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Background: The present study aimed to investigate the impact of the duration of hepatic pedicle clamping (HPC) on tumor growth after major hepatectomy in a rat model., Methods: Rats were divided into four groups according to the length of HPC during 70% partial hepatectomy followed by N1S1 tumor cell implantation: group 1, without HPC; group 2, with 5-min HPC; group 3, 10-min HPC; and group 4, 15-min HPC. At three weeks after tumor cell implantation, liver tumor growth and its possible mechanisms were investigated., Results: The number and largest diameter of liver tumor were significantly greater in group 4. At 6 h after reperfusion, serum levels of inflammatory cytokines including interleukin (IL)-6 were significantly higher in group 4 compared with the other groups. In the tumor tissues, the expression of hypoxia inducible factor (HIF)-1α (P < 0.001 versus group 2, P < 0.001 versus group 3) and that of phospho-signal transducer and activator of transcription 3 (STAT3) (P < 0.001 versus group 2, P = 0.026 versus group 3) were significantly upregulated in group 4., Conclusions: Longer HPC followed by reperfusion accelerated hepatocellular carcinoma growth through the induction of HIF-1α and the activation of the IL-6-JAK-STAT3 signaling pathway., (© 2016 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Microthrombi formation provoked by warm ischemia and vascular stasis is thought to increase the risk of nonanastomotic strictures (NAS) in liver grafts obtained by donation after circulatory death (DCD). Therefore, potentially harmful intraoperative thrombolytic therapy has been suggested as a preventive strategy against NAS. Here, we investigated whether there is histological evidence of microthrombi formation during graft preservation or directly after reperfusion in DCD livers and the development of NAS. Liver biopsies collected at different time points during graft preservation and after reperfusion were triple-stained with hematoxylin-eosin (H & E), von Willebrand factor VIII (VWF), and Fibrin Lendrum (FL) to evaluate the presence of microthrombi. In a first series of 282 sections obtained from multiple liver segments of discarded DCD grafts, microthrombi were only present in 1%-3% of the VWF stainings, without evidence of thrombus formation in paired H & E and FL stainings. Additionally, analysis of 132 sections obtained from matched, transplanted donation after brain death and DCD grafts showed no difference in microthrombi formation (11.3% versus 3.3% respectively; P = 0.082), and no relation to the development of NAS (P = 0.73). Furthermore, no microthrombi were present in perioperative biopsies in recipients who developed early hepatic artery thrombosis. Finally, the presence of microthrombi did not differ before or after additional flushing of the graft with preservation solution. In conclusion, the results of our study derogate from the hypothesis that DCD livers have an increased tendency to form microthrombi. It weakens the explanation that microthrombi formation is a main causal factor in the development of NAS in DCD and that recipients could benefit from intraoperative thrombolytic therapy to prevent NAS following liver transplantation. Liver Transplantation 22 1676-1687 2016 AASLD., (© 2016 by the American Association for the Study of Liver Diseases.)

Renal ischemia reperfusion injury (IRI) is a major problem, currently without treatments in clinical use. This reflects the failure of animal models to mimic the severity of IRI observed in clinical practice. Most described models lack both the ability to inflict a permanent reduction in renal function and the sensitivity to demonstrate the protective efficacy of different therapies in vivo. To test novel cell-based therapies, we have developed a model of renal IRI in Fisher 344 rats. Animals were subjected to 120 min of unilateral warm ischemia, during which they underwent an intra-renal artery infusion of therapeutic agents or vehicle. At either 2 or 6 weeks post-surgery, animals underwent terminal glomerular filtration rate (GFR) studies by inulin clearance to most accurately quantify renal function. Harvested kidneys underwent histological analysis. Compared to sham operations, saline treated animals suffered a long-term reduction in GFR of ≈50%. Histology revealed short- and long-term disruption of renal architecture. Despite the injury severity, post-operative animal losses are <5%. This model produces a severe, consistent renal injury that closely replicates the pathological processes encountered in clinical medicine. Renal artery infusion mimics the route likely employed in clinical transplantation, where the renal artery is accessible. Inulin clearance characterizes GFR, allowing full assessment of therapeutic intervention. This model is useful for screening therapeutic agents prior to testing in a transplant model. This reduces animal numbers needed to test drugs for clinical transplantation and allows for refinement of dosing schedules.

Background: Acute ischemic injury in the operated kidney after partial nephrectomy (PN) is often masked by a functional contralateral kidney; however, there is no practical method to assess this and its prognostic significance has not been defined., Objective: We propose a spectrum score to reflect the degree of ischemic insult in the ipsilateral kidney and study its relationship to subsequent functional recovery., Design, Setting, and Participants: From 2007 to 2014, 243 patients with a functional contralateral kidney underwent PN with necessary studies for detailed analysis of function and parenchymal mass before and after surgery in the ipsilateral kidney. Based on split function and percent parenchymal mass preserved in the ipsilateral kidney, we determined: serum creatinine (SCr) ideal-peak : expected peak SCr presuming no ischemic injury; and SCr worstcase-peak : expected peak SCr presuming temporary complete nonfunction of the ipsilateral kidney. The acute ipsilateral renal dysfunction spectrum score was defined: (observed peak SCr - SCr ideal-peak )/(SCr worstcase-peak - SCr ideal-peak ). Subsequent functional recovery was defined: (percent function preserved)/(percent mass saved)., Intervention: PN., Outcome Measurements and Statistical Analysis: Factors associated with spectrum score and relationship between spectrum score and subsequent functional recovery were evaluated by linear regression., Results and Limitations: Median duration of warm ischemia (n=152) was 21min (interquartile range [IQR] = 15-27) and hypothermia (n=91) 26min (IQR=23-30). Median parenchymal mass preservation was 83% (IQR=74-91%). Warm ischemia and longer ischemia duration associated with higher spectrum score (both p<0.05). Increased spectrum score (<25%, 25-50%, 50-75%, and >75% quartiles) had decreased functional recovery (98%, 94%, 90%, and 89%, respectively, p<0.001). However, this trend was not observed in the hypothermia cohort. On multivariable analysis spectrum score and ischemia type significantly associated with functional recovery (both p<0.01), while age and comorbidities failed to associate (p=0.3-0.7)., Conclusions: Acute ipsilateral renal dysfunction spectrum score unmasks the degree of ischemic insult in the operated kidney after PN and associates with functional recovery. While increased spectrum score associates with suboptimal recovery, even patients with a high spectrum score reached 89-90% recovery., Patient Summary: Acute functional decline after partial nephrectomy is difficult to evaluate in patients with two kidneys, but a proposed spectrum score can be used to evaluate this. Increased spectrum score reflects increased ischemia and may impact the functional recovery of the kidney., (Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Donation after circulatory death (DCD) donor pool remains underutilized for liver transplantation (LT). We describe optimizing "modifiable risk factors," such as cold ischemia time (CIT) recipient warm ischemia time (WIT) and the use of thrombolytic flush at the time of procurement to minimize ischemic cholangiopathy (IC)., Methods: From July 2011 (era II), to improve outcomes after DCD LT, measures were taken to minimize CIT, operative time and recipient WIT along with the use of tissue plasminogen activator (tPA) flush during DCD procurements. Thirty consecutive DCD LTs were performed prospectively in era II. Outcomes were compared with 61 historic controls (era I). Reperfusion biopsies were evaluated for the presence of necrosis and biliary epithelial damage., Results: Median CIT (4.9 [3.5-5.9] vs 6.4 [4.3-12]; P < 0.001), hepatectomy time (70 [42-120] vs 81 [58-207]; P = 0.02), and recipient WIT (16 [13-31] vs 24[15-40]; P < 0.001) were significantly shorter in era II. All patients in era II received tPA flushed liver grafts. None of the patients in era II developed IC (0% vs 18%; P = 0.013). There were fewer biliary complications in era II, and there was no increased risk of bleeding associated with the use of tPA. One-year graft survival was slightly better in era II (n = 24 patients with 1 year follow-up) (88% vs 80%; P = 0.14)., Conclusions: Optimizing peritransplant conditions, such as shortening ischemic times with the use of thrombolytic donor flush, may prevent IC after DCD LT. With this approach, the DCD donor pool may be expanded.

