Progress in subclinical research of kidney xenotransplantation / 器官移植

Xenotransplantation is an efficient pathway to solve the problem of transplant organ source deficiency in clinical settings. With the increasing progress of gene editing technique and immune suppression regimen, important development has been achieved on researches regarding pig to non-human primate kidney xenotransplantation, which provides a good condition for the introduction of the technique in the clinical application. In view of the substantial difference between human and non-human primate, and to meet the needs of current ethic requirements, it is necessary to perform subclinical studies for pig to human kidney xenotransplantation. In recent years, such subclinical studies with regard to the genetically modified pig to brain death recipient kidney xenotransplantation had been performed, indicating that kidney xenotransplantation gradually began to transit to the clinical development stage. However, donor/recipient selection and immune suppression regimen has not reached a consensus yet, and has to be clarified in subclinical studies. In this article, the current status and confronted problems of donor/recipient selection, immune suppression regimen and post transplantation management in the subclinical studies of kidney xenotransplantation were reviewed, aiming to promote the clinical transformation of kidney xenotransplantation to the clinical application.

Xenotransplantation literature update March 2021-March 2023.

After a significant hiatus imposed by the COVID-19 pandemic, we hereby restart Xenotransplantation literature updates. With the recently performed clinical xenotransplantation cases and the much-heightened interest in the field, we have determined that this is an optimal time to reinstate this section. There has been an invigorated focus on unique challenges posed by pig-to-human xenotransplantation, and specific attention will be given to this aspect. In this issue, we aimed to cover the gap and compiled the most relevant publications from March 2021 to March 2023.

Kidney Xenotransplantation: Are We Ready for Prime Time?

PURPOSE OF REVIEW: With the exponential increase in interest and great strides toward clinical application, many experts believe we are ready for kidney xenotransplant human trials. In this review, we will examine the obstacles overcome and those yet to be conquered, discussing the human trials performed and the questions they raised. Additionally, we will revisit overlooked aspects that may be crucial for improvements and suggest future approaches for xenotransplant research. RECENT FINDINGS: Improving survival in pig-to-non-human-primate models with the identification of an ideal immunosuppression regimen led to 3 cases of kidney xenotransplant in brain-dead humans with limited follow-up and a single clinical case of pig-to-human heart xenotransplant with 2-month survival. With limited human results and unlimited potential, xenotransplantation shines a beacon of hope for a brighter future. However, we must navigate through the complexities of balancing scientific progress and patient welfare, avoiding being blinded by xenotransplantation's unquestionable potential.

Cryopreservation of Fetal Porcine Kidneys for Xenogeneic Regenerative Medicine.

Kidney xenotransplantation has been attracting attention as a treatment option for end-stage renal disease. Fetal porcine kidneys are particularly promising grafts because they can reduce rejection through vascularization from host vessels. We are proposing xenogeneic regenerative medicine using fetal porcine kidneys injected with human nephron progenitor cells. For clinical application, it is desirable to establish reliable methods for the preservation and quality assessment of grafts. We evaluated the differentiation potency of vitrified porcine fetal kidneys compared with nonfrozen kidneys, using an in vivo differentiation model. Fetal porcine kidneys connected to the bladder were frozen via vitrification and stored in liquid nitrogen. Several days later, they were thawed and transplanted under the retroperitoneum of immunocompromised mice. After 14 days, the frozen kidneys grew and differentiated into mature nephrons, and the findings were comparable to those of nonfrozen kidneys. In conclusion, we demonstrated that the differentiation potency of vitrified fetal porcine kidneys could be evaluated using this model, thereby providing a practical protocol to assess the quality of individual lots.

Developments in kidney xenotransplantation.

The search for kidney xenografts that are appropriate for patients with end-stage renal disease has been ongoing since the beginning of the last century. The major cause of xenograft loss is hyperacute and acute rejection, and this has almost been overcome via scientific progress. The success of two pre-clinical trials of α1,3-galactosyltransferase gene-knockout porcine kidneys in brain-dead patients in 2021 triggered research enthusiasm for kidney xenotransplantation. This minireview summarizes key issues from an immunological perspective: the discovery of key xenoantigens, investigations into key co-stimulatory signal inhibition, gene-editing technology, and immune tolerance induction. Further developments in immunology, particularly immunometabolism, might help promote the long-term outcomes of kidney xenografts.

Kidney xenotransplantation: Recent progress in preclinical research.

Kidney transplantation is the most effective treatment for end-stage renal disease, but is limited by the increasing shortage of deceased and living human donor kidneys. Xenotransplantation using pig organs provides the possibility to resolve the issue of organ supply shortage and is regarded as the next great medical revolution. In the past five years, there have been sequential advances toward the prolongation of life-supporting pig kidney xenograft survival in non-human primates, with the longest survival being 499 days. This progress is due to the growing availability of pigs with multi-layered genetic modifications to overcome the pathobiological barriers and the application of a costimulation blockade-based immunosuppressive regimen. These encouraging results bring the hope to initiate the clinical trials of pig kidney transplantation in the near future. In this review, we summarized the latest advances regarding pig kidney xenotransplantation in preclinical models to provide a basis for future investigation and potential clinical translation.

Detection of Pig Cells Harboring Porcine Endogenous Retroviruses in Non-Human Primate Bladder After Renal Xenotransplantation.

Pigs are used as potential donor animals for xenotransplantation. However, porcine endogenous retrovirus (PERV), shown to infect both human and non-human primate (NHP) cells in vitro, presents a risk of transmission to humans in xenotransplantation. In this study, we analyzed PERV transmission in various organs after pig-to-NHP xenotransplantation. We utilized pig-to-NHP xenotransplant tissue samples obtained using two types of transgenic pigs from the National Institute of Animal Science (NIAS, Republic of Korea), and examined them for the existence of PERV genes in different organs via PCR and RT-PCR with specific primers. To determine PERV insertion into chromosomes, inverse PCR using PERV long terminal repeat (LTR) region-specific primers was conducted. The PERV gene was not detected in NHP organs in cardiac xenotransplantation but detected in NHP bladders in renal xenotransplantation. The insertion experiment confirmed that PERVs originate from porcine donor cells rather than integrated provirus in the NHP chromosome. We also demonstrate the presence of pig cells in the NHP bladder after renal xenotransplantation using specific-porcine mitochondrial DNA gene PCR. The PERV sequence was detected in the bladder of NHPs after renal xenotransplantation by porcine cell-microchimerism but did not integrate into the NHP chromosome.