Tacrolimus Drug Exposure Level and Smoking Are Modifiable Risk Factors for Early De Novo Malignancy After Liver Transplantation for Alcohol-Related Liver Disease.

De novo malignancy (DNM) is the primary cause of mortality after liver transplantation (LT) for alcohol-related liver disease (ALD). However, data on risk factors for DNM development after LT are limited, specifically in patients with ALD. Therefore, we retrospectively analyzed all patients transplanted for ALD at our center before October 2016. Patients with a post-LT follow-up of <12 months, DNM within 12 months after LT, patients not on tacrolimus in the 1st year post-LT, and unknown smoking habits were excluded. Tacrolimus drug exposure level (TDEL) was calculated by area under the curve of trough levels in the 1st year post-LT. 174 patients received tacrolimus of which 19 (10.9%) patients developed a DNM between 12 and 60 months post-LT. Multivariate cox regression analysis identified TDEL [HR: 1.710 (1.211-2.414); p = 0.002], age [1.158 (1.076-1.246); p < 0.001], number of pack years pre-LT [HR: 1.021 (1.004-1.038); p = 0.014] and active smoking at LT [HR: 3.056 (1.072-8.715); p = 0.037] as independent risk factors for DNM. Tacrolimus dose minimization in the 1st year after LT and smoking cessation before LT might lower DNM risk in patients transplanted for ALD.

Case report: Immediate revascularization for symptomatic hepatic artery pseudoaneurysm after orthotopic liver transplantation? A case series and literature review.

Introduction: Hepatic artery pseudoaneurysm (HAPA), a rare vascular complication that can develop after liver transplantation, is associated with a high mortality rate and graft loss. To salvage the liver graft, immediate revascularization, either through surgical or endovascular intervention, is required. However, currently there is no consensus on the optimal strategy. Here, we report three cases of liver transplant recipients diagnosed with HAPA and treated with immediate revascularization. In addition, we present an overview of HAPA cases described in the literature and make recommendations on how to treat this rare complication. Methods: All adults transplanted in our center between 2005 and 2021 were retrospectively reviewed. Literature search was done in PubMed for original studies between 1980 and 2021 reporting early hepatic artery (pseudo) aneurysm after liver transplantation requiring either surgical or endovascular intervention. Results: From a total of 1,172, 3 liver transplant patients were identified with a symptomatic HAPA and treated with immediate revascularization. HAPA occurred 73, 27, and 8 days after liver transplantation and was treated with immediate revascularization (two surgical and one endovascular intervention). Literature review identified 127 cases of HAPA. HAPA was managed with endovascular therapy in 20 cases and by surgical intervention in 89 cases. Overall reported mortality rate was 39.6%, whereas overall graft survival was 45.2%. Conclusion: Immediate surgical or radiological interventional excision and prompt revascularization to salvage liver grafts is feasible but still associated with a high mortality.

Recanalization of portal axis after cavoportal hemitransposition in a liver transplant recipient with complete splanchnic thrombosis.

BACKGROUND: Diffuse splanchnic thrombosis may render standard LTx difficult or even technically impossible. A 19-year-old woman with acute-on-chronic Budd-Chiari syndrome and complete splanchnic thrombosis underwent conventional LTx. Only limited anatomical portal inflow could be restored, and urgent re-transplantation for recurrent splanchnic vein thrombosis became necessary. METHODS: At re-transplant, and in addition to the reestablishment of some portal inflow through the preserved original porto (native)-portal (graft) connection, a cavoportal shunt was created (first partial via 30% tapering of the vena cava, but eventually complete by total occlusion of the vena cava). RESULTS: The postoperative course was then uneventful, and interestingly, the native portomesenteric axis gradually reopened. Two years post-transplant, the liver graft is perfused via both physiological and non-physiological sources. Liver function is normal. There is no IVC syndrome and no residual PHT. She is leading a normal life. CONCLUSION: Creation of CPHT, in addition to the preservation of portal inflow from the native splanchnic system, should be considered in patients with diffuse splanchnic thrombosis, when sufficient physiological portal inflow cannot be restored at the time of LTx, but in whom the splanchnic circulation may reopen up later.

