Growth and Pubertal Development in Children and Adolescents Receiving Chronic Dialysis 28 Dieter Haffner and John D. Mahan Introduction and making psychosocial integration even more difficult [13] Beyond this, the degree of growth Body growth is an exceedingly complex and tem- retardation and mortality are closely associated, porally regulated biological process which suggesting that the growth rate is a sensitive depends on adequate nutrition as well as meta- marker of overall patient wellbeing [14–16] bolic and endocrine homeostasis Infancy, mid- There is, however, evidence that alongside childhood, and puberty are characterized by advancements in the medical and technical mandistinct growth patterns (Fig. 28.1), with nutri- agement of CKD and RRT, height prognosis has tion being most critical during infancy, the substantially improved during the past few somatotropic hormone axis during mid-decades [5, 8, 9, 17] Yet this is not the case in all childhood, and the gonadotropic hormones dur- parts of the world, particularly in those regions ing puberty [1, 2] Chronic kidney disease (CKD) with inadequate local resources, where height interferes with this complex network at various prognosis remains dismally low [5, 18] Beyond levels, and pediatric patients are at high risk of careful monitoring of growth, adequate measures growth failure and disproportionate growth pat- to prevent and treat growth failure are of crucial terns (Fig. 28.2) [3, 4] Approximately 50% of importance for pediatric CKD patients at all ages children requiring renal replacement therapy and any degree of renal failure In fact, while this (RRT) before their 13th birthday have a final chapter focuses on the growth of children on height below the normal range [5–12] The maintenance dialysis, it should be emphasized younger the patient at onset of CKD, the higher is that early intervention is critical since measures the risk of severe growth retardation and stunting, such as the correction of malnutrition and CKD- putting additional strain on patients and families mineral bone disease (CKD-MBD) and treatment with recombinant human growth hormone (rhGH) are considerably more effective when D Haffner (*) started before the initiation of dialysis Pediatric Kidney, Liver and Metabolic Diseases, Unfortunately, there is still substantial variation Hannover Medical School, Hannover, Lower Saxony, Germany in pediatric nephrology practice in addressing e-mail: Haffner.dieter@mh-hannover.de short stature and rhGH utilization in children J D Mahan with CKD [19] Standardized care is of utmost Department of Pediatric Nephrology, Nationwide importance in order to improve growth outcomes Children’s Hospital, The Ohio State University in short children with CKD [20–22] College of Medicine, Columbus, OH, USA e-mail: John.Mahan@nationwidechildrens.org © Springer Nature Switzerland AG 2021 B A Warady et al (eds.), Pediatric Dialysis, https://doi.org/10.1007/978-3-030-66861-7_28 509 510 D Haffner and J D Mahan Fig 28.1 Typical growth pattern in congenital chronic kidney disease (red dots) if measures such as adequate nutrition and growth hormone therapy and early renal transplantation with minimized steroid exposure are not provided Relative loss in the nutrient- dependent infantile and gonadal hormone- dependent puberty phases and percentile- parallel growth in the mainly GH-dependent growth period in mid-childhood are shown The shaded area represents the normal range, 3rd to 97th centiles (Reproduced with permission of Ref [2]) Final Height and Height Prediction When interpreting the final heights of patients treated for CKD in childhood, it has to be remembered that data obtained at any time will reflect treatment practices spanning the previous two decades Furthermore, most reports of final heights not or incompletely discriminate according to patient characteristics (e.g., diagnoses, ages of onset of CKD, types, and duration of RRT) and, in particular registries, not separate out children with comorbidities that affect growth in their own right With those limitations in mind, reduced adult heights have been reported in up to 50% of pediatric CKD patients [5, 7, 8, 11, 12, 23–26] Mean final heights vary from 148 to 158 cm for females and 162 to 168 cm for males (with third centiles of 151 and 163 cm, respectively) However, there is evidence that over the years, the final height in ESKD patients is improving [5, 7, 9] This is likely due to a combination of factors such as better growth attained pre-transplant as a result of the provision of adequate nutrition and rhGH therapy, preemptive transplantation thus avoiding dialysis, and the development of protocols that minimize the use of corticosteroids In Germany, the overall mean standardized height in children on RRT has increased over the past 20 years