One of the most critical differences between the posttransplant care of children and adults is the requirement in children to maintain a state of health that supports normal physical and psychological growth and development. Most children with organ failure have some degree of growth failure and developmental delay, which is not quickly reversed after successful transplantation. The challenge for clinicians caring for these children is to use strategies that minimize these deficits before transplantation and provide maximal opportunity for recovery of normal developmental processes during posttransplant rehabilitation. The effect of chronic organ failure, frequently complicated by malnutrition, on growth potential and cognitive development is poorly understood. This review presents a summary of what is known regarding risk factors for suboptimal growth and development following solid-organ transplant and describe possible strategies to improve these outcomes.
One of the most critical differences between the posttransplant care of children and adults is the essential requirement in children to maintain a state of health that supports normal physical and psychological growth and development. Most children with organ failure have some degree of growth failure and developmental delay, which is not quickly reversed after successful transplantation. Thus, the challenge for clinicians caring for these children is to use strategies that minimize these deficits before transplantation and provide maximal opportunity for recovery of normal developmental processes during posttransplant rehabilitation. The effect of chronic organ failure, frequently complicated by malnutrition, on growth potential and cognitive development is poorly understood. Likewise, although immunosuppressive medications including corticosteroids and calcineurin inhibitors have known side effects that negatively affect growth and neurologic function the dose-response relationships of these medications and time course of their toxicities are still an area of active investigation. This review presents a summary of what is known regarding risk factors for suboptimal growth and development following solid-organ transplant and describes possible strategies to improve these outcomes.
Growth
Measurements of physical growth include height, weight, and lean muscle mass. Few studies of pediatric solid-organ transplantation recipients have included measurements of muscle mass, making it difficult to comment on this element of growth. Weight gain is a parameter that has been carefully studied and it seems to be an aspect of growth that recovers fully in patients with adequate graft function, despite a history of previous malnutrition. Therefore, this review focuses on optimizing linear growth following transplantation in recipients of kidney, liver, cardiac, lung, and intestinal transplantation.
Kidney Recipients
There are multiple factors that impair linear growth in children with chronic kidney disease, including inadequate nutritional intake, chronic acidosis, renal osteodystrophy, and growth hormone resistance. Improvements in the care of children with end-stage renal disease (ESRD) targeting these clinical problems have reduced the severity of growth retardation in children approaching renal transplantation. Data collected through the North American Pediatric Renal Trials Collaborative (NAPRTCS) show the improvement in linear growth in children with ESRD in the past 20 years. The mean height standard deviation score (SDS or z score) at the time of initial transplant has improved from a −2.4 in 1987 to −1.3 in the 2007 cohort ( Fig. 1 ). Catch-up growth has been demonstrated in the youngest recipients, with a mean increase in height SDS of 0.55 for those aged 2 to 5 years and 0.66 for those aged 0 to 1 year by 2 years after transplant. However, children older than 6 years at the time of transplant exhibit almost no increase in SDS for height in the early posttransplant period ( Fig. 2 ).
Several factors have been identified that adversely affect catch-up linear growth following kidney transplant. A recent review by Fine details early age at transplant, maintenance of normal graft function, and early withdrawal of corticosteroids as measures that improve final height. However, patients who are transplanted later in childhood are less likely to achieve their predicted adult height despite these strategies.
Steroid-sparing strategies have been shown to be safe and effective in pediatric kidney recipients with a 5-year graft survival of 88%, which is comparable with current NAPRTCS data. Steroid-sparing regimens improve catch-up growth at 1 year after transplant for patients aged 0 to 15 years with continued improvement up to 2 years in a subset of patients aged 0 to 5 years. Children less than 5 years of age also show an increase in height percentiles at 6 and 12 months when compared with patients on steroid-based therapy. The effectiveness of recombinant human growth hormone (rhGH) therapy to promote growth in growth-stunted children is reasonably well established. Serum insulinlike growth factor 1 (IGF-1) levels are increased in response to rhGH therapy; however, in many patients there seems to be a dose-dependent IGF-1 insensitivity resulting from prolonged corticosteroid exposure. Studies with rhGH have demonstrated an improvement in final height without an increased risk of kidney dysfunction. A significant increase in lipoprotein(a) levels, a risk factor for cardiovascular disease, has also been noted, but without corresponding increases in serum cholesterol and triglyceride levels.
Of all clinical interventions, transplantation in children before age 6 years has the greatest beneficial effect on subsequent statural growth. There is speculation that timing transplantation to ensure an optimal pubertal growth spurt is key. As detailed earlier, ensuring adequate nutrition, minimizing steroid exposure, and administering rhGH to the most growth-retarded recipients are also important strategies to maximize linear growth. However, despite these interventions up to 25% of children do not reach their predicted adult height based on midparental height values.
Liver Recipients
Linear growth failure in children with cirrhosis seems to be mediated in part by growth hormone resistance. Malnutrition caused by fat malabsorption, abnormal nitrogen metabolism, and increased energy expenditure, which are all well-established features of end-stage liver disease in children, are also important determinants of growth failure in these patients. Following successful liver transplantation, GH, and IGF-I levels return to normal and the rate of linear growth improves. However, it seems that many children do not achieve their height potential even years after transplantation.
Similar to kidney transplant recipients there does seem to have been an improvement in mean height z scores at the time of transplant and in catch-up growth for children with end-stage liver disease ( Fig. 3 ). When examining height z scores in cohorts including children transplanted in the 1990s the mean height z score at transplant is approximately −1.5. Separating patients by era of transplant reveals that with more recent experience, the mean height z scores are similar at transplant, but catch-up growth is more accelerated and prolonged. Catch-up growth is usually not observed until the second 12 months following liver transplantation. Catch-up proceeds through intermediate follow-up after transplant (2–3 years) and then stalls, leaving up to 25% of these patients with heights that are less than the 5% for age in long-term follow-up. A recent multivariate analysis of patients included in the Studies of Pediatric Liver Transplant (SPLIT) registry revealed that linear growth impairment was more likely in patients with metabolic disease (odds ratio [OR] 4.4) and greater than 18 months of steroids exposure (OR 3.02). Higher percentiles for weight (OR 0.80) and height (OR 0.62) at liver transplantation were protective. Less linear catch-up growth was observed in patients with metabolic diseases, cholestatic diseases other than biliary atresia, and lower weight and higher height percentiles before liver transplantation. Prolonged steroid exposure and increased calculated glomerular filtration rate were also associated with less catch-up growth. However, the strongest predictors of catch-up growth following liver transplantation seem to be weight and height z scores at transplant. Patients with lower weight percentiles exhibit less growth acceleration, suggesting that complications of malnutrition must be reversed before catch-up growth is achievable. Conversely, patients with lower height percentiles at transplant exhibit more linear growth acceleration in early follow-up. Previous reports examining the relationships between pre- and posttransplant growth have been inconclusive, with some investigators reporting pretransplant growth failure to have a positive effect and others reporting a negative effect. Experience from the SPLIT registry suggests both observations may be valid. Children with more severe growth arrest before transplant have the most to recover, and without other limitations, the acceleration of their posttransplant linear growth may be more pronounced than that of patients with growth patterns closer to normal before transplant. However, even with an above-average degree of catch-up growth following transplant, patients with the lowest height percentiles at transplant would be less likely to achieve normal percentiles after transplant. Thus, catch-up growth occurs, but is incomplete.
