1

NON-RENAL INDICATIONS: INTOXICATIONS & INBORN ERRORS OF METABOLISM

STEFANO PICCA, MDDialysis Unit- Dept of Nephrology and Urology

“Bambino Gesù” Pediatric Research HospitalROMA, 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 CVVHADULT-CHILD-NEONATE

BW(kg)

TBW(l)

Qb(ml/min)

UF/h(=K urea)

(l/h)

K urea per liter of TBW(l/h)

NEONATE 3 2.4 30 0.25 0.10

CHILD 25 15 80 1.2 0.08

ADULT 70 42 150 2.5 0.05

Vancomycin: • Relatively high molecular weight (1500 kDa)• High protein binding (55%) • Poorly cleared by hemodialysis and peritoneal dialysis

EXAMPLE 1: VANCOMYCIN

0 10 20 30 40 50 60 70 8002468

1012141618202224

150 mg150 mg300 mg300 mg300 mg

VAN

CO

pla

sma

e UF

(g/

ml)

TIME (hrs.)

CVVH:Mean Sieving Coefficient: 0.67

Picca, unpublished

Author n membrane modality T 1/2

Bunchman (1999) 2 cellulose triacetate

HD 31 to 1.9 hrs

Akil (2011) 1 polysulfone CVVH 231 to 31.5 hrsGoebel (1999) 1 polysulfone CVVHD 41.5 hrs during

CVVHDShah (2000) 1 polysulfone CVVH From 250 to 27

mcg/ml in 58 hrs

VANCOMYCIN OVERDOSE TREATMENT IN CHILDREN

EXAMPLE 2: MYOGLOBIN

Author N membrane modality

MG clearance

Picca (2009)

1 (ch) Polyethersulfone CVVH 15.8 ml/min

Sorrentino (2010)

6(ad)

Polysulfone Ultraflux®

HD 90.5 ml/min

Premru (2011)

6(5 ad, 1 ch)

Theralite® HDF 42-131 ml/min

0 50 100 150 200 250 300 3500

1000

4000

5000

6000

7000

8000

LDH

(IU/l)

TIME (hours)

0 50 100 150 200 250 300 3500

5001000150020002500

100000

350

153500

CK (I

U/l)

TIME (hours)

M, 46 kg, Crush Syndrome

CVVH:Membrane: PESQb: 150 ml/minQrf: 2.5 l/hKMG = 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.

0 5 10 15 20 25 30 35 40

0

50

100

150

200

250

300

BO

RO

N (

µg/m

L)

TIME (hrs)

0

50

100

150

200

250

BO

RO

N m

g

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,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

McBryde, 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)

Pela,2008

• pre-treatment coma duration < 10 hrs

Arbeiter,2009

• Citrullinemia

Westrope,2010

• Favorable PRISM score• Lesser cardioactive drug requirement

SINPITALIAN 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) 23 22 2

Metabolic defect Carbamoyl phosphate synthetase def. n (%) 1 (4.3) 6 (27.3) 1 <0.05Argininosuccinic aciduria n (%) 7 (30.4) 2 (9.1) 0 n.s.Citrullinemia n (%) 4 (17.4) 6 (27.3) 1 n.s.Propionic aciduria n (%) 6 (26.1) 5 (22.7) 0 n.s.Methylmalonic aciduria n (%) 5 (21.7) 3 (13.6) 0 n.s.

General characteristics Gender M:F 16:7 13:9 2:0 n.s.Gestational age weeks 39.0 ± 1.4 39.2 ± 1.8 37 n.s.Agar score 1 min score 8 [6-9] 9 [7-10] 8.5 n.s.Agar score 5 min score 10 [8-10] 10 [8-10] 9.5 n.s.Age at admission days 3.3 [2.0-11.0] 3.8 [2.0-20.0] 2.6 n.s.Age at start medical treatment days 3.4 [2.0-10.0] 3.7 [2.0-20.0] 3.0 n.s.Age at start dialysis days 4.4 [3.0-12.0] 4.5 [2.0-21.0] 3.4 n.s.Birth weight gr 3244 ± 535 3306 ± 434 3300 n.s.Weight at admission gr 2948 ± 519 3024 ± 434 3025 n.s.Weight loss until admission gr/day -84 ± 41 -75 ± 70 -112 n.s.Serum creatinine mg/dl 1.22 ± 0.62 1.10 ± 0.46 1.13 n.s.S. creatinine > 0.8 mg/dl at admission n (%) 11 (68.8) 14 (70) 2 n.s.Base excess at admission mEq/l -12.6 ± 11.0 -7.5 ± 6.7 -3.6 n.s.

