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INBORN ERRORS OF METABOLISM

INBORN ERRORS OF METABOLISM. 9th International pCRRT Conference on Pediatric Continuous Renal Replacement Therapy August 31-September 2, 2017 Disney’s Yacht & Beach Club Resorts . Lake Buena Vista, Florida. Stefano Picca, MD ISN Educational Ambassador

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INBORN ERRORS OF METABOLISM

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  1. INBORN ERRORS OFMETABOLISM 9th International pCRRTConference on PediatricContinuousRenalReplacementTherapy August 31-September 2, 2017 Disney’s Yacht & Beach Club Resorts. Lake Buena Vista, Florida Stefano Picca,MD ISN Educational Ambassador Dept. of Pediatrics, DialysisUnit “Bambino Gesù” Pediatric Research Hospital ROMA,Italy

  2. OUTLINE • HYPERAMMONEMIA • OXALOSIS

  3. BACKGROUND #1: IEM TOXIN CHARACTERISTICS • •All IEM toxiccompounds: small, non-proteinboundmolecules , relativelysmalldistribution volume • Best clearedbydiffusion • High tovery high generation rate → high clearancesneeded • Manypatients are neonates (complexclinical management)

  4. BACKGROUND #2: IEM DIALYZABLE TOXINS DISTRIBUTION • Usually in acute patients (UCD, OA): • Solute is distributed in a known volume , more or less bound to proteins in a stable physico-chemical condition • → FIRST ORDER KINETICS • Usually in chronic patients (Oxalosis): • Solute undergoes variable physico-chemical changes causing its reversible accumulation • → COMPLEX KINETICS

  5. KEY POINTS OF NEONATALHYPERAMMONEMIA Extremelyneurotoxic (per se or through intracellular excess glutamine formation) → astrocyteswelling, brain edema, coma, deathor severedisability thus: emergency treatment has to be started even before having aprecise diagnosis since prognosis may dependon a numberoffactors

  6. PROGNOSTIC INDICATORS IN DIALYZED AND NON-DIALYZED NEONATES: SURVIVAL Dialysisefficiency Timing ofintervention pNH4 level

  7. Ke KD PLASMA NH4 (DIS)EQUILIBRIUM • Ana/Catabolism • Defectseverity/phenotype • Different starting conditions • Different previous medical therapy G KC VC Modified from Sargent JA, Gotch FA, 1996

  8. AMMONIUM CLEARANCE AND FILTRATION FRACTIONUSING DIFFERENT DIALYSISMODALITIES Picca et al.,2001 Arbeiter et al.,2009

  9. CONCLUSIONS- RRT inHYPERAMMONEMIA • RRT induces rapid decrease of ammoniumlevels • Four hours seem a reasonable time for pharmacological treatment before RRT initiation • HD/CVVHD with high dialysate flow seem the best available options • However, PD induces similar plasma ammonium decay in the face of lower ammonium clearance (glucose utilization → anabolism? Negative nitrogenbalance→decreasedammonium generation rate? Better expertise with PD in neonates? -Bunchman2016-shorter predialysis comaduration?–Picca 2015-) • Severe hyperammonemia can be reversed also by pharmacological treatment alone.Response to dialysis can be useless if coma duration before treatment is toolong

  10. KEY POINTS OFOXALOSIS • • Accumulation of insoluble oxalate in bone, kidney, heart and liver occurring in hyperoxaluria type 1 (PH1), a rare autosomal recessive disorder (1:120,000 live births) caused by the defect of liver-specific peroxisomal enzyme alanine:glyoxylate aminotransferase(AGT) • In early expressed phenotype, oxalosis can lead to ESRD even in neonatalage • In these patients, combined liver-kidney transplantation is presently the therapeutic gold standard • No form of chronic dialysis is recommended in oxalosis but dialysis isneeded: • awaitingtransplantation • when small patient size does not allowtransplantation or Tx not available • right after combined transplantation topreventoxalosisrelapse • • Cochat, modified

  11. Oxalate mass balance in oxalosis Not a single-pool model! G2 G1 C C V K ● ● Oxalosis - bones - heart - peripheral nerves - joints - skin, soft tissues, retina…

