Growth Hormone & IGF Research 16 (2006) S68S78 www.elsevier.

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Applying the Growth Failure in CKD Consensus Conference: Evaluation and treatment algorithm in children with chronic kidney disease
John D. Mahan
*
Department of Pediatrics, Division of Pediatric Nephrology, The Ohio State University College of Medicine, Columbus, OH, United States Available online 5 June 2006

Abstract Growth failure is a common and signicant clinical problem for children with chronic kidney disease (CKD), particularly those with chronic renal insuciency (CRI). Children with CRI (typically dened by a glomerular ltration rate [GFR] <75 mL/min/ 1.73 m2) who have growth impairment exhibit a variety of medical and psychological problems in addition to increased mortality. Growth failure in children with CKD is usually multifactorial in etiology, including abnormalities in the growth hormone (GH)insulin-like growth factor (IGF)-I axis and a variety of nutritional and metabolic concerns characteristic of CKD. Proper management of these factors contributes to better growth in aected children. Although the safety and ecacy of recombinant human GH (rhGH) therapy in promoting growth in children with CKD are well established, recent data indicate that the use of rhGH administration in children with CKD and growth failure remains low. Recently, guidelines were developed by the Consensus Conference for Evaluation and Treatment of Growth Failure in Children with CKD. This paper focuses on the application of these guidelines to children with CKD. 2006 Elsevier Ltd. All rights reserved.
Keywords: Chronic renal insuciency; Linear growth; Growth hormone

1. Introduction In early studies evaluating the ecacy of rhGH therapy in children with chronic kidney disease, the term chronic renal insuciency (CRI) was used to describe patients with a glomerular ltration rate (GFR) <75 mL/min/1.73 m2. In 2001, clinical practice guidelines developed by the National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (K/DOQI) introduced the term chronic kidney disease (CKD) and a classication schema to promote early disease detection, delay disease progression, and prevent related complications [1]. This classication identies 5

Tel.: +1 614 722 4360; fax: +1 614 722 6482. E-mail address: MahanJ@pediatrics.ohio-state.edu.

stages of CKD based on the presence of kidney damage and the degree of functional impairment, irrespective of the underlying diagnosis (Table 1). Functional impairment, as determined by estimating GFR, must be present for at least 3 months to assess the CKD stage. For example, GFR values between 60 and 89 mL/min/ 1.73 m2 for at least 3 months signify stage 2 CKD. At stage 3, the GFR is reduced by at least 50%, and clinical complications become more prevalent. The GFR cuto values shown in Table 1 apply only to children aged 2 years and older, because younger children normally have a lower GFR. Growth failure is an area of signicant clinical concern for children with CKD stage 2 (GFR <70 mL/min/1.73 m2) through stage 5 [2,3]. The 2005 annual report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) demonstrates that growth failure remains an important

1096-6374/$ - see front matter 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.ghir.2006.04.005

J.D. Mahan / Growth Hormone & IGF Research 16 (2006) S68S78 Table 1 NKF K/DOQI classication of the stages of CKD Stage 1 2 3 4 5 GFR (mL/min/1.73 m2) P90 6089 3059 1529 <15 (or dialysis) Description Kidney damage and co-morbid conditions Kidney damage with mild reduction of GFR Moderate reduction of GFR Severe reduction of GFR Kidney failure

S69

60 50 40

Percent

30 20 10 0 0-1 (n=138) 2-5 (n=949) 6-12 (n=1909) >12 (n=1831)

GRF, glomerular ltration rate.