Identifying which liver transplantation (LT) candidates with severe kidney injury will have a full recovery of renal function after liver transplantation alone (LTA) is difficult. Avoiding unnecessary simultaneous liver-kidney transplantation (SLKT) can optimize the use of scarce kidney grafts. Incorrect predictions of spontaneous renal recovery after LTA can lead to increased morbidity and mortality. We retrospectively analyzed all LTA patients at our institution from February 2002 to February 2013 (n = 583) and identified a cohort with severe subacute renal injury (n = 40; creatinine <2 mg/dL in the 14-89 days prior to LTA and not on renal replacement therapy [RRT] yet, ≥2 mg/dL within 14 days of LTA and/or on RRT). Of 40 LTA recipients, 26 (65%) had renal recovery and 14 (35%) did not. The median (interquartile range) warm ischemia time (WIT) in recipients with and without renal recovery after LTA was 31 minutes (24-46 minutes) and 39 minutes (34-49 minutes; P = 0.02), respectively. Adjusting for the severity of the subacute kidney injury with either Acute Kidney Injury Network or Risk, Injury, Failure, Loss, and End-Stage Kidney Disease criteria, increasing WIT was associated with lack of renal recovery (serum creatinine <2 mg/dL after LTA, not on RRT), with an odds ratio (OR) of 1.08 (1.01-1.16; P = 0.03) and 1.09 (1.01-1.17; P = 0.02), respectively. For each minute of increased WIT, there was an 8%-9% increase in the risk of lack of renal recovery after LTA. In a separate cohort of 98 LTA recipients with subacute kidney injury, we confirmed the association of WIT and lack of renal recovery (OR, 1.04; P = 0.04). In LT candidates with severe subacute renal injury, operative measures to minimize WIT may improve renal recovery potentially avoiding RRT and the need for subsequent kidney transplant. Liver Transplantation 22 1085-1091 2016 AASLD., (© 2016 American Association for the Study of Liver Diseases.)

Donation after circulatory death (DCD) liver transplantation (LT) may imply a risk for decreased graft survival, caused by posttransplantation complications such as primary nonfunction or ischemic-type biliary lesions. However, similar survival rates for DCD and donation after brain death (DBD) LT have been reported. The objective of this study is to determine the longterm outcome of DCD LT in the Eurotransplant region corrected for the Eurotransplant donor risk index (ET-DRI). Transplants performed in Belgium and the Netherlands (January 1, 2003 to December 31, 2007) in adult recipients were included. Graft failure was defined as either the date of recipient death or retransplantation whichever occurred first (death-uncensored graft survival). Mean follow-up was 7.2 years. In total, 126 DCD and 1264 DBD LTs were performed. Kaplan-Meier survival analyses showed different graft survival for DBD and DCD at 1 year (77.7% versus 74.8%, respectively; P = 0.71), 5 years (65.6% versus 54.4%, respectively; P = 0.02), and 10 years (47.3% versus 44.2%, respectively; P = 0.55; log-rank P = 0.038). Although there was an overall significant difference, the survival curves almost reach each other after 10 years, which is most likely caused by other risk factors being less in DCD livers. Patient survival was not significantly different (P = 0.59). Multivariate Cox regression analysis showed a hazard ratio of 1.7 (P < 0.001) for DCD (corrected for ET-DRI and recipient factors). First warm ischemia time (WIT), which is the time from the end of circulation until aortic cold perfusion, over 25 minutes was associated with a lower graft survival in univariate analysis of all DCD transplants (P = 0.002). In conclusion, DCD LT has an increased risk for diminished graft survival compared to DBD. There was no significant difference in patient survival. DCD allografts with a first WIT > 25 minutes have an increased risk for a decrease in graft survival. Liver Transplantation 22 1107-1114 2016 AASLD., (© 2016 American Association for the Study of Liver Diseases.)

Objectives: Retrospective studies suggest that donor desmopressin (DDAVP) treatment improves renal transplant outcome. The present study tests the hypothesis that desmopressin neutralizes the graft's endothelium from proinflammatory angiopoietin 2 containing Weibel-Palade bodies in the donor, resulting in reduced Weibel-Palade body release at the time of reperfusion in the recipient., Materials and Methods: Using rat models, we examined the influence of desmopressin treatment on the expression of vasopressin 2 receptors and adhesion molecules in brain-dead donors, with renal function examined in allogeneic recipients. The influence of desmopressin on the expression of adhesion molecules also was tested in vitro., Results: Vasopressin 2 receptors were restricted to collecting ducts and distal tubules and only scarcely found in the renal vasculature. Vasopressin 2 receptor expression was down-regulated in brain-dead rats by desmopressin. Renal expression of vascular cellular adhesion molecule 1 and intercellular adhesion molecule 1 were significantly reduced in these rats. In contrast, angiopoietin 2 did not influence the expression of adhesion molecules in in vitro cultured endothelial cells after tumor necrosis factor ? stimulation. Donor desmopressin treatment improved neither renal function nor histology in allogeneic renal transplant recipients., Conclusions: Our data do not support the hypothesis that the clinically observed salutary effect of desmopressin is mediated by depletion of Weibel-Palade bodies in renal allografts.

Objective: To assess the 1-year renal functional changes in patients undergoing partial nephrectomy with intra-operative renal biopsies., Patients and Methods: A total of 40 patients with a single renal mass deemed fit for a partial nephrectomy were recruited prospectively between January 2009 and October 2010. We performed renal biopsies of normal renal parenchyma and collected serum markers before, during and after surgically induced renal clamp ischaemia during the partial nephrectomy. We then followed patients clinically with interval serum creatinine and physical examination., Results: Peri-operative data from 40 patients showed a transient increase in creatinine levels which did not correlate with ischaemia time. Renal ultrastructural changes were generally mild and included mitochondrial swelling, which resolved at the post-perfusion biopsy. A total of 37 patients had 1-year follow-up data. Creatinine at 1 year increased by 0.121 mg/dL, which represents a 12.99% decrease in renal function from baseline (preoperative creatinine 0.823 mg/dL, estimated glomerular filtration rate = 93.9 mL/min/1.73 m(2) ). The only factors predicting creatinine change on multivariate analysis were patient age, race and ischaemia type, with cold ischaemia being associated with higher creatinine level. Importantly, the duration of ischaemia did not show any significant correlation with renal function change, either as a continuous variable (P = 0.452) or as a categorical variable (P = 0.792)., Conclusions: Our data suggest that limited ischaemia is generally well tolerated in the setting of partial nephrectomy and does not directly correspond to long-term renal functional decline. For surgeons performing partial nephrectomy, the kidney can be safely clamped to ensure optimum oncological outcomes., Competing Interests: Conflicts of Interest: None declared., (© 2015 The Authors BJU International © 2015 BJU International Published by John Wiley & Sons Ltd.)

