Acute kidney injury and post-reperfusion syndrome in liver transplantation

In the past decades liver transplantation(LT) has become the treatment of choice for patients with end stage liver disease(ESLD). The chronic shortage of cadaveric organs for transplantation led to the utilization of a greater number of marginal donors such as older donors or donors after circulatory death(DCD). The improved survival of transplanted patients has increased the frequency of long-term complications, in particular chronic kidney disease(CKD). Acute kidney injury(AKI) post-LT has been recently recognized as an important risk factor for the occurrence of denovo CKD in the long-term outcome. The onset of AKI post-LT is multifactorial, with pre-LT risk factors involved, including higher Model for End-stage Liver Disease score, more sever ESLD and pre-existing renal dysfunction, either with intra-operative conditions, in particular ischaemia reperfusion injury responsible for post-reperfusion syndrome(PRS) that can influence recipient's morbidity and mortality. Post-reperfusion syndrome-induced AKI is an important complication post-LT that characterizes kidney involvement caused by PRS with mechanisms not clearly understood and implication on graft and patient survival. Since preLT risk factors may influence intra-operative events responsible for PRS-induced AKI, we aim to consider all the relevant aspects involved in PRS-induced AKI in the setting of LT and to identify all studies that better clarified the specific mechanisms linking PRS and AKI. A Pub Med search was conducted using the terms liver transplantation AND acute kidney injury; liver transplantation AND post-reperfusion syndrome; acute kidney injury AND post-reperfusion syndrome; acute kidney injury AND DCD AND liver transplantation. Five hundred seventy four articles were retrieved on Pub Med search. Results were limited to title/abstract of English-language articles published between 2000 and 2015. Twenty-three studies were identified that specifically evaluated incidence, risk factors and outcome for patients developing PRS-induced AKI in liver transplantation. In order to identify intra-operative risk factors/mechanisms specifically involved in PRSinduced AKI, avoiding confounding factors, we have limited our study to "acute kidney injury AND DCD AND liver transplantation". Accordingly, three out of five studies were selected for our purpose.

Role of gut microbiota-immunity axis in patients undergoing surgery for colorectal cancer:Focus on short and long-term outcomes

Human body is colonized by a huge amount of microorganisms mostly located in the gastrointestinal tract.These dynamic communities,the environment and their metabolites constitute the microbiota.Growing data suggests a causal role of a dysbiotic microbiota in several pathologies,such as metabolic and neurological disorders,immunity dysregulations and cancer,especially the well-studied colorectal cancer development.However,many were preclinical studies and a complete knowledge of the pathogenetic mechanisms in humans is still absent.The gut microbiota can exert direct or indirect effects in different phases of colorectal cancer genesis.For example,Fusobacterium nucleatum promotes cancer through cellular proliferation and some strains of Escherichia coli and Bacteroides fragilis produce genotoxins.However,dysbiosis may also cause a proinflammatory state and the stimulation of a Th17 response with IL-17 and IL-22 secretion that have a pro-oncogenic activity,as demonstrated for Fusobacterium nucleatum.Microbiota has a crucial role in several stages of postoperative course;dysbiosis in fact seems related with surgical site infections and Enterococcus faecalis(and other collagenase-producers microbes)are suggested as a cause of anastomotic leak.Consequently,unbalanced presence of some species,together with altered immune response may also have a prognostic role.Microbiota has also a substantial role in effectiveness of chemotherapy,chemoresistance and in the related side effects.In other words,a complete knowledge of the fine pathological mechanisms of gut microbiota may provide a wide range of new diagnostic tools other than therapeutic targets in the light of tailored medicine.

Gut microbiota and immune system in liver cancer:Promising therapeutic implication from development to treatment

Liver cancer is a leading cause of death worldwide,and hepatocellular carcinoma(HCC)is the most frequent primary liver tumour,followed by cholangiocarcinoma.Notably,secondary tumours represent up to 90% of liver tumours.Chronic liver disease is a recognised risk factor for liver cancer development.Up to 90% of the patients with HCC and about 20% of those with cholangiocarcinoma have an underlying liver alteration.The gut microbiota-liver axis represents the bidirectional relationship between gut microbiota,its metabolites and the liver through the portal flow.The interplay between the immune system and gut microbiota is also well-known.Although primarily resulting from experiments in animal models and on HCC,growing evidence suggests a causal role for the gut microbiota in the development and progression of chronic liver pathologies and liver tumours.Despite the curative intent of“traditional”treatments,tumour recurrence remains high.Therefore,microbiota modulation is an appealing therapeutic target for liver cancer prevention and treatment.Furthermore,microbiota could represent a non-invasive biomarker for early liver cancer diagnosis.This review summarises the potential role of the microbiota and immune system in primary and secondary liver cancer development,focusing on the potential therapeutic implications.

