How to apply ex-vivo split liver transplantation safely and feasibly: A three-step approach

BACKGROUND Given the current organ shortage crisis,split liver transplantation(SLT)has emerged as a promising alternative for select end-stage liver disease patients.AIM To introduce an ex-vivo liver graft splitting approach and evaluate its safety and feasibility in SLT.METHODS A retrospective analysis was conducted on the liver transplantation data from cases performed at our center between April 1,2022,and May 31,2023.The study included 25 SLT cases and 81 whole liver transplantation(WLT)cases.Total ex-vivo liver splitting was employed for SLT graft procurement in three steps.Patient outcomes were determined,including liver function parameters,postoperative complications,and perioperative mortality.Group comparisons for categorical variables were performed using theχ²-test.RESULTS In the study,postoperative complications in the 25 SLT cases included hepatic artery thrombosis(n=1)and pulmonary infections(n=3),with no perioperative mortality.In contrast,among the 81 patients who underwent WLT,complications included perioperative mortality(n=1),postoperative pulmonary infections(n=8),abdominal infection(n=1),hepatic artery thromboses(n=3),portal vein thrombosis(n=1),and intra-abdominal bleeding(n=5).Comparative analysis demonstrated significant differences in alanine aminotransferase(176.0 vs 73.5,P=0.000)and aspartate aminotransferase(AST)(42.0 vs 29.0,P=0.004)at 1 wk postoperatively,and in total bilirubin(11.8 vs 20.8,P=0.003)and AST(41.5 vs 26.0,P=0.014)at 2 wk postoperatively.However,the overall incidence of complications was comparable between the two groups(P>0.05).CONCLUSION Our findings suggest that the total ex-vivo liver graft splitting technique is a safe and feasible approach,especially under the expertise of an experienced transplant center.The approach developed by our center can serve as a valuable reference for other transplantation centers.

Using on-site liver 3-D reconstruction and volumetric calculations in split liver transplantation

BACKGROUND： Split liver transplantation increases the number of grafts available for transplantation. Pre-recovery assessment of liver graft volume is essential for selecting suitable recipients. The purpose of this study was to determine the ability and feasibility of constructing a 3-D model to aid in surgical planning and to predict graft weight prior to an in situ division of the donor liver. METHODS： Over 11 months, 3-D volumetric reconstruction of 4 deceased donors was performed using Pathfinder Scout liver volumetric software. Demographic, laboratory, operative, perioperative and survival data for these patients along with donor demographic data were collected prospectively and analyzed retrospectively. RESULTS： The average predicted weight of the grafts from the adult donors obtained from an in situ split procedure were 1130 g （930-1458 g） for the extended right lobe donors and 312 g （222-396 g） for left lateral segment grafts. Actual adult graft weight was 92% of the predicted weight for both the extended right grafts and the left lateral segment grafts. The predicted and actual graft weights for the pediatric donors were 176 g and 210 g for the left lateral segment grafts and 308 g and 280 g for the extended right lobe grafts,respectively. All grafts were transplanted except for the right lobe from the pediatric donors due to the small graft weight.CONCLUSIONS： On-site volumetric assessment of donors provides useful information for the planning of an in situ split and for selection of recipients. This information may expand the donor pool to recipients previously felt to be unsuitable due to donor and/or recipient weight.

Topological approach of liver segmentation based on 3D visualization technology in surgical planning for split liver transplantation