Liver-Related and Cardiovascular Outcome of Patients Transplanted for Nonalcoholic Fatty Liver Disease: A European Single-Center Study.

BACKGROUND: The increasing rate of liver transplantation (LT) for nonalcoholic fatty liver disease (NAFLD) raises concerns on cardiovascular morbidity and mortality after LT in these patients. METHODS: We collected variables regarding the presence of metabolic risk factors, NAFLD recurrence, cardiovascular morbidity, and overall survival at time of listing and after LT of 112 patients with NAFLD and a control group of 120 patients with hepatitis C (HCV). RESULTS: Metabolic syndrome and cardiovascular morbidity component rates (24.1% vs 12.5%) at the time of LT listing were higher in patients with NAFLD compared with patients with HCV (for all, P < .0390). Median follow-up after LT was 5.6 years in patients with NAFLD vs 13.5 years in patients with HCV (P = .0009). There was no difference in 6-weeks postoperative mortality (1.7% vs 2.5%) (P =1.0000). Metabolic syndrome components after LT were more frequent in patients with NAFLD than in patients with HCV (for all, P < .0008). The incidence of NAFLD 5 years after LT was higher in patients transplanted for NAFLD compared with HCV (43.5% vs 4.2%) (P < .0001). Patients with recurrent NAFLD more often had myocardial infarction compared with those without recurrence (8.3% vs 0%) (P = .0313). Five years after LT, cardiovascular morbidity was more frequent in the NAFLD group than in the HCV group (12.8% vs 9.3%) (P = .0256), whereas no difference in overall survival was observed. CONCLUSION: LT for NAFLD is associated with satisfactory 5-year outcomes; however, our data underscore the need for close monitoring and aggressive management of cardiovascular risk factors in these patients.

Donor Hepatectomy and Implantation Time Are Associated With Early Complications After Liver Transplantation: A Single-center Retrospective Study.

BACKGROUND: Donor hepatectomy and liver implantation time reduce long-term graft and patient survival after liver transplantation. It is not known whether these surgical times influence early outcomes after liver transplantation. METHODS: This single-center study evaluated the effect of donor hepatectomy and implantation time on the risk of nonanastomotic biliary strictures (NAS) occurring within 1 year and of early allograft dysfunction (EAD) after deceased-donor solitary liver transplantation, adjusting for other donors, recipient, and surgical factors. RESULTS: Of 917 transplants performed between January 2000 and December 2016, 106 (11.56%) developed NAS and 247 (27%) developed EAD. Donor hepatectomy time (median 35 min, IQR: 26-46) was an independent risk factor of NAS [adjusted hazard ratio, 1.19; 95% CI, 1.04-1.35; P = 0.01]. Implantation time (median 80 min, IQR: 69-95) was independently associated with EAD [adjusted odds ratio (OR), 1.15; 95% CI,1.07-1.23; P < 0.0001). The risk of EAD was increased by anastomosis time of both portal vein (adjusted OR, 1.26; 95% CI, 1.12-14.42; P = 0.0001) and hepatic artery (adjusted OR, 1.13; 95% CI, 1.04-1.22; P = 0.005). The magnitude of these effects was similar in donation after circulatory death liver grafts. CONCLUSIONS: Donor hepatectomy and implantation time negatively affect short-term outcomes.

The effect of IGL-1 preservation solution on outcome after kidney transplantation: A retrospective single-center analysis.

