Stepwise Approach for Acquisition of Microsurgical Skills through Rat Orthotopic Liver Transplantation Experiments.

Although rat liver transplantation (LT) is useful in training surgeons to perform microsurgery, mastering these surgical techniques remains difficult. Systematized training protocols that enable learning of the proper skills in a short period of time are needed. The present study describes an efficient five-step rat LT training protocol for surgeons designed to be mastered within 3 months through continuous training. The first step was to review all procedures by watching full videos of rat LT and to watch actual LT operations performed by a skilled surgeon, enabling recognition of the anatomy of rat abdominal organs. The second step was to perform ten donor operations, including ex vivo graft preparation, to learn the atraumatic and delicate techniques. The third step was to perform ten LTs, with the goal of achieving an anhepatic time <20 min and surviving until the next day. The fourth step was to perform ten additional LTs, with the goal of achieving 7 days of survival. The fifth step was to perform 5-10 more LTs, with the goal of achieving 7 days of survival in five consecutive LT operations. Systematizing the training was found to increase its efficiency. Furthermore, determining the specific number of operations in advance is useful to maintain motivation for training. Mastering efficient rat LT will not only enhance the success of preclinical research but will enable young surgeons to better perform vascular anastomoses under a microscope in humans.

TAZ inhibits acinar cell differentiation but promotes immature ductal cell proliferation in adult mouse salivary glands.

There are currently no treatments for salivary gland diseases, making it vital to understand signaling mechanisms operating in acinar and ductal cells so as to develop regenerative therapies. To date, little work has focused on elucidating the signaling cascades controlling the differentiation of these cell types in adult mammals. To analyze the function of the Hippo-TAZ/YAP1 pathway in adult mouse salivary glands, we generated adMOB1DKO mice in which both MOB1A and MOB1B were TAM-inducibly deleted when the animals were adults. Three weeks after TAM treatment, adMOB1DKO mice exhibited smaller submandibular glands (SMGs) than controls with a decreased number of acinar cells and an increased number of immature dysplastic ductal cells. The mutants suffered from reduced saliva production accompanied by mild inflammatory cell infiltration and fibrosis in SMGs, similar to the Sjogren's syndrome. MOB1-deficient acinar cells showed normal proliferation and apoptosis but decreased differentiation, leading to an increase in acinar/ductal bilineage progenitor cells. These changes were TAZ-dependent but YAP1-independent. Biochemically, MOB1-deficient salivary epithelial cells showed activation of the TAZ/YAP1 and ß-catenin in ductal cells, but reduced SOX2 and SOX10 expression in acinar cells. Thus, Hippo-TAZ signaling is critical for proper ductal and acinar cell differentiation and function in adult mice.

Muscularity Defined by the Combination of Muscle Quantity and Quality is Closely Related to Both Liver Hypertrophy and Postoperative Outcomes Following Portal Vein Embolization in Cancer Patients.

BACKGROUND: Portal vein embolization (PVE) is a common procedure for preventing hepatic insufficiency after major hepatectomy. While evaluating the body composition of surgical patients is common, the impact of muscularity defined by both muscle quantity and quality on liver hypertrophy after PVE and associated outcomes after major hepatectomy in patients with hepatobiliary cancer remain unclear. METHODS: This retrospective review included 126 patients who had undergone hepatobiliary cancer resection after PVE. Muscularity was measured on preoperative computed tomography images by combining the skeletal mass index and intramuscular adipose content. Various factors including the degree of hypertrophy (DH) of the future liver remnant and post-hepatectomy outcomes were compared according to muscularity. RESULTS: DH did not differ by malignancy type. Patients with high muscularity had better DH after PVE (P = 0.028), and low muscularity was an independent predictor for poor liver hypertrophy after PVE [odds ratio (OR), 3.418; 95% confidence interval (CI), 1.129-10.352; P = 0.030]. In subgroup analyses in which patients were stratified into groups based on primary hepatobiliary tumors and metastases, low muscularity was associated with higher incidence of post-hepatectomy liver failure (PHLF) ≥ grade B (P = 0.018) and was identified as an independent predictor for high-grade PHLF (OR 3.931; 95% CI 1.113-13.885; P = 0.034) among the primary tumor group. In contrast, muscularity did not affect surgical outcomes in patients with metastases. CONCLUSIONS: Low muscularity leads to poor liver hypertrophy after PVE and is also a predictor of PHLF, particularly in primary hepatobiliary cancer.

