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Indicaciones de Indicaciones de Hormona de Hormona de
Crecimiento en Crecimiento en Nefrologia:Nefrologia:
Insuficiencia Renal CronicaInsuficiencia Renal CronicaTubulopatiasTubulopatias
Post transplante renalPost transplante renalMarco Danon, M.D.Marco Danon, M.D.
Miami Children’s HospitalMiami Children’s Hospital
IV CONGRESO COLOMBIANO DE NEFROLOGÍA PEDIÁTRICA
Approved Uses of Growth Hormone Approval Approval YearYear
Childhood growth hormone Childhood growth hormone deficiencydeficiency
19851985
Chronic renal insufficiencyChronic renal insufficiency 19931993
HIV-wastingHIV-wasting 19961996
Adult growth hormone deficiencyAdult growth hormone deficiency 19971997
Turner syndromeTurner syndrome 19971997
Prader-Willi syndromePrader-Willi syndrome 20002000
Short children born SFD (SGA)Short children born SFD (SGA) 20012001
Idiopathic short statureIdiopathic short stature 20032003
Short bowel syndromeShort bowel syndrome 20042004
Short Stature with SHOX deficiencyShort Stature with SHOX deficiency 20062006
Noonan syndromeNoonan syndrome 20072007
The GH-IGF-IGFBP Axis
Transport
CellularIGFBP
ReceptorsRXR-Nuclear actions
NuclearReceptors
Cell surfaceBP-receptors
---IGFBPs
TypeIGF Receptor
I
Survival &MitogenesisVia 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
TypeIGF Receptor
II
IGF2 binding
Mannose-6-phosphate bindingRetinoid binding
Growthinhibition
GH
New Revelations about the New Revelations about the Role of STATs in StatureRole of STATs in Stature
signal transducer and activator signal transducer and activator of transcription 5b ( of transcription 5b ( STAT5b STAT5b ) )
Growth Hormone Insensitivity Growth Hormone Insensitivity Associated with a Associated with a STAT5bSTAT5b
Mutation Mutation
Growth hormone for children Growth hormone for children with chronic kidney diseasewith chronic kidney disease
BACKGROUND: BACKGROUND: Chronic kidney disease (CKD) condition Chronic kidney disease (CKD) condition
with growth retardationwith growth retardation rhGH helps short children with CKD attain rhGH helps short children with CKD attain
height of their age groupheight of their age group rhGH may have adverse effects on native rhGH may have adverse effects on native
kidney function, predispose to acute kidney function, predispose to acute rejection in transplant recipients, and rejection in transplant recipients, and cause benign intracranial hypertension and cause benign intracranial hypertension and slipped capital femoral epiphysisslipped capital femoral epiphysis
OBJECTIVES:OBJECTIVES: evaluate benefits and evaluate benefits and harms of rhGH in children with CKD. harms of rhGH in children with CKD.
