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Pediatrics and neonatology

Clinical practice recommendations for growth hormone treatment in children with chronic kidney disease

ESPN2019Full text
Full text · CC BYDrube J, Wan M, Bonthuis M, Wühl E, Bacchetta J, Santos F et al.. Clinical practice recommendations for growth hormone treatment in children with chronic kidney disease. Nat Rev Nephrol, 2019. Licensed under CC BY. Changes: reformatted for the web. Original: https://doi.org/10.1038/s41581-019-0161-4

Summary

Achieving normal growth is one of the most challenging problems in the management of children with chronic kidney disease (CKD). Treatment with recombinant human growth hormone (GH) promotes longitudinal growth and likely enables children with CKD and short stature to reach normal adult height. Here, members of the European Society for Paediatric Nephrology (ESPN) CKD–Mineral and Bone Disorder (MBD), Dialysis and Transplantation working groups present clinical practice recommendations for the use of GH in children with CKD on dialysis and after renal transplantation. These recommendations have been developed with input from an external advisory group of paediatric endocrinologists, paediatric nephrologists and patient representatives. We recommend that children with stage 3–5 CKD or on dialysis should be candidates for GH therapy if they have persistent growth failure, defined as a height below the third percentile for age and sex and a height velocity below the twenty-fifth percentile, once other potentially treatable risk factors for growth failure have been adequately addressed and provided the child has growth potential. In children who have received a kidney transplant and fulfil the above growth criteria, we recommend initiation of GH therapy 1 year after transplantation if spontaneous catch-up growth does not occur and steroid-free immunosuppression is not a feasible option. GH should be given at dosages of 0.045–0.05 mg/kg per day by daily subcutaneous injections until the patient has reached their final height or until renal transplantation. In addition to providing treatment recommendations, a cost-effectiveness analysis is provided that might help guide decision-making.

Introduction

In the past two decades, major progress has been made in our understanding of the pathophysiology and treatment of growth failure in children with chronic kidney disease (CKD). Nevertheless, approximately 40% of children with end-stage renal disease (ESRD) have a reduced final height (below the third percentile) compared with that of healthy age-matched and sex-matched controls1,2. Short stature impairs quality of life, self-esteem and social rehabilitation and is associated with increased mortality3–6. The aetiology of growth failure in CKD is multifactorial and includes intrauterine growth restriction, malnutrition, mineral and bone disorder (MBD), metabolic acidosis, loss of electrolytes and disturbances of the somatotropic and gonadotropic hormone axes (Fig. 1). In particular, advanced CKD is a state of growth hormone (GH) insensitivity, characterized by deficiency of functional insulin-like growth factor 1 (IGF1)7. This GH insensitivity can be overcome by the administration of supraphysiological doses of recombinant human GH (abbreviated to GH hereafter), which stimulates IGF1 synthesis, normalizes somatomedin bioactivity, promotes longitudinal growth and likely improves adult height8,9. Consequently, GH has been licensed for the treatment of CKD-induced growth failure in Europe, North America and many other high-income countries.

Fig. 1 Factors that contribute to growth failure in children with CKD.

The aetiology of growth failure in chronic kidney disease (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. CKD–mineral and bone disorder (CKD-MBD), metabolic acidosis, anaemia, loss of electrolytes and water and disturbances of the somatotropic and gonadotropic hormone axes also contribute to growth failure. CKD is a state of growth hormone (GH) insensitivity that is characterized by deficiency of functional insulin-like growth factor 1 (IGF1) due to reduced GH receptor expression in target organs such as the liver and disturbed GH receptor signalling via the Janus kinase 2 (JAK2)–signal transducer and activator of transcription 5 (STAT5) pathway due to inflammation-induced suppressor of cytokine signalling (SOCS) expression and increased IGF binding capacity due to excess of IGF binding proteins (IGFBPs). Finally, reduced release of hypothalamic gonadotropin-releasing hormone (GnRH), due to uraemia-related inhibitory factors such as angiotensin II (ANGII) and steroid treatment, might result in decreased circulating levels of bioactive luteinizing hormone (LH), hypogonadism and reduced pubertal growth spurt. The GH insensitivity in CKD can be overcome by the administration of supraphysiological doses of recombinant human GH, which stimulates IGF1 synthesis, normalizes somatomedin bioactivity, promotes longitudinal growth and likely improves adult height. FSH, follicle-stimulating hormone; PTH, parathyroid hormone.

— figure not reproduced here; see the original article.

However, other than a treatment algorithm proposed by members of a consensus conference held in 2003 (ref.10) and a brief guidance from the Kidney Disease Outcomes Quality Initiative (KDOQI)11, no comprehensive evidence-based recommendations are available for the use of GH in children with CKD. To address this gap, members of the European Society for Paediatric Nephrology (ESPN) CKD-MBD, Dialysis and Transplantation working groups have developed clinical practice recommendations (CPRs) for the use of GH in children with CKD on dialysis and after renal transplantation with input from experts in paediatric nephrology, paediatric endocrinology, pharmacy, epidemiology and patient representatives. Recommendations are based on evidence where possible. In the absence of suitable evidence, the opinion of experts from the working groups is provided but clearly graded as such and must be carefully considered by the treating physician and adapted to individual patient needs as appropriate. Although the CPRs have been generated by a European society, they are intended to be useful to clinicians within and beyond Europe. These CPRs will be audited and revised periodically. Research recommendations to study key GH outcome measures in children with CKD are also suggested.

Methods

Overview of the guideline project

We have followed the RIGHT (Reporting Items for practice Guidelines in Healthcare) Statement for Practice Guidelines12. To generate this Evidence-Based Guideline, three groups were assembled: a core leadership group, an external advisory panel and a voting panel. The core group comprised paediatric nephrologists who are members of the ESPN CKD-MBD, Dialysis and Transplantation working groups, a paediatric pharmacist and an epidemiologist. The external advisory group included two paediatric endocrinologists, four patient representatives and two additional paediatric nephrologists with expertise in GH treatment in children. The patient representatives discussed the manuscript provided by the core group members within their local parents’ association and their suggestions were incorporated into the manuscript by members of the core leadership group. The voting group included 37 members of the ESPN CKD-MBD, Dialysis and Transplantation working groups with expertise in paediatric CKD. Voting group members were asked by use of an e-questionnaire to provide a level of agreement on a five-point scale (strongly disagree, disagree, neither agree/disagree, agree and strongly agree) (Delphi method). Failing a 70% level of consensus, recommendations were modified after discussion by the core group and reviewed again by the voting panel until a consensus level of at least 70% was achieved.

Developing the PICO questions

We developed PICO (Patient or Population covered, Intervention, Comparator, Outcome) questions as follows13. These PICO elements were arranged into the questions to be addressed in the literature searches. Each PICO question then formed the basis for a recommendation.

The population covered included children with CKD on dialysis and after transplantation. The intervention and comparators considered included treatment with GH compared with no treatment or placebo. We addressed recommendations for the initiation, continuation and discontinuation of GH therapy, its growth-promoting effects (including biochemical and skeletal effects) and its safety. Although some reports suggest that GH may have anabolic effects and improve muscle strength and quality of life, most of these data are based on preclinical or low-grade association studies and were not considered in this document.

Literature search

The PubMed database was searched for studies published up to 15 May 2018; all systematic reviews of randomized controlled trials (RCTs) on GH for the promotion of growth in children with CKD for growth and all RCTs, prospective uncontrolled trials, observational studies and registry studies on GH in children with CKD, irrespective of the number of patients, were included. Registry data were used only for final height analyses and safety measures. The following key words were used to identify suitable studies: “chronic renal failure” OR “CKD” OR “chronic renal insufficiency” OR “dialysis” OR “renal transplantation” OR “kidney transplantation”) AND (“children” OR “paediatric” OR “pediatric” OR “child”) AND (“growth hormone” OR “GH”) AND (“treatment” OR “therapy”). Included studies were limited to those published in English, with at least 6 months of follow-up, and containing data on standardized height before and at the end of study, data on CKD stage (as assessed by glomerular filtration rate (GFR) or degree of renal impairment), mode of renal replacement therapy, child participants only (aged 0–18 years) and with at least five GH-treated patients. The search retrieved 530 results, and 62 articles are referenced here.

Further details and a summary of the publications used for this CPR are given in the Supplementary material (Supplementary Tables 1–4).

