Severity-adjusted evaluation of initial dialysis on short-term health outcomes in urea cycle disorders

Matthias Zielonka; Stefan Kölker; Sven F Garbade; Florian Gleich; Sandesh C S Nagamani; Andrea L Gropman; Ann-Catrin Druck; Nesrine Ramdhouni; Laura Göde; Georg F Hoffmann; Roland Posset; Urea Cycle Disorders Consortium (UCDC)

doi:10.1016/j.ymgme.2024.108566

Severity-adjusted evaluation of initial dialysis on short-term health outcomes in urea cycle disorders

Mol Genet Metab. 2024 Sep-Oct;143(1-2):108566. doi: 10.1016/j.ymgme.2024.108566. Epub 2024 Aug 19.

Collaborators

Urea Cycle Disorders Consortium (UCDC):
Andreas Schulze⁶, Can Ficicioglu⁷, Cary O Harding⁸, Christina Lam⁹, Curtis R Coughlin 2nd¹⁰, Derek Wong¹¹, George A Diaz¹², Gerard T Berry¹³, Gregory M Enns¹⁴, Greta Wilkening¹⁵, Jennifer Seminara¹⁶, Laura Konczal¹⁷, J Lawrence Merritt 2nd¹⁸, Lindsay C Burrage³, Margo Breilyn¹⁹, Matthias R Baumgartner²⁰, Nicholas Ah Mew²¹, Renata C Gallagher²², Shawn E McCandless²³, Susan A Berry²⁴, Tamar Stricker²⁰

Affiliations

¹ Heidelberg University, Medical Faculty Heidelberg, and Center for Pediatric and Adolescent Medicine, Department I, Division of Pediatric Neurology and Metabolic Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany. Electronic address: [email protected].
² Heidelberg University, Medical Faculty Heidelberg, and Center for Pediatric and Adolescent Medicine, Department I, Division of Pediatric Neurology and Metabolic Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany.
³ Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.
⁴ Children's National Health System and The George Washington School of Medicine, Washington, DC, USA.
⁵ Heidelberg University, Medical Faculty Heidelberg, and Center for Pediatric and Adolescent Medicine, Department I, Division of Pediatric Neurology and Metabolic Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany. Electronic address: [email protected].
⁶ The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.
⁷ Children' Hospital of Philadelphia, Philadelphia, USA.
⁸ Oregon Health and Science University, Portland, OR, USA.
⁹ Department of Pediatrics, Seattle Children's Research Institute, University of Washington, Washington, USA.
¹⁰ Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹¹ David Geffen School of Medicine at UCLA, California, LA, USA.
¹² Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹³ Harvard Medical School and Boston Children's Hospital, Boston, MA, USA.
¹⁴ Division of Medical Genetics, Department of Pediatrics, Lucile Packard Children's Hospital, Stanford University, Stanford, CA, USA.
¹⁵ Department of Neurology, Children's Hospital of Colorado, Aurora, CO, USA.
¹⁶ Children's National Health System, Washington DC, USA.
¹⁷ University Hospitals Cleveland Medical Center, Cleveland, OH, USA.
¹⁸ Seattle Children's Hospital, University of Washington, Seattle, WA, USA.
¹⁹ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁰ Division of Metabolism and Children's Research Center, University Children's Hospital Zurich, University of Zurich, Switzerland.
²¹ Children's National Health System, The George Washington School of Medicine, Washington DC, USA.
²² Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.
²³ Children's Hospital Colorado, Aurora, CO, USA.
²⁴ University of Minnesota, Minneapolis, MN, USA.

PMID: 39299137
DOI: 10.1016/j.ymgme.2024.108566

Abstract

Objective: In individuals with urea cycle disorders (UCDs) and neonatal disease onset, extracorporeal detoxification by continuous kidney replacement therapy is considered the therapeutic method of choice in addition to metabolic emergency treatment to resolve hyperammonemic decompensation. However, the indications for the initiation of dialysis are heterogeneously implemented transnationally, thereby hampering our understanding of (optimal) short-term health outcomes.

Methods: We performed a retrospective comparative analysis evaluating the therapeutic effects of initial dialysis on survival as well as neurocognitive outcome parameters in individuals with UCDs in comparison to a severity-adjusted non-dialyzed control cohort. Overall, 108 individuals with a severe phenotype of male ornithine transcarbamylase deficiency (mOTC-D), citrullinemia type 1 (CTLN1) and argininosuccinic aciduria (ASA) were investigated by stratification based on a recently established and validated genotype-specific disease prediction model.

Results: Mortality is associated with the height of initial peak plasma ammonium concentration, but appears to be independent from treatment with initial dialysis in mOTC-D. However, improved survival after initial dialysis was observed in CTLN1, while there was a trend towards improved survival in ASA. In survivors, annual frequency of (subsequent) metabolic decompensations did not differ between the dialyzed and non-dialyzed cohorts. Moreover, treatment with initial dialysis was not associated with improved neurocognitive outcomes.

Interpretation: The present severity-adjusted comparative analysis reveals that general practice of initial dialysis is neither associated with improved survival in individuals with mOTC-D nor does it differ with regard to the neurocognitive outcome for the investigated UCD subtypes. However, initial dialysis might potentially prove beneficial for survival in CTLN1 and ASA.

Clinical trial registration: The UCDC database is recorded at the US National Library of Medicine (https://clinicaltrials.gov).

Keywords: Dialysis; Health outcomes; Survival; UCDC; Urea cycle disorders.

MeSH terms

Adolescent
Adult
Argininosuccinic Aciduria / genetics
Argininosuccinic Aciduria / therapy
Child
Child, Preschool
Citrullinemia / genetics
Citrullinemia / therapy
Female
Humans
Infant
Infant, Newborn
Male
Ornithine Carbamoyltransferase Deficiency Disease / genetics
Ornithine Carbamoyltransferase Deficiency Disease / therapy
Renal Dialysis*
Retrospective Studies
Severity of Illness Index
Treatment Outcome
Urea Cycle Disorders, Inborn* / genetics
Urea Cycle Disorders, Inborn* / pathology
Urea Cycle Disorders, Inborn* / therapy
Young Adult