Primary and Secondary Insensitivity to Growth Hormone in Short Children

1. Otto Mehls University Hospital for Childen and Adolescents Devision of Pediatric Nephrology Heidelberg, Germany Primary and Secondary Insensitivity to Growth Hormone in Short Children

2. Hypothalamic dysfunction Pituitary GHD GH insensitivity A. Primary GH insensitivity 1. GH receptor defect B. Secondary insensitivity 1. Malnutrition 2. Liver disease 3. Chronic disease like chronic kidney disease (CKD) Reasons for Short Stature : Insulin-like Growth Factor Deficiency

3. Growth Hormone Receptor

4. GH action on liver and extrahepatic tissue

5. Molecular defects resulting in severe primary IGF deficiency after Rosenfeld 2009

6. I. GHR abnormalities 1. Mutations/deletions of the GHR affecting the extracellular domain of the GHR and resulting in decreased GH binding 2. Mutations/deletions of the GHR affecting the ability of the GHR to dimerize 3. Mutations/deletions of the GHR affecting the transmembrane domain of the receptor and resulting in defective anchoring in the cell membrane 4. Mutations/deletions of the GHR affecting the intracellular domain and signaling Severe Primary IGF Deficiency

7. Molecular defects resulting in severe primary IGF deficiency after Rosenfeld 2009

8. II. Post-GHR signaling defects 1. Mutations of STAT5b resulting in defective or absent GH signal transduction III. Mutations/deletions of IGF-I 1. Deletions of IGF-I 2. Mutations of the IGF-I resulting in bioinactive IGF-I IV. Defects of IGF transport and/or clearance 1. Mutations/deletions of –ALSIGF, resulting in defective IGF transport and rapid IGF clearance V. IGF resistance 1. Mutations of the IGF1R, resulting in decreased sensitivity to IGF-I Severe Primary IGF DeficiencyContinuation

9. Secondary GH insensitivity/resistance Example : Chronic renal failure

11. 27 infants, age < 2 years. 22 NG tube, 5 PEG Mean energy intake 100 % RDA, protein intake 125 % RDA Effect of Forced Feeding in Infants on PD Heidelberg Experience BMI SDS Height SDS 0 0 Initial BMI > -2 SDS Initial BMI < -2 SDS -1 -1 SDS SDS -2 -2 Initial BMI > -2 SDS Initial BMI < -2 SDS -3 -3 0 3 6 9 12 15 18 21 24 0 3 6 9 12 15 18 21 24 Months on Tube Feeding Months on Tube Feeding

12. Treatment: 20 PD, 2 HD patients Age at gastrostomy: 2.3 (0.2-10.3) years Observation period: 14.5 (2.5 - 56) months Mean Energy Intake: 115 % RDA (98-155%) Effect of Gastrostomy Feeding in ESRD ChildrenNottingham Experience SDS Coleman et al. NDT 1998

13. Resistance to GH/IGF in CKD • Serum concentration of GH increased, metabolic clearance decreased Haffner et al, J Clin Invest 93, 1163-71, 1994 • GH pulsatility disturbed Schaefer et al, J Pediatr 119, 568-77 • GH receptor expression decreased Tönshoff et al, J Clin Endocrinol Metab 82, 1007-13, 1997 • Signal transduction of GHR impairedSchaefer et al, J Clin Invest 108, 467-75, 2001 • IGF-I production decreasedBlum et al, Pediatr Nephrol 5, 539-44, 1991 • IGF activity decreased by binding proteinsTönshoff et al, J Pediatr 370, 28-34, 1990 • Endorgan (postreceptor) resistance to GH and IGF-I Mak and Pak, Kidney Int 50, 40-6, 1996

15. Resistance to GH/IGF in CKD • Serum concentration of GH increased, metabolic clearance decreased Haffner et al, J Clin Invest 93, 1163-71, 1994 • GH pulsatility disturbed Schaefer et al, J Pediatr 119, 568-77 • GH receptor expression decreased Tönshoff et al, J Clin Endocrinol Metab 82, 1007-13, 1997 • Signal transduction of GHR impairedSchaefer et al, J Clin Invest 108, 467-75, 2001 • IGF-I production decreasedBlum et al, Pediatr Nephrol 5, 539-44, 1991 • IGF activity decreased by excess of binding proteinsTönshoff et al, J Pediatr 370, 28-34, 1990 • Endorgan (postreceptor) resistance to GH and IGF-I Mak and Pak, Kidney Int 50, 40-6, 1996

16. Post-R Defect Derangements of Somatotropic Hormone Axis in CRF

17. Improvement of response to GH following dayly hemodialysis Fischbach et al ,Ped Neph 2006 Fischbach et al, Pediatr Nephrol 2006

18. General clinical problem: Some short patients respond better to GH treatment than others. • Why ? What is the reason ? • Prediction possible ?