Background: Acute increase of serum creatinine (SCr) after partial nephrectomy (PN) is primarily due to parenchymal mass reduction or ischemia; however, only ischemia can impact subsequent functional recovery., Objective: We evaluate etiologies of acute kidney injury (AKI) after PN and their prognostic significance., Design, Setting, and Participants: From 2007-2014, 83 solitary kidneys managed with PN had necessary studies for detailed analysis of function and parenchymal mass before/after surgery. AKI was classified by Risk/Injury/Failure/Loss/Endstage classification and defined by either standard criteria (comparison to preoperative SCr) or proposed criteria (comparison to projected postoperative SCr based on parenchymal mass reduction). Subsequent recovery was defined as percent function preserved/percent mass saved., Intervention: PN., Outcome Measurements and Statistical Analysis: Predictive factors for AKI were evaluated by logistic regression. Relationship between AKI grade and subsequent functional recovery was assessed by linear regression., Results and Limitations: Median duration warm ischemia (n=39) was 20 min and hypothermia (n=44) was 29 min. Median parenchymal mass reduction was 11%. AKI occurred in 45 patients based on standard criteria and 38 based on proposed criteria, and reflected injury/failure (grade = 2/3) in 23 and 16 patients, respectively. On multivariable analysis, only ischemia time associated with AKI occurrence (p=0.016). Based on the proposed criteria, median recovery from ischemia was 99% in patients without AKI and 95%/90%/88% for patients with grades 1/2/3 AKI, respectively. The coefficient for association between AKI grade based on proposed criteria and subsequent functional recovery was -4.168 (p=0.018). Main limitation is limited patient cohort., Conclusions: Parenchymal mass reduction and ischemia both contribute to acute changes in SCr after PN. Classification of AKI by proposed criteria significantly associates with subsequent functional recovery. However, more robust numbers will be needed to further assess the merits of the proposed criteria. While AKI is associated with suboptimal recovery, even patients with grade 2/3 AKI reached 88-90% of recovery expected., Patient Summary: Acute decline in function after partial nephrectomy associates with more prolonged ischemia time, and appears to impact subsequent functional recovery. However, most kidneys eventually recover strongly, even if their function is sluggish in the first few days after surgery., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Warm ischemia time is a potentially modifiable insult to transplanted kidneys, but little is known about its effect on long-term outcomes. Here we conducted a study of United States kidney transplant recipients (years 2000-2013) to determine the association between warm ischemia time (the time from organ removal from cold storage to reperfusion with warm blood) and death/graft failure. Times under 10 minutes were potentially attributed to coding error. Therefore, the 10-to-under-20-minute interval was chosen as the reference group. The primary outcome was mortality and graft failure (return to chronic dialysis or preemptive retransplantation) adjusted for recipient, donor, immunologic, and surgical factors. The study included 131,677 patients with 35,901 events. Relative to the reference patients, times of 10 to under 20, 20 to under 30, 30 to under 40, 40 to under 50, 50 to under 60, and 60 and more minutes were associated with hazard ratios of 1.07 (95% confidence interval, 0.99-1.15), 1.13 (1.06-1.22), 1.17 (1.09-1.26), 1.20 (1.12-1.30), and 1.23 (1.15-1.33) for the composite event, respectively. Association between prolonged warm ischemia time and death/graft failure persisted after stratification by donor type (living vs. deceased donor) and delayed graft function status. Thus, warm ischemia time is associated with adverse long-term patient and graft survival after kidney transplantation. Identifying strategies to reduce warm ischemia time is an important consideration for future study., (Copyright © 2015 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Warm ischemia and reperfusion (WIR) causes hepatic damage and may lead to liver failure, however the mechanisms involved are largely unknown. Here we have characterized the microcirculatory status and endothelial phenotype of livers undergoing WIR, and evaluated the use of simvastatin in WIR injury prevention. Male Wistar rats received simvastatin, or vehicle, 30 min before undergoing 60 min of partial warm ischemia (70%) followed by 2 h or 24 h of reperfusion. Hepatic and systemic hemodynamics, liver injury (AST, ALT, LDH), endothelial function (vasodilatation in response to acetylcholine), KLF2 and nitric oxide pathways, oxidative stress, inflammation (neutrophil and macrophage infiltration) and cell death were evaluated. Profound microcirculatory dysfunction occurred rapidly following WIR. This was evidenced by down-regulation of the KLF2 vasoprotective pathway, impaired vasodilatory capability and endothelial activation, altogether leading to increased hepatic vascular resistance and liver inflammation, with significant leukocyte infiltration, oxidative stress and cell death. Simvastatin preserved the hepatic endothelial phenotype, and blunted the detrimental effects of WIR on liver hemodynamics and organ integrity. In conclusion, WIR-induced injury to liver sinusoidal endothelial cells is mitigated by pre-treatment with Simvastatin probably through a KLF2-dependent mechanism.

The quality of a donor liver after cardiac death is closely associated with energy metabolism during preservation. Ex vivo mechanical perfusion has broad application prospects because this technique can help energy metabolism and repair ischemia injury of donors' livers. Some core issues are presented in this review in order to provide references for propelling secure application of liver transplantation based on donation after cardiac death.

Background: Intestinal ischemia-reperfusion injury occurs after different surgical treatments, including intestinal transplantation. This harmful process may have an effect in remote organs, leading to multiple organ dysfunction syndrome and death. Therefore, to establish strategies to attenuate local and remote damage constitutes a challenge for experimental and clinical surgeons in the intestinal surgical field., Methods: We evaluated the effect of ischemic preconditioning and tacrolimus pretreatment applied alone and in combination against local and remote damage caused by prolonged intestinal ischemia-reperfusion injury in a mouse model of warm ischemia., Results: Ischemic preconditioning applied alone and in combination with tacrolimus decreased histological damage (P < .05), number of apoptotic cells (P < .05), nitrosative stress (P < .01), and serum lactate dehydrogenase activity (P < .05) and lowered uremia (P < .05) compared with untreated post-reperfused intestines. Regarding remote organ damage, combination therapy was the unique condition able to attenuate lung (mainly neutrophil infiltration and hemorrhage), liver (sinusoidal congestion and hepatic vacuolization), and kidney (acute tubular necrosis and hydropic degeneration) histological alterations (P < .05), compared with the untreated group., Conclusions: These results support the application of these strategies in combination to minimize the impact of ischemia-reperfusion injury in the whole organism as a strategy to prevent multiple organ dysfunction syndromes and minimize the clinical impact., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: The number of heart transplantations is limited by donor organ availability. Donation after circulatory determination of death (DCDD) could significantly improve graft availability; however, organs undergo warm ischaemia followed by reperfusion, leading to tissue damage. Laboratory studies suggest that mechanical postconditioning [(MPC); brief, intermittent periods of ischaemia at the onset of reperfusion] can limit reperfusion injury; however, clinical translation has been disappointing. We hypothesized that MPC-induced cardioprotection depends on fatty acid levels at reperfusion., Methods: Experiments were performed with an isolated rat heart model of DCDD. Hearts of male Wistar rats (n = 42) underwent working-mode perfusion for 20 min (baseline), 27 min of global ischaemia and 60 min reperfusion with or without MPC (two cycles of 30 s reperfusion/30 s ischaemia) in the presence or absence of high fat [(HF); 1.2 mM palmitate]. Haemodynamic parameters, necrosis factors and oxygen consumption (O2C) were assessed. Recovery rate was calculated as the value at 60 min reperfusion expressed as a percentage of the mean baseline value. The Kruskal-Wallis test was used to provide an overview of differences between experimental groups, and pairwise comparisons were performed to compare specific time points of interest for parameters with significant overall results., Results: Percent recovery of left ventricular (LV) work [developed pressure (DP)-heart rate product] at 60 min reperfusion was higher in hearts reperfused without fat versus with fat (58 ± 8 vs 23 ± 26%, P < 0.01) in the absence of MPC. In the absence of fat, MPC did not affect post-ischaemic haemodynamic recovery. Among the hearts reperfused with HF, two significantly different subgroups emerged according to recovery of LV work: low recovery (LoR) and high recovery (HiR) subgroups. At 60 min reperfusion, recovery was increased with MPC versus no MPC for LV work (79 ± 6 vs 55 ± 7, respectively; P < 0.05) in HiR subgroups and for DP (40 ± 27 vs 4 ± 2%), dP/dtmax (37 ± 24 vs 5 ± 3%) and dP/dtmin (33 ± 21 vs 5 ± 4%; P < 0.01 for all) in LoR subgroups., Conclusions: Effects of MPC depend on energy substrate availability; MPC increased recovery of LV work in the presence, but not in the absence, of HF. Controlled reperfusion may be useful for therapeutic strategies aimed at improving post-ischaemic recovery of cardiac DCDD grafts, and ultimately in increasing donor heart availability., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Introduction: Biliary complications can cause morbidity, graft loss, and mortality after liver transplantation. The most troublesome biliary complications are ischemic-type biliary lesions (ITBL), which occur since transplants can now be performed after the donor has undergone circulatory death. The exact origin of this type of biliary complication remains unknown., Material and Methods: A total of 528 patients were retrospectively analyzed following liver transplantation after excluding 30 patients with primary sclerosing cholangitis and those lost to follow-up from January 2007 to January 2014. The incidence of and risk factors for ITBL were evaluated., Results: Cold ischemia time (CIT) (P = 0.042) and warm ischemia time (WIT) (P = 0.006) were found to be independent risk factors for the development of ITBL. Use of the cytochrome P450 (CYP) 3A5 genotype assay to guide individualization of immunosuppressive medications resulted in significantly fewer ITBL (P = 0.027. Autoimmune hepatitis might be a risk factor for ITBL, as determined using univariate analysis (P = 0.047)., Conclusions: Efforts should be taken to minimize risk factors associated with ITBL, such as CIT and WIT. The CYP3A5 genotype assay should be used to guide selection of immunosuppressive therapy in an effort to reduce the occurrence of ITBL.

