Faculty Bibliography

PURPOSE OF REVIEW/OBJECTIVE:The aim of this study was to highlight recent progress in xenotransplantation and discuss the remaining obstacles/steps before the FDA is likely to approve a clinical trial. RECENT FINDINGS/RESULTS:Long-term survival of life-supporting xenografts in preclinical models has led to discussion of clinical trials of xenotransplantation. The reports of clinical cardiac xenotransplant based on compassionate use FDA approval and renal xenotransplants to brain-dead humans have led to further considerations of clinical trials. Discussions between the transplant community and the FDA have established critical next steps before a clinical trial of xenotransplants is likely to be approved. These steps include testing the clinical immunosuppression protocol and the organ from a genetically modified source animal in nonhuman primates with reproducible survival of at least 6 months. In addition, appropriate viral surveillance protocols and confirmation that the xenografts support appropriate human physiology are likely to be critical elements for FDA-approval. Finally, further studies in the human decedent model are likely to provide critical information about human immune and physiologic responses to xenografts. SUMMARY/CONCLUSIONS:This review highlights the current progress in nonhuman primate models and recent reports of human xenotransplantation. It also describes the remaining hurdles and currently understood FDA requirements that remain to be achieved before a clinical trial of xenotransplantation can be approved.

PURPOSE OF REVIEW/OBJECTIVE:The greatest challenge facing end-stage kidney disease (ESKD) patients is the scarcity of transplantable organs. Advances in genetic engineering that mitigate xenogeneic immune responses have made transplantation across species a potentially viable solution to this unmet need. Preclinical studies and recent reports of pig-to-human decedent renal xenotransplantation signify that clinical trials are on the horizon. Here, we review the physiologic differences between porcine and human kidneys that could impede xenograft survival. Topics addressed include porcine renin and sodium handling, xenograft water handling, calcium, phosphate and acid-base balance, responses to porcine erythropoietin and xenograft growth. RECENT FINDINGS/RESULTS:Studies in nonhuman primates (NHPs) have demonstrated that genetically modified pig kidneys can survive for an extended period when transplanted into baboons. In recent studies conducted by our group and others, hyperacute rejection did not occur in pig kidneys lacking the α1,3Gal epitope transplanted into brain-dead human recipients. These experimental trials did not study potential clinical abnormalities arising from idiosyncratic xenograft responses to human physiologic stimuli due to the brief duration of observation this model entails. SUMMARY/CONCLUSIONS:Progress in biotechnology is heralding an era of xenotransplantation. We highlight the physiologic considerations for xenogeneic grafts to succeed.

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.