Impact of early immunosuppression on pediatric liver transplant outcomes within 1 year.

OBJECTIVES: The Starzl Network for Excellence in Pediatric Transplantation identified optimizing immunosuppression (IS) as a priority practice improvement area for patients, families, and providers. We aimed to evaluate associations between clinical characteristics, early IS, and outcomes. METHODS: We analyzed pediatric liver transplant (LT) data from 2013 to 2018 in the United Network for Organ Sharing (UNOS) and the Society of Pediatric Liver Transplantation (SPLIT) registries. RESULTS: We included 2542 LT recipients in UNOS and 1590 in SPLIT. IS choice varied between centers with steroid induction and mycophenolate mofetil (MMF) use each ranging from 0% to 100% across centers. Clinical characteristics associated with early IS choice were inconsistent between the two data sets. T-cell depleting antibody use was associated with improved 1-year graft (hazard ratio [HR] 0.50, 95% confidence interval [CI] 0.34-0.76) and patient (HR 0.40, 95% CI 0.20-0.79) survival in UNOS but decreased 1-year patient survival (HR 4.12, 95% CI 1.31-12.93) and increased acute rejection (HR 1.58, 95% CI 1.07-2.34) in SPLIT. Non-T-cell depleting antibody use was not associated with differential risk of survival nor rejection. MMF use was associated with improved 1-year graft survival (HR 0.73, 95% CI 0.54-0.99) in UNOS only. CONCLUSIONS: Variation exists in center choice of early IS regimen. UNOS and SPLIT data provide conflicting associations between IS and outcomes in multivariable analysis. These results highlight the need for future multicenter collaborative work to identify evidence-based IS best practices.

Alagille syndrome: understanding the genotype-phenotype relationship and its potential therapeutic impact.

INTRODUCTION: Alagille syndrome (ALGS) is an autosomal dominant, multisystem genetic disorder with wide phenotypic variability caused by mutations in the Notch signaling pathway, specifically from mutations in either the Jagged1 (JAG1) or NOTCH2 gene. The range of clinical features in ALGS can involve various organ systems including the liver, heart, eyes, skeleton, kidney, and vasculature. Despite the genetic mutations being well-defined, there is variable expressivity and individuals with the same mutation may have different clinical phenotypes. AREAS COVERED: While no clear genotype-phenotype correlation has been identified in ALGS, this review will summarize what is currently known about the genotype-phenotype relationship and how this relationship influences the treatment of the multisystemic disorder. This review includes discussion of numerous studies which have focused on describing the genotype-phenotype relationship of different organ systems in ALGS as well as relevant basic science and population studies of ALGS. A thorough literature search was completed via the PubMed and National Library of Medicine GeneReviews databases including dates from 1969, when ALGS was first identified, to February 2023. EXPERT OPINION: The genetics of ALGS are well defined; however, ongoing investigation to identify genotype-phenotype relationships as well as genetic modifiers as potential therapeutic targets is needed. Clinicians and patients alike would benefit from identification of a correlation to aid in diagnostic evaluation and management.

Nonanaphylactic Variant of Alpha-Gal Syndrome as an Etiology for Chronic Gastrointestinal Symptoms in Children.

We report 3 pediatric patients who presented with only nonanaphylactic symptoms of alpha-gal syndrome. This report highlights the necessity of not discounting alpha-gal syndrome from a differential diagnosis for patients with recurrent gastrointestinal distress and emesis after consuming mammalian meat, even in the absence of an anaphylactic reaction.

Natural killer cells in liver transplantation: Can we harness the power of the immune checkpoint to promote tolerance?

The roles that natural killer (NK) cells play in liver disease and transplantation remain ill-defined. Reports on the matter are often contradictory, and the mechanisms elucidated are complex and dependent on the context of the model tested. Moreover, NK cell attributes, such as receptor protein expression and function differ among species, make study of primate or rodent transplant models challenging. Recent insights into NK function and NK-mediated therapy in the context of cancer therapy may prove applicable to transplantation. Of specific interest are immune checkpoint molecules and the mechanisms by which they modulate NK cells in the tumor micro-environment. In this review, we summarize NK cell populations in the peripheral blood and liver, and we explore the data regarding the expression and function of immune checkpoint molecules on NK cells. We also hypothesize about the roles they could play in liver transplantation and discuss how they might be harnessed therapeutically in transplant sciences.