Growth in Children With End-Stage Kidney Disease

Introduction

Growth is a complex biologic process dependent on adequate nutrition as well as the integrated homeostasis of metabolic and endocrine pathways. Growth failure has long been recognized as one of the most common and profound complications seen in children with chronic kidney disease (CKD) and advances in our understanding of the crucial role of nutrition and benefits of treatment directed to the growth hormone-insulin-like growth factor-1 (GH/IGF-1) axis has expanded over the last two decades. Growth impairment may be seen in up to 50% of children with moderate to severe renal dysfunction (CKD 3–5). Despite available treatments, including renal replacement therapy, 30%–60% of children with end-stage kidney disease (ESKD) ultimately have reduced adult height. Data from the North American Pediatric Renal Trials and Cooperative Studies (NAPRTCS) 2011 annual report included 7039 patients and provided patient characteristics and height data for children at the initiation of maintenance dialysis. Baseline height scores for children at dialysis initiation were 1.60 standard deviation scores (SDS) below appropriate age- and sex-adjusted height levels. During the first 36 months of dialysis, mean changes in height SDS ( z scores) for patients stratified by age continued to lag for all but children < 2 years of age ( Fig. 80.1 ), and the absolute height deficits were worse for younger patients and males. A more recent paper described a cohort of 732 German adults who had onset of ESKD in childhood, with 88% transplanted during childhood. Their mean adult height SDS was low at -1.80, and the majority qualified as having short stature as adults.

Although a trend toward improved final adult height for children with CKD has been noted over the last two decades, mean final height in several studies of adults who had CKD stage 3–5 in childhood still ranges between − 0.6 and − 3.5 SD. Children who required dialysis during childhood manifest the greatest adult impairment in height. This outcome is a significant burden for these young adult survivors of childhood CKD with long-term negative consequences on their adult quality of life (QOL), self-esteem, employment, and life satisfaction. Broyer et al. studied the social outcomes of 244 adults who had received kidney transplants as children with ESKD (mean age at transplantation 11.9 ± 4.0 years) and found that better adult height correlated with higher educational attainment, better employment rates, more successful marriages, and greater rates of independent living. Rosencrantz explored quality of life in 29 adults with the onset of ESKD in childhood who had low mean adult height SDS at –1.56 ± 1.55; 36% were dissatisfied with their adult height (compared with 4% of healthy controls), and their height dissatisfaction correlated with poorer quality of life.

Children receiving kidney transplants and/or treatment with recombinant human GH (rhGH) show better mean final height than those children who continue on long-term dialysis and/or did not receive concomitant rhGH therapy. Young age at onset of ESKD, long duration of renal failure, male gender, and the presence of congenital nephropathies are the most relevant risk factors for decreased final adult height in these survivors of childhood ESKD.

The multifactorial pathogenesis of growth failure in children with CKD complicates the approach to prevention and treatment. Congenital and acquired renal abnormalities can impact growth and development at variable time points, but congenital issues tend to affect growth in childhood more than acquired renal disorders. Moreover, clinical manifestations related to CKD can be highly variable and result in very diverse issues, including fluid and electrolyte abnormalities, metabolic acidosis, abnormal bone metabolism, and malnutrition, all of which can significantly affect growth. In addition, children with CKD undergo different medical interventions and modes of renal replacement therapy at important times during their growth and development. The most important factors that impact growth in children with CKD are the age of onset of CKD and its severity. The complexity of growth impairment, however, is ultimately related to (1) patient genetic factors and nonrenal comorbidities, (2) specific aspects of the timing, type, and severity of the underlying renal disorder, (3) specific types and severity of CKD complications, and (4) the impact of the different types and timing of renal therapies.