BACKGROUND Split liver transplantation(SLT)is a complex procedure.The left-lateral and right tri-segment splits are the most common surgical approaches and are based on the Couinaud liver segmentation theory.Notably,the liver surface following right trisegment splits may exhibit different degrees of ischemic changes related to the destruction of the local portal vein blood flow topology.There is currently no consensus on preoperative evaluation and predictive strategy for hepatic segmental necrosis after SLT.AIM To investigate the application of the topological approach in liver segmentation based on 3D visualization technology in the surgical planning of SLT.METHODS Clinical data of 10 recipients and 5 donors who underwent SLT at Shenzhen Third People’s Hospital from January 2020 to January 2021 were retrospectively analyzed.Before surgery,all the donors were subjected to 3D modeling and evaluation.Based on the 3D-reconstructed models,the liver splitting procedure was simulated using the liver segmentation system described by Couinaud and a blood flow topology liver segmentation(BFTLS)method.In addition,the volume of the liver was also quantified.Statistical indexes mainly included the hepatic vasculature and expected volume of split grafts evaluated by 3D models,the actual liver volume,and the ischemia state of the hepatic segments during the actual surgery.RESULTS Among the 5 cases of split liver surgery,the liver was split into a left-lateral segment and right trisegment in 4 cases,while 1 case was split using the left and right half liver splitting.All operations were successfully implemented according to the preoperative plan.According to Couinaud liver segmentation system and BFTLS methods,the volume of the left lateral segment was 359.00±101.57 mL and 367.75±99.73 mL,respectively,while that measured during the actual surgery was 397.50±37.97 mL.The volume of segment IV(the portion of ischemic liver lobes)allocated to the right tri-segment was 136.31±86.10 mL,as determined using the topological approach to liver segmentation.However,during the actual surgical intervention,ischemia of the right tri-segment section was observed in 4 cases,including 1 case of necrosis and bile leakage,with an ischemic liver volume of 238.7 mL.CONCLUSION 3D visualization technology can guide the preoperative planning of SLT and improve accuracy during the intervention.The simulated operation based on 3D visualization of blood flow topology may be useful to predict the degree of ischemia in the liver segment and provide a reference for determining whether the ischemic liver tissue should be removed during the surgery.

Outcome of split liver transplantation vs living donor liver transplantation:A systematic review and meta-analysis

BACKGROUND The outcomes of liver transplantation(LT)from different grafts have been studied individually and in combination,but the reports were conflicting with some researchers finding no difference in both short-term and long-term outcomes between the deceased donor split LT(DD-SLT)and living donor LT(LDLT).AIM To compare the outcomes of DD-SLT and LDLT we performed this systematic review and meta-analysis.METHODS This systematic review was performed in compliance with the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines.The following databases were searched for articles comparing outcomes of DD-SLT and LDLT:PubMed;Google Scholar;Embase;Cochrane Central Register of Controlled Trials;the Cochrane Database of Systematic Reviews;and Reference Citation Analysis(https://www.referencecitationanalysis.com/).The search terms used were:“liver transplantation;”“liver transplant;”“split liver transplant;”“living donor liver transplant;”“partial liver transplant;”“partial liver graft;”“ex vivo splitting;”and“in vivo splitting.”RESULTS Ten studies were included for the data synthesis and meta-analysis.There were a total of 4836 patients.The overall survival rate at 1 year,3 years and 5 years was superior in patients that received LDLT compared to DD-SLT.At 1 year,the hazard ratios was 1.44(95%confidence interval:1.16-1.78;P=0.001).The graft survival rate at 3 years and 5 years was superior in the LDLT group(3 year hazard ratio:1.28;95%confidence interval:1.01-1.63;P=0.04).CONCLUSION This meta-analysis showed that LDLT has better graft survival and overall survival when compared to DD-SLT.

Progress of mechanical perfusion in split liver transplantation

Split liver transplantation is an essential means which expand the donor pool currently and the two livers obtained after splitting are marginal donor livers.The adoption of Static Cold Storage during allocation and preservation leads to a higher cold ischemia time,thus increasing the occurrence of related postoperative complications,which limits the further development of split-liver transplantation.Mechanical perfusion as a complement to split liver transplantation can minimize the damage to the marginal donor liver during preservation and reduce the occurrence of ischemia-reperfusion.At present,mechanical perfusion has achieved better efficacy in other types of marginal donor liver transplantation such as DCD,elderly donor liver,fatty liver,and so on.In recent years,mechanical perfusion has also shown great potential for application in split-liver transplantation,and limited clinical studies have shown outstanding therapeutic effects.Therefore,this paper will summarize the research progress and mechanisms related to the application of mechanical perfusion in split liver transplantation in order to promote the application of mechanical perfusion in split liver transplantation and reduce the damage of the organ during preservation.