Objective: The use of positron-emission tomography (PET) with (18)F-fluorodeoxyglucose (FDG) -labeled islets has been considered to be a potential modality to visualize and quantify early engraftment of islet transplantation. The objective of this study was to evaluate the early islets' survival of the FDG-labeled islets with or without warm ischemic stress in portal transplanted rats using PET and autoradiography., Methods: Islets were isolated from Lewis rat pancreata with or without 30-minute warm ischemia times (WITs). For islets' labeling, 300 islets were incubated with 3 MBq FDG for 60 minutes. FDG-labeled islets were transplanted into the liver via portal vein. In in vivo study, a PET study was scanned for 90 minutes and the FDG uptake was expressed as percentage of liver injection dose (ID). In ex vivo study, the liver was exposed for 30 minutes with single fluorescence autoradiography., Results: In the PET study, the percentage of liver ID of the islets without WIT was 27.8 and that of the WIT islets was 20.1 at the end of islet transplantation. At 90 minutes after transplantation, the percentage of liver ID was decreased to 14.7 in the islets without WIT and 10.1 in the WIT islets. In the autoradiogram, the number of hot spots was more obviously visualized in the liver transplanted without WIT islets than in the liver transplanted with WIT islets., Conclusion: Almost 50% of the islets were immediately lost in both the islets without WIT and those with WIT transplantation in the early period. However, islet survival was 1.4 times higher in the islets without WIT than that in those with WIT in the early engraftment phase., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background/aim: The global shortage of donor organs for transplantation has necessitated the expansion of the organ pool through increased use of organs from less ideal donors. Venous systemic oxygen persufflation (VSOP) and oxygenated machine perfusion (OMP) have previously demonstrated beneficial results compared to cold storage (CS) in the preservation of warm-ischemia-damaged kidney grafts. The aim of this study was to compare the efficacy of VSOP and OMP for the preservation of warm-ischemia-damaged porcine kidneys using the recently introduced Ecosol preservation solution compared to CS using Ecosol or histidine-tryptophan-ketoglutarate solution (HTK)., Materials and Methods: Kidneys from German Landrace pigs (n = 5/group) were retrieved and washed out with either Ecosol or HTK after 45 min of clamping of the renal pedicle. As controls, kidneys without warm ischemia, cold stored for 24 h in HTK, were employed. Following 24 h of preservation by VSOP, OMP, CS-Ecosol, or CS-HTK, renal function and damage were assessed during 1 h using the isolated perfused porcine kidney model., Results: During reperfusion, urine production was significantly higher in the VSOP and OMP groups than in the CS-HTK group; however, only VSOP could demonstrate lower urine protein concentrations and fractional excretion of sodium, which did not differ from the non-warm-ischemia-damaged control group. VSOP, CS-Ecosol, and controls showed better maintenance of the acid-base balance than CS-HTK. Reduced lipid peroxidation, as reflected in postreperfusion tissue thiobarbituric acid-reactive substance levels, was observed in the VSOP group compared to the OMP group, and the VSOP and CS-Ecosol groups had concentrations similar to the controls. The ratio of reduced to oxidized glutathione was higher in the VSOP, OMP, and CS-Ecosol groups than in the CS-HTK group and controls, with a higher ratio in the VSOP than in the OMP group., Conclusion: VSOP was associated with mitigation of oxidative stress in comparison to OMP and CS. Preservation of warm-ischemia-damaged porcine kidneys by VSOP was improved compared to OMP and CS, and was comparable to preservation of non-warm-ischemia-damaged cold-stored kidneys., (© 2016 S. Karger AG, Basel.)

Kidney is the organ transplanted most often. An increase in the number of expanded criteria donors (ECD) has been observed for years, and consequently the condition of transplanted organs worsened. In recent years, the possibility to recover organs from donors after cardiac death (DCD) became legally available in Poland, which will result in the increase of donors. Every DCD donor is at the same time ECD donor. One of the most important challenges the transplantology has to face is the improvement of the quality of transplanted organs. In this study the available data on the reduction of warm ischemic time (WIT) on transplanted kidney has been presented. WIT may influence early and late outcome of kidney allograft. Long WIT increases the risk of delayed graft function (DGF). DGF occurs more often in transplanted kidneys from DCD. One of the main reasons for that is the fact that DCD have longer WIT compared to donors after brain death (DBD). So-called WIT II appearing during vascular anastomosis in kidney transplantation may be reduced by various techniques. The model of clear sterilized polyethylene bag developed by the authors has been presented. The construction of the bag, consisting of three compartments, allow to safely perform vascular anastomosis while keeping the temperature of the transplanted kidney low. The article describes as well other techniques used to decrease WIT II. The effect of anastomosis time on allograft outcome is still not well researched. The article presents the newest information regarding the influence of WIT on graft and patient survival.

Objectives: To determine the influence of the early unclamping technique on the risk of renal artery pseudoaneurysm during robot-assisted laparoscopic partial nephrectomy., Methods: From January 2013 to October 2014, 96 patients underwent robot-assisted laparoscopic partial nephrectomy for renal masses at Tokyo Women's Medical University Hospital, Tokyo, Japan. Computed tomography angiography was carried out 3-4 days after surgery. Early in the series, renal hilum was left unclamped and renorrhaphy was subsequently carried out (conventional unclamping technique). An early unclamping technique has been used since November 2013., Results: A total of 61 patients underwent robot-assisted laparoscopic partial nephrectomy with early unclamping, and 35 patients underwent robot-assisted laparoscopic partial nephrectomy with conventional unclamping. Ischemia time was significantly shorter in the early unclamping group (16.5 vs. 23.1 min; P < 0.01). The early unclamping group showed a significantly lower incidence of asymptomatic renal artery pseudoaneurysm relative to the conventional unclamping group (11.4% vs. 28.6%; P = 0.03). Multivariate analysis showed that the early unclamping technique was a significant independent factor in reducing the risk of renal artery pseudoaneurysm (hazard ratio 0.27; P = 0.01)., Conclusions: The present findings suggest that an early unclamping technique might reduce ischemic time and risk of renal artery pseudoaneurysm. The absence of arterial bleeding before renorrhaphy is likely to be a key step in preventing renal artery pseudoaneurysm during robot-assisted laparoscopic partial nephrectomy., (© 2015 The Japanese Urological Association.)

Objectives: To study the possible renoprotective effect of sildenafil against renal ischemia/reperfusion (I/R) injury and its effect on the expression of some antioxidant, antiapoptotic gene and proinflammatory cytokine genes in rat model of renal I/R injury., Materials and Methods: One hundred and twenty male Sprague Dawley rats were subdivided into three equal groups: sham (underwent right nephrectomy without ischemia), control (underwent right nephrectomy and left ischemia for 45 min) and study [as control with 1 mg/kg sildenafil (per oral) 60 min before anesthesia]. Serum creatinine and BUN were measured at the baseline and the study endpoints (2, 24, 48 h and 7 days), and the left kidney was harvested at study endpoints for histopathological examination as well as for assessment of the expression of antioxidant genes (Nrf-2, HO-1 and NQO-1), antiapoptotic gene (Bcl-2) and inflammatory cytokines, e.g., TNF-a, IL-1β and ICAM-1., Results: I/R caused significant increase in serum creatinine, BUN, histopathological damage score (p < 0.001) and significant reduction in antioxidant genes (nrf2, HO-1 and NQO-1) and antiapoptotic gene (Bcl2) with significant increase in TNF-a, IL-1β and ICAM-1 genes in kidney tissues. Pretreatment with sildenafil caused significant attenuation of serum creatinine and BUN as well as significant increase in the expression of antioxidant genes and Bcl-2 genes with significant reduction in the expression of proinflammatory cytokine genes (p value < 0.001)., Conclusion: The renoprotective effect of sildenafil against renal I/R might be due to the activation of antioxidant genes (Nrf2, HO-1 and NQO-1) and antiapoptotic gene (Bcl2) and attenuation of proinflammatory cytokines (TNF-a, IL-1β and ICAM-1).

A short period of oxygenated machine perfusion (MP) after static cold storage (SCS) may reduce biliary injury in donation after cardiac death (DCD) donor livers. However, the ideal perfusion temperature for protection of the bile ducts is unknown. In this study, the optimal perfusion temperature for protection of the bile ducts was assessed. DCD rat livers were preserved by SCS for 6 hours. Thereafter, 1 hour of oxygenated MP was performed using either hypothermic machine perfusion, subnormothermic machine perfusion, or with controlled oxygenated rewarming (COR) conditions. Subsequently, graft and bile duct viability were assessed during 2 hours of normothermic ex situ reperfusion. In the MP study groups, lower levels of transaminases, lactate dehydrogenase (LDH), and thiobarbituric acid reactive substances were measured compared to SCS. In parallel, mitochondrial oxygen consumption and adenosine triphosphate (ATP) production were significantly higher in the MP groups. Biomarkers of biliary function, including bile production, biliary bicarbonate concentration, and pH, were significantly higher in the MP groups, whereas biomarkers of biliary epithelial injury (biliary gamma-glutamyltransferase [GGT] and LDH), were significantly lower in MP preserved livers. Histological analysis revealed less injury of large bile duct epithelium in the MP groups compared to SCS. In conclusion, compared to SCS, end-ischemic oxygenated MP of DCD livers provides better preservation of biliary epithelial function and morphology, independent of the temperature at which MP is performed. End-ischemic oxygenated MP could reduce biliary injury after DCD liver transplantation., (© 2015 American Association for the Study of Liver Diseases.)