Grading system

We have followed the grading system of the American Academy of Pediatrics to develop the recommendations14 (Fig. 2). The quality of evidence is graded high (A), moderate (B), low (C), very low (D) or not applicable (X). The latter grading (X) refers to exceptional situations in which validating studies cannot be performed and benefit or harm clearly predominates and was used to grade contraindications for GH use and safety parameters. The strength of a recommendation is graded strong, moderate, weak or discretionary (when no recommendation can be made).

Fig. 2 Matrix for the grading of evidence and assigning strength of recommendations as currently used by the American Academy of Pediatrics.

Reproduced with permission from ref.14: Pediatrics 140, e20171904 Copyright © 2017 by the AAP.

— figure not reproduced here; see the original article.

Cost-effectiveness analysis

A cost-effectiveness analysis was performed on the basis of an expected gain in final height of 7.2 cm given treatment for 2–5 years and an average cost of €22 per 1 mg GH in two clinical scenarios: a child aged 5 years at the start of GH therapy and an adolescent aged 12 years at the start of GH therapy, both in the twenty-fifth percentile for age-related and sex-related weight (Supplementary Box 1; Supplementary Tables 5, 6).

Limitations of the guideline process

Most RCTs of GH use in children with CKD were performed in the 1990s when the conduct of trials was not as robust as that of current trials. For example, many of these RCTs did not include all enrolled participants in their analyses. In addition, the size of many RCTs was small owing to the low incidence of childhood CKD; thus, the strength of most recommendations is weak to moderate. Owing to the limited budget of this ESPN initiative, the core group did not include physicians outside Europe or patient representatives. The lack of patient representatives in the core group was partly mitigated by including patient representatives from Germany, Italy, Belgium and the UK as external experts.

Initial work-up

Assessment of statural growth

As for any child suffering from a potentially growth-limiting chronic disease, length (before 2 years of age) and height (from 2 years of age) should be assessed regularly by trained personnel using calibrated equipment and standardized techniques and compared with sex-specific and age-specific reference charts for healthy children (Box 1). Gestational age is taken into account when assessing length of infants born prematurely. Supine length is measured using a validated length board or mat up to a length of 80 cm or if assessment of standing height is not feasible. In older children, standing height is measured using a wall-mounted stadiometer11.

The frequency of monitoring is based on the patient’s age and stage of CKD (Table 1). Children with evidence of growth delay, comorbidities including central nervous system, liver or heart involvement and rapid changes in health status or dietary intake might warrant more frequent assessment than those with milder or more stable disease11,15,16. The calculation of height velocity over a minimum follow-up of 6 months is a more sensitive index of growth than a single height measurement17. This approach enables the identification of children with reduced growth rates (that is, those below the twenty-fifth percentile) who might benefit from growth-promoting measures. By contrast, a growth velocity above the seventy-fifth percentile indicates catch-up growth18. Optimal growth monitoring requires updated national growth charts. If unavailable, northern or southern European growth charts are preferable over other national or international growth charts for European children with CKD19.

Table 1

Assessment intervals for statural growth in CKD

Assessment typeAge (years)Recommended intervals of assessment (months)
CKD stage 3CKD stage 4CKD stage 4–5CKD stage 5D
Lengtha or height0–10.5–20.5–20.5–20.5–2
1–31–31–21–21–2
>33–61–31–31–3
Length velocitya or height velocity0–10.5–20.5–20.5–20.5–1
1–31–61–31–31–2
>36666

Recommendations were generated by combining those from the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines; the Caring for Australasians with Renal Impairment (CARI) guidelines; and the Clinical Guideline from the British Society for Paediatric Endocrinology and Diabetes (BSPED), the British Association for Paediatric Nephrology (BAPN) and the Paediatric Renal Interest Nutrition Group (PRING)11,15,16. CKD, chronic kidney disease. aSupine length is measured using a validated length board or mat up to a length of 80 cm (before 2 years of age) or if assessment of standing height is not feasible.

Assessment of growth potential

Assessment of the extent to which the epiphysis of the left wrist is open on a radiography image is the standard approach for assessing a child’s growth potential20. The calculation of genetic target height (TH, in cm) can be performed using Tanner’s formula for girls (equation 1) and for boys (equation 2):

1\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\frac{{H}_{{\rm{mother}}}+{H}_{{\rm{father}}}-13}{2}$$\end{document}Hmother+Hfather-132

2\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\frac{{H}_{{\rm{mother}}}+{H}_{{\rm{father}}}+13}{2}$$\end{document}Hmother+Hfather+132

These equations are based on mid-parental height and assume that the parents do not have a chronic disease21. Alternatively, the Molinari formula can be used for girls (equation 3) and for boys (equation 4):

3\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\frac{{H}_{{\rm{mother}}}+{H}_{{\rm{father}}}}{2}-2.6$$\end{document}Hmother+Hfather2-2.6

4\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\frac{{H}_{{\rm{mother}}}+{H}_{{\rm{father}}}}{2}+10.2$$\end{document}Hmother+Hfather2+10.2

These equations assume a secular trend across generations of 3.8 cm (ref.22). The application of adult height prediction methods such as the Tanner–Whitehouse Mark II method is not generally recommended for children with CKD because several validation studies have shown that these formulae overestimated final height by 3–10 cm (refs23,24).

CKD-associated growth-limiting factors

The pathogenesis of growth retardation in CKD is multifactorial (Box 2). The two most important factors are CKD severity and age at disease onset. In order to maximize the growth-promoting effect of GH and to reduce the risk of adverse events, CKD-associated factors that adversely interfere with growth or affect the therapeutic response need to be adequately addressed before GH treatment is initiated.

Nutrition

Nutritional deficiency is a major cause of growth failure and is particularly important in infancy and early childhood, which represent the most nutrition-sensitive phases of growth25. Prescription of a nutritionally appropriate feed, if needed via gastrostomy or nasogastric tube, is therefore recommended to optimize growth26 before GH treatment is considered11. Optimal nutritional management might result in catch-up growth in infants even with severe CKD27,28.

Hormonal disturbances

The main hormonal disturbance that leads to growth failure in CKD is GH insensitivity (described earlier). Pubertal delay and reduced pubertal growth spurts are characteristic findings of longstanding ESRD and probably result from the reduced release of hypothalamic gonadotropin-releasing hormone (GnRH) and decreased circulating levels of bioactive luteinizing hormone (LH) due to CKD-related inhibitory factors such as angiotensin II29. Patients who demonstrate delayed puberty — that is, boys with a testicular volume less than 4 ml at the age of 14 years and girls with breast stage less than B2 at age 13.5 years — should be referred to a paediatric endocrinologist for full work-up and eventual induction of puberty. Hypothyroidism and GH deficiency can cause growth failure in children independent of underlying CKD. Therefore, we recommend that thyroid hormone levels, including serum TSH and free T3, and serum IGF1 levels are measured before GH therapy is initiated. We do not recommend assessment of IGF binding protein 3 (IGFBP3) serum concentrations in patients with CKD because low-molecular-mass immunoreactive IGFBP3 fragments accumulate in CKD30 and thus most commercially available IGFBP3 assays deliver falsely elevated IGFBP3 serum levels.

Metabolic control

Indirect evidence suggests that good metabolic control is necessary to facilitate longitudinal growth in CKD. Children with isolated tubular disorders resulting in urinary salt, water or bicarbonate losses show severe growth retardation31–33. Therefore, we recommend that children with CKD resulting in hyponatraemia and polyuria receive free water and sodium supplementation to avoid chronic intravascular volume depletion and permit optimal growth. Metabolic acidosis should be corrected (to serum bicarbonate levels ≥22 mEq/l) by administration of sodium bicarbonate and/or the use of HCO3-based or lactate-based dialysis solutions in children on dialysis34.

CKD-MBD

Although reduced height velocity is considered a clinical manifestation of CKD-MBD, the relationship of longitudinal growth with serum parathyroid hormone (PTH) and vitamin D values is unclear35. Increased serum PTH and vitamin D deficiency might contribute to growth retardation; therefore, marked secondary hyperparathyroidism should be controlled before GH therapy is commenced9. Thus, serum PTH levels should be kept within the recommended CKD-stage-dependent target range for children35–37. Serum concentrations of total 25-hydroxyvitamin D3 should be kept at above 30 ng/ml in all stages of CKD38.