Growth hormone for Growth hormone for children with chronic children with chronic
kidney disease.kidney disease. SEARCH STRATEGY:SEARCH STRATEGY: RCTs identified from the Cochrane RCTs identified from the Cochrane
Central Register of Controlled Trials Central Register of Controlled Trials with experts in the fieldwith experts in the field
SELECTION CRITERIA:SELECTION CRITERIA: RCTs included children aged 0-18 years, RCTs included children aged 0-18 years,
with CKD, pre-dialysis, on dialysis or with CKD, pre-dialysis, on dialysis or post-transplant; compared rhGH post-transplant; compared rhGH treatment with placebo/no treatment or treatment with placebo/no treatment or two doses of rhGH treatments; included two doses of rhGH treatments; included height outcomesheight outcomes
Growth hormone for children Growth hormone for children with chronic kidney diseasewith chronic kidney disease
DATA COLLECTION AND ANALYSIS:DATA COLLECTION AND ANALYSIS: Reviewers independently assessed Reviewers independently assessed
studies for methodological quality and studies for methodological quality and extracted data from eligible trialsextracted data from eligible trials
Data was pooled using a random effects Data was pooled using a random effects model with calculation of weighted mean model with calculation of weighted mean difference (MD) for continuous outcomes difference (MD) for continuous outcomes and relative risk (RR) for categorical and relative risk (RR) for categorical outcomes with 95% confidence intervals outcomes with 95% confidence intervals (CI)(CI)
Growth hormone for children Growth hormone for children with chronic kidney diseasewith chronic kidney disease
MAIN RESULTS:MAIN RESULTS: Fifteen RCTs (629 children) were identifiedFifteen RCTs (629 children) were identified rhGH (rhGH (28 IU/m²/wk28 IU/m²/wk) resulted in a ) resulted in a
significant increase in height (SDS) at one significant increase in height (SDS) at one year (MD 0.78 SDS, 95% CI 0.52 to 1.04), a year (MD 0.78 SDS, 95% CI 0.52 to 1.04), a significant increase in height velocity at six significant increase in height velocity at six months ( 2.85 cm/6 mo, 95%CI 2.22-3.48) months ( 2.85 cm/6 mo, 95%CI 2.22-3.48) and one year ( 3.80 cm/y, 95%CI 3.20-4.39) and one year ( 3.80 cm/y, 95%CI 3.20-4.39)
When compared to When compared to 14 IU/m²/wk14 IU/m²/wk, 1.34 , 1.34 cm/y (0.55 to 2.13) increase in height cm/y (0.55 to 2.13) increase in height velocity in the velocity in the 28 IU/m²/wk28 IU/m²/wk
Side effects of rhGH similar to controls Side effects of rhGH similar to controls
Growth hormone for children Growth hormone for children with chronic kidney diseasewith chronic kidney disease
AUTHORS' CONCLUSIONS:AUTHORS' CONCLUSIONS: Yearly Yearly 28 IU/m²/wk28 IU/m²/wk rhGH in children rhGH in children
with CKD resulted in a 3.80 cm/y with CKD resulted in a 3.80 cm/y increase in height velocity above that of increase in height velocity above that of untreated patientsuntreated patients
Trials determined treatment resulted in Trials determined treatment resulted in an increase in final adult height when an increase in final adult height when compared to untreated children compared to untreated children
Cochrane Database Syst Rev 1-41, Cochrane Database Syst Rev 1-41, 20062006
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
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
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
N Engl J Med 343: 923, 2000
Characteristics of Growth Hormone-Treated and Control Children with Chronic Renal Failure
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
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
Rosenfeld R. N Engl J Med 2003;349:2184-2186
Roles of Insulin-like Growth Factor (IGF) and Growth Hormone (GH) in Prenatal and Postnatal Growth
Factors contributing to GH Factors contributing to GH Resistance in CKDResistance in CKD
Serum concentration of GH increased, Serum concentration of GH increased, metabolic clearence decreased metabolic clearence decreased
