METABOLIC DERANGEMENTS, METABOLIC DERANGEMENTS, HEPATIC FAILURE & PCRRT HEPATIC FAILURE & PCRRT Patrick D. Brophy MD Patrick D. Brophy MD University of Michigan University of Michigan Pediatric Nephrology Pediatric Nephrology
Jan 14, 2016
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)