Growth and Development After Transplantation

Growth and development are important challenges to physicians caring for children with end-stage organ (ie, kidney, heart, liver) failure. ^{[1, 2, 3]} Transplantation may successfully reverse the growth impairment in these children, for whom it remains the most physiologic treatment for growth retardation. Nutritional status improves after transplantation, and most children have the potential to experience accelerated growth, to obtain normal height, and to improve cognitive and developmental skills, including behavioral, motor, and social functions. Appropriate neurologic development can be expected after transplantation, and children have the potential to perform at levels that are adequate for their ages.

Nevertheless, many neuropsychological deficits, as well as physical impairments and growth failure, may still occur and persist after transplantation. In one study, pediatric recipients of liver transplants scored lower in many motor and psychological tests and obtained fewer academic achievements, when compared with other groups of chronically ill children. ^[4] Mild functional impairment was present in 79% of children after liver transplantation, when the children were compared with a reference population.

This article discusses general principles of growth and development in children after transplantation, with a special focus on recipients of kidney and liver transplants.

Pathophysiology of growth failure in children with chronic disease

Linear growth is one of the most important differences between adults and children. A multitude of factors affect somatic growth, such as the hypothalamic-pituitary axis, growth hormones, insulinlike growth factors, and binding proteins. Thyroid and adrenal hormones, and the sex steroid hormones released during puberty, are also under the central control of the hypothalamic-pituitary axis and play an important role in achieving optimal growth potential. ^{[3, 5]}

Kidney disease

Growth restriction is a hallmark of chronic illnesses such as chronic kidney disease (CKD) in children, and it is associated with increased morbidity and mortality, owing to abnormal mineral metabolism and the resultant cardiovascular disease. Growth retardation is assessed by the standard-deviation score (SDS) or height-deficit score (Z-score). These scores measure the patient's height in relation to that of unaffected children of similar age. Children with congenital CKD exhibit a relative loss in the nutrient-dependent infant phase and the gonadal hormone–dependent pubertal phase, as well as reduced percentile-parallel growth in the mainly growth hormone–dependent growth period in mid-childhood.

Classification of the stages of CKD (as per the National Kidney Foundation–Kidney Disease Outcomes Quality Initiative [NKF-K/DOQI]) using glomerular filtration rate (GFR) measurements (mL/min/1.73 m²) are provided:

• ≥90 GFR - Kidney damage with normal or increased GFR

• 60-89 GFR - Kidney damage with mild reduction of GFR

• 30-59 GFR - Kidney damage with moderate reduction of GFR

• 15-29 GFR - Kidney damage with severe reduction of GFR

• < 15 GFR or dialysis - Kidney failure

The impact of CKD on growth is multifactorial and includes prior corticosteroid therapy, chronic metabolic acidosis, anorexia, inadequate nutrient and caloric intake, hyposthenuria (urine with low specific gravity due to the kidneys' inability to concentrate the urine), sodium depletion, hormonal imbalance, growth hormone resistance, hypothyroidism, and renal osteodystrophy (a disorder of bone remodeling). Some of these factors are more modifiable than others, and, therefore, management of protein/calorie malnutrition, anemia, metabolic acidosis, hypothyroidism, and salt wasting is essential.

CKD in infancy

The severity of growth retardation is directly related to the age of onset of renal failure—the earlier the onset, the more severe the growth disturbance. Because one third of a child's growth occurs during the first 2 years of life, any disturbance of the rapid growth during infancy reduces height potential more than a growth disturbance in later childhood. The main contributing factor to growth retardation in infants is inadequate nutritional intake and water and electrolyte losses, since the majority of growth in the first 2 years of life is dependent on nutritional status. Therefore, utilization of enteral nutritional support is very important in this patient population. Additional factors include metabolic acidosis, renal osteodystrophy, and catabolic states associated with infections.

CKD in childhood and puberty

The mid-childhood period of growth is characterized by a relative constant growth rate of 5-7 cm/y and is mainly regulated by growth hormone, thyroid hormone, and adequate nutrition. The growth pattern of a child with congenital CKD often follows the percentile achieved at the end of infancy. In children who develop CKD after age 2 years, growth usually follows the percentile achieved after stabilization of the disease. Growth retardation in this age group is mainly determined by the degree of renal insufficiency. Relative height tends to decrease in patients with GFR below 25 mL/min/1.73 m²; growth is usually stable when the GFR is above that threshold.

