METABOLIC DERANGEMENTS, METABOLIC DERANGEMENTS, HEPATIC FAILURE & PCRRTHEPATIC FAILURE & PCRRT

Patrick D. Brophy MD Patrick D. Brophy MD

University of MichiganUniversity of Michigan

Pediatric NephrologyPediatric Nephrology

ObjectivesObjectives

Metabolic Disorders and Amenability to CRRTMetabolic Disorders and Amenability to CRRT

HyperammonemiaHyperammonemia– PrescriptionPrescription– Fine points of careFine points of care– Combination therapyCombination therapy

Considerations of CRRT in Hepatic FailureConsiderations of CRRT in Hepatic Failure– Hepatic InsufficiencyHepatic Insufficiency– Role of CRRT-bridge to transplantRole of CRRT-bridge to transplant– Liver supportLiver support

Metabolic DisordersMetabolic Disorders

Multiple metabolic disorders have been Multiple metabolic disorders have been described that are amenable to various forms of described that are amenable to various forms of RRT.RRT.– Maple Syrup Urine Disease (BCAA—Build up lead to Maple Syrup Urine Disease (BCAA—Build up lead to

cerebral edema)cerebral edema)Puliyanda et.al. 2002:17:239-242Puliyanda et.al. 2002:17:239-242

Jouvet et.al. 2001:27:1798-1806Jouvet et.al. 2001:27:1798-1806

– Urea Cycle Defects- hyperammonemiaUrea Cycle Defects- hyperammonemia– Organic Acidemias (accumulation of Acyl Co-A Organic Acidemias (accumulation of Acyl Co-A

esters-secondary inhibition of urea cycle enzymes)esters-secondary inhibition of urea cycle enzymes)

Hyperammonemia- clinicalHyperammonemia- clinical

Most Cases develop in neonatal periodMost Cases develop in neonatal period– Feeding refusal/intoleranceFeeding refusal/intolerance– VomitingVomiting– Abnormal muscle toneAbnormal muscle tone– LethargyLethargy– SeizuresSeizures– ComaComa– DeathDeath

Hyperammonemia-etiologyHyperammonemia-etiology

Urea Cycle DefectsUrea Cycle Defects– Carbamyl Phosphate Synthetase (CPS)Carbamyl Phosphate Synthetase (CPS)– N-acetylglutamate synthetaseN-acetylglutamate synthetase– Ornithine Transcarbamylase (OTC)Ornithine Transcarbamylase (OTC)– Argininosuccinate synthetase (ASA)Argininosuccinate synthetase (ASA)– Argininosuccinate Lyase (AL)Argininosuccinate Lyase (AL)– ArginaseArginase

Hyperammonemia-etiologyHyperammonemia-etiology

Organic AcidemiasOrganic Acidemias– Propionic AcidemiaPropionic Acidemia– Methylmalonic AcidemiaMethylmalonic Acidemia– Isovaleric AcidemiaIsovaleric Acidemia– Ketothiolase AcidemiaKetothiolase Acidemia– Multiple carboxylase deficiencyMultiple carboxylase deficiency– Glutaric Acidemia Type IIGlutaric Acidemia Type II– 3-Hydroxy-3-methylglutaric acidemia 3-Hydroxy-3-methylglutaric acidemia

Hyperammonemia-etiologyHyperammonemia-etiology

OtherOther– Lysinuric protein intoleranceLysinuric protein intolerance– Hyperornithinemia-Hyperammonemia-Hyperornithinemia-Hyperammonemia-

HomocitrullinemiaHomocitrullinemia– Periodic Hyperlysinuria with Periodic Hyperlysinuria with

HyperammonemiaHyperammonemia– Transient Hyperammonemia of the Newborn Transient Hyperammonemia of the Newborn

(THN)(THN)

Flow Diagram to Evaluate Flow Diagram to Evaluate Hyperammonemia Hyperammonemia

Plasma amino acids

citrulline

citrullinemia

Nl. Or sl. increased

ASA

Nl.

Incr.

