Organ transplantation is regarded as the pinnacle of medical achievement in the 21st century, with innovation serving as the core engine driving the advancement of transplant surgery. Taking the decades of practical exploration in organ transplantation (especially liver transplantation) in China as its main thread, this article systematically analyzes the core logic of transplant surgical innovation. This logic adheres to a three-pronged developmental pathway characterized by being clinically problem-solving oriented, patient-need centered, and critical-technology-conquering driven. By reviewing major milestones such as living donor liver transplantation, auxiliary partial orthotopic liver transplantation, combined multi-organ transplantation, and xenotransplantation, the study elucidates how surgical innovation should be grounded in resolving clinical pain points, return to medical humanism, and leverage technological iteration to foster revolutionary progress. Furthermore, the article explores the empowering role of cutting-edge technologies-including artificial intelligence, machine perfusion, and gene editing-in driving the next surgical revolution. It aims to construct a theoretical framework and provide practical insights for the future development of transplant surgery in China.

Objective To establish an "human serum - porcine aortic endothelial cells (PAEC) - human platelets" in vitro model and explore the mechanism of xenotransplantation-related coagulation dysfunction mediated by immune complexes - platelet FcγRⅡa (CD32a) receptor. Methods Healthy human serum was co-incubated with PAEC to prepare the supernatant containing immune complexes, which was then used to stimulate healthy human platelets, or directly treated with the serum of xenogeneic liver transplant recipients. Flow cytometry was used to detect platelet activation markers CD62P and surface IgG binding levels, and the platelet adhesion function was evaluated by platelet-PAEC adhesion experiments. CD32a blocking antibody IV.3 and SYK blocker SKYIN 4 were used to clarify the signaling pathways. Results The supernatant from the co-incubation of healthy human serum and PAEC could significantly induce platelet activation and endothelial adhesion. The use of the serum from xenogeneic liver transplant recipients could also significantly induce platelet activation. Antibody IV.3 and SYK blocker SKYIN 4 could significantly inhibit these effects. Conclusions In xenotransplantation, the immune complexes formed by human serum antibodies and porcine endothelial antigens may induce abnormal platelet activation through the platelet CD32a receptor, which is an important mechanism of non-complement-dependent post-transplant coagulation dysfunction, providing a new target for the intervention of coagulation complications in xenotransplantation.

Organ transplantation is regarded as the pinnacle of medical achievement in the 21st century, with innovation serving as the core engine driving the advancement of transplant surgery. Taking the decades of practical exploration in organ transplantation (especially liver transplantation) in China as its main thread, this article systematically analyzes the core logic of transplant surgical innovation. This logic adheres to a three-pronged developmental pathway characterized by being clinically problem-solving oriented, patient-need centered, and critical-technology-conquering driven. By reviewing major milestones such as living donor liver transplantation, auxiliary partial orthotopic liver transplantation, combined multi-organ transplantation, and xenotransplantation, the study elucidates how surgical innovation should be grounded in resolving clinical pain points, return to medical humanism, and leverage technological iteration to foster revolutionary progress. Furthermore, the article explores the empowering role of cutting-edge technologies-including artificial intelligence, machine perfusion, and gene editing-in driving the next surgical revolution. It aims to construct a theoretical framework and provide practical insights for the future development of transplant surgery in China.

BACKGROUND: The primary limitation to kidney transplantation is organ shortage. Recent progress in gene editing and immunosuppressive regimens has made xenotransplantation with porcine organs a possibility. However, evidence in pig-to-human xenotransplantation remains scarce, and antibody-mediated rejection (AMR) is a major obstacle to clinical applications of xenotransplantation. METHODS: We conducted a kidney xenotransplantation in a brain-dead human recipient using a porcine kidney with five gene edits (5GE) on March 25, 2024 at Xijing Hospital, China. Clinical-grade immunosuppressive regimens were employed, and the observation period lasted 22 days. We collected and analyzed the xenograft function, ultrasound findings, sequential protocol biopsies, and immune surveillance of the recipient during the observation. RESULTS: The combination of 5GE in the porcine kidney and clinical-grade immunosuppressive regimens prevented hyperacute rejection. The xenograft kidney underwent delayed graft function in the first week, but urine output increased later and the single xenograft kidney maintained electrolyte and pH homeostasis from postoperative day (POD) 12 to 19. We observed AMR at 24 h post-transplantation, due to the presence of pre-existing anti-porcine antibodies and cytotoxicity before transplantation; this AMR persisted throughout the observation period. Plasma exchange and intravenous immunoglobulin treatment mitigated the AMR. We observed activation of latent porcine cytomegalovirus toward the end of the study, which might have contributed to coagulation disorder in the recipient. CONCLUSIONS 5GE and clinical-grade immunosuppressive regimens were sufficient to prevent hyperacute rejection during pig-to-human kidney xenotransplantation. Pre-existing anti-porcine antibodies predisposed the xenograft to AMR. Plasma exchange and intravenous immunoglobulin were safe and effective in the treatment of AMR after kidney xenotransplantation.
Transplantation, Heterologous/methods* ; Kidney Transplantation/methods* ; Heterografts/pathology* ; Immunoglobulins, Intravenous/administration & dosage* ; Graft Survival/immunology* ; Humans ; Animals ; Sus scrofa ; Graft Rejection/prevention & control* ; Kidney/pathology* ; Gene Editing ; Species Specificity ; Immunosuppression Therapy/methods* ; Plasma Exchange ; Brain Death ; Biopsy ; Male ; Aged

