1. "Panel discussion: Inborn Errors of Metabolism – perspectives from a Nephrologist" Stefano Picca, MD Department of Nephrology and Urology, Dialysis Unit “Bambino Gesù” Pediatric Research Hospital, IRCCS ROMA, Italy

2. In summary, it is recommended …initially with pump-driven dialysis (ECMO/HD) followed by continuous hemofiltration with the same pump system….

3. Statement #19. Grade of recommendation: C …The method of choice for ammonia detoxification is hemodiafiltration. Peritoneal dialysis is a far less effective method…

4. …PD remains an effective method for exogenous detoxification in newborns with hyperammonemia caused by metabolic diseases…

5. AMMONIUM CLEARANCE AND FILTRATION FRACTION USING DIFFERENT DIALYSIS MODALITIES Picca et al., 2001 Patient (n) Type of Dialysis Ammonium Clearance (ml/min) 4PD 0.48-2.7 (1.4±1.1, about 0.48 ml/min/kg) Arbeiter et al., 2009

6. PROGNOSTIC INDICATORS IN DIALYZED AND NON-DIALYZED NEONATES: SURVIVAL Enns 2008 Early metabolic defect diagnosis Bachmann 2003 Initial pNH 4 <300  mol/L Peak pNH 4 <480  mol/L McBryde, 2006 pNH 4 at admission<180  mol/L Time to RRT<24 hrs Medical treatment<24 hrs BP> 5%ile at RRT initiation HD initial RRT (trend) Schaefer, 1999 50% pNH 4 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 pNH 4 levelDialysis efficiency Timing of intervention

7. Msall M, N Engl J Med. 1984 26 neonates medically treated At 1 year: 92% survival 79% neurologic impairment Significant neg correlation between coma duration and IQ and CT abnormalities All neonates with coma duration < 48 hrs: normal neurodevelopment PROGNOSIS AND TIMING OF INTERVENTION

8. 10 neonates No difference in 50% ammonium reduction time between patients with good and bad outcome No difference among the different dialysis modalities (CAVHD, CVVHD, HD) Outcome related to predialysis not to post dialysis start coma duration

9. 04812162024 0 250 500 750 1000 2000 4000 6000 pNH 4 ( m mol/l) HOURS non-responders (dialysis) responders (med. treatment alone) 0-4 HOURS MEDICAL TREATMENT IN NEONATAL HYPERAMMONEMIA Picca, 2002, unpublished

10. 051015202530354045505560 0 500 1000 1500 2000 2500 3000 3500 4000 4500 6000 7000 hours peak pNH 4 (  mol/l) n=14 good outcome bad outcome DIALYZED PATIENTS: NH 4 LEVELS AND COMA DURATION BEFORE DIALYSIS

11. 0510152025303540455055606570758085 0 500 1000 1500 2000 2500 3000 3500 4000 4500 6000 7000 peak pNH 4 (  mol/l) hours ALL PATIENTS: NH 4 LEVELS AND COMA DURATION BEFORE ANY TREATMENT good outcome bad outcome n=21

16. Dialysis modality seems not to influence the outcome Main outcome determinants: pNH4 levels, coma duration before treatment Early referral and treatment initiation (medical and/or dialysis) are the key point of hyperammonemia therapy DIALYSIS AND OUTCOME IN NEONATAL HYPERAMMONEMIA

17. Dialysis Unit, “Bambino Gesù” Pediatric Hospital Roma, Italy. Doctor: S. Picca Headnurse: V. Bandinu Nurses: N. Avari D. Ciullo E. Iacoella P. Iovine P. Lozzi L. Stefani Nurse Coordinator: M. D’Agostino

19. Uchino, 1998 216 pts with UCD (1978-1995) 92 with neonatal onset 5-yr survival: 22% (90% with severe neuro-deficit) Kido, 2012 254 pts with UCD (1999-2009) 77 with neonatal onset 5-yr survival: 83% (neuro-deficit NA) THE EVOLUTION OF UCD LONG TERM SURVIVAL

21. Short-term <2 nd year of life (median 1.3 yrs,range 0-2) Mortality 27.5% Cognitive development Normal 71% Mild MR 4.7% Severe MR 23% Outcome Neonatal Onset pts (n=29) Long-term >2 nd year of life (median 12.5 yrs,range 3-21) 48% 28.5% 9.5% 57% No significative difference between UCDs and OAs

22. 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

23. 0102030405060 0 20 40 60 80 100 CAVHD patients 0102030405060 0 20 40 60 80 100 HD patients TIME (hours) 0102030405060 0 20 40 60 80 100 CVVHD patients NH4p (percent of initial value) Picca et al. Ped Nephrol 2001