1. Growth and Nutrition Constantinos J. Stefanidis “P. & A. Kyriakou” Children's Hospital, Athens, Greece

2. CJ Stefanidis 2003 Why growth retardation is a problem in children on PD ?

3. CJ Stefanidis 2003 Why growth retardation is a problem in children on PD ? Why aggressive management of growth failure should start early ?

4. CJ Stefanidis 2003 Why growth retardation is a problem in children on PD ? Why aggressive management of growth failure should start early ? Is it possible to prevent growth retardation in children on PD ?

5. CJ Stefanidis 2003 Why growth retardation is a problem in children on PD ? Why aggressive management of growth failure should start early ? Is it possible to prevent growth retardation in children on PD ? The role of growth hormone therapy in children on PD

6. CJ Stefanidis 2003 Why growth retardation is a problem in children on PD ?

7. CJ Stefanidis 2003 Children with CRI and extreme short stature are at risk that this disability may affect their : O physical, O psychological and O social well-being. Henning P Arch Dis Child (1988) 1. Psychosocial problems

8. CJ Stefanidis 2003 Law CM. Arch Dis Child 1987 They might have difficulties in peer relationships and self esteem Children with CRI and extreme short stature are at risk that this disability may affect their : O physical, O psychological and O social well-being. Henning P Arch Dis Child (1988) 1. Psychosocial problems

9. CJ Stefanidis 2003 Short stature and chronic renal failure: what concerns children and parents? Growth was a major concern for 30% of parents and 28% of children. Reynolds JM et al Arch Dis Child 1995

10. CJ Stefanidis 2003 2. Percentage of children with height < 3rd percentile (SDS < -1.88) 1701 patients with GFR < 75 ml/min/1.73m 2 Fivush BA et al Pediatr Nephrol 1998,12:328-3750% < 5 35 % 6-12 27% 13-17 years North American Pediatric Renal Transplant Cooperative Study NAPRTCS, 1996 ANNUAL REPORT

11. CJ Stefanidis 2003 3. Children with CRI and growth retardation are at risk of a more-complicated clinical course Why growth retardation is a problem in children on PD ?

12. CJ Stefanidis 2003 Incremental growth (Δ SDS) during one year of children on dialysis and transplantation Severe growth failure z <-3 29 % < 4 years N=124 25 %25 %25 %25 % 5-9 N=299 6 % 10-14 years N=488 Furth SL et al Pediatr Nephrol 2002 U.S. Renal Data System Data from the U.S. Renal Data System (USRDS) Pediatric Growth and Development Study from 548 dialysis and transplant units and 1112 patients

13. CJ Stefanidis 2003 Incremental growth (Δ SDS) during one year of children on dialysis and transplantation Severe growth failure z <-3 29 % < 4 years N=124 25 %25 %25 %25 % 5-9 N=299 6 % 10-14 years N=488 Furth SL et al Pediatr Nephrol 2002 Moderate growth failure z <-2 12% 16% 17% Data from the U.S. Renal Data System (USRDS) Pediatric Growth and Development Study from 548 dialysis and transplant units and 1112 patients

14. CJ Stefanidis 2003 Furth SL et al Pediatr Nephrol 2002 CharacteristicsHospitalizations Risk ratio per patient/year per patient/year Severe growth retardation 1.651.50 Moderate1.591.51 Normal growth1.051.0

15. CJ Stefanidis 2003 Furth SL et al Pediatr Nephrol 2002 CharacteristicsHospitalizations Risk ratio per patient/year per patient/year Severe growth retardation 1.651.50 Moderate1.591.51 Normal growth1.051.0 Dialysis1.993.50 Transplantation0.581.0

16. CJ Stefanidis 2003 Furth SL et al Pediatr Nephrol 2002 CharacteristicsCrude 5-year Relative hazard death rate (%) Severe growth retardation 16.23.20 Moderate11.52.12 Normal growth 5.61.0 Age <414.51.97 5-9 5.7 0.72 10-14 7.1 1.0

17. CJ Stefanidis 2003 The risk of death associated with poor growth mirrored the risk associated with low body mass index Poor nutrition is associated with increased risk of infection Wong CS et al Am J Kidney Dis 2000

18. CJ Stefanidis 2003 Furth SL et a l Pediatrics 2002 2036 patients </=21 years old initiated on dialysis between 1992 and 2000 in pediatric nephrology centers of the North American Pediatric Renal Transplant Cooperative Study. School-aged children with short stature (z score <-2.5 ) were less likely to be attending school full-time than were their counterparts with more normal height, even if medically capable. Short-stature patients have significantly more hospital days per month of dialysis follow-up than those patients with better growth.