Growth failure in patients with CKD is largely caused by perturbations in the growth hormone–insulinlike growth factor–I (GH-IGF-I) axis. ^{[6, 7]} The IGF system plays a critical role in all phases of mammalian growth. The prenatal contribution of the IGFs is independent of GH. Shortly after birth, GH-dependent IGF-I production becomes the critical regulator of skeletal growth. The relatively stable growth in childhood is principally under the control of the GH-IGF-I axis and thyrotropin. Twenty percent of adult height is attained during puberty, which is modulated both by the GH-IGF-I axis and sex hormones. ^[8] GH is the most potent secretagogue for IGF-I, which mediates most of the action of GH. GH levels are reported to be high normal or elevated in children with CKD. Despite the GH levels, somatic growth is not stimulated, because the bioactivity of IGF-I is decreased in uremia.

IGF-I is transported in plasma bound to IGF-binding proteins (IGFBPs), mostly to IGFBP-3. Only about 1% of plasma IGF-I occurs in the free bioactive form. There are 6 main IGFBPs in the circulation, two of which, IGFBP-1 and IGFBP-2, have inhibitory effects on IGF action. Children with CKD have normal levels of intact IGFBP-3 but elevated levels of other IGFBPs in proportion to the degree of renal failure, leading to an inhibition of IGF activity and a GH-resistant state. CKD also reduces the expression of IGF-I by reducing postreceptor signaling.

Treatment with supraphysiologic doses of recombinant human GH (rhGH) increases the bioactivity of serum IGF-I, thus overcoming the inhibitory effects of excess IGFBPs. Children who have the lowest growth velocity before treatment benefit the most from rhGH.

The effects of chronic metabolic acidosis on growth may be partially mediated by the GH-IGF-I axis. Animal studies have shown an anti-anabolic effect of acidosis in bone growth centers, which is partly related to a state of resistance to GH and IGF. Therefore, an inhibitory effect of metabolic acidosis on GH secretion and expression may be a contributing factor in the development of delayed longitudinal growth and may contribute to renal osteodystrophy in patients with CKD. ^[9]

The onset of puberty is delayed in adolescents with CKD, with an average delay of about 2 years for the appearance of clinical signs of puberty, and many children with chronic renal insufficiency enter puberty with preexisting growth restriction. The pubertal growth spurt is then delayed, shortened, and associated with a reduced growth velocity. The mean pubertal height gain is only 50% that of normal late-maturing children, and the loss of growth potential may be irreversible, due to closure of epiphyseal growth plates.

With careful monitoring and management of the modifiable factors mentioned above, the hope is that growth restriction can be minimized to the extent possible in pediatric patients with CKD. The steps involved include the following:

• Correction of metabolic acidosis
• Optimization of nutritional status
• Management of anemia and hypothyroidism
• Maintenance of an acceptable calcium × phosphorus product
• Treatment with rhGH, when appropriate

Neurodevelopment

Chronic renal failure has adverse effects on neurodevelopment. The 2 critical periods of brain development occur at 15-20 weeks of gestation, involving neuronal proliferation, and at 25-30 weeks after birth, with focus on glial proliferation. Thus, any developmental problem during the first year of life may result in irreversible brain damage. Studies have suggested that developmental delay of 60-85% occurs in infants with renal insufficiency, related to the early onset and longer duration of the renal disease. Tube feedings have become an important component in the care of these children because malnutrition has repeatedly been implicated as a detrimental influence on development.

Liver disease

Growth failure in end-stage liver disease (ESLD) is a significant problem, especially in patients younger than 5 years. Multiple factors are involved, such as anorexia, deficiencies of fat-soluble vitamins and trace elements, fat malabsorption, decreased hepatic protein synthesis, and increased energy requirements. Psychological factors and acquired dietary behavior are also considerations, particularly in patients with a history of prolonged tube feeding and long hospitalization.

Imbalance of growth-promoting hormones also plays an important role. The endocrinologic network of GH, IGF (somatomedins), and IGFBP is altered in patients with ESLD, as well as in liver transplant patients. ^[10] Children with cirrhosis have normal or elevated hormone levels but develop resistance to the hormone's biologic activities, which is reversed by liver transplantation.

