1. Miami Children’s Hospital
IV CONGRESO
COLOMBIANO
DE NEFROLOGÍA
PEDIÁTRICA
Indicaciones de Hormona de Crecimiento en Nefrologia: Insuficiencia Renal Cronica Tubulopatias Post transplante renal
Marco Danon, M.D.
Miami Children’s Hospital

2. Approved Uses of Growth Hormone Childhood growth hormone deficiency
Approval Year
Childhood growth hormone deficiency
1985
Chronic renal insufficiency
1993
HIV-wasting
1996
Adult growth hormone deficiency
1997
Turner syndrome
Prader-Willi syndrome
2000
Short children born SFD (SGA)
2001
Idiopathic short stature
2003
Short bowel syndrome
2004
Short Stature with SHOX deficiency
2006
Noonan syndrome
2007

5. The GH-IGF-IGFBP Axis GH
Transport
Cellular
IGFBP
Receptors
RXR-
Nuclear
actions
Cell surface
BP-receptors
---IGFBPs
Type
IGF Receptor I a b
Survival &
Mitogenesis
Via IRS-1 --
Akt, MAPK
and other
pathways
IGF-I
IGF-II
Insulin GH
Differentiation, growth, aging, metabolism & carcinogenesis
ALS
150 kDa complex
IGFBP-1
IGFBP-2
IGFBP-3
IGFBP-4
IGFBP-5
IGFBP-6 II
IGF2 binding
Mannose-6-
phosphate binding
Retinoid binding
Growth
inhibition
Figure 1 legend:
The GH-IGF-IGFBP axis. The IGF system is shown with its major components including the IGF ligands, the IGF binding proteins, the IGF receptors, and the signaling pathways of the IGFs and IGFBPs. GH regulates circulating IGF-1 and the other two components of the 150 kD complex, IGFBP-3 and ALS.

6. New Revelations about the Role of STATs in Stature
signal transducer and activator of transcription 5b ( STAT5b )
Growth Hormone Insensitivity Associated with a STAT5b Mutation

7. Growth Hormone-Activated Intracellular Signaling
Growth Hormone-Activated Intracellular Signaling. Phosphorylation of the growth hormone receptor is followed by the activation of metabolic, proliferative, and transcriptional pathways. STAT5b stimulates the transcription of factors (shown in the box) that are critical for normal linear growth. P denotes phosphorylation, and STAT signal transducer and activator of transcription.

10. Growth hormone for children with chronic kidney disease
BACKGROUND:
Chronic kidney disease (CKD) condition with growth retardation
rhGH helps short children with CKD attain height of their age group
rhGH may have adverse effects on native kidney function, predispose to acute rejection in transplant recipients, and cause benign intracranial hypertension and slipped capital femoral epiphysis
OBJECTIVES: evaluate benefits and harms of rhGH in children with CKD.

11. Growth hormone for children with chronic kidney disease.
SEARCH STRATEGY:
RCTs identified from the Cochrane Central Register of Controlled Trials with experts in the field
SELECTION CRITERIA:
RCTs included children aged 0-18 years, with CKD, pre-dialysis, on dialysis or post-transplant; compared rhGH treatment with placebo/no treatment or two doses of rhGH treatments; included height outcomes

12. Growth hormone for children with chronic kidney disease
DATA COLLECTION AND ANALYSIS:
Reviewers independently assessed studies for methodological quality and extracted data from eligible trials
Data was pooled using a random effects model with calculation of weighted mean difference (MD) for continuous outcomes and relative risk (RR) for categorical outcomes with 95% confidence intervals (CI)

13. Growth hormone for children with chronic kidney disease
MAIN RESULTS:
Fifteen RCTs (629 children) were identified
rhGH (28 IU/m²/wk) resulted in a significant increase in height (SDS) at one year (MD 0.78 SDS, 95% CI 0.52 to 1.04), a significant increase in height velocity at six months ( 2.85 cm/6 mo, 95%CI ) and one year ( 3.80 cm/y, 95%CI )
When compared to 14 IU/m²/wk, 1.34 cm/y (0.55 to 2.13) increase in height velocity in the 28 IU/m²/wk
Side effects of rhGH similar to controls

14. Growth hormone for children with chronic kidney disease
AUTHORS' CONCLUSIONS:
Yearly 28 IU/m²/wk rhGH in children with CKD resulted in a 3.80 cm/y increase in height velocity above that of untreated patients
Trials determined treatment resulted in an increase in final adult height when compared to untreated children
Cochrane Database Syst Rev 1-41, 2006

15. Haffner D et al. N Engl J Med 343: 923, 2000
GH in 38 CRF Children (32 Boys and 6 Girls) Compared with 50 CRF Children No GH and 232 Normal Children
Figure 1. Synchronized Mean Height-Velocity Curves during Growth Hormone Treatment for 38 Children (32 Boys and 6 Girls) with Chronic Renal Failure, as Compared with 50 Control Children with Chronic Renal Failure Not Treated with Growth Hormone and 232 Normal Children, According to Sex. The circles indicate the time of the first observation (the start of growth hormone treatment in the treated children), the time of minimal prespurt height velocity, and the end of the pubertal growth spurt.
Haffner D et al. N Engl J Med 343: 923, 2000

