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

2. Reasons for Short Stature : Insulin-like Growth Factor Deficiency 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)

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. Severe Primary IGF Deficiency 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

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

8. Severe Primary IGF Deficiency Continuation 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

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

11. Effect of Forced Feeding in Infants on PD Heidelberg Experience 27 infants, age < 2 years. 22 NG tube, 5 PEG Mean energy intake 100 % RDA, protein intake 125 % RDA BMI SDS Months on Tube Feeding 03691215182124 SDS -3 -2 0 Height SDS 03691215182124 SDS -3 -2 0 Initial BMI > -2 SDS Initial BMI < -2 SDS Months on Tube Feeding Initial BMI > -2 SDS Initial BMI < -2 SDS

12. Effect of Gastrostomy Feeding in ESRD Children Nottingham Experience 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%) 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 impaired Schaefer et al, J Clin Invest 108, 467-75, 2001 IGF-I production decreased Blum et al, Pediatr Nephrol 5, 539-44, 1991 IGF activity decreased by binding proteins Tönshoff 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 impaired Schaefer et al, J Clin Invest 108, 467-75, 2001 IGF-I production decreased Blum et al, Pediatr Nephrol 5, 539-44, 1991 IGF activity decreased by excess of binding proteins Tönshoff 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. Derangements of Somatotropic Hormone Axis in CRF Post-R Defect

17. Improvement of response to GH following dayly hemodialysis Fischbach et al,Ped Neph 2006Fischbach 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)- Response in 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 Parameter estimate RankPartial R 2 Variable significance Intercept (constant) 13.3 Age at start (years) -0.3810.203< 0.001 Weight SDS at start 0.3920.062< 0.001 Hereditary renal disorder -1.1630.0390.0008 GFR (ml/min x 1.73 m²) 0.02340.0390.0005 Log dose GH (mg/kg per week) 1.0450.0220.0090 Cumulative R² 0.37 Error SD (cm)1.6

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. Studentized Residuals vs. predicted height velocity KIGSDutch Controls

31. Effect of GH on liver and other tissue

32. Reasons for Short Stature : Insulin-like Growth Factor Deficiency 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

33. Studentized Residuals vs. predicted height velocity KIGSDutch Controls

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

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

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

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

38. Schaefer et al. Pediatr Nephrol 1996; 10:288–93 Impact of Renal Function on Prepubertal Growth 320 children with congenital CKD Height (cm) 40 4100 Age (years) 150 90 100 110 120 130 140 80 70 60 682 90 75 50 25 10 50 Moderate CRF GFR > 25 ml/min/1.73 m 2 40 4100 Age (years) 150 90 100 110 120 130 140 80 70 60 682 90 75 50 25 10 50 Severe CRF GFR < 25 ml/min/1.73 m 2

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

41. Insulin-like Growth Factor Deficiency I. Hypothalamic dysfunction II. Pituitary GHD III. GHI A. Primary GHI 1. GH receptor deficiency a. Mutations/deletions of the extracellular domain affecting the GHR b. Mutations/deletions of the transmembrane domain affecting the GHR c. Mutations/deletions of the intracellular domain affecting the GHR d. Abnormal GH signal transduction due to defects distal to the GHR

42. Insulin-like Growth Factor Deficiency Continuation B. Secondary GHI 1. Malnutrition 2. Liver disease 3. Chronic disease IV. Primary defects of IGF synthesis V. Primary defects of IGF transport/clearance VI. IGF resistance

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

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

46. 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.

47. 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.