from −3.0 SD to −1.8 SD [9] An analysis from the ESPN/EDTA registry revealed an improvement in final height from −2.06 SDS in children who reached adulthood in 1990–1995 to −1.33 SDS in 2006–2011 (Fig. 28.3) [5] Older age at the start of RRT, starting RRT more recently, cumulative time with a transplant, and greater height SDS at initiation of RRT were independently associated with a higher final adult 28 Growth and Pubertal Development in Children and Adolescents Receiving Chronic Dialysis 511 Fig 28.2 The etiology of growth failure in CKD is multifactorial and includes intrauterine growth restriction (IUGR), genetic factors such as parental height and primary renal disease, prematurity, and malnutrition which especially limits growth in children with congenital CKD Mineral and bone disorder (CKD-MBD), metabolic acidosis, anemia, loss of electrolytes and water, and disturbances of the somatotropic and gonadotropic hormone axes are additional factors CKD is a state of growth hormone (GH) insensitivity, characterized by deficiency of functional insulin-like growth factor I (IGF-I), to reduced GH receptor expression in target organs like the liver, disturbed GH receptor signaling via the Janus kinase-signal transducers, activators of transcription (JAK2-STAT5) due to inflammation-induced SOCS (suppressor of cytokine signaling), and increased IGF-binding capacity due to excess IGFBPs Finally, reduced release of hypothalamic gonadotropin-releasing hormone (GnRH), due to uremia-related inhibitory factors such as angiotensin II (AngII), and steroid treatment may result in decreased circulating levels of bioactive luteinizing hormone (LH), hypogonadism, and reduced pubertal growth spurt PTH, parathyroid hormone; FSH, follicle-stimulating hormone; IGFBP, insulin-like growth factor binding proteins (Reproduced with permission of Ref [22]) height SDS. In general, the poorest growth outcomes were associated with an earlier start and longer duration of dialysis or a diagnosis of a metabolic disorder such as cystinosis and hyperoxaluria, whereas those treated with rhGH did the best [5, 11, 27, 28] The applicability of adult height prediction methods in children suffering from CKD is questionable Final height was overpredicted by 3–10 cm in several validation studies testing final height prediction in children with CKD [12, 23, 29] Most likely, this reflects the complexity and thus unpredictability of growth and development under the condition of chronic uremia, with a highly variable and dynamic impact of disease progression, medications, renal replacement treatment modalities, skeletal maturation, and pubertal timing Clinical Presentation Children with congenital CKD are prone to marked growth retardation already in utero and during the first years of life Whereas growth during mid-childhood tends to be percentile- parallel, height velocity decreases disproportionately during the last 2–3 prepubertal years in these children Eventually, growth potential is irreversibly lost in the peripubertal period due to a delayed pubertal growth spurt that is also of insufficient magnitude (Fig. 28.1) 512 D Haffner and J D Mahan Fig 28.3 Changes in final height SDS over time according to age and period of start of RRT (n = 981) The horizontal line in the middle of the box represents the median; the bottom and top of the box represent the lower and upper quartiles, respectively; and the ends of the whiskers represent the 10th and the 90th percentiles (Reproduced with permission of Ref [5]) Intrauterine Growth tional age) in 14% Interestingly, 40% had also received intensive care unit (ICU) care at birth The comparable overall incidence of abnormal birth history in the US population is 7–8% Low birth weight, prematurity, SGA, and requirement for ICU care were all risk factors for poor growth outcomes, independent of renal function [33] Likewise, intrauterine growth retardation and neonatal distress were shown to be important independent predictors of poor growth outcome in a cohort of 509 German children with CKD stage 3–5 [34] Potential explanations for these findings could be poor intrauterine growth conditions (e.g., maternal malnutrition, smoking) or genetic abnormalities which may cause both intrauterine growth retardation and kidney hypoplasia Reduced fetal growth has been described in several studies in children with CKD [30–34] Both prematurity and low birth weights are often seen The incidence is particularly high in infants on dialysis, but it also occurs in children with less severe CKD. Although registry data not always distinguish between infants who or not have comorbidities (and the latter often have below normal mean birth weight and length), it has been shown that of over 400 children with a mean GFR of around 40 ml/min/1.73 m2 in the CKiD study, low birth weight (LBW,