Normal Graft Function After Pig-to-Human Kidney Xenotransplant.
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ABSTRACT:
SUBMITTER: Locke JE
PROVIDER: S-EPMC10433134 | biostudies-literature | 2023 Aug
REPOSITORIES: biostudies-literature
Publications
Normal Graft Function After Pig-to-Human Kidney Xenotransplant.
Locke Jayme E JE Kumar Vineeta V Anderson Douglas D Porrett Paige M PM
JAMA surgery 20231001 10
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Project description:Pig-to-human xenotransplantation is rapidly approaching the clinical arena; however, it is unclear which immunomodulatory regimens will effectively control human immune responses to pig xenografts. Here, we transplant a gene-edited pig kidney into a brain-dead human recipient on pharmacologic immunosuppression and study the human immune response to the xenograft using spatial transcriptomics and single-cell RNA sequencing. Human immune cells are uncommon in the porcine kidney cortex early after xenotransplantation and consist of primarily myeloid cells. Both the porcine resident macrophages and human infiltrating macrophages express genes consistent with an alternatively activated, anti-inflammatory phenotype. No significant infiltration of human B or T cells into the porcine kidney xenograft is detectable. Altogether, these findings provide proof of concept that conventional pharmacologic immunosuppression may be able to restrict infiltration of human immune cells into the xenograft early after compatible pig-to-human kidney xenotransplantation.
| S-EPMC11009229 | biostudies-literature
Project description:Pig-to-human xenotransplantation is rapidly approaching the clinical arena; however, it is unclear which immunomodulatory regimens will effectively control human immune responses to pig xenografts. We transplanted a gene-edited pig kidney into a brain-dead human recipient on pharmacologic immunosuppression and studied the human immune response to the xenograft using spatial transcriptomics and single-cell RNA sequencing. Human immune cells were uncommon in the porcine kidney cortex early after xenotransplantation and consisted of primarily myeloid cells. Both the porcine resident macrophages and human infiltrating macrophages expressed genes consistent with an alternatively activated, anti-inflammatory phenotype. No significant infiltration of human B or T cells into the porcine kidney xenograft was detected. Altogether, these findings provide proof of concept that conventional pharmacologic immunosuppression is sufficient to restrict infiltration of human immune cells into the xenograft early after compatible pig-to-human kidney xenotransplantation.
| S-EPMC9882594 | biostudies-literature
Project description:First-in-human pig xenotransplant clinical trials may soon begin, which raises ethical concerns about patients' decision-making to participate in such trials. We assessed kidney transplant candidates' attitudes and hypothetical decision-making about participating in xenotransplant trials through semi-structured telephone interviews and an online survey. We analyzed qualitative data by thematic analysis and quantitative data by descriptive statistics. Twenty-eight patients participated in interviews; 142 patients participated in the survey. Most interview and survey respondents were male (68%, 56%), White (54%, 61%), or Black (36%, 22%). Although interview participants appreciated xenotransplantation research's potential to advance science, they expressed concerns about infection transmission and graft function. Few survey respondents were willing to participate in a pig kidney trial to test the safety of pig kidneys (12.6%) or pig kidney function (16.9%). Interview participants would be more likely to participate in a first-in-human pig kidney trial if receiving a human kidney was unlikely and their health status declined. Willingness would also depend on how long the pig kidney would function. Most interview participants were receptive to long-term monitoring, but not to family monitoring. Transplant programs planning xenotransplant trials should anticipate these types of concerns for optimizing human subject protections and conducting a robust informed consent process.
| S-EPMC11800742 | biostudies-literature
Project description:Pig-to-human xenotransplantation is rapidly approaching the clinical arena; however, it is unclear which immunomodulatory regimens will effectively control human immune responses to pig xenografts. Here, we transplant a gene-edited pig kidney into a brain-dead human recipient on pharmacologic immunosuppression and study the human immune response to the xenograft using spatial transcriptomics and single-cell RNA sequencing. Human immune cells are uncommon in the porcine kidney cortex early after xenotransplantation and consist of primarily myeloid cells. Both the porcine resident macrophages and human infiltrating macrophages express genes consistent with an alternatively activated, anti-inflammatory phenotype. No significant infiltration of human B or T cells into the porcine kidney xenograft is detectable. Altogether, these findings provide proof of concept that conventional pharmacologic immunosuppression is sufficient to restrict infiltration of human immune cells into the xenograft early after compatible pig-to-human kidney xenotransplantation.
2024-03-27 | GSE242270 | GEO
Project description:BackgroundTransplant programs preparing to initiate first-in-human pig kidney xenotransplant clinical trials must be especially careful when obtaining participants' informed consent. Little is known about the kind of information patients want for making an informed decision about trial participation.MethodsWe conducted semi-structured telephone interviews with waitlisted kidney transplant patients about information needs regarding participating in a first-in-human pig kidney xenotransplant trial, which guided development of a prototype consent form. Subsequent usability testing interviews sought patient feedback on the consent form. We analyzed qualitative data by thematic analysis and quantitative data by descriptive statistics.ResultsTwenty-eight patients participated in semi-structured interviews; 16 patients participated in usability testing interviews. Most interview participants were male (68%, 56%), White (54%, 56%), or Black (36%, 31%), respectively. Interview participants identified five types of information needs: (1) the potential for infection contraction and transmission; (2) risks, benefits, and impact of xenotransplant trials; (3) xenotransplant clinical trial and recipient experience; (4) clinical trial logistics; and (5) the pig and its kidney. Usability testing participants suggested adding details to the prototype. Participants' preparedness to make a decision about participating in a xenotransplant trial increased after reviewing the prototype (12.5% vs. 31.3%, n.s.).ConclusionWe identified multiple unique types of information patients desired to make informed decisions about pig kidney xenotransplant trial participation. Transplant programs initiating xenotransplant trials should be prepared to address patients' information needs to optimize informed decision-making for trial participation. The prototype consent form may support a patient-centered approach to informed consent.