The use of banked human tissue, obtained with informed consent after elective surgical procedures, represents a powerful model for understanding underlying mechanisms of diseases or therapeutic interventions and for establishing prognostic markers. However, donated tissues typically have varying times of warm ischaemia in situ due to blood arrest or cold ischaemia due to procurement and transportation. Hence, before using these tissues, it is important to carry out pre-analytical studies to ensure that they are representative of the in vivo state. In particular, tissues of the gastrointestinal tract have been thought to have low RNA stability. Therefore, this study aimed to determine if extended warm or cold ischaemia times and snap-freezing or banking in RNA stabilization solution affects RNA integrity or gene expression in human ileum mucosa. In short, ileum mucosa was collected for up to 1.5 h and 6 h of simulated warm or cold ischaemia respectively. Subsequently, RNA integrity and gene expressions were determined. It was found that RNA integrity remained high over the course of warm and cold ischaemia examined and there were in general no significant differences between snap-freezing and banking in RNA stabilization solution. Following the same trend, there were in general no significant changes in gene expressions measured (MYC, HIF1α, CDX, HMOX1 and IL1β). In conclusion, RNA in the ileum mucosa is maintained at a high integrity and has stable gene expression over the examined time course of warm or cold ischaemia when banked in RNA stabilization solution or snap-frozen in liquid nitrogen. As the average warm and cold ischaemia times imposed by surgery and the process of tissue banking are shorter than the time period examined in this study, human ileum mucosa samples collected after surgeries could be used for gene expression studies.

Introduction: The aim of this study is to evaluate the risk factors for acute kidney injury (AKI) and 30-day mortality after liver transplantation., Material and Methods: This is a retrospective cohort of consecutive adults undergoing orthotopic liver transplantation (OLT) at a referral hospital in Brazil, from January 2013 to January 2014. Risk factors for AKI and death were investigated., Results: A total 134 patients were included, with median age of 56 years. AKI was found in 46.7% of patients in the first 72 h after OLT. Risk factors for AKI were: viral hepatitis (OR 2.9, 95% CI = 1.2-7), warm ischemia time (OR 1.1, 95% CI = 1.01-1.2) and serum lactate (OR 1.3, 95%CI = 1.02-1.89). The length of intensive care unit (ICU) stay was longer in AKI group: 4 (3-7) days vs. 3 (2-4) days (p = 0.001), as well as overall hospitalization stay: 16 (9-26) days vs. 10 (8- 14) days (p = 0.001). The 30-day mortality was 15%. AKI was an independent risk factor for mortality (OR 4.3, 95% CI = 1.3-14.6). MELD-Na ≥ 22 was a predictor for hemodialysis need (OR 8.4, 95%CI = 1.5-46.5). Chronic kidney disease (CKD) was found in 36 patients (56.2% of AKI patients)., Conclusions: Viral hepatitis, longer warm ischemia time and high levels of serum lactate are risk factors for AKI after OLT. AKI is a risk factor for death and can lead to CKD in a high percentage of patients after OLT. A high MELD-Na score is a predictor for hemodialysis need.

Background: There is increasing evidence that ischemia-reperfusion injury (IRI) promotes vasculogenesis and tumor outgrowth in the liver. Hepatic IRI is exaggerated by prolongation of ischemia times., Aims: The aim of this retrospective analysis was to assess the impact of ischemia times on risk of hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT). Subgroup analysis focused on patients with (18)F-fluoro-deoxy-glucose ((18)F-FDG)-avid HCC on pretransplant positron emission tomography (PET)., Methods: A total of 103 liver transplant patients with HCC were included in this study. The impact of cold (CIT), warm (WIT), and total ischemia times (TIT) along with other prognostic variables on posttransplant outcome was analyzed in uni- and multivariate analysis., Results: Twenty-four patients (23.3 %) developed tumor relapse after LT. Mean durations of CIT (468.0 vs. 375.5 min; P = 0.001), WIT (58.4 vs. 45.7 min; P = 0.001), and TIT (525.8 vs. 422.0 min; P < 0.001) were significantly longer in patients with compared to those without HCC recurrence. In multivariate regression analysis, (18)F-FDG-avid HCC (odds ratio [OR] 73.4), WIT >50 min (OR 52.5), alpha-fetoprotein level >400 IU/ml (OR 11.1), and Milan Out status (OR 7.4) were identified as independent predictors of HCC recurrence. In the subgroup of patients with PET-positive HCC, WIT remained the only independent variable to predict HCC recurrence (OR 15.5)., Conclusion: Prolongation of ischemia times promotes the risk of HCC recurrence after LT, especially in patients with unfavorable tumor biology on PET imaging.

Ischaemia/reperfusion injury is an important cause of liver damage during surgical procedures such as hepatic resection and liver transplantation, and represents the main cause of graft dysfunction post-transplantation. Molecular processes occurring during hepatic ischaemia/reperfusion are diverse, and continuously include new and complex mechanisms. The present review aims to summarize the newest concepts and hypotheses regarding the pathophysiology of liver ischaemia/reperfusion, making clear distinction between situations of cold and warm ischaemia. Moreover, the most updated therapeutic strategies including pharmacological, genetic and surgical interventions, as well as some of the scientific controversies in the field are described.

Background and Purpose: Hydrogen sulfide (H2S) ameliorates hepatic ischemia and reperfusion injury (IRI), but the precise mechanism remains elusive. We investigated whether sodium hydrogen sulfide (NaHS), a soluble derivative of H2S, would ameliorate hepatic IRI, and if so, via what mechanism., Methods: Mice were subjected to partial warm ischemia for 75 min followed by reperfusion. Either NaHS or saline was administered intravenously 10 min before reperfusion. The liver and serum were collected 3, 6, and 24 h after reperfusion., Results: In the NaHS(-) group, severe IRI was apparent by the ALT leakage, tissue injury score, apoptosis, lipid peroxidation, and inflammation (higher plasma TNF-α, IL-6, IL-1β, IFN-γ, IL-23, IL-17, and CD40L), whereas IRI was significantly ameliorated in the NaHS(+) group. These effects could be explained by the augmented nuclear translocation of Nrf2, and the resulting up-regulation of HO-1 and thioredoxin-1. Phosphorylation of the PDK-1/Akt/mTOR/p70S6k axis, which is known to mediate pro-survival and anti-apoptotic signals, was significantly augmented in the NaHS(+) group, with a higher rate of PCNA-positive cells thereafter., Conclusion: NaHS ameliorated hepatic IRI by direct and indirect anti-oxidant activities by augmenting pro-survival, anti-apoptotic, and anti-inflammatory signals via mechanisms involving Nrf-2, and by accelerating hepatic regeneration via mechanisms involving Akt-p70S6k.