Heart disease

Most pediatric heart transplant recipients have suboptimal growth parameters before transplantation. Some of the contributing factors are poor intestinal perfusion leading to nutrient malabsorption, inadequate renal perfusion, and hemodynamic instability leading to ischemic injury to the hypothalamic-pituitary axis. Poor feeding, which may be mandated or caused by poor appetite, coupled with increased energy expenditure, may lead to negative nitrogen balance and growth deceleration.

Growth and development after kidney transplantation

One goal of pediatric kidney transplantation is attainment of target final adult height. Even though growth velocity improves after renal transplantation, most children do not experience catch-up growth; height deficit is not compensated, so the standard-deviation score does not improve. ^[11] Englund et al have shown that the growth increment following transplantation is maximal for the most growth-retarded children and that the growth is most marked in the first 3 years after transplantation. ^[12]

Linear growth patterns differ by the age of the patient at the time of transplantation. Patients who were younger than 6 years when transplanted experience greater improvement in their growth deficit, as a result of catch-up growth. The majority of allograft recipients who are older than 6 years at the time of transplantation fail to demonstrate catch-up growth and manifest a negative change (delta) in standardized height (Z-score) following transplantation. Both allograft dysfunction and steroid use may impair growth after transplantation. A large number of patients may still not achieve ideal adult height. This is likely related to renal osteodystrophy, which is exclusive to patients with CKD.

Management of post-transplant issues such as metabolic acidosis, anemia, and secondary hyperparathyroidism are important steps in promoting growth, as is good nutrition. Therapy with rhGH has been demonstrated to be beneficial in promoting linear growth in the post-renal transplant population. Factors that may improve growth after transplantation include receiving an allograft from a living donor, as opposed to a deceased donor.

Overall, terminal height in pediatric kidney transplant recipients has improved significantly since the NAPRTCS study first began in 1987, demonstrating the improvements in the care of pediatric patients with CKD over the years. In terms of weight, most pediatric patients experience a rapid increase in standardized weight scores within the first 6 months of kidney transplantation.

Neurodevelopment

In a study by Valanne et al of renal transplant recipients younger than 5 years, 18 of 33 patients (54%) had ischemic lesions in the vascular border zones, with good correlation to pretransplant hemodynamic crises. Those patients with border-zone infarcts were older at time of transplantation and had received dialysis for a longer period, suggesting that most of the lesions in these patients could have been prevented by careful monitoring and early transplantation. ^[13]

Successful renal transplantation during infancy is associated with improvement of developmental outcome. Children with renal transplants have been shown to achieve a level of cognitive function similar to that of healthy children. In studies of pretransplantation and posttransplantation development, up to 80% of children attended normal school and had normal motor skills, providing additional benefit of early transplantation. ^[14]

Growth and development after liver transplantation

It is estimated that about 20% of pediatric liver transplant recipients experience growth impairment at some point after transplantation. One suggested explanation is that these patients may have a pretransplantation growth defect that transplantation does not completely correct, although an increasing percentage of children are demonstrating catch-up growth. Growth may initially worsen after transplantation (during the initial 6 months), but catch-up growth begins afterward. ^[15]

The SPLIT 2000 (Studies of Pediatric Liver Transplantation) annual report demonstrated that growth failure was more significant in patients younger than 5 years but that these same patients also manifested the greatest improvement 18 months after transplantation. According to the report, important pretransplantation factors that affect posttransplantation growth include the following ^[16] :

• Age at transplantation (patients younger than 2 years had the greatest catch-up growth)
• Z-score at transplantation
• Primary diagnosis (patients with biliary atresia seem to have the most catch-up growth) 

Analysis of 167 10-year survivors after pediatric liver transplantation found that their linear height is significantly below that of the general population, with 69% of patients below the 50th percentile and 23% below the 10th percentile. There was a strong association between low linear height and ongoing use of corticosteroids as part of the immunosuppression regimen. ^[17]

Posttransplantation factors that may impact growth include graft function and the need for retransplantation, steroid use, and occurrence of posttransplant lymphoproliferative disease (PTLD). Corticosteroids influence the GH-IGF axis by suppression of pituitary GH production, inducing IGF inhibitors in serum and increasing IGFBPs. Steroids also directly inhibit skeletal matrix production by decreasing synthesis of type 1 collagen, chondrocyte proliferation, and bone matrix production. GH counteracts the catabolic activity through increased synthesis of protein and collagen.