| S-EPMC11851052 | biostudies-literature
Project description:This dataset includes CosMx spatial transcriptomic data from human kidney biopsies collected one hour post-transplantation. Patients were then monitored and categorized into two groups: those with immediate graft function (IGF) and those with delayed graft function (DGF). DGF refers to cases where patients required dialysis for one or more weeks before kidney function was restored. The biopsies were formalin-fixed, paraffin-embedded, and sectioned using a microtome. Sample processing followed NanoString's standard protocol, utilizing a pre-made 6175-gene panel to detect the spatial location and expression levels of each gene, without any additional custom probes.
2025-02-15 | GSE282193 | GEO
Project description:This dataset includes CosMx spatial transcriptomic data from human kidney biopsies collected one hour post-transplantation. Patients were then monitored and categorized into two groups: immediate graft function (IGF) and primary nonfunction (PNF). PNF refers to cases where the transplanted kidney never functions. The biopsies were formalin-fixed, paraffin-embedded, and sectioned using a microtome. Sample processing followed NanoString's standard protocol, utilizing a pre-made 6,175-gene panel to detect the spatial location and expression levels of each gene, without any additional custom probes.
2024-11-29 | GSE282026 | GEO
Project description:BackgroundGraft loss is a major health concern for kidney transplant (KTx) recipients. It is of clinical interest to develop a prognostic model for both graft function, quantified by estimated glomerular filtration rate (eGFR), and the risk of graft failure. Additionally, the model should be dynamic in the sense that it adapts to accumulating longitudinal information, including time-varying at-risk population, predictor-outcome association, and clinical history. Finally, the model should also properly account for the competing risk by death with a functioning graft. A model with the features above is not yet available in the literature and is the focus of this research.MethodsWe built and internally validated a prediction model on 3,893 patients from the Wisconsin Allograft Recipient Database (WisARD) who had a functioning graft 6 months after kidney transplantation. The landmark analysis approach was used to build a proof-of-concept dynamic prediction model to address the aforementioned methodological issues: the prediction of graft failure, accounted for competing risk of death, as well as the future eGFR value, are updated at each post-transplant time. We used 21 predictors including recipient characteristics, donor characteristics, transplant-related and post-transplant factors, longitudinal eGFR, hospitalization, and rejection history. A sensitivity analysis explored a less conservative variable selection rule that resulted in a more parsimonious model with reduced predictors.ResultsFor prediction up to the next 1 to 5 years, the model achieved high accuracy in predicting graft failure, with the AUC between 0.80 and 0.95, and moderately high accuracy in predicting eGFR, with the root mean squared error between 10 and 18 mL/min/1.73m2 and 70%-90% of predicted eGFR falling within 30% of the observed eGFR. The model demonstrated substantial accuracy improvement compared to a conventional prediction model that used only baseline predictors.ConclusionThe model outperformed conventional prediction model that used only baseline predictors. It is a useful tool for patient counseling and clinical management of KTx and is currently available as a web app.
| S-EPMC11687162 | biostudies-literature
Project description:BackgroundIschemia reperfusion injury (IRI) induced immune response is a critical issue in transplantation. Complement and contact system activation are among its key mechanisms.Study designWe investigated the benefits of pre-reperfusion treatment with recombinant human C1INH (rhC1INH), inhibitor of both complement and contact activation, in a pig model of kidney autotransplantation, subjecting the organ to 60 min warm ischemia prior to 24 h static preservation to maximize damage.ResultsSerum creatinine measurement showed that treated animals recovered glomerular function quicker than the Vehicle group. However, no difference was observed in tubular function recovery, and elevated level of urinary NGal (Neutrophil gelatinase-associated lipocalin) and plasma AST (Aspartate Aminotransferase) were detected, indicating that treatment did not influence IRI-mediated tubular cell necrosis. Regarding chronic graft outcome, rhC1INH significantly prevented fibrosis development and improved function. Immunohistochemistry and western blot showed decreased invasion by macrophages and T lymphocytes, and reduction of epithelial to mesenchymal transition. We determined the effect of treatment on complement activation with immunofluorescence analyses at 30 min post reperfusion, showing an inhibition of C4d deposition and MBL staining in treated animals.ConclusionsIn this model, the inhibition of complement activation by rhC1INH at reperfusion, while not completely counteracting IRI, limited immune system activation, significantly improving graft outcome on the short and long term.
| S-EPMC5035455 | biostudies-literature
Project description:CosMx 6175 human gene for human kidney delayed graft function (DGF) and immediate graft function (IGF)
| PRJNA1187562 | ENA