Institut Georges Lopez-1 (IGL-1) solution is increasingly used for kidney preservation, although little information on outcomes is available. Outcomes of all deceased donor kidneys preserved by IGL-1, University of Wisconsin solution (UW), or histidine-tryptophan-ketoglutarate (HTK) and transplanted in our center (2000-2018) were analyzed. Multivariable analysis for delayed graft function (DGF), functional DGF, estimated glomerular filtration rate (eGFR, CKD-EPI equation), proteinuria, acute rejection, death-censored graft loss, and patient survival were performed. A double robust approach, consisting of propensity score weighting and correction for confounders, minimized the risk of bias. In total, 1943 transplants were included: 234 with IGL-1, 1046 with UW, and 663 with HTK. As IGL-1 was only introduced in 2014, a prespecified sensitivity analysis of 917 kidneys (2010-2018) was performed using the same statistical approach. After weighting, IGL-1 retained a higher proportion of kidneys donated after circulatory death (DCD). IGL-1 was not independently associated with any of the outcomes when compared to UW or HTK. Sensitivity analysis between 2010 and 2018 showed similar results. In this retrospective analysis, using robust methodology to reduce the risk of bias, IGL-1 preservation results in equal outcomes compared to UW or HTK, despite more DCD transplants in the IGL-1 group.

The effect of organ preservation solutions on short-term outcomes after liver transplantation: a single-center retrospective study.

The effect of preservation solutions on outcomes has been subject of many debates but the relative benefits of the various solutions remain unclear. We retrospectively compared short-term outcomes of 885 liver transplantations performed between 1/2000 and 12/2017 and preserved with either Histidine-Tryptophan-Ketoglutarate (HTK, n = 190), University of Wisconsin (UW, n = 557), or Institute George Lopez 1 preservation solution (IGL-1, n = 139). Inverse probability of treatment weighting (IPTW) was performed to account for baseline differences between groups and analyses were adjusted for confounders. In the IPTW analyses, peak AST within 7 days was 44% higher (95% CI 15-81%, P < 0.001) in HTK than in UW. Mean model of early allograft function (MEAF) score was 0.61 points (95% CI 0.12-1.10, P = 0.01) higher in HTK than in UW. Early allograft dysfunction (EAD) was more likely to occur with HTK compared to IGL-1 (IPTW OR = 2.87, 95% CI = 1.00-8.19, P = 0.049) and UW (IPTW OR = 1.75, 95% CI = 1.06-2.88, P = 0.023). The type of preservation solution had no impact on hospital stay, ICU stay, incidence of biliary strictures, or graft and recipient survival. HTK was the least effective on reducing graft injury and increased the probability of graft dysfunction after transplantation. UW and IGL-1 were equally effective in reducing graft injury and dysfunction.

The Histological Picture of Indication Biopsies in the First 2 Weeks after Kidney Transplantation.

BACKGROUND AND OBJECTIVES: In preclinical studies, ischemia-reperfusion injury and older donor age are associated with graft inflammation in the early phase after transplantation. In human kidney transplantation, impaired allograft function in the first days after transplantation is often adjudicated to donor- and procedure-related characteristics, such as donor age, donor type, and ischemia times. DESIGN: , setting, participants, & measurementsIn a cohort of 984 kidney recipients, 329 indication biopsies were performed within the first 14 days after transplantation. The histologic picture of these biopsies and its relationship with alloimmune risk factors and donor- and procedure-related characteristics were studied, as well as the association with graft failure. Multivariable Cox models were applied to quantify the cause-specific hazard ratios for early rejection and early inflammatory scores, adjusted for potential confounders. For quantification of hazard ratios of early events for death-censored graft failure, landmark analyses starting from day 15 were used. RESULTS: Early indication biopsy specimens displayed microvascular inflammation score ≥2 in 30% and tubulointerstitial inflammation score ≥2 in 49%. Rejection was diagnosed in 186 of 329 (57%) biopsies and associated with the presence of pretransplant donor-specific HLA antibodies and the number of HLA mismatches, but not nonimmune risk factors in multivariable Cox proportional hazards analysis. In multivariable Cox proportional hazards analysis, delayed graft function, the graft dysfunction that prompted an early indication biopsy, HLA mismatches, and pretransplant donor-specific HLA antibodies were significantly associated with a higher risk for death-censored graft failure, whereas early acute rejection was not. CONCLUSIONS: Indication biopsies performed early after kidney transplantation display inflammatory changes related to alloimmune risk factors. Nonimmune risk factors for ischemia-reperfusion injury, such as cold and warm ischemia time, older donor age, and donor type, were not identified as strong risk factors for early inflammation after human kidney transplantation.