Dysbiosis and Depletion of Fecal Organic Acids Correlate With the Severity of Rejection After Rat Liver Transplantation.

The impact of T cell-mediated rejection (TCMR) after liver transplantation (LT) on the alterations in the gut microbiota (GM) and associated intestinal environment represented by fecal organic acids (OAs) require further elucidation. A rat allogeneic LT model was prepared without immunosuppressants or antibiotics, and a syngeneic model was used as a control. Qualitative and quantitative analyses of fecal samples at fixed time points were performed. Correlation analyses were also performed between liver function and GMs and OA levels. In the allogeneic TCMR group, the number of predominant obligate anaerobes decreased as liver function declined. Clostridioides difficile, Enterobacteriaceae, Enterococcus, Streptococcus, and Staphylococcus were significantly increased. Regarding fecal OA concentration, short-chain fatty acid (SCFA) concentrations were depleted as liver function declined. In contrast, in the syngeneic group, GM and OAs exhibited only slight, transient, and reversible disturbances. In addition, alanine aminotransferase and total bilirubin were positively correlated with the number of Enterobacteriaceae and Enterococcus, and negatively correlated with the fecal concentration of SCFAs. The allogeneic TCMR model demonstrated distinct dysbiosis and depletion of fecal OAs as TCMR progressed after LT. The degree of graft injury was closely related to the number of specific bacterial strains and the concentrations of fecal SCFAs.

Intraoperative High Fraction of Inspiratory Oxygen is Independently Associated with Worse Outcome After Living-Donor Liver Transplantation: A Retrospective Study.

BACKGROUND: Ischemia and reperfusion injury is an important factor that determines graft function after liver transplantation, and oxygen plays a crucial role in this process. However, the relationship between the intraoperative high fraction of inspiratory oxygen (FiO2) and living-donor-liver-transplantation (LDLT) outcome remains unclear. PATIENTS AND METHODS: A total of 199 primary adult-to-adult LDLT cases in Kyoto University Hospital between January 2010 and December 2017 were enrolled in this study. The intraoperative FiO2 was averaged using the total amount of intraoperative oxygen and air and defined as the calculated FiO2 (cFiO2). The cutoff value of cFiO2 was set at 0.5. RESULTS: Between the cFiO2 <0.5 (n = 156) and ≥0.5 group (n = 43), preoperative recipients' background, donor factors, and intraoperative parameters were almost comparable. Postoperatively, the cFiO2 ≥0.5 group showed a higher early allograft dysfunction (EAD) rate (P = 0.049) and worse overall graft survival (P = 0.036) than the cFiO2 <0.5 group. Although the cFiO2 ≥0.5 was not an independent risk factor for EAD in multivariable analysis (OR 2.038, 95%CI 0.992-4.186, P = 0.053), it was an independent risk factor for overall graft survival after LDLT (HR 1.897, 95%CI 1.007-3.432, P = 0.048). CONCLUSION: The results of this study suggest that intraoperative high FiO2 may be associated with worse graft survival after LDLT. Avoiding higher intraoperative FiO2 may be beneficial for LDLT recipients.

Loss of Mob1a/b in mice results in chondrodysplasia due to YAP1/TAZ-TEAD-dependent repression of SOX9.

