Liver transplantation as an alternative for the treatment of non-resectable liver colorectal cancer: Advancing the therapeutic algorithm

Colorectal cancer is a leading cause of cancerrelated mortality,with nearly half of the affected patients developing liver metastases.For three decades,liver resection(LR)has been the primary curative strategy,yet its applicability is limited to about 20%of cases.Liver transplantation(LT)for unresectable metastases was attempted unsuccessfully in the 1990s,with high rates of perioperative death and recurrence.There is now more interest in this strategy due to improvements in systemic therapies and surgical techniques.A significant study conducted by the Oslo group showed that patients receiving liver transplants had a 60%chance of survival after five years.Significantly better results have been achieved by using advanced imaging for risk stratification and further refining selection criteria,especially in the Norvegian SECA trials.This review carefully charts the development and history of LT as a treatment option for colorectal cancer liver metastases.The revolutionary path from the early days of exploratory surgery to the current situation of cautious optimism is traced,highlighting the critical clinical developments and improved patient selection standards that have made LT a potentially curative treatment for such challenging very well selected cases.

Right versus left fully robotic live donor nephrectomy and open kidney transplantation:Does the laterality of the donor kidney really matter?

Objective Robotic-assisted live donor nephrectomy(LDN)is being gradually adopted across transplant centers.The left donor kidney is preferred over right due to anatomical factors and ease of procurement.We aimed to study donor and recipient outcomes after robotic procurement and subsequent open implantation of right and left kidneys.Methods All fully robotic LDNs and their corresponding open kidney transplants performed at our center between February 2016 and December 2021 were retrospectively analyzed.Results Out of 196 robotic LDN(49[right]vs.147[left]),10(5.1%)donors had intra-operative events(6.1%[right]vs.4.8%[left],p=0.71).None of the LDN required conversion to open surgery.The operative times were comparable for the two groups.Nausea(13.3%)was the most common post-operative complication.There was no mortality in either LDN group.Herein,we report our outcomes on 156 recipients(39 right and 117 left allografts)excluding robotic implants,exports,and pediatric recipients.There were no significant differences between right and left kidney recipients with respect to 1-year post-transplant patient survival(100.0%vs.98.1%,p=0.45)or graft survival(93.9%vs.97.1%,p=0.11),or delayed graft function(7.7%vs.5.1%,p=0.55).Conclusion Non-hand-assisted robotic live donor nephrectomies can be safely performed with excellent outcomes.Right LDN was not associated with higher incidence of complications compared to left LDN.Open implantation of robotically procured right renal allografts was not associated with higher risk of recipient complications.

Analysis of the effects of donor and recipient hepatitis C infection on kidney transplant outcomes in the United States

BACKGROUND As Hepatitis C virus infection(HCV+)rates in kidney donors and transplant recipients rise,direct-acting antivirals(DAA)may affect outcomes.AIM To analyze the effects of HCV+in donors,recipients,or both,on deceased-donor(DD)kidney transplantation(KT)outcomes,and the impact of DAAs on those effects.METHODS The Organ Procurement and Transplantation Network data of adult first solitary DD-KT recipients 1994-2019 were allocated into four groups by donor and recipient HCV+status.We performed patient survival(PS)and death-censored graft survival(DCGS)pairwise comparisons after propensity score matching to assess the effects of HCV+in donors and/or recipients,stratifying our study by DAA era to evaluate potential effect modification.RESULTS Pre-DAA,for HCV+recipients,receiving an HCV+kidney was associated with 1.28-fold higher mortality(HR 1.151.281.42)and 1.22-fold higher death-censored graft failure(HR 1.081.221.39)compared to receiving an HCV-kidney and the absolute risk difference was 3.3%(95%CI:1.8%-4.7%)for PS and 3.1%(95%CI:1.2%-5%)for DCGS at 3 years.The HCV dual-infection(donor plus recipient)group had worse PS(0.56-fold)and DCGS(0.71-fold)than the dual-uninfected.Donor HCV+derived worse post-transplant outcomes than recipient HCV+(PS 0.36-fold,DCGS 0.34-fold).In the DAA era,the risk associated with HCV+in donors and/or recipients was no longer statistically significant,except for impaired PS in the dual-infected vs dual-uninfected(0.43-fold).CONCLUSION Prior to DAA introduction,donor HCV+negatively influenced kidney transplant outcomes in all recipients,while recipient infection only relatively impaired outcomes for uninfected donors.These adverse effects disappeared with the introduction of DAA.