problem that is not being adequately managed in children with CKD [4]. In this report, more than one third of the 5927 children with CRI had signicant growth failure (height standard deviation score [SDS] 6 1.88) at the time of enrollment. Younger children more frequently demonstrated short stature, with signicant growth failure reported in 58%, 43%, 33%, and 23% of patients aged 01 years, 25 years, 612 years, and more than 12 years, respectively (Fig. 1A). It is striking that only 17% of children of all ages with CRI had height SDS > 0. Although children with more severe renal insuciency demonstrated growth impairment more frequently, signicant short stature was seen at all levels of renal function (Fig. 1B). Even in the group of children with relatively mild CRI (5075 mL/min/1.73 m2), more than 20% exhibited signicant short stature. Growth failure has also been observed in children representing all levels of metabolic control, including those with and without secondary hyperparathyroidism (a marker of renal osteodystrophy) and those with and without evidence of metabolic acidosis. In this report, the youngest children (<1 year) with CKD demonstrated the best growth following registry enrollment, but disappointingly, little improvement was seen in height SDS in children >1 year of age (Fig. 1C). The following case typies the growth-related issues encountered in children with chronic renal disorders. The ensuing discussion will expand upon the signicance of growth failure in this population and present an algorithm and an additional case scenario to increase understanding of its long-term management. 1.1. Case study Patient A.C. is a Caucasian male who was born at 39 weeks of gestation, weighing 3030 g and measuring 47 cm in length, with prune belly syndrome and bilateral renal dysplasia. At 2.9 years of age his serum creatinine was 1.2 mg/dL and calculated GFR 37 mL/min/1.73 m2. He was polyuric, and he required treatment with dihydrotachysterol, sodium bicarbonate, and sodium polystyrene for CKD complications. He was fed with PM 60/40 formula. He experienced signicant growth delay, and short stature was evident at 2.9 years of age, although it was

Age (years)

70 60 50

Percent

40 30 20 10 0 50-75 25-49 10-24 <10

Calculated creatinine clearance (mL/min/1.73m2)

0.8 0.7

Change in height z- score

0.6 0.5 0.4 0.3 0.2 0.1 0 -0.1 0-1 2-5 6-12 12-20

Age (years)

Fig. 1. Growth data from children with chronic renal insuciency enrolled in the North American Pediatric Renal Transplant Cooperative Study 2005. Panel A, incidence of growth failure (height z-score 6 1.88) among children aged 01 year (n = 1138), 25 years (n = 949), 612 years (n = 1909), and >12 years (n = 1831) at the time of registry enrollment. Panel B, incidence of growth failure by calculated creatinine clearance (mL/min/1.73 m2). Panel C, change in height z-score at 24 months after enrollment by age [4].

noted that his heightweight ratio was in the normal range at that time (Fig. 2A). Reversible causes for growth delay were sought. Thyroid status was normal. Other laboratory data were evaluated, and medications were adjusted to ensure that serum bicarbonate, calcium, and phosphorus concentrations were within the normal

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Fig. 2. Height and weight data for a male patient with CRI and growth failure from (A) 0 to 36 months, and (B) 2 to 9 years of age. Growth hormone therapy was initiated at 3.5 years.

range. His nutritional status was considered to be adequate, as determined by his heightweight ratio. N-terminal-specic parathyroid hormone (n-PTH) was within normal limits. No improvement in growth was observed following these interventions, so recombinant GH (rhGH) therapy was initiated at 3.5 years of age. Over the next year of rhGH treatment, the patient exhibited a signicant increase in height (11.8 cm versus 3.2 cm observed during the year prior to rhGH treatment). rhGH was continued for 5 years, and the patients height SD remained in the normal range without treatmentrelated complications (Fig. 2B). A.C. is currently undergoing evaluation for renal transplantation and will undergo that procedure with his height in the normal range for age. He is expected to not require rhGH for normal growth after successful renal transplantation.