16. Haffner D et al. N Engl J Med 343: 923, 2000
PAH at Base Line in 38 CRF Children (32 Boys and 6 Girls) on GH Compared with 50 CRF Children with No GH
Figure 3. Change from Initially Predicted Adult Height at Base Line in 38 Children (32 Boys and 6 Girls) with Chronic Renal Failure Who Received Growth Hormone Treatment, as Compared with 50 Control Children with Chronic Renal Failure Who Did Not Receive Growth Hormone, According to Sex. Values are means {+/-}SD. Asterisks indicate significant differences from the previous period (P<0.001), and daggers significant differences from the children who were not treated with growth hormone (P<0.001).
Haffner D et al. N Engl J Med 343: 923, 2000

17. Haffner D et al. N Engl J Med 2000;343:923-930
Growth during GH in 38 CRF Children (32 Boys and 6 Girls) Compared with 50 CRF Children with No GH
Figure 2. Synchronized Mean Growth Curves during Growth Hormone Treatment for 38 Children (32 Boys and 6 Girls) with Chronic Renal Failure, as Compared with 50 Control Children with Chronic Renal Failure Not Treated with Growth Hormone, According to Sex. Normal values are indicated by the 3rd, 50th, and 97th percentiles. The circles indicate the time of the first observation (the start of growth hormone treatment in the treated children) and the end of the pubertal growth spurt.
Haffner D et al. N Engl J Med 2000;343:

18. Characteristics of Growth Hormone-Treated and Control Children with Chronic Renal Failure
Table 1. Anthropometric Characteristics of Growth Hormone-Treated and Control Children with Chronic Renal Failure.
N Engl J Med 343: 923, 2000

19. Haffner D et al. N Engl J Med 2000;343:923-930
Treatment for Chronic Renal Failure and Change in Glomerular Filtration Rate during the Observation Period in Growth Hormone-Treated and Control Children
Table 2. Treatment for Chronic Renal Failure and Change in Glomerular Filtration Rate during the Observation Period in Growth Hormone-Treated and Control Children.
Haffner D et al. N Engl J Med 2000;343:

20. Haffner D et al. N Engl J Med 2000;343:923-930
Predictors of Growth during Observation Period in the GH-Treated and Control Children Combined
Table 3. Predictors of Growth during the Observation Period in the Growth Hormone-Treated and Control Children Combined.
Haffner D et al. N Engl J Med 2000;343:

21. Roles of Insulin-like Growth Factor (IGF) and Growth Hormone (GH) in Prenatal and Postnatal Growth
Figure. Roles of Insulin-like Growth Factor (IGF) and Growth Hormone (GH) in Prenatal and Postnatal Growth. The upper (gray) line of the height-velocity curve in both panels approximates the 50th percentile in boys. Different scales are used for prenatal growth (expressed as crown-heel length velocity in centimeters per four weeks) and postnatal height velocity (expressed as centimeters per year). The lower (red) line in the postnatal height-velocity curves indicates the expected growth rate in children totally lacking GH. Clinical evidence suggests that a similar line can be drawn for children with severe IGF deficiency. The shaded region thus reflects IGF-dependent growth. A small, direct sex steroid effect that is independent of IGF is seen during puberty. Prenatally, the red line reflects the best estimate of intrauterine growth in the absence of IGFs (derived from limited case reports and murine models). IGF-dependent growth in prenatal life is largely independent of GH, except for a small effect in the last few weeks before birth. (Modified from Daughaday WH and Rotwein P. Endocr Rev 1989;10:68-91.)‏
Rosenfeld R. N Engl J Med 2003;349:

22. Factors contributing to GH Resistance in CKD
Serum concentration of GH increased, metabolic clearence decreased
GH receptor expression decreased
Signal transduction of GHR impaired
IGF-I production decreased
IGF activity decreased by inhibitory IGF binding proteins
Resistance to GH and IGF-I

23. Growth hormone treatment started in the first year of life in infants with chronic renal failure
rhGH
Controls
Number of patients
Bilateral renal hypo-dysplasia, Posterior urethral valves,
Bilateral reflux with renal dysplasia, ARPKD, cortical necrosis
12 ( 9♂ 3♀)
15 (11♂ 4♀)
Creatinine clearence (ml/min per 1.73 m²)
5-22
7-35
Age at the beginning of rhGH
Dose of rhGH (mg/kg/week)
0.5 ± 0.3
0.24 ± 0.07
Complications : Infections- episodes
Number of surgeries 20
0.73 12
0.53
FOLLOW-UP Chronic renal failure
(5 years) Chronic peritoneal dialysis
Renal transplantation 1 4 7 9 2
Age at transplantation
Pediatr Nephrol 24: 1039, 2009