Current status and perspectives in split liver transplantation

Growing experience with the liver splitting technique and favorable results equivalent to those of whole liver transplant have led to wider application of split liver transplantation(SLT) for adult and pediatric recipients in the last decade. Conversely, SLT for two adult recipients remains a challenging surgical procedure and outcomes have yet to improve. Differences in organ shortages together with religious and ethical issues related to cadaveric organ donation have had an impact on the worldwide distribution of SLT. Despite technical refinements and a better understanding of the complex liver anatomy, SLT remains a technically and logistically demanding surgical procedure. This article reviews the surgical and clinical advances in this field of liver transplantation focusing on the role of SLT and the issues that may lead a further expansion of this complex surgical procedure.

Split liver transplantation in adults

Split liver transplantation(SLT),while widely accepted in pediatrics,remains underutilized in adults. Advancements in surgical techniques and donor-recipient matching,however,have allowed expansion of SLT from utilization of the right trisegment graft to now include use of the hemiliver graft as well. Despite less favorable outcomes in the early experience,better outcomes have been reported by experienced centers and have further validated the feasibility of SLT. Importantly,more than two decades of experience have identified key requirements for successful SLT in adults. When these requirements are met,SLT can achieve outcomes equivalent to those achieved with other types of liver transplantation for adults. However,substantial challenges,such as surgical techniques,logistics,and ethics,persist as ongoing barriers to further expansion of this highly complex procedure. This review outlines the current state of SLT in adults,focusing on donor and recipient selection based on physiology,surgical techniques,surgical outcomes,and ethical issues.

Hepatic flow optimization in full right split liver transplantation

Split liver transplantation for two adults offers a valuable opportunity to expand the donor pool for adult recipients.However,its application is mainly hampered by the physiological limits of these partial grafts.Small for size syndrome is a major concern during transplantation with partial graft and different techniques have been developed in living donor liver transplantation to prevent the graft dysfunction.Herein,we report the first application of synergic approaches to optimise the hepatic hemodynamic in a split liver graft for two adults. A Caucasian woman underwent liver transplantation for alcoholic cirrhosis(MELD 21)with a full right liver graft (S5-S8)without middle hepatic vein.Minor and accessory inferior hepatic veins were preserved by splitting the vena cava;V5 and V8 were anastomosed with a donor venous iliac patch.After implantation,a 16G catheter was advanced in the main portal trunk.Inflow modulation was achieved by splenic artery ligation.Intraportal infusion of PGE1 was started intraoperatively and discontinued after 5 d.Graft function was immediate withnormalization of liver test after 7 d.Nineteen months after transplantation,liver function is normal and graft volume is 110%of the recipient standard liver volume. Optimisation of the venous outflow,inflow modulation and intraportal infusion of PGE1 may represent a valuable synergic strategy to prevent the graft dysfunction and it may increase the safety of split liver graft for two adults.

Split liver transplantation: a reliable approach to expand donor pool

Orthotopic liver transplantation as a successful treatment of end-stage liver disease is hampered by a persistent lack of cadaveric organs. Split liver transplantation, which was first successfully performed by Medical School of Hannover in 1988, has become a mature surgical technique to expand the donor pool. Between 1993 and 1999, split liver transplantation activities have increased in Europe from 1. 2% to 10. 4% in all performed liver transplantations. Current data have strongly supported that the survival rate of patients after split liver transplantation is not significantly different from that of patients after whole-size orthotopic liver transplantation. The most important step of donor graft selection is surgeon' s observation judged by the experience of individual transplant center. The paper aims to provide the guideline of donor selection, hepatic graft splitting, and recipient management as well. DATA SOURCES: Medical School of Hannover has accumulated plentiful experience of split liver transplantation for more than 10 cases ever since 1998. Besides that, we also reviewed a variety of literatures from other famous European and American centers specialized in this field for many years. RESULTS:According to our experience combined with the view points of others, the donor should meet the following criteria as well: (1) age less than 50 years; (2) hemodynamics stable; (3) ICU less than 5 days; (4) Na less than 170 mmol/L or better if less than 150 mmol/L. In 1996 and 1997, the Hamburg group and the UCLA group separately introduced a breakthrough technique performing split liver transplantation in situ. Evidently, the in situ technique has been limited by prolonged time of donor organ procurement , coordination with other organ procurement teams, and even extra burden on donor hospital. Some groups, therefore, have restored the ex situ or bench splitting technique , and fortunately the transplant outcomes of the ex situ technique are equivalent to those of the in situ one. Recently some new techniques have been introduced to split the liver for two adult patients, including the split-cava technique. CONCLUSIONS:It is clear that the most important factor for determining the prognosis of the patient is the time of receiving liver transplantation, not the type of liver transplantation. We still need to pay close attention to the graft to recipient weight ratio (GRWR) and the UNOS classification or MELD score before the patient is subjected to split liver transplantation.

