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INBORN ERRORS OF METABOLISM

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Title: 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.

3
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)

4
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Picca, 2002, unpublished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
12
AMMONIUM CLEARANCE AND FILTRATION FRACTION USING
DIFFERENT DIALYSIS MODALITIES.
Picca et al., 2001
13
Dialysis in hyperammonemia the beyond ammonium
removal effects
BAD
NH4 removal
GOOD
14
THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-5
Starts (continues) Pharmacological Treatment
NO RESPONSE
RESPONSE
RE-FEEDING
DIALYSIS
15
PROGNOSTIC INDICATORS SURVIVAL
McBryde, 2006 pNH4 at admissionlt180 ?mol/L Time to RRTlt24 hrs Medical treatmentlt24 hrs BPgt 5ile at RRT initiation HD initial RRT (trend)
Bachman, 2003 pNH4 at admissionlt300 ?mol/L Peak pNH4 lt480 ?mol/L
Uchino, 1998 pNH4 at admissionlt180 ?mol/L
Schaefer, 1999 50 pNH4 decay time lt 7 hrs (catheter gt 5F)
Picca, 2001 pre-treatment coma duration lt 33 hrs (no influence of post-treatment duration) responsiveness to pharmacological therapy
Pela, 2008 pre-treatment coma duration lt 10 hrs
16
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
18
DESCRIPTIVE (1)
Continuous Variable n Mean SEM
Year of treatment (yrs after 1985) 47 14.0 0.6
GA 39 39.0 0.28
Birth BW (g) 43 3240 67.6
Apgar (1 min) 31 8.45 0.18
Apgar (5 min) 31 9.6 0.11
Creatinine (mg/dl) 36 1.13 0.09
Age at admission (hrs) 46 120.8 18.5
BW at admission (g) 46 2985 69.6
BE at admission 29 -9.10 1.7
pNH4 pre-medical treatment (?mol/L) 46 685 103
pNH4 pre-dialysis (?mol/L) 47 839 84
pNH4 peak (?mol/L) 39 1124 141
pNH4 dialysis 50 decay time (hrs) 37 11.4 1.8
Dialysis duration (hrs) 45 50.9 7.2
Coma total duration (hrs) 39 75.5 7.8
Predialysis coma duration (hrs) 44 18.3 2.4
19
DESCRIPTIVE (2)
Non continuous variable n
CAVHD 6
CVVHD 16
HD 3
PD 25
Gender M 32/46
Intubation 31/ 42
Survival at discharge 35/46 (76)
Survival at 2 years (follow up N/A in 6 pts) 23/39 (59)
Normal development at 2 years 12/ 27 (44)
20
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
PD n25 No PD n21 p
pNH4 pre-medical treatment (?mol/L) 54682 850202 0.146
pNH4 pre-dialysis (?mol/L) 848112 829128 0.914
pNH4 increase (?mol/L) 30280 -8154 0.061
Dialysis duration (hrs) 75 11 22 3.9 lt0.001
Predialysis coma duration (hrs) 13.2 2.3 24.3 18.2 0.017
23
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
25
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.

26
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.

27
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
28
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.
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