INBORN ERRORS OF METABOLISM

Stefano Picca, MDDept. of Nephrology and Urology,

Dialysis Unit

“Bambino Gesù” Pediatric Research Hospital

ROMA, Italy

5th International Conference on Pediatric Continuous Renal Replacement Therapy Orlando, FLA. 2008, June 19 – 21

INCIDENCE•Overall: 1:9160•Organic Acidurias: 1:21422•Urea Cycle Defects: 1:41506•Fatty Acids Oxidation Defects: 1:91599

AGE OF ONSETNeonate: 40%Infant: 30%Child: 20%Adult: 5-10% (?) Dionisi-Vici et al, J Pediatrics, 2002.

“SMALL MOLECULES” DISEASES INDUCING CONGENITAL HYPERAMMONEMIA

• 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)

KEY POINTS FACING TO A HYPERAMMONEMIC NEWBORN

THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-1

PATIENT DIAGNOSIS TREATMENT

home Mother: “sleeps too long”

(May) Start Pharmacological Treatment

peripheral hospital

Hyperammonemia

3rd level hospital

Metabolic defect Starts (continues) Pharmacological Treatment

DIALYSIS

NO RESPONSERESPONSE

RE-FEEDING

Metabolism expert

Biochemistry Lab

Neonatologist

Nephrologist

OUTCOME ANALYSIS

• Pharmacological “cocktail”

NO RESPONSERESPONSE

Starts (continues) Pharmacological Treatment

DIALYSISRE-FEEDING

OUTCOME ANALYSIS

THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-2

Pharmacological treatmentbefore having a diagnosis

AIMSprecursors 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

• Pharmacological “cocktail”

NO RESPONSERESPONSE

Starts (continues) Pharmacological Treatment

DIALYSISRE-FEEDING

OUTCOME ANALYSIS

THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-3

• Waiting for…

0 4 8 12 16 20 24

0

250

500

750

1000

200040006000

pN

H4 (

m

ol/l

)

HOURS

non-responders(dialysis)

responders(med. treatment

alone)

0-4 HOURS MEDICAL TREATMENT IN NEONATAL

HYPERAMMONEMIA

Picca, 2002, unpublished

• Pharmacological “cocktail”

NO RESPONSERESPONSE

Starts (continues) Pharmacological Treatment

DIALYSISRE-FEEDING

OUTCOME ANALYSIS

THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-4

• Waiting for…

• Dialysis

VCG KC

KD

Ke

PLASMA NH4 (DIS)EQUILIBRIUM

Modified from Sargent JA, Gotch FA, 1996.

Glutamate dehydrogenase

NADH NAD+

-Ketoglutarate + NH4+ Glutamate

Glutamine synthetase

Glutamine

NH4+ + ATP

ADP + Pi

Figure 3. In non-hepatic tissues the linked reactions of glutamate dehydrogenaseand glutamine synthetase remove two ammonia molecules from the tissues as a way of ridding the tissues of nitrogen waste.

PLASMA NH4 AND GLUTAMINE DURING NEONATAL HYPERAMMONEMIA

from Scriver CR et al, 1995.

0 10 20 30 40 50 60

0

20

40

60

80

100 CAVHD patients

0 10 20 30 40 50 600

20

40

60

80

100 HD patients

TIME (hours)

0 10 20 30 40 50 60

0

20

40

60

80

100 CVVHD patients

NH

4p (

per

cen

t o

f in

itia

l val

ue)

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

NH4

removalGOOD

BAD

Protein loss in the dialysate:

10-12 g/1.73m2/day(Maxvold, 2000)

Dialysis-inducedcatabolism

(Schulman, 2004)

NH4 scavengers (NaBz+NaPh)

removal(Bunchman, 2007)

Correction of AKI

Citrulline removal(McBryde, 2004)

Glutamine removal(McBryde, 2004)

Starts (continues) Pharmacological Treatment

DIALYSIS

NO RESPONSERESPONSE

RE-FEEDING

• Pharmacological “cocktail”

OUTCOME ANALYSIS

• Waiting for…

• Dialysis

THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-5

• Have we been successful?

PROGNOSTIC INDICATORS: SURVIVALMcBryde,

2006•pNH4 at admission<180 mol/L

•Time to RRT<24 hrs•Medical treatment<24 hrs•BP> 5%ile at RRT initiation •HD initial RRT (trend)

Bachman, 2003

•pNH4 at admission<300 mol/L

•Peak pNH4 <480 mol/L

Uchino,

1998

•pNH4 at admission<180 mol/L

Schaefer,

1999

•50% pNH4 decay time < 7 hrs

•(catheter > 5F)

Picca,

2001

•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)

1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 20060

1

2

3

4

5

6p

atie

nts

years

n= 48

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

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%)

DEP. VARIABLE 1: SURVIVAL AT DISCHARGE

Year of treatment Birth BW (g)Age at admission (hrs)BW at admission (g)BE at admissionCreatinine (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) CAVHDCVVHDHDDPGenderIntubation

NS

0.0560.620.25

0.930.075

NS

NS

0.08

NS

0 8 16 24 32 40 48

0

20

40

60

80

100A

mm

onia

Dec

ay (

%)

Time (h)

PD

CVVH, HD, CAVH

PD

n=25

No PD

n=21

p

pNH4 pre-medical treatment (mol/L) 546±82 850±202 0.146

pNH4 pre-dialysis (mol/L) 848±112 829±128 0.914

pNH4 increase (mol/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

PD vs. EXTRACORPOREAL

DEP. VARIABLE 2: DEVELOPMENT AT 2 YEARS

Year of treatment Birth BW (g)Age at admission (hrs)BW at admission (g)BE at admissionCreatinine (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) CAVHDCVVHDHDDPGenderIntubation

0.017 (M-W); 0.056 (Regr. analysis)

0.150.073

NS

NS

NS

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

997±124 vs 606 ±69 p 0.034

NS

779±121 vs 550±183 p 0.041

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) CAVHDCVVHDHDDPGenderIntubation

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.

• 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.

CONCLUSIONS-OUTCOME

Short-term <2nd year of life

Mortality 27.5%

Cognitive development

Normal 71%

Mild MR 4.7%

Severe MR 23%

Outcome Neonatal Onset pts

Long-term >2nd year of life (2-18 yrs)

48%

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.