INBORN ERROR S 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: 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.

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

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

8. non-responders (dialysis) mol/l) responders (med. treatment alone) m ( 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. Pharmacological • “cocktail” Starts (continues) Pharmacological Treatment RESPONSE NO RESPONSE • Waiting for… • Dialysis RE-FEEDING DIALYSIS OUTCOME ANALYSIS THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-4

10. Ke KD 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 Picca et al. Ped Nephrol 2001 TIME (hours)

12. AMMONIUM CLEARANCE AND FILTRATION FRACTION USING DIFFERENT DIALYSIS MODALITIES. Picca et al., 2001

13. Protein loss in the dialysate: 10-12 g/1.73m2/day (Maxvold, 2000) NH4 scavengers (NaBz+NaPh) removal (Bunchman, 2007) Dialysis-induced catabolism (Schulman, 2004) Correction of AKI DIALYSIS Glutamine removal (McBryde, 2004) Citrulline removal (McBryde, 2004) Dialysis in hyperammonemia: the “beyond ammonium removal” effects BAD NH4 removal GOOD

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

15. PROGNOSTIC INDICATORS: SURVIVAL

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)

19. DESCRIPTIVE (2)

20. DEP. VARIABLE 1: SURVIVAL AT DISCHARGE NS 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 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

23. DEP. VARIABLE 2: DEVELOPMENT AT 2 YEARS NS 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 0.017 (M-W); 0.056 (Regr. analysis) NS 0.15 0.073 NS

24. DEP. VARIABLE 3: UCD vs OA 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 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 Intubation 779±121 vs 550±183 p 0.041 997±124 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. No significant difference between UCDs and OAs Outcome Neonatal Onset pts Long-term >2nd year of life (2-18 yrs) Short-term <2nd 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.