Hippo signaling is modulated in response to cell density, external mechanical forces, and rigidity of the extracellular matrix (ECM). The Mps one binder kinase activator (MOB) adaptor proteins are core components of Hippo signaling and influence Yes-associated protein 1 (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ), which are potent transcriptional regulators. YAP1/TAZ are key contributors to cartilage and bone development but the molecular mechanisms by which the Hippo pathway controls chondrogenesis are largely unknown. Cartilage is rich in ECM and also subject to strong external forces - two upstream factors regulating Hippo signaling. Chondrogenesis and endochondral ossification are tightly controlled by growth factors, morphogens, hormones, and transcriptional factors that engage in crosstalk with Hippo-YAP1/TAZ signaling. Here, we generated tamoxifen-inducible, chondrocyte-specific Mob1a/b-deficient mice and show that hyperactivation of endogenous YAP1/TAZ impairs chondrocyte proliferation and differentiation/maturation, leading to chondrodysplasia. These defects were linked to suppression of SOX9, a master regulator of chondrogenesis, the expression of which is mediated by TEAD transcription factors. Our data indicate that a MOB1-dependent YAP1/TAZ-TEAD complex functions as a transcriptional repressor of SOX9 and thereby negatively regulates chondrogenesis.

Donor-dominant one-way matching of human leukocyte antigen-A/B/DR alleles predicts graft-versus-host disease following living donor liver transplantation.

AIM: Graft-versus-host disease (GVHD) following liver transplantation is rare but fatal. Therefore, it is important to identify possible risk factors before transplantation. Although it has been suggested that donor-dominant one-way human leukocyte antigen (HLA) matching of three loci (HLA-A/B/DR) is associated with the occurrence of GVHD, the precise significance of HLA matching including HLA-C/DQ/DP remains unclear. METHODS: We retrospectively analyzed the impact of donor-dominant one-way HLA matching at six HLA loci at the allele level on GVHD using clinical registry data from 1759 cases who underwent living donor liver transplantation between June 1990 and June 2019. We extracted cases with donor-dominant one-way HLA matching at the antigen level and reconfirmed them at the allele level using preserved DNA samples. RESULTS: Three of four cases (75%) who developed GVHD showed donor-dominant one-way HLA matching at three HLA-A/B/DR loci. These cases also showed donor-dominant one-way HLA matching at HLA-C/DQ/DP. Three of six cases (50%) with donor-dominant one-way HLA matching at three loci of HLA-A/B/DR developed GVHD. Notably, none of the cases with donor-dominant one-way HLA matching at one or two HLA-A/B/DR loci developed GVHD, irrespective of matching status at HLA-C/DQ/DP. The HLA matching status at the antigen level was revised in 22 of 56 cases, following reconfirmation at the allele level. CONCLUSIONS: Pairing of donors and recipients with donor-dominant one-way HLA matching at three HLA-A/B/DR loci should be avoided to prevent GVHD. No impact of HLA-C/DQ/DP on GVHD was identified. For liver transplantation, HLA genotypes should be determined at the allele level.

The combination of a male donor's high muscle mass and quality is an independent protective factor for graft loss after living donor liver transplantation.

We evaluated the hypothesis that grafts from donors with high muscle mass and quality may have a better outcome after living-donor-liver-transplantation (LDLT) than those from usual donors. A total of 376 primary adult-to-adult LDLT cases were enrolled in this study. Donor skeletal muscle mass index (SMI) and intramuscular adipose tissue content (IMAC) were used as markers of muscle mass and quality. In male donor cases (n = 198), those with higher SMI and lower IMAC than age-adjusted values were defined as the "high muscularity donors" (n = 38) and the others were defined as the "control" (n = 160). The high muscularity donor showed better 1-year (97% vs 82%, P = .020) and overall graft survival rate (88% vs 67%, P = .024) than the control group after LDLT. Contrastingly, the influence of the muscularity was not observed in female donor cases. Multivariable analysis including donor age confirmed that a high muscularity donor was an independent protective factor for overall graft survival after LDLT (hazard ratio, 0.337; 95% CI: 0.101-0.838; P = .017). Our study first confirmed that high muscle mass and quality of a male donor is a protective factor of allograft loss after LDLT, independently from donor age.