Table 2 Factors contributing to poor growth in children with CKD Young age at onset of CKD Renal tubular disorders (e.g., renal dysplasia) Reduced caloric intake (anorexia, loss of taste, GI dysfunction) Inecient utilization of calories Metabolic acidosis Renal osteodystrophy Excessive sodium or water losses Corticosteroids GHIGF-I resistance

2. Characterizing growth failure in children with CKD Many factors aect growth in children with CKD (Table 2), some of which cannot be modied [511]. For example, children who are younger at the onset of

CKD more frequently display short stature than those who develop CKD at an older age [7,12]. In addition, children with renal dysplasia and other tubular disorders more frequently exhibit growth impairment than those with glomerular disorders, which may be related to increased loss of electrolytes and/or growth factors in these tubular disorders [4]. However, a number of factors that contribute to growth failure in children with CKD are modiable, and eorts to prevent or treat growth impairment should be directed toward those factors, as discussed below.

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2.1. Malnutrition Malnutrition may be an important contributor to growth impairment in some children, particularly younger children, with CKD [7,9,13,14]. Decreased caloric intake, complicated by an increased incidence of nausea and emesis, is often seen in children with CKD. Anorexia, emotional distress, and altered taste sensation may also play a role. Betts and Magrath demonstrated a strong correlation between energy intake and growth velocity in children who developed CRI during infancy; normal growth was typically observed only when energy intake exceeded 80% of recommended values [13]. Although there are no data to support the premise that excessive protein intake leads to hyperltration and accelerated progression to endstage renal disease (ESRD) in children, inadequate protein has clearly been linked to malnutrition and impaired growth [15]. Most important, several studies have demonstrated convincingly that nutritional supplementation in malnourished children with CRI can improve growth [2,16,17]. 2.2. Metabolic acidosis Metabolic acidosis is well recognized as a cause of impaired growth, as previously demonstrated in children with untreated renal tubular acidosis [18]. Metabolic acidosis can suppress albumin synthesis [19], increase degradation of branched-chain amino acids and muscle proteins [20,21], and exacerbate calcium eux from bone [22]. Moreover, metabolic acidosis may contribute to derangements in the GHIGF-I axis by reducing GH secretion and serum IGF-I levels. Boirie and colleagues demonstrated a signicant inverse correlation between plasma bicarbonate and the leucine rate of appearance (a measure of protein breakdown) in children with CRI [22], a process that could account for some degree of growth failure in children with CKD. Correction of acidosis in children with renal tubular acidosis has been shown to improve statural growth [23], although this intervention has not been studied in an isolated manner in children with CKD. 2.3. Renal osteodystrophy Growth in children with CKD may be signicantly impaired by the presence of any of the constellation of ndings referred to as renal osteodystrophy (ROD). ROD represents a range of disorders, from highturnover bone disease due to secondary hyperparathyroidism to low-turnover osteomalacia and adynamic bone, that may aect skeletal growth and remodeling [7]. In addition to growth impairment, the consequences of long-standing ROD can include reduced bone mineral density, increased fractures, and bone deformities

[7,9]. Treatment of ROD in children with CKD has been associated with improved growth [24]. 2.4. Other causes Other causes of growth failure in children with CRI must also be considered. Children with concentrating defects or salt-wasting may experience growth failure if salt and water losses are not corrected [15]. Corticosteroid therapy, often used in children with glomerular disorders, may also aect growth through several mechanisms, including impairment of calcium absorption in the GI tract; interference with nitrogen retention, cartilage metabolism, and bone formation; reduction in pulsatile GH secretion; and inhibition of hepatic IGF-I production. The latter two mechanisms are discussed in detail below [25].