Adequacy of dialysis

The use of biocompatible peritoneal dialysate is associated with improved height in young children on chronic peritoneal dialysis39. Increased protein administration and increased urea clearance were associated with improved growth in well-nourished children receiving haemodialysis even in the absence of GH treatment40. Therefore, optimization of dialysis regimens should always be attempted to improve growth.

Anaemia

Anaemia may contribute to CKD-related growth failure41,42. Target haemoglobin concentrations as recommended by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines should therefore be achieved before starting GH therapy43.

Comorbidities

Systemic diseases or genetic syndromes that are often associated with paediatric CKD, including Schimke immune-osseous dysplasia, Bardet–Biedl syndrome and Galloway–Mowat syndrome, can interfere markedly with normal growth27. These patients have typically been excluded from RCTs of GH therapy; therefore, the efficacy and safety of GH in patients with these conditions have not been evaluated. Coexisting or preceding history of malignancies contraindicate GH therapy.

Clinical and organ assessments and contraindications

We suggest that all paediatric patients who are being considered for GH therapy undergo a fundoscopic examination to rule out pre-existing papilledema, which could be suggestive of intracranial hypertension that might progress during GH therapy44. Radiography of the left wrist is recommended in order to assess bone age to document open epiphyses for the assessment of growth potential, as mentioned above. Assessment of pubertal stage should be performed according to Tanner stages in patients older than 10 years of age. Furthermore, GH must not be started in the case of known hypersensitivity against this drug or its constituent parts, or in patients with an active tumour or uncontrolled diabetes mellitus.

Indications and contraindications

Although it might be assumed that short children with CKD wish to be tall, the pros and cons of GH therapy, including the burden of receiving daily subcutaneous injections for many years, must be discussed with the patient and their family (Box 3). These considerations are of particular importance for immobilized patients and those with syndromic kidney diseases.

Specific indicators for starting GH therapy

A height velocity below the twenty-fifth percentile for age and sex indicates progressive growth failure in a child presenting with short stature (that is, below the third percentile or with a height standard deviation score (SDS) below −1.88). Infancy is the most sensitive phase for the growth-suppressing effects of GH insensitivity. Any decrease in growth rate during this phase can result in severe growth retardation and a potentially irreversible loss of growth potential45,46. We therefore recommend that persistent growth failure, defined as height below the third percentile and height velocity below the twenty-fifth percentile beyond a period of 3 months in infants or 6 months in children and adolescents, be an indication for GH therapy once other potentially treatable risk factors for growth failure have been adequately addressed. Owing to the small size of available RCTs and a lack of long-term follow-up data from RCTs, the strength of this recommendation is graded as moderate.

Whether a height velocity below the twenty-fifth percentile is an indication to start GH even before height drops below the third percentile is unclear. Such early, preventive therapy might be more cost-effective than initiating GH therapy at an older age, when growth retardation has become evident and higher absolute GH doses are required to account for the higher body weight. The KDOQI guidelines for nutritional management in children with CKD suggest that GH should be initiated promptly if catch-up growth has not been induced within 3 months of initiating nutritional management11. Because a persistently reduced growth rate will ultimately result in short stature, we suggest that GH therapy is considered in children with height between the third and tenth percentile who have low height velocity (below the twenty-fifth percentile) that persists beyond 3 months in infants and beyond 6 months in children with growth potential provided that other potentially treatable risk factors for growth failure have been adequately addressed. However, no RCTs are available to support this approach; therefore, this recommendation is graded as weak.

Benefits of GH in specific patient subgroups

Prepubertal patients

RCTs have demonstrated that GH stimulates growth in prepubertal children with pre-dialysis CKD, in patients on dialysis and after renal transplantation. A meta-analysis that included 16 RCTs and 809 patients47 showed that, compared with patients who received placebo or no additional treatment, patients in the intervention group who received 1 year of GH had a higher mean height SDS (difference of 0.91; 95% CI 0.58–1.23) and a higher mean height velocity (difference of 3.88 cm per year; 95% CI 3.32–4.44). Moreover, although reduced compared with levels in the first year of treatment, height velocity remained significantly greater in treated children than in untreated children during the second year of therapy (mean difference 2.3 cm per year; 95% CI 1.39–3.21).

To date, all except one RCT48 on GH treatment in children with pre-dialysis CKD have included only patients with CKD stage 3 or higher. Owing to insufficient data on the efficacy of GH in children with GFR above 60 ml/min/1.73 m2 and the weak effect of mildly decreased GFR on longitudinal growth, we do not recommend use of GH in short children with CKD stage 1 or 2 (ref.49) unless they have other conditions, such as nephropathic cystinosis, that predispose to poor growth50. Patients with cystinosis are prone to severe growth failure in early life despite a mild reduction in GFR due mainly to the presence of renal Fanconi syndrome. An uncontrolled study reported that GH treatment for up to 3 years increased growth rates in short children with nephropathic cystinosis compared with baseline, with superior growth responses observed in patients with early CKD (stage 1–3) compared with those with advanced CKD and on dialysis50.

Children before dialysis and on dialysis

Long-term follow-up of short-term RCTs and nonrandomized studies of GH treatment in prepubertal children with nondialysis-dependent CKD demonstrated that catch-up growth continues asymptotically over an extended treatment period, with reports of a cumulative increase in standardized height of 1.1–1.9 SDS within 5–6 years51–53. The growth response to GH treatment has been positively associated with residual renal function, target height, initial target height deficit and treatment duration and negatively associated with age at start of treatment51.

The response to GH treatment is significantly attenuated in children on dialysis compared with children with earlier stages of CKD, irrespective of dialysis modality, most likely owing to a higher degree of GH insensitivity51,54. However, the response to GH can be markedly improved by augmenting dialytic clearance with daily haemodialfiltration55,56. GH therapy also increases height in paediatric patients on dialysis irrespective of underlying bone histological features; bone formation rates are also higher in GH-treated patients than in controls owing to its osteoanabolic effects57. Although, renal transplantation does not uniformly result in catch-up growth in paediatric patients previously treated with GH, transplantation should not be withheld in these patients.

Paediatric renal transplant recipients

Persistent growth failure is common in children after renal transplantation as a result of reduced graft function and maintenance glucocorticoid (steroid) therapy58,59. A meta-analysis of five RCTs on growth outcome using steroid minimization protocols showed a significant increase in height SDS in the steroid avoidance group (mean difference of 0.38; 95% CI 0.07–0.68), particularly within the first year after steroid withdrawal (mean difference of 0.22; 95% CI 0.10–0.35), and in prepubertal patients (mean difference of 0.60; 95% CI 0.21–0.98)60.

Several RCTs have shown the benefit of GH therapy in short prepubertal renal transplant recipients. A meta-analysis of five prospective RCTs involving a total of 401 patients showed that patients receiving GH therapy had a significantly higher growth velocity 1 year after initiation of therapy than the control group, with a mean height SDS difference of 0.68 (95% CI 0.25–1.11)61. The mean difference in height SDS change between the treated and control group was 0.52 (95% CI 0.37–0.68), and the growth response to GH therapy was better in children younger than 10 years of age than in older patients62. We therefore recommend that GH therapy is considered for paediatric renal transplant recipients for whom expected catch-up growth cannot be achieved by steroid minimization or for patients in whom steroid withdrawal is not feasible owing to high immunological risk, particularly in children with suboptimal graft function (estimated GFR (eGFR) <50 ml/min/1.73 m2). We recommend that growth is monitored for at least 1 year post-transplantation before GH therapy is considered in order to allow for spontaneous catch-up growth.

Infants

In a study of 16 well-nourished infants with CKD stage 3–4, those randomly assigned to GH showed significantly higher length gains28. A second study of 12 infants treated with GH (8 of whom were on dialysis) reported similar rates of growth as in 15 matched controls with less severe CKD63. Data from the International Pediatric Peritoneal Dialysis Network (IPPN) registry showed that administration of GH was independently associated with improved length in infants and young children on chronic peritoneal dialysis39. Although the provision of adequate nutrition is certainly essential to promote the growth and development of infants with CKD, some infants show growth failure despite adequate caloric supply. Therefore, we recommend that early GH therapy is considered for infants with CKD stage 3–5 and those on dialysis to accelerate length and weight gain and to achieve the body size required for renal transplantation64. Given that the majority of infants included in the aforementioned studies were older than 3 months of age at the start of GH therapy as well as the need to assess spontaneous growth before GH treatment, we do not recommend GH therapy for infants younger than 6 months of age.