Background & Aims: We studied new-onset diabetes after transplantation (NODAT) in liver transplantation with grafts donated after brain death (DBD) or circulatory death (DCD), focusing on the early post-transplant period., Methods: A total of 430 non-diabetic primary liver transplant recipients [DCD, n = 90 (21%)] were followed up for 30 months (range 5-69). NODAT was defined as the composite endpoint of one of following: (i) Two non-fasting plasma glucose levels > 11.1 mmol/L ≥ 30 days apart, (ii) oral hypoglycaemic drugs ≥ 30 days consecutively (iii) insulin therapy ≥ 30 days and (iv) HbA1c ≥ 48 mmol/L. Resolution of NODAT was defined as cessation of treatment or hyperglycaemia., Results: Total of 81/430 (19%) patients developed NODAT. Incidence and resolution of NODAT over time showed significantly different patterns between DCD and DBD liver graft recipients; early occurrence, high peak incidence and early resolution were seen in DCD. In multivariate logistic regression including age, ethnicity, HCV, tacrolimus level and pulsed steroids, only DCD was independently associated with NODAT at day 15 post-transplant (OR 6.5, 95% CI 2.3-18.4, P < 0.001), whereas age and pulsed steroids were significant factors between 30-90 days. Combined in multivariate Cox regression model for NODAT-free survival, graft type, age and pulsed steroids were each independent predictor for decreased NODAT-free survival in the first 90-postoperative days., Conclusion: Early peak of NODAT in DCD graft recipients is a novel finding, occurring independently from known risk factors. Donor warm ischaemia and impact on insulin sensitivity should be further studied and could perhaps be associated with graft function., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Ischemia is a potential contributor to decline of function after partial nephrectomy (PN), although loss of parenchymal mass related to excision and reconstruction appears to be a more significant factor. However, loss of parenchymal mass could also be due to global effects of ischemia leading to parenchymal atrophy. In this study, we evaluated parenchymal volumes in regions away from the operated site to assess for atrophy., Materials and Methods: A total of 164 patients undergoing PN for whom detailed analysis of function and parenchymal mass within the operated kidney could be performed were assessed for opposite pole volume (OPV) before and 4-12 months after surgery. Tumor location was required to be ≥2 cm away from the opposite polar line to exclude local effects related to excision or reconstruction. OPV was estimated by software analysis, and the ratio of the estimates (OPV ratio = postoperative OPV to preoperative OPV) was used to assess for atrophy., Results: Patient demographics and tumor characteristics were representative of conventional PN populations, and warm ischemia (n = 101; median, 21 minutes) and cold ischemia (n = 63; median, 26 minutes) were applied by surgeon discretion. OPVs before and after PN were 63.2 and 62.5 cm(3), respectively (P = .76). The median OPV ratio was 0.99 suggesting that significant atrophy did not occur. OPV ratio was 0.99 for warm ischemia cases and 0.99 for cold ischemia cases (P = .95)., Conclusion: Limited warm ischemia or hypothermia was not associated with significant parenchymal atrophy after PN, which suggests that parenchymal volume loss in this setting is primarily due to excision or reconstruction., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Kidney ischemia and reperfusion (I/R) injury-associated acute and chronic kidney injury often leads to cardiac dysfunction, which may involve depletion of intracellular NAD(+) (the oxidized form of the nicotinamide adenine dinucleotide coenzyme) and reduction in intracellular adenosine triphosphate (ATP) levels, resulting in mitochondrial dysfunction. We examined whether treatment with niacin, an antioxidant and a component of NAD+, protects cardiac function and improves myocardial mitochondrial metabolism during kidney I/R injury., Methods: Studies were performed in Sprague-Dawley male rats divided into sham-operated, kidney I/R, and niacin-treated kidney I/R groups. Niacin was administered 3 days before the ischemia through 7 days of reperfusion. Kidney ischemia was conducted by bilateral occlusion of renal pedicles for 45 minutes, followed by releasing the clamps and closing the abdominal incision. After 7 days of reperfusion, we measured the cardiac function using a simultaneous pressure-volume catheter, cardiac biomarker (troponin T; cTnT), and kidney injury marker (creatinine and blood urea nitrogen). Myocardial malondialdehyde level and peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α mRNA expression also were measured., Results: Kidney I/R injury impairs cardiac function, induces myocardial and kidney injury, and markedly increases myocardial PGC-1α mRNA expression, suggesting utilizing more free fatty acid for ATP production. Niacin treatment improved cardiac function, reduced oxidative stress, and sustained PGC-1α expression (P < .05)., Conclusions: Kidney I/R-associated cardiac dysfunction is likely associated with increases in myocardial lipid peroxidation and utilizing more free fatty acid for ATP production. Niacin improves mitochondrial metabolism and reduced myocardial oxidative stress., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To compare between the effects of cold and warm ischemia on the risk of deterioration of renal insufficiency in patients with T1 renal tumor managed by partial nephrectomy., Methods: This prospective randomized study was performed on 120 patients with chronic kidney disease, all having T1 renal tumors. Renal function was estimated by estimated glomerular filtration rate (eGFR), using the Modification of Diet in Renal Disease formula. Patients were randomly divided into 2 groups: in group A, warm ischemia was used, and in group B, cold ischemia was used. All patients were treated by open partial nephrectomy. Patients were followed up for 2 years. The primary outcome of the study was eGFR at 2 years. Secondary outcomes were tumor recurrence, loss of follow-up, or patient death., Results: Mean age of patients was 60.7 ± 5.3 years. Associated chronic disease (diabetes and/or hypertension) was present in 93 patients. Worsening of renal insufficiency occurred within 1 month of surgery in 38 patients (27 in group A and 11 in group B). At 3 months follow-up, 21 of these 38 patients returned to their baseline eGFR. Warm ischemia rendered patients more prone to a decrease in eGFR after partial nephrectomy, with relative risk of 1.34 and 2 times at 3 months and 2 years of follow-up, respectively., Conclusion: Warm ischemia increases the risk of deterioration of renal functions in patients with renal insufficiency undergoing open partial nephrectomy for renal tumors., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Liver transplantation plays a pivotal role in the treatment of patients with end-stage liver disease. Despite excellent outcomes, the field is strained by a severe shortage of viable liver grafts. To meet high demands, attempts are made to increase the use of suboptimal livers by both pretransplant recovery and assessment of donor livers. Here we aim to assess hepatic injury in the measurement of routine markers in the post-ischemic flush effluent of discarded human liver with a wide warm ischemic range., Methods: Six human livers discarded for transplantation with variable warm and cold ischemia times were flushed at the end of preservation. The liver grafts were flushed with NaCl or Lactated Ringer's, 2 L through the portal vein and 1 L through the hepatic artery. The vena caval effluent was sampled and analyzed for biochemical markers of injury; lactate dehydrogenase (LDH), alanine transaminase (ALT), and alkaline phosphatase (ALP). Liver tissue biopsies were analyzed for ATP content and histologically (H&E) examined., Results: The duration of warm ischemia in the six livers correlated significantly to the concentration of LDH, ALT, and ALP in the effluent from the portal vein flush. No correlation was found with cold ischemia time. Tissue ATP content at the end of preservation correlated very strongly with the concentration of ALP in the arterial effluent (P<0.0007, R2 = 0.96)., Conclusion: Biochemical injury markers released during the cold preservation period were reflective of the duration of warm ischemic injury sustained prior to release of the markers, as well as the hepatic energy status. As such, assessment of the flush effluent at the end of cold preservation may be a useful tool in evaluating suboptimal livers prior to transplantation, particularly in situations with undeterminable ischemic durations.

Aim: To investigate the efficacy and molecular mechanisms of induced heme oxygenase (HO)-1 in protecting liver from warm ischemia/reperfusion (I/R) injury., Methods: Partial warm ischemia was produced in the left and middle hepatic lobes of SD rats for 75 min, followed by 6 h of reperfusion. Rats were treated with saline, cobalt protoporphyrin (CoPP) or zinc protoporphyrin (ZnPP) at 24 h prior to the ischemia insult. Blood and samples of ischemic lobes subjected to ischemia were collected at 6 h after reperfusion. Serum transaminases level, plasma lactate dehydrogenase and myeloperoxidase activity in liver were measured. Liver histological injury and inflammatory cell infiltration were evaluated by tissue section and liver immunohistochemical analysis. We used quantitative reverse transcription polymerase chain reaction to analyze liver expression of inflammatory cytokines and chemokines. The cell lysates were subjected to immunoprecipitation with anti-Toll-IL-1R-containing adaptor inducing interferon-β (TRIF) and anti-myeloid differentiation factor 88 (MyD88), and then the immunoprecipitates were analyzed by SDS-PAGE and immunoblotted with the indicated antibodies., Results: HO-1 protected livers from I/R injury, as evidenced by diminished liver enzymes and well-preserved tissue architecture. In comparison with ZnPP livers 6 h after surgery, CoPP treatment livers showed a significant increase inflammatory cell infiltration of lymphocytes, plasma cells, neutrophils and macrophages. The Toll-like receptor (TLR)-4 and TANK binding kinase 1 protein levels of rats treated with CoPP significantly reduced in TRIF-immunoprecipitated complex, as compared with ZnPP treatment. In addition, pretreatment with CoPP reduced the expression levels of TLR2, TLR4, IL-1R-associated kinase (IRAK)-1 and tumor necrosis factor receptor-associated factor 6 in MyD88-immunoprecipitated complex. The inflammatory cytokines and chemokines mRNA expression rapidly decreased in CoPP-pretreated liver, compared with the ZnPP-treated group. However, the expression of negative regulators Toll-interacting protein, suppressor of cytokine signaling-1, IRAK-M and Src homology 2 domain-containing inositol-5-phosphatase-1 in CoPP treatment rats were markedly up-regulated as compared with ZnPP-treated rats., Conclusion: HO-1 protects liver against I/R injury by inhibiting TLR2/TLR4-triggered MyD88- and TRIF-dependent signaling pathways and increasing expression of negative regulators of TLR signaling in rats.