19. CJ Stefanidis 2003 Why aggressive management of growth failure should start early ?

20. CJ Stefanidis 2003 Height (cm) Age (years) + 2 SDS - 2 SDS Mean 2 4 6 8 10 12 14 16 18 180 160 140 120 100 80 60 Infancy Height velocity 20 cm/yr Childhood Height velocity 5 cm/yr Adolescence growth spurt: 2.5 - 3 years Starting in girls 11 yrs, boys 13 yrs Height velocity 10 cm/yr The three phases of growth in height

21. CJ Stefanidis 2003 Height (cm) Age (years) + 2 SDS - 2 SDS Mean 2 4 6 8 10 12 14 16 18 180 160 140 120 100 80 60 Infancy Childhood Adolescence Fetal growth Nutrition GH (and thyroid hormones) Sex hormones The three phases of growth in height of children with CRI The heights of CRF children dropped below the 3 rd % during the first 15 months of life. Thereafter, growth patterns usually were percentile parallel, with a mean height SDS of -2.37 Schaefer F et al Pediatr Nephrol 1996

22. CJ Stefanidis 2003

23. Is it possible to prevent growth retardation in children on PD ?

24. CJ Stefanidis 2003 Nutrition Etiology of growth failure in CRI Anemia ROD Adequacy Kt/V DisorderedGHMetabolismMetabolicacidosis Na waste  Growth

25. CJ Stefanidis 2003 Nutrition Etiology of growth failure in CRI Anemia ROD Adequacy Kt/V DisorderedGHMetabolismMetabolicacidosis Na waste  Growth

26. CJ Stefanidis 2003 Etiology of malnutrition   Intake LossesNeeds 

27. CJ Stefanidis 2003 Etiology of malnutrition   Intake LossesNeeds  AnorexiaVomiting Inadequate dialysis Psychogenic Financial constraints

28. CJ Stefanidis 2003 Etiology of malnutrition   Intake LossesNeeds  AnorexiaVomiting Inadequate dialysis Psychogenic Financial constraints DialysisVomitingPeritonitisProteinuria

29. CJ Stefanidis 2003 Etiology of malnutrition   Intake LossesNeeds  AnorexiaVomiting Inadequate dialysis Psychogenic Financial constraints DialysisVomitingPeritonitisProteinuria Metabolic Acidosis Physical Inactivity Frequent Peritonitis Medications Intercurrent Illness Catch-up Growth

30. CJ Stefanidis 2003 Mortality morbility growth (peritonitis, hospitalizations) Complications of malnutrition

31. CJ Stefanidis 2003 Malnutrition and growth The negative effect of malnutrition on growth during the first two year of life is well established No correlation was found between energy intake and growth rate in older children Attempts to improve growth in older children with high-energy diets were generally disappointing

32. CJ Stefanidis 2003 Comprehensive evaluation of nutritional status Nephrologist (s) Renal dietician Specialized nurses Psychologist Social worker Multidisciplinary pediatric team approach

33. CJ Stefanidis 2003 0 -2.0 -3.0 -4.0 0.5 1.5 2.5 3.5 4.5 5.5 6.5 7.5 8.5 9.5 10.5 11.5 12.5 Age, years Mean height SDS 63757875716862595547444342403427242019181510752 Growth data from 81 children with CRF in the first 6 months of life (GFR < 20 ml/min/1.73m 2 ) 81%: enterally fed for 0.1 to 6.8 years 46% gastrostomy, and 22% a Nissen fundoplication Kari JA, Gonzalez C, Ledermann SE, Shaw V, Rees L. Kidney Int 2000 -2.2 -2.0 -1.8 -1.3 -0.85 Growth and nutrition in children with CRI

34. CJ Stefanidis 2003 Stefanidis C.J et al. Nutritional Status and growth of children less than 12 kg treated with CAPD. Perit Dial Int.1992 Growth and nutrition in children on CAPD Growth data from 13 children (<12 kg) at the start of CAPD and 1 year later. 7/12 children on NG tube feeding. Energy intake 94 +/- 7% of RDA Protein intake 2.6 +/- 0.2 g/kg/day No correlation was found between energy intake and growth rate. Midarm circumference and triceps skin fold thickness

35. CJ Stefanidis 2003 Dialysis adequacy and growth The native C(Cr) - and not the dialysis C(Cr) - had a significant (but weak) positive correlation with delta height SDS. No correlation of RRF and baseline height SDS. Chadha V et al Perit Dial Int 2001. Positive correlation between KT/V and caloric intake. Fischbach M et al Adv Perit Dial. 1995.