Pubertal patients

One study that followed GH-treated CKD patients from late prepubertal age to final height revealed that there was no overall effect of GH treatment on pubertal height gain8. By contrast, however, two studies of short pubertal transplant recipients reported that GH treatment initiated during puberty was associated with a higher mean gain in height than that of matched historical controls65,66. Likewise, an analysis of data from the Pfizer International Growth Database (KIGS) demonstrated that CKD patients who were either in early or late puberty at the time of GH therapy initiation experienced catch-up growth, with a significant cumulative increase in mean height SDS of 1.3 and 1.0 until near-adult height67.

GH to improve adult height

Data on adult or near-adult height are available from ten nonrandomized trials and the KIGS, in which GH was administered for at least 2 years, comprising a total of 836 patients on various modes of renal replacement therapy. In five studies, a matched historical control group was included. The median change in standardized height until attainment of (near) adult height amounted to 1.1 SDS (range 0.2–1.6 SDS) in GH-treated patients (P < 0.05 for each final height measurement versus initial height measurement; Supplementary Table 4). This change corresponded to a median absolute increase in GH-treated patients of 7.4 cm (range 1.4–10.8 cm) in boys and 7.0 cm (range 1.3–10.1 cm) in girls on the basis of European reference values19. This calculation may represent a poor estimate (likely an underestimate) of median absolute height increase, because adult height was significantly lower in non-GH-treated controls than initial standardized height indices in all except one study8,52,62,67–72. Heights attained at the start of GH and throughout the duration of GH treatment were positively associated with final height, whereas time spent on dialysis, age at puberty onset and age of start of GH were negatively associated with final height8,67. Taken together, the available studies suggest that GH improves adult height in short prepubertal and pubertal CKD patients before and after renal transplantation.

Contraindications

GH therapy improves height in paediatric dialysis patients, irrespective of the presence of underlying bone histological features, for example, high bone turnover due to secondary hyperparathyroidism61. However, severe secondary hyperparathyroidism (that is, characterized by intact PTH serum levels >500 pg/ml or increase ninefold above the normal range) is associated with diminished longitudinal growth and an increased risk of slipped capital femoral epiphysis in paediatric patients with CKD73,74. Because GH markedly stimulates bone growth, the risk of slipped capital femoral epiphysis might be further increased by GH treatment. Therefore, severe secondary hyperparathyroidism is a contraindication for GH therapy. Owing to its potential proliferative properties, GH is also contraindicated in patients with severe diabetic retinopathy or active malignancy. Finally, GH should not be used in patients with known hypersensitivity to the active substance or to any of the excipients (such as m-cresol) and in patients with acute critical illness suffering complications following heart surgery, abdominal surgery, multiple accidental trauma, acute respiratory failure or similar conditions75.

Cost–benefit ratio of GH therapy

As outlined above, the expected increase in adult height after 2–5 years of GH treatment amounts to 7.2 cm (7.4 cm in boys and 7.0 cm in girls). According to our cost-effectiveness analysis (Supplementary Box 1; Supplementary Table 5), the corresponding total drug-related costs for a patient aged 5 or 12 years at start of treatment range from €13,000 to €37,900 and €27,100 to €80,100, respectively, depending on the length of treatment (2–5 years). The corresponding incremental cost per centimetre gained in adult height for a patient aged 5 or 12 years at the start of treatment ranges from €1,800 to €5,300 and from €3,800 to €11,100, respectively, again depending on the length of treatment (Supplementary Table 5). However, the actual cost of GH treatment might differ substantially among European countries. Our calculation was based on a cost of €22 per 1 mg GH, but the median country-specific costs range between €7 and €54 per 1 mg GH (Supplementary Table 6). The incremental cost-effectiveness of GH treatment obviously depends on the length of treatment and the required daily amount of GH, which is related to body weight; therefore, earlier initiation of GH therapy in a young patient would be more cost-effective if long-term dialysis is prevented by early renal transplantation. Finally, early initiation of GH treatment in a small child may substantially shorten the time taken to achieve the body size required for renal transplantation. We therefore recommend that the cost–benefit ratio is considered before initiating GH therapy in short children with CKD (Box 4).

Schedule for GH therapy and monitoring

GH dosage

The GH dosage used in the available RCTs and observational studies was 28–30 international units (IU)/m2 per week (equivalent to 0.045–0.05 mg/kg per day) by daily subcutaneous injections (Supplementary Tables 2–4). Twelve RCTs compared this dosage to placebo or no treatment28,48,57,68,76–83, 5 studies compared doses of 14 IU/m2 per week (equivalent to 0.023 mg/kg per day) to 28 IU/m2 per week84–88 and 1 study65 compared 28 IU/m2 per week to 56 IU/m2 per week (equivalent to 0.09 mg/kg per day). A 2012 meta-analysis demonstrated that compared with patients in the 14 IU/m2 per week group, patients in the 28 IU/m2 per week group experienced a 1.18 cm per year (95% CI 0.52–1.84) higher increase in height velocity and a 1.48 higher (95% CI 0.03–2.93) height velocity SDS after 1 year of treatment47. The one study that compared 28 IU/m2 per week with 56 IU/m2 per week reported no significant difference between the groups in the change in mean height SDS and mean height velocity. Therefore, we recommend that GH therapy is administered with a dosage of 0.045–0.05 mg/kg per day, irrespective of patients’ age, with dose adjustment according to body weight on regular intervals (Box 5).

Frequency of GH administration

In healthy controls and in patients with GH deficiency, the bioavailability of GH after subcutaneous injection is approximately 80%, independent of sex. The Tmax of GH is 3–6 hours and its half-life is 2–3 hours89. We recommend that GH is administered as daily subcutaneous injections because this was the mode of application used by all RCTs. To mimic the physiological circadian rhythm of endogenous GH secretion, evening injections are recommended. The injection side should be changed daily to avoid lipoatrophy.

Type of GH

The available studies have used a variety of brands of GH47. In addition, GH biosimilars have been approved for the same indications as the reference product in Europe since 2006 following the completion of comprehensive comparability studies that assessed safety and efficacy90. Ongoing pharmacovigilance activities over the past 10 years have also not identified any relevant difference in safety profile. Therefore, we recommend both GH reference and GH biosimilar products for use in short children with CKD.

Monitoring

Ongoing monitoring is necessary to evaluate the response to GH and to detect any potential adverse effects. The ultimate goal of GH treatment in children with CKD is to ‘normalize’ adult height. The therapeutic end point could be the attainment of the patient’s individual genetic target height or of a normal population-related adult height (that is, above the third percentile). Although the latter goal is certainly desirable, it may not be a feasible target if the patient’s genetic height potential is below the third percentile.

Potential adverse events

The adverse effects of GH reported by RCTs are similar across different dosages and to those reported by participants in untreated control populations (Supplementary Tables 7, 8). However, the follow-up of RCTs to date has been relatively short; thus, monitoring the effect of long-term treatment requires assessment of registry data. A comprehensive comparison of the incidence of adverse events in large cohorts of paediatric CKD patients with and without GH treatment revealed no significant association between GH therapy and the incidence of malignancy, slipped capital femoral epiphysis, avascular necrosis, glucose intolerance, pancreatitis, rapid progression of CKD, acute allograft rejection or fluid retention91. Commonly reported adverse effects are discussed below.

Intracranial hypertension

An analysis of registry data from the Genentech National Cooperative Growth Study showed that intracranial hypertension was reported in 3 of 1,376 CKD patients44. Although in all three patients intracranial hypertension occurred after discontinuation of GH, we recommend a baseline fundoscopy before initiation of GH and, in the presence of persistent headache or vomiting, an immediate work-up including fundoscopy should be performed.

Glucose intolerance

Although insulin secretion increases during the first year of GH treatment and hyperinsulinaemia persists during long-term therapy, evidence suggests that GH treatment for ≤5 years does not typically have an adverse effect on glucose tolerance92. The incidence of obesity in CKD patients has markedly increased over the past decade, and close monitoring of glucose metabolism is advised when initiating GH therapy in these patients owing to an increased risk of impaired glucose tolerance. Patients with nephropathic cystinosis have an increased risk of diabetes mellitus, irrespective of GH treatment93.

