Ischemia-free liver transplantation improves the prognosis of recipients using functionally marginal liver grafts.

BACKGROUND/AIMS: The shortage of donor liver hinders the development of liver transplantation. This study aimed to clarify the poor outcomes of functionally marginal liver grafts (FMLs) and provide evidence for the improvement of ischemia-free liver transplantation (IFLT) after FML transplantation. METHODS: Propensity score matching was used to control for confounding factors. The outcomes of the control group and FML group were compared to demonstrate the negative impact of FMLs on liver transplantation patients. We compared the clinical improvements of the different surgical types. To elucidate the underlying mechanism, we conducted bioinformatic analysis based on transcriptome and single-cell profiles. RESULTS: FMLs had a significantly greater hazard ratio (HR: 1.969, P=0.018) than did other marginal livers. A worse 90-day survival (Mortality: 12.3% vs. 5.0%, P=0.007) was observed in patients who underwent FML transplantation. Patients who received FMLs had a significant improvement in overall survival after IFLT (Mortality: 10.4% vs 31.3%, P=0.006). Pyroptosis and inflammation were inhibited in patients who underwent IFLT. The infiltration of natural killer cells was lower in liver grafts from these patients. Bulk transcriptome profiles revealed a positive relationship between IL-32 and Caspase 1 (R=0.73, P=0.01) and between IL-32 and Gasdermin D (R=0.84, P=0.0012). CONCLUSION: FML is a more important negative prognostic parameter than other marginal liver parameters. IFLT might ameliorate liver injury in FMLs by inhibiting the infiltration of NK cells, consequently leading to the abortion of IL-32, which drives pyroptosis in monocytes and macrophages.

How to Preserve Steatotic Liver Grafts for Transplantation.

Liver allograft steatosis is a significant risk factor for postoperative graft dysfunction and has been associated with inferior patient and graft survival, particularly in the case of moderate or severe macrovesicular steatosis. In recent years, the increasing incidence of obesity and fatty liver disease in the population has led to a higher proportion of steatotic liver grafts being used for transplantation, making the optimization of their preservation an urgent necessity. This review discusses the mechanisms behind the increased susceptibility of fatty livers to ischemia-reperfusion injury and provides an overview of the available strategies to improve their utilization for transplantation, with a focus on preclinical and clinical evidence supporting donor interventions, novel preservation solutions, and machine perfusion techniques.

A randomized-controlled trial of ischemia-free liver transplantation for end-stage liver disease.

BACKGROUND & AIMS: Ischemia-reperfusion injury (IRI) has thus far been considered as an inevitable component of organ transplantation, compromising outcomes, and limiting organ availability. Ischemia-free organ transplantation is a novel approach designed to avoid IRI, with the potential to improve outcomes. METHODS: In this randomized-controlled clinical trial, recipients of livers from donors after brain death were randomly assigned to receive either an ischemia-free or a 'conventional' transplant. The primary endpoint was the incidence of early allograft dysfunction. Secondary endpoints included complications related to graft IRI. RESULTS: Out of 68 randomized patients, 65 underwent transplants and were included in the analysis. 32 patients received ischemia-free liver transplantation (IFLT), and 33 received conventional liver transplantation (CLT). Early allograft dysfunction occurred in two recipients (6%) randomized to IFLT and in eight (24%) randomized to CLT (difference -18%; 95% CI -35% to -1%; p = 0.044). Post-reperfusion syndrome occurred in three recipients (9%) randomized to IFLT and in 21 (64%) randomized to CLT (difference -54%; 95% CI -74% to -35%; p <0.001). Non-anastomotic biliary strictures diagnosed with protocol magnetic resonance cholangiopancreatography at 12 months were observed in two recipients (8%) randomized to IFLT and in nine (36%) randomized to CLT (difference, -28%; 95% CI -50% to -7%; p = 0.014). The comprehensive complication index at 1 year after transplantation was 30.48 (95% CI 23.25-37.71) in the IFLT group vs. 42.14 (95% CI 35.01-49.26) in the CLT group (difference -11.66; 95% CI -21.81 to -1.51; p = 0.025). CONCLUSIONS: Among patients with end-stage liver disease, IFLT significantly reduced complications related to IRI compared to a conventional approach. CLINICAL TRIAL REGISTRATION: chictr.org. ChiCTR1900021158. IMPACT AND IMPLICATIONS: Ischemia-reperfusion injury has thus far been considered as an inevitable event in organ transplantation, compromising outcomes and limiting organ availability. Ischemia-free liver transplantation is a novel approach of transplanting donor livers without interruption of blood supply. We showed that in patients with end-stage liver disease, ischemia-free liver transplantation, compared with a conventional approach, led to reduced complications related to ischemia-reperfusion injury in this randomized trial. This new approach is expected to change the current practice in organ transplantation, improving transplant outcomes, increasing organ utilization, while providing a clinical model to delineate the impact of organ injury on alloimmunity.

