Safety of advanced laparoscopic hepatectomy for elderly patients: a Japanese nationwide analysis.

BACKGROUND: Although basic laparoscopic hepatectomy (LH) has become the standard procedure for hepatectomy, the safety of advanced LH remains to be clarified, especially in elderly patients. We investigated the safety of advanced LH in elderly Japanese patients. METHODS: Elderly patients (≥ 65 years) who underwent advanced LH between 2016 and 2021 were analyzed using a nationwide claims database in Japan. The perioperative outcomes of patients who underwent open hepatectomy (OH group) or LH (LH group) were compared using propensity score matching (PSM). The primary outcome was in-hospital mortality. The E-value method was performed to assess the strength of the outcome point estimates against possible unmeasured confounding factors. RESULTS: Among 5,021 patients, eligible patients were classified into the OH (n = 4,152) and LH (n = 527) groups. The median patient age was 74 years in both groups. Hepatocellular carcinoma and metastatic liver tumors were the major indications for hepatectomy (OH: 52.5% versus 30.6%; LH: 60.7% versus 26.4%). After PSM, in-hospital mortality rates for OH and LH were 1.7 and 0.76%, respectively. The risk ratio was 0.45 (95% confidence interval, 0.16-1.25; E-value = 3.87). Compared with OH, LH was associated with a longer anesthesia time (411 versus 432 min), lower rate of blood product use (red blood concentrate: 33.5% versus 20.3%; fresh frozen plasma: 29.2% versus 17.1%), and shorter hospital stay (13 versus 12 days). CONCLUSIONS: In elderly patients, the safety of advanced LH was similar to that of advanced OH, or might be better in Japan under the current policy of hospital accreditation.

Association of Early Bifurcation of Hepatic Artery With Arterial Injury in Right-Sided Living-Donor Hepatectomy: Retrospective Analysis of 500 Cases.

OBJECTIVE: The aim of this study was to explore the incidence of early bifurcation of the right hepatic artery (RHA) and the right posterior hepatic artery (RPHA), which is crucial in right lobe graft (RLG) and right posterior sector graft (RPSG) procurement for living-donor liver transplantation. SUMMARY BACKGROUND DATA: Early bifurcation of the hepatic artery tends to induce oversight of one of the bifurcated arteries and its injury in RLG/RPSG procurement. Unrecognizable on conventional 3-dimensional (3-D) images, its significance is underestimated. METHODS: We enrolled 500 patients who underwent preoperative imaging for scheduled surgeries at two major transplant centers. All-in-one 3-D images consisting of the hepatic artery, portal vein, and bile duct were constructed. Early bifurcation of the RHA and the RPHA was defined as the arteries bifurcating proximal to the cutting line of the right hepatic duct and the right posterior duct, respectively. RESULTS: Early bifurcation of the RHA was seen in 11.3% of cases of an infra-portal RPHA and in 46.0% of cases of a supraportal RPHA ( P < 0.001). Early bifurcation of the RPHA was encountered in 35.3% of cases of an infra-portal RPHA, in no cases of a supra-portal RPHA, and in 100% of cases in which the arteries to segment 6/7 arose individually from the RHA. The overall incidence of early bifurcation was 19.9% for RHA and 43.6% for RPHA. CONCLUSIONS: Early bifurcation of the RHA and the RPHA is frequently encountered and requires caution for RLG/RPSG procurement. Special attention should be paid to supraportal RPHA for RLG procurement.

Left Lobe First With Purely Laparoscopic Approach: A Novel Strategy to Maximize Donor Safety in Adult Living Donor Liver Transplantation.