Secondary hyperparathyroidism and orthopaedic complications

Aggravation of secondary hyperparathyroidism has been reported as an occasional complication of GH therapy. GH might have a direct stimulatory effect on the parathyroid gland or might have subtle effects on calcium and phosphate homeostasis, which in turn stimulate PTH secretion57,74. In addition, increased longitudinal bone growth by GH treatment might unmask pre-existing renal osteodystrophy57. Therefore, CKD-MBD should be adequately treated according to current guidelines before initiation of GH therapy94. GH therapy should be withheld in patients with persistent severe secondary hyperparathyroidism (PTH >500 pg/ml) and can be reinstituted when PTH levels return to the desired target range35–37. In addition, rapid growth might contribute to an increased risk of slipped capital femoral epiphysis. We therefore recommend obtaining bone radiographs if symptoms occur and to discontinuing GH therapy if a diagnosis of slipped capital femoral epiphysis is confirmed.

Renal function

RCTs have not shown adverse effects of GH on renal function in paediatric patients with nondialysis CKD47. Likewise, an analysis of two large cohort studies did not show evidence of accelerated eGFR decline in children with CKD treated with GH compared with untreated patients over 10 years of follow-up95. However, because anecdotal reports of increases in serum creatinine level exist, we recommend close monitoring of renal function according to the stage of CKD, for example, monitoring in 3-month intervals in patients with CKD stage 3–4. GH therapy may need to be stopped if an unexplained decrease in eGFR occurs.

Bone and sexual maturation

No evidence exists to support an association between advanced pubertal growth spurts or accelerated bone age maturation with GH therapy8,47. However, anecdotal reports of accelerated pubertal development with GH therapy exist; therefore, yearly assessment of pubertal stages according to the Tanner stages is recommended for children older than 10 years of age. In addition, yearly assessment of bone age by radiography of the left wrist is suggested to exclude accelerated bone maturation. Discontinuation of GH treatment should be considered for patients with evidence of accelerated bone maturation.

Safety aspects of GH therapy in transplanted patients

Registry data and post-marketing surveillance by GH manufacturers have revealed no increased risk of malignancy in paediatric renal transplant recipients treated with GH96–98. RCTs have also not reported differences in the rate of rejection episodes (risk ratio 1.56; 95% CI 0.97–2.53) or eGFR between treatment groups61.

Identification and management of non-responders

An adequate growth response can be assumed if height velocity during the first year of GH treatment is greater than 2 cm per year over baseline. Such an increase would be approximately half of that reported in RCTs (mean increase 3.88 cm per year; 95% CI 3.32–4.44)47. For patients who do not adequately respond to GH therapy, we recommend assessment of patient adherence to GH therapy, including measurement of serum IGF1 levels, weight-adjusted GH dosage and assessment of nutritional and metabolic factors, as recommended before initiation of GH therapy9. As outlined above, higher GH doses are not more efficient than lower doses; therefore, higher GH doses cannot be recommended in non-responders.

Discontinuation of GH therapy

Termination of GH therapy should be considered in patients who do not adequately respond to GH treatment for a period of at least 6 months. Syndromic kidney disease might be one reason for a poor response to GH treatment. However, non-adherence to daily subcutaneous injections or inadequate GH dosing for the individual’s weight should be excluded. CKD-associated growth-limiting factors (see above) should also be adequately addressed in all non-responders, and GH may be transiently stopped to address these issues. GH treatment must be stopped in all patients at the time of renal transplantation. It seems to be reasonable to stop GH when the patient has attained his or her genetic target height. In addition, GH may be stopped when a patient reaches his or her genetic target height percentile. However, in a study of 22 patients who had a pause in GH therapy after attainment of target height percentile, withdrawal of GH led to maintenance of height SDS in only 27% of patients and a marked reduction in growth velocity in 73% of patients, who subsequently required reinstitution of GH therapy99. Alternatively, the dose of GH may be reduced when a patient reaches their genetic target height percentile, but the outcomes associated with this approach have not been systematically studied.

In late-pubertal adolescents, if height velocity drops below 2 cm per year and/or epiphyseal growth plate closure is evident on radiography, GH should be stopped as no further growth potential can be expected. Stopping GH in the case of severe adverse effects, a severe illness or trauma is recommended100–102.

Implementation and audit recommendations

The CPRs reported here will be disseminated widely through teaching lectures and webinars at an international level (for example, through International Pediatric Nephrology Association (IPNA) teaching courses and webinars), at the European level (for example, through the annual ESPN precongress teaching course, ESPN-IPNA master classes and webinars) and at an individual country level (for example, through annual National Pediatric Nephrology Congresses). The ESPN CKD-MBD, Dialysis and Transplantation working groups will audit the effectiveness and safety of the recommendations. To achieve this aim, growth outcome in children with CKD on GH treatment will be measured and reported in a European patient registry. The audit outcomes will be published and recommendations updated as necessary.

Research recommendations

Several areas of study have the potential to guide future evidence-based recommendations for GH therapy in children with CKD on dialysis and after renal transplantation. For example, animal studies suggest additive effects of treatment with recombinant IGF1 in combination with GH103. This combination approach should therefore be tested in short children on dialysis in whom growth failure is often incompletely resolved by GH treatment.

Animal studies also suggest that linear bone growth in CKD is adversely affected by the increased presence of inflammatory cytokines, which activate the suppressor of cytokine signalling 2 (SOCS2) pathway104. Future studies should therefore address the growth-promoting effects of measures targeting the SOCS2 pathway in short children with CKD.

One study showed that pharmacological inhibition of epiphyseal growth plate closure with the aromatase inhibitor anastrozole extended the duration of the growth potential period and increased adult height in short male adolescents treated with GH105. This approach should therefore be tested in severely growth-restricted adolescents on long-term dialysis because these patients are prone to persistent growth failure despite GH treatment51,54.

A study of the intra-individual variations in body proportions (for example, the ratio between trunk length and leg length) before and after GH treatment is warranted (because CKD is associated with disproportionate short stature) to identify how GH treatment affects different aspects of growth106.

Further research is also needed into the effect of GH treatment before renal transplantation on growth after renal transplantation, precision (personalized) medicine approaches to better provide individualized approaches to therapeutic management and the development of lower cost biosimilars with the need for less frequent injections or even oral preparations.

Conclusions and perspectives

Short stature is a frequent complication in children with chronically impaired renal function (typically defined as <50% of normal function), even after renal transplantation. We recommend that children with stage 3–5 CKD or those on dialysis older than 6 months of age should be candidates for GH therapy if they have persistent growth failure (defined as a height below the third percentile for age and sex and a height velocity below the twenty-fifth percentile) once other potentially treatable risk factors for growth failure have been adequately addressed and provided the child has growth potential. In children who have received a kidney transplant and fulfil the above growth criteria, we recommend initiating GH therapy 1 year after transplantation if spontaneous catch-up growth does not occur and steroid-free immunosuppression is not a feasible option. GH is given by daily subcutaneous injections, usually for a duration of several years until the patient reaches their final height or until renal transplantation. The expected increase in final height after 2–5 years of GH treatment amounts to approximately 7.2 cm. Patients and their families should be informed before initiation of GH therapy that individual growth responses differ widely. The GH injections usually do not hurt, and school-aged children may do the injections on their own if adequate training and adherence are ensured. Adverse effects of GH treatment are rare and include glucose intolerance and increased cranial pressure. The benefits of GH treatment with respect to increased stature must be weighed against the burden of daily subcutaneous injections on an individual basis (Boxes 1,3–5; Supplementary Table 9).