3. Abnormalities of the GHIGF-I axis in CRI Abnormalities of the GHIGF-I axis are inherent in CRI and comprise an important cause of growth failure in children with CKD [12]. Normal GH production and release by the anterior pituitary is regulated by hypothalamic GH-releasing hormone (GHRH) and somatostatin (SRIF), with circulating GH and IGF-I levels providing negative feedback to the hypothalamus (Fig. 3A). Release of GH is also stimulated by the GH-releasing peptide ghrelin, which is expressed by the stomach and hypothalamus and is possibly involved in nutritional regulation of the GHIGF-I axis. Circulating GH stimulates the production and release of IGF-I, primarily from the liver. Most circulating IGFI is bound as a complex with IGF-binding protein 3 (IGFBP-3) and acid-labile subunit (ALS), and a smaller amount is associated with other IGFBPs; less than 1% occurs in the free or bioactive form. Circulating free IGF-I mediates many of the biologic eects of GH, including stimulation of longitudinal bone growth (in a paracrine/autocrine fashion) and regulation of renal hemodynamics. GH also has a direct eect on several tissues, including bone [12]. Multiple abnormalities in the GHIGF-I axis are seen in children with CKD (Fig. 3B). Interestingly, GH levels are not reduced in children with CRI; rather there is an increase in pituitary pulsatile release of GH and a reduction in renal GH clearance by as much as 50% [12]. Given the normal to elevated levels of GH, and the fact that IGF-I levels are normal to low in children with CRI, there is both insucient IGF-I production and lack of responsiveness of GH to feedback. The most prominent aberration in CRI is a decreased cellular responsiveness to GH and IGF-I. This resistance is thought to play an important role in the reduction of linear bone growth seen in

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A SRIF

Hypothalamus GHRH + Ghrelin Pituitary + GH Protease IGF-I ALS IGFBP-3 Free IGF-I IGF-I IGF-I + +

IGFBP-1 IGFBP-2 IGFBP-3 IGFBP-4 IGFBP-5 IGFBP-6 B SRIF

GFR

Cartilage growth rate Hypothalamus GHRH + Ghrelin Pituitary +

GH + Protease IGF-I +

IGF-I ALS IGFBP-3 Free IGF-I IGF-I GFR

IGFBP-1 IGFBP-2 IGFBP-3 IGFBP-4 IGFBP-5 IGFBP-6

Cartilage growth rate

Fig. 3. The growth hormone (GH)insulin-like growth factor (IGF)-I axis. Panel A, normal GHIGF-I physiology. Panel B, several abnormalities in the GHIGF-I axis occur in patients with chronic renal insuciency (CRI), including IGF-I resistance, which reects an increase in circulating IGF-binding proteins (IGFBP)-1, -2, -4, and -6 and leads to a reduction in bioavailable IGF-I [12].

children CRI and, thus, in growth impairment in these children. A major mechanism that leads to GH and IGF-I resistance in children with CRI is an increase in the hepatic production of circulating insulin-like growth factor binding proteins (IGFBP)-1, -2, -4, and -6, which increases IGF-I binding capacity by seven- to tenfold and reduces the concentration of bioavailable or free IGF-I by as much as 50%. The elevated levels of IGFBPs complex with IGF-I and inhibit the paracrine/autocrine eects of IGF-I on the target tissues. In addition, increased proteolysis of IGFBP-3 leads to a reduction in the levels of IGF-I circulating in the

IGF-IALSIGFBP-3 complex. As a result, IGF-I receptor activity is reduced (because of lack of free IGF-I-mediated stimulation), and there is less feedback to the hypothalamus and pituitary. In cell culture, cells exposed to uremic conditions express diminished eects from GH (cartilage and bone); a decreased number of receptors and/or aberrant signaling from GH receptors (liver) may be additional mechanisms for the observed insensitivity to GH seen in CRI [12]. A recently identied but important mechanism for GH resistance in uremia involves a defect in the postreceptor GH-activated Janus kinase 2 (JAK2) signal transducer and activator of the transcription (STAT)

