American Journal of Transplantation最新文献

The increasing availability of clinically approved genetic tests for kidney disease has spurred the growth in the use of these tests in kidney transplant practice. Neither the testing options nor the patient population where this should be deployed has been defined and its value in kidney transplant evaluation has not been demonstrated. Transplant providers may not always be aware of the limitations of genetic testing and may need guidance on comprehending test results and providing counsel, as many centers do not have easy access to a renal genetic counselor or a clinical geneticist. In this practice resource, a working group of nephrologists, geneticists and a genetic counselor provide a pragmatic, tailored approach to genetic testing, advocating for its use only where the genetic diagnosis or its exclusion can impact the choices available for transplantation or post-transplant management or the work-up of living donor candidates at increased risk for heritable disease.

Static cold storage (SCS) is the standard technique for organ preservation during transplantation, resulting in cold ischemic injury. Hypoxia can induce Panx1 channels open, leading to release of ATP. However, it is unknown whether Panx1 play a role in SCS. Our research demonstrates that livers from Panx1^-/- mice exhibited reduced ATP release, resulting in protected hepatocytes during preservation. The donor liver damage is decreased during SCS with blocking Panx1. Transmission electron microscopy revealed a decreased mitochondria-associated ER membranes (MAMs) and an improved mitochondria morphology. Mechanistically, Panx1 blockade upregulated the PI3K-AKT pathway and increased Bcl2 level to combat apoptosis during liver preservation. The data indicate that blocking Panx1 during preservation of the donor liver can effectively improve mitochondrial function, reducing cellular stress damage. Then cold ischemia and reperfusion-related injuries are obviously decreased in liver transplantation.

As a result of the increasing number of transplants being facilitated by kidney paired donation, and newer initiatives such as voucher donation, end-chain kidneys now constitute a considerable proportion of kidney paired donation transplants in the United States. Data on end-chain kidneys are limited. They may be lower in quality compared to non-end chain 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 end-chain kidneys accepted by a transplant center. Considering the ethical principles of utility, justice, and respect for persons that underlie organ allocation, we discuss three 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 non-directed donor organs, and to out-of-sequence allocation for deceased organ donors. Since end-chain kidneys represent an increasingproportion 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.

Contrary to immune cells, the response of the kidney structural cells in rejection is less established. We performed single-cell RNA sequencing on 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 HLA genes, adhesion molecules and cytokines and chemokines, suggesting an 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 two large micro-array 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 associated with poor kidney function. These observations highlight the critical role of the graft in triggering and sustaining rejection after transplantation.

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 impact on transplant probability, waitlist mortality, and likelihood of receiving HCV NAT+ organs using the United Network for Organ Sharing dataset of adult patients waitlisted for liver transplantation from 1/2016-9/2023. Multivariable regression models accounting for competing risks were fit to study waitlist outcomes. 21,776 patients were initially listed for HCV NAT+ organs while 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<0.001). Initial HCV NAT+ listing was associated with a waitlist mortality benefit in 2021-2023 (SHR 0.73, 95% CI 0.68-0.79, p<0.001) and 17% reduced hazard of overall mortality (HR 0.83, 95% CI 0.78-0.89, p<0.001). 16.0% of the total protective effect associated with HCV NAT+ listing on overall survival was mediated through actual receipt of HCV NAT+ organs (TERERI of -0.160 and a PIE of -0.026; p<0.001). Patients not listed for HCV NAT+ organs in the modern era are relatively disadvantaged in terms of waitlist outcomes. While listings have risen over time, there remains center-level and geographic variation.

The direct alloresponse, pivotal in transplant rejection, occurs when recipient T cells recognize intact allogeneic peptide-MHC 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 utilizing K562 cell-based artificial antigen-presenting cells (aAPCs) expressing 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, IFN-γ secretion, and cytolytic ability, with limited cross-reactivity towards non-targeted MHC alleles. Focusing on anti-A2 alloreactive CD8+ T cells, we developed a peptide-exchangeable aAPC 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 two 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.