Background: Existing data suggest that increased interstitial fibrosis may occur abnormally in renal transplants from donations after uncontrolled circulatory death (uDCD)., Methods: To evaluate the factors that are associated with the progression of fibrosis and its functional impact on renal grafts, we compared 76 uDCD recipients with 86 recipients of kidney donations after brain death at 1-year after transplantation. Groups were matched for donor age, rank of transplantation, and absence of human leukocyte antigen sensitization. Histology was performed on sequential biopsies in uDCD recipients. Associations between variables were analyzed using linear mixed models and univariate analyses., Results: In the uDCD group, increased fibrosis was detected 3 months after transplantation compared to before implantation. After 1 year, interstitial fibrosis and tubular atrophy score was significantly greater (1.5±0.7 vs. 1.0±0.9; P=0.003) and estimated glomerular filtration rate (49.5±17.4 vs. 60.6±19.1 mL/min/1.73 m2; P=0.0003) was significantly lower in the uDCD group than in the donations after brain death group. No flow duration and donor age were significantly associated with accelerated fibrosis. Interstitial fibrosis and tubular atrophy score, interstitial inflammation score, and estimated glomerular filtration rate were significantly worse in uDCD patients with no flow longer than 10 min., Conclusion: Donations after uncontrolled circulatory death grafts show more fibrosis after transplantation. No flow duration is associated with accelerated fibrosis and should be considered during uDCD graft allocation.

Purpose: To evaluate whether ischemic time is related to ipsilateral parenchymal atrophy (IPA) and contralateral compensational hypertrophy (CCH) and how CCH affects late functional outcome after partial nephrectomy., Methods: Parenchymal kidney volumes and glomerular filtration rate (GFR) were determined preoperatively and at 3, 6, and 12 months postoperatively in 79 patients. Kidney volume was measured by Voxel Plus® 2.5 with a tissue segmentation tool. Correlation analysis and univariate and multivariate regression models were used to evaluate the recovery of IPA, CCH, and GFR., Results: The mean preserved ipsilateral kidney volume was 86.7%. At 12 months, mean IPA and CCH were 3.0 and 4.8%, respectively, and the mean GFR decrease was 8.0%. Ipsilateral volume decrease and contralateral volume increase were significant until 6 months postoperatively (p<0.05, for each). IPA and CCH were greater with a longer ischemic time (>35 min; p=0.029 and 0.003, respectively), and CCH correlated positively with IPA (r2=0.052, p=0.045). On multivariate analysis, IPA correlated with a longer ischemic time and percent of preserved normal parenchymal volume (PPV), and CCH correlated with a longer ischemic time, IPA, PPV, and total parenchymal volume increase. At 12 months postoperatively, CCH correlated with GFR recovery (r2=0.072, p=0.026), and significant predictors of GFR recovery were age, sex, PPV, and CCH., Conclusions: We present the meaningful possibility that longer ischemic time and less preservation of normal parenchyma cause greater parenchymal atrophy, thereby promoting CCH, which contributes to renal function recovery after partial nephrectomy.

Context: Hepatic ischemia/reperfusion injury (IRI) is a major cause of liver damage during liver surgery and transplantation. Plants have historically been used in treating liver damage, and Hammada scoparia (Pomel) (Chenopodiaceae) has been reported to possess a broad spectrum of pharmacological and therapeutic activities., Objective: In this study, a flavonoid-enriched fraction was used before the warm ischemia (WI) process as pharmacological preconditioning and in combination with technical postconditioning to evaluate their protective effects., Materials and Methods: The rats were divided into five groups: a sham group; a control group (Control-IR) that was submitted to 60 min WI; a Pharmacological Preconditioning group (PreC-IR) that received flavonoid-enriched fraction (200 mg/kg body weight); a Postconditioning group (PostC) and a PreC + PostC group., Results: The use of the flavonoid-enriched fraction was noted to significantly (p < 0.05) reduce liver injury, as evidenced by the decrease in liver transaminase activities (AST and ALT) and lactic dehydrogenase (LDH), alkaline phosphatase (ALP), and lipid peroxidation (TBARS), levels as well as the enhancement of antioxidant enzymes (catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx)) responses. The results also indicated that, compared with the separate application of pharmacological preconditioning and postconditioning, the combination of both treatments was more effective in reducing tissue oxidative stress levels through modulating SOD, GSH-PX, and CAT activities. Furthermore, the combined protocol further decreased the liver morphological score compared with solo treatment., Discussion and Conclusion: Overall, the results indicate that the H. scoparia flavonoid-enriched fraction could be a promising candidate for future application as a pharmacological preconditioning agent against hepatic IRI.

Purpose: To evaluate renal function and to identify factors associated with renal dysfunction in the elective indications setting of nephron-sparing surgery (NSS)., Methods: We retrospectively reviewed operative data and glomerular filtration rate (GFR) of 519 patients treated by NSS in an elective indications setting between 1984 and 2006 in eight academic institutions. A GFR decrease under the thresholds of 60 or 45 ml/min at last follow-up was considered a significant renal dysfunction. Univariate and multivariate regression models were used to assess multiple factors of renal function., Results: Median age, tumor size, preoperative, and final GFR were 59.5 years (27-84), 2.7 cm (0.9-11), 79 (45-137), and 69 ml/min (p < 0.0001), respectively, with a median follow-up of 23 months (1-416). Hilar clamping was performed in 375 procedures (72.3 %). Significant GFR decrease was observed in 89 patients (17.1 %). Median operating time, hilar clamping duration, and blood loss were 137 min (55-350), 22 min (0-90), and 150 ml (0-4150), respectively. At univariate analysis, age (p = 0.002), preoperative GFR (p = 0.001), pedicular clamping (p = 0.01), and ischemia time (p = 0.0001) were associated with renal dysfunction. Age (p = 0.004; HR 1.2), pedicular clamping (p = 0.04; HR 1.3), and ischemia time (p = 0.0001; HR 1.8) remained independent risk factors for renal function deterioration in multivariate analysis., Conclusion: Non- or time-limited clamping techniques are associated with preservation of renal function in the elective indications setting of NSS.

Objectives: In this study, we report a simple closure technique of the renal parenchyma using a knotless running suture with Hem-o-lok(®) (Teleflex(®) Medical, Research Triangle Park, NC) clips (running-clip renorrhaphy) to minimize warm ischemic time (WIT) and reduce intraoperative blood loss (IBL)., Materials and Methods: From 2008 to 2010, laparoscopic partial nephrectomy (LPN) was performed by traditional interrupted knot-tying suture renorrhaphy (Group I; n=28). Since then, from 2011 to 2013, LPN was performed by running-clip technique renorrhaphy (Group II; n=51). A comparative analysis of WIT and IBL between Groups I and II patients was investigated., Results: All the LPNs were performed successfully without open conversion. No significant differences were observed for patients of different ages, body mass indexes, and preoperative estimated glomerular filtration rates. In Group I, the operative time, WIT, and IBL were 170.0±27.0 minutes, 32.3±6.5 minutes, and 369±201 mL, respectively. In Group II, the operative time, WIT, and IBL were 148.7±31.9 minutes, 21.5±5.8 minutes, and 254±162 mL, respectively. There was significant difference in operative time, WIT, and IBL between Groups I and II (P=.004, .001, and .008, respectively)., Conclusions: The running-clip renorrhaphy reduced operative time, WIT, and IBL during the LPN. Therefore, running-clip renorrhaphy is a safe, efficient, and operative technique for performing the LPN.

Objective: To analyze current evidence comparing the safety and outcomes of regional and global ischemia for partial nephrectomy (PN)., Materials and Methods: A systematic search of the PubMed and Web of Science databases was conducted in May 2014 to identify studies comparing the safety and outcomes of regional and global ischemia for PN. A systematic review and meta-analysis was also performed., Results: Six retrospective observational studies were selected for the analysis, including 363 patients who underwent PN (162 regional ischemia and 201 global ischemia cases). Operation times were not statistically different [weighted mean difference (WMD) = 20.35 min, 95% CI: -0.28-40.97, p = 0.05], but estimated blood loss was significantly higher in the regional ischemia group (WMD = 52.04 ml, 95% CI: 14.30-89.78, p = 0.007) than in the global ischemia group. Complication rates [odds ratio (OR) = 1.16; 95% CI: 0.63-2.15, p = 0.63] and blood transfusion rates (OR = 1.85; 95% CI: 0.86-4.01, p = 0.12) of the two groups were not significantly different. The regional ischemia group showed better postoperative renal function (WMD = 4.23 ml/min, 95% CI: 2.61-5.85, p < 0.00001) than the global ischemia group, and all cases in the regional ischemia group showed negative margins., Conclusions: Regional ischemia is as safe to perform as global ischemia, and the former leads to better postoperative renal functions than the latter. These findings support the application of regional ischemia for PN., (© 2015 S. Karger AG, Basel.)