Performance assessment of medical service for organ transplant department based on diagnosis-related groups: A programme incorporating ischemia-free liver transplantation in China.

Background: In July 2017, the first affiliated hospital of Sun Yat-sen university carried out the world's first case of ischemia-free liver transplantation (IFLT). This study aimed to evaluate the performance of medical services pre- and post-IFLT implementation in the organ transplant department of this hospital based on diagnosis-related groups, so as to provide a data basis for the clinical practice of the organ transplant specialty. Methods: The first pages of medical records of inpatients in the organ transplant department from 2016 to 2019 were collected. The China version Diagnosis-related groups (DRGs) were used as a risk adjustment tool to compare the income structure, service availability, service efficiency and service safety of the organ transplant department between the pre- and post-IFLT implementation periods. Results: Income structure of the organ transplant department was more optimized in the post-IFLT period compared with that in the pre-IFLT period. Medical service performance parameters of the organ transplant department in the post-IFLT period were better than those in the pre-IFLT period. Specifically, case mix index values were 2.65 and 2.89 in the pre- and post-IFLT periods, respectively (p = 0.173). Proportions of organ transplantation cases were 14.16 and 18.27%, respectively (p < 0.001). Compared with that in the pre-IFLT period, the average postoperative hospital stay of liver transplants decreased by 11.40% (30.17 vs. 26.73 days, p = 0.006), and the average postoperative hospital stay of renal transplants decreased by 7.61% (25.23 vs.23.31 days, p = 0.092). Cost efficiency index decreased significantly compared with that in the pre-IFLT period (p < 0.001), while time efficiency index fluctuated around 0.83 in the pre- and post-IFLT periods (p = 0.725). Moreover, the average postoperative hospital stay of IFLT cases was significantly shorter than that of conventional liver transplant cases (p = 0.001). Conclusion: The application of IFLT technology could contribute to improving the medical service performance of the organ transplant department. Meanwhile, the DRGs tool may help transplant departments to coordinate the future delivery planning of medical service.

Abrogation of graft ischemia-reperfusion injury in ischemia-free liver transplantation.

BACKGROUND: Ischemia-reperfusion injury (IRI) is considered an inherent component of organ transplantation that compromises transplant outcomes and organ availability. The ischemia-free liver transplantation (IFLT) procedure has been developed to avoid interruption of blood supply to liver grafts. It is unknown how IFLT might change the characteristics of graft IRI. METHODS: Serum and liver biopsy samples were collected from IFLT and conventional liver transplantation (CLT) recipients. Pathological, metabolomics, transcriptomics, and proteomics analyses were performed to identify the characteristic changes in graft IRI in IFLT. RESULTS: Peak aspartate aminotransferase (539.59 ± 661.76 U/L versus 2622.28 ± 3291.57 U/L) and alanine aminotransferase (297.64 ± 549.50 U/L versus 1184.16 ± 1502.76 U/L) levels within the first 7 days and total bilirubin levels by day 7 (3.27 ± 2.82 mg/dl versus 8.33 ± 8.76 mg/dl) were lower in the IFLT versus CLT group (all p values < 0.001). The pathological characteristics of IRI were more obvious in CLT grafts. The antioxidant pentose phosphate pathway remained active throughout the procedure in IFLT grafts and was suppressed during preservation and overactivated postrevascularization in CLT grafts. Gene transcriptional reprogramming was almost absent during IFLT but was profound during CLT. Proteomics analysis showed that "metabolism of RNA" was the major differentially expressed process between the two groups. Several proinflammatory pathways were not activated post-IFLT as they were post-CLT. The activities of natural killer cells, macrophages, and neutrophils were lower in IFLT grafts than in CLT grafts. The serum levels of 14 cytokines were increased in CLT versus IFLT recipients. CONCLUSIONS: IFLT can largely avoid the biological consequences of graft IRI, thus has the potential to improve transplant outcome while increasing organ utilization.