25. Recombinant human growth hormone and Gitelman's syndrome
Growth Hormone improves growth rate and preserves renal function in Dent Disease J Pediatr Endocrinol Metab 21: 279, 2008
Effects of Growth Hormone Treatment on Body Proportions and Final
Height Among Small Children With X-Linked Hypophosphatemic Rickets Pediatrics 113: e593, 2004
Amelioration of Hypophosphatemic Rickets and Osteoporosis With Pamidronate and Growth Hormone in Lowe Syndrome J Formos Med Assoc 108: 730, 2009
Metabolic control and growth during exclusive growth hormone treatment in X-linked hypophosphatemic rickets Horm Res 69: 212, 2008
Recombinant human growth hormone and Gitelman's syndrome
Am J Kidney Dis 33: , 1999
Gitelman disease associated with growth hormone deficiency: a new hereditary renal tubular-pituitary syndrome? Pediatr Res 46: 232,1999

26. Incidence of adverse events associated with growth hormone therapy
Pediatr Nephrol 21: 917, 2006

27. Pediatr Transplantation 2008: 12: 689–695
Recombinant growth hormone use pretransplant and risk for post-transplant lymphoproliferative disease (LPD) - A report of the NAPRTCS
194 LPD patients
41 enrolled in CRI registry: 18/41 (43.9%) used rhGH
and received a transplant, rates of PTLD post-
transplant were significantly higher in rhGH users (18/407
or 4.4%) compared to patients who never used rhGH and
received transplant (23/1240 or 1.9%,p = 0.009).
rhGH pretransplant-was associated with a borderline
higher risk for PTLD (odds ratio 1.88,95% CI = 1.00–3.55,
p = 0.05).
rhGH during dialysis or post-transplant was not
associated with a higher risk forPTLD.
Continued monitoring is recommended.
Pediatr Transplantation 2008: 12: 689–695

28. Richard N. Fine & Karen Martz & Donald Stablein
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?
Richard N. Fine & Karen Martz & Donald Stablein
Pediatr Nephrol 25:739–746, 2010

29. Pediatr Nephrol 25:739–746, 2010

30. Pediatr Nephrol 25:739–746, 2010

31. Pediatr Nephrol 25:739–746, 2010

32. Pediatr Nephrol 25:739–746, 2010

33. Monitor GH therapy: Ht, Wt, BA, hip-knees x-rays, PTH
Consider GH therapy: GFR < 15 mL/min/1.73 m²
Height < SDS or 3rd %ile
Assess and treat complications:
Acidosis, malnutrition, salt-wasting, osteodystrophy, hypothyroidism No
Is Growth Velocity improved?
Yes
Perform baseline assessments for GH therapy:
Puberty, BA, hip-knees x-rays, PTH, TSH
Continue current therapy
Start GH therapy (0.35 mg/kg/week)
Monitor GH therapy: Ht, Wt, BA, hip-knees x-rays, PTH
Is growth adequate? HV 2 cm/yr > baseline No
Yes
Continue GH
Is growth adequate?
Yes
Assess & Correct:
Dose
Metabolic status
Nutrition
Compliance
Discontinue GH:
Achieved height
Closed epiphyses
Active neoplasia
Slipped femoral epiphyses
Intracranial hypertension
Noncompliance
Severe HyperPTH
Consider Pedi endo No
If HV < 2 cm/year consider reinitiating
NAPRTCS Consensus 2006

34. IV CONGRESO
COLOMBIANO
DE NEFROLOGÍA
PEDIÁTRICA
Albright’s dictum
He hablado de hormona de crecimiento mas de lo que yo mismo se
Mucho de lo que he dicho esta sujeto a cambios sin previo aviso
Espero que haya originado mas preguntas que respuestas
De todos modos hay que continuar investigando aun mas

35. IV CONGRESO
COLOMBIANO
DE NEFROLOGÍA
PEDIÁTRICA
Muchas Gracias

36. Congreso Colombiano de Pediatria 2009, Cartagena

37. 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.
Moderate-to-severe growth retardation in CKD is associated with increased morbidity and mortality.
Renal failure is a state of GH resistance and not GH deficiency. Some mechanisms of GH resistance are: reduced density of GH receptors in target organs, impaired GH-activated post-receptor Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling, and reduced levels of free IGF-1 due to increased inhibitory IGF-binding proteins (IGFBPs).
Treatment with recombinant human growth hormone (rhGH) has been proven to be safe and efficacious in children with CKD. Even though rhGH has been shown to improve catch-up growth and to allow the child to achieve normal adult height, the final adult height is still significantly below the genetic target.
Growth retardation may persist after renal transplantation due to multiple factors, such as steroid use, decreased renal function and an abnormal GH–IGF1 axis.
Those below age 6 years are the ones to benefit most from transplantation in demonstrating acceleration in linear growth.
Newer treatment modalities targeting the GH resistance with recombinant human IGF-1 (rhIGF-1), recombinant human IGFBP3 (rhIGFBP3) and IGFBP displacers are under investigation and may prove to be more effective in treating growth failure in CKD.