Supplementary information

References

  1. Franke D Growth and maturation improvement in children on renal replacement therapy over the past 20 years Pediatr. Nephrol. 2013 28 2043 2051 23708760 10.1007/s00467-013-2502-z PubMed DOI
  2. Harambat J Adult height in patients with advanced CKD requiring renal replacement therapy during childhood Clin. J. Am. Soc. Nephrol. 2014 9 92 99 24178977 10.2215/CJN.00890113 PMC3878688 PubMed DOI
  3. Wong CS Anthropometric measures and risk of death in children with end-stage renal disease Am. J. Kidney Dis. 2000 36 811 819 11007685 10.1053/ajkd.2000.17674 PubMed DOI
  4. Furth SL Stablein D Fine RN Powe NR Fivush BA Adverse clinical outcomes associated with short stature at dialysis initiation: a report of the North American Pediatric Renal Transplant Cooperative Study Pediatrics 2002 109 909 913 11986455 10.1542/peds.109.5.909 PubMed DOI
  5. Mekahli D Ledermann S Gullett A Rees L Evaluation of quality of life by young adult survivors of severe chronic kidney disease in infancy Pediatr. Nephrol. 2014 29 1387 1393 24609826 10.1007/s00467-014-2785-8 PubMed DOI
  6. Al-Uzri A The impact of short stature on health-related quality of life in children with chronic kidney disease J. Pediatr. 2013 163 736 741 23628375 10.1016/j.jpeds.2013.03.016 PMC3755086 PubMed DOI
  7. Tönshoff B Kiepe D Ciarmatori S Growth hormone/insulin-like growth factor system in children with chronic renal failure Pediatr. Nephrol. 2005 20 279 289 15692833 10.1007/s00467-005-1821-0 PubMed DOI
  8. Haffner D Effect of growth hormone treatment on the adult height of children with chronic renal failure. German Study Group for Growth Hormone Treatment in Chronic Renal Failure N. Engl. J. Med. 2000 343 923 930 11006368 10.1056/NEJM200009283431304 PubMed DOI
  9. Rees L Growth hormone therapy in children with CKD after more than two decades of practice Pediatr. Nephrol. 2016 31 1421 1435 26369925 10.1007/s00467-015-3179-2 PubMed DOI
  10. Mahan JD Warady BA & Consensus Committee. Assessment and treatment of short stature in pediatric patients with chronic kidney disease: a consensus statement Pediatr. Nephrol. 2006 21 917 930 16773402 10.1007/s00467-006-0020-y PubMed DOI
  11. National Kidney Foundation KDOQI Clinical Practice Guideline for Nutrition in Children with CKD: 2008 update Am. J. Kidney Dis. 2009 53 Suppl. 3 1 126 19231749 10.1053/j.ajkd.2008.11.017 PubMed DOI
  12. Chen Y A reporting tool for practice guidelines in health care: the RIGHT Statement Ann. Intern. Med. 2017 166 128 132 27893062 10.7326/M16-1565 PubMed DOI
  13. Guyatt GH GRADE guidelines: 2. Framing the question and deciding on important outcomes J. Clin. Epidemiol. 2011 64 395 400 21194891 10.1016/j.jclinepi.2010.09.012 PubMed DOI
  14. Flynn JT Clinical practice guideline for screening and management of high blood pressure in children and adolescents Pediatrics 2017 140 e20171904 28827377 10.1542/peds.2017-1904 PubMed DOI
  15. KHA-CARI. The CARI Guidelines. Evaluation and management of nutrition in children. CARI.org.au http://www.cari.org.au/CKD/CKD%20nutrition%20growth/Evaluation_and_management_of_nutrition.pdf (2005).
  16. Trace, S. et al. Clinical guideline. Monitoring growth in children with chronic kidney disease. BSPED.org.uk https://www.bsped.org.uk/media/1436/growthmonitoringinchildrenwithchronickidneydisease.pdf (2018).
  17. Foster BJ Leonard MB Measuring nutritional status in children with chronic kidney disease Am. J. Clin. Nutr. 2004 80 801 814 15447884 10.1093/ajcn/80.4.801 PubMed DOI
  18. Wit JM Boersma B Catch-up growth: definition, mechanisms, and models J. Pediatr. Endocrinol. Metab. 2002 15 Suppl. 5 1229 1241 12510974 PubMed
  19. Bonthuis M Use of national and international growth charts for studying height in European children: development of up-to-date European height-for-age charts PLOS ONE 2012 7 e42506 22916131 10.1371/journal.pone.0042506 PMC3419735 PubMed DOI
  20. De Sanctis V Hand X-ray in pediatric endocrinology: skeletal age assessment and beyond Indian J. Endocrinol. Metab. 2014 18 63 71 25538880 10.4103/2230-8210.145076 PMC4266871 PubMed DOI
  21. Tanner JM Whitehouse RH Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty Arch. Dis. Child 1976 51 170 179 952550 10.1136/adc.51.3.170 PMC1545912 PubMed DOI
  22. Molinari, L., Largo, R. H. & Prader, A. in Human Growth and Development (ed. Borms, J.) 193–200 (Springer, 1985).
  23. Schaefer F Seidel C Pubertal growth in chronic renal failure Pediatr. Res. 1990 28 5 10 2377395 10.1203/00006450-199007000-00002 PubMed DOI
  24. Nissel R Effect of renal transplantation in childhood on longitudinal growth and adult height Kidney Int. 2004 66 792 800 15253735 10.1111/j.1523-1755.2004.00805.x PubMed DOI
  25. Rees L Mak R Nutrition and growth in children with chronic kidney disease Nat. Rev. Nephrol. 2011 7 615 623 21947116 10.1038/nrneph.2011.137 PubMed DOI
  26. Gat-Yablonski G Phillip M Nutritionally-induced catch-up growth Nutrients 2015 7 517 551 25594438 10.3390/nu7010517 PMC4303852 PubMed DOI
  27. Kari JA Gonzalez C Ledermann SE Shaw V Rees L Outcome and growth of infants with severe chronic renal failure Kidney Int. 2000 57 1681 1687 10760104 10.1046/j.1523-1755.2000.00013.x PubMed DOI
  28. Santos F Improvement in growth after 1 year of growth hormone therapy in well-nourished infants with growth retardation secondary to chronic renal failure: results of a multicenter, controlled, randomized, open clinical trial Clin. J. Am. Soc. Nephrol. 2010 5 1190 1197 20522533 10.2215/CJN.07791109 PMC2893059 PubMed DOI
  29. Haffner D Zivicnjak M Pubertal development in children with chronic kidney disease Pediatr. Nephrol. 2017 32 949 964 27464647 10.1007/s00467-016-3432-3 PubMed DOI
  30. Blum, W. F. et al. Growth hormone resistance and inhibition of somatomedin activity by excess of insulin-like growth factor binding protein in uraemia. Pediatr. Nephrol. 5 , 539–544 (1991). 10.1007/BF01453697 1716946 DOI PubMed
  31. Fulchiero R Seo-Mayer P Bartter syndrome and Gitelman syndrome Pediatr. Clin. North Am. 2019 66 121 134 30454738 10.1016/j.pcl.2018.08.010 PubMed DOI
  32. Lejarraga H Caletti MG Caino S Jiménez A Long-term growth of children with nephrogenic diabetes insipidus Pediatr. Nephrol. 2008 23 2007 2012 18584216 10.1007/s00467-008-0844-8 PubMed DOI
  33. Alexander RT Bitzan M Renal tubular acidosis Pediatr. Clin. North Am. 2019 66 135 157 30454739 10.1016/j.pcl.2018.08.011 PubMed DOI
  34. Rodig NM Growth in children with chronic kidney disease: a report from the Chronic Kidney Disease in Children Study Pediatr. Nephrol. 2014 29 1987 1995 24728472 10.1007/s00467-014-2812-9 PMC4470271 PubMed DOI
  35. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Kidney Int. Suppl. 2009 113 S1 S130 10.1038/ki.2009.188 19644521 DOI PubMed
  36. Klaus G Prevention and treatment of renal osteodystrophy in children on chronic renal failure: European guidelines Pediatr. Nephrol. 2006 21 151 159 16247644 10.1007/s00467-005-2082-7 PMC1766475 PubMed DOI
  37. Haffner D Schaefer F Searching the optimal PTH target range in children undergoing peritoneal dialysis: new insights from international cohort studies Pediatr. Nephrol. 2013 28 537 545 22893310 10.1007/s00467-012-2270-1 PubMed DOI
  38. Shroff R Clinical practice recommendations for treatment with active vitamin D analogues in children with chronic kidney disease Stages 2-5 and on dialysis Nephrol. Dial. Transplant. 2017 32 1114 1127 28873971 10.1093/ndt/gfx080 PMC5837664 PubMed DOI
