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Hyperammonaemia and IEM

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Critical Care Nephrology and Renal Replacement Therapy in Children

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Abstract

Hyperammonaemia is a metabolic emergency and prompt treatment is paramount to optimize neurological outcome. Ammonia is extremely neurotoxic and increased levels can arise from an inherited or acquired defect in hepatic detoxification. Inborn errors of metabolism leading to hyperammonaemia mainly affect the hepatic urea cycle due to single enzyme deficiencies, transporter defects or mitochondrial dysfunction. Primary hyperammonaemia is a consequence of direct urea cycle dysfunction whereas secondary hyperammonaemia can result from disturbance of the urea cycle by toxic metabolites or substrate deficiencies. Immediate recognition and early initiation of specific treatment are of utmost importance. Prognostic factors include duration of hyperammonaemic coma and the extent of ammonia accumulation (Häberle et al. Orphanet J Rare Dis 7:32, 2012). The principles of management in the acute situation aim to rapidly remove ammonia, decrease production and replace rate limiting amino acids.

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References

  1. Adeva MM, Souto G, Blanco N, Donapetry C. Ammonium metabolism in humans. Metabolism. 2012;61(11):1495–511.

    Article  CAS  PubMed  Google Scholar 

  2. Jackson MJ, Beaudet AL, O’Brien WE. Mammalian urea cycle enzymes. Annu Rev Genet. 1986;20:431–64.

    Article  CAS  PubMed  Google Scholar 

  3. Häberle J, Boddaert N, Burlina A, Chakrapani A, Dixon M, Huemer M, Karall D, Martinelli D, Crespo PS, Santer R, Servais A, Valayannopoulos V, Lindner M, Rubio V, Dionisi-Vici C. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. 2012;7:32.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Bowker R, Green A, Bonham JR. Guidelines for the investigation and management of a reduced level of consciousness in children: implications for clinical biochemistry laboratories. Ann Clin Biochem. 2007;44:506–11.

    Article  CAS  PubMed  Google Scholar 

  5. Smith W, Kishnani PS, Lee B, Singh RH, Rhead WJ, Sniderman King L, Smith M, Summar M. Urea cycle disorders: clinical presentation outside the newborn period. Crit Care Clin. 2005;21(4 Suppl):S9–17.

    Article  PubMed  Google Scholar 

  6. Saudubray JM, Nassogne MC, de Lonlay P, Touati G. Clinical approach to inherited metabolic disorders in neonates: an overview. Semin Neonatol. 2002;7(1):3–15.

    Article  CAS  PubMed  Google Scholar 

  7. Barsotti RJ. Measurement of ammonia in blood. J Pediatr. 2001;138(1 Suppl):S11–9.

    Article  CAS  PubMed  Google Scholar 

  8. Wertheim-Tysarowska K, Gos M, Sykut-Cegielska J. Bal J; genetic analysis in inherited metabolic disorders--from diagnosis to treatment. Own experience, current state of knowledge and perspectives. Dev Period Med. 2015;19(4):413–31.

    PubMed  Google Scholar 

  9. Yamaguchi S, Brailey LL, Morizono H, Bale AE, Tuchman M. Mutations and polymorphisms in the human ornithine transcarbamylase (OTC) gene. Hum Mutat. 2006;27(7):626–32.

    Article  CAS  PubMed  Google Scholar 

  10. Summar ML, Koelker S, Freedenberg D, Le Mons C, Haberle J, Lee HS, Kirmse B. The incidence of urea cycle disorders. European registry and network for intoxication type metabolic diseases (E-IMD). Mol Genet Metab. 2013;110(1–2):179–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Legido-Quigley C, Cloarec O, Parker DA, Murphy GM, Holmes E, Lindon JC, Nicholson JK, Mitry RR, Vilca-Melendez H, Rela M, Dhawan A, Heaton N. First example of hepatocyte transplantation to alleviate ornithine transcarbamylase deficiency, monitored by NMR-based metabonomics. Bioanalysis. 2009;1(9):1527–35.