Sarcopenia in cirrhotic patients: Does frailty matter while waiting for a liver transplant?

Sarcopenia reflects patient frailty and should be routinely assessed due to its high prevalence in cirrhotic patients awaiting liver transplants.Pre-transplant nutritional optimization should be tailored for patients with a definitive diagnosis of sarcopenia,therefore improving functional status at transplant and reducing posttransplant mortality.Hepatologists and transplant surgeons should have raised awareness regarding sarcopenia and the reflected frailty that hinder posttransplant outcomes.The policymakers should also take into account when modifying the organ allocation model that sarcopenia or frailty might become a decisive factor in allocating organs for cirrhotic patients,in order to ensure post-transplant survival and quality of life.

Sarcopenic obesity in patients awaiting liver transplant: Unique challenges for nutritional recommendations

Sarcopenic obesity increases the risk of mortality in patients with liver disease awaiting liver transplantation and in the post-transplant period.Nutrition recommendations for individuals with sarcopenia differ from recommendations for patients with obesity or sarcopenic obesity.While these nutrition guidelines have been established in non-cirrhotic patients,established guidelines for liver transplant candidates with sarcopenic obesity are lacking.In this paper,we review existing literature on sarcopenic obesity in patients with chronic liver disease and address opportunities to improve nutritional counseling in patients awaiting liver transplantation.

Role of nitric oxide in liver transplantation:Should it be routinely used?

Ischemia-reperfusion injury(IRI) continues to be a major contributor to graft dysfunction, thus supporting the need for therapeutic strategies focused on minimizing organ damage especially with growing numbers of extended criteria grafts being utilized which are more vulnerable to cold and warm ischemia. Nitric oxide(NO·) is highly reactive gaseous molecule found in air and regarded as a pollutant. Not surprising, it is extremely bioactive, and has been demonstrated to play major roles in vascular homeostasis, neurotransmission, and host defense inflammatory reactions. Under conditions of ischemia, NO· has consistently been demonstrated to enhance microcirculatory vasorelaxation and mitigate pro-inflammatory responses, making it an excellent strategy for patients undergoing organ transplantation. Clinical studies designed to test this hypothesis have yielded very promising results that includes reduced hepatocellular injury and enhanced graft recovery without any identifiable complications. By what means NO· facilitates extra-pulmonary actions is up for debate and speculation. The general premise is that they are NO· containing intermediates in the circulation, that ultimately mediate either direct or indirect effects. A plethora of data exists explaining how NO·-containing intermediate molecules form in the plasma as S-nitrosothiols(e.g., S-nitrosoalbumin), whereas other compelling data suggest nitrite to be a protective mediator. In this article, we discuss the use of inhaled NO· as a way to protect the donor liver graft against IRI in patients undergoing liver transplantation.

Reactivation of hepatitis B after liver transplantation: Current knowledge, molecular mechanisms and implications in management