Current status and prospect of surgical technique of liver transplantation / 器官移植

Along with the increasing quantity of patients with end-stage liver diseases year by year, as an efficacious treatment, the safety and efficacy of liver transplantation are critical issues to be considered. In addition, liver transplant techniques have become a new research hot spot. In recent years, liver transplant techniques are constantly innovating and developing with the unremitting efforts of researchers. Researchers have successively developed multiple liver transplant techniques, such as split liver transplantation, ischemia-free liver transplantation, liver xenotransplantation, domino liver transplantation, delayed total hepatectomy combined with liver resection and segment Ⅱ-Ⅲ liver transplantation, heterotopic auxiliary liver transplantation on splenic fossa and magnetic anastomosis. It has laid a foundation for expanding the donor pool, improving clinical efficacy of liver transplantation and enhancing the quality of life of liver transplant recipients. In this article, the exploration, development, innovation and improvement of liver transplant techniques were reviewed and prospected, aiming to provide reference for clinical application of liver transplantation.

Normothermic machine perfusion of kidney and ischemia-free kidney transplantation / 器官移植

To increase the utilization rate of expanded criteria donor (ECD) kidney, the kidney preservation methods have been ever advancing in recent years. The application of normothermic machine perfusion (NMP) promotes the preservation, evaluation and repair of ex vivo donor kidneys and accelerates the innovation of surgical approaches of kidney transplantation. Ischemia-free kidney transplantation (IFKT), which initiated by Organ Transplantation Center of the First Affiliated Hospital of Sun Yat-sen University, keeps the blood flow and oxygen supply of the donor kidney with NMP machine during the entire process of acquisition, preservation and transplantation, thereby fundamentally avoiding ischemia-reperfusion injury (IRI) of the donor kidney and reducing the risk of delayed graft function (DGF) and acute rejection after surgery. In this article, recent progresses upon the kidney NMP, surgical procedures and short-term outcomes of IFKT were reviewed, aiming to provide reference for enhancing the utilization rate of ECD donor kidney and resolving the issue of organ shortage.

A marginal liver graft with hyperbilirubinemia transplanted successfully by ischemia-free liver transplantation.

The shortage of transplant organs remains a serious issue worldwide, and using liver grafts from extended criteria donors could expand the donor pool. Extended criteria donor liver allografts have a high chance of complications such as primary nonfunction, early allograft dysfunction, and ischemic-type biliary lesions. How to employ these extended criteria donors safely and effectively warrants further investigation. Herein, we report the successful use of a marginal donor liver with hyperbilirubinemia to save the life of an acute-on-chronic liver failure recipient using a new surgical technique: ischemia-free liver transplantation (IFLT). The graft was retrieved for transplantation due to the following reasons: (I) the recipient was in a life-threatening situation and no living donor donation candidate was available; (II) the graft was considered transplantable except for cholestasis; and (III) IFLT could reduce ischemia/reperfusion injury (IRI), resuscitate the allograft ex situ, and maintain organ viability before transplantation. The graft was transplanted successfully using the IFLT procedure. Although anatomic biliary stricture occurred after surgery, no IRI-related complications were found during the follow-up. The use of liver grafts from extended criteria donors is safe and effective under IFLT. Additional IFLT clinical studies need to be performed, particularly concerning donor management, graft selection, and ex situ resuscitation.

Non-re-cooling implantation of marginal liver graft after machine perfusion: report of a case.

Early allograft dysfunction (EAD), primary graft nonfunction (PNF) and biliary complications affect postoperative survival after liver transplantation (LT). Ischemia injury is one of the major factors affecting liver allograft functional recovery. Ischemia-free liver transplantation (IFLT) has obvious advantages for the recovery of allograft function and complication incidence compared with conventional procedures. However, its use is limited when the donor and the recipient are not in the same hospital and donors should be donor after brain death (DBD). We propose an approach to avoid double warm ischemic injury by implanting marginal donor liver directly by using normothermic machine perfusion (NMP) without re-cooling. Here, we report the first case of non-re-cooling implantation for marginal donor in LT. Donor liver biopsies before procurement showed 50% macrovesicular steatosis, and the recipient was a 67-year-old man with decompensated cirrhosis secondary to a 21-year hepatitis B virus (HBV) infection. The donor liver was maintained by NMP without re-cooling before implantation. The highest levels of alanine transaminase (ALT) and aspartate transaminase (AST) after surgery were 235 and 1,076 U/L, respectively, on the first postoperative day (POD). The patient was discharged within 2 weeks and showed good recovery. Thus, it is feasible to use Non-re-cooling implantation for marginal donor in LT.

