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1
Long-Term Outcomes of Chronic Renal Failure in
Children How Do the Children Grow?
F. Schaefer Division of Pediatric Nephrology
Hospital for Pediatric and Adolescent Medicine
Heidelberg, Germany
2
Mechanisms of Growth FailureAcidosisFluid/Elect
rolyte ImbalancesAnorexia/Malnutrition/Inflammati
onSomatotropic Hormone ResistanceGlucocorticoids

3
Mechanisms of Anorexia in CKD
Delayed gastric emptying due to - altered vagal
nerve function - gastric distension due to NO
deficiencyAbdominal discomfort in PD
patients Accumulation of satiety hormones
4
Leptin Central Regulator of Food Intake in
Uremia?

• Marker of body fat cell mass

• Leptin administration induces (moderate) weight
  loss

Daschner et al. JASN 1998 91074
5
Leptin Receptor Deficient Mice Gain Weight
Despite CKD
Cumulative food consumption (g)
80
60
40
20
0
3
plt0.001
2
Cumulative weight gain (g)
1
0
db/db-S (n6)
db/db-N (n6)
WT-N (n30)
WT-S (n30)
Cheung, Mak. J Clin Invest 2005
6
Derangements of Somatotropic Hormone Axis in CRF
7
Glucocorticoid Interactions with Somatotropic
Hormone Axis
8
Growth Outcomes in CKD Where Do we Stand Today ?
9
Growth in Children with Chronic Renal
Insufficiency
GFR lt3rd pct
lt10 64 10-24 54 25-49 37
50-75 22
Mean -1.3 SDS 10th pct
From NAPRTCS Annual Report 2006
10
Effect of rhGH on Adult Height
rhGH
non-rhGH
11
Correction of Growth Failure by rGH in CKD
Patients
Adapted from Hokken-Koelega et al. Pediatr
Nephrol 2000147016
12

50th (0) 25th (-0.75) 16th (-1.0) 10th
(-1.34) 5th (-1.45) 3rd (-1.88)
13

50th (0) 25th (-0.75) 16th (-1.0) 10th
(-1.34) 5th (-1.45) 3rd (-1.88)
Growth in CRI
14
Growth on Dialysis
From NAPRTCS Annual Report 2006
15
Drash Syndrome, Born Anuric Tube feeding started
5th day of life
Weight
CCPD NG Tube
Weiblich 3,5 Jahre alt
Length
16
Effect of Forced Feeding in Infants on PD
Heidelberg Experience

• 27 infants, age lt 2 years. 22 NG tube, 5 PEG
• Mean energy intake 100 RDA, protein intake 125
  RDA

BMI SDS
Height SDS
0
0
Initial BMI gt -2 SDS Initial BMI lt -2 SDS
-1
-1
SDS
SDS
-2
-2
Initial BMI gt -2 SDS Initial BMI lt -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
17
Effect of Gastrostomy Feeding in ESRD
ChildrenNottingham 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
18
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
19
Predictors of Final Height in Children with
Renal Growth Failureon Long-Term rGH Treatment
Change in height SDS
partial r² () Duration of rhGH therapy
0.54 () Initial target height deficit
0.06 (-) Percentage time on
dialysis 0.04 0.64
20
Standardized Height at Time of Transplantation
From NAPRTCS Annual Report 2006
21
Improved Growth by Intensified Dialysis Daily
Hemodiafiltration
Fischbach et al. NDT 2004
22

50th (0) 25th (-0.75) 16th (-1.0) 10th
(-1.34) 5th (-1.45) 3rd (-1.88)
Growth on Dialysis
23
Growth after Renal Transplantation
From NAPRTCS Annual Report 2006
24
Change in Standardized Height after
Transplantation
From NAPRTCS Annual Report 2006
25
Final Height in Renal Allograft Recipients
without rGH Treatment
André et al. Pediatr Nephrol 2003
26
GH Stimulates Growth in Renal Allograft
Recipients European Pharmacia Study
Prepubertal
Präpubertär
Pubertal
No rGH
rGH
Height velocity (cm/year)
n63
n55
n34
n51
27
Effect of GH on Final Height in Children with CRF
28
Partial Catch-Up Growth by Steroid Withdrawal
Prepubertal renal allograft recipients, Case
Control Study
n20






n20
48
0
12
24
Höcker et al. Transplantation 2004
29

50th (0) 25th (-0.75) 16th (-1.0) 10th
(-1.34) 5th (-1.45) 3rd (-1.88)
Post-transplant growth
30
Growth Outcomes in CKD Can we do better ?
31
Regional Distribution of BMI SDS in Children on
Chronic PD

IPPR 2006
32
Prevalence of Feeding Aids in Infants on PD
Younger than 4 Years
Argentina 100 USA 84 Western
Europe 49 Eastern Europe, Turkey,
Mexico, Asia 5.7 (2/35)
IPPR 2006
33
GH Utilization in Children with CRI and Height
below 3rd Percentile, Tanner Stage I-III
From NAPRTCS Annual Report 2006
34
Estimated Annual Treatment Costs

• NG tube CKD formula 1,500

rGH treatment (0.33 mg/kg/wk) 10 kg 30
kg 60 kg Patented rGH 6,000 18,000 36,000
rGH biosimilar 4,500 13.000 26.000
35
Key Open Issues in CKD Growth Management
Lack of good population based outcome data-gt
Need for international registries Physicians
awareness? Growth retardation most effectively
prevented prior to ESRD! Penetration of
therapeutic standards (e.g. nutritional
management) Costs of rGH prohibitive to many
health systems
36
Effect of Forced Feeding in Children on
PDToronto Experience
Ramage et al. PDI 1999 19 231-6
37
Inflammation and Cachectic Chronic Disease

• IL-1, IL-6, IL-8, TNF-?, leptin
• IL-1, IL-6, TNF-?
• IL-1, IL-6, IL-8, TNF-?,
• IL-6, TNF-?
• IL-1, IL-6, IL-8, TNF-?

• CKD
• Cancer
• HIV Infection
• Heart Failure
• Cystic Fibrosis

38
Bologa et al. Am J Kidney Dis 1998 32 10714
Inflammation in ESRD Interleukin 6
39
High Peritoneal Transporter Status Predicts Poor
Growth on PD
1.6
r -0.37 p lt 0.02
1.2
0.8
0.4
Height SDS change per year
0.0
-0.4
-0.8
-1.2
0.1
0.2
0.3
0.4
0.5
0.6
0.7
Slope of D/P creatinine
Schaefer et al. JASN 1999
40
Growth Failure in Chronic Renal Insufficiency
Schaefer et al. Pediatr Nephrol 1996
41
Mid European Pediatric PD Study GroupHeight SDS
at Start of Dialysis
42

43
Impact of Renal Function on Prepubertal
Growth320 children with congenital CKD
Moderate CRF GFR gt 25 ml/min/1.73 m2
Severe CRF GFR lt 25 ml/min/1.73 m2
150
150
140
140
90
90
75
130
130
50
75
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
4
10
0
6
8
2
4
10
0
6
8
2
Age (years)
Age (years)
Schaefer et al. Pediatr Nephrol 19961028893