INBORN ERRORS OF METABOLISM

1
INBORN ERRORS OF METABOLISM
5th International Conference on Pediatric
Continuous Renal Replacement Therapy Orlando,
FLA. 2008, June 19 21

• Stefano Picca, MD
• Dept. of Nephrology and Urology,
• Dialysis Unit
• Bambino Gesù Pediatric Research Hospital
• ROMA, Italy

2
SMALL MOLECULES DISEASES INDUCING CONGENITAL
HYPERAMMONEMIA

• INCIDENCE
• Overall
  19160
• Organic Acidurias 121422
• Urea Cycle Defects 141506
• Fatty Acids Oxidation Defects 191599
• AGE OF ONSET
• Neonate 40
• Infant 30
• Child 20
• Adult 5-10 (?)
  Dionisi-Vici et al, J Pediatrics, 2002.

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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)

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THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-1
5
THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-2
6
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
7
THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-3
8
0-4 HOURS MEDICAL TREATMENT IN NEONATAL
HYPERAMMONEMIA
6000
4000
2000
1000
750
4
500
pNH
250
0
0
4
8
12
16
20
24
HOURS
Picca, 2002, unpublished
9
THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-4
10
PLASMA NH4 (DIS)EQUILIBRIUM
G
KC
VC
Modified from Sargent JA, Gotch FA, 1996.
11
CAVHD patients
100
80
60
40
20
0
0
10
20
30
40
50
60
100
CVVHD patients
80
NH4p (percent of initial value)
60
40
20
0
0
10
20
30
40
50
60
HD patients
100
80
60
40
20
0
0
10
20
30
40
50
60
TIME (hours)
Picca et al. Ped Nephrol 2001
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AMMONIUM CLEARANCE AND FILTRATION FRACTION USING
DIFFERENT DIALYSIS MODALITIES.
Picca et al., 2001
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Dialysis in hyperammonemia the beyond ammonium
removal effects
BAD
NH4 removal
GOOD
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THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-5
Starts (continues) Pharmacological Treatment
NO RESPONSE
RESPONSE
RE-FEEDING
DIALYSIS
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PROGNOSTIC INDICATORS SURVIVAL
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SINP ITALIAN SOCIETY OF PEDIATRIC
NEPHROLOGY   Italian Study Group Dialysis
Treatment of Neonatal hyperammonemia (Coord. S.
Picca, MD)
17
6
n 48
5
4
3
patients
2
1
0
1986
1988
1990
1992
1994
1996
1998
2000
2002
2004
2006
years
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DESCRIPTIVE (1)
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DESCRIPTIVE (2)
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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)
• pNH4 pre-medical treatment (?mol/L)
• pNH4 pre-dialysis (?mol/L)
• pNH4 peak (?mol/L)
• pNH4 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
NS
0.93 0.075
NS
0.08
NS
21
100
80
60
Ammonia Decay ()
40
PD
20
CVVH, HD, CAVH
0
0
8
16
24
32
40
48
Time (h)
22
PD vs. EXTRACORPOREAL
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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)
• pNH4 pre-medical treatment (?mol/L)
• pNH4 pre-dialysis (?mol/L)
• pNH4 peak (?mol/L)
• pNH4 dialysis 50 decay time (hrs)
• Dialysis duration (hrs)
• Coma total duration (hrs)
• Predialysis coma duration (hrs)
• CAVHD
• CVVHD
• HD
• DP
• Gender
• Intubation

NS
0.017 (M-W) 0.056 (Regr. analysis)
NS
0.15 0.073
NS
24
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
• pNH4 pre-medical treatment (?mol/L)
• pNH4 pre-dialysis (?mol/L)
• pNH4 peak (?mol/L)
• pNH4 dialysis 50 decay time (hrs)
• Creatinine (mg/dl)
• Dialysis duration (hrs)
• Coma total duration (hrs)
• Predialysis coma duration (hrs)
• CAVHD
• CVVHD
• HD
• DP
• Gender

NS
312691 vs 276588 p 0.018 -6.30.8 vs
-12.21.0 p 0.018 -5.72 vs -14.61.9
p 0.023
779121 vs 550183 p 0.041
997124 vs 606 69 p 0.034
NS
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CONCLUSIONS-DIALYSIS

• PD provides NH4 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.

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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.

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Outcome Neonatal Onset pts
Long-term gt2nd year of life (2-18 yrs)
Short-term lt2nd year of life
48 28.5 9.5 57

Mortality 27.5 Cognitive
development Normal 71
Mild MR 4.7 Severe MR
23
Deodato F et al, 2004
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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.