19. First year response to daily growth hormone treatment in males with IGHD Bakker et al JCEM 93,352, 2008

20. Prediction of Growth Hormone (GH)-Responsein Short Children with CKD O. Mehls, A. Lindberg, R. Nissel, D. Haffner, A. Hokken-Koelega, M. B. Ranke Submitted to JCEM

21. Design Data from 208 prepubertal children on conservative treatment or dialysis from a large pharmaco-epidemiological survey (KIGS) Independent control Data from 67 similar CKD patients registered at the Dutch Growth Research Foundation

22. Statistical Analysis Multiple linear regression analysis fitted by least squares and REG procedure in the SAS computer program. Variation of response to GH was expressed in terms of Studentized residuals.

23. Regression equation variables used for prediction

24. Studentized Residuals Residual = observed height velocity(HV) – predicted HV) / Standard error of predicted HV = index of responsiveness

25. Individual Prediction ● o

26. Identification of Non-Responders Dutch non responders = Dutch patients with HV SDS < 0.0

27. Summary • Primary resistance to GH resulting in very low or defective IGF1 is explained by various molecular defects of the GH receptor and along its signaling pathway • Secondary resistance to GH is due to functional, reversible defects of the GH-IGF axis • Low , normal or high response to GH treatment can be seen from Bakker charts or predicted using KIGS prediction models.

30. Hypothalamic dysfunction Pituitary GHD GH insensitivity A. Primary GH insensitivity 1. GH receptor defect B. Secondary insensitivity 1. Malnutrition 2. Liver disease 3. Chronic disease Primary defects of IGF synthesis Primary defects of IGF transport/clearance IGF resistance Reasons for Short Stature : Insulin-like Growth Factor Deficiency

31. Studentized Residuals vs. predicted height velocity KIGS Dutch Controls

32. Growth Response to GH ( Height SDS) 1st Year According to Primary Renal Disease Prepubertal Patients  Height SDS 1st year

33. Growth Response to GH ( Height SDS) 0-2years According to Primary Renal Disease Prepubertal Patients  Height SDS 2years

34. Clinical problem Short stature in children with CKD: -Variable diagnosis Varable renal function Variable response to GH Aim: -Prediction ofindividual growth response and identify non-responders

35. CRI Height SDS Dialysis Years of Observation rGH Treatment Efficacy in Prepubertal Children with CRIGerman GH in CRI Study Group 74 CRI, 29 dialysis patients from 27 centers, observation up to 5 years Haffner et al. J Am Soc Nephrol 1998

36. Impact of Renal Function on Prepubertal Growth320 children with congenital CKD Moderate CRF GFR > 25 ml/min/1.73 m2 Severe CRF GFR < 25 ml/min/1.73 m2 150 150 140 140 90 90 75 130 130 75 50 50 25 120 120 25 10 10 110 110 Height (cm) 100 100 90 90 80 80 70 70 60 60 50 50 40 40 0 2 4 6 8 10 0 2 4 6 8 10 Age (years) Age (years) Schaefer et al. Pediatr Nephrol 1996; 10:288–93

37. First year response to dayly growth hormone treatment according to primary disease Bakker et al JCEM 93,352, 2008

39. Growth of uremic rats is impaired by reduced food intake and uremia , but reduced food intake might only be associated with poor growth

40. Growth of uremic rats is impaired by reduced food intake and uremia, but reduced food intake might only be associated with poor growth

42. Studentized Residuals Residual = observed height velocity(HV) – predicted HV) / Standard error of predicted HV = index of responsiveness Patients with an observed height velocity (HV) of < 0.0 height velocity SDS were excluded to allow identification of non-responders by the model.

43. Statistical Analysis Multiple linear regression analysis fitted by least squares and REG procedure in the SAS computer program. The hierarchy of predicting factors was derived by the all-possible regression approach as described for other prediction models. Differences were expressed in terms of Studentized residuals.