    Article  CAS  PubMed  Google Scholar 

  12. Kido J, Matsumoto S, Momosaki K, Sakamoto R, Mitsubuchi H, Endo F, Nakamura K. Liver transplantation may prevent neurodevelopmental deterioration in high-risk patients with urea cycle disorders. Pediatr Transplant. 2017;21(6)

    Google Scholar 

  13. Yu L, Rayhill SC, Hsu EK, Landis CS. Liver transplantation for urea cycle disorders: analysis of the united network for organ sharing database. Transplant Proc. 2015;47(8):2413–8.

    Article  CAS  PubMed  Google Scholar 

  14. Bachmann C. Outcome and survival of 88 patients with urea cycle disorders: a retrospective evaluation. Eur J Pediatr. 2003;162(6):410–6.

    PubMed  Google Scholar 

  15. Batshaw ML, Tuchman M, Summar M, Seminara J, Members of the Urea Cycle Disorders Consortium. A longitudinal study of urea cycle disorders. Mol Genet Metab. 2014;113(1–2):127–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Burgard P, Kölker S, Haege G, Lindner M, Hoffmann GF. Neonatal mortality and outcome at the end of the first year of life in early onset urea cycle disorders—review and meta-analysis of observational studies published over more than 35 years. J Inherit Metab Dis. 2016;39(2):219–2.

    Article  PubMed  Google Scholar 

  17. Posset R, Garcia-Cazorla A, Valayannopoulos V, Teles EL, Dionisi-Vici C, Brassier A, Burlina AB, Burgard P, Cortès-Saladelafont E, Dobbelaere D, Couce ML, Sykut-Cegielska J, Häberle J, Lund AM, Chakrapani A, Schiff M, Walter JH, Zeman J, Vara R, Kölker S. Additional individual contributors of the E-IMD consortium; age at disease onset and peak ammonium level rather than interventional variables predict the neurological outcome in urea cycle disorders. J Inherit Metab Dis. 2016;39(5):661–72.

    Article  CAS  PubMed  Google Scholar 

  18. Fraser JL, Venditti CP. Methylmalonic and propionic acidemias: clinical management update. Curr Opin Pediatr. 2016;28(6):682–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Oplin SE. Pathophysiology of fatty acid oxidation disorders and resultant phenotypic variability. J Inherit Metab Dis. 2013;36(4):645–58.

    Article  CAS  Google Scholar 

  20. Ogier de Baulny H, Schiff M, Dionisi-Vici C. Lysinuric protein intolerance (LPI): a multi organ disease by far more complex than a classic urea cycle disorder. Mol Genet Metab. 2012;106(1):12–7.

    Article  CAS  PubMed  Google Scholar 

  21. Martinelli D, Diodato D, Ponzi E, Monné M, Boenzi S, Bertini E, Fiermonte G, Dionisi-Vici C. The hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. Orphanet J Rare Dis. 2015;10:29.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Palladino AA, Stanley CA. The hyperinsulinism/hyperammonemia syndrome. Rev Endocr Metab Disord. 2010;11(3):171–8.

    Article  CAS  PubMed  Google Scholar 

  23. Häberle J. Clinical and biochemical aspects of primary and secondary hyperammonemic disorders. Arch Biochem Biophys. 2013;536(2):101–8.

    Article  CAS  PubMed  Google Scholar 

  24. Magner M, Dvorakova V, Tesarova M, Mazurova S, Hansikova H, Zahorec M, Brennerova K, Bzduch V, Spiegel R, Horovitz Y, Mandel H, Eminoğlu FT, Mayr JA, Koch J, Martinelli D, Bertini E, Konstantopoulou V, Smet J, Rahman S, Broomfield A, Stojanović V, Dionisi-Vici C, van Coster R, Morava E, Sperl W, Zeman J, Honzik T. TMEM70 deficiency: long-term outcome of 48 patients. J Inherit Metab Dis. 2015;38(3):417–26.