  12. From Marangella M et al,1992

  13. mol/l) m pOxalate ( 0 18 Pt#1: CURVILINEAR INTERDIALYSIS pOXALATE INCREASE CVVHD CVVHD CVVHD CVVHD 220 R2 = 0.980 R2 = 0.988 180 200 160 180 140 160 mol/l) 120 140 m 2 =57.1 Y0 = 175.7 ± 11.4 A1 = -253.8 ± 32 T1 = 7.18 ± 1.72 2 =37.68 Y0 = 194.5 ± 8.99 A1 = -311.9 ± 60.6 T1 = 6.77 ± 1.53 120 100 100 80 pOxalate ( 80 60 60 40 40 20 20 0 0 0 6 6 12 6 0 5/0 5 10 15 20 TIME (hrs) TIME (hrs)

  14. 5 15 15 Pt#1: HD plasma OXALATE KINETICS. Oxalate Generation Rate r = 0.982 r = 0.999 CVVHD CVVHD CVVHD CVVHD 220 180 200 160 180 140 160 mol/l) 120 140 mol/l) m y= 19.5x + 9.08 p< 0.0001 y= 13.9x + 10.9 p= 0.017 120 100 m 100 80 pOxalate ( pOxalate ( 80 60 60 40 40 20 20 0 0 0 0 6 6 12 6 18 0 5/0 TIME (hrs) TIME (hrs)

  15. Clinicalcharacteristics, Genetics and Outcome

  16. Characteristics of Dialysis

  17. V = Mass Removal (Cpre – Cpost) + (G * Td) G = Cpost + t – Cpost t TD = (G * V * 24) – Mass Removal CALCULATIONS V: Oxdistribution volume (L) CpreCpost: Oxconcentrationpre and post HD (mol/L) Tid: HD duration (hrs) Ct: Oxconcentration at t(hrs) after HD session end G: Ox generation rate (mol/L per hour) TD: tissuedeposition rate (mol/24 h) AdaptedfromMarangella, Yamauchi

  18. OXALATE KINETICS in SIX CHILDREN ON CHRONIC HEMODIALYSIS

  19. Intensive dialysis can limit oxalate deposition Patient #1: migration of a single translucent band 6 months 12 months 16 months 18 months

  20. 1) Estimating quantity of tissue deposition of oxalate

  21. 2) Estimating quantity of tissue deposition of oxalate

  22. 8 h hemodialysis q48h

  23. 4 h hemodialysis q24h

  24. 2 h hemodialysis q12h

  25. CONCLUSIONS- RRT inOXALOSIS • RRT may be needed under particularcircumstances • Intensive dialysis regimens (daily extracorporeal and nocturnal PD) arerecommended • High frequency is more important than highefficiency • Oxalatekineticsprovidesevidencethatoxalategenerationrateis moreseverein children than inadults

  26. ACKNOWLEDGEMENTS Bambino Gesù ChildrenHospital: • Metabolic Unit: Carlo Dionisi-Vici, MD; Andrea Bartuli, MD; Gaetano Sabetta, MD ClinicalBiochemistryLab: Cristiano Rizzo BSc, PhD; Anna Pastore BSc,PhD NICU: all doctors andnurses DialysisUnit: Francesco Emma, MD, all doctors and nurses(thanks!) • • • InItaly: • • SINP (Italian Society of PediatricNephrology) All doctors from Pediatric NephrologyandNICUs of Genova,Milan,Turin, Padua, Florence, Naples,Bari. InTurin • Michele Petrarulo and Martino Marangella, MD for Ox determination and preciousadvices Roberto Bonaudo, MD and Rosanna Coppo, MD for data about oxalosis pt#2 • InUSA • TimothyE.Bunchman MD, forthisopportunity. Thanks,Tim.

  27. stefano.picca@opbg.net

  28. Dialysis Unit, “Bambino Gesù” Pediatric Hospital Roma, Italy. Doctor: S. Picca Headnurse: V. Bandinu Nurses: N. Avari D. Ciullo E. Iacoella P. Lozzi C. Pia L. Stefani Nurse Coordinator: M. D’Agostino

  29. PECULIARITIES OF TOXIN DEPURATION IN IEM • •All IEM toxiccompounds are small, non-proteinboundmoleculeswithrelativelysmalldistribution volume • As such, they are best clearedbydiffusion • Allofthem show a high tovery high generation rate . So theoretically, high clearances are needed • Mostofthesepatients are neonates. Thiscomplicatesclinical management duringdialysis

  30. 0-4 HOURS MEDICAL TREATMENT INNEONATAL HYPERAMMONEMIA 6000 4000 2000 1000 non-responders (dialysis) pNH (mmol/l) responders (med.treatment alone) 750 4 500 250 0 0 4 8 12162024 HOURS Picca, 2002

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