OBJECTIVE: Evaluate outcome of left-lobe graft (LLG) first combined with purely laparoscopic donor hemihepatectomy (PLDH) as a strategy to minimize donor risk. BACKGROUND: An LLG first approach and a PLDH are 2 methods used to reduce surgical stress for donors in adult living donor liver transplantation (LDLT). But the risk associated with application LLG first combined with PLDH is not known. METHODS: From 2012 to 2023, 186 adult LDLTs were performed with hemiliver grafts, procured by open surgery in 95 and PLDH in 91 cases. LLGs were considered first when graft-to-recipient weight ratio ≥0.6%. Following a 4-month adoption process, all donor hepatectomies, since December 2019, were performed laparoscopically. RESULTS: There was one intraoperative conversion to open (1%). Mean operative times were similar in laparoscopic and open cases (366 vs 371 minutes). PLDH provided shorter hospital stays, lower blood loss, and lower peak aspartate aminotransferase. Peak bilirubin was lower in LLG donors compared with right-lobe graft donors (1.4 vs 2.4 mg/dL, P < 0.01), and PLDH further improved the bilirubin levels in LLG donors (1.2 vs 1.6 mg/dL, P < 0.01). PLDH also afforded a low rate of early complications (Clavien-Dindo grade ≥ II, 8% vs 22%, P = 0.007) and late complications, including incisional hernia (0% vs 13.7%, P < 0.001), compared with open cases. LLG was more likely to have a single duct than a right-lobe graft (89% vs 60%, P < 0.01). Importantly, with the aggressive use of LLG in 47% of adult LDLT, favorable graft survival was achieved without any differences between the type of graft and surgical approach. CONCLUSIONS: The LLG first with PLDH approach minimizes surgical stress for donors in adult LDLT without compromising recipient outcomes. This strategy can lighten the burden for living donors, which could help expand the donor pool.

Risk factors for antibody-mediated rejection in ABO blood-type incompatible and donor-specific antibody-positive liver transplantation.

Antibody-mediated rejection (AMR) is a refractory rejection after ABO blood-type incompatible (ABOi) or donor-specific antibody (DSA)-positive liver transplantation (LT). Pretransplant rituximab desensitization dramatically reduced posttransplant AMR development; however, risk factors for AMR in the rituximab era remain unclear in both ABOi living-donor LT (ABOi-LDLT) and preformed DSA-positive LT (pDSA-LT). Of our 596 adult LDLTs (≥18 y) after rituximab introduction (2004-2019), 136 were ABOi-LDLT (22.8%). After excluding retransplants (9), acute liver failure (7), and protocol deviations (16), 104 ABOi-LDLTs were finally enrolled. Of these, 19 recipients developed AMR, 18 of which occurred within 2 weeks after transplantation (95%). ABOi-AMR significantly worsened graft and recipient survival than those without ( p =0.02 and 0.04, respectively). Model for End-stage Liver Disease (MELD) ≤13 (OR: 5.15 [1.63-16.3], p =0.005) and pre-rituximab anti-ABO IgM-titer ≥128 (OR: 3.25 [1.05-10.0], p =0.03) were identified as independent risk factors for ABOi-AMR development. Recipients fulfilling both factors showed significantly worse survival rates than those who did not ( p =0.003). Of 352 adult LTs, after introducing the LABScreen Single Ag method (2009-2019), pDSA with mean fluorescence intensity (MFI) ≥500 was detected in 50 cases (14.2%). After excluding 10 ABOi-LDLTs, 40 pDSA-LTs were finally analyzed, of which 5 developed AMR. The combination of high-titer (sum-MFI ≥10,000) and multi-loci pDSAs was a significant risk factor for pDSA-AMR development ( p <0.001); however, it did not affect the 5-year recipient survival compared with those without ( p =0.56). In conclusion, preoperative MELD ≤13 and pre-rituximab anti-ABO IgM-titer ≥128 for ABOi-LDLT, and the combination of sum-MFI ≥10,000 and multi-loci pDSAs for pDSA-LT, are risk factors for AMR in the era of rituximab desensitization. Characteristically, ABOi-AMR significantly deteriorated graft and recipient survival, whereas pDSA-AMR did not.

The impact of human leukocyte antigen mismatch on recipient outcomes in living-donor liver transplantation.

