Liver Transplantation in Children with Urea Cycle Disorders: The Importance of Minimizing Waiting Time

Abstract

Liver transplantation (LT) for children with urea cycle disorders (UCDs) is capable of correcting the enzymatic defect and preventing progressive neurologic injury. We describe the characteristics and outcomes of pediatric LT recipients with UCDs. We identified all pediatric (<18 years) LT candidates with UCDs in the United Network for Organ Sharing (UNOS) database (February 2002 to September 2020). Multivariable Cox and logistic regression were used to determine risk factors for graft loss and cognitive delay, respectively. Of 424 patients, 1.9% (8/424) experienced waitlist mortality and 95.0% underwent LT (403/424). The most frequently encountered UCDs in our cohort were ornithine transcarbamylase deficiency (46.2%), citrullinemia (20.3%), and argininosuccinic aciduria (ASA; 12.9%). The 1-, 3-, and 5-year graft survival rates were 90.4%, 86.3%, and 85.2%, respectively. Multivariable analysis showed a decreased risk of graft loss with increasing weight at LT (adjusted hazard ratio [aHR], 0.96; 95% confidence interval [CI], 0.94-0.99; P = 0.02), male sex (aHR, 0.49; 95% CI, 0.28-0.85; P = 0.01), and ASA diagnosis (aHR, 0.29; 95% CI, 0.09-0.98; P = 0.047), when adjusting for location (intensive care/hospital/home) and graft type (both P ≥ 0.65). In multivariable logistic regression, waitlist time (adjusted odds ratio [aOR], 1.10; 95% CI, 1.02-1.17; P = 0.009) and male sex (aOR, 1.71; 95% CI, 1.02-2.88; P = 0.04) were associated with increased odds of long-term cognitive delay. Waitlist duration is associated with a long-term risk of cognitive delay. Given excellent long-term outcomes, early LT evaluation should be considered in all children with UCDs to prevent progressive neurologic injury and optimize cognitive outcomes.

Liver transplantation in the treatment of ornithine transcarbamylase deficiency

“…According to the data from United Network for Organ Sharing (UNOS) database including 403 patients with urea cycle disorders (46.2% were OTCD) who underwent transplantation, the 1-, 3-, and 5-year graft survival rates were 90.4%, 86.3%, and 85.2%, respectively. Increased mass of the liver graft and male sex are related to decreased risk of graft loss [8]. In Japan, the 1-, 5-, 10-, and 15-year graft survival rates comprised 91.2%, 87.9%, 87.0%, and 79.3% among pediatric patients with metabolic disorders (OTCD, 20.6% of total) as shown by Kasahara et al [18].…”

“…Analysis of data on the patients under 18 year subjected to LTx between February 2002 and September 2020, the waiting list time and male sex were associated with long-term risk for a cognitive delay. Minimizing the waiting time is quite important, in order to maintain the patient's cognition capacities at later terms and improve the quality of life [8].…”

Ammonia and nutritional therapy in the critically ill: when to worry, when to test and how to treat?

“…Liver transplantation has been shown to improve survival outcomes for patients with nonparacetamol-associated acute liver failure and is currently the only known cure for patients with UCDs [39]. The decision to proceed with liver transplantation is complex and requires the involvement of experienced clinicians to guide patient and family decision-making [40]. Considerations include the likelihood of survival and quality of life without transplantation compared with the overall immediate risks as well as the long-term burden and complications of transplantation.…”

The challenge of understanding and predicting phenotypic diversity in urea cycle disorders

“…Preliminary analyses suggested that in contrast to nitrogen scavenger therapy, liver transplantation, which becomes relevant if intensified conservative management has failed to protect individuals from potentially life‐threatening recurrent HAEs, appeared to be beneficial for the preservation of cognitive functions 19,21 . This was supported by a recent analysis from the United Network for Organs Sharing database, suggesting that early liver transplantation should be considered in individuals with UCDs to prevent progressive neurological injury, 41 and moreover by data from Japan investigating neonatal‐onset and high‐risk individuals with UCDs 42,43 . However, for individuals with a severe phenotype, the life‐long impact of the first HAE on cognitive function cannot be reversed by liver transplantation, 44 while it is effective for preventing individuals from recurrent hyperammonemic attacks and improving long‐term survival 44,45 .…”