Faculty Bibliography

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.).

BACKGROUND Solid-phase assays to investigate the complement-activating capacity of HLA antibodies have been utilized to optimize organ allocation and improve transplant outcomes. The clinical utility of C1q/C3d-binding characteristics of de novo donor-specific anti-HLA antibodies (dnDSA) associated with C4d-positive antibody-mediated rejection (C4d⁺ AMR) in kidney transplants (KTx) has not been defined. MATERIAL AND METHODS Sera from 120 KTx recipients that had dnDSA concurrent with protocol/cause biopsy (median 3.8 years after transplantation) were screened for C1q and C3d-binding dnDSA. The difference in the incidence of C4d⁺ AMR between recipients with and without C1q/C3d-binding dnDSA was assessed. RESULTS Over 86% of dnDSAs were class II antibodies. The immunodominant dnDSAs characterized by the highest median fluorescence intensity (MFI) in most recipients were HLA-DQ antibodies (67%). Most recipients (62%, n=74) had either C1q⁺ (56%), C3d⁺ (48%), or both C1q⁺C3d⁺ (41.2%) dnDSA, while the remaining 38% were negative for both C1q and C3d. Of those with C1q⁺/C3d⁺ dnDSA, 87% had high-MFI IgG (MFI=14144±5363 and 13932±5278, respectively), while 65% of C1q⁻C3d⁻ dnDSA had low-MFI IgG (MFI=5970±3347). The incidence of C4d+ AMR was significantly higher in recipients with C1q⁺ (66%), C3d+ (74%), and C1q⁺C3d⁺ (72%) dnDSA than in those with C1q⁻C3d⁻ dnDSA (30%) recipients. Recipients with C3d⁺/C1q⁺ dnDSA had higher C4d⁺ scores on biopsy. CONCLUSIONS C1q⁺/C3d⁺ dnDSA were associated with C4d⁺ AMR and high-IgG MFI. Our data call into question the predictive utility of C1q/C3d-binding assays in identifying KTx recipients at risk of allograft failure. In conclusion, IgG MFI is sufficient for clinical management, and the C1q/C3d-assays with added cost do not provide any additional information.

The current kidney allocation system (KAS) preferentially allocates kidneys from blood type A2 or A2B (A/A2B) donors to blood type B candidates. We used national data to evaluate center-level performance of A2/A2B to B transplants, and organ procurement organization (OPO) reporting of type A or AB donor subtyping, in 5-year time periods prior to (2009-2014) and following (2015-2019) KAS implementation. The number of centers performing A2/A2B to B transplants increased from 17 pre-KAS to 76 post-KAS, though this still represents only a minority of centers (7.3% pre-KAS and 32.6% post-KAS). For high-performing centers, the median net increase in A2/A2B to B transplants was 19 cases (range -2-72) per center in the 5 years post-KAS. The median net increase in total B recipient transplants was 21 cases (range -17-119) per center. Despite requirements for performance of subtyping, in 2019 subtyping was reported on only 56.4% of A/AB donors. This translates into potential missed opportunities for B recipients, and even post-KAS up to 2322 A2/A2B donor kidneys may have been allocated for transplantation as A/AB. Further progress must be made both at center and OPO levels to broaden implementation of A2/A2B to B transplants for the benefit of underserved recipients.