Chronic hepatitis B(CHB) is a major global health problem affecting an estimated 350 million people with more than 786000 individuals dying annually due to complications, such as cirrhosis, liver failure and hepatocellular carcinoma(HCC). Liver transplantation(LT) is considered gold standard for treatment of hepatitis B virus(HBV)-related liver failure and HCC. However, post-transplant viral reactivation can be detrimental to allograft function, leading to poor survival. Prophylaxis with high-dose hepatitis B immunoglobulin(HBIG) and anti-viral drugs have achieved remarkable progress in LT by suppressingviral replication and improving long-term survival. The combination of lamivudine(LAM) plus HBIG has been for many years the most widely used. However, life-long HBIG use is both cumbersome and costly, whereas long-term use of LAM results in resistant virus. Recently, in an effort to develop HBIG-free protocols, high potency nucleos(t)ide analogues, such as Entecavir or Tenofovir, have been tried either as monotherapy or in combination with low-dose HBIG with excellent results. Current focus is on novel antiviral targets, especially for covalently closed circular DNA(ccc DNA), in an effort to eradicate HBV infection instead of viral suppression. However, there are several other molecular mechanisms through which HBV may reactivate and need equal attention. The purpose of this review is to address post-LT HBV reactivation, its risk factors, underlying molecular mechanisms, and recent advancements and future of anti-viral therapy.

Diaphragmatic hernia after right donor and hepatectomy: a rare donor complication of partial hepatectomy for transplantation

BACKGROUND: Because of the critical worldwide shortage of cadaveric organ donors, transplant professionals have increasingly turned to living donors. Partial hepatectomy for adult living donor liver transplantation has been performed since the late 1990s. Most often,the complications of living donor hepatectomy have been related to the biliary tract, specifically biliary leaks. METHODS: A 54-year-old man underwent donor right hepatectomy for living donor liver transplantation. Three years after liver donation he presented with upper abdominal pain and fullness. Radiographic workup revealed a diaphragmatic hernia of the right hemithorax. RESULTS: After thoracoscopic evaluation of the right hemithorax, diaphragmatic hernia was repaired. Currently the patient remains well several months after the repair with complete resolution of abdominal pain, normal chest X-ray examination demonstrating no recurrence of diaphragmatic hernia, and normal liver functions tests. CONCLUSIONS: Multiple complications of living donor liver transplantation have been described the transplant literature. Diaphragmatic hernia is a formerly-undescribed complication of right donor hepatectomy for transplantation.

Utility of liver biopsy in predicting clinical outcomes after percutaneous angioplasty for hepatic venous obstruction in liver transplant patients

AIM: To determine utility of transplant liver biopsy in evaluating efficacy of percutaneous transluminal angioplasty(PTA) for hepatic venous obstruction(HVOO). METHODS: Adult liver transplant patients treated with PTA for HVOO(2003-2013) at a single institution were reviewed for pre/post-PTA imaging findings, manometry(gradient with right atrium), presence of HVOO on prePTA and post-PTA early and late biopsy(EB and LB, < or > 60 d after PTA), and clinical outcome, defined as good(no clinical issues, non-HVOO-related death) or poor(surgical correction, recurrent HVOO, or HVOOrelated death). RESULTS: Fifteen patients meeting inclusion criteria underwent 21 PTA, 658 ± 1293 d after transplant.In procedures with pre-PTA biopsy(n = 19), no difference was seen between pre-PTA gradient in 13/19 procedures with HVOO on biopsy and 6/19 procedures without HVOO(8 ± 2.4 mm Hg vs 6.8 ± 4.3 mm Hg; P = 0.35). Post-PTA, 10/21 livers had EB(29 ± 21 d) and 9/21 livers had LB(153 ± 81 d). On clinical follow-up(392 ± 773 d), HVOO on LB resulted in poor outcomes and absence of HVOO on LB resulted good outcomes. Patients with HVOO on EB(3/7 good, 4/7 poor) and no HVOO on EB(2/3 good, 1/3 poor) had mixed outcomes. CONCLUSION: Negative liver biopsy greater than 60 d after PTA accurately identifies patients with good clinical outcomes.

