantation by decreasing acute allograft rejection and early graft loss, and increasing patient and graft survival. Due to these advances, the population of long-term survivors with liver transplantas is now 10-fold greater than the number of transplantations done each year. With 1-year survival rates approaching 90%, other measures must be employed to advance our understanding of the impact of liver transplantation on outcome. Ultimately, outcomes of liver transplantation will need to be judged not only by survival, but also by the number of quality life years restored, a measure which incorporates both survival rate and the quality of the time survived (1-4).
Care for liver transplant recipients is highly technical, expensive and regionalized. The total health care expenditures of organ transplantation are increasingly directed toward the costs of maintaining wellness and graft function in long-term survivors. The direct health care costs to achieve these aims in solid organ transplant recipients exceed 2 billion dollars each year, half of which are directed to medications and therapeutic drug monitoring. For an individual patient, the cost of immunosuppressive medications is estimated to be between $2500 and $10,000 each year (5).
Pediatric liver transplant recipients are a distinct population not only with respect to age, but also with respect to primary diagnosis, pretransplant comorbidities, type of graft, posttransplant complications and potential for a longer period of posttransplant survival. Although candidates under 18 years of age accounted for only 5% of deaths on the waiting list in 2002, the death rate for children younger than 1 year was 6-fold higher than the death rate for all other candidates (6). When examined as a function of donor type, graft and patient survival for children younger than 2 years was greater if they received an allograft from a living donor compared with a deceased donor, a trend not detected for any other age group (6,7).
In the posttransplant phase, more attention has been directed toward the risk of adverse events associated with use of immunosuppressive medications, both immune-related complications (cancer and opportunistic infections), and nonimmune complications (bone, cardiovascular and renal disease). For both children and adults, the risk is substantial. The goal is to maintain graft function and wellness while decreasing the morbidity associated with long-term immunosuppression. For any morbidity such as osteoporosis or renal insufficiency, the clinical condition moves at variable rates through a series of stages beginning with normal physiologic functioning, progressing to minor variation from the norm, perceived symptoms, early diagnosed disease and finally to disabling illness. Since children have a longer potential life span following liver transplantation, they have a greater potential to develop significant end organ damage. This is commensurate with the greater benefits of transplantation for children. For example, the cumulative risks from long-term immunosuppression and the potential for years of life gained for a 2-year old undergoing transplantation are much greater than those for a 40-year old.
The population of pediatric liver transplant recipients serves as a disease model for children with chronic illness. Models of care for patient populations with chronic conditions require interaction between informed patients and health care providers. The models suggest that best outcomes depends on commitment to self-management, decision support, a reliable clinical information system, an effective care delivery system and community support (8). Despite our knowledge of these components, care is far from perfect. In Crossing the Quality Chasm, the Institute of Medicine's 1999 report on Health Care Delivery in America, the committee concluded that the American health care delivery system is in need of fundamental change (9). The Committee proposed that health care delivery systems for all, and particularly for those with chronic illness, should be timely, efficient, effective, patient-centered, safe and equitable and that the care should be customized based on patient needs and values with the patient as a source of control.
To achieve the best outcome for pediatric liver transplant recipients, we need to understand clinical outcomes, functional health or health-related quality of life as perceived by the patient and their family, costs of care, and family perception of the care delivered (10-15). We need to ensure that our care addresses the components of quality outlined by the Institute of Medicine. Finally, we must be able to gain new knowledge through research and apply this knowledge to patients. In this review, we would like to share our efforts at Cincinnati Children's Hospital Medical Center (CCHMC) over the last 8 years to address these challenges. We recognize that single center studies may not be representative of the population at large since patient demographics and care processes differ among centers. Consequently, studies done at a single center are subject to biases introduced by disease severity, demographics and process of care including, but not limited to type of immunosuppression. Nevertheless, our efforts are first steps toward Dr. Balistreri caveat that as we care for these patients we "keep the end in mind."