Etiology of Liver Steatosis Influences the Severity of Ischemia/Reperfusion Injury and Survival After Liver Transplantation in Rats.

Liver steatosis is a leading cause of graft disposal in liver transplantation, though the degree of steatosis is often the single factor determining acceptability of the graft. We investigated how the cause of liver steatosis affects graft function in rat orthotopic liver transplantation (OLT). OLT was performed using 2 types of steatotic liver grafts: the fasting and hyperalimentation (FHA) model and the methionine- and choline-deficient diet models. The FHA and 4-week feeding of a methionine- and choline-deficient diet (MCDD4wk) groups showed similar liver triglyceride levels without signs of steatohepatitis. Therefore, the 2 groups were compared in the following experiment. With 6-hour cold storage, the 7-day survival rate after OLT was far worse in the FHA than in the MCDD4wk group (0% versus 100%, P = 0.002). With 1-hour cold storage, the FHA group showed higher aspartate aminotransferase and alanine aminotransferase levels and histological injury scores in zones 1 and 2 at 24 hours after reperfusion than the normal liver and MCDD4wk groups. Intrahepatic microcirculation and tissue adenosine triphosphate levels were significantly lower in the FHA group after reperfusion. Hepatocyte necrosis, sinusoidal endothelial cell injury, and abnormal swelling of the mitochondria were also found in the FHA group after reperfusion. Tissue malondialdehyde levels were higher in the MCDD4wk group before and after reperfusion. However, the grafts up-regulated several antioxidant enzymes soon after reperfusion. Even though the degree of steatosis was equivalent, the 2 liver steatosis models possessed quite unique basal characteristics and showed completely different responses against ischemia/reperfusion injury and survival after transplantation. Our results demonstrate that the degree of fat accumulation is not a single determinant for the usability of steatotic liver grafts.

Impact of the preoperative bone mineral density on the outcomes after resection of pancreatic cancer.

PURPOSE: The aim of this study is to evaluate the correlation between bone mineral density (BMD) and other body composition markers, as well as, the impact of preoperative BMD on the surgical outcomes after resection of pancreatic cancer. METHODS: This retrospective study included 275 patients who underwent surgical resection of pancreatic cancer in our institute between 2003 and 2016. Patients were divided according to BMD into low and normal groups and their postoperative outcomes were compared. Risk factors for mortality and tumor recurrence were also evaluated. RESULTS: Patients with low BMD were older (P < 0.001), had a higher intramuscular adipose tissue content (P = 0.011) and higher visceral fat area (P = 0.003). The incidence of postoperative pancreatic fistula (POPF) (grade ≥ B) was higher in the low BMD group. No significant difference was observed between the two groups regarding overall survival and recurrence-free survival and low BMD was not a risk factor for mortality or tumor recurrence after resection of pancreatic cancer. CONCLUSION: A low preoperative BMD was not found to be a risk factor for mortality or tumor recurrence after resection of pancreatic cancer; however, it was associated with a higher incidence of clinically relevant POPF.

Liver Regeneration after Hepatectomy and Partial Liver Transplantation.

The liver is a unique organ with an abundant regenerative capacity. Therefore, partial hepatectomy (PHx) or partial liver transplantation (PLTx) can be safely performed. Liver regeneration involves a complex network of numerous hepatotropic factors, cytokines, pathways, and transcriptional factors. Compared with liver regeneration after a viral- or drug-induced liver injury, that of post-PHx or -PLTx has several distinct features, such as hemodynamic changes in portal venous flow or pressure, tissue ischemia/hypoxia, and hemostasis/platelet activation. Although some of these changes also occur during liver regeneration after a viral- or drug-induced liver injury, they are more abrupt and drastic following PHx or PLTx, and can thus be the main trigger and driving force of liver regeneration. In this review, we first provide an overview of the molecular biology of liver regeneration post-PHx and -PLTx. Subsequently, we summarize some clinical conditions that negatively, or sometimes positively, interfere with liver regeneration after PHx or PLTx, such as marginal livers including aged or fatty liver and the influence of immunosuppression.