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pathway [26]. GH-stimulated IGF-I gene expression is dependent on this signaling pathway. Manifestations of diminished GH receptor density are also seen in children with CKD, in whom the level of growth hormone-binding protein (GHBP), the product of limited proteolytic cleavage of the GH receptor and release of the extracellular domain into the circulation, decreases as renal function is diminished [27]. Taken together, these diverse but related abnormalities provide an understanding of how aberrant GH and IGF-I actions may impair growth in children with CRI. In addition to the abnormalities associated with the GHIGF-I axis, a number of disturbances in the gonadotropic hormone axis occur in children with CKD and may explain some portion of growth impairment [28]. Gonadotropin levels may be elevated due to decreased renal clearance in patients with CRI. Conversely, pituitary secretion of bioactive luteinizing hormone is substantially reduced in children with CRI compared to normal adolescents. Plasma testosterone levels are also reduced in children with CRI. In addition, free testosterone levels are further decreased due to a rise in sex hormone-binding globulins [29]; these physiologic abnormalities may contribute to suboptimal pubertal growth and development in aected children. Because children attain one third of their nal adult height during the rst 2 years of life, growth impairment during infancy has a greater impact on adult stature than later-onset CKD [9,30]. Nevertheless, renal insuciency may limit growth at any stage of childhood. A delay in the pubertal growth spurt is often seen in children with CKD, and reduced pubertal height gain is common in these children. As the preceding discussion indicates, there are multiple potential mechanisms for impaired growth in any child with CKD. Although the relative contribution of these multiple factors in any particular child will be impossible to determine, the clinicians attention should focus on correcting modiable causes of growth failure. Once these factors have been addressed, the contribution of GHIGF-I abnormalities characteristic of CKD will remain. As rst reported in 1988 by Mehls et al. [31] and Lippe et al. [32], the administration of rhGH can improve statural growth in these children.

4. Rationale for GH therapy in children with CKD stages 25 (CRI) The seminal study by Fine et al. [33] showed that rhGH therapy signicantly enhances growth rates in growth-impaired children with CRI. This randomized, double-blind, placebo-controlled, multicenter study included children with irreversible renal insuciency, with GFR between 5 and 75 mL/min/1.73 m2, height <3rd percentile for age, bone age <10 years for girls

and <11 years for boys, and prepubertal status. In total, 125 children were randomized to receive rhGH 0.05 mg/ kg/day via subcutaneous injection (n = 82) or placebo (n = 43) for 2 years [33]. At the time of publication, 55 patients in the GH group and 27 patients in the placebo group had completed 2 years of treatment. GH-treated patients demonstrated signicantly higher growth rates compared with those receiving placebo in the rst year (10.7 3.1 versus 6.5 2.6 cm/year, respectively) and the second year (7.8 2.1 versus 5.5 1.9 cm/year, respectively) of treatment (P < .00005, both comparisons). A number of clinical trials have subsequently demonstrated the safety and ecacy of GH therapy in promoting linear growth in children with CRI, on dialysis, or following renal transplantation. The augmentation of nal adult height by rhGH therapy was conrmed by Haner and colleagues, who studied 38 prepubertal children with chronic renal failure treated with GH for a mean of 5.3 years [34]. Mean (SD) age at the start of treatment was 10.4 (2.2 years); mean bone age was 7.1 (2.3) years; and mean height was 3.1 1.2 SD below normal. Fifty age- and gender-matched children with CKD who were not treated with GH served as controls. GH-treated children achieved sustained catch-up growth, while untreated controls experienced continued growth failure. At baseline, GH-treated boys and girls demonstrated a mean height SD score of 3.2 (1.3) and 2.5 (1.0), respectively. At the end of treatment, corresponding height SD scores were 1.7 (1.2) and 1.3 (1.6). In contrast, although untreated children with CKD were taller at baseline (height SDS, 1.4 1.3 [boys]; 1.6 1.3 [girls]), nal adult height SDS declined in both boys (2.1 1.3) and girls (2.1 1.2) [34]. There may be a number of additional benets of rhGH therapy in children with CKD, including better quality of life (QOL) [35], improved bone density [36], neurodevelopmental benets [37], and cardiovascular benets [38]. Although studies in children and adults treated with rhGH for isolated GH deciency support these observations [39,40], data addressing these potential benets in children with CKD are limited. Data are available to support the general safety of rhGH therapy in children with CKD [41]. Clinical studies have demonstrated no increased incidence of malignancy, slipped capital femoral epiphysis, avascular necrosis, intracranial hypertension, glucose intolerance, pancreatitis, or uid retention [4143]. In terms of safety issues related specically to children with CKD, rhGH has not produced acceleration in bone age, acceleration in progression to ESRD, or increased risk of acute rejection in renal transplant recipients [42,4446]. Transient elevation in insulin levels has been observed, but no changes in glucose levels or HbA1C have been documented [47].

