inborn-errors-of-metabolism63

5th International Conference on Pediatric Continuous Renal Replacement Therapy
Orlando, FLA. 2008, June 19 – 21
INBORN ERRORS OF
METABOLISM
Stefano Picca, MD
Dept. of Nephrology and Urology,
Dialysis Unit
“Bambino Gesù” Pediatric Research Hospital
ROMA, Italy

“SMALL MOLECULES” DISEASES INDUCING
CONGENITAL HYPERAMMONEMIA
INCIDENCE
•Overall: 1:9160
•Organic Acidurias: 1:21422
•Urea Cycle Defects: 1:41506
•Fatty Acids Oxidation Defects: 1:91599
AGE OF ONSET
Neonate: 40%
Infant: 30%
Child: 20%
Adult: 5-10% (?) Dionisi-Vici et al, J Pediatrics, 2002.

KEY POINTS FACING TO A HYPERAMMONEMIC
NEWBORN
• hyperammonemia is extremely toxic (per se or through
intracellular excess glutamine formation) to the brain causing
astrocyte swelling, brain edema, coma, death or severe disability,
thus:
• emergency treatment has to be started even before having a
precise diagnosis since prognosis may depend on:
coma duration (total and/or before treatment)
(Msall, 1984; Picca, 2001; McBryde, 2006)
peak ammonium level
(Enns, 2007)
detoxification rapidity
(Schaefer, 1999)

THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-1
PATIENT DIAGNOSIS TREATMENT
home
Mother: “sleeps too long”
peripheral
hospital
Hyperammonemia
(May) Start Pharmacological
Treatment
3 rd
level
hospital
Metabolic defect
Starts (continues) Pharmacological
Treatment
Metabolism expert
Neonatologist
RESPONSE
NO RESPONSE
Biochemistry Lab
Nephrologist
RE-FEEDING
DIALYSIS
OUTCOME ANALYSIS

THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-2
• Pharmacological
“cocktail”
Starts (continues) Pharmacological
Treatment
RESPONSE
NO RESPONSE
RE-FEEDING
DIALYSIS
OUTCOME ANALYSIS

Pharmacological treatment
before having a diagnosis
AIMS
⇓precursors ⇓catabolism ⇑anabolism
• stop protein
• caloric intake ≥100 kcal/kg
• insulin …and
endogenous depuration
• arginine 250 mg/Kg/2 hrs + 250 - 500 mg/Kg/day
• carnitine 1g i.v. bolus 250 - 500 mg/Kg/day
• vitamins (B12 1 mg,biotin 5-15 mg)
• benzoate/phenylbutyrate 250 mg/Kg/2 hrs + 250
mg/Kg/day (UCD only?)
• peroral carbamylglutamate 100 – 300 mg/kg
Picca et al. Ped Nephrol 2001

THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-3
• Pharmacological
“cocktail”
Starts (continues) Pharmacological
Treatment
• Waiting for…
RESPONSE
NO RESPONSE
RE-FEEDING
DIALYSIS
OUTCOME ANALYSIS

0-4 HOURS MEDICAL TREATMENT IN NEONATAL
HYPERAMMONEMIA
pNH 4
( µ mol/l)
6000
4000
2000
1000
750
500
250
0
0 4 8 12 16 20 24
HOURS
non-responders
(dialysis)
responders
(med. treatment
alone)
Picca, 2002, unpublished

THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-4
• Pharmacological
“cocktail”
Starts (continues) Pharmacological
Treatment
• Waiting for…
• Dialysis
RESPONSE
NO RESPONSE
RE-FEEDING
DIALYSIS
OUTCOME ANALYSIS

PLASMA NH 4
(DIS)EQUILIBRIUM
G
VC
KC
Ke
PLASMA NH 4 AND GLUTAMINE DURING
NEONATAL HYPERAMMONEMIA
NADH NAD +
α-Ketoglutarate + NH 4
+
Glutamate dehydrogenase
Glutamate
NH 4+
+ ATP
Glutamine synthetase
Glutamine
ADP + P i
Figure 3. In non-hepatic tissues the linked reactions of glutamate dehydrogenase
and glutamine synthetase remove two ammonia molecules from the tissues as a
way of ridding the tissues of nitrogen waste.
K D
from Scriver CR et al, 1995.
Modified from Sargent JA, Gotch FA, 1996.

