Faculty Bibliography

Background: Pediatric transplant candidates have historically been disadvantaged on the transplant waitlist, with nearly half of pediatric deceased donor organs allocated to adult recipients (Hsu, Gastroenterology, 2017), and allocation pediatric end-stage liver disease (PELD) scores that underestimate children's expected 3-month mortality compared to that of adult patients (Chang, JAMA Pediatrics, 2018). Disparities in organ distribution prompted revision of the liver allocation policy in 2020 from donation services areas (DSA) to a series of distance-based concentric circles called acuity circles (AC) before being offered nationally (US GAO, 2022), which was designed to minimize geographic inequity in liver transplant. Prior to implementation of the new liver allocation policy, analysis using the Liver Simulated Allocation Model projected that AC allocation would decrease disparities for pediatric liver transplant candidates and recipients by increasing transplants and decreasing waitlist mortality (Mogul, Transplantation, 2020). In this study, we evaluate differences in pediatric whole liver transplants performed before and after the implementation of acuity circle liver allocation policy.
Study Design: We evaluated patient characteristics, adjusted MELD/PELD at time of transplant, calculated donor age at time of transplant among pediatric whole liver transplant recipients in low versus high-volume pediatric liver transplant centers performed before and after implementation of AC-based liver allocation policy using the Scientific Registry of Transplant Recipients.
Result(s): Before and after the implementation of ACs, differences in pediatric liver transplants by age group (<2 years, 2-5 years old, 5-12 years old, and 12-18 years old) remained significantly different between low and high-volume pediatric transplant centers. Under DSA allocation policy, the median MELD/PELD at transplant was 37.0 (IQR 30.0-41.0) in low-volume centers and 40.0 (IQR 30.0-41.0) in high-volume centers. After the implementation of acuity circles, median MELD/PELD at transplant decreased to 35.0 (IQR 21.0-41.0) in low-volume centers and 35.0 (IQR 25.0-41.0) in high-volume centers. Finally, donor age at time of transplant increased from 8.0 (IQR 2.00-18.0) to 13.5 (IQR 4.5-21.0) at low-volume centers, and from 3.0 (IQR 1.0-14.0) to 4.0 (IQR 1.0-14.0) at high-volume centers before and after the implementation of ACs.
Conclusion(s): The change from DSAs to ACs in allocation policy and the shift from regional to national review boards have affected the characteristics of organ recipients, adjusted MELD/PELD at time of transplant, and donor age at time of transplant differentially between whole liver transplant recipients at low-and high-volume pediatric liver transplant centers

To assess the impact of technical variant grafts (TVG) (including living donor [LD] and deceased donor split/partial grafts) on waitlist (WL) and transplant outcomes for pediatric liver transplant (LT) candidates, we performed a retrospective analysis of OPTN data on first-time LT or liver-kidney pediatric candidates listed at centers that performed >10 LT during the study period, 2004-2020. Center variance was plotted for LT volume, TVG usage, and survival. A composite center metric of TVG usage and WL mortality was developed to demonstrate existing variation and potential for improvement. 64 centers performed 7842 LT; 657 children died on the WL. Proportions of WL mortality by center ranged from 0-31% and TVG usage from 0-76%. Higher TVG usage, from deceased or LD, independently or in combination, significantly correlated with lower WL mortality. In multivariable analyses, death from listing was significantly lower with increased center TVG usage (HR 0.611, CI [0.40-0.92]) and LT volume (HR 0.995, CI [0.99-1.0]). Recipients of living donor transplants (HR 0.637, CI [0.51-0.79]) had significantly increased survival from transplant compared with other graft types, and recipients of deceased donor technical variant grafts (HR 1.066, CI [0.93-1.22]) had statistically similar outcomes compared to whole graft recipients. Increased TVG utilization may decrease WL mortality in the U.S. Policy and training to increase TVG usage, availability and expertise is critical.

BACKGROUND:Xenografts from genetically modified pigs have become one of the most promising solutions to the dearth of human organs available for transplantation. The challenge in this model has been hyperacute rejection. To avoid this, pigs have been bred with a knockout of the alpha-1,3-galactosyltransferase gene and with subcapsular autologous thymic tissue. METHODS:We transplanted kidneys from these genetically modified pigs into two brain-dead human recipients whose circulatory and respiratory activity was maintained on ventilators for the duration of the study. We performed serial biopsies and monitored the urine output and kinetic estimated glomerular filtration rate (eGFR) to assess renal function and xenograft rejection. RESULTS:in Recipient 2. In both recipients, the creatinine level, which had been at a steady state, decreased after implantation of the xenograft, from 1.97 to 0.82 mg per deciliter in Recipient 1 and from 1.10 to 0.57 mg per deciliter in Recipient 2. The transplanted kidneys remained pink and well-perfused, continuing to make urine throughout the study. Biopsies that were performed at 6, 24, 48, and 54 hours revealed no signs of hyperacute or antibody-mediated rejection. Hourly urine output with the xenograft was more than double the output with the native kidneys. CONCLUSIONS:Genetically modified kidney xenografts from pigs remained viable and functioning in brain-dead human recipients for 54 hours, without signs of hyperacute rejection. (Funded by Lung Biotechnology.).

BACKGROUND:Immunotherapy, specifically immune checkpoint inhibitors (ICIs), including anti-programmed cell death 1 (anti-PD1), has recently received clinical approval for the treatment of adult hepatocellular carcinoma (HCC). However, the safety and efficacy of ICIs prior to solid organ transplant are unknown, especially in pediatrics. Safety reports are variable in adults, with some series describing subsequent allograft rejection and loss while others report successful transplants without allograft rejection.As ICIs stimulate the immune system by blocking the interaction between PD1 and the ligand-receptor pair programmed cell death-ligand 1 (PDL1), the downstream effects of T-cell activation increase the risk of graft rejection. METHODS:Here, we present a case of an adolescent with moderately differentiated non-fibrolamellar HCC treated with pembrolizumab, an anti-PD1 therapy, who subsequently underwent successful orthotopic liver transplantation (OLT). RESULTS:Our patient received an OLT 138 days from the last pembrolizumab dose with graft preservation. The patient has no evidence of recurrent disease or any episode of allograft rejection 48 months post OLT. Staining of tumor and normal tissues from longitudinal specimens finds PDL1 positive Kupffer cells present in normal liver and peritumoral areas with no changes post anti-PD1 therapy. In contrast, tumor cells were negative for PDL1. CONCLUSION/CONCLUSIONS:This case represents a basis for optimism in potential use of anti-PD1 therapy in liver transplant candidates and supports further investigation of immune checkpoint inhibitors use in this unique patient population.