Impact of imbalanced graft-to-spleen volume ratio on outcomes following living donor liver transplantation in an era when simultaneous splenectomy is not typically indicated.

The impact of an imbalanced graft-to-spleen volume ratio (GSVR) on posttransplant outcomes other than postreperfusion portal hypertension remains unknown. The importance of GSVR might vary according to whether simultaneous splenectomy (SPX) is performed. This retrospective study divided 349 living donor liver transplantation (LDLT) recipients from 2006 to 2017 into 2 groups: low GSVR (≤0.70 g/mL) and normal GSVR (>0.70 g/mL). The cutoff value of GSVR was set based on the first quartile of the distributed data. Graft survival and associations with various clinical factors were investigated between the groups according to whether SPX was performed. Low GSVR did not affect outcomes when SPX was performed. In contrast, it was associated with an increased incidence of early graft loss (EGL) and poor graft survival by presenting posttransplant thrombocytopenia, cholestasis, coagulopathy, and massive ascites when the spleen was preserved. Among patients with a preserved spleen, the multivariable analysis results revealed that older donor age and low GSVR were independent risk factors for graft loss. In conclusion, low GSVR was an independent predictor of graft loss after LDLT when the spleen was preserved. Preserved spleen with extremely low GSVR may be related to persistent hypersplenism, impaired graft function, and consequent EGL.

Auxiliary xenotransplantation as an in vivo bioreactor-Development of a transplantable liver graft from a tiny partial liver.

BACKGROUND: We established a completely novel method of auxiliary xenogeneic partial liver transplantation and examined whether liver grafts procured from Syrian hamsters regenerated in nude rats, which were used as in vivo bioreactors. METHODS: The hamsters and the rats were all males (n = 10). Partial liver grafts from hamsters were transplanted into nude rats in an auxiliary manner. We evaluated liver graft injury, rejection, and regeneration during 7 days after auxiliary xenogeneic partial liver transplantation. RESULTS: All rats survived until sacrifice on post-operative day (POD) 1, 3, and 7. HE-staining showed normal at POD1, mild periportal edema, and slight bile duct and venous endothelial inflammation at POD3, and moderate acute cellular rejection at POD7 without parenchymal necrosis. The liver regeneration rates at POD3 and 7 were 1.54 ± 0.23 and 2.54 ± 0.43, respectively. The Ki-67 labeling index was also elevated at POD3 (27.5 ± 4.1%). Serum HGF and VEGF were elevated at POD1 and 3. ATP levels of liver grafts recovered at POD7. CONCLUSIONS: These results revealed that with appropriate immunosuppressive therapy, partial liver graft regeneration occurred in a xenogeneic animal, which suggests liver grafts regenerated in xenogeneic environments, such as an in vivo bioreactor, have potential to be transplantable liver grafts for humans.

Risk-benefit point of the Model for End-stage Liver Disease score in patients waiting for deceased-donor liver transplantation: A single-center experience.

AIM: To clarify the risk-benefit point of the Model for End-stage Liver Disease (MELD) score in patients waiting for deceased-donor liver transplantation (DDLT). METHODS: The present study retrospectively investigated 213 patients registered on the waiting list at Kyoto University (Kyoto, Japan) between 2005 and 2016. Patients were stratified by MELD score (6-9/10-14/15-20/21-30/31-40) and classified into two groups: the DDLT group (30 patients) and the waiting group (183 patients). Their post-registration mortality risk and long-term survival were compared. RESULTS: For all MELD categories, the mortality risk was lower in the DDLT group than in the waiting group. The hazard ratio of post-registration mortality decreased in the DDLT group compared to the waiting group as the MELD score increased (0.36/0.12/0.06/0.042/0.004). Survival was significantly better among patients in the DDLT group with a MELD score of 15 or more than among patients in the waiting group. CONCLUSION: For all MELD categories, DDLT reduced the mortality risk of patients on the waiting list.