36. CJ Stefanidis 2003 Dialysis adequacy and growth The native C(Cr) - and not the dialysis C(Cr) - had a significant (but weak) positive correlation with delta height SDS. No correlation of RRF and baseline height SDS. Chadha V et al Perit Dial Int 2001. Positive correlation between KT/V and caloric intake. Fischbach M et al Adv Perit Dial. 1995. A trend for a positive change in height SDS with increasing C(Cr) was seen. Holtta T et al Ped Nephrol 2000. Low C(Cr), high transport capacity and high total dialysate volume had a negative effect on delta height SDS. Correlation of RRF and baseline height SDS. Schaefer F et al J Am Soc Nephrol 1999.

37. CJ Stefanidis 2003 Anemia and growth Growth data from 10 children at the start of recombinat human erythropoietin and 1 year later Stefanidis CJ, et al : Adv Perit Dial. 1992 Weight, midarm circumference and triceps skin fold thickness SDS

38. CJ Stefanidis 2003 Nutrition, dialysis adequacy,anemia, ROD and growth  Nutrition was achieved orally with human milk during the first 6 months of life.  A high dialysis dose Kt/V urea 3.8/week and Kcreatinine 105 l/week/1.73 m2.  Hemoglobin was maintained over 13 g/dl  Low levels of vitamin D analogue were prescribed to avoid adynamic bone disease. At the age of 1 year her height was 75 cm. i.e. in the normal range for age. Normal statural growth in 2 infants on CPD: anecdotal or whole management-related. Fischbach M et al Clin Nephrol 2001

39. CJ Stefanidis 2003 Management before the initiation of rhGH treatment 1.Appropriate dose of dialysis should be provided 1.Appropriate dose of dialysis should be provided.

40. CJ Stefanidis 2003 Management before the initiation of rhGH treatment 1.Appropriate dose of dialysis should be provided 1.Appropriate dose of dialysis should be provided. 2.Aggressive nutritional intervention should be planed (especially when the weight for height sds< -2).

41. CJ Stefanidis 2003 Management before the initiation of rhGH treatment 1.Appropriate dose of dialysis should be provided. 2.Aggressive nutritional intervention should be planed (especially when the weight for height sds< -2). 3.Anemia with recombinant human erythropoietin and iron administration should be corrected.

42. CJ Stefanidis 2003 Management before the initiation of rhGH treatment 1.Appropriate dose of dialysis should be provided. 2.Aggressive nutritional intervention should be planed (especially when the weight for height sds< -2). 3.Anemia with recombinant human erythropoietin and iron administration should be corrected. 4.Renal osteodystrophy should be treated appropriately.

43. CJ Stefanidis 2003 Management before the initiation of rhGH treatment 1.Appropriate dose of dialysis should be provided. 2.Aggressive nutritional intervention should be planed (especially when the weight for height sds< -2). 3.Anemia with recombinant human erythropoietin and iron administration should be corrected. 4.Renal osteodystrophy should be treated appropriately. 5.Sodium losses of children with hypoplastic dysplastic kidneys should be replaced.

44. CJ Stefanidis 2003 Management before the initiation of rhGH treatment 1.Appropriate dose of dialysis should be provided. 2.Aggressive nutritional intervention should be planed (especially when the weight for height sds< -2). 3.Anemia with recombinant human erythropoietin and iron administration should be corrected. 4.Renal osteodystrophy should be treated appropriately. 5.Sodium losses of children with hypoplastic dysplastic kidneys should be replaced. 6.Metabolic acidosis should be corrected to reduce protein catabolism.

45. CJ Stefanidis 2003 Management after the initiation of rhGH treatment 1.Appropriate dose of dialysis should be provided. 2.Aggressive nutritional intervention should be planed (especially when the weight for height sds< -2). 3.Anemia with recombinant human erythropoietin and iron administration should be corrected. 4.Renal osteodystrophy should be treated appropriately. 5.Sodium losses of children with hypoplastic dysplastic kidneys should be replaced. 6.Metabolic acidosis should be corrected to reduce protein catabolism.

46. CJ Stefanidis 2003 Growth hormone therapy in children on PD

47. CJ Stefanidis 2003 Indications for growth hormone therapy in children on PD Standard deviation score (SDS) for height < -2 SDS for height velocity < -2 SDS At least two separate height measurements during the previous year are necessary to assess height velocity.