Donor-recipient human leukocyte antigen (HLA) compatibility has not been considered to significantly affect liver transplantation (LT) outcomes; however, its significance in living-donor LT (LDLT), which is mostly performed between blood relatives, remains unclear. This retrospective cohort study included 1954 LDLTs at our institution (1990-2020). The primary and secondary endpoints were recipient survival and the incidence of T cell-mediated rejection (TCMR) after LDLT, respectively, according to the number of HLA mismatches at all five loci: HLA-A, HLA-B, HLA-C, HLA-DR, and HLA-DQ. Subgroup analyses were also performed in between-siblings that characteristically have widely distributed 0-10 HLA mismatches. A total of 1304 cases of primary LDLTs were finally enrolled, including 631 adults (recipient age at LT ≥18 years) and 673 children (<18 years). In adult-to-adult LDLT, the more HLA mismatches at each locus, the significantly worse the recipient survival was (p = 0.03, 0.01, 0.03, 0.001, and <0.001 for HLA-A, HLA-B, HLA-C, HLA-DR, and HLA-DQ, respectively). This trend was more pronounced when multiple loci were combined (all p < 0.001 for A + B + DR, A + B + C, DR + DQ, and A + B + C + DR + DQ). Notably, a total of three or more HLA-B + DR mismatches was an independent risk factor for both TCMR (hazard ratio [HR] 2.66, 95% confidence interval [CI] 1.21-5.87; p = 0.02) and recipient survival (HR 2.44, 95% CI 1.11-5.35; p = 0.03) in between-siblings. By contrast, HLA mismatch did not affect pediatric LDLT outcomes at any locus or in any combinations; however, it should be noted that all donor-recipient relationships are parent-to-child that characteristically possesses one or less HLA mismatch at each locus and maximally five or less mismatches in total. In conclusion, HLA mismatch significantly affects not only TCMR development but also recipient survival in adult LDLT, but not in children.

Impact of the donor hepatectomy time on short-term outcomes in liver transplantation using donation after circulatory death: A review of the US national registry.

BACKGROUND: During the donor hepatectomy time (dHT), defined as the time from the start of cold perfusion to the end of the hepatectomy, liver grafts have a suboptimal temperature. The aim of this study was to analyze the impact of prolonged dHT on outcomes in donation after circulatory death (DCD) liver transplantation (LT). METHODS: Using the US national registry data between 2012 and 2020, DCD LT patients were separated into two groups based on their dHT: standard dHT (< 42 min) and prolonged dHT (≥42 min). RESULTS: There were 3810 DCD LTs during the study period. Median dHT was 32 min (interquartile range 25-41 min). Kaplan-Meier graft survival curves demonstrated inferior outcomes in the prolonged dHT group at 1-year after DCD LT compared to those in the standard dHT group (85.3% vs 89.9%; P < .01). Multivariate Cox proportional hazards models for 1-year graft survival identified that prolonged dHT [hazard ratio (HR) 1.46, 95% confidence interval (CI) 1.19 - 1.79], recipient age ≥ 64 years (HR 1.40, 95% CI 1.14 - 1.72), and MELD score ≥ 24 (HR 1.43, 95% CI 1.16 - 1.76) were significant predictors of 1-year graft loss. Spline analysis shows that the dHT effects on the risk for 1-year graft loss with an increase in the slope after median dHT of 32 min. CONCLUSION: Prolonged dHTs significantly reduced graft and patient survival after DCD LT. Because dHT is a modifiable factor, donor surgeons should take on cases with caution by setting the dHT target of < 32 min.

Post-transplant Lymphoproliferative Disorders After Liver Transplantation: A Retrospective Cohort Study Including 1954 Transplants.