    Article  CAS  PubMed  Google Scholar 

  25. Diez-Fernandez C, Rüfenacht V, Santra S, Lund AM, Santer R, Lindner M, Tangeraas T, Unsinn C, de Lonlay P, Burlina A, van Karnebeek CD, Häberle J. Defective hepatic bicarbonate production due to carbonic anhydrase VA deficiency leads to early-onset life-threatening metabolic crisis. Genet Med. 2016;18(10):991–1000.

    Article  CAS  PubMed  Google Scholar 

  26. Auron A, Brophy PD. Hyperammonemia in review: pathophysiology, diagnosis, and treatment. Pediatr Nephrol. 2012;27(2):207–22.

    Article  PubMed  Google Scholar 

  27. Häberle J. Clinical practice: the management of hyperammonemia. Eur J Pediatr. 2011;170(1):21–34.

    Article  PubMed  Google Scholar 

  28. Lang W, Blöck TM, Zander R. Solubility of NH3 and apparent pK of NH4+ in human plasma, isotonic salt solutions and water at 37 degrees C. Clin Chim Acta. 1998;273(1):43–58.

    Article  CAS  PubMed  Google Scholar 

  29. da Fonseca-Wollheim F, Heinze KG. Solubility of NH3 and apparent pK of NH4+ in human plasma, isotonic salt solutions and water at 37 degrees C. Eur J Clin Chem Clin Biochem. 1992;30(12):867–9.

    PubMed  Google Scholar 

  30. Thrane V, Thrane A, Wang W, et al. Solubility of NH3 and apparent pK of NH4+ in human plasma, isotonic salt solutions and water at 37 degrees C. Nat Med. 2013;19(12):1643–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Berry E, Rhead S, Brusilow W, Hamosh S. Survival after treatment with phenyl acetate and benzoate for urea cycle disorders. NEJM. 2007;356:2282–92.

    Article  PubMed  Google Scholar 

  32. Uchino T, Endo F, Matsuda I. Neurodevelopmental outcome of long-term therapy of urea cycle disorders in Japan. J Inherit Metab Dis. 1998;21(Suppl 1):151–9.

    Article  PubMed  Google Scholar 

  33. Msall M, Batshaw ML, Suus R, Brusilow SW, Mellitis ED. Neurologic outcome in children with inborn errors of urea synthesis. Outcome of urea-cycle enzymopathies. N Engl J Med. 1984;310(23):1500–5.

    Article  CAS  PubMed  Google Scholar 

  34. Westrope C, Morris K, Burford D, Morrison G. Continuous hemofiltration in the control of neonatal hyperammonemia: a 10-year experience. Pediatr Nephrol. 2010;25(9):1725–30.

    Article  PubMed  Google Scholar 

  35. Picca S, Dionisi-Vici C, Bartuli A, De Palo T, Papadia F, Montini G, Materassi M, Donati MA, Verrina E, Schiaffino MC, Pecoraro C, Iaccarino E, Vidal E, Burlina A, Emma F. Short-term survival of hyperammonemic neonates treated with dialysis. Pediatr Nephrol. 2015;30:839–47.

    Article  PubMed  Google Scholar 

  36. Schaefer F, Straube E, Oh J, Mayatepeck E. Dialysis in neonates with inborn errors of metabolism. Nephrol Dial Transplant. 1999;14:910–8.

    Article  CAS  PubMed  Google Scholar 

  37. Arbeiter AK, Kranz B, Wingen AM, Bonzel KE, Dohna-Schwake C, Hanssler L, Neudorf U, Hoyer PF, Büscher R. Continuous venovenous haemodialysis (CVVHD) and continuous peritoneal dialysis (CPD) in the acute management of 21 children with inborn errors of metabolism. Nephrol Dial Transplant. 2010;25(4):1257–65.

