American Journal of Transplantation最新文献

As a result of the increasing number of transplants being facilitated by kidney paired donation and newer initiatives such as voucher donation, end-chain (EC) kidneys now constitute a considerable proportion of kidney paired donation transplants in the United States. Data on EC kidneys are limited. They may be lower in quality compared with non-EC living donor kidneys. However, they can provide unique opportunities for recipient candidates without living donors. There are no data or algorithms available to guide recipient selection for EC kidneys accepted by a transplant center. Considering the ethical principles of utility, justice, and respect for persons that underlie organ allocation, we discuss 3 potential approaches for recipient selection: (1) adherence to the kidney allocation system, (2) utility maximization; and (3) priority to high-risk candidates, along with examples from our own center's experience. Similar considerations are also relevant to selection of recipients for nondirected donor organs and to out-of-sequence allocation for deceased organ donors. Because EC kidneys represent an increasing proportion of kidney paired donation-facilitated living kidney donor transplantation in the United States and will likely get more medically and surgically complex over time, ongoing research on their utilization and outcomes is needed.

Direct-acting antiviral agents have facilitated the utilization of hepatitis C virus (HCV)+ organs in HCV nucleic acid amplification test (NAT)- recipients. We evaluated trends in HCV NAT+ listing and its impact on transplant probability, waitlist mortality, and likelihood of receiving HCV NAT+ organs using the United Network for Organ Sharing data set of adult patients waitlisted for liver transplantation from January 2016 to September 2023. Multivariable regression models accounting for competing risks were fit to study waitlist outcomes. Initially, 21 776 patients were listed for HCV NAT+ organs whereas 45 378 were not. The percentage of waitlisted patients listed for these organs increased significantly from 2016 to 2023 (8.8% to 60.8%, P < .001). Initial HCV NAT+ listing was associated with a waitlist mortality benefit in 2021-2023 (subhazard ratio 0.73, 95% CI 0.68-0.79, P < .001) and 17% reduced hazard of overall mortality (hazard ratio 0.83, 95% CI 0.78-0.89, P < .001). Sixteen percent of the total protective effect associated with HCV NAT+ listing on overall survival was mediated through actual receipt of HCV NAT+ organs (total excess relative risk of -0.160 and a pure indirect effect of -0.026; P < .001). Patients not listed for HCV NAT+ organs in the modern era are relatively disadvantaged in terms of waitlist outcomes. Although listings have risen over time, there remains center-level and geographic variation.

Contrary to immune cells, the response of the kidney structural cells in rejection is less established. We performed single-cell RNA sequencing of 18 kidney transplant biopsies from 14 recipients. Single-cell RNA sequencing identified cells from the major compartments of the kidney, next to infiltrated immune cells. Endothelial cells from the glomerulus, peritubular capillaries, and vasa recta showed upregulation of class I and II human leukocyte antigen genes, adhesion molecules, cytokines, and chemokines, suggesting active participation in the alloimmune process, with compartment-specific differences. Epithelial cells including proximal tubular, loop of Henle, and collecting duct cells, also showed increased expression of immune genes. Strikingly, in proximal tubule cells, a strong downregulation of energy metabolism upon inflammation was observed. There was a large overlap between the cell-specific expression changes upon alloimmune inflammation and those observed in 2 large microarray biopsy cohorts. In conclusion, the kidney structural cells, being the main target of the alloimmune process, appear to actively contribute herein, enhancing the damaging effects of the infiltrating immune cells. In epithelial cells, a profound shutdown of metabolism was seen upon inflammation, which is associated with poor kidney function. These observations highlight the critical role of the graft in triggering and sustaining rejection after transplantation.

The direct alloresponse, pivotal in transplant rejection, occurs when recipient T cells recognize intact allogeneic peptide-major histocompatibility complex (pMHC) complexes. Despite extensive research, our understanding of alloreactive CD8⁺ T cells against an individual MHC allele in humans remains limited, especially their precursor frequency, MHC specificity, and peptide specificity. By using K562 cell-based artificial antigen-presenting cells expressing human leukocyte antigen (HLA)-A∗01:01, HLA-A∗02:01, or HLA-A∗03:01, we determined that the precursor frequency of alloreactive CD8⁺ T cells against a single MHC allele ranges from 0.1% to 0.5%. Further, these cells exhibited MHC specificity regarding proliferation, activation, interferon gamma secretion, and cytolytic ability, with limited crossreactivity toward nontargeted MHC alleles. Focusing on anti-A2 alloreactive CD8⁺ T cells, we developed a peptide-exchangeable artificial antigen-presenting cell that displays selected peptides on HLA-A∗02:01. From a set of 95 computationally curated A2-restricted peptides most abundant in renal tubular cells, we identified 2 immunogenic kidney peptides across multiple donors. Overall, our findings significantly enhance the understanding of direct alloresponse and provide a toolkit for future mechanistic studies and reproducible patient monitoring.