Split liver transplantation:What's unique?

The intraoperative management of split liver transplantation(SLT) has some unique features as compared to routine whole liver transplantations. Only the liver has this special ability to regenerate that confers benefits in survival and quality of life for two instead of one by splitting livers. Primary graft dysfunction may result from small for size syndrome. Graft weight to recipient body weight ratio is significant for both trisegmental and hemiliver grafts. Intraoperative surgical techniques aim to reduce portal hyperperfusion and decrease venous portal pressure. Ischemic preconditioning can be instituted to protect against ischemic reperfusion injury which impacts graft regeneration. Advancement of the technique of SLT is essential as use of split cadaveric grafts expands the donor pool and potentially has an excellent future.

Split liver transplantation: Current developments

In 1988, Rudolf Pichlmayr pioneered split liver transplantation(SLT), enabling the transplantation of one donor liver into two recipients-one pediatric and one adult patient. In the same year, Henri Bismuth and colleagues performed the first full right/full left split procedure with two adult recipients. Both splitting techniques were rapidly adopted within the transplant community. However, a SLT is technically demanding, may cause increased perioperative complications, and may potentially transform an excellent deceased donor organ into two marginal quality grafts. Thus, crucial evaluation of donor organs suitable for splitting and careful screening of potential SLT recipients is warranted. Furthermore, the logistic background of the splitting procedure as well as the organ allocation policy must be adapted to further increase the number and the safety of SLT. Under defined circumstances, in selected patients and at experienced transplant centers, SLT outcomes can be similar to those obtained in full organ LT. Thus, SLT is an important tool to reduce the donor organ shortage and waitlist mortality, especially for pediatric patients and small adults. The present review gives an overview of technical aspects, current developments, and clinical outcomes of SLT.

Chinese expert consensus on evaluation of donor and donor liver for split liver transplantation

With the advent of the era of organ donation after citizen's death,split liver transplantation(SLT)can effectively increase the supply of donor livers and shorten the transplantation wait time for patients,especially pediatric recipients.In recent years,SLT has been performed to varying degrees in many transplant centers in China,and varying levels of efficacy have been achieved.The quality of donors and donor livers for SLT is an important factor affecting the outcome of the surgery.At this stage,it is necessary to reach a consensus on the evaluation of SLT donor and liver donor that is suitable for the conditions in China by combining the well-established experience of the international community with advanced transplantation technology.This approach will aid in enhancing the efficacy of SLT.Based on the experience of experts,a consensus on the evaluation of donors and donor livers for SLT has been formulated in this study,which focuses on evaluation of donors and donor livers,evaluating the functional and anatomical aspects of the donor liver and donorerecipient matching.

Complete or partial split in associating liver partition and portal vein ligation for staged hepatectomy: A systematic review and meta-analysis

