1. Continuous Veno-venous Hemodiafiltration Therapy for Acute Decompensation with Cerebral Edema in Maple Syrup Urine Disease Joshua J. Zaritsky M.D., Julian A. Martinez M.D., Ora Yadin M.D. David Geffen School of Medicine, Mattel Children’s Hospital at UCLA, Los Angeles, United States

2. Maple Syrup Urine Disease Autosomal recessive disorder characterized by psychomotor retardation, feeding problems and maple syrup odor of the urine Autosomal recessive disorder characterized by psychomotor retardation, feeding problems and maple syrup odor of the urine Caused by deficiency of branched-chained alpha- ketoacid dehydrogenase complex Caused by deficiency of branched-chained alpha- ketoacid dehydrogenase complex Results in increased plasma concentrations of the branched-chained amino acids: leucine, isoleucine and valine Results in increased plasma concentrations of the branched-chained amino acids: leucine, isoleucine and valine Five phenotypes have been described based on both clinical and biochemical findings Five phenotypes have been described based on both clinical and biochemical findings

3. Management of MSUD Dietary therapy to promote normal growth and development Dietary therapy to promote normal growth and development Prompt recognition and treatment of acute metabolic decompensation usually triggered by an intercurrent illness Prompt recognition and treatment of acute metabolic decompensation usually triggered by an intercurrent illness Characterized by acute rises in the BCAA with leucine accumulation leading to neurotoxicty Characterized by acute rises in the BCAA with leucine accumulation leading to neurotoxicty

4. Cerebral Edema during Episodes of Metabolic Decompenstation Cerebral edema is the leading cause of death during periods of acute decompensation Cerebral edema is the leading cause of death during periods of acute decompensation Remains unclear why MSUD patients are prone to cerebral edema (Morton et.al. 2002) Remains unclear why MSUD patients are prone to cerebral edema (Morton et.al. 2002) Intracellular entrapment of osmotically active amino acids caused by high intracellular leucine levels Intracellular entrapment of osmotically active amino acids caused by high intracellular leucine levels Impairment of normal regulatory volume defense- disrupution of intracellular protein synthesis Impairment of normal regulatory volume defense- disrupution of intracellular protein synthesis Pathological or iatrogenic decreases in serum sodium and osmolarity with rapid water flux into cells Pathological or iatrogenic decreases in serum sodium and osmolarity with rapid water flux into cells

5. Treatment of Acute Decompensation Native urinary clearance is low so strategies for removal of BCAA include Native urinary clearance is low so strategies for removal of BCAA include Nutritional support: Nutritional support: Inhibition of protein catabolism Inhibition of protein catabolism Enhancement of protein synthesis with amino acid supplementation aimed at promoting leucine incorporation Enhancement of protein synthesis with amino acid supplementation aimed at promoting leucine incorporation Extracorporeal Removal Extracorporeal Removal Exchange transfusions Exchange transfusions Dialysis; PD, HD and CRRT Dialysis; PD, HD and CRRT

6. Choice of Dialysis Modality Literature is largely case based Literature is largely case based Guoyon et. al. (1994) compared BCAA clearance between PD, CAVH and CAVHD in a rabbit model of MSUD Guoyon et. al. (1994) compared BCAA clearance between PD, CAVH and CAVHD in a rabbit model of MSUD PD was less efficient than CRRT PD was less efficient than CRRT Using CRRT; BCAA clearance paralleled that of urea Using CRRT; BCAA clearance paralleled that of urea No comparisons of HD vs. CRRT in cases complicated by cerebral edema No comparisons of HD vs. CRRT in cases complicated by cerebral edema

7. Case Presentation 7 yo male with neonatal diagnosis of MSUD presented to outside hospital with a 2 week history of URI symptoms and difficulty walking 7 yo male with neonatal diagnosis of MSUD presented to outside hospital with a 2 week history of URI symptoms and difficulty walking Diagnosed with pneumonia with a superimposed asthma exacerbation Diagnosed with pneumonia with a superimposed asthma exacerbation Over the period of one week he became progressively encephalopathic with new onset spastic diplegia despite dietary modifications Over the period of one week he became progressively encephalopathic with new onset spastic diplegia despite dietary modifications CT upon arrival at UCLA revealed diffuse cerebral edema with no visible sulcation CT upon arrival at UCLA revealed diffuse cerebral edema with no visible sulcation Initial leucine level of 285 µmoles/L at outside hospital. At time of transfer had reached a peak of 1581 µmoles/L Initial leucine level of 285 µmoles/L at outside hospital. At time of transfer had reached a peak of 1581 µmoles/L

8. Therapeutic CVVHDF Based on his cerebral edema decision made to initiate CVVHDF Based on his cerebral edema decision made to initiate CVVHDF Gambro circuit with M60 filter; Qb of 100ml/min, Qd of 1500ml/hr and Qr of 750ml/hr, no net ultrafiltration Gambro circuit with M60 filter; Qb of 100ml/min, Qd of 1500ml/hr and Qr of 750ml/hr, no net ultrafiltration Predicted small molecule clearance of 57ml/min/1.73m 2 Predicted small molecule clearance of 57ml/min/1.73m 2 Given an estimated Vd of leucine of 17L (Based on a weight of 27kg; see Jouvet et.al. 2001) Given an estimated Vd of leucine of 17L (Based on a weight of 27kg; see Jouvet et.al. 2001) acceptable steady state levels of leucine were predicted to be reached in 16 hours

9. Plasma Amino Acid Levels CVVHDF 481216 36

10. Amino Acid Clearances Clearance (ml/min) Clearance (ml/min/1.73m 2 ) Leucine30.452.6 Isoleucine30.953.4 Valine30.753.2 Creatinine32.255.8

11. Summary CRRT clearances of BCAA are similar to those of other small molecules CRRT clearances of BCAA are similar to those of other small molecules CVVHDF is effective in acutely lowering serum leucine levels during acute decompensation in MSUD CVVHDF is effective in acutely lowering serum leucine levels during acute decompensation in MSUD CVVHDF is a safe therapy for decompensation in MSUD when complicated by cerebral edema CVVHDF is a safe therapy for decompensation in MSUD when complicated by cerebral edema