Chronic Renal Insufficiency

Chronic renal insufficiency (CRI), which may include end‑stage renal disease, is defined as a persistent elevation of serum creatinine and/or urea. CRI can be caused by a variety of conditions, including congenital disorders, glomerular disorders and infections. 1

Chronic kidney disease (CKD) in children is associated with dramatic changes in the growth hormone (GH) and insulin-like growth factor (IGF-1) axis, resulting in growth retardation. 1,2

Growth failure associated with CRI usually begins when the glomerular filtration rate falls to 50% of normal. However, significant short stature has been seen at all levels of renal function. 2,3,4

Somatropin efficacy in normalisation of height at puberty in children with chronic renal insufficiency

Prepubertal height gain and normalisation of height 2

Change from initially predicted adult height at baseline in children receiving growth hormone (GH; 0.33 mg/kg body weight/week) vs 50 untreated children 2

Change growth hormone vs untreated graph

 

Adapted from Haffner et al. 2000 2

* Significant differences from the previous period (p < 0.001)

† Significant differences from the children who were not treated with growth hormone (p < 0.001)

Study conclusions

Long-term GH treatment induced persistent catch-up growth and enabled the majority of patients to reach adult height.2

Of the children treated with GH, 65% reached a final adult height within the normal range, although it was significantly below the genetic target. 2

Study methods

38 children (32 boys and 6 girls) from a German multicentre study, who had reached final adult height at the time of analysis. The control group consisted of 50 children (31 boys and 19 girls) with chronic renal failure, who were matched with GH treated children. Values are means ± standard deviation (SD).

Possible mechanisms of growth disturbance in CRI

Growth hormone resistance

Pubertal patients with advanced CKD have a reduced GH secretion rate, indicating altered sensitivity of somatotropic hormones to the stimulatory effects of sex steroids and GH resistance.5

JAK2 signalling

An intact JAK2-STAT5b signalling pathway is essential for GH stimulation of IGF-1 gene expression. In uremia, a defect in the post-receptor GH-activated JAK2 signal transducer and STAT transduction is described as one of the mechanisms of GH resistance.6

Low levels of serum growth hormone binding protein (GHBP)

The concentration of serum growth hormone binding protein (GHBP) is low in children and adults with CKD and proportionate to the degree of renal dysfunction. 7,8

Congenital disorders leading to CRI

Children with congenital disorders leading to CRI (approximately 60% of children with CRI) are of normal length at birth, but are below the 3rd percentile for height within their first year and remain so throughout childhood; one-third of the total growth occurs in a child’s first 2 years of life.3

Effects of CRI at puberty

Chronic kidney disease (CKD) in children is associated with dramatic changes in the growth hormone (GH) and insulin-like growth factor (IGF-1) axis, resulting in growth retardation.

The pubertal height gain is about 65% of that seen in healthy children without CKD and is likely due to the shortened growth spurt. 2

At the onset of puberty, the growth hormone/insulin-like growth factor (GH/IGF-1) axis is activated by small increases in estrogen and testosterone in girls and boys, respectively. The onset of puberty is delayed in adolescents with CKD; peak height velocity is delayed by approximately 2.5 years. The pubertal growth spurt is delayed, shortened and associated with a reduced growth velocity. 2

Frequency of growth disturbance in CRI

Not all people with CRI in childhood will be shorter than average; figures from the UK Renal Registry indicate that 29% of children who undergo renal transplantation and 41% of children on dialysis are below the 2nd percentile for height within their first year and remain so throughout childhood because of more pronounced deceleration in height velocity.1

Genotropin dosage in chronic renal insufficiency (CRI) 9

In chronic renal insufficiency, renal function should be below 50% of normal before institution of therapy.

In children, a dose of 0.045 - 0.050 mg/kg body weight per day (1.4 mg/m2 body surface area per day) is recommended. Higher doses can be needed if growth velocity is too low; a dose correction may be needed after six months of treatment.

To verify growth disturbance, growth should be followed for a year preceding institution of therapy. Treatment should be discontinued at renal transplantation.

Adverse events associated with Genotropin therapy 9

Long-Term Treatment of Children with Growth Disturbance due to Chronic Renal Insufficiency

System Organ Class

Very Common

≥ 1/10

Common

≥ 1/100 to <1/10

Uncommon ≥ 1/1000 to <1/100

Rare ≥ 1/10,000 to <1/1000

Very Rare <1/10,000

Not Known (cannot be estimated from available data)

Neoplasms Benign, Malignant, and Unspecified (including cysts and polyps)

 

 

 

 

 

Leukaemia†

Metabolism and Nutrition Disorders

 

 

 

 

 

Type 2 diabetes mellitus

Nervous System Disorders

 

 

 

 

 

Paraesthesia*

Benign intracranial hypertension

Musculoskeletal, Connective Tissue, and Bone Disorders

 

 

 

 

 

Arthralgia*

Myalgia*

Musculoskeletal stiffness*

General Disorders and Administration Site Conditions

 

Injection site reaction$

 

 

 

Oedema peripheral*

Investigations

 

 

 

 

 

Blood cortisol decreased

*In general, these adverse effects are mild to moderate, arise within the first months of treatment, and subside spontaneously or with dose-reduction. The incidence of these adverse effects is related to the administered dose, the age of the patients, and possibly inversely related to the age of the patients at the onset of growth hormone deficiency.

$ Transient injection site reactions in children have been reported.

‡ Clinical significance is unknown.

† Reported in growth hormone deficient children treated with somatropin, but the incidence appears to be similar to that in children without growth hormone deficiency.

References

1. NICE guideline [TA188] May 2010.  Last accessed March 2018

2. Haffner D, Schaefer F, Nissel R, Wuhl E, Tonshoff B, Mehls O (2000) 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 343(13):923–930

3. Van Dyck M, Bilem N, Proesmans W (1999) Conservative treatment for chronic renal failure from birth: a 3-year follow-up study. Pediatr Nephrol 13(9):865–869

4. Mahan JD, Warady BA; the Consensus Committee (2006) Assessment and treatment of short stature in pediatric patients with chronic kidney disease: a consensus statement. Pediatr Nephrol 21(7):917–930

5. Schaefer F, Veldhuis JD, Stanhope R, Jones J, Scharer K (1994) Alterations in growth hormone secretion and clearance in peripubertal boys with chronic renal failure and after renal transplantation. Cooperative Study Group of Pubertal Development in Chronic Renal Failure. J Clin Endocrinol Metab 78(6):1298–1306

6. Rabkin R, Sun DF, Chen Y, Tan J, Schaefer F (2005) Growth hormone resistance in uremia, a role for impaired JAK/STAT signaling. Pediatr Nephrol 20(3):313–318

7. Postel-Vinay MC, Tar A, Crosnier H, Broyer M, Rappaport R, Tonshoff B, Mehls O (1991) Plasma growth hormone-binding activity is low in uraemic children. Pediatr Nephrol 5(4):545–547

8. Tonshoff B, Cronin MJ, Reichert M, Haffner D, Wingen AM, Blum WF, Mehls O (1997) Reduced concentration of serum growth hormone (GH)-binding protein in children with chronic renal failure: correlation with GH insensitivity. The European Study Group for Nutritional Treatment of Chronic Renal Failure in Childhood. The German Study Group for Growth Hormone Treatment in Chronic Renal Failure. J Clin Endocrinol Metab 82(4):1007-1013.

9. Genotropin Summary of Product Characteristics

Abbreviations: CRI, chronic renal insufficiency; GH, growth hormone; SD, standard deviation.

 

PP-GEN-GBR-0364.  March 2018