Different behaviour of BK-virus infection in liver transplantrecipients

Polyomavirus BK(BKV) infects up to 90% of the general population. After primary infection, occurring early during childhood, a state of non-replicative infection is established in the reno-urinary tract, without complications for immunocompetent hosts. In immunocompromised individuals, particularly transplanted patients, asymptomatic BKV viremia and/or viruria can be observed. Renal grafts may also be sources of infection as BKV prefers kidneys rather than other solid organs for transplantation such as the liver. The mechanism behind the higher incidence of BKV infection in kidney transplant patients, compared to liver or heart transplantation, is unclear and the prevalence of BKV infection in non-renal solid organ transplants has not been yet thoroughly investigated. We evaluated the prevalence of Polyomavirus BK infection among liver transplant recipients. A Pub Med search was conducted using the terms BKV infection AND liver transplant recipients; BKV AND non-renal solid organ transplant*; BKV infection AND immunosuppression; the search was limited to title/abstract and English-language articles published from 2000, to March 2015. Eleven relevant studies suggest that the prevalence of BKV viruria and/or viremia among liver transplant recipients is less than that reported in kidney or heart transplant recipients, except when chronic kidney disease(CKD) is present at the same time. Data also suggest that viruric and viremic patients have higher levels of serum creatinine than BKV negative patients. Moreover, no specific immunosuppressive drugs are associated with the onset of BKV nephropathy. The comorbidity of transplantation and CKD could play a major role in promoting BKV replication.

Contemporary techniques and outcomes of surgery for locally advanced renal cell carcinoma with focus on inferior vena cava thrombectomy:The value of a multidisciplinary team

Objective:To report the outcomes of surgery for a contemporary series of patients with locally advanced non-metastatic renal cell carcinoma(RCC)treated at a referral academic centre,focusing on technical nuances and on the value of a multidisciplinary team.Methods:We queried our prospective institutional database to identify patients undergoing surgical treatment for locally advanced(cT3-T4 N0-1 M0)renal masses suspected of RCC at our centre between January 2017 and December 2020.Results:Overall,32 patients were included in the analytic cohort.Of these,12(37.5%)tumours were staged as cT3a,8(25.0%)as cT3b,5(15.6%)as cT3c,and 7(21.9%)as cT4;6(18.8%)patients had preoperative evidence of lymph node involvement.Nine(28.1%)patients underwent nephron-sparing surgery while 23(71.9%)received radical nephrectomy.A template-based lymphadenectomy was performed in 12 cases,with evidence of disease in 3(25.0%)at definitive histopathological analysis.Four cases of RCC with level IV inferior vena cava thrombosis were successfully treated using liver transplant techniques without the need for extracorporeal circulation.While intraoperative complications were recorded in 3(9.4%)patients,no postoperative major complications(Clavien-Dindo3)were observed.At histopathological analysis,2(6.2%)patients who underwent partial nephrectomy harboured oncocytoma,while the most common malignant histotype was clear cell RCC(62.5%),with a median Leibovich score of 6(interquartile range 5e7).Conclusion:Locally advanced RCC is a complex and heterogenous disease posing several challenges to surgical teams.Our experience confirms that provided careful patient selection,surgery in experienced hands can achieve favourable perioperative,oncological,and functional outcomes.

Evaluation of prognostic factors and clinicopathological patterns of recurrence after curative surgery for colorectal cancer

