Faculty Bibliography

Genetically modified xenografts are one of the most promising solutions to the discrepancy between the numbers of available human organs for transplantation and potential recipients. To date, a porcine heart has been implanted into only one human recipient. Here, using 10-gene-edited pigs, we transplanted porcine hearts into two brain-dead human recipients and monitored xenograft function, hemodynamics and systemic responses over the course of 66 hours. Although both xenografts demonstrated excellent cardiac function immediately after transplantation and continued to function for the duration of the study, cardiac function declined postoperatively in one case, attributed to a size mismatch between the donor pig and the recipient. For both hearts, we confirmed transgene expression and found no evidence of cellular or antibody-mediated rejection, as assessed using histology, flow cytometry and a cytotoxic crossmatch assay. Moreover, we found no evidence of zoonotic transmission from the donor pigs to the human recipients. While substantial additional work will be needed to advance this technology to human trials, these results indicate that pig-to-human heart xenotransplantation can be performed successfully without hyperacute rejection or zoonosis.

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.

BACKGROUND:Clinical decisions are mainly driven by the ability of physicians to apply risk stratification to patients. However, this task is difficult as it requires complex integration of numerous parameters and is impacted by patient heterogeneity. We sought to evaluate the ability of transplant physicians to predict the risk of long-term allograft failure and compare them to a validated artificial intelligence (AI) prediction algorithm. METHODS:We randomly selected 400 kidney transplant recipients from a qualified dataset of 4000 patients. For each patient, 44 features routinely collected during the first-year post-transplant were compiled in an electronic health record (EHR). We enrolled 9 transplant physicians at various career stages. At 1-year post-transplant, they blindly predicted the long-term graft survival with probabilities for each patient. Their predictions were compared with those of a validated prediction system (iBox). We assessed the determinants of each physician's prediction using a random forest survival model. RESULTS:Among the 400 patients included, 84 graft failures occurred at 7 years post-evaluation. The iBox system demonstrates the best predictive performance with a discrimination of 0.79 and a median calibration error of 5.79%, while physicians tend to overestimate the risk of graft failure. Physicians' risk predictions show wide heterogeneity with a moderate intraclass correlation of 0.58. The determinants of physicians' prediction are disparate, with poor agreement regardless of their clinical experience. CONCLUSIONS:This study shows the overall limited performance and consistency of physicians to predict the risk of long-term graft failure, demonstrated by the superior performances of the iBox. This study supports the use of a companion tool to help physicians in their prognostic judgement and decision-making in clinical care.

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.).