For each of the studies presented, all patients who underwent liver transplantation at CCHMC were considered eligible. The details of the specific patient population, the study design and the analyses are discussed with the results and may also be found in the original references. Since we examined issues related to long-term outcome, we included those patients who were more than 3 months after liver transplantation unless stated otherwise. We chose 3 months, since mortality risk decreases after the perioperative phase of care and transplant recipients enter a period of stability both with respect to allograft function and CNI pharmacodynamics. Since 1996, we have used tacrolimus as our primary immunosuppressive medication. Before 1996, the primary immunosuppressive medication used was cyclosporine. These studies and improvement efforts were approved by the Institutional Review Board of CCHMC. All data are depicted as mean ± SD unless otherwise noted.
RESULTS AND DISCUSSION
Since 1986, three hundred children have undergone transplantation at our center. Forty-five children underwent retransplantation. The median age at transplantation was 4.2 years. Children with biliary atresia accounted for 38% of the study population. Thirty-seven percent of the patients were UNOS Status I at the time of transplantation. Fifty-four percent of the population received reduced-sized grafts. Six percent received transplants from living donors. Seventy-seven percent of patients were white and 37% were Medicaid recipients (Table 1).
In this section, clinical outcome, health-related quality of life and cost will be examined to increase our understanding of overall outcome for children who survive liver transplantation.
Clinical Outcome and Risks
Abnormally, low bone mineral density (BMD) has been reported in adults following liver transplantation (16-22) and longitudinal studies have demonstrated improvement but not normalization of BMD (17-20,23). Since bone accretion occurs during the first 3 decades of life, peaking late in the second decade in women and early in the third decade in men, the immunosuppression required to prevent allograft rejection and associated complications may adversely affect long-term bone health. We performed a cross-sectional study assessing the BMD of 109 patients who had undergone liver transplantation in infancy, childhood or adolescence (24). Lumbar spine BMD was assessed using dual energy x-ray absorptiometry, and clinical data was obtained from chart review. The mean age at transplantation of this patient sample was 4.3 years (median 1.8 years), and the mean time since transplantation was 6.2 years. Decreased BMD (defined as a LS-BMD z-score < 2.0) was identified in 7.3% of patients; these subjects were more likely to have been treated for rejection, and had greater cumulative glucocorticoid exposure over the year preceding the dual energy x-ray absorptiometry (Fig. 1). Importantly, the BMD z-scores were not significantly different than those of age-matched controls. Taken together, these data suggest that long-term bone mineralization in infants, children and adolescents recovers following liver transplantation, especially in those who remain free of allograft rejection. Nevertheless, a subgroup exists which is at increased risk of diminished bone mineralization. Identification of this subgroup will allow consideration of alternative, steroid-minimizing protocols, targeting those most likely to benefit from changes in immunosuppression.
While the use of the CNIs in liver transplantation has markedly improved patient and allograft survival, these improvements have come at a cost. Acute and chronic nephrotoxicity are common adverse effects of both cyclosporine and tacrolimus (25-29). Data from long-term follow-up of adult liver transplant recipients indicate that the incidence of renal insufficiency and end-stage renal disease (ESRD) increase with time following transplantation, with a cumulative incidence of ESRD as high as 10% by 10 years posttransplantation (30,31). A number of variables have been identified as risk factors for chronic renal dysfunction in adult liver transplant recipients, including increased age at transplant, hepatorenal syndrome, diabetes mellitus, coronary artery disease, hepatitis C virus infection and immunosuppression with cyclosporine versus tacrolimus (26,30-32). Surprisingly, renal function at the time of liver transplantation is not a reliable predictor of subsequent renal function, while serum creatinine and measured GFR (mGFR) at one year posttransplant may be better predictors (32).
Data on the incidence of and risk factors for long-term renal dysfunction in pediatric liver transplant recipients are not as clear. Lack of long-term follow-up of renal function has precluded an accurate assessment of the prevalence of chronic renal dysfunction, making identification of risk factors difficult. In addition, pediatric studies are limited by the adequacy of methods used to assess renal function. Most often serum creatinine levels or calculated GFR (using the Schwartz formula) have been used. Both of these are insensitive measures of decreased renal function, particularly in the pediatric population (33,34).