Background: Steatotic livers are vulnerable to the deleterious effects of ischaemia-reperfusion injury (IRI) that occur after hepatic surgery. Ischaemic preconditioning (IPC) has been shown to abrogate the effects of IRI in patients undergoing hepatic surgery. Experimental studies have suggested that IPC may be beneficial in steatotic livers subjected to IRI., Objective: The aim of this systematic review was to evaluate the effects of IPC on steatotic livers following hepatic IRI in experimental models., Methods: An electronic search of the OVID Medline and EMBASE databases was performed to identify studies that reported clinically relevant outcomes in animal models of hepatic steatosis subjected to IPC and IRI., Results: A total of 1093 articles were identified, of which 18 met the inclusion criteria. There was considerable heterogeneity in the type of animal model, and duration and type of IRI. Increased macrovesicular steatosis (> 30%) was associated with a poor outcome following IRI. Ischaemic preconditioning was found to be beneficial in > 30% steatotic livers and provided for decreased histological damage, improved liver function findings and increased survival., Conclusions: Experimental evidence supports the use of IPC in steatotic livers undergoing IRI. These findings may be applicable to patients undergoing liver surgery. However, clinical studies are required to validate the efficacy of IPC in this setting., (© 2014 International Hepato-Pancreato-Biliary Association.)

Objective: To assess renal functional deterioration after partial nephrectomy with warm and cold ischemia using (99m)Tc-mercaptoacetyltriglycine ((99m)Tc-MAG3) renal scintigraphy parameters., Methods: Open partial nephrectomy was performed in 59 patients with warm ischemia and 64 patients with cold ischemia. (99m)Tc-MAG3 renal scintigraphy was performed and effective renal plasma flow was calculated to evaluate split renal function. In addition, regional (99m)Tc-MAG3 uptake was analyzed in the surgically unaffected parts to evaluate ischemic damage., Results: The mean tumor size in the warm and cold ischemia groups was 2.9 and 3.2 cm, respectively, and the mean ischemic time was 24.2 minutes (range, 8-46 minutes) and 26.7 min (range, 8-58 minutes), respectively. One week after surgery, effective renal plasma flow in the operated kidney decreased to 66.2% (from 160.2 to 105.4 mL/min/1.73 m(2)) in the warm ischemia group and to 77.4% (from 152.3 to 116.6 mL/min/1.73 m(2)) in the cold ischemia group. Regional (99m)Tc-MAG3 uptake changed to 89.2% of baseline in the warm ischemia group and 101.5% of baseline in the cold ischemia group. When the ischemic time was ≥ 25 minutes, regional (99m)Tc-MAG3 uptake in the warm ischemia group did not recover to the baseline level at 6 months. Multiple regression analyses demonstrated a significant correlation between ischemic time and the decrease in regional (99m)Tc-MAG3 uptake in the warm ischemia group, but not in the cold ischemia group., Conclusion: Warm ischemia for ≥ 25 minutes caused long lasting diffuse damage throughout the operated kidney, whereas cold ischemia for up to 58 minutes prevented ischemic injury to the renal remnant., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: To determine if patients with pathological, medical renal disease, defined as evidence of pathological abnormalities indicative of renal damage in the non-neoplastic partial nephrectomy specimens, have worsened functional outcomes following robot-assisted partial nephrectomy (RPN)., Materials and Methods: Sixty patients with and 101 without pathologically proven renal disease on non-neoplastic renal specimens were evaluated for differences in postoperative outcomes following RPN. Multiple linear regression modeling assessed for factors influencing early and late declines in renal function., Results: The two groups were similar in all preoperative parameters. Both patients with and without pathological renal disease had similar lengths of hospitalization, transfusions, and complication rates. The percent change in the glomerular filtration rate was similar for patients with and without pathological renal disease (-8.8% vs -12.2%, p=0.194). Patients with pathological renal disease had less chronic kidney disease (CKD) upstaging than patients without renal disease (18.3% vs 39.6%, p=0.006). Increasing age (p=0.030) and higher preoperative glomerular filtration rates (p=0.044) predicted worse late percentage declines in renal function, while increased warm ischemia time predicted late CKD upstaging (p=0.043)., Conclusion: The presence of pathological renal disease in non-neoplastic renal tissue did not place patients at risk for worsened postoperative complications or renal function deterioration following RPN.

Objective: The aims of this study were to present the results of hand-assisted laparoscopic partial nephrectomy according to the margin, ischaemia and complications system; to assess the role of the learning curve; and to compare this approach with other approaches., Material and Methods: Data from 60 consecutive patients were obtained from a prospectively maintained database. The patients were divided into three cohorts (1, 2 and 3), with 20 patients each, according to their surgery dates., Results: The overall margin, ischaemia and complications rate was 90%. The warm ischaemia time was 9.5 min in cohort 1, decreasing to 5 min in cohort 3 (p < 0.0001). The Padua score (p = 0.0287) and tumour size (p = 0.0003) were significantly increased in cohort 3, but loss of kidney function decreased significantly to 3.5% in this cohort. Loss of kidney function of less than 5% was reported for eight (40%), nine (45%) and 14 (70%) patients in cohorts 1, 2 and 3, respectively (p = 0.0185)., Conclusions: Hand-assisted laparoscopic partial nephrectomy with early removal of arterial clamps is safe and easy to learn. An expert laparoscopic surgeon can perform hand-assisted laparoscopic partial nephrectomy for complex tumours with a relatively high success rate according to the margin, ischaemia and complications system. Warm ischaemia time could be obtained within 5 min after 40 procedures.

Objective: To analyze the risk factors for biliary complications of liver transplantation from donation after cardiac death (DCD)., Methods: Clinical data of 109 patients undergoing liver transplantation from DCD in First Affiliated Hospital of Zhejiang University School of Medicine from October 2010 to October 2013 were studied retrospectively. The risk factors of biliary complications following DCD liver transplantation were analyzed., Results: Twenty-four (22%) patients developed biliary complications after DCD liver transplantation. Univariate analysis showed that biliary complications were associated with warm ischemia time (P<0.001) and length of ICU stay (P=0.013), but not associated with ABO blood types match (P>0.05). Administration of inotropic agents and fatty liver increased the trend of biliary complications. Multivariate analysis demonstrated that warm ischemia time and length of ICU stay were independent risk factors for predicting biliary complications., Conclusion: Warm ischemia time and days of ICU stay are independent risk factors for predicting biliary complications after DCD liver transplantation.

The aim of our study was to retrospectively evaluate the impact of ischemia time and other clinical factors on the development of liver allograft primary nonfunction (PNF). We enrolled 531 consecutive liver transplantations from 1998 to 2013, identifying 10 PNF (1.9%). PNF was found to be statistically related to 4 different variables: donor age>60 years (P=.01), female donor gender (P=.01), total ischemia time>10 hours (P=.03) and infusion of more than 30 fresh frozen plasma units during surgery (P=.02). The study focused on the clinical impact of total ischemia time. We grouped total ischemia time into 4 groups (Group 1: ≤7.5 hours; Group 2: between 7.5 and 10 hours; Group 3: between 10 and 12 hours; Group 4: >12 hours) and 2 groups (assigning a cut-off value of 10 hours): both these grouping systems significantly influenced the development of PNF and 1-year graft survival, with limited impact on long-term survival. We split total ischemia time in a "technical time," "hepatectomy time," and "warm ischemia time." Only the first 2 components were found to be statistically related to PNF development with P=.02 and P=.003, respectively. Further studies should focus on these aspects of PNF., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Liver transplantation (LT) is the best treatment for end-stage hepatic failure, with an excellent survival rates over the last decade. Biliary complications after LT pose a major challenge especially with the increasing number of procured organs after circulatory death. Ischaemic cholangiopathy (IC) is a set of disorders characterized by multiple diffuse strictures affecting the graft biliary system in the absence of hepatic artery thrombosis or stenosis. It commonly presents with cholestasis and cholangitis resulting in higher readmission rates, longer length of stay, repeated therapeutic interventions, and eventually re-transplantation with consequent effects on the patient's quality of life and increased health care costs. The pathogenesis of IC is unclear and exhibits a higher prevalence with prolonged ischaemia time, donation after circulatory death (DCD), rejection, and cytomegalovirus infection. The majority of IC occurs within 12 mo after LT. Prolonged warm ischaemic times predispose to a profound injury with a subsequently higher prevalence of IC. Biliary complications and IC rates are between 16% and 29% in DCD grafts compared to between 3% and 17% in donation after brain death (DBD) grafts. The majority of ischaemic biliary lesions occur within 30 d in DCD compared to 90 d in DBD grafts following transplantation. However, there are many other risk factors for IC that should be considered. The benefits of DCD in expanding the donor pool are hindered by the higher incidence of IC with increased rates of re-transplantation. Careful donor selection and procurement might help to optimize the utilization of DCD grafts.