PATIENTS CHARACTERISTICS (1)

Units

A.PD

B.ECD

C.PD + ECD

p value(A vs. B)

Number of patients (47) 23 22 2

Dialysis modality

PD n (%) 23 (100) - 2 -

CAVHD n (%) - 5 (22.7) 1 -

CVVHD n (%) - 14 (63.6) 2 -

HD n (%) - 3 (13.6) 0 -

Duration of dialysis hours 55 [24-216] 21 [2-60] 26 <0.001

Ammonium levels

At admission mol/l 725 [490-6479] 683 [289-3203] 1104 n.s.

Before dialysis mol/l 980 [402-3212] 1185 [304-4531] 2315 n.s.

Peak mol/l 1405 [632-7024] 1338 [590-6479] 2317 n.s.

Outcome at 4 weeks

Survived without neurological sequelae n (%) 11 (47.8) 9 (40.9) 1 n.s.

Survived with neurological sequelae n (%) 8 (34.8) 4 (18.2) 1 n.s.

Death n (%) 4 (17.4) 9 (40.9) 0 n.s.

PATIENTS CHARACTERISTICS (2)

Risk of death at 4 weeks 95% CI

b S.E. O.R. Lower Upper p

Carbamoyl phosphate synthetase def. 2.24 0.93 9.37 1.52 57.6 0.016

Argininosuccinic aciduria - - 0.00 - - 0.999

Citrullinemia -0.61 0.87 0.55 0.01 3.00 0.486

Propionic aciduria -0.77 0.86 0.46 0.09 2.52 0.375

Methylmalonic aciduria 1.13 0.80 3.11 0.64 15.1 0.158

Composite end-point at 4 weeks(death + neurological sequelae)Carbamoyl phosphate synthetase def. 1.69 1.13 5.40 0.59 49.3 0.135

Argininosuccinic aciduria -0.68 0.75 0.51 0.12 2.23 0.370

Citrullinemia 0.12 0.73 1.12 0.27 4.71 0.872

Propionic aciduria -0.66 0.70 0.52 0.13 2.04 0.345

Methylmalonic aciduria 0.24 0.80 1.27 0.26 6.12 0.766

RISK OF ADVERSE OUTCOME RELATED TO THE UNDERLYING DEFECT

Risk of death at 4 weeks 95% CI

b S.E. O.R. Lower Upper pGender (male) 0.30 0.70 1.350 0.21 1.81 0.670

Gestational age (wks) 0.27 0.24 1.308 0.82 2.09 0.262Birth Weight 0.00 0.00 1.000 0.19 1.92 0.978

Apgar score at 5 min -0.45 0.56 0.641 0.70 5.36 0.431Center 0.902

Year of birth from 1990 0.02 0.08 1.02 0.86 1.20 0.831

Composite end-point at 4 weeks(death + neurological sequelae)Gender (male) 0.89 0.64 2.443 0.19 1.81 0.159

Gestational age (wks) 0.00 0.19 1.004 0.69 1.45 0.979Birth weight (gr) 0.00 0.00 1.000 0.21 1.92 0.924

Apgar score at 5 min -0.53 0.57 0.587 0.34 5.36 0.352Center 0.985

Year of birth from 1990 -0.14 0.08 .867 .734 1.023 0.091

RISK OF ADVERSE OUTCOME RELATED TO OTHER NON-MODIFIABLE VARIABLES

95% CI

b S.E. Adj. O.R. Lower Upper p

Peritoneal dialysis 0.077 0.752 1.080 0.247 4.715 0.919

Extracorporeal dialysis -0.077 0.752 0.926 0.212 4.045 0.919

Weight loss1 (% of birth weight) 0.147 0.100 1.158 0.953 1.408 0.141

Age at admission (days) 0.184 0.186 1.203 0.835 1.732 0.322

Age start medical treatment (days) 0.341 0.284 1.406 0.807 2.452 0.229

Age start dialysis (days) 0.285 0.228 1.329 0.851 2.078 0.211

Serum creatinine on admission (mg/dl) 0.764 0.853 2.146 0.404 11.413 0.370

Base excess on admission (mEq/l) 0.029 0.078 1.029 0.884 1.199 0.709

Ammonium pre-med. (x100 mol/l) 0.189 0.100 1.208 0.993 1.470 0.059

Ammonium pre-dial. (x100 mol/l) 0.126 0.056 1.134 1.015 1.266 0.026

Total coma duration (days) 0.785 0.685 2.192 0.572 8.396 0.252

Duration of coma before dialysis (hours) 0.166 0.201 1.181 0.797 1.750 0.408

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, 1998

• 216 pts with UCD (1978-1995)• 92 with neonatal onset• 1-yr survival: 43% (90% with severe neuro-deficit)

Kido, 2012

• 254 pts with UCD (1999-2009)• 77 with neonatal onset• 1-yr survival: 83% (neuro-deficit NA)

THE EVOLUTION OF UCD LONG TERM SURVIVAL

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%

Outcome Neonatal Onset pts (n=29)

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

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.