Bone Mineral Density as a Risk Factor for Patients Undergoing Surgery for Hepatocellular Carcinoma.

BACKGROUND: We have reported the impact of sarcopenia and body composition on patients undergoing hepatectomy for hepatocellular carcinoma (HCC). However, the impact of bone mineral density (BMD) on outcomes after hepatectomy for HCC and correlation with other parameters including sarcopenia are unclear. METHODS: We retrospectively analyzed 465 patients who underwent primary hepatectomy for HCC between April 2005 and March 2015. We analyzed the plain CT images at the level of the eleventh thoracic vertebra with the region of interest and defined as preoperative BMD. RESULTS: In this cohort, male (n = 367) and female (n = 98) patients showed significant heterogeneity in age, body composition markers, tumor factors, peri-operative parameters and so on. The median preoperative BMD in male and female patients was 155 and 139 HU, respectively (P = 0.005). BMD was negatively correlated with age in female (r = -0.590, P < 0.001) and intramuscular adipose tissue content in both male and female (r = -0.332 and -0.359, respectively, P < 0.001). For males, BMD < 160 HU was associated with worse cancer-specific survival post-hepatectomy (P = 0.015). In contrast, females were not (P = 0.135). For male patients, multivariate analysis identified low BMD as an independent risk factor for death (hazard ratio 1.720, 95% confidence interval 1.038-2.922, P = 0.035) after hepatectomy for HCC. CONCLUSION: Preoperative low BMD was an independent risk factor for cancer-specific mortality after hepatectomy for HCC.

Dysregulated YAP1/TAZ and TGF-ß signaling mediate hepatocarcinogenesis in Mob1a/1b-deficient mice.

Mps One Binder Kinase Activator (MOB)1A/1B are core components of the Hippo pathway that coactivate large tumor suppressor homolog (LATS) kinases. Mob1a/1b double deficiency in mouse liver (LMob1DKO) results in hyperplasia of oval cells and immature cholangiocytes accompanied by inflammatory cell infiltration and fibrosis. More than half of mutant mice die within 3 wk of birth. All survivors eventually develop liver cancers, particularly combined hepatocellular and cholangiocarcinomas (cHC-CCs) and intrahepatic cholangiocellular carcinomas (ICCs), and die by age 60 wk. Because this phenotype is the most severe among mutant mice lacking a Hippo signaling component, MOB1A/1B constitute the critical hub of Hippo signaling in mammalian liver. LMob1DKO liver cells show hyperproliferation, increased cell saturation density, hepatocyte dedifferentiation, enhanced epithelial-mesenchymal transition and cell migration, and elevated transforming growth factor beta(TGF-ß)2/3 production. These changes are strongly dependent on Yes-Associated Protein-1 (Yap1) and partially dependent on PDZ-binding motif (Taz) and Tgfbr2, but independent of connective tissue growth factor (Ctgf). In human liver cancers, YAP1 activation is frequent in cHC-CCs and ICCs and correlates with SMAD family member 2 activation. Drug screening revealed that antiparasitic macrocyclic lactones inhibit YAP1 activation in vitro and in vivo. Targeting YAP1/TAZ with these drugs in combination with inhibition of the TGF-ß pathway may be effective treatment for cHC-CCs and ICCs.

Hippo vs. Crab: tissue-specific functions of the mammalian Hippo pathway.