  39. Rees L Growth in very young children undergoing chronic peritoneal dialysis J. Am. Soc. Nephrol. 2011 22 2303 2312 22021715 10.1681/ASN.2010020192 PMC3279935 PubMed DOI
  40. Tom A Growth during maintenance hemodialysis: impact of enhanced nutrition and clearance J. Pediatr. 1999 134 464 471 10190922 10.1016/s0022-3476(99)70205-2 PubMed DOI
  41. Fine RN Stimulating growth in uremic children Kidney Int. 1992 42 188 197 1635349 10.1038/ki.1992.277 PubMed DOI
  42. Boehm M Early erythropoietin therapy is associated with improved growth in children with chronic kidney disease Pediatr. Nephrol. 2007 22 1189 1193 17394020 10.1007/s00467-007-0472-8 PubMed DOI
  43. Levin A Stevens PE Summary of KDIGO 2012 CKD Guideline: behind the scenes, need for guidance, and a framework for moving forward Kidney Int. 2014 85 49 61 24284513 10.1038/ki.2013.444 PubMed DOI
  44. Noto R Intracranial hypertension in pediatric patients treated with recombinant human growth hormone: data from 25 years of the Genentech national cooperative growth study J. Pediatr. Endocrinol. Metab. 2011 24 627 631 22145447 10.1515/jpem.2011.319 PubMed DOI
  45. Jones RW Rigden SP Barratt TM Chantler C The effects of chronic renal failure in infancy on growth, nutritional status and body composition Pediatr. Res. 1982 16 784 791 7133814 10.1203/00006450-198209000-00016 PubMed DOI
  46. Kleinknecht C Broyer M Huot D Marti-Henneberg C Dartois AM Growth and development of nondialyzed children with chronic renal failure Kidney Int. Suppl. 1983 15 S40 S47 6584675 PubMed
  47. Hodson EM Willis NS Craig JC Growth hormone for children with chronic kidney disease Cochrane Database Syst. Rev. 2012 2 CD003264 10.1002/14651858.CD003264.pub3 PMC6599873 22336787 DOI PubMed
  48. Fine RN Kohaut EC Brown D Perlman AJ Growth after recombinant human growth hormone treatment in children with chronic renal failure: report of a multicenter randomized double-blind placebo-controlled study. Genentech Cooperative Study Group J. Pediatr. 1994 124 374 382 8120705 10.1016/s0022-3476(94)70358-2 PubMed DOI
  49. Rees L Jones H Nutritional management and growth in children with chronic kidney disease Pediatr. Nephrol. 2013 28 527 536 22825360 10.1007/s00467-012-2258-x PubMed DOI
  50. Wühl E Long-term treatment with growth hormone in short children with nephropathic cystinosis J. Pediatr. 2001 138 880 887 11391333 10.1067/mpd.2001.113263 PubMed DOI
  51. Haffner D Factors predictive of the short- and long-term efficacy of growth hormone treatment in prepubertal children with chronic renal failure. The German Study Group for Growth Hormone Treatment in Chronic Renal Failure J. Am. Soc. Nephrol. 1998 9 1899 1907 9773791 10.1681/ASN.V9101899 PubMed DOI
  52. Hokken-Koelega A Long-term effects of growth hormone treatment on growth and puberty in patients with chronic renal insufficiency Pediatr. Nephrol. 2000 14 701 706 10912546 10.1007/s004670000340 PubMed DOI
  53. Fine RN Kohaut E Brown D Kuntze J Attie KM Long-term treatment of growth retarded children with chronic renal insufficiency, with recombinant human growth hormone Kidney Int. 1996 49 781 785 8648920 10.1038/ki.1996.108 PubMed DOI
  54. Wühl E Haffner D Nissel R Schaefer F Mehls O Short dialyzed children respond less to growth hormone than patients prior to dialysis. German Study Group for Growth Hormone Treatment in Chronic Renal Failure Pediatr. Nephrol. 1996 10 294 298 8792393 10.1007/BF00866763 PubMed DOI
  55. Fischbach M Daily on line haemodiafiltration promotes catch-up growth in children on chronic dialysis Nephrol. Dial. Transplant. 2010 25 867 873 19889872 10.1093/ndt/gfp565 PubMed DOI
  56. Fischbach M Fothergill H Seuge L Zaloszyc A Dialysis strategies to improve growth in children with chronic kidney disease J. Ren. Nutr. 2011 21 43 46 21195918 10.1053/j.jrn.2010.10.022 PubMed DOI
  57. Bacchetta J The skeletal consequences of growth hormone therapy in dialyzed children: a randomized trial Clin. J. Am. Soc. Nephrol. 2013 8 824 832 23559676 10.2215/CJN.00330112 PMC3641609 PubMed DOI
  58. Tönshoff B Mehls O Factors affecting growth and strategies for treatment in children after renal transplantation Pediatr. Transplant. 1997 1 176 182 10084778 PubMed
  59. Fine RN Martz K Stablein D What have 20 years of data from the North American Pediatric Renal Transplant Cooperative Study taught us about growth following renal transplantation in infants, children, and adolescents with end-stage renal disease? Pediatr. Nephrol. 2010 25 739 746 20013293 10.1007/s00467-009-1387-3 PubMed DOI
  60. Zhang H Steroid avoidance or withdrawal regimens in paediatric kidney transplantation: a meta-analysis of randomised controlled trials PLOS ONE 2016 11 e0146523 26991793 10.1371/journal.pone.0146523 PMC4798578 PubMed DOI
  61. Wu Y Cheng W Yang XD Xiang B Growth hormone improves growth in pediatric renal transplant recipients-a systemic review and meta-analysis of randomized controlled trials Pediatr. Nephrol. 2013 28 129 133 22660958 10.1007/s00467-012-2208-7 PubMed DOI
  62. Fine RN Stablein D Long-term use of recombinant human growth hormone in pediatric allograft recipients: a report of the NAPRTCS Transplant Registry Pediatr. Nephrol. 2005 20 404 408 15682317 10.1007/s00467-004-1688-5 PubMed DOI
  63. Mencarelli F Growth hormone treatment started in the first year of life in infants with chronic renal failure Pediatr. Nephrol. 2009 24 1039 1046 19159957 10.1007/s00467-008-1084-7 PubMed DOI
  64. Franke D Zivicnjak M Ehrich JH Growth hormone treatment of renal growth failure during infancy and early childhood Pediatr. Nephrol. 2009 24 1093 1096 19367419 10.1007/s00467-009-1190-1 PubMed DOI
  65. Hokken-Koelega AC Growth hormone treatment in growth-retarded adolescents after renal transplant Lancet 1994 343 1313 1317 7910322 10.1016/s0140-6736(94)92465-1 PubMed DOI
  66. Gil S Aziz M Adragna M Monteverde M Belgorosky A Near-adult height in male kidney transplant recipients started on growth hormone treatment in late puberty Pediatr. Nephrol. 2018 33 175 180 28821968 10.1007/s00467-017-3777-2 PubMed DOI
  67. Nissel R Lindberg A Mehls O Haffner D Pfizer International Growth Database (KIGS) International Board Factors predicting the near-final height in growth hormone-treated children and adolescents with chronic kidney disease J. Clin. Endocrinol. Metab. 2008 93 1359 1365 18198222 10.1210/jc.2007-2302 PubMed DOI
  68. Hokken-Koelega AC A placebo-controlled, double-blind trial of growth hormone treatment in prepubertal children after renal transplant Kidney Int. Suppl. 1996 53 128 134 8771007 PubMed
  69. Janssen F Impact of growth hormone treatment on a belgian population of short children with renal allografts Pediatr. Transplant. 1997 1 190 196 10084780 PubMed
  70. Fine RN Sullivan EK Tejani A The impact of recombinant human growth hormone treatment on final adult height Pediatr. Nephrol. 2000 14 679 681 10912542 10.1007/s004670000383 PubMed DOI
  71. Rees L Ward G Rigden SP Growth over 10 years following a 1-year trial of growth hormone therapy Pediatr. Nephrol. 2000 14 309 314 10775075 10.1007/s004670050765 PubMed DOI
  72. Berard E Long-term results of rhGH treatment in children with renal failure: experience of the French Society of Pediatric Nephrology Pediatr. Nephrol. 2008 23 2031 2038 18584215 10.1007/s00467-008-0849-3 PubMed DOI
