NON-RENAL INDICATIONS: INTOXICATIONS & INBORN ERRORS OF METABOLISM

1. NON-RENAL INDICATIONS: INTOXICATIONS & INBORN ERRORS OF METABOLISM STEFANO PICCA, MD Dialysis Unit- Dept of Nephrology and Urology “Bambino Gesù” Pediatric Research Hospital ROMA, Italy

2. OUTLINE • Variables in toxic agents elimination • Exogenous toxicity: • Experience with toxic agents in PICU • Endogenous toxicity: • Inborn Errors of Metabolism: which is the role of RRT in determining the outcome?

3. FACTORS POTENTIALLY AFFECTING DRUG CLEARANCE DURING RENAL REPLACEMENT THERAPY • DEVICE PROPERTIES • COMPOSITION • SURFACE AREA • PORE SIZE • ADSORPTION DRUG PROPERTIES • MOLECULAR WEIGHT • PLASMA PROTEIN BINDING • VOLUME OF DISTRIBUTION • PROPORTION OF RENAL CLEARANCE • What is unique to Pediatric Intoxications? • Vehicle in which the medication was delivered • Metabolism of drug • Volume of distribution • Variable size of the child Adapted from Pea F and Bunchman TE, 2010

4. “MAXIMAL”(?) EFFICIENCY IN CVVHADULT-CHILD-NEONATE

5. EXAMPLE 1: VANCOMYCIN • Vancomycin: • Relatively high molecular weight (1500 kDa) • High protein binding (55%) • Poorly cleared by hemodialysis and peritoneal dialysis CVVH: Mean Sieving Coefficient: 0.67 Picca, unpublished

6. VANCOMYCIN OVERDOSE TREATMENT IN CHILDREN

8. EXAMPLE 2: MYOGLOBIN

9. M, 46 kg, Crush Syndrome CVVH: Membrane: PES Qb: 150 ml/min Qrf: 2.5 l/h KMG = 15.8 ml/min

10. EXAMPLE 3: BORON • Boron (boric acid): component of topical disinfectants • Acute boron intoxication: erythematous rash (“boiled lobster”), AKI, vomiting, diarrhea, restlessness, headache, irritability, delirium, seizure, and coma • 65% boron acute intoxications in pediatric age • (2009 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 27th Annual Report, 2009) • Although severe toxicity is reported only with very high boron serum levels (>300 µg/ml), lethal dose in infants is considered to be 3-6 g • Dialysis is known to be effective in adults. No data in children with extracorporeal dialysis. • Case: 5.5 kg, three-month infant, accidental ingestion of 160 ml of milk and water saturated solution of boric acid (3,6 g). At admittance: no symptoms, normal hepatic and kidney function. Metabolic acidosis.

11. CVVH IN BORON INTOXICATION TREATMENT: MASS REMOVAL AND CONCENTRATION DECAY 250 200 150 BORON mg 100 50 0 300 250 200 150 BORON (µg/mL) 100 50 0 0 5 10 15 20 25 30 35 40 TIME (hrs) Picca, 2009, unpublished

12. KEY POINTS OF NEONATAL HYPERAMMONEMIA • Neonatal hyperammonemia is mainly due to urea cycle defects and organic acidurias • Hyperammonemia is extremely toxic(per se and through intracellular excess glutamine formation) to the brain causing astrocyte swelling, brain edema, coma, death or severe disability • When hyperammonemia does not respond to medical and dietetic treatment, dialysis has to be established in order to achieve rapid ammonium removal before neurological impairment or death occur • Ammonium easily diffuses through membranes . Extracorporeal dialysis provides higher and faster ammonium removal than peritoneal dialysis.

13. PROGNOSTIC INDICATORS IN DIALYZED NEONATES ASSOCIATED WITH SURVIVAL

14. SINP ITALIAN SOCIETY OF PEDIATRIC NEPHROLOGY Italian Study Group “Dialysis Treatment of Neonatal hyperammonemia” (Coord.: S. Picca, MD)

15. PATIENTS CHARACTERISTICS (1)

16. PATIENTS CHARACTERISTICS (2)

17. RISK OF ADVERSE OUTCOME RELATED TO THE UNDERLYING DEFECT

18. RISK OF ADVERSE OUTCOME RELATED TO OTHER NON-MODIFIABLE VARIABLES

19. COMPOSITE RISK: DEATH OR NEUROLOGICAL SEQUELAE *Adjusted for metabolic defect and year of treatment

20. FOREST PLOT COMPOSITE END-POINT: DEATH OR NEUROLOGICAL SEQUELAE

21. p: NS

22. THE EVOLUTION OF UCD LONG TERM SURVIVAL • Uchino, 1998 • 216 pts with UCD (1978-1995) • 92 with neonatalonset • 1-yr survival: 43%(90% with severe neuro-deficit) • Kido, 2012 • 254 pts with UCD (1999-2009) • 77 with neonatalonset • 1-yr survival: 83% (neuro-deficit NA)

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

26. CONCLUSIONS • RRT represent a key step in the treatment of endogenous and exogenous intoxications unresponsive to medical treatment • Compared with adults, the depuration of toxic compounds in children is facilitated by the small patient volume • In general, extracorporeal dialysis provides higher and faster detoxification if compared with peritoneal dialysis • In neonatal hyperammonemia, extracorporeal dialysis provides fastest ammonium removal • However, surprisingly, in our cohort extracorporeal and peritoneal dialysis induced a similar ammonium decay (higher glucose uptake with PD? Lesser degree of severity in PD patients?) • Early initiation of medical treatment may be more important in decreasing ammonium generation rate than using more efficient dialysis techniques (i.e.: extracorporeal dialysis) • Last but most important, dialysis modality did not affect the short term outcome In light of these findings and waiting for validation of these results in other cohorts of patients, peritoneal dialysis in the treatment of neonatal hyperammonemia must be considered as a valid alternative to extracorporeal dialysis .

27. 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. In USA • Tim Bunchman, Stuart Goldstein for this opportunity. • Thanks guys.