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

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.


Supplementary Box 1 | Cost-effectiveness analysis
Most pediatric CKD patients have advanced CKD at the time of initiation of GH treatment, and will undergo renal transplantation when GH treatment is terminated. The duration of GH treatment is mainly determined by the age at onset of CKD, its rate of progression and the availability of a renal transplant. Therefore, our cost-effectiveness analysis included two hypothetical scenarios: (i) case 1, a child with early-onset CKD requiring GH therapy at the age of 5 years, (ii) case 2, an adolescent with late onset or slowly progressive CKD requiring GH treatment at the age of 12 years. The mean duration of GH treatment in studies reporting on final height ranged between 2 and 5 years; therefore, we used this range to estimate the cumulative drug-related costs. In addition, the estimates for drug dose were based on daily GH doses of 0.045 mg/kg body weight and were calculated for the respective age-and sex-related 25 th weight percentile using the WHO reference data, assuming that patients will have a height below the 3 rd percentile at the time of initiation of GH treatment and will show catch-up growth into the lower normal range thereafter (Supplementary Table 5) [S1].
Since the costs for patient monitoring are less than 3% of total treatment-related costs, only drug-related costs were taken into account for this analysis [S2]. The cost for GH differs considerably among European countries, and a price of €22 per 1 mg GH, based on the median cost in eight representative European countries, was used (Supplementary Table 6).
In clinical studies the height standard deviation score (height SDS) is often used to compare growth in children differing in age and sex. Height SDS is a conversion of height (or length) that represents the number of standard deviations (SD) from the mean height for age and sex. A child with a height SDS less than -1.88, which corresponds to the 3 rd percentile, has short stature. Therefore, the mean increase in final height in GH treated patients was calculated as the difference between standardized final height (height SDS) and standardized height at the start of GH therapy for all available studies reporting on adult height with treatment periods of at least 2 years (Supplementary Table 4). The median increase in standardized height in these studies (1.1 SDS) was converted to cm (7.4 cm in boys, 7.0 cm in girls) by use of European reference values. Thus, an expected gain in final height of 7.2 cm was used in the costeffectiveness analysis; that is, a calculation of the incremental cost per centimeter gained in final height [S3].  Kawaguchi et al. (1996) [S15]  GH 0.5: 0.5 IU/kg/wk for 12 months GH 1.0: 1.0 IU/kg/wk for 12 months CKD stage 3-5: HV significantly increased in both groups, and was higher in GH 1.0 vs. GH 0.5 (each P<0.01). CKD stage 5D: HV significantly increased in both groups, and was higher in GH 1.0 vs. GH 0.5 (each P<0.01). CKD stage 5T: HV increased increased in both groups (each P<0.05) and did not differ between groups; 7/23 patients showed acute rejection episodes. Hokken-Koelega et al. (1996) [S16] Height SDS in CKD stage 3-5: Baseline -3.4 ± 0.1 1st yr -2.6 ± 0.1 2nd yr -2.1 ± 0.2 3rd yr -1.8 ± 0.3 4th yr -1.7 ± 1.5 5th yr -1.9 ± 1.5 (each P<0.05) Height SDS in CKD stage 5D Baseline -3.6 ± 0.2 1st yr -3.1 ± 0.3 2nd yr -3.0 ± 0.4 3rd yr -3.7 ± 0. Suppl.  Assumes a child aged 5 years and benefit uniformly sperad over treatment period. b Assumes a child aged 12 years and benefit uniformly sperad over treatment period. NA, not applicable. Costs were obtained from national data sources or local pharmacies; n.a., not available. Adverse effects not addressed

Supplementary
Powell 1997 (CT) [S11]Kuizo 1998 (CKD VD) [S9] KTx, Kidney transplant; CT, conservative treatment (CKD prior to dialysis); CKD 5D, dialysis; N, total no. of patients randomized (no treatment group, GH group); NS, Non-significant; OGTT, Oral glucose tolerance test. We recommend that children with stage 3-5 chronic kidney disease (CKD) or on dialysis aged above 6 months 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.

Supplementary
B, moderate 2.3 We recommend that GH therapy is considered for children with stage 3-5 CKD or on dialysis aged above 6 months who present with a height between the third and tenth percentile but persistent low height velocity (below the twenty-fifth percentile) once other potentially treatable risk factors for growth failure have been adequately addressed.