BACKGROUND Colorectal cancer is a common tumor with a quite high-related mortality.Despite the used curative treatments,patients will develop cancer recurrence in up to 50%of the cases and/or other primary neoplasms.Although most of the recurrences are discovered within 3 years from the first treatment,a small percentage is found after 5 years.The early detection of recurrence is crucial to allow further therapies improving patients’survival.Several follow-up programs have been developed but the optimal one is far from being established.AIM To evaluation of potential prognostic factors for timing and patterns of recurrence in order to plan tailored follow-up programs.METHODS Perioperative and long-term data of all consecutive patients surgically treated with curative intent,from January 2006 to June 2009,for colorectal adenocarcinoma,were retrospectively reviewed to find potential prognostic factors associated with:(1)Recurrence incidence;(2)Incidence of an early(within 3 years from surgery)or late recurrence;and(3)Different sites of recurrence.In addition,the incidence of other primary neoplasms has been evaluated in a cohort of patients with a minimum potential follow-up of 10 years.RESULTS Our study included 234 patients.The median follow-up period has been 119±46.2 mo.The recurrence rate has been 25.6%.Patients with a higher chance to develop recurrence had also the following characteristics:Higher levels of preoperative glycemia and carcinoembryonic antigen,highest anaesthesiologists Score score,occlusion,received a complex operation performed with an open technique,after a longer hospital stay,and showed advanced tumors.The independent prognostic factors for recurrence were the hospital stay,N stage 2,and M stage 1(multivariate analysis).Younger ages were significantly associated with an early recurrence onset.Patients that received intermediate colectomies or segmental resections,having an N stage 2 or American Joint Committee on Cancer stage 3 tumors were also associated with a higher risk of liver recurrence,while metastatic diseases at diagnosis were linked with local recurrence.Neoadjuvant treatments showed lung recurrence.Finally,bigger tumors and higher lymph node ratio were associated with peritoneal recurrence(marginally significant).Thirty patients developed a second malignancy during the follow-up time.CONCLUSION Several prognostic factors should be considered for tailored follow-up programs,eventually,beyond 5 years from the first treatment.

Evaluating the best treatment for multifocal hepatocellular carcinoma:A propensity score-matched analysis

BACKGROUND Hepatocellular carcinoma(HCC)is a common tumour often diagnosed with a multifocal presentation.Patients with multifocal HCC represent a heterogeneous group.Although Trans-Arterial ChemoEmbolization(TACE)is the most frequently employed treatment for these patients,previous data suggested that liver resection(LR)could be a safe and effective procedure.AIM To compare LR and TACE in patients with multifocal HCC in terms of procedurerelated morbidity and oncologic outcomes.METHODS All patients with multifocal HCC who underwent LR or TACE as the first procedure between May 2011 and March 2021 were enrolled.The decision to perform surgery or TACE was made after a multidisciplinary team evaluation.Only patients in Child-Pugh class A or B7 and stage B(according to the Barcelona Clinic Liver Cancer staging system,without severe portal hypertension,vascular invasion,or extrahepatic spread)were included in the final analysis.Propensity score matching was used to adjust the baseline differences between patients undergoing LR and the TACE group[number and diameter of lesions,presence of cirrhosis,alpha-fetoprotein(AFP)levels,and Model for End-Stage Liver Disease score].The Kaplan-Meier method was used to estimate overall survival(OS)and disease-free survival(DFS).The outcomes of LR and TACE were compared using the log-rank test.RESULTS After matching,30 patients were eligible for the final analysis,15 in each group.Morbidity rates were 42.9% and 40% for LR and TACE,respectively(P=0.876).Median OS was not different in the LR and TACE groups(53 mo vs 18 mo,P=0.312),while DFS was significantly longer with LR(19 mo vs 0 mo,P=0.0001).Subgroup analysis showed that patients in the Italian Liver Cancer(ITA.LI.CA)B2 stage,with AFP levels lower than 400 ng/mL,less than 3 lesions,and lesions bigger than 41 mm,benefited more from LR in terms of DFS.Patients classified as ITA.LI.CA B3,with AFP levels higher than 400 ng/mL and with more than 3 lesions,appeared to receive more benefit from TACE in terms of OS.CONCLUSION In a small cohort of patients with multifocal HCC,LR confers longer DFS compared with TACE,with similar OS and post-procedural morbidity.

Machine perfusion of the liver:Putting the puzzle pieces together

The realm of extended criteria liver transplantation created the'adjacent possible'for dynamic organ preservation.Machine perfusion of the liver greatly expanded donor organ preservation possibilities,reaching before unattainable goals,including the mitigation of ischemia-reperfusion injury,viability assessment,and organ reconditioning prior to transplantation.However,current scientific evidence lacks uniformity between studies,perfusion protocols,and acceptance criteria.Construction of collaborative research networks for sharing knowledge should,therefore,enable the development of high-level evidence and guidelines for machine perfusion utilization,including donor acceptance criteria.Finally,this approach shall guarantee conditions for further progress to occur.