Limitations of current liver transplant immunosuppressive regimens: renal considerations

BACKGROUND： The use of calcineurin inhibitor （CNI）-based immunosuppressive regimens following liver transplantation （LTx） has improved the outcomes of the recipients. However, CNI has nephrotoxicity and causes shortand long-term renal complications. The progressive structural changes can be irreversible in the long-term, leading to chronic kidney dysfunction. The present review was to evaluate the different strategies of CNI application to renal function in liver recipients. DATA SOURCES： PubMed database was searched for relevant articles in English on the issue of immunosuppressive regimen and kidney injury that related to early minimization of CNI after LTx. RESULTS： Total avoidance of CNI from post-LTx immunosuppressive regimens has been associated with unacceptable high rates of acute, steroid resistant rejections; late conversion from CNI to non-nephrotoxic immunosuppressant failed to recover renal function. Early CNI minimization and conversion to non-nephrotoxic immunosuppressant, although had no effect on patient survival rates, improved glomerular filtration rate. The combination of everolimus （a mammalian target of rapamycin inhibitor） and tacrolimus not only maintains immunosuppressive efficacy but also minimizes kidney injury. CONCLUSIONS： Up to now, protocols entirely avoiding CNI have not passed the primary safety endpoint of patient and graft survival, as well as the FDA mandated endpoint of biopsy proven acute rejection. Thus, early CNI minimization after LTx is the most rational approach preserving post-transplant renal function.

Rituximab or plasmapheresis for prevention of recurrent focal segmental glomerulosclerosis after kidney transplantation:A systematic review and meta-analysis

BACKGROUND Focal segmental glomerulosclerosis(FSGS)is one of the most common glomerular diseases leading to renal failure.FSGS has a high risk of recurrence after kidney transplantation.Prevention of recurrent FSGS using rituximab and/or plasmapheresis has been evaluated in multiple small studies with conflicting results.AIM To assess the risk of recurrence of FSGS after transplantation using prophylactic rituximab with or without plasmapheresis,and plasmapheresis alone compared to the standard treatment group without preventive therapy.METHODS This meta-analysis and systematic review were performed by first conducting a literature search of the MEDLINE,EMBASE,and Cochrane databases,from inception through March 2021;search terms included‘FSGS,’’steroid-resistant nephrotic syndrome’,‘rituximab,’and‘plasmapheresis,’.We identified studies that assessed the risk of post-transplant FSGS after use of rituximab with or without plasmapheresis,or plasmapheresis alone.Inclusion criteria were:Original,published,randomized controlled trials or cohort studies(either prospective or retrospective),case-control,or cross-sectional studies;inclusion of odds ratio,relative risk,and standardized incidence ratio with 95%confidence intervals(CI),or sufficient raw data to calculate these ratios;and subjects without interventions(controls)being used as comparators in cohort and cross-sectional studies.Effect estimates from individual studies were extracted and combined using a random effects model.RESULTS Eleven studies,with a total of 399 kidney transplant recipients with FSGS,evaluated the use of rituximab with or without plasmapheresis;thirteen studies,with a total of 571 kidney transplant recipients with FSGS,evaluated plasmapheresis alone.Post-transplant FSGS recurred relatively early.There was no significant difference in recurrence between the group that received rituximab(with or without plasmapheresis)and the standard treatment group,with a pooled risk ratio of 0.82(95%CI:0.47-1.45,I2=65%).Similarly,plasmapheresis alone was not associated with any significant difference in FSGS recurrence when compared with no plasmapheresis;the pooled risk ratio was 0.85(95%CI:0.60-1.21,I2=23%).Subgroup analyses in the pediatric and adult groups did not yield a significant difference in recurrence risk.We also reviewed and analyzed posttransplant outcomes including timing of recurrence and graft survival.CONCLUSION Overall,the use of rituximab with or without plasmapheresis,or plasmapheresis alone,is not associated with a lower risk of FSGS recurrence after kidney transplantation.Future studies are required to assess the effectiveness of rituximab with or without plasmapheresis among specific patient subgroups with high-risk for FSGS recurrence.