We performed a cross-sectional study to define the prevalence of chronic renal dysfunction in children who are long-term survivors of liver transplantation using measured GFR, the gold standard for assessment of renal function and to identify factors associated with renal dysfunction in this population (35). We analyzed data from 117 patients who survived more than 3 years following liver transplantation. Demographic and clinical information was obtained from chart review and from a clinical care database. The outcome variable was renal dysfunction as defined by a measured glomerular filtration rate (mGFR) less than 70 mL/min/1.73m2. The mean time since liver transplant was 7.6 ± 3.4 years (range 3-14.6 yrs). When the last available mGFR for all patients was analyzed, renal dysfunction was present in 32%. In the univariate analysis, mGFR at 1-year posttransplant, cyclosporine immunosuppression and time since transplant were significant; the second two were strongly colinear (Table 2). We concluded that renal dysfunction is a common complication in children who survive liver transplantation. Our observations are of critical importance since children may live long enough to move from a stage of renal insufficiency characterized by asymptomatic decreased GFR to symptomatic ESRD.
In the observations presented here, we show that a proportion of children who undergo liver transplantation are at increased risk for renal disease and bone disease. While the development of these complications is clearly multifactorial, currently used standard immunosuppressive therapy is likely to be a major risk factor for both disorders. In pediatric liver transplant recipients, the relative contribution of CNI nephrotoxicity to posttransplant renal dysfunction may be greater, as children generally lack many of the coexisting risk factors for renal dysfunction common in adult transplant recipients. The potential impact of renal dysfunction on a child is also distinct from that for an adult, in part because as children grow and enter puberty, their renal function needs increase. Moreover, in the event that renal dysfunction continues to progress, children may live long enough to develop significant end organ damage. To preserve renal function in pediatric liver transplant recipients, it is critical to identify patients at increased risk so that we can move rapidly to mechanistic studies and clinical trials of renal-sparing immunosuppressive agents. Equally important, we need to identify those at low risk who do not require a change from present immunosuppressive therapy.
Health-related Quality of Life
Health-related quality of life (HRQOL) refers to those aspects of quality of life that are directly related to health and are potentially affected by the health care system. At our center, parents of 176 patients who were at least 1 year after transplantation were queried regarding their child's health and quality of life. Approximately 70% rated their child's health and quality of life as excellent or very good. However, this survey did not address all five of the domains that constitute nonpreference-based HRQOL-physical health, mental health, social functioning, role functioning and general health perceptions. To gain a better understanding of HRQOL in a population of pediatric liver transplant recipients, we conducted 2 studies.
We performed a cross-sectional study in 77 patients, age 5-18 years, who underwent liver transplantation between 1985 and 2000, and survived at least 6 months after transplantation. We assessed the HRQOL of this population using two instruments, the Child Health Questionnaire Parent Form 50 (CHQPF50) and the PedsQL4.0 (36). The mean scores for physical and psychosocial health and for emotional, social and school functioning were lower in our study population than population norms and were similar to those children with chronic illness (Table 3). The score for physical function was higher for white patients and for patients who had not been hospitalized in the previous 12 months. Age at transplantation, time elapsed since transplantation, hospitalizations within the previous year, maternal education and race were significant predictors of physical function. Age at transplantation and maternal education predicted psychosocial function.
Since the median age at transplantation in our center is less than 5 years, and the above study included children from 5-18 years, the results from this cross-sectional study do not reflect early posttransplant HRQOL for the majority of our population, many of whom are transplanted before 5 years of age. Consequently, we conducted a prospective longitudinal study of HRQOL, from the parent's perspective, in 61 pediatric liver transplant recipients less than 5 years of age. Our purpose was to define the impact of liver transplantation on HRQOL and identify factors that predict HRQOL after transplantation (37). We used the infant and toddler health status questionnaire (ITHQ) to assess HRQOL at the time of listing for liver transplantation and at 6 and 12 months after transplantation. ITHQ subscale scores increased steadily after transplantation (Fig. 2). The greatest increase was in the first 6 months posttransplant. At 1 year after transplantation, there were significant increases in all of the ITHQ subscale scores except Global Mental Health (GlobalMH). In both the cross-sectional and longitudinal studies, the time elapsed since transplantation was a significant predictor of functional health in all of the models generated.