Liver resection in liver transplant recipients

BACKGROUND:Liver resection after liver transplantation is a relatively uncommon procedure.Indications for liver resection include hepatic artery thrombosis(HAT),non- anastomotic biliary stricture(ischemic biliary lesions), liver abscess,liver trauma and recurrence of hepatocellular carcinoma(HCC).Organ shortage and lower survival after re-transplantation have encouraged us to make attempts at graft salvage. METHODS:Eleven resections at a mean of 59 months after liver transplantation were made over 18 years.Indications for liver resection included HCC recurrence in 4 patients, ischemic cholangiopathy,segmental HAT,sepsis and infected hematoma in 2 each,and ischemic segmentⅣafter split liver transplantation in 1. RESULTS:There was no perioperative mortality.Morbidity included one re-laparotomy for small bowel perforation, one bile leak treated conservatively,one right subphrenic collection,one wound infection and 5 episodes of Gram- negative sepsis.One patient underwent re-transplantation 4 months after resection for chronic rejection.There were 3 deaths,two from HCC recurrence and one from post- transplant lymphoproliferative disorder.The overall mean follow-up after resection was 48 months. CONCLUSIONS:Liver resection in liver transplant recipients is safe,and has good outcome in selected patients and avoids re-transplantation in the majority of patients. Recipients with recurrent HCC in graft may benefit from resection,but cure is uncommon.

Large Riedel’s lobe and atrophic left liver in a donor-Accept for transplant or call off?

BACKGROUND In context of suboptimal liver utilisation,grafts with various risk factors are under consideration today.For example,impaired vascularity with severe arterial calcifications and modified liver shapes are no longer contraindications and their use depends on the centre policy and experience of the surgical team.Riedel liver lobes represent a tongue-like liver shape with inferior projection in the right liver lobe.Such development modifications were initially described when patients developed a lesion and subsequently presented with symptoms.We here present the first case report in the literature,where such livers with anatomical variations were used for transplantation.CASE SUMMARY We describe here two cases of adult human liver transplantation,where we have accepted two donor livers with modified shape.The technical considerations for transplantation of such livers,found with enlarged right lobes,or Riedel shape,and hypo-trophic left lateral segment are highlighted.Both recipients experienced immediate liver function and overall good outcomes with a minimum follow up of 1 year.We also provide detailed pictures and outcome analysis in combination with a literature review.CONCLUSION The utilisation of donor livers with modified shape,such as Riedel’s Lobe appears safe and will increase the donor pool.

Development and internal validation of the Comprehensive ALPPS Preoperative Risk Assessment(CAPRA)score:is the patient suitable for Associating Liver Partition and Portal vein ligation for Staged hepatectomy(ALPPS)?

Background:Preoperative patient selection in Associating Liver Partition and Portal vein ligation for Staged hepatectomy(ALPPS)is not always reliable with currently available scores,particularly in patients with primary liver tumor.This study aims to(I)to determine whether comorbidities and patients characteristics are a risk factor in ALPPS and(II)to create a score predicting 90-day mortality preoperatively.Methods:Thirteen high-volume centers participated in this retrospective multicentric study.A risk analysis based on patient characteristics,underlying disease and procedure type was performed to identify risk factors and model the Comprehensive ALPPS Preoperative Risk Assessment(CAPRA)score.A nonparametric receiver operating characteristic analysis was performed to estimate the predictive ability of our score against the Charlson Comorbidity Index(CCI),the age-adjusted CCI(aCCI),the ALPPS risk score before Stage 1(ALPPS-RS1)and Stage 2(ALPPS-RS2).The model was internally validated applying bootstrapping.Results:A total of 451 patients were included.Mortality was 14.4%.The CAPRA score is calculated based on the following formula:(0.1×age)−(2×BSA)+1(in the presence of primary liver tumor)+1(in the presence of severe cardiovascular disease)+2(in the presence of moderate or severe diabetes)+2(in the presence of renal disease)+2(if classic ALPPS is planned).The predictive ability was 0.837 for the CAPRA score,0.443 for CCI,0.519 for aCCI,0.693 for ALPPS-RS1 and 0.807 for ALPPS-RS2.After 1,000 cycles of bootstrapping the C statistic was 0.793.The accuracy plot revealed a cut-off for optimal prediction of postoperative mortality of 4.70.Conclusions:Comorbidities play an important role in ALPPS and should be carefully considered when planning the procedure.By assessing the patient’s preoperative condition in relation to ALPPS,the CAPRA score has a very good ability to predict postoperative mortality.