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Table 3 Major barriers to GH therapy in children with CKD Lack of urgency Belief that GH treatment can be delayed Short stature perceived as a cosmetic issue Evaluation and documentation Uncertainty about evaluation, GH dosing, and monitoring Uncertainty about appropriate clinical assessment to support reimbursement Patient non-compliance Lack of physician guidelines Lack of patient education materials Physician concerns about safety and ecacy Lack of quality-of-life data Lack of clarity about target height Belief that treatment might not be reimbursed Cost considerations

In summary, rhGH therapy is eective in improving height velocity and height SDS in children with CKD and growth failure. rhGH is safe in all stages of CKD and after renal transplantation. The incidence of adverse events is similar to that observed in CKD patients not treated with rhGH. However, despite the known ecacy and safety of rhGH treatment, the majority of children with CKD and growth failure in North America still do not receive this therapy [4]. The reasons for this are not well understood, but there are certainly some children with limiting co-morbid conditions or other issues that may preclude rhGH therapy. Table 3 summarizes the major barriers to rhGH therapy in children with CKD and growth failure, as identied by consensus conference participants [11].

5. Applying the consensus conference algorithm for evaluation and treatment of growth failure in children with CKD In 2003, a panel of pediatric nephrologists convened to address the need for clear clinical guidelines for rhGH use in children with CRI [11]. As a result, an algorithm was developed to facilitate the evaluation and treatment of growth failure in children with CKD (Fig. 4). These recommendations are based on the results of clinical studies demonstrating the safety and ecacy of rhGH therapy in this population, appraisal of relevant rhGH and CRI guidelines, and the expert opinion of the consensus conference participants. At this time, data are limited regarding the non-growth-related benets of GH therapy in children with CRI, such as psychosocial and QOL benets, bone development, neurodevelopment, and cardiovascular eects. Therefore, these potential benets are not addressed in this algorithm. The target population for detailed evaluation includes children with clinically dened CRI (GFR <75 mL/min/1.73 m2) and signicant growth impair-

ment (height SDS < 1.88 or height velocity SDS <2.0) [1]. Modiable factors that may lead to poor growth such as metabolic acidosis, malnutrition, salt-wasting, ROD, and hypothyroidism must be adequately addressed before considering a trial of rhGH therapy [4851]. Correction of these abnormalities is not likely to completely resolve growth problems, but it is necessary to ensure an optimal growth response in those patients who ultimately receive rhGH therapy. Patients with active malignancies should not receive rhGH treatment, and treatment should be used with caution in patients who have disorders associated with an increased risk of malignancy. Once metabolic and nutritional factors aecting growth have been addressed over a 3- to 6-month period, children may be evaluated for rhGH therapy. Height SDS, height velocity SDS, absolute height velocity, pubertal stage, and bone age should be reassessed before treatment is begun to conrm the childs eligibility for rhGH and to allow accurate monitoring of growth during treatment. Baseline hip and knee X-rays, funduscopic examination, blood chemistries, PTH levels, and thyroid studies should also be performed to provide an accurate baseline status and to assist in the detection of rare complications, such as slipped capital femoral epiphysis, glucose intolerance, and benign intracranial hypertension. Following a comprehensive pretreatment workup, patients may begin rhGH therapy at a dose of 0.05 mg/kg/day (0.35 mg/kg/week or 28 IU/m2/week) administered by subcutaneous injection [52]. Throughout rhGH therapy, patients must be monitored regularly to identify the need for dose modication based on weight gain, response to therapy, adverse events, and complicating factors that may result in poor growth. Clinic visits every 34 months are recommended for assessing height, weight, and rhGH dosage requirement; occipitofrontal circumference (until 3 years of age); pubertal maturation; nutritional status; funduscopic examination; serum chemistries; and PTH. Yearly monitoring of bone age should be accompanied by hip and knee X-rays only if persistent hip or leg pain is present. Patients demonstrating an inadequate growth response may require correction of their weight-based GH dosage or complicating nutritional or metabolic factors and should be assessed for treatment compliance. Patients with persistent poor growth despite resolution of these problems may require referral to a pediatric endocrinologist for further evaluation of other possible causes for inadequate growth. GH therapy should be discontinued when the childs epiphyses close or if the childs height goal has been achieved (based on midparental height or 50th percentile for age). GH therapy should be discontinued at least temporarily in the presence of active neoplasia, slipped capital femoral epiphyses, benign intracranial