Post-transplant lymphoproliferative disorders (PTLDs) are life-threatening neoplasms after organ transplantation. Because of their rarity and multiple grades of malignancy, the incidence, outcomes, and clinicopathological features affecting patient survival after liver transplantation (LT) remain unclear. We reviewed 1954 LTs in 1849 recipients (1990-2020), including 886 pediatric (<18 years of age) and 963 adult recipients. The following clinicopathological factors were studied: age, sex, liver etiologies, malignancy grades, Epstein-Barr virus status, performance status (PS), Ann Arbor stage, international prognostic index, and histopathological diagnosis. Of 1849 recipients, 79 PTLD lesions (4.3%) were identified in 70 patients (3.8%). After excluding 3 autopsy cases incidentally found, 67 (45 pediatric [5.1%] and 22 adult [2.3%]) patients were finally enrolled. Comorbid PTLDs significantly worsened recipient survival compared with non-complicated cases (P < 0.001). The 3-year, 5-year, and 10-year overall survival rates after PTLD diagnosis were 74%, 66%, and 58%, respectively. The incidence of PTLDs after LT (LT-PTLDs) was significantly higher (P < 0.001) with earlier onset (P = 0.002) in children, whereas patient survival was significantly worse in adults (P = 0.002). Univariate and multivariate analyses identified the following 3 prognostic factors: age at PTLD diagnosis ≥18 years (hazard ratio [HR], 11.2; 95% confidence interval [CI], 2.63-47.4; P = 0.001), PS ≥2 at diagnosis (HR, 6.77; 95% CI, 1.56-29.3; P = 0.01), and monomorphic type (HR, 6.78; 95% CI, 1.40-32.9; P = 0.02). A prognostic index, the "LT-PTLD score," that consists of these 3 factors effectively stratified patient survival and progression-free survival (P = 0.003 and <0.001, respectively). In conclusion, comorbid PTLDs significantly worsened patient survival after LT. Age ≥18 years and PS ≥2 at PTLD diagnosis, and monomorphic type are independent prognostic factors, and the LT-PTLD score that consists of these 3 factors may distinguish high-risk cases and guide adequate interventions.

Prognostic index consisting of early post-transplant variables <2 weeks in adult living-donor liver transplantation.

AIM: Six-month recipient mortality after adult-to-adult living-donor liver transplantation (LDLT) remains high. Early and accurate prediction of recipient outcome and continuous monitoring of recipient severity after surgery are both essential for guiding appropriate care. This study was designed to identify early post-transplant parameters associated with 6-month mortality, and thereby to construct a discriminatory prognostic index (PI). METHODS: We retrospectively analyzed 400 consecutive primary adult-to-adult LDLTs in our center (2006-2017). Perioperative variables were comprehensively analyzed for their accuracy in predicting recipient mortality by comparing the area under the receiver operating characteristic (AUROC) of each factor. RESULTS: The AUROCs of preoperative predictive factors, for example, Model for End-stage Liver Disease (MELD) score and donor age, were 0.56 and 0.64, respectively, whereas those of post-transplant platelet count (PLT), total bilirubin (T-BIL), and prothrombin time - international normalized ratio (INR) on postoperative day (POD)-7-14 were 0.71/0.84, 0.68/0.82, and 0.71/0.78, respectively. Logistic regression analysis provided a formula: PIPOD-14 = 3.39 + 0.12 × PLTPOD-14 - 0.09 × T-BILPOD-14 - 1.23 × INRPOD-14 , indicating a high AUROC of 0.87. Recipient 6-month survival with PIPOD-14 < 2.38 (n = 173) was 71.7%, whereas that with PIPOD-14 ≥ 2.38 (n = 222) was 97.7% (P < 0.001). The AUROCs of PIPOD-7 were as high as 0.8 in the subgroups with younger donors (<50 years of age), right lobe grafts, ABO-identical/compatible combinations, or low MELD score (<20), indicating usefulness of PI to identify unexpectedly complicated cases within the first week. CONCLUSIONS: A novel, post-transplant survival estimator, PI, accurately predicts recipient 6-month mortality within 1-2 weeks after adult LDLT. Daily monitoring of PI could facilitate early interventions including retransplantation in critically ill patients.

Impact of Donor Age on Recipient Survival in Adult-to-Adult Living-donor Liver Transplantation.