Expanding indications for liver transplantation in the era of liver transplant oncology

Despite numerous advances and emerging data,liver transplantation in the setting of gastrointestinal malignancies remains controversial outside of certain accepted indications.In an era of persistent organ shortage and increasing organ demand,allocation of liver grafts must be considered carefully.While hepatocellular carcinoma and hilar cholangiocarcinoma have become accepted indications for transplantation,tumor size and standardized multi-disciplinary treatment protocols are necessary to ensure optimal patient outcomes.As more studies seeking to expand the oncologic indications for liver transplantation are emerging,it is becoming increasingly clear that tumor biology and response to therapy are key factors for optimal oncologic outcomes.In addition,time from diagnosis to transplantation appears to correlate with survival,as stable disease over time portends better outcomes post-operatively.Identifying aggressive disease pre-transplant remains difficult with current imaging and tissue sampling techniques.While tumor size and stage are important prognostic predictors for most malignancies,patient and tumor selection protocols are necessary.As the fields of medical and surgical oncology continue to evolve,it is clear that a protocolized interdisciplinary treatment approach is necessary for combatting any cancer effectively.Disease stability over time and response to neoadjuvant therapy may be the best predictors for successful patient outcomes and can be easily incorporated in our treatment paradigms.Current data evaluating liver transplantation for expanded oncologic indications such as:expanded criteria hepatocellular carcinoma,intrahepatic cholangiocarcinoma,mixed tumors,and liver limited metastatic colorectal carcinomas,incorporate multi-modal therapies and evaluation of tumor treatment response.While further investigation is necessary,initial results suggest there is an expanded role for transplant surgery in malignancy in a new era of liver transplant oncology.

Detection of Portal Venous Gas by Ultrasonography after Liver Transplantation: A Possible Early Sign of Bacterial Translocation

This Portal venous gas (PVG) is usually associated with intra-abdominal catastrophe. However, there are some reports regarding benign causes of PVG, including the cases related to organ transplantation. We present 3 cases with PVG undergoing living donor liver transplantation (LDLT). All cases simultaneously demonstrated intra-abdominal complications and revealed a bacterial blood culture. We successfully managed all cases with immediate intervention for the possible occurrence of bacterial translocation. Our experience indicates that the detection of PVG by USG is an alarming finding, as a possible early sign of bacterial translocation after liver transplantation. When PVG is detected by USG, it is important to pay prompt attention to bacterial translocation.

Long-Term Management of Post-Transplant Ureteral Stricture with Surgical Reconstruction: A Case Series and Literature Review

Introduction: Ureteral stricture is the most common complication after kidney transplant and is largely responsible for graft dysfunction. Surgical intervention is the definitive treatment if conservative management with stenting and percutaneous nephrostomy tube placement fails and has been shown to have comparable long-term survival rates and limited post-operative complications. Methods: This is a single-center retrospective study following seven patients who received a kidney or a kidney and pancreas transplant between August 2012 and January 2021. These patients underwent surgical ureteral reconstruction after failed conservative management of a ureteral stricture. The reconstruction procedures performed were native ureter to transplanted kidney ureteropyelostomy, native bladder to transplanted renal pelvis vesicopyelostomy, non-transecting side-to-side ureteroneocystostomy, and a Boari flap creation. Data collected from electronic medical records included recipient age, gender, delayed post-transplant complications, ureteral reconstruction technique, and post-reconstruction outcomes. Renal ultrasound (RUS), renogram, nephrostogram, serum creatinine (Cr), and graft biopsy were used to assess for severity of hydronephrosis, ureteral stricture, and graft dysfunction. Serum Cr and RUS were used to assess renal function after the ureteral reconstruction. Results: Six out of seven cases resulted in reduced or resolved hydronephrosis and preserved graft function without future nephrostomy or ureteral stenting. One case required immediate revision due to persistent obstruction, and this patient had concomitant rejection leading to intrarenal stricture requiring ureterocalycostomy. Conclusions: Formal ureteral reconstruction is the definitive treatment for many cases of ureteral strictures after transplant. The surgical technique chosen for these procedures must consider the physical and functional state of the bladder, ureter, and kidney. Our series outlines multiple surgical approaches that should be considered early in the management of post-transplant ureteral strictures to limit graft dysfunction.