100 CAVHD patients
NH4p (percent of initial value)
80
60
40
20
0
100
80
60
40
20
0
100
80
60
40
0 10 20 30 40 50 60
CVVHD patients
0 10 20 30 40 50 60
HD patients
20
0
0 10 20 30 40 50 60
TIME (hours)
Picca et al. Ped Nephrol 2001

AMMONIUM CLEARANCE AND FILTRATION FRACTION
USING DIFFERENT DIALYSIS MODALITIES.
Patient
(n)
Type of
Dialysis
Qb
(ml/min)
Qd
(ml/min)
Ammonium
Clearance
(ml/min/kg
BW)
Ammonium
Filtration
Fraction
(%)
3 CAVHD 10-20 8.3
(0.5 l/h)
0.87-0.97 12.5-14.3
3 CVVHD 20-40 33.3-83.3
(2-5 l/h)
2.65-6.80 53.0-58.0
2 HD 10-15 500 3.95-5.37 95.0-96.0
Picca et al., 2001

Dialysis in hyperammonemia:
the “beyond ammonium removal” effects
DIALYSIS
Protein loss
in the dialysate:
10-12 g/1.73m 2 /day
(Maxvold, 2000)
Dialysis-induced
catabolism
(Schulman, 2004)
BAD
Correction of AKI
Citrulline removal
(McBryde, 2004)
NH 4
scavengers
(NaBz+NaPh)
removal
(Bunchman, 2007)
GOOD
Glutamine removal
(McBryde, 2004)
NH 4
removal

THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-5
• Pharmacological
“cocktail”
Starts (continues) Pharmacological
Treatment
• Waiting for…
RESPONSE
NO RESPONSE
• Dialysis
• Have we been
successful?
RE-FEEDING
DIALYSIS
OUTCOME ANALYSIS

PROGNOSTIC INDICATORS: SURVIVAL
McBryde,
2006
Bachman,
2003
Uchino,
1998
Schaefer,
1999
Picca,
2001
•pNH 4
at admission<180 µmol/L
•Time to RRT<24 hrs
•Medical treatment<24 hrs
•BP> 5%ile at RRT initiation
•HD initial RRT (trend)
•pNH 4
at admission<300 µmol/L
•Peak pNH 4
<480 µmol/L
•pNH 4
at admission<180 µmol/L
•50% pNH 4
decay time < 7 hrs
•(catheter > 5F)
•pre-treatment coma duration < 33 hrs (no influence of post-treatment duration)
•responsiveness to pharmacological therapy
Pela,
2008
• pre-treatment coma duration < 10 hrs

SINP
ITALIAN SOCIETY OF PEDIATRIC NEPHROLOGY
Italian Study Group
“Dialysis Treatment of Neonatal
hyperammonemia”
(Coord.: S. Picca, MD)

6
5
n= 48
4
patients
3
2
1
0
1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006
years

DESCRIPTIVE (1)
Continuous Variable
n
Year of treatment (yrs after 1985)
47
GA
39
Birth BW (g)
43
Apgar (1 min)
31
Apgar (5 min)
31
Creatinine (mg/dl)
36
Age at admission (hrs)
46
BW at admission (g)
46
BE at admission
29
pNH 4
pre-medical treatment (µmol/L) 46
pNH 4
pre-dialysis (µmol/L)
47
pNH 4
peak (µmol/L)
39
pNH 4
dialysis 50% decay time (hrs) 37
Dialysis duration (hrs)
45
Coma total duration (hrs)
39
Predialysis coma duration (hrs)
44
Mean
14.0
39.0
3240
8.45
9.6
1.13
120.8
2985
-9.10
685
839
1124
11.4
50.9
75.5
18.3
SEM
0.6
0.28
67.6
0.18
0.11
0.09
18.5
69.6
1.7
103
84
141
1.8
7.2
7.8
2.4

DESCRIPTIVE (2)
Non continuous variable
CAVHD
CVVHD
HD
PD
Gender
Intubation
Survival at discharge
Survival at 2 years *
(*follow up N/A in 6 pts)
Normal development at 2 years
n
6
16
3
25
M
32/46
31/ 42
35/46
(76%)
23/39
(59%)
12/ 27
(44%)

DEP. VARIABLE 1: SURVIVAL AT DISCHARGE
Year of treatment
Birth BW (g)
Age at admission (hrs)
BW at admission (g)
BE at admission
Creatinine (mg/dl)
pNH 4
pre-medical treatment (µmol/L)
pNH 4
pre-dialysis (µmol/L)
pNH 4
peak (µmol/L)
pNH 4
dialysis 50% decay time (hrs)
Dialysis duration (hrs)
Coma total duration (hrs)
Predialysis coma duration (hrs)
CAVHD
CVVHD
HD
DP
Gender
Intubation
NS
0.056
0.62
0.25
0.93
0.075
0.08
NS
NS
NS