OBJECTIVE: To investigate the influence of donor age on recipient outcome after living-donor partial liver transplantation (LDLT). BACKGROUND: Donor age is a well-known prognostic factor in deceased donor liver transplantation; however, its role in LDLT remains unclear. METHODS: We retrospectively analyzed 315 consecutive cases of primary adult-to-adult LDLT in our center between April 2006 and March 2014. Recipients were divided into 5 groups according to the donor age: D-20s (n = 60); D-30s (n = 72); D-40s (n = 57); D-50s (n = 94); and D-60s (n = 32). The recipient survival and the association with various clinical factors were investigated. RESULTS: Recipient survival proportions were significantly higher in D-20s compared with all the other groups (P = 0.008, < 0.001, < 0.001, and = 0.006, vs D-30s, -40s, -50s, and -60s, respectively), whereas there was no association between recipient survival and their own age. There are 3 typical relationships between donors and recipients in adult-to-adult LDLT: from child-to-parent, between spouses/siblings, and from parent-to-child. The overall survival in child-to-parent was significantly higher than in spouses/siblings (P = 0.002) and in parent-to-child (P = 0.005), despite significantly higher recipient age in child-to-parent [59 (42-69) years, P < 0.001]. Contrastingly, parent-to-child exhibited the lowest survival, despite the youngest recipient age [26 (20-43) years, P < 0.001]. In addition, younger donor age exhibited significantly better recipient survival both in hepatitis C virus-related and in non-hepatitis C virus diseases. Univariate and multivariate analyses both demonstrated that donor age and graft-type (right-sided livers) are independent prognostic factors for recipient survival. CONCLUSIONS: Donor age is an independent, strong prognostic factor in adult-to-adult LDLT.

Hydrogen Flush After Cold Storage as a New End-Ischemic Ex Vivo Treatment for Liver Grafts Against Ischemia/Reperfusion Injury.

Cold storage (CS) remains the gold standard for organ preservation worldwide, although it is inevitably associated with ischemia/reperfusion injury (IRI). Molecular hydrogen (H2 ) is well known to have antioxidative properties. However, its unfavorable features, ie, inflammability, low solubility, and high tissue/substance permeability, have hampered its clinical application. To overcome such obstacles, we developed a novel reconditioning method for donor organs named hydrogen flush after cold storage (HyFACS), which is just an end-ischemic H2 flush directly to donor organs ex vivo, and, herein, we report its therapeutic impact against hepatic IRI. Whole liver grafts were retrieved from Wistar rats. After 24-hour CS in UW solution, livers were cold-flushed with H2 solution (1.0 ppm) via the portal vein (PV), the hepatic artery (HA), or both (PV + HA). Functional integrity and morphological damages were then evaluated by 2-hour oxygenated reperfusion at 37°C. HyFACS significantly lowered portal venous pressure, transaminase, and high mobility group box protein 1 release compared with vehicle-treated controls (P < 0.01). Hyaluronic acid clearance was significantly higher in the HyFACS-PV and -PV + HA groups when compared with the others (P < 0.01), demonstrating the efficacy of the PV route to maintain the sinusoidal endothelia. In contrast, bile production and lactate dehydrogenase leakage therein were both significantly improved in HyFACS-HA and -PV + HA (P < 0.01), representing the superiority of the arterial route to attenuate biliary damage. Electron microscopy consistently revealed that sinusoidal ultrastructures were well maintained by portal HyFACS, while microvilli in bile canaliculi were well preserved by arterial flush. As an underlying mechanism, HyFACS significantly lowered oxidative damages, thus improving the glutathione/glutathione disulfide ratio in liver tissue. In conclusion, HyFACS significantly protected liver grafts from IRI by ameliorating oxidative damage upon reperfusion in the characteristic manner with its route of administration. Given its safety, simplicity, and cost-effectiveness, end-ischemic HyFACS may be a novel pretransplant conditioning for cold-stored donor organs.