GH receptor expression decreasedGH receptor expression decreased Signal transduction of GHR impairedSignal transduction of GHR impaired IGF-I production decreasedIGF-I production decreased IGF activity decreased by inhibitory IGF activity decreased by inhibitory
IGF binding proteinsIGF binding proteins Resistance to GH and IGF-IResistance to GH and IGF-I
Growth hormone treatment started in Growth hormone treatment started in the first year of life in infants with the first year of life in infants with
chronic renal failurechronic renal failure
Number of patientsNumber of patientsBilateral renal hypo-dysplasia, Posterior Bilateral renal hypo-dysplasia, Posterior urethral valves, urethral valves, Bilateral reflux with renal dysplasia, ARPKD, Bilateral reflux with renal dysplasia, ARPKD, cortical necrosiscortical necrosis
12 ( 912 ( 9♂♂ 3♀)3♀)
15 (11♂ 15 (11♂ 4♀)4♀)
Creatinine clearence (ml/min per Creatinine clearence (ml/min per 1.73 m²)1.73 m²)
5-225-22 7-357-35
Age at the beginning of rhGHAge at the beginning of rhGH
Dose of rhGH (mg/kg/week)Dose of rhGH (mg/kg/week)0.5 ± 0.30.5 ± 0.3
0.24 ± 0.24 ± 0.070.07
Complications : Infections- episodesComplications : Infections- episodes
Number of surgeriesNumber of surgeries2020
0.730.731212
0.530.53
FOLLOW-UPFOLLOW-UP Chronic renal failureChronic renal failure (5 years) Chronic peritoneal (5 years) Chronic peritoneal dialysisdialysis Renal transplantationRenal transplantation
114477
994422
Age at transplantationAge at transplantation 2.7-4.92.7-4.9 3.9-4.93.9-4.9Pediatr Nephrol 24: 1039, 2009
rhGH Controls
Amelioration of Hypophosphatemic Rickets and Amelioration of Hypophosphatemic Rickets and Osteoporosis With Pamidronate and Growth Osteoporosis With Pamidronate and Growth
Hormone in Lowe SyndromeHormone in Lowe SyndromeJ Formos Med Assoc 108: 730, 2009J Formos Med Assoc 108: 730, 2009
Effects of Growth Hormone Treatment on Body Proportions and FinalHeight Among Small Children With X-Linked Hypophosphatemic Rickets Pediatrics 113: e593, 2004
Growth Hormone improves growth rate and preserves renal function in Dent Disease J Pediatr Endocrinol Metab 21: 279, 2008
Recombinant human growth hormone and Recombinant human growth hormone and Gitelman's syndromeGitelman's syndrome
Am J Kidney Dis 33: 778-81, 1999Am J Kidney Dis 33: 778-81, 1999
Metabolic control and growth during exclusive growth hormone treatment in X-linked hypophosphatemic rickets Horm Res 69: 212, 2008
Gitelman disease associated with growth hormone deficiency: a new hereditary renal tubular-pituitary syndrome? Pediatr Res 46: 232,1999
CRI Dialysis TransplantGH No GH GH No GH GH No GH
Number of patients 1,376 4,550 478 2,030 479 1,953Mean (± SD) duration of therapy (years) 3.2 ± 5.9 NA 2.1 ± 2.9 NA 7.7 ± 8.5 NAMean (± SD) GH dose (mg/kg per week) 0.33 ± 0.20 NA 0.35 ± 0.13 NA NA NASlipped capital femoral epiphysis Number of events 1 1 2 4 1 2 Events per 1,000 patients 0.726 0.22 4.184 1.97 2.088 1.024Avascular necrosis Number of events 1 2 0 0 4 12 Events per 1,000 patients 0.726 0.44 0 0 8.351 6.144Benign intracranial hypertension Number of events 3 0 0 2 0 5 Events per 1,000 patients 2.18 0 0 0.985 0 2.56Other serious adverse events Number of events 34 106 68 183 86 247 Events per 1,000 patients 13.081 14.066 50.206 45.32 102.296 76.805
Incidence of adverse events associated with growth hormone therapy
Pediatr Nephrol 21: 917, 2006
Pediatr Transplantation 2008: 12: Pediatr Transplantation 2008: 12: 689–695689–695
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.
Recombinant growth hormone use pretransplant and risk for post-transplant lymphoproliferative disease (LPD) - A report of the NAPRTCS
Pediatr Nephrol 25:739–746, 2010
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
Pediatr Nephrol 25:739–746, 2010
Pediatr Nephrol 25:739–746, 2010
Pediatr Nephrol 25:739–746, 2010
Consider GH therapy: GFR < 15 mL/min/1.73 m² Height < - 1.8 SDS or 3rd %ile
Assess and treat complications:Acidosis, malnutrition, salt-wasting, osteodystrophy, hypothyroidism
Is Growth Velocity improved? YesNo
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 > baselineNo Yes
Assess & Correct: Dose Metabolic status Nutrition Compliance
Continue GHIs growth adequate?