    Article  PubMed  Google Scholar 

  38. McBryde KD, Kershaw DB, Bunchman TE, Maxvold NJ, Mottes TA, Kudelka TL, Brophy PD. Renal replacement therapy in the treatment of confirmed or suspected inborn errors of metabolism. J Pediatr. 2006;148:770–8.

    Article  PubMed  Google Scholar 

  39. Spinale JM, Laskin BL, Sondheimer N, Swartz SJ, Goldstein SL. High-dose continuous renal replacement therapy for neonatal hyperammonemia. Pediatr Nephrol. 2013;28:983–6.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Hackbarth R, Bunchman TE, Chua AN, et al. The effect of vascular access location and size on circuit survival in pediatric continuous renal replacement therapy: a report from the PPCRRT registry. Int J Artif Organs. 2007;30:1116–21.

    Article  CAS  PubMed  Google Scholar 

  41. Picca S, Dionisi-Vici C, Abeni D, Pastore A, Rizzo C, Orzalesi M, Sabetta G, Rizzoni G, Bartuli A. Extracorporeal dialysis in neonatal hyperammonemia: modalities and prognostic indicators. Pediatr Nephrol. 2001;16(11):862–7.

    Article  CAS  PubMed  Google Scholar 

  42. Lai Y-C, Huang H-P, Tsai I-J, Tsau Y-K. High-volume continuous venovenous hemofiltration as an effective therapy for acute management of inborn errors of metabolism in young children. Blood Purif. 2007;25:303–8.

    Article  PubMed  Google Scholar 

  43. Clark WR, Turk JE, Kraus MA, Gao D. Dose determinants in continuous renal replacement therapy. Int J Artif Organs. 2003;27:815–20.

    Article  Google Scholar 

  44. Huang Z, Letteri J, Clark WJ, Ronco C, Gao D. Operational characteristics of continuous renal replacement modalities used for critically ill patients with acute kidney injury. Int J Artif Organs. 2008;31(6):525–34.

    Article  CAS  PubMed  Google Scholar 

  45. Troyanov S, Cardinal J, Geadah D, Parent D, Courteau S, et al. Solute clearances during continuous venovenous haemofiltration at various ultrafiltration flow rates using Multiflow-100 and HF1000 filters. Nephrol Dial Transplant. 2003;18:961–6.

    Article  PubMed  Google Scholar 

  46. Little MA, Conlon PJ, Walshe JJ. Access recirculation in temporary hemodialysis catheters as measured by the saline dilution technique. Am J Kidney Dis. 2000;6:1135–9.

    Article  Google Scholar 

  47. Bunchman TE, Barletta GM, Winters JW, Gardner JJ, Crumb TL, McBryde KD. Phenylacetate and benzoate clearance in a hyperammonemic infant on sequential hemodialysis and haemofiltration. Pediatr Nephrol. 2007;22(7):1062–5.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Paediatric Inherited Metabolic Disease, Evelina London Children’s Hospital, London, UK

    Roshni Vara

  2. Paediatric Intensive Care Unit, Evelina London Children’s Hospital, London, UK

    Andrew Durward

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  1. Roshni Vara
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  2. Andrew Durward
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Correspondence to Roshni Vara .

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Editors and Affiliations

  1. Paediatric Intensive Care Unit, King’s College Hospital, London, United Kingdom

    Akash Deep

  2. Center for Acute Care Nephrology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA

    Stuart L. Goldstein

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Vara, R., Durward, A. (2018). Hyperammonaemia and IEM. In: Deep, A., Goldstein, S. (eds) Critical Care Nephrology and Renal Replacement Therapy in Children. Springer, Cham. https://doi.org/10.1007/978-3-319-90281-4_27

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  • DOI: https://doi.org/10.1007/978-3-319-90281-4_27

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