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Consider GH therapy in patients with: GFR <75 mL/min/1.73 m2 and Height SDS <1.88 (3rd percentile) or height velocity SDS <2

Assess and treat complicating factors for poor growth, including acidosis, malnutrition, salt-wasting, osteodystrophy, and hypothyroidism

NO

Is growth velocity improved?

YES

Perform baseline assessments for GH therapy: Recalculate: Height SDS, height velocity SDS, and height velocity Assess: Pubertal stage, bone age, hip and knee x-rays, funduscopic exam, chemistries, PTH, and thyroid studies

Continue current therapy

Start GH therapy: 0.05 mg/kg/day SC (0.35 mg/kg/wk)

Monitor during GH therapy: Every 3-4 months: Height, weight, OFC (until 3 yr of age), pubertal stage, nutritional evaluation, funduscopic exam, chemistries, PTH, and toxicity Every year: Bone age For symptoms: Hip and knee x-rays

NO

Is growth adequate? (ie, height velocity 2 cm/yr >baseline) Is growth adequate? YES

YES

Assess and correct: Dose for weight Metabolic status Nutrition Compliance

Continue GH therapy, and adjust dose every 3-4 months based on weight

Consider Pediatric Endocrinology consult

NO

Discontinue GH therapy in the following circumstances: Achieved height goal based on midparental height or 50th percentile for age Closed epiphyses Active neoplasia Slipped femoral epiphyses Intracranial hypertension Noncompliance Severe hyperparathyroidism, per CKD stage: Stage 2-4: PTH >400 pg/mL Stage 5: PTH >800 pg/mL

If height velocity remains <2 cm/yr and reason for discontinuation resolved, consider reinitiation of GH therapy

Fig. 4. An algorithm for the evaluation and treatment of growth failure in children with chronic kidney disease.

hypertension, severe hyperparathyroidism (PTH >800 pg/mL for stage 5 CKD and lower values for early CKD), non-compliance with treatment, or at the time of renal transplantation. Continued monitoring of growth after the patient discontinues GH therapy is critical, since re-initiation of GH may be appropriate if the height velocity decreases and the reasons for the discontinuation of GH are resolved. Several therapeutic dosing considerations deserve future evaluation in children with CKD. The benet of

specic dosing adjustments for pubertal patients, the value of rhGH dose adjustments based on achieving specic IGF-I level targets, and information regarding the benet of initiating rhGH before height falls below the 3rd percentile for age remain to be dened. 5.1. Case study D.G. is a Caucasian male born at 36 weeks of gestation, weighing 2610 g and measuring 44 cm in