The Effect of Non-Invasive Goal Directed Fluid Administration on Graft Function in Deceased Donor Renal Transplantation: A Pilot Study

Background: Non-invasive goal directed fluid therapy during deceased donor renal transplant (CRT) may reduce the incidence of delayed graft function. Plethysmograph Variability Index (PVI) has been shown to predict fluid responsiveness during surgery. This pilot study evaluated the feasibility of goal directed fluid administration protocol based upon PVI studying the incidence of delayed graft function (DGF) in renal transplant recipients. Methods: Twenty patients underwent primary CRT. The Control group received intravenous fluid (IVF) at a calculated constant rate. The Treatment group received a baseline IVF infusion throughout the surgery. PVI values greater than 13% were treated with 250 ml boluses of IVF. Primary end point was DGF;total IVF administration and urinary biomarker NGAL levels were secondary endpoints. Results: Treatment group at every time point received significantly less IVF. There was no significant difference in incidence of DGF between the groups. 2 patients in the Control group and 6 in the Treatment group developed DGF. NGAL was not associated with the group assignment or total IVF given (p < 0.2). Conclusions: The effectiveness of goal directed fluid therapy with non-invasive dynamic parameters has not been validated in renal transplant surgery and larger prospective studies are needed to determine its utility in renal transplantation.

Prognostic and diagnostic scoring models in acute alcoholassociated hepatitis:A review comparing the performance of different scoring systems

Alcohol-associated hepatitis(AAH)is a severe form of liver disease caused by alcohol consumption.In the absence of confounding factors,clinical features and laboratory markers are sufficient to diagnose AAH,rule out alternative causes of liver injury and assess disease severity.Due to the elevated mortality of AAH,assessing the prognosis is a radical step in management.The Maddrey discriminant function(MDF)is the first established clinical prognostic score for AAH and was commonly used in the earliest AAH clinical trials.A MDF>32 indicates a poor prognosis and a potential benefit of initiating corticosteroids.The model for end stage liver disease(MELD)score has been studied for AAH prognostication and new evidence suggests MELD may predict mortality more accurately than MDF.The Lille score is usually combined to MDF or MELD score after corticosteroid initiation and offers the advantage of assessing response to treatment a 4-7 d into the course.Other commonly used scores include the Glasgow Alcoholic Hepatitis Score and the Age Bilirubin international normalized ratio Creatinine model.Clinical AAH correlate adequately with histologic severity scores and leave little indication for liver biopsy in assessing AAH prognosis.AAH presenting as acute on chronic liver failure(ACLF)is so far prognosticated with ACLF-specific scoring systems.New artificial intelligence-generated prognostic models have emerged and are being studied for use in AAH.Acute kidney injury(AKI)is one possible complication of AAH and is significantly associated with increased AAH mortality.Predicting AKI and alcohol relapse are important steps in the management of AAH.The aim of this review is to discuss the performance and limitations of different scoring models for AAH mortality,emphasize the most useful tools in prognostication and review predictors of recurrence.

Liver transplantation: Current status and challenges

Great progress has been made in the field of liver transplantation over the past two decades. This progress, however, also brings up the next set of challenges: First, organ shortage remains a major limitation, and accounts for a large proportion of wait list mortality. While living donation has successfully increased the total number of liver transplants done in Asian countries, the total number of such transplants has been stagnant in the western hemisphere. As such, there has been a significant effort over the past decade to increase the existing deceased donor pool. This effort has resulted in a greater use of liver allografts following donation after cardiac death(DCD) along with marginal and extended criteria donors. Improved understanding of the pathophysiology of liver allografts procured after circulatory arrest has not only resulted in better selection and management of DCD donors, but has also helped in the development of mechanical perfusion strategies. Early outcomes demonstrating the clinical applicability of both hypothermic and normothermic perfusion and its potential to impact patient survival and allograft function have generated much interest. Second, long-term outcomes of liver transplant recipients have not improved significantly, as recipients continue to succumb to complications of long-term immunosuppression, such as infection, malignancy and renal failure. Furthermore, recent evidence suggests that chronic immune-mediated injury to the liver may also impact graft function.