[A case of mixed adenoneuroendocrine carcinoma of the transverse colon].

A 7 1-year-old man presented to our hospital with constipation and abdominal pain. Computed tomography of the abdomen and colonoscopy revealed advanced cancer of the transverse colon. The biopsy specimen indicated a highly differentiated adenocarcinoma. The patient underwent extended right hemicolectomy with regional lymph node dissection. Pathological examination showed a neuroendocrine carcinoma (NEC) with concurrent adenocarcinoma of the transverse colon and regional lymph node metastases of the NEC and adenocarcinoma. The histopathological examination confirmed a diagnosis of mixed adenoneuroendocrine carcinoma (MANEC) in accordance with the 2010 WHO Classification of Tumors of the Digestive System. Liver and lung metastases were identified 8 months after the surgery. We administered chemotherapy including 5-fluorouracil, Leucovorin, and oxaliplatin (mFOLFOX) plus bevacizumab, with limited therapeutic effect, as the disease progressed despite treatment. The patient chose best supportive care 13 months after the surgery. Several studies have reported that most patients with adenoendocrine cell carcinoma, including MANEC, experience relapse within 1 year after surgery, and few patients remain disease-free for long periods after surgery. The optimal strategy for the management of MANEC is variable owing to its rarity; only 2 cases of MANEC in the colon, including the present case, have been reported in Japan. It is thus important to gather more evidence on this disease and its management.

Chronological alterations in de novo malignancies after living-donor liver transplantation: A cohort study of 1781 recipients using annual comparisons of standardized incidence ratios.

BACKGROUND: De novo malignancies (DNMs) are a major adverse event after solid organ transplantation; however, their characteristics and recent trends after living-donor liver transplantation (LDLT) remain unclear. METHODS: We retrospectively reviewed 1781 primary LDLT recipients (1990-2020) and annually calculated standardized incidence ratios (SIRs) of DNMs compared to the age-adjusted Japanese general population. RESULTS: After 21 845 person-years follow-up, 153 DNM lesions (8.6%) were identified in 131 patients (7.4%). The incidence was 0.007 person-years. DNMs included 81 post-transplant lymphoproliferative disorders (PTLDs), 14 colorectal, 12 lung, and 12 gastric cancers, and so on. Comorbid DNMs significantly worsened recipient survival than those without (p < .001). The 5- and 10-year recipient survival after DNM diagnosis were 65% and 58%, respectively. Notably, SIR1993-1995: 8.12 (95% CI: 3.71-15.4, p < .001) and SIR1996-1998: 3.11 (1.34-6.12, p = .01) were significantly high, but had decreased time-dependently to SIR2005-2007: 1.31 (0.68-2.29, p = .42) and SIR2008-2010: 1.34 (0.75-2.20, p = .33), indicating no longer significant difference in DNMs development. Currently, however, SIR2014-2016: 2.27 (1.54-3.22, p < .001) and SIR2017-2019: 2.07 (1.40-2.96, p < .001) have become significantly higher again, reflecting recent aging of recipients (>50 years) and resultant increases in non-PTLD DNMs. Furthermore, characteristically in LDLT, the fewer the donor-recipient HLA-mismatches, the less the post-transplant DNMs development. CONCLUSION: DNM development after LDLT was significantly higher than in the general population due to higher PTLD incidence (1993-1998), but once became equivalent (2005-2013), then significantly increased again (2014-2019) due to recent recipient aging and resultant increase in solid cancers.

Expanding Selection Criteria in Deceased Donor Liver Transplantation for Hepatocellular Carcinoma: Long-term Follow-up of a National Registry and 2 Transplant Centers.