Endogenous cortisol levels appear to be reduced in liver transplant patients and correlate with growth impairment. An increase in the percentage of liver transplant patients who demonstrate catch-up growth has been attributed to steroid withdrawal and supplemental use of GH.

Liver transplant recipients have been shown to have more catch-up growth than kidney transplant recipients, especially after steroid withdrawal. A careful multispecialty approach is therefore necessary to decrease the incidence of growth failure after solid-organ transplantation in children. Pretransplantation nutritional therapy can be optimized; the most appropriate timing of surgery can be selected; and the best immunosuppressive regimen can be determined.

Neurodevelopment

Cognitive and emotional difficulties have been shown to occur more often in liver transplant patients than in age-matched controls. Visual spatial deficits seem to occur in children with liver transplants, but motor abilities are generally not affected. Studies have shown that infants who undergo liver transplantation in the first year of life can achieve healthy neurodevelopment. In the first year after transplantation, however, language skills may be blunted, probably because of nasogastric tube feeding.

Psychoneurologic scores were maintained during 4 years of follow-up observation, although a transient reduction in social skills and eye-hand coordination occurred during the same period, when the children spent longer times in the hospital. In older children, neurologic deficits that are established at the time of transplantation are more difficult to overcome. Liver transplant recipients seem to experience greater psychosocial problems than kidney transplant recipients, which is likely related to body image, especially in the adolescent age group.

Growth and development after small bowel transplantation

Small bowel transplantation poses specific nutritional problems. ^[18] Small bowel transplant patients commonly have macronutrient and micronutrient deficiencies because of high stomal output and diarrhea. Decreased intestinal motility and malabsorption may also be present. Long-term dependence on parenteral nutrition may lead to food aversion; however, preliminary data demonstrate that growth is normal in 50% of transplant recipients, and 15% may experience catch-up growth.

Studies have shown that most patients continue to experience cognitive delays several years after small bowel transplantation. Children who receive small bowel transplants when they are infants may also demonstrate motor delays. ^[19]

Growth and development after heart transplantation

Growth outcomes in pediatric heart transplantation patients have been encouraging. Some reports have suggested that growth delay may be less of a problem for heart transplant recipients than for liver and kidney transplant recipients. This difference may be due to the fact that children with congenital heart disease receive heart transplants at a very young age and those with acquired conditions are much older when they receive transplants, thus bypassing the critical periods of growth. ^[20]

Studies of growth after heart transplantation reveal varied results, as follows:

• Chinnock and Baum (1998) reported on 66 infants younger than 6 months who received heart transplants and did not receive maintenance steroid therapy. Catch-up growth for these patients was almost universal in the first year after heart transplantation. ^[21]

• Cohen et al performed a retrospective analysis of the effects of cardiac transplantation on skeletal maturation and linear growth. ^[22] Bone age delays as great as 3-4 years were seen in the years before transplantation. Bone age delay greater than 12 months was seen in 38.5% of patients at the time of transplantation. Children who received heart transplants before age 7 years and those with a pretransplantation diagnosis of cardiomyopathy experienced the greatest decrease in skeletal growth.

• The seventh pediatric report of the Registry for the International Society for Heart and Lung Transplantation reveals that adolescent heart transplant recipients had no major changes in growth Z-score after transplantation and no dramatic changes when stratified for steroid use. ^[23] The patients did have an increase in weight Z-scores, again with no stratification for steroid use.

Important factors that affect growth after transplantation include age at transplantation, etiology of cardiac failure, graft function, chronic renal dysfunction after heart transplantation, and steroid use. Children initiated on a steroid-free protocol almost universally demonstrate catch-up growth. Evidence suggests that the growth-suppressive effects of steroids can be overcome by exogenously administered growth hormone. Data suggest that growth hormone modulates cardiac growth independent of somatic growth. Children who have growth hormone deficiencies have subnormal left ventricular mass.

Neurodevelopment

Very few studies have been performed on neurocognitive development after heart transplantation in pediatric patients, but the data suggest that patients do not suffer major deficits in mental or psychomotor development. Wray et al demonstrated that though the overall mean developmental score of infants and young children was within normal range after heart transplantation, scores were significantly lower than those of healthy children. Patients with congenital heart disease had a significantly lower developmental quotient and lower scores in locomotor ability, speech and hearing, eye-hand coordination, and performance than those patients with cardiomyopathy.