Xenotransplantation using pigs as donors is considered one of the most promising approaches to address the shortage of allogeneic organs and has been seen rapid development in recent years. However, the clinical application of xenotransplantation still faces challenges in immune rejection, physiological compatibility, and biosafety. Among these, humoral rejection is a major barrier affecting the long-term survival of xenografts, and human recipients may have pre-existing antibodies against triple gene knockout (TKO) donor pigs. Nevertheless, early antibody-mediated humoral rejection can still be prevented. Additionally, cellular rejection and inflammatory responses are closely related to the long-term survival of grafts, and the introduction of humanized molecules in donor pigs, combined with the use of anti-inflammatory drugs by recipients, can help improve the survival of xenografts. Moreover, physiological challenges are mainly reflected in the incompatibility of the coagulation cascade and the structural and functional differences between pig proteins and human proteins. In terms of biosafety, breeding donor pigs free of designed pathogens and developing highly sensitive detection methods for pig-derived microorganisms are key to reduce transplant rejection and interspecies infections. At present, further research is needed in gene editing strategies, immunosuppressive regimens, and infection monitoring methods to improve the long-term survival of grafts and recipients.

Liver transplantation is the only effective cure for end-stage liver disease. However,donor liver shortage has become a major problem,limiting the development of liver transplantation. Among the many ways to solve the problem of donor liver shortage,xenotransplantation has high feasibility and prospect of clinical application. In recent years,heart and kidney xenotransplantation have been successfully carried out in clinical trials,while there are few studies on liver xenotransplantation. The survival time of preclinical models in liver xenotransplantation is limited to 34 days,which is not sufficient for clinical trials. The future clinical trials of liver xenotransplantation will face multiple challenges such as immune rejection,interspecific incompatibility,social and ethical issues,which require the joint efforts of government,society,research institution and medical institution and to promote the basic and clinical research of liver xenotransplantation in China.

Xenotransplantation using pigs as donors is considered one of the most promising approaches to address the shortage of allogeneic organs and has been seen rapid development in recent years. However, the clinical application of xenotransplantation still faces challenges in immune rejection, physiological compatibility, and biosafety. Among these, humoral rejection is a major barrier affecting the long-term survival of xenografts, and human recipients may have pre-existing antibodies against triple gene knockout (TKO) donor pigs. Nevertheless, early antibody-mediated humoral rejection can still be prevented. Additionally, cellular rejection and inflammatory responses are closely related to the long-term survival of grafts, and the introduction of humanized molecules in donor pigs, combined with the use of anti-inflammatory drugs by recipients, can help improve the survival of xenografts. Moreover, physiological challenges are mainly reflected in the incompatibility of the coagulation cascade and the structural and functional differences between pig proteins and human proteins. In terms of biosafety, breeding donor pigs free of designed pathogens and developing highly sensitive detection methods for pig-derived microorganisms are key to reduce transplant rejection and interspecies infections. At present, further research is needed in gene editing strategies, immunosuppressive regimens, and infection monitoring methods to improve the long-term survival of grafts and recipients.

Liver transplantation is the only effective cure for end-stage liver disease. However,donor liver shortage has become a major problem,limiting the development of liver transplantation. Among the many ways to solve the problem of donor liver shortage,xenotransplantation has high feasibility and prospect of clinical application. In recent years,heart and kidney xenotransplantation have been successfully carried out in clinical trials,while there are few studies on liver xenotransplantation. The survival time of preclinical models in liver xenotransplantation is limited to 34 days,which is not sufficient for clinical trials. The future clinical trials of liver xenotransplantation will face multiple challenges such as immune rejection,interspecific incompatibility,social and ethical issues,which require the joint efforts of government,society,research institution and medical institution and to promote the basic and clinical research of liver xenotransplantation in China.

Subclinical research of xenotransplantation involves xenotransplantation trial using brain death donors,which is an important intermediate step from basic research and animal experiments to the clinical application of xenotransplantation.It provides necessary data support for the safety and efficacy of xenotransplantation.In order to promote the safe,orderly,scientific and standardized development of subclinical research on xenotransplantation,the Xenotransplantation Group of Branch of Organ Transplantation of Chinese Medical Association formulated the"Expert Consensus on Subclinical Research of Xenotransplantation(2024 Edition)"based on relevant laws and regulations.The consensus includes aspects such as the selection of donor pigs,recipient selection criteria,legal and ethical requirements,determination of trial termination time,family informed consent system,and brain death determination standards.

Organ shortage has become one of the major challenges hindering the development of organ transplantation. Xenotransplantation is one of the most valuable methods to resolve global organ shortage. In recent years, the development of genetic engineering technique and research and development of new immunosuppressant have provided novel theoretical basis for xenotransplantation. International scholars have successively carried out researches on xenotransplantation in genetically modified pigs to non-human primates or brain death recipients, making certain substantial progresses. However, most of the researches are still in the preclinical stage, far from clinical application. Therefore, according to the latest preclinical experimental research progress at home and abroad, the history of xenotransplantation, the development of gene modification technology, xenotransplantation rejection and immunosuppression regimens were reviewed, aiming to provide reference for subsequent research of xenotransplantation, promote clinical application of xenotransplantation and bring benefits to more patients with end-stage diseases.