Sig incr

ASA

THN

low

Orotic acid

Low or absent CPS

Incr. OTC

urine

Treatment of Treatment of HyperAmmonemiaHyperAmmonemia

Aim: rapid therapy to prevent permanent brain Aim: rapid therapy to prevent permanent brain damage or deathdamage or death

Prevent further catabolism by providing Prevent further catabolism by providing adequate calories, fluids and electrolytesadequate calories, fluids and electrolytes

Minimize protein intakeMinimize protein intake

Provide alternate pathways for ammonia Provide alternate pathways for ammonia removalremoval– Sodium benzoateSodium benzoate– Sodium phenylacetateSodium phenylacetate– Arginine supplementationArginine supplementation

Mode of RRTMode of RRT

PDPD– Some clearance-but less than optimalSome clearance-but less than optimal– Too long for optimal removal, may not be able Too long for optimal removal, may not be able

to keep place with NH4 generationto keep place with NH4 generation

Hemodialysis Hemodialysis – looks like a good place to startlooks like a good place to start

HemofiltrationHemofiltration– a great way to go home at nighta great way to go home at night

HD Rx of ammonemiaHD Rx of ammonemia((Gregory et al, Vol. 5,abst. 55P,1994:Gregory et al, Vol. 5,abst. 55P,1994: ))

0200400600800100012001400160018002000

0 1 2 3 4 5 6 10 11 12 13 17 18 19 20

N

H4

mic

rom

oles

/l

Time(Hrs)

NH4 rebound with reinstitution of HD

HD to CRRTHD to CRRT(prevention of the rebound)(prevention of the rebound)

0

200

400

600

800

1000

1200

0 1 2 3 4 5 10 11 17

Time (Hrs)

N

H4

mic

rom

oles

/L Transition from HD to CVVHD

Hyperammonemia Hyperammonemia (McBryde et al, paper in progress)(McBryde et al, paper in progress)

18 children underwent 20 therapies of 18 children underwent 20 therapies of RRT due to in-born error of metabolismRRT due to in-born error of metabolismmean age 56 mean age 56 ++ 7.9 mos 7.9 mosmean weight 15 mean weight 15 ++ 3.7 kg (smallest 1.2 kg) 3.7 kg (smallest 1.2 kg)mean duration of therapy 6.1 mean duration of therapy 6.1 ++ 1.3 days 1.3 days

Modalities used Modalities used – HD only-9 HD only-9

time on HD 2.2 time on HD 2.2 ++ 0.9 days 0.9 days

– HF only-3 HF only-3 time on HF 6.3 time on HF 6.3 ++ 2.9 days 2.9 days

– HD followed by HF-8HD followed by HF-8time on HD + HF 10.25 time on HD + HF 10.25 ++ 1.8 days 1.8 days

Hyperammonemia Hyperammonemia (McBryde et al, paper in progress)(McBryde et al, paper in progress)

OutcomeOutcome– 12/18 patients survived 12/18 patients survived – 2/12 continued to be medication and RRT 2/12 continued to be medication and RRT

dependentdependent

Hyperammonemia Hyperammonemia (McBryde et al, JASN 2000)(McBryde et al, JASN 2000)

Neonatal HyperammonemiaNeonatal Hyperammonemia

Picca et.al Pediatr Nephrol 2001:16:862-Picca et.al Pediatr Nephrol 2001:16:862-867867

Reviewed prognostic indicatorsReviewed prognostic indicators– CAVHD N=4CAVHD N=4– CVVHD N=4CVVHD N=4– HD N=2HD N=2

Neonatal HyperammonemiaNeonatal Hyperammonemia

Findings:Findings:– NH4 levels decreased with all modalities NH4 levels decreased with all modalities

(1419 to 114 micromoles/L) with CVVHD (1419 to 114 micromoles/L) with CVVHD giving the highest NH4 clearance & HD giving giving the highest NH4 clearance & HD giving best NH4 extraction (hemodynamic instability)best NH4 extraction (hemodynamic instability)

– 5 had good outcome/5 had poor (not specific 5 had good outcome/5 had poor (not specific to modality) primarily associated with Coma to modality) primarily associated with Coma duration < 33 hrs (CNS delay/Death)duration < 33 hrs (CNS delay/Death)

– Early intervention is key!Early intervention is key!