BACKGROUND: This study compares selection criteria for liver transplant (LT) for hepatocellular carcinoma (HCC) for inclusivity and predictive ability to identify the most permissive criteria that maintain patient outcomes. METHODS: The Scientific Registry of Transplant Recipients (SRTR) database was queried for deceased donor LT's for HCC (2003-2020) with 3-y follow-up; these data were compared with a 2-center experience. Milan, University of California, San Francisco (UCSF), 5-5-500, Up-to-seven (U7), HALT-HCC, and Metroticket 2.0 scores were calculated. RESULTS: Nationally, 26 409 patients were included, and 547 at the 2 institutions. Median SRTR-follow-up was 6.8 y (interquartile range 3.9-10.1). Three criteria allowed the expansion of candidacy versus Milan: UCSF (7.7%, n = 1898), Metroticket 2.0 (4.2%, n = 1037), and U7 (3.5%, n = 828). The absolute difference in 3-y overall survival (OS) between scores was 1.5%. HALT-HCC (area under the curve [AUC] = 0.559, 0.551-0.567) best predicted 3-y OS although AUC was notably similar between criteria (0.506 < AUC < 0.527, Mila n = 0.513, UCSF = 0.506, 5-5-500 = 0.522, U7 = 0.511, HALT-HCC = 0.559, and Metroticket 2.0 = 0.520), as was Harrall's c-statistic (0.507 < c-statistic < 0.532). All scores predicted survival to P < 0.001 on competing risk analysis. Median follow-up in our enterprise was 9.8 y (interquartile range 7.1-13.3). U7 (13.0%, n = 58), UCSF (11.1%, n = 50), HALT-HCC (6.4%, n = 29), and Metroticket 2.0 (6.3%, n = 28) allowed candidate expansion. HALT-HCC (AUC = 0.768, 0.713-0.823) and Metroticket 2.0 (AUC = 0.739, 0.677-0.801) were the most predictive of recurrence. All scores predicted recurrence and survival to P < 0.001 using competing risk analysis. CONCLUSIONS: Less restrictive criteria such as Metroticket 2.0, UCSF, or U7 allow broader application of transplants for HCC without sacrificing outcomes. Thus, the criteria for Model for End-stage Liver Disease-exception points for HCC should be expanded to allow more patients to receive life-saving transplantation.

Properdin inhibition ameliorates hepatic ischemia/reperfusion injury without interfering with liver regeneration in mice.

Hepatic ischemia/reperfusion injury (IRI) often causes serious complications in liver surgeries, including transplantation. Complement activation seems to be involved in hepatic IRI; however, no complement-targeted intervention has been clinically applied. We investigated the therapeutic potential of Properdin-targeted complement regulation in hepatic IRI. Male wild-type mice (B10D2/nSn) were exposed to 90-minute partial hepatic IRI to the left and median lobes with either monoclonal anti-Properdin-antibody (Ab) or control-immunoglobulin (IgG) administration. Since the complement system is closely involved in liver regeneration, the influence of anti-Properdin-Ab on liver regeneration was also evaluated in a mouse model of 70% partial hepatectomy. Anti-Properdin-Ab significantly reduced serum transaminases and histopathological damages at 2 and 6 hours after reperfusion (P <0.001, respectively). These improvements at 2 hours was accompanied by significant reductions in CD41+ platelet aggregation (P =0.010) and ssDNA+ cells (P <0.001), indicating significant amelioration in hepatic microcirculation and apoptosis, respectively. Characteristically, F4/80+ cells representing macrophages, mainly Kupffer cells, were maintained by anti-Properdin-Ab (P <0.001). Western blot showed decreased phosphorylation of only Erk1/2 among MAPKs (P =0.004). After 6 hours of reperfusion, anti-Properdin-Ab significantly attenuated the release of HMGB-1, which provokes the release of proinflammatory cytokines/chemokines (P =0.002). Infiltration of CD11b+ and Ly6-G+ cells, representing infiltrating macrophages and neutrophils, respectively, were significantly alleviated by anti-Properdin-Ab (both P <0.001). Notably, anti-Properdin-Ab did not affect remnant liver weight and BrdU+ cells at 48 hours after 70% partial hepatectomy (P =0.13 and 0.31, respectively). In conclusion, Properdin inhibition significantly ameliorates hepatic IRI without interfering with liver regeneration.