BACKGROUND Associating liver partition and portal vein ligation for staged hepatectomy(ALPPS)has been adopted by liver surgeons in recent years.However,high morbidity and mortality rates have limited the promotion of this technique.Some recent studies have suggested that ALPPS with a partial split can effectively induce the growth of future liver remnant(FLR)similar to a complete split with better postoperative safety profiles.However,some others have suggested that ALPPS can induce more rapid and adequate FLR growth,but with the same postoperative morbidity and mortality rates as in partial split of the liver parenchyma in ALPPS(p-ALPPS).AIM To perform a systematic review and meta-analysis on ALPPS and p-ALPPS.METHODS A systematic literature search of PubMed,Embase,the Cochrane Library,and ClinicalTrials.gov was performed for articles published until June 2019.Studies comparing the outcomes of p-ALPPS and ALPPS for a small FLR in consecutive patients were included.Our main endpoints were the morbidity,mortality,and FLR hypertrophy rates.We performed a subgroup analysis to evaluate patients with and without liver cirrhosis.We assessed pooled data using a random-effects model.RESULTS Four studies met the inclusion criteria.Four studies reported data on morbidity and mortality,and two studies reported the FLR hypertrophy rate and one study involved patients with cirrhosis.In the non-cirrhotic group,p-ALPPS-treated patients had significantly lower morbidity and mortality rates than ALPPStreated patients[odds ratio(OR)=0.2;95%confidence interval(CI):0.07–0.57;P=0.003 and OR=0.16;95%CI:0.03-0.9;P=0.04].No significant difference in the FLR hypertrophy rate was observed between the two groups(P>0.05).The total effects indicated no difference in the FLR hypertrophy rate or perioperative morbidity and mortality rates between the ALPPS and p-ALPPS groups.In contrast,ALPPS seemed to have a better outcome in the cirrhotic group.CONCLUSION The findings of our study suggest that p-ALPPS is safer than ALPPS in patients without cirrhosis and exhibits the same rate of FLR hypertrophy.

Beyond the Pediatric end-stage liver disease system: Solutions for infants with biliary atresia requiring liver transplant

Biliary atresia(BA), a chronic progressive cholestatic disease of infants, is the leading cause for liver transplant in children, especially in patients under two years of age. BA can be successfully treated with the Kasai portoenterostomy; however most patients still require a liver transplant, with up to one half of BA children needing a transplant by age two. In the current pediatric end-stage liver disease system, children with BA face the risk of not receiving a liver in a safe and timely manner. In this review, we discuss a number of possible solutions to help these children. We focus on two general approaches:(1) preventing/delaying need for transplantation, by optimizing the success of the Kasai operation; and(2) expediting transplantation when needed, by performing techniques other than the standard deceased-donor, whole, ABO-matched organ transplant.

Role of basic studies in expanding the donor pool for liver transplantation

BACKGROUND: Liver transplantation is an effective treatment for end-stage liver disease, but a huge gap remains between the number of people who need a liver transplant and the number of organs available. In order to maximize donor organ access for adult and pediatric recipients, novel surgical and liver replacement procedures have evolved. Newer surgical techniques include split cadaveric liver transplantation and living donor liver transplantation (LDLT). With marginal and abnormal donor livers, despite tremendous advances in surgical technology, individual surgical procedure can not be completely brought into play unless effective measurements and basal studies are undertaken. DATA SOURCES: A literature search of MEDLINE and the Web of Science database using 'liver transplantation' and 'expanding donor pool' was conducted and research articles were reviewed. RESULTS: Therapies directed toward scavenging O(2-), inhibiting nicotinamide adenine dinucleotide phosphate oxidase, and/or immuno-neutralizing tumor necrosis factor-alpha may prove useful in limiting the liver injury induced by surgical procedures such as split liver transplantation or LDLT. Improved donor organ perfusion and preservation methods, modulation of inflammatory cytokines, energy status enhancement, microcirculation amelioration, and antioxidant usage can improve non-heart beating donor liver transplantation. Effective measures have been taken to improve the local conditions of donor cells with steatosis, including usage of fat-derived hormone and inflammatory mediators, ischemic preconditioning, depletion of Kupffer cells, and cytokine antibody and gene therapy. Double-filtration plasmapheresis can effectively reduce HCV viremia and prevent HCV recurrence in patient with high HCV RNA levels after LDLT. CONCLUSIONS: Shortage of grafts and poor function of marginal and abnormal donor grafts put many patients at risk of death in waiting for liver transplantation. Advances in surgical technology, combined with improvement and breakthroughs in basic studies hold a promise in expanding the liver donor pool.

