METABOLIC DERANGEMENTS, HEPATIC FAILURE & PCRRT

1. METABOLIC DERANGEMENTS, HEPATIC FAILURE & PCRRT Patrick D. Brophy MD University of Michigan Pediatric Nephrology

2. Objectives • Metabolic Disorders and Amenability to CRRT • Hyperammonemia • Prescription • Fine points of care • Combination therapy • Considerations of CRRT in Hepatic Failure • Hepatic Insufficiency • Role of CRRT-bridge to transplant • Liver support

3. Metabolic Disorders • Multiple metabolic disorders have been described that are amenable to various forms of RRT. • Maple Syrup Urine Disease (BCAA—Build up lead to cerebral edema) • Puliyanda et.al. 2002:17:239-242 • Jouvet et.al. 2001:27:1798-1806 • Urea Cycle Defects- hyperammonemia • Organic Acidemias (accumulation of Acyl Co-A esters-secondary inhibition of urea cycle enzymes)

4. Hyperammonemia- clinical • Most Cases develop in neonatal period • Feeding refusal/intolerance • Vomiting • Abnormal muscle tone • Lethargy • Seizures • Coma • Death

5. Hyperammonemia-etiology • Urea Cycle Defects • Carbamyl Phosphate Synthetase (CPS) • N-acetylglutamate synthetase • Ornithine Transcarbamylase (OTC) • Argininosuccinate synthetase (ASA) • Argininosuccinate Lyase (AL) • Arginase

6. Hyperammonemia-etiology • Organic Acidemias • Propionic Acidemia • Methylmalonic Acidemia • Isovaleric Acidemia • Ketothiolase Acidemia • Multiple carboxylase deficiency • Glutaric Acidemia Type II • 3-Hydroxy-3-methylglutaric acidemia

7. Hyperammonemia-etiology • Other • Lysinuric protein intolerance • Hyperornithinemia-Hyperammonemia-Homocitrullinemia • Periodic Hyperlysinuria with Hyperammonemia • Transient Hyperammonemia of the Newborn (THN)

8. Flow Diagram to Evaluate Hyperammonemia citrullinemia Sig incr THN Nl. Plasma amino acids Nl. Or sl. increased citrulline ASA Incr. ASA low Low or absent CPS urine Orotic acid OTC Incr.

9. Treatment of HyperAmmonemia • Aim: rapid therapy to prevent permanent brain damage or death • Prevent further catabolism by providing adequate calories, fluids and electrolytes • Minimize protein intake • Provide alternate pathways for ammonia removal • Sodium benzoate • Sodium phenylacetate • Arginine supplementation

10. Mode of RRT • PD • Some clearance-but less than optimal • Too long for optimal removal, may not be able to keep place with NH4 generation • Hemodialysis • looks like a good place to start • Hemofiltration • a great way to go home at night

11. HD Rx of ammonemia(Gregory et al, Vol. 5,abst. 55P,1994:) NH4 rebound with reinstitution of HD NH4 micromoles/l Time (Hrs)

12. HD to CRRT(prevention of the rebound) Transition from HD to CVVHD NH4 micromoles/L Time (Hrs)

13. Hyperammonemia (McBryde et al, paper in progress) • 18 children underwent 20 therapies of RRT due to in-born error of metabolism • mean age 56 + 7.9 mos • mean weight 15 + 3.7 kg (smallest 1.2 kg) • mean duration of therapy 6.1 + 1.3 days

14. Hyperammonemia (McBryde et al, paper in progress) • Modalities used • HD only-9 • time on HD 2.2 + 0.9 days • HF only-3 • time on HF 6.3 + 2.9 days • HD followed by HF-8 • time on HD + HF 10.25 + 1.8 days

15. Hyperammonemia (McBryde et al, JASN 2000) • Outcome • 12/18 patients survived • 2/12 continued to be medication and RRT dependent

16. Neonatal Hyperammonemia • Picca et.al Pediatr Nephrol 2001:16:862-867 • Reviewed prognostic indicators • CAVHD N=4 • CVVHD N=4 • HD N=2

17. Neonatal Hyperammonemia • Findings: • NH4 levels decreased with all modalities (1419 to 114 micromoles/L) with CVVHD giving the highest NH4 clearance & HD giving best NH4 extraction (hemodynamic instability) • 5 had good outcome/5 had poor (not specific to modality) primarily associated with Coma duration < 33 hrs (CNS delay/Death) • Early intervention is key!

18. Hepatic Failure • Definition: Loss of functional liver cell mass below a critical level results in liver failure (acute or complicating a chronic liver disease) • Results in: hepatic encephalopathy & Coma, Jaundice, cholestasis, ascites, bleeding, renal failure, death

19. Hepatic Failure • Production of Endogenous Toxins & Drug metabolic Failure • Bile Acids, Bilirubin, Prostacyclins, NO, Toxic fatty acids, Thiols, Indol-phenol metabolites • These toxins cause further necrosis/apoptosis and a vicious cycle • Detrimental to renal, brain and bone marrow function; results in poor vascular tone

20. Hepatic Failure- Role of CRRT • Objective: • CRRT support can buy time, help prevent further deterioration/complication and allow • Potential recovery of functional critical cell mass • Management of precipitating events that lead to decompensated disease • Bridge to liver transplantation

21. CVVHD for NH4 Bridge to Hepatic Transplantation Successful Liver Transplantation NH4 micromoles/L Time (days)

22. Hepatic Failure-Role of CRRT • CRRT may not improve overall outcome of liver failure- but does provide stability and prolongs life in the setting of hepatic failure • Primary applications include use in control of elevated ICP in fulminant hepatic failure (Davenport Lancet 1991:2:1604) • Management of Cerebral Edema through middle molecule removal- reversal of Coma (Matsubara et.al. Crit Care Med1990:8:1331)

23. Hepatic Failure-Role of CRRT • Improved Cardiac Stability also noted in patients with Hepatic & Renal Failure • IHD vs CAVH vs CAVHD compared • Noted a decrease in Cardiac Index of ~ 15% in HD treated patients (also increase in ICP ~ 45% in HD) • CAVHD/CVVHD- cardiac index decreased by ~3% and no change noted in ICP • Davenport et.al. Crit Care Med 1993: 21:328-338

24. Hepatic Failure-Role of CRRT • Others: • Fluid Balance • Nutritional support • Uremic Clearance

25. Future Horizons • Currently Undergoing Clinical Evaluation • Liver Assist Devices – several companies (ie MARS- Molecular Adsorbents Recycling System) • Both Biological and non- biological systems (ie porcine hepatocytes/hemodialysis filters/hemofilters • Engage principles of both convection and diffusion (ie albumin dialysate) and anionic trapping with charcoal regeneration chambers for albumin • Huge potential Impact on critical care & Transplantation!

26. ACKNOWLEDGEMENTS MELISSA GREGORY ANDREE GARDNER JOHN GARDNER THERESA MOTTES TIM KUDELKA LAURA DORSEY & BETSY ADAMS (p. brophy)