No
Yes
Discontinue GH: Achieved height Closed epiphyses Active neoplasia Slipped femoral epiphyses Intracranial hypertension Noncompliance Severe HyperPTH
If HV < 2 cm/year consider reinitiating
Consider Pedi endo
NAPRTCS Consensus 2006
Albright’s dictumAlbright’s dictum He hablado de hormona de He hablado de hormona de
crecimiento mas de lo que yo crecimiento mas de lo que yo mismo semismo se
Mucho de lo que he dicho esta Mucho de lo que he dicho esta sujeto a cambios sin previo sujeto a cambios sin previo avisoaviso
Espero que haya originado mas Espero que haya originado mas preguntas que respuestaspreguntas que respuestas
De todos modos hay que De todos modos hay que continuar investigando aun mascontinuar investigando aun mas
IV CONGRESO COLOMBIANO DE NEFROLOGÍA PEDIÁTRICA
MuchasMuchasGraciasGracias
IV CONGRESO COLOMBIANO DE NEFROLOGÍA PEDIÁTRICA
Congreso Colombiano de Pediatria 2009, Cartagena
Chronic kidney disease (CKD) in children is associated with Chronic kidney disease (CKD) in children is associated with dramatic changes in the growth hormone (GH) and insulin-like dramatic changes in the growth hormone (GH) and insulin-like growth factor (IGF-1) axis, resulting in growth retardation. growth factor (IGF-1) axis, resulting in growth retardation. Moderate-to-severe growth retardation in CKD is associated Moderate-to-severe growth retardation in CKD is associated with increased morbidity and mortality. with increased morbidity and mortality. Renal failure is a state of GH resistance and not GH deficiency. Renal failure is a state of GH resistance and not GH deficiency. Some mechanisms of GH resistance are: reduced density of Some mechanisms of GH resistance are: reduced density of GH receptors in target organs, impaired GH-activated post-GH receptors in target organs, impaired GH-activated post-receptor Janus kinase/signal transducer and activator of receptor Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling, and reduced levels of free transcription (JAK/STAT) signaling, and reduced levels of free IGF-1 due to increased inhibitory IGF-binding proteins IGF-1 due to increased inhibitory IGF-binding proteins (IGFBPs). (IGFBPs). Treatment with recombinant human growth hormone (rhGH) Treatment with recombinant human growth hormone (rhGH) has been proven to be safe and efficacious in children with has been proven to be safe and efficacious in children with CKD. Even though rhGH has been shown to improve catch-up CKD. Even though rhGH has been shown to improve catch-up growth and to allow the child to achieve normal adult height, growth and to allow the child to achieve normal adult height, the final adult height is still significantly below the genetic the final adult height is still significantly below the genetic target. target. Growth retardation may persist after renal transplantation due Growth retardation may persist after renal transplantation due to multiple factors, such as steroid use, decreased renal to multiple factors, such as steroid use, decreased renal function and an abnormal GH–IGF1 axis. function and an abnormal GH–IGF1 axis. Those below age 6 years are the ones to benefit most from Those below age 6 years are the ones to benefit most from transplantation in demonstrating acceleration in linear transplantation in demonstrating acceleration in linear growth. growth. Newer treatment modalities targeting the GH resistance with Newer treatment modalities targeting the GH resistance with recombinant human IGF-1 (rhIGF-1), recombinant human recombinant human IGF-1 (rhIGF-1), recombinant human IGFBP3 (rhIGFBP3) and IGFBP displacers are under IGFBP3 (rhIGFBP3) and IGFBP displacers are under investigation and may prove to be more effective in treating investigation and may prove to be more effective in treating growth failure in CKD. growth failure in CKD.