Current developments in pediatric liver transplantation

In 1953, the pioneer of human orthotopic liver transplantation(LT), Thomas E Starzl, was the first to attempt an orthotopic liver transplant into a 3 years old patient suffering from biliary atresia. Thus, the first LT in humans was attempted in a disease, which, up until today, remains the main indication for pediatric LT(p LT). During the last sixty years, refinements in diagnostics and surgical technique, the introduction of new immunosuppressive medications and improvements in perioperative pediatric care have established LT as routine procedure for childhood acute and chronic liver failure as well as inherited liver diseases. In contrast to adult recipients, p LT differs greatly in indications for LT, allocation practice, surgical technique, immunosuppression and postoperative life-long aftercare. Many aspects are focus of ongoing preclinical and clinical research. The present review gives an overview of current developments and the clinical outcome of p LT, with a focus on alternatives to full-size deceased-donor organ transplantation.

Is there new hope for patients with marginally resectable liver malignancies?

Advances in surgical technique and better perioperative management have significantly improved patient outcomes after liver surgery. Even major hepatectomy can be performed safely with low morbidity and mortality. Post-resection liver failure is among the most feared complications after extended hepatectomy. In order to increase the future liver remnant (FLR) and to expand the pool of candidates for surgical resection, Schnitzbauer et al recently presented a new 2-stage surgical approach which combines right portal vein ligation (rPVL) with in situ splitting (ISS) of the liver parenchyma. In comparison to other current strategies, such as interventional portal vein embolization, hypertrophy of the FLR was more pronounced (median volume increase = 74%; range: 21%-192%) and more rapid (after a median of 9 d; range:5-28 d) after rPVL and ISS. In this commentary, we discuss the technical aspects and clinical impact of rPVL combined with ISS. Based on the reported data, this new 2-stage therapeutic approach represents a promising new strategy for patients with locally advanced liver disease, previously regarded as marginally resectable or even unresectable, potentially enabling curative resection. However, morbidity is significant and mortality not negligible.

Liver resections for liver transplantations

Split-Liver and living-related donor liver transplantation are the newest and both technically and ethically most challenging developments in liver transplantation and have contributed to a reduction in donor shortage.We report the technical aspects of surgical procedures performed to achieve a partial graft from a cadaveric and a live donor.

劈离式供肝儿童肝移植门静脉并发症的诊断与治疗

目的探讨劈离式供肝儿童肝移植门静脉并发症的诊断及治疗策略。方法回顾性分析接受劈离式肝移植的88例儿童受者的临床资料。术中根据受者门静脉内径、发育情况,利用门静脉左右分支处进行吻合或间置供者髂静脉搭桥吻合,围手术期采用规范化的门静脉血流监测,术后按肝素钠桥接华法林的方案进行抗凝治疗。经增强CT或门静脉造影确诊门静脉狭窄或血栓形成后,予切开取栓、全身抗凝、介入下取栓、球囊扩张和(或)支架置入等处理。结果88例受者中共10例患儿确诊门静脉并发症,其中4例门静脉狭窄,确诊时间分别为术后1 d、2个月、8个月、11个月,6例门静脉血栓形成,确诊时间分别为术中、术后2 d、术后3 d(2例)、术后6 d、术后11个月。1例门静脉狭窄者和1例门静脉血栓形成者于围手术期死亡,门静脉并发症相关病死率为2%(2/88)。其余8例患者中,1例行全身抗凝治疗、2例行门静脉切开取栓术、1例行介入下球囊扩张、4例行介入下球囊扩张及支架置入,术后均长期随访,未再出现门静脉相关症状,复查门静脉血流参数正常。结论规范化的术中及术后门静脉血流监测有助于早期发现门静脉并发症,及时采取术中门静脉切开取栓,术后介入下球囊扩张、支架置入等手段可有效治疗门静脉并发症,减少门静脉并发症导致的移植物丢失和受者死亡。

Host factors are dominant in the development of post-liver transplant non-alcoholic steatohepatitis

Non-alcoholic fatty liver disease(NAFLD) is a recognized problem in patients after orthotopic liver transplantation and may lead to recurrent graft injury. As the increased demand for liver allografts fail to match the available supply of donor organs, split liver transplantation(SLT) has emerged as an important technique to increase the supply of liver grafts. SLT allows two transplants to occur from one donor organ, and provides a unique model for observing the pathogenesis of NAFLD with respect to the role of recipient environmental and genetic factors. Here we report on two recipients of a SLT from the same deceased donor where only one developed non-alcoholic steatohepatitis(NASH), suggesting that host factors are critical for the development of NASH.