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Indicaciones de Hormona de Crecimiento en Nefrologia: Insuficiencia Renal Cronica Tubulopatias Post transplante renal Marco Danon, M.D. Miami Children’s.

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Presentation on theme: "Indicaciones de Hormona de Crecimiento en Nefrologia: Insuficiencia Renal Cronica Tubulopatias Post transplante renal Marco Danon, M.D. Miami Children’s."— Presentation transcript:

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

2 Approved Uses of Growth Hormone Approval Year Childhood growth hormone deficiency Childhood growth hormone deficiency Chronic renal insufficiency Chronic renal insufficiency HIV-wasting HIV-wasting Adult growth hormone deficiency Adult growth hormone deficiency Turner syndrome Turner syndrome Prader-Willi syndrome Prader-Willi syndrome Short children born SFD (SGA) Short children born SFD (SGA) Idiopathic short stature Idiopathic short stature Short bowel syndrome Short bowel syndrome Short Stature with SHOX deficiency Short Stature with SHOX deficiency Noonan syndrome Noonan syndrome

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5 The GH-IGF-IGFBP Axis Transport Cellular IGFBP Receptors RXR- Nuclear actions Nuclear Receptors Cell surface BP-receptors ---IGFBPs Type IGF Receptor I   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-1IGFBP-2IGFBP-3IGFBP-4IGFBP-5 IGFBP-6 Type IGF Receptor II IGF2 binding Mannose-6- phosphate binding Retinoid binding Growth inhibition GH

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

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10 Growth hormone for children with chronic kidney disease BACKGROUND: BACKGROUND: Chronic kidney disease (CKD) condition with growth retardation Chronic kidney disease (CKD) condition with growth retardation rhGH helps short children with CKD attain height of their age group 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 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. OBJECTIVES: evaluate benefits and harms of rhGH in children with CKD.

11 Growth hormone for children with chronic kidney disease. SEARCH STRATEGY: SEARCH STRATEGY: RCTs identified from the Cochrane Central Register of Controlled Trials with experts in the field RCTs identified from the Cochrane Central Register of Controlled Trials with experts in the field SELECTION CRITERIA: 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 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: DATA COLLECTION AND ANALYSIS: Reviewers independently assessed studies for methodological quality and extracted data from eligible trials 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) 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 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 ) 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 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 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 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 Trials determined treatment resulted in an increase in final adult height when compared to untreated children Cochrane Database Syst Rev 1-41, 2006 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

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

17 Haffner D et al. N Engl J Med 2000;343: Growth during GH in 38 CRF Children (32 Boys and 6 Girls) Compared with 50 CRF Children with No GH

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

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

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

21 Rosenfeld R. N Engl J Med 2003;349: Roles of Insulin-like Growth Factor (IGF) and Growth Hormone (GH) in Prenatal and Postnatal Growth

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

23 Growth hormone treatment started in the first year of life in infants with chronic renal failure 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) Age at the beginning of rhGH Dose of rhGH (mg/kg/week) 0.5 ± ± 0.07 Complications : Infections- episodes Number of surgeries FOLLOW-UP Chronic renal failure (5 years) Chronic peritoneal dialysis (5 years) Chronic peritoneal dialysis Renal transplantation Renal transplantation Age at transplantation Pediatr Nephrol 24: 1039, 2009 rhGHControls

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25 Amelioration of Hypophosphatemic Rickets and Osteoporosis With Pamidronate and Growth Hormone in Lowe Syndrome J Formos Med Assoc 108: 730, 2009 Effects of Growth Hormone Treatment on Body Proportions and Final Height 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 Gitelman's syndrome Am J Kidney Dis 33: , 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? 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– 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

28 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

29 Pediatr Nephrol 25:739–746, 2010

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33 Consider GH therapy: GFR < 15 mL/min/1.73 m² Height < SDS or 3 rd %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 > baseline NoYes Assess & Correct: Dose Metabolic status Nutrition Compliance Continue GH Is 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

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

35 Muchas Gracias IV CONGRESO COLOMBIANO DE NEFROLOGÍA PEDIÁTRICA

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.


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