100
80
Ammonia Decay (%)
60
40
20
PD
0
0 8 16 24 32 40 48
Time (h)
CVVH, HD, CAVH

PD vs. EXTRACORPOREAL
PD
No PD
p
n=25
n=21
pNH 4
pre-medical treatment (µmol/L)
546±82
850±202
0.146
pNH 4
pre-dialysis (µmol/L)
848±112
829±128
0.914
pNH 4
increase (µmol/L)
302±80
-8±154
0.061
Dialysis duration (hrs)
75 ± 11
22 ± 3.9
<0.001
Predialysis coma duration (hrs)
13.2± 2.3
24.3± 18.2
0.017

DEP. VARIABLE 2: DEVELOPMENT AT 2 YEARS
Year of treatment
Birth BW (g)
Age at admission (hrs)
BW at admission (g)
BE at admission
Creatinine (mg/dl)
pNH 4
pre-medical treatment (µmol/L)
pNH 4
pre-dialysis (µmol/L)
pNH 4
peak (µmol/L)
pNH 4
dialysis 50% decay time (hrs)
Dialysis duration (hrs)
Coma total duration (hrs)
Predialysis coma duration (hrs)
CAVHD
CVVHD
HD
DP
Gender
Intubation
0.017 (M-W); 0.056 (Regr. analysis)
0.15
0.073
NS
NS
NS

DEP. VARIABLE 3: UCD vs OA
Year of treatment
Birth BW (g)
Age at admission (hrs)
BW at admission (g)
BW loss from birth BW at admission (%)
BE at admission
pNH 4
pre-medical treatment (µmol/L)
pNH 4
pre-dialysis (µmol/L)
pNH 4
peak (µmol/L)
pNH 4
dialysis 50% decay time (hrs)
Creatinine (mg/dl)
Dialysis duration (hrs)
Coma total duration (hrs)
Predialysis coma duration (hrs)
CAVHD
CVVHD
HD
DP
Gender
Intubation
NS
3126±91 vs 2765±88 p 0.018
-6.3±0.8 vs -12.2±1.0 p 0.018
-5.7±2 vs -14.6±1.9 p 0.023
779±121 vs 550±183 p 0.041
997±124 vs 606 ±69 p 0.034
NS

CONCLUSIONS-DIALYSIS
• PD provides NH 4
clearance lower than HD and CRRT
• However, in this series and in that of Schaefer (1999)
detoxification rapidity was not significantly different from that of
extracorporeal dialysis and patients treated with PD showed a
trend toward a better survival
• This may have been the consequence of a shorter coma duration
and of a lower intoxication level before dialysis initiation
• Extracorporeal should be the first-line dialysis modality in
neonatal hyperammonemia
• When HD and/or CRRT facilities are not available, PD should be
considered. However, results are likely similar to those obtained
with extracorporeal dialysis only in less intoxicated patients.

CONCLUSIONS-OUTCOME
• In our and in other series, dialysis modality did not affect the
outcome in the presence of a long mean pre-treatment duration
• In fact, plasma ammonium level before every treatment and
predialysis coma duration resulted to be the main determinants
of survival both at short and long term
• It is thus likely that the influence of detoxification rapidity on the
outcome becomes evident when pre-treatment duration is
shorter than that reported in our series, as reported by others
(Schaefer 1999, Pela 2008)
• However, as high intoxication level and long pre-treatment
duration are the consequence of a delayed intervention, the
need for an early diagnosis and treatment remains the crucial
issue of neonatal hyperammonemia.

Outcome Neonatal Onset pts
Short-term
<2 nd year of life
Mortality 27.5%
Long-term
>2 nd year of life (2-18 yrs)
48%
Cognitive development
Normal 71%
Mild MR 4.7%
Severe MR 23%
28.5%
9.5%
57%
No significant difference between UCDs and OAs
Deodato F et al, 2004

ACKNOWLEDGEMENTS
Bambino Gesù Children Hospital:
• Metabolic Unit: Carlo Dionisi-Vici, MD; Andrea Bartuli, MD;
Gaetano Sabetta, MD
• Clinical Biochemistry Lab: Cristiano Rizzo BSc, PhD; Anna
Pastore BSc, PhD
• NICU: all doctors and nurses
• Dialysis Unit: Francesco Emma, MD, all doctors and nurses
(thanks!)
In Italy:
• SINP (Italian Society of Pediatric Nephrology)
• All doctors from Pediatric Nephrology and NICUs of
Genova, Milan, Turin, Padua, Florence, Naples, Bari.