48. CJ Stefanidis 2003 30 children < 2.5 years with CRI Placebo vs rhGH treatment for 2 years Fine et al. Pediatr Nephrol 1995 Growth hormone therapy

49. CJ Stefanidis 2003 rhGH in infants and young children Maxwell H et al Arch Dis Child 1996 One year trial of the use of rhGH in 8 infants and young children of age 1.3 - 2.7 years with CRF Height standard deviation score (SDS) increased from an average -3.3 SDS to -2.2 (p = 0.0002) Height velocity SDS increased from -1.3 to 1.1 (p = 0.006) There were no serious adverse events

50. CJ Stefanidis 2003 9 children 1.8- 9.7 years on CAPD Energy intake > 90% Pr. intake rhGH 3yrs 2- 2.5 g/kg/day Stefanidis CJ Br J Clin Pract. 1996 Growth hormone therapy and protein metabolism

51. CJ Stefanidis 2003 Ht SDS At start-3.4 (0.9) Hokken-Koelega et al. Pediatr Nephrol 2000 Long-term (8 years) therapy rhGH at 4 IU/m 2 /day GFR < 20 ml/min/1.73m 2 n=7 Growth hormone therapy Year 2-2.5 (0.8) Year 4-1.7 (0.8)

52. CJ Stefanidis 2003 Ht SDS At start-3.4 (0.9) Hokken-Koelega et al. Pediatr Nephrol 2000 Long-term (8 years) therapy rhGH at 4 IU/m 2 /day GFR < 20 ml/min/1.73m 2 n=7 Growth hormone therapy Year 2-2.5 (0.8) Year 4-1.7 (0.8) Year 6-1.1 (1.0) Year 8 -0.8 (1.4) Year 8 -0.8 (1.4)

53. CJ Stefanidis 2003 Long-term (5.3 years) therapy 38 initially prepubertal children with CRI treated with were followed until they reached their final adult height Growth hormone therapy Mean final Ht- 1.6+/-1.2 SD Initial Ht- 3.1+/-1.2 SD In contrast, the final height of the untreated children (2.1+/-1.2 SD below normal) was 0.6 SD below their standardized height at base line (P<0.001). Haffner D J et al N Engl J Med 2000

54. CJ Stefanidis 2003 Factors predictive of the efficacy of rhGH treatment Haffner D J et al Am Soc Nephrol 1998 103 prepubertal children on conservative treatment (n = 74) or dialysis (n = 29) were treated with rhGH for up to 5 yrs. rhGH treatment persistently increased height (+ 1.6 SD scores)

55. CJ Stefanidis 2003 Factors predictive of the efficacy of rhGH treatment Haffner D J et al Am Soc Nephrol 1998 103 prepubertal children on conservative treatment (n = 74) or dialysis (n = 29) were treated with rhGH for up to 5 yrs. rhGH treatment persistently increased height (+ 1.6 SD scores) Age, GFR, target height, and prestudy growth rate were the predictors of the response to rhGH treatment The growth response during the first treatment year positively predicted the long-term response

56. CJ Stefanidis 2003 3748 children on maintenance dialysis Peritoneal dialysis was the main modality in 67% of them 15% of these patients received rhGH NAPRTCS data on growth after rhGH Lewy JE et al Med Arh 2001

57. CJ Stefanidis 2003 Characteristics Nr Baseline 6 months 12 months All patients 482 9 20 25 NAPRTCS data on rhGH utilisation (%) for patients with Ht SDS<1.8 GFR < 75 ml/min/1.73m 2 Seikaly MG et al Ped Nephrol 2003 0-1 yrs 143 3 10 14 2-5 yrs 145 8 21 23 6-12 yrs 170 14 23 30 13-16 yrs 4 17 31 38

58. CJ Stefanidis 2003 North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) 2002 Annual Report. Mean (with SE) of height at time of initial transplant, by year of transplant

59. CJ Stefanidis 2003 Prevension of growth failure EarlyPD Appropriatemanagement Early rhGH

60. CJ Stefanidis 2003 Growth retardation might be the result of late referral and/or suboptimal clinical care Key points for clinical practice

61. CJ Stefanidis 2003 Growth retardation might be the result of late referral and/or suboptimal clinical care Key points for clinical practice Management of malnutrition, renal osteodystrophy, metabolic acidosis, salt wasting and anemia should be optimal before rhGH initiation

62. CJ Stefanidis 2003 Growth retardation might be the result of late referral and/or suboptimal clinical care Key points for clinical practice Management of malnutrition, renal osteodystrophy, metabolic acidosis, salt wasting and anemia should be optimal before rhGH initiation Growth hormone treatment should start in early childhood, when there is no improvement with optimal care and should be continued at least until renal transplantation