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.