Treatment modalities for hypersplenism in liver transplant recipients with recurrent hepatitis C

Hepatitis C is the most common indication for orthotopic liver transplantation in the United States. Unfortunately, hepatitis C recurs universally in the transplanted liver and is the major cause of decreased graft and patient survival. The combination therapy of interferon and ribavirin has been shown to be the most effective therapy for recurrent hepatitis C. However, pre-and post-transplant hypersplenism often precludes patients from receiving the antiviral therapy. Splenectomy and partial splenic embolization are the two invasive modalities that can correct the cytopenia associated with hypersplenism. In this report we review the two treatment options, their associated outcomes and complications.

An extended treatment protocol with pegylated interferon and ribavirin for hepatitis C recurrence after liver transplantation

AIM: To evaluate the efflicacy and tolerability of an extended treatment protocol and to determine the predictors of sustained virological response (SVR) after liver transplantation (LT).METHODS: Between August 2005 and November 2008, patients with recurrent hepatitis C virus (HCV) after LT were selected for treatment if liver biopsy showed at least grade 2 inflammation and/or stage 2 flibrosis. All patients were to receive pegylated interferon (PEG)/regimens combining ribavirin (RBV) for an additional 48 wk after HCV undetectability.RESULTS: Extended protocol treatment was initiated in thirty patients. Overall, 73% had end of treatmentresponse and 60% had SVR. Nineteen patients completed treatment per protocol, of them, sixteen (84%) had end of treatment response, and fourteen (74%) achieved SVR. Both early virological response and 24-week virological response were individually associated with SVR but this association was not signif icant on multivariate analysis. Eleven patients (37%) discontinued therapy due to adverse effects. Cytopenias were the most common and most severe adverse effect, and required frquent growth factor use, dose adjustments and treatment cessations. The risk of rejection was not increased.CONCLUSION: Recurrent HCV after LT can be safely treated with extended virological responseguided therpy using PEG/RBV, but requires close monitoring for treatment-related adverse effects, particularly cytopenias.

Oxidative stress and extracellular matrices after hepatectomy and liver transplantation in rats

AIM:To investigate oxidative stress(OS)-mediated damage and the behavior of extracellular matrices in various rat models because shear stress with portal hypertension and cold ischemia/warm reperfusion injury trigger the liver regeneration cascade after surgery. These injuries also cause fatal liver damage.METHODS: Rats were divided into four groups according to the surgery performed: control; hepatectomy with 40% liver remnant(60% hepatectomy); orthotopic liver transplantation(OLT) with whole liver graft(100% OLT); and split OLT(SOLT) with 40% graft(40% SOLT). Survival was evaluated. Blood and liver samples were collected at 6 h after surgery. Biochemical and histopathological examinations were performed. OSinduced damage, 4-hydroxynonenal, ataxia-telangiectasia mutated kinase, histone H2AX, phosphatidylinositol 3-kinase(PI3K) and Akt were evaluated by western blotting. Behavior of extracellular matrices, matrix metalloproteinase(MMP)-9, MMP-2, tissue inhibitor of metalloproteinase(TIMP)-1 and TIMP-2 were also evaluated by western blotting and zymography. RESULTS: Although 100% OLT survived, 60% hepatectomy and 40% SOLT showed poor survival. Histopathological, immunohistological, biochemical and protein assays revealed that 60% hepatectomy, 100% OLT and 40% SOLT showed liver damage. PI3K and Akt were decreased in 60% hepatectomy and 40% SOLT. For protein expression, 40% SOLT showed differences in MMP-9, MMP-2 and TIMP-2. TIMP-1 showed differences in 60% hepatectomy and 40% SOLT. For protein activity, MMP-9 demonstrated significant differences in 60% hepatectomy, 100% OLT and 40% SOLT. CONCLUSION: Under conditions with an insufficient liver remnant, prevention of OS-induced damage via the Akt/PI3K pathway may be key to improve the postoperative course. MMP-9 may be also a therapeutic target after surgery.