  73. Borzych D The bone and mineral disorder of children undergoing chronic peritoneal dialysis Kidney Int. 2010 78 1295 1304 20811335 10.1038/ki.2010.316 PubMed DOI
  74. Watkins SL Is severe renal osteodystrophy a contraindication for recombinant human growth hormone treatment? Pediatr. Nephrol. 1996 10 351 354 8792404 10.1007/BF00866781 PubMed DOI
  75. European Medicines Agency. Summary of product characteristics. EMA https://www.ema.europa.eu/en/documents/product-information/omnitrope-epar-product-information_en.pdf (updated 6 Mar 2018).
  76. Hokken-Koelega AC Placebo-controlled, double-blind, cross-over trial of growth hormone treatment in prepubertal children with chronic renal failure Lancet 1991 338 585 590 1715501 10.1016/0140-6736(91)90604-n PubMed DOI
  77. Broyer M Results and side-effects of treating children with growth hormone after kidney transplantation — a preliminary report. Pharmacia & Upjohn Study Group Acta Paediatr. Suppl. 1996 417 76 79 9055918 10.1111/j.1651-2227.1996.tb14304.x PubMed DOI
  78. Fine RN Recombinant human growth hormone post-renal transplantation in children: a randomized controlled study of the NAPRTCS Kidney Int. 2002 62 688 696 12110034 10.1046/j.1523-1755.2002.00489.x PubMed DOI
  79. Kuizon BD Goodman WG Gales B Juppner H Salusky IB Effects of growth hormone on bone and mineral metabolism in dialyzed children [abstract] J. Am. Soc. Nephrol. 1998 9 546 547
  80. Maxwell H Rees L Randomised controlled trial of recombinant human growth hormone in prepubertal and pubertal renal transplant recipients Arch. Dis. Child. 1998 79 481 487 10210991 10.1136/adc.79.6.481 PMC1717762 PubMed DOI
  81. Powell DR Modulation of growth factors by growth hormone in children with chronic renal failure. The Southwest Pediatric Nephrology Study Group Kidney Int. 1997 51 1970 1979 9186890 10.1038/ki.1997.268 PubMed DOI
  82. Sanchez CP Growth hormone and the skeleton in pediatric renal allograft recipients Pediatr. Nephrol. 2002 17 322 328 12042887 10.1007/s00467-002-0824-3 PubMed DOI
  83. Fine RN Attie KM Kuntze J Brown DF Kohaut EC Recombinant human growth hormone in infants and young children with chronic renal insufficiency. Genentech Collaborative Study Group Pediatr. Nephrol. 1995 9 451 457 7577408 10.1007/BF00866726 PubMed DOI
  84. Callis LL Randomized open multicentre study to assess treatment with recombinant human growth hormone in children with low height and chronic renal insufficiency [abstract] An. Esp. Pediatr. 1996 45 328
  85. Hertel NT Recombinant human growth hormone treatment, using two dose regimens in children with chronic renal failure—a report on linear growth and adverse effects J. Pediatr. Endocrinol. Metab. 2002 15 577 588 12014516 10.1515/jpem.2002.15.5.577 PubMed DOI
  86. Hokken-Koelega AC Double blind trial comparing the effects of two doses of growth hormone in prepubertal patients with chronic renal insufficiency J. Clin. Endocrinol. Metab. 1994 79 1185 1190 7525628 10.1210/jcem.79.4.7525628 PubMed DOI
  87. Ito K Kawaguchi H The use of recombinant human GH (rhGH) in growth failure in children with various renal diseases Clin. Pediatr. Endocrinol. 1997 6 49 53
  88. Kitagawa T GH treatment of children with chronic renal insufficiency: a Japanese clinical trial Clin. Pediatr. Endocrinol. 1997 6 73 80
  89. Pfizer. Genotropin® (somatropin): highlights of prescribing information. Pfizer https://www.pfizermedicalinformation.com/en-us/genotropin (2019).
  90. Saenger P Ten years of biosimilar recombinant human growth hormone in Europe Drug Des. Devel. Ther. 2017 11 1505 1507 28553081 10.2147/DDDT.S130317 PMC5439961 PubMed DOI
  91. Fine RN Ho M Tejani A Blethen S Adverse events with rhGH treatment of patients with chronic renal insufficiency and end-stage renal disease J. Pediatr. 2003 142 539 545 12756387 10.1067/mpd.2003.189 PubMed DOI
  92. Haffner D Metabolic effects of long-term growth hormone treatment in prepubertal children with chronic renal failure and after kidney transplantation. The German Study Group for Growth Hormone Treatment in Chronic Renal Failure Pediatr. Res. 1998 43 209 215 9475286 10.1203/00006450-199802000-00009 PubMed DOI
  93. Filler G Amendt P von Bredow MA Rohde W Ehrich JH Slowly deteriorating insulin secretion and C-peptide production characterizes diabetes mellitus in infantile cystinosis Eur. J. Pediatr. 1998 157 738 742 9776533 10.1007/s004310050926 PubMed DOI
  94. Ketteler M Diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder: synopsis of the kidney disease: Improving Global Outcomes 2017 Clinical Practice Guideline Update Ann. Intern. Med. 2018 168 422 430 29459980 10.7326/M17-2640 PubMed DOI
  95. Mehls O Long-term growth hormone treatment in short children with CKD does not accelerate decline of renal function: results from the KIGS registry and ESCAPE trial Pediatr. Nephrol. 2015 30 2145 2151 26198275 10.1007/s00467-015-3157-8 PubMed DOI
  96. Dharnidharka VR Talley LI Martz KL Stablein DM Fine RN Recombinant growth hormone use pretransplant and risk for post-transplant lymphoproliferative disease--a report of the NAPRTCS Pediatr. Transplant. 2008 12 689 695 18179637 10.1111/j.1399-3046.2007.00881.x PubMed DOI
  97. Mehls O Does growth hormone treatment affect the risk of post-transplant renal cancer? Pediatr. Nephrol. 2002 17 984 989 12520324 10.1007/s00467-002-0962-7 PubMed DOI
  98. Longmore DK Conwell LS Burke JR McDonald SP McTaggart SJ Post-transplant lymphoproliferative disorder: no relationship to recombinant human growth hormone use in Australian and New Zealand pediatric kidney transplant recipients Pediatr. Transplant. 2013 17 731 736 24164826 10.1111/petr.12167 PubMed DOI
  99. Fine RN Growth after discontinuation of recombinant human growth hormone therapy in children with chronic renal insufficiency J. Pediatr. 1996 129 883 891 8969731 10.1016/s0022-3476(96)70033-1 PubMed DOI
  100. Teng Chung T Hinds CJ Treatment with GH and IGF-1 in critical illness Crit. Care Clin. 2006 22 29 40 16399018 10.1016/j.ccc.2005.09.003 PubMed DOI
  101. Breederveld RS Tuinebreijer WE Recombinant human growth hormone for treating burns and donor sites Cochrane Database Syst. Rev. 2014 9 CD008990 10.1002/14651858.CD008990.pub3 PMC7119450 25222766 DOI PubMed
  102. Takala J Increased mortality associated with growth hormone treatment in critically ill adults N. Engl. J. Med. 1999 341 785 792 10477776 10.1056/NEJM199909093411102 PubMed DOI
  103. Kovacs GT Growth promoting effects of growth hormone and IGF-I are additive in experimental uremia Kidney Int. 1996 49 1413 1421 8731108 10.1038/ki.1996.199 PubMed DOI
  104. Farquharson C Ahmed SF Inflammation and linear bone growth: The inhibitory role of SOCS2 on GH/IGF-1 signaling Pediatr. Nephrol. 2013 28 547 556 22886280 10.1007/s00467-012-2271-0 PubMed DOI
  105. Mauras N Anastrozole increases predicted adult height of short adolescent males treated with growth hormone: a randomized, placebo-controlled, multicenter trial for one to three years J. Clin. Endocrinol. Metab. 2008 93 823 831 18165285 10.1210/jc.2007-1559 PMC2266949 PubMed DOI
  106. Zivicnjak M Growth impairment shows an age-dependent pattern in boys with chronic kidney disease Pediatr. Nephrol. 2007 22 420 429 17131161 10.1007/s00467-006-0345-6 PubMed DOI

Conditions covered

Chronic kidney diseaseGrowth hormone treatmentShort stature

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