Variability in Pediatric Transplant Center Immunosuppression Practices Impact Rejection Rates

Vikram Raghu, MD, MS

Credit: Pitt Pediatrics

New research is shedding light on the impact of inconsistent early immunosuppression practices on short-term outcomes following pediatric liver transplantation, with results suggesting centers with greater variability in induction type face higher rejection rates within the first year.¹

Leveraging data from the United Network for Organ Sharing (UNOS) Standard Transplant Analysis and Research (STAR) registry, the study found induction coefficient of immunosuppression variability (CIV) at pediatric liver transplant centers is associated with increased rates of 1-year rejection but no difference in short-term graft and patient survival.¹

According to data from the Organ Procurement and Transplantation Network, more than 103,000 men, women, and children are currently on the national transplant wait list, roughly 9500 of whom are seeking a liver transplant. In children, the most common indication for a liver transplant is biliary atresia, a rare disease affecting 1 in 10,000 to 1 in 20,000 live births worldwide.^2,3

“Early immunosuppression in liver transplantation plays a critical role in protecting the liver, yet little data exist supporting the optimal regimen,” Vikram Raghu, MD, MS, an instructor of pediatrics in the division of gastroenterology, hepatology, and nutrition at the University of Pittsburgh School of Medicine, and colleagues wrote.¹ “As immunosuppression largely follows center practices, there is a critical need to understand how center-based immunosuppression practices affect outcomes: Are we effectively personalizing immunosuppression to optimize outcomes or are we introducing unnecessary complexity with potentially increased side effects and costs?”

To assess the relationship between CIV and early outcomes following pediatric liver transplantation, investigators conducted a retrospective analysis of prospectively collected data for pediatric liver transplants using the UNOS STAR files. They identified children 0–18 years of age who received a liver-only transplant between 2013 and 2018 and had ≥ 1 year of post-transplant follow-up data available, or died or lost their graft within the first year. Of note, the data were aggregated by transplant center.¹

Investigators classified individual patients by induction regimen and whether they received perioperative mycophenolate mofetil (MMF). The induction regimen was defined as either corticosteroid alone, T-cell depleting antibody with or without corticosteroids, or non-T-cell depleting antibody with or without corticosteroids. For induction regimen and MMF, CIV was calculated using the concept of unalikeability.1¹

The study’s primary outcomes were 1-year graft survival, patient survival, and acute rejection rate within the first year after transplant.¹

In total, the study included 2542 liver transplant recipients from 67 centers. Center volume ranged from 1 to 179 transplants during the study period. Of note, 37% of centers had no induction variability and 24% had no MMF variability.¹

In multivariable analysis, induction CIV was associated with 2.72 times greater odds of acute rejection in the first year (odds ratio [OR], 2.72; 95% CI, 1.66–4.45; P <.001), meaning greater within-center variability in induction type was associated with a higher incidence of rejection at that center. However, investigators noted MMF CIV was not associated with rejection (OR, 1.22; 95% CI, 0.66–2.25; P = .527).¹

Graft loss rates varied by center with a median of 8% (interquartile range [IQR], 0%–12%) in the first year. In multivariable analysis, neither induction nor MMF CIV was associated with 1-year graft loss. In the final model, only center volume had a significant association with 1-year graft loss, with small volume centers associated with greater odds of graft loss.¹

Additionally, patient death in the first year occurred at a median rate of 2% (IQR, 0%–5%), with 28 centers having no reported deaths in the first year after transplant. In multivariable analysis, no significant predictors of death were identified, including both induction and MMF CIV.¹

Investigators outlined multiple limitations to these findings, including the absence of certain outcomes in the UNOS data; the potential for misclassification in the registry; and the use of data from 2013 to 2018 rather than more recent data.¹

“These findings suggest that reducing induction variability could reduce rejection rates, which may have downstream impacts on long-term graft survival,” investigators concluded.¹ “Our future work with Starzl Network for Excellence in Pediatric Transplantation will aim to distinguish between intended and unintended variability and to reduce unnecessary variability in order to systematically study how intentional variation in immunosuppression can impact liver transplant outcomes.”

References

1. ^{Raghu VK, Rothenberger SD, Squires JE, et al. Association Between Early Immunosuppression Center Variability and One-Year Outcomes After Pediatric Liver Transplant. Pediatric Transplantation. https://doi.org/10.1111/petr.70018}
2. ^{Health Resources and Services Administration. Organ Donation Statistics. October 2024. Accessed January 10, 2025. https://www.organdonor.gov/learn/organ-donation-statistics}
3. ^{Yale Medicine. Pediatric Liver Transplants. Accessed January 10, 2025. https://www.yalemedicine.org/conditions/pediatric-liver-transplants}