Growth Management in Chronic Renal Insufficiency

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Growth Management in Chronic Renal Insufficiency

• PE Clayton
• Endocrine Science Research Group
• University of Manchester

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North American Pediatric Renal Transplant
Cooperative Study CRI on dialysis or after
transplant 5927 (in 2005) Overall One Third
showed poor growth age dependent Growth failure
at all levels of renal function
Mahan Warady Pediatr Nephrol 2006
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Ht SDS (a) one month into dialysis (n3910), (b)
at time of transplantation (n8141, 1987-2004)
a.
b.
Mahan Warady Pediatr Nephrol 2006
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Normal GH-IGF axis
The GH-IGF axis in CRI Increased pulsatile GH
release Decreased GH receptor expression Decreased
IGF-I generation Increased IGFBPs, thus less
free IGF-I Also increased IGFBP-3 protease
activity, thus less IGF-I in ternary complex
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GH sex steroid dependent
Nutrition dependent phase
GH dependent
GV gt8 cm/yr
Parental target range
GV gt5 cm/yr
Height
Age
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What is short stature?

• Height
• Ht lt 0.4th centile

Parental target Target height in relation to
parental heights Boys FH MH 7
2 Girls FH MH - 7 2
Growth velocity Pre-puberty
Puberty lt 5 cm/yr lt 8 cm/yr
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If delayed compared to chronological age
suggestive of chronic underlying problem, but not
necessarily endocrine.
Bone Age
Normal BA CA /- 1 year
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Caveats Genuine GH deficiency or other growth
disorders may co-exist Unsure of value of
initiation hip knee XRs rhGH dose adjustment
Mahan Warady Pediatr Nephrol 2006
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Initiation of rhGH treatment

• Pen system, subcut. daily injection (can deliver
  via needle-free)
• Depot GH preparations being developed
• No reliable test for compliance
• IGF-I and IGFBP-3
• Prescriptions used
• Local knowledge

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rhGH utilisation in children with CRI and growth
failure from the NAPRTCS registry
Mahan Warady Pediatr Nephrol 2006
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11 patients treated with rhGH for 12m Basal Ht
sds -2.9 (0.9) Basal IGF-I sds -1 (1.2) not
correlated to GFR Gain in Ht sds at 12m 0.5
(0.3) Increase in IGF-I sds at 12m 1.2
(1.4) Increment in IGF-I at 10d inversely
correlated with age but not GFR Ht sds at 12 m
correlated with basal IGF-I sds (but not change)
Patel et al Pediatr Nephrol 2002
No systematic studies of titrating rhGH dose
against IGF-I levels
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Response to rhGH

• Numerous studies have demonstrated a significant
  early effect of rhGH on growth rate
• prepubertal pubertal
• post-transplant
• Meta-analysis (Vimalachandra et al J Pediatr
  2001)
• 4 randomised controlled trials
• After 1 yr, GH generated a significant increase
  in Ht sds weighted mean difference 0.77 (95 CI
  0.51 to 1.04)
• For a 10yr old, this translates into a height
  gain of 4.7cm
• Little consideration given to other potential
  benefits body composition, bone density, QoL,
  lipid status

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45 prepubertal children with CRI and marked short
stature, treated long-term with rhGH
Factors associated with Ht sds at 4yrs Ht sds at
start () Age at start (-) Duration of dialysis
(-)
Hokken Koelega et al Pediatr Nephrol 2000
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Comparison of gain in height (cms) on rhGH
treatment to final height
Gain in height GH dose (mg/kg/day) from start
(cm) Turner syndrome1 0.045 12
0.069 16 Chronic renal insufficiency2
0.045 16 SGA 0.033 12 0.067 14
1 van Pareren et al. 2003 2 Hokken-Koelega et
al. 2000
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Mahan Warady Pediatr Nephrol 2006
Incidence in general population 10-13 per 100,000
Clayton Cowell GH IGF Res 2000
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Adverse Events

• Raised insulin but development of DM not a
  problem
• Benign intracranial hypertension
• No deterioration of renal function
• No increase in rejection episodes
• Care interaction with immunosupressive regimens,
  including steroids

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Cumulative incidence of renal carcinoma 10 years
after transplant in those lt19 yrs at time of Tx
185 per 100,000 patients Main risk factors Age
immunosuppressive treatment Possible Chronic
Tx nephropathy accelerated senescence rhGH NOT
an additional risk factor
Mehls et al Pediatr Nephrol 2002
Cumulative incidence of renal cancer in Tx
recipients 1985-2000 (a) Incidence increases
with time age, (b) Incidence compared to
expected rates
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Pubertal Evaluation

• In CRI, gonadotrophins may be high due to poor
  clearance but bioactive LH can be reduced
• Examination of pubertal status critical
• May need to carry out a GnRH test measure sex
  steroid SHBG levels
• May need treatment with courses of sex steroids

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Summary

• Growth failure frequent
• Growth pubertal assessment should be a routine
  part of care
• Multi-factorial aetiology for growth failure
• rhGH has proven efficacy is safe, but treatment
  uptake has been low