The impact of growth failure in children with CKD can be profound. In CKD, chronic malnutrition can lead to significant neurodevelopmental and behavioral issues such as irritability, apathy, attention deficits, and impaired developmental milestones and learning. Growth failure in children with CKD has been associated with an increased incidence of hospitalizations as well as a reported threefold increased risk of mortality after initiation of dialysis. Furth evaluated the risk of death in a cohort of 2306 patients with CKD from the NAPRTCS registry in 2002. Eligible patients (21 years or younger) who had height data at the initiation of dialysis Fig. 80.2 were stratified by standardized height (height z score < or > – 2.5) and age (≤ or > 1 years). Children with better height had lower risk of death than shorter children in both age groups. The burden of significant impairments in both psychosocial and psychological development as well as long-standing decreased QOL, are now recognized as major adverse outcomes in children with CKD who demonstrate growth failure, amplifying the need for prevention and early intervention to promote good growth in these children.

Growth Patterns

Physiologic growth patterns can be divided into the periods of infancy, mid-childhood, and puberty. Adequate nutritional intake is the most important requirement for growth during the first 2 years of life, where growth and neurologic development are more directly dependent on caloric intake than in older age groups. In mid-childhood, growth is greatly driven by the somatotropic hormone axis. During puberty, the gonadotropic hormone axis provides an additional influence on growth by stimulating growth plate chondrocytes, modulating GH secretion from the pituitary gland, and directly affecting all somatic cells. The growth pattern typically seen with congenital chronic renal failure and the sequence of primary growth factors are depicted in Fig. 80.3 .

Children with congenital renal disorders, where renal impairment is present in the first two years of life, are particularly affected because an astounding 33% of final adult height is normally attained during the first 2 years of life. Growth progresses steadily through childhood but typically at a lower rate, and CKD during this period can have a profound impact over time. Height velocity again decreases during the last 2–3 years of prepubertal growth, resulting in further growth impairment. Height and weight velocity then accelerate during puberty, especially the first few years of puberty, and the impact of CKD during this period can be quite impactful, accounting for up to 12–18 inches less adult height than predicted for affected children with CKD. Reduced adult height is an all-too-common consequence of CKD-mediated growth impairment during childhood.

Assessment of Growth

Because growth failure is a common concern in children with CKD, anthropometric measurements must be incorporated into the routine care of these children. In fact, these anthropometric values should be considered as a fifth vital sign for the child with CKD evaluated in the outpatient setting. Regular assessment of head circumference (until 3 years of age), height, weight, and body mass index (BMI) permits early detection of failing growth and provides opportunities for appropriate focused interventions. Height (length for children not standing yet), weight, and BMI must be measured and recorded at each routine health care visit. Plotting these values on age- and gender-appropriate growth charts and calculating percentiles and SDS allows detection of concerning measures or trends. Importantly, calculating height velocity SDS score facilitates detection of suboptimal growth before the height value is out of the normal range.

Growth failure is defined as height and/or weight below the third percentile (< –1.88 SDS) for age and gender. BMI below the third percentile (< –.88 SDS) for age and gender is also an important marker of growth failure. Although detection of height, weight, or BMI below –1.88 SDS is a clear sign of growth failure, earlier detection of a disturbing growth pattern (e.g., height velocity SDS < –1.88) can alert the care team to address the issues of growth in the affected child.

Growth Failure in Chronic Kidney Disease

There is no single cause of growth failure in most children with CKD; multiple factors often are in play ( Table 80.1 ). Although genetic and nonrenal comorbidities exert significant effects on growth, the influence of nonmodifiable and modifiable factors ultimately defines the course of growth in children with CKD.

Underlying Renal Disease

The earlier in life CKD develops, the more likely the child is to have growth failure. Congenital renal dysplasia or hypoplasia, with or without urinary tract obstruction, is the most common cause of ESRD during infancy and childhood. Renal dysplasia is often associated with significant water and electrolyte losses, which can additively contribute to poor growth beyond the impact of uremia. Children with chronic glomerulopathies may show a decline in growth rates even with only mild renal insufficiency, in the presence of significant protein losses and/or glucocorticoid exposure. Among the various causes of renal disease, children with nephropathic cystinosis or primary hyperoxaluria show the most markedly compromised final adult heights, with their growth failure linked to the combination of proximal tubular dysfunction and uremia.