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length, with posterior urethral valves and renal dysplasia after a vesicoamniotic stent was placed in utero at 24 weeks of gestation. A vesicostomy was performed after birth to ensure urinary drainage. He required treatment with sodium citrate/citric acid, calcium carbonate, and calcitriol. D.G.s growth data are presented in Table 4 and Fig. 5. Prior to the initiation of supplemental feedings through a gastrostomy tube (at age 19 months of age), D.G.s weight-height ratio was suboptimal, suggesting caloric deciency and/or cachexia. Even when rhGH therapy was started at 3.9 years of age, his height velocity did not improve (Fig. 5) Questions to consider include: (1) What was distinctive about D.G.s growth pattern after enteral feeding was started? and (2) What happened to his growth after rhGH therapy was initiated? After the initiation of tube feedings at 19 months of age, D.G.s weightheight ratio improved slightly, but his height velocity did not. However, even with supplemental gastrostomy tube feedings, his weight SD score and weightheight ratio remained below normal for his age. His height velocity actually declined after starting gastrostomy feeds, with his height standard deviation score 3.0 at age 2 years and 3.86 at age 3.9 years. Weightheight percentile scores of 2% and 1%, respectively, attested to his poor weight gain and probable caloric insuciency. Additional attention to the modiable factors that can contribute to growth failure in children with CKD (e.g., acidosis, malnutrition, saltwasting, osteodystrophy, hypothyroidism) is recommended when a child with CKD does not grow at a normal rate. Even with the administration of rhGH therapy at 3.9 years of age, his height velocity did not improve. In this case, D.G.s gastrostomy tube feedings were not being administered as prescribed, so the patient did not receive sucient calories to support growth. Even with supplemental rhGH, his growth was suboptimal. Closer attention to educating D.G.s parents about the importance of enteral nutrition was needed to ensure good calorie intake.

Fig. 5. Height and weight data for a male child with chronic renal insuciency and growth failure from birth to 36 months. A gastrostomy tube was placed to initiate enteral feedings at 1.9 years of age. Growth response was poor due to parental non-compliance with the enteral feeding program. Better height velocity was not obtained until both additional calories and rhGH therapy were provided.

6. Summary Signicant growth failure can occur in children at any stage of CKD. Early screening for growth delay in children with CKD can prevent associated complications. Growth assessments should be a routine component of pediatric nephrology care. CKD-related

Table 4 D.G.s growth pattern Age (year) Birth 0.3 1.0 1.5 1.9 Wt (kg) 2.61 4.6 6.5 7.2 8.1 Wt SDS 1.54 2.97 4.50 4.74 2.09 Ht (cm) 44 55.5 68 70 74 Ht SDS 2.21 2.31 3.04 4.07 1.81 Wt/Ht %tile 39 1 1 1 Cr 1.9 1.4 1.4 1.2 1.2 GFR (mL/min/1.73 m2) 11.1 17.9 26.7 32.1 31.9

Gastrostomy tube feedings initiated 2.8 9.88 3.9 10.5

3.31 4.41

82 86

3.00 3.86

2 1

1.0 1.3

45 36.4

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conditions that can impair growth, such as acidosis, malnutrition, renal osteodystrophy, and salt and water wasting, should be addressed before considering rhGH therapy. The treatment of children with growth failure related to CKD requires a multidisciplinary team eort of physicians, nurses, nutritionists, and social workers. To achieve optimal growth outcomes, rhGH therapy should be started at an early age and stage of CKD. Children with CKD require higher doses of rhGH than those with growth hormone deciency to achieve target height.

Acknowledgements The authors wish to acknowledge the members of the Growth in Children with CKD Consensus Committee (Shawna Field, RD; Paul Fielder, PhD; Debbie S. Gipson, MD; Larry Greenbaum, MD, PhD; Marisa D. Juarez-Congelosi, BS, RD, LD; Frederick J. Kaskel, MD, PhD; Craig B. Langman, MD; Lynn D. Long, RN, MS; Dina Macdonald, RN, BSN, CNN; Deborah H. Miller, RN, MSN, CNN; Mark M. Mitsnefes, MD; Valerie M. Panzarino, MD; Ron G. Rosenfeld, MD; Mouin G. Seikaly, MD; Brian Stabler, PhD; and Sandra L. Watkins, MD) for their valuable input in the development of the algorithm presented in this manuscript.

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