Researchers at Loma Linda University Medical Center found that infants with hypoplastic left heart syndrome who received heart transplants before age 6 months had ultimately normal growth and developmental outcomes within normal limits.

Growth and development after lung transplantation

Few lung transplantations are performed in the pediatric population. Cystic fibrosis, pulmonary hypertension, and pulmonary fibrosis being the most common primary diagnoses leading to lung transplantation in children. ^[24]

Malnutrition in pediatric patients with cystic fibrosis is multifactorial (eg, pancreatic insufficiency causing fat malabsorption, diabetes mellitus, anorexia, poor appetite, and intestinal obstruction). Some of these patients are severely malnourished before transplantation. Decreased bone density due to vitamin D deficiency and long-term steroid use can further erode bone mass. At some adult transplant centers, patients who are below 80% of ideal body weight are not considered good candidates for lung transplantation. Body mass index is an important indicator of good nutritional status before and after transplantation.

Osteoporosis is another important risk factor, especially because bone mineral density may worsen after transplantation as a result of long-term steroid use. Daily administration of steroids, which is the rule in pediatric lung transplantation, unlike in other solid-organ transplantations, further decreases bone growth. Long-term survival after lung transplantation is not as encouraging as that seen after heart transplantation (about 70% of pediatric lung transplant recipients are alive 3 years after transplantation). ^[24]

Frequency

United States

A review of the 2010 North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) Annual Report of kidney transplant recipients demonstrated that at time of transplantation, the mean height deficits for all patients is -1.75; that is, the average patient is nearly 1.8 standard deviations below the appropriate age- and sex-adjusted height level, or is shorter than the fourth percentile of his or her peers. ^[25] Patients aged 2-5 years and those pediatric patients who had a prior transplant have greater height deficits at the time of transplantation. ^[25]

At the time of transplantation, linear growth is impaired more often in recipients of livers than in those who receive kidneys. However, the frequency of catch-up growth in liver recipients can be greater than that in kidney recipients, probably because of decreased administration of corticosteroids.

Exact incidence of catch-up growth varies according to different groups and immunosuppressive regimens. In 294 unselected candidates for liver transplants, Bartosh et al (1999) reported the mean height Z-score at the time of transplantation to be -1.6 ± 1.8, with 39% of patients below 2.0. As many as 47% of patients demonstrated catch-up growth after transplantation. ^[3] In infants who receive heart transplants, 88% reach a normal height after 5 years, mainly because of good catch-up growth.

International

Sarna et al from Finland reported 79% of liver recipients as being below the reference range for height at 3 years after transplantation. ^[5] In the same series, the catch-up growth after transplantation was reported to be 26% in the first year, 47% in the second year, and 56% in the third year. ^{[26, 27]} In 1999, Viner et al from the United Kingdom reported severe growth retardation in 20% of patients at the time of liver transplantation. ^[28]

Mortality/Morbidity

Nutritional status and growth failure are directly correlated with overall mortality and morbidity after liver and renal transplantation. Children with weight less than -1 standard-deviation score have a lower survival rate at 2 years after transplantation (57%) than those with weight greater than -1 standard-deviation score (95%). The same is true for height.

Race-, sex-, and age-related demographics

Growth impairment after renal transplantation appears to be greater in black and Hispanics than in whites.

In the NAPRTCS 2010 Annual Report of kidney transplant patients, mean height deficit is greater for males (-1.78) than females (-1.70) at the time of transplantation. ^[25] Most studies do not report an association between sex and growth retardation after transplantation.

Age is usually correlated directly with growth retardation at the time of transplantation; however, age is inversely correlated with the rate of growth after transplantation.

Of pediatric patients receiving kidney transplants, only those patients younger than 6 years demonstrate significant recovery, with catch-up growth of 47% in patients younger than 2 years and 43% in those aged 2-5 years. Children older than 5 years have, as a group, not been shown to experience catch-up growth.

Although liver transplantation in persons younger than 2 years was initially associated with poor height outcome, later results did not confirm such findings. The current view is that transplantation in infancy better preserves the height potential of the patient and prevents growth retardation before transplantation. The greatest catch-up growth has been seen in patients younger than 2 years.

Patients with early onset of liver disease but older age at the time of transplantation have an increased incidence of neuropsychological impairment because of the prolonged neurotoxic effect of liver toxins on brain development. Infants who receive transplants before any damage is established can be expected to experience healthy neuropsychological development.