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

Abstract

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.

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.

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.: Pediatrics 140, e20171904 Copyright © 2017 by the AAP.