Hepatic FailureHepatic Failure

Definition: Loss of functional liver cell Definition: Loss of functional liver cell mass below a critical level results in liver mass below a critical level results in liver failure (acute or complicating a chronic failure (acute or complicating a chronic liver disease)liver disease)

Results in: hepatic encephalopathy & Results in: hepatic encephalopathy & Coma, Jaundice, cholestasis, ascites, Coma, Jaundice, cholestasis, ascites, bleeding, renal failure, deathbleeding, renal failure, death

Hepatic FailureHepatic Failure

Production of Endogenous Toxins & Drug Production of Endogenous Toxins & Drug metabolic Failuremetabolic Failure

Bile Acids, Bilirubin, Prostacyclins, NO, Toxic fatty Bile Acids, Bilirubin, Prostacyclins, NO, Toxic fatty acids, Thiols, Indol-phenol metabolitesacids, Thiols, Indol-phenol metabolites

These toxins cause further necrosis/apoptosis and These toxins cause further necrosis/apoptosis and a vicious cyclea vicious cycle

Detrimental to renal, brain and bone Detrimental to renal, brain and bone marrow function; results in poor vascular marrow function; results in poor vascular tonetone

Hepatic Failure- Role of CRRTHepatic Failure- Role of CRRT

Objective:Objective:– CRRT support can buy time, help prevent CRRT support can buy time, help prevent

further deterioration/complication and allowfurther deterioration/complication and allowPotential recovery of functional critical cell massPotential recovery of functional critical cell mass

Management of precipitating events that lead to Management of precipitating events that lead to decompensated diseasedecompensated disease

Bridge to liver transplantation Bridge to liver transplantation

CVVHD for NH4 Bridge to CVVHD for NH4 Bridge to Hepatic TransplantationHepatic Transplantation

0

100

200

300

400

500

600

700

800

1 2 4 6 8 10 12 14 16

NH

4m

icro

mol

es/L

Time(days)

Successful Liver Transplantation

Hepatic Failure-Role of CRRTHepatic Failure-Role of CRRT

CRRT may not improve overall outcome of CRRT may not improve overall outcome of liver failure- but does provide stability and liver failure- but does provide stability and prolongs life in the setting of hepatic failureprolongs life in the setting of hepatic failurePrimary applications include use in control Primary applications include use in control of elevated ICP in fulminant hepatic failure of elevated ICP in fulminant hepatic failure (Davenport Lancet 1991:2:1604)(Davenport Lancet 1991:2:1604)

Management of Cerebral Edema through Management of Cerebral Edema through middle molecule removal- reversal of middle molecule removal- reversal of Coma Coma (Matsubara et.al. Crit Care Med1990:8:1331)(Matsubara et.al. Crit Care Med1990:8:1331)

Hepatic Failure-Role of CRRTHepatic Failure-Role of CRRT

Improved Cardiac Stability also noted in Improved Cardiac Stability also noted in patients with Hepatic & Renal Failure patients with Hepatic & Renal Failure – IHD vs CAVH vs CAVHD comparedIHD vs CAVH vs CAVHD compared– Noted a decrease in Cardiac Index of ~ 15% Noted a decrease in Cardiac Index of ~ 15%

in HD treated patients (also increase in ICP ~ in HD treated patients (also increase in ICP ~ 45% in HD)45% in HD)

– CAVHD/CVVHD- cardiac index decreased by CAVHD/CVVHD- cardiac index decreased by ~3% and no change noted in ICP~3% and no change noted in ICP

– Davenport et.al. Crit Care Med 1993: 21:328-338 Davenport et.al. Crit Care Med 1993: 21:328-338

Hepatic Failure-Role of CRRTHepatic Failure-Role of CRRT

Others:Others:– Fluid BalanceFluid Balance– Nutritional supportNutritional support– Uremic ClearanceUremic Clearance

Future HorizonsFuture Horizons

Currently Undergoing Clinical EvaluationCurrently Undergoing Clinical Evaluation– Liver Assist Devices – several companies (ie MARS- Liver Assist Devices – several companies (ie MARS-

Molecular Adsorbents Recycling System)Molecular Adsorbents Recycling System)– Both Biological and non- biological systems (ie Both Biological and non- biological systems (ie

porcine hepatocytes/hemodialysis filters/hemofiltersporcine hepatocytes/hemodialysis filters/hemofilters– Engage principles of both convection and diffusion (ie Engage principles of both convection and diffusion (ie

albumin dialysate) and anionic trapping with charcoal albumin dialysate) and anionic trapping with charcoal regeneration chambers for albuminregeneration chambers for albumin

– Huge potential Impact on critical care & Huge potential Impact on critical care & Transplantation!Transplantation!

ACKNOWLEDGEMENTSACKNOWLEDGEMENTS– MELISSA GREGORYMELISSA GREGORY– ANDREE GARDNERANDREE GARDNER– JOHN GARDNERJOHN GARDNER– THERESA MOTTESTHERESA MOTTES– TIM KUDELKATIM KUDELKA– LAURA DORSEY & BETSY ADAMSLAURA DORSEY & BETSY ADAMS

(p. brophy)