The Hippo signaling pathway is a vital suppressor of tumorigenesis that is often inactivated in human cancers. In normal cells, the Hippo pathway is triggered by external forces such as cell crowding, or changes to the extracellular matrix or cell polarity. Once activated, Hippo signaling down-regulates transcription supported by the paralogous cofactors YAP1 and TAZ. The Hippo pathway's functions in normal and cancer biology have been dissected by studies of mutant mice with null or conditional tissue-specific mutations of Hippo signaling elements. In this review, we attempt to systematically summarize results that have been gleaned from detailed in vivo characterizations of these mutants. Our goal is to describe the physiological roles of Hippo signaling in several normal organ systems, as well as to emphasize how disruption of the Hippo pathway, and particularly hyperactivation of YAP1/TAZ, can be oncogenic.

Is Portal Venous Pressure Modulation Still Indicated for All Recipients in Living Donor Liver Transplantation?

There is a consensus that portal venous pressure (PVP) modulation prevents portal hypertension (PHT) and consequent complications after adult-to-adult living donor liver transplantation (ALDLT). However, PVP-modulation strategies need to be updated based on the most recent findings. We examined our 10-year experience of PVP modulation and reevaluated whether it was necessary for all recipients or for selected recipients in ALDLT. In this retrospective study, 319 patients who underwent ALDLT from 2007 to 2016 were divided into 3 groups according to the necessity and results of PVP modulation: not indicated (n = 189), indicated and succeeded (n = 92), and indicated but failed (n = 38). Graft survival and associations with various clinical factors were investigated. PVP modulation was performed mainly by splenectomy to lower final PVP to ≤15 mm Hg. Successful PVP modulation improved prognosis to be equivalent to that of patients who did not need modulation, whereas failed modulation was associated with increased incidence of small-for-size syndrome (SFSS; P = 0.003) and early graft loss (EGL; P = 0.006). Among patients with failed modulation, donor age ≥ 45 years (hazard ratio [HR], 3.67; P = 0.02) and ABO incompatibility (HR, 3.90; P = 0.01) were independent risk factors for graft loss. Survival analysis showed that PVP > 15 mm Hg was related to poor prognosis in grafts from either ABO-incompatible or older donor age ≥ 45 years (P < 0.001), but it did not negatively affect grafts from ABO-compatible/identical and young donor age < 45 years (P = 0.27). In conclusion, intentional PVP modulation is not necessarily required in all recipients. Although grafts from both ABO-compatible/identical and young donors can tolerate PHT, lowering PVP to ≤15 mm Hg is a key to preventing SFSS and consequent EGL with grafts from either ABO-incompatible or older donors.

Etiologies, risk factors, and outcomes of bacterial cholangitis after living donor liver transplantation.

The interpretation of bacterial cholangitis after liver transplantation (LT) remains vague, because the presence of bacteria in bile, namely bacteriobilia, does not necessarily indicate an active infection. We investigated the association between post-LT bacterial cholangitis and a variety of short- and long-term outcomes. Two-hundred-seventy-four primary adult-to-adult living donor LT recipients from 2008 to 2016 were divided into three groups according the presence or absence of bacteriobilia and clinical symptoms: (1) no bacteriobilia (N group), (2) asymptomatic bacteriobilia (B group), and (3) cholangitis (C group). The number of patients was by group: N, 161; B, 64; and C, 49. Donor age ≥ 45 years (p = 0.012), choledochojejunostomy (p < 0.001), and post-LT portal hypertension (p = 0.023) were independent risk factors for developing cholangitis. Survival analysis revealed that the C group had significantly worse short- and long-term graft survival. The C group was associated with an increased incidence of early graft loss (EGL) (p < 0.001). While the frequency of readmission for recurrent cholangitis was significantly higher in both the B and C groups (p < 0.001), late graft loss (LGL) due to chronic cholangitis was only commonly observed in the C group (p = 0.002). Post-LT cholangitis could result in not only EGL but also chronic cholangitis and associated LGL.