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

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? OUTLINE

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

“MAXIMAL”(?) EFFICIENCY IN CVVH ADULT-CHILD-NEONATE BW (kg) TBW (l) Qb (ml/min) UF/h (=K urea) (l/h) K urea per liter of TBW (l/h) NEONATE CHILD ADULT

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cleared by hemodialysis and peritoneal dialysis EXAMPLE 1: VANCOMYCIN CVVH: Mean Sieving Coefficient: 0.67 Picca, unpublished

AuthornmembranemodalityT 1/2 Bunchman (1999)2cellulose triacetateHD31 to 1.9 hrs Akil (2011)1polysulfoneCVVH231 to 31.5 hrs Goebel (1999)1polysulfoneCVVHD41.5 hrs during CVVHD Shah (2000)1polysulfoneCVVHFrom 250 to 27 mcg/ml in 58 hrs VANCOMYCIN OVERDOSE TREATMENT IN CHILDREN

EXAMPLE 2: MYOGLOBIN AuthorNmembranemodalityMG clearance Picca (2009) 1 (ch)PolyethersulfoneCVVH15.8 ml/min Sorrentino (2010) 6 (ad) Polysulfone Ultraflux® HD90.5 ml/min Premru (2011) 6 (5 ad, 1 ch) Theralite®HDF ml/min

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

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.

BORON (µg/mL) TIME (hrs) BORON mg CVVH IN BORON INTOXICATION TREATMENT: MASS REMOVAL AND CONCENTRATION DECAY Picca, 2009, unpublished

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. KEY POINTS OF NEONATAL HYPERAMMONEMIA

PROGNOSTIC INDICATORS IN DIALYZED NEONATES ASSOCIATED WITH SURVIVAL Schaefer, % 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 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) Pela, 2008 pre-treatment coma duration < 10 hrs Arbeiter, 2009 Citrullinemia Westrope, 2010 Favorable PRISM score Lesser cardioactive drug requirement

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

Units A. PD B. ECD C. PD + ECD p value (A vs. B) Number of patients (47) Metabolic defect Carbamoyl phosphate synthetase def.n (%)1 (4.3)6 (27.3)1<0.05 Argininosuccinic acidurian (%)7 (30.4)2 (9.1)0n.s. Citrullinemian (%)4 (17.4)6 (27.3)1n.s. Propionic acidurian (%)6 (26.1)5 (22.7)0n.s. Methylmalonic acidurian (%)5 (21.7)3 (13.6)0n.s. General characteristics GenderM:F16:713:92:0n.s. Gestational ageweeks39.0 ± ± 1.837n.s. Agar score 1 minscore8 [6-9]9 [7-10]8.5n.s. Agar score 5 minscore10 [8-10] 9.5n.s. Age at admissiondays3.3 [ ]3.8 [ ]2.6n.s. Age at start medical treatmentdays3.4 [ ]3.7 [ ]3.0n.s. Age at start dialysisdays4.4 [ ]4.5 [ ]3.4n.s. Birth weightgr3244 ± ± n.s. Weight at admissiongr2948 ± ± n.s. Weight loss until admissiongr/day-84 ± ± n.s. Serum creatininemg/dl1.22 ± ± n.s. S. creatinine > 0.8 mg/dl at admissionn (%)11 (68.8)14 (70)2n.s. Base excess at admissionmEq/l-12.6 ± ± n.s. PATIENTS CHARACTERISTICS (1)

Units A. PD B. ECD C. PD + ECD p value (A vs. B) Number of patients (47) Dialysis modality PDn (%)23 (100)-2- CAVHDn (%)-5 (22.7)1- CVVHDn (%)-14 (63.6)2- HDn (%)-3 (13.6)0- Duration of dialysishours55 [24-216] 21 [2-60]26<0.001 Ammonium levels At admission  mol/l 725 [ ]683 [ ]1104n.s. Before dialysis  mol/l 980 [ ]1185 [ ]2315n.s. Peak  mol/l 1405 [ ]1338 [ ]2317n.s. Outcome at 4 weeks Survived without neurological sequelaen (%)11 (47.8)9 (40.9)1n.s. Survived with neurological sequelaen (%)8 (34.8)4 (18.2)1n.s. Deathn (%)4 (17.4)9 (40.9)0n.s. PATIENTS CHARACTERISTICS (2)

Risk of death at 4 weeks 95% CI  S.E.O.R.LowerUpperp Carbamoyl phosphate synthetase def Argininosuccinic aciduria Citrullinemia Propionic aciduria Methylmalonic aciduria Composite end-point at 4 weeks(death + neurological sequelae) Carbamoyl phosphate synthetase def Argininosuccinic aciduria Citrullinemia Propionic aciduria Methylmalonic aciduria RISK OF ADVERSE OUTCOME RELATED TO THE UNDERLYING DEFECT

Risk of death at 4 weeks 95% CI  S.E.O.R.LowerUpperp Gender (male) Gestational age (wks) Birth Weight Apgar score at 5 min Center0.902 Year of birth from Composite end-point at 4 weeks(death + neurological sequelae) Gender (male) Gestational age (wks) Birth weight (gr) Apgar score at 5 min Center0.985 Year of birth from RISK OF ADVERSE OUTCOME RELATED TO OTHER NON-MODIFIABLE VARIABLES

95% CI  S.E.Adj. O.R.LowerUpperp Peritoneal dialysis Extracorporeal dialysis Weight loss 1 (% of birth weight) Age at admission (days) Age start medical treatment (days) Age start dialysis (days) Serum creatinine on admission (mg/dl) Base excess on admission (mEq/l) Ammonium pre-med. (x100  mol/l) Ammonium pre-dial. (x100  mol/l) Total coma duration (days) Duration of coma before dialysis (hours) COMPOSITE RISK: DEATH OR NEUROLOGICAL SEQUELAE *Adjusted for metabolic defect and year of treatment

FOREST PLOT COMPOSITE END-POINT: DEATH OR NEUROLOGICAL SEQUELAE

p: NS

Uchino, pts with UCD ( ) 92 with neonatal onset 1-yr survival: 43% (90% with severe neuro-deficit) Kido, pts with UCD ( ) 77 with neonatal onset 1-yr survival: 83% (neuro-deficit NA) THE EVOLUTION OF UCD LONG TERM SURVIVAL

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

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.

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.