Monitoring plasma regenerating islet‐derived 3α and citrulline levels during pediatric allogeneic hematopoietic stem cell transplantation to predict acute gastrointestinal graft‐versus‐host disease

Acute graft-versus-host disease (aGvHD) with gastrointestinal (GI) involvement is a significant cause of transplant-related morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HSCT). Although elevated plasma Regenerating islet-derived 3α (REG3α) and reduced citrulline levels have been associated with GI aGvHD, their kinetics and predictive value in pediatric HSCT remains unclear. We measured plasma REG3α and citrulline levels weekly from pre-conditioning to day +30 post-transplant in 117 children (1-18 years) undergoing myeloablative, matched-donor HSCT. Patients developing GI aGvHD (n = 16, 14%) exhibited significantly increased REG3α levels from day +7 and onward, while citrulline levels were consistently reduced from before conditioning and during the first 2 weeks post-HSCT, particularly in those with lower GI aGvHD (all p < 0.05). No influence of GI infections was observed. In age-, sex-, diagnosis- and donor type-adjusted analyses, increasing REG3α (day +7) and decreasing citrulline (day 0) levels were independently associated with increased odds of lower GI aGvHD (OR = 2.25 (1.36-3.70), and OR = 15.43 (1.72-138.15) per doubling/5 μmol/L decrease, p < 0.05). Both markers showed notable predictive value, with a sensitivity and specificity of 0.86 and 0.79 for REG3α and 0.80/0.83 for citrulline. Early post-HSCT increases in REG3α and reductions in citrulline may serve as prognostic biomarkers for GI aGvHD, particularly for identifying lower GI involvement, supporting their use for risk-stratified immunosuppressive interventions.