In these studies, we observed that pediatric liver transplant recipients had HRQOL similar to those of children with other chronic medical conditions such as heart disease, rheumatologic disease and diabetes (38,39). For each of the observational studies reviewed here, the design prevented us from assigning causality to the association between the identified predictors and outcome. Furthermore, these studies also have the attendant limitations of a single center study. Moreover, the outcomes reported reflect the population at a point in time and are subject to bias. For instance, assume first that ESRD affects HRQOL. If the incidence of ESRD is low for patients within 5 years of liver transplant, then HRQOL might not be impacted or predicted by renal status. Alternatively, a population of patients more than 10 years after liver transplantation might have a higher incidence of renal dysfunction and consequently, worse HRQOL.
To determine the cost of pediatric liver transplantation as a function of phase of care, we conducted 2 studies. In the first study, we sought to identify predictors of length of stay and total cost for hospitalization in 83 children following liver transplantation (40). The CCHMC hospital-based accounting system was used to determine health care costs as previously described. Total costs were directly correlated to posttransplant length of stay. Costs were lower for patients who received whole organs, were white, had early allograft rejection or higher z-score. Costs were also lower for patients who participated in a transition to home program in which patients were discharged to a family living center when they met established clinical criteria and their families met predefined educational goals compared with those who did not participate in the transition program (Table 4). These observations did not address cost of care after the initial recovery period.
In a second study, we sought to identify predictors of the costs of care for the first year after liver transplantation for children who received allografts from living donors as compared with deceased donors (41). The subjects in the two groups were matched for age, diagnosis and nutritional status at transplantation. The mean cost of care in the first year was 60.3% higher for living donor transplants as compared to deceased donor liver transplants (P = 0.01), in part related to the increased frequency of biliary complications in the patients who received allografts from living donors (Table 5). Multivariate analysis identified biliary complications and pediatric end stage liver disease (PELD) scores as predictors of cost of care in the first year after transplant (R2 = 0.77).
Improving Our Care Delivery
Access to Clinical Information
The models of care for populations with chronic illness suggest that best outcomes depend, in part, on a reliable clinical information system (8). As part of an effort to improve care delivery to pediatric liver transplant recipients, we developed a web-based system in which patients, their families, remote health care providers and those within CCHMC would have access to accurate, up to the minute data on which to base decisions regarding treatment. The development and implementation of the Liver Care Portal was an iterative process driven by an interdisciplinary team consisting of physicians, nurses, application specialists and developers from information technology. The Portal provides the family with accurate, up-to-date data including laboratory results, a complete list of medications and allergies, immunizations, hospital admissions and annual-visit clinical data on growth and renal function. The Portal also provides a function which permits submission of a question electronically to the liver care team; questions and answers can be viewed online.
Our efforts to improve the quality of care by improving effectiveness have focused on the management of immunosuppressive drug levels. The CNIs display complex pharmacokinetics, with marked inter-individual and intra-individual variability in drug dose and trough drug concentration (23,42-52). This mandates the use of therapeutic drug monitoring to optimize the use of CNIs in transplant recipients. In an effort to more effectively manage CNI blood levels, we applied statistical process control, a method developed by Walter Shewhart in the 1920s and first applied to the manufacturing industry (53). As part of our improvement effort, we defined target ranges for the CNIs, introduced a web-based tool which displays CNI blood levels on a control chart and implemented a protocol and a checklist for management of CNI blood levels. The principal outcome measure was the proportion of CNI blood levels in the target range. When the protocol was spread to the entire population, the proportion of drug levels in the target range increased from 50% to 81% (P < 0.001) (Fig. 3).
A reliable process to ensure effective therapeutic monitoring of CNI levels would increase safety and potentially decrease resource utilization for the growing population of solid organ transplant recipients. In the future, it may be possible to reduce exposure to CNIs by conversion to alternative immunosuppressive agents or innovative regimens which promote tolerance. These new and exciting approaches will require randomized controlled studies of large populations to demonstrate efficacy and evaluate long-term adverse events. However, we must do what we can to avoid unnecessary risk and limit unintended and/or unnecessary exposure to CNIs. The use of statistical process control as described here has helped us to do so.
We have conducted a series of studies, the common goal of which was to better characterize the outcome for children who undergo liver transplantation. In doing so, we have been able to better understand the course of patients after liver transplantation and have identified focus areas for further research and improvement of care delivery.
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