The First Case of Ischemia-Free Kidney Transplantation in Humans.

Background: Ischemia-reperfusion injury (IRI) has been considered an inevitable event in organ transplantation since the first successful kidney transplant was performed in 1954. To avoid IRI, we have established a novel procedure called ischemia-free organ transplantation. Here, we describe the first case of ischemia-free kidney transplantation (IFKT). Materials and Methods: The kidney graft was donated by a 19-year-old brain-dead donor. The recipient was a 47-year-old man with end-stage diabetic nephropathy. The graft was procured, preserved, and implanted without cessation of blood supply using normothermic machine perfusion. Results: The graft appearance, perfusion flow, and urine production suggested that the kidney was functioning well-during the whole procedure. The creatinine dropped rapidly to normal range within 3 days post-transplantation. The levels of serum renal injury markers were low post-transplantation. No rejection or vascular or infectious complications occurred. The patient had an uneventful recovery. Conclusion: This paper marks the first case of IFKT in humans. This innovation may offer a unique solution to optimizing transplant outcomes in kidney transplantation.

Perioperative nursing of a patient with ischemia-free liver transplantation / 中国实用护理杂志

Objective To summarize the perioperative nursing care of a patient with ischemia-free liver transplantation. Methods The nursing measures were developed according to the characteristics of the disease and the individual conditions of the patients: including preoperative psychological care;preoperative preparation; prevention of postoperative infection; meticulous observation of the patient′s conditions, transplanted liver function and postoperative complications; the early guidance of rehabilitation activity, nutritional support treatment and the care of water and electrolyte balance. Results The patient recovered well with careful nursing care and no nursing-related complications occurred, and he was discharged successfully on the 18th day after surgery. Conclusion According to the patient's condition and individual situation, the development of nursing measures can effectively prevent the potential infection, timely discover the changes of the patient′s condition, understand the recovery of the transplanted liver function and observe the related postoperative complications, and help to promote the early recovery of patients.

Ischemia-free liver transplantation (Reports of 3 cases) / 中华器官移植杂志

Objective Ischemia reperfusion injury (IRI) is a major limiting factor of graft survival in organ transplantation.We've established a novel procedure called ischemia-free liver transplantation (IFLT) in big animal study.In this report,we aimed to investigate the feasibility and early outcomes of IFLT.Methods We have performed 3 cases of IFLT during July 23,2017 to August 9,2017.We analyzed the surgical methods,normothermic perfusion parameters,blood gas analysis,liver function tests and complications early after liver transplantation.Pathologic studies and immunohistochemical staining of donor liver biopsies were conducted before procurement,at the end of machine perfusion,as well as after re-vascularization for evaluating IRI.Results The surgical procedures of all 3 patients were successful,without stoppage of blood supply for the liver grafts throughout organ procurement,ex vivo preservation and implantation.During normothermic perfusion,the pH value was stable within the normal range and the lactate levels dropped quickly to lower than detected (＜0.3 mmol/L) within 1.5-3 h.The livers continued to produce bile with the volume of 2-6 mL/h.Hematoxylin and eosin (HE) staining evaluation and TdT-mediated dUTP nick end labeling (TUNEL) assay of biopsies taken from liver tissues before procurement,at the end of machine perfusion and after re-vascularization,showed few necrostic and apoptotic hepatocytes in the liver biopsies.The immunohistochemical staining of IL-1β and vWF suggested no inflammatory cytokine release and sinusoidal endothelial cell activation.The three patients recovered smoothly without rejection,vascular and biliary complications.Conclusion IFLT is a feasible and effective procedure,which is able to overcome the major limitations of conventional procedure.The novel IFLT will become one of the mainstream transplant procedures in the future.