Solid organ donation after death from listeria encephalitis: A case report.

Despite organ shortage, organs from donors with listeria infections have been discarded for transplantation. We present the first-reported case of liver transplantation following listeria encephalitis. The patient was admitted with progressing neurological symptoms after an episode of gastroenteritis. Rhombo-encephalitis was diagnosed, and Listeria monocytogenes was found to be the causative pathogen. Despite proper antibiotic treatment and rapid clearance of bacteremia, he continued to deteriorate and became brain dead, after which organ donation was performed. At procurement, he had been treated with amoxicillin for 9 days. The recipient was treated with pipercillin/tazobactam for 21 days. Besides an anastomotic biliary stricture, necessitating endoscopic dilatation and stenting, further clinical course was uneventful and she is doing well eleven months post-transplant. Our case suggests that listeria encephalitis is not an absolute contra-indication to solid organ donation. We suggest that donors should be treated with adequate antibiotics for at least 48h prior to procurement and advocate confirmation of sterile blood cultures as a prerequisite for donation. According to listeriosis guidelines, we suggest that the recipient should be treated with targeted antibiotics for at least 2 weeks. The risk of transmission should, however, always be balanced carefully against the suspected waiting list mortality.

Somatostatin as Inflow Modulator in Liver-transplant Recipients With Severe Portal Hypertension: A Randomized Trial.

OBJECTIVE: To investigate the safety and efficacy of somatostatin as liver inflow modulator in patients with end-stage liver disease (ESLD) and clinically significant portal hypertension (CSPH) undergoing liver transplantation (LT) (ClinicalTrials.gov number,01290172). BACKGROUND: In LT, portal hyperperfusion can severely impair graft function and survival, mainly in cases of partial LT. METHODS: Thirty-three patients undergoing LT for ESLD and CSPH were randomized double-blindly to receive somatostatin or placebo (2:1). The study drug was administered intraoperatively as 5-mL bolus (somatostatin: 500 µg), followed by a 2.5 mL/h infusion (somatostatin: 250 µg/h) for 5 days. Hepatic and systemic hemodynamics were measured, along with liver function tests and clinical outcomes. The ischemia-reperfusion injury (IRI) was analyzed through histological and protein expression analysis. RESULTS: Twenty-nine patients (18 receiving somatostatin, 11 placebo) were included in the final analysis. Ten patients responded to somatostatin bolus, with a significant decrease in hepatic venous portal gradient (HVPG) and portal flow of -28.3% and -29.1%, respectively. At graft reperfusion, HVPG was lower in patients receiving somatostatin (-81.7% vs -58.8%; P = 0.0084), whereas no difference was observed in the portal flow (P = 0.4185). Somatostatin infusion counteracted the decrease in arterial flow (-10% vs -45%; P = 0.0431). There was no difference between the groups in the severity of IRI, incidence of adverse events, long-term complications, graft, and patient survival. CONCLUSIONS: Somatostatin infusion during LT in patients with CSPH is safe, reduces the HVPG, and preserves the arterial inflow to the graft. This study establishes the efficacy of somatostatin as a liver inflow modulator.

Age Matching of Elderly Liver Grafts With Elderly Recipients Does Not Have a Synergistic Effect on Long-term Outcomes When Both Are Carefully Selected.

BACKGROUND: Older donors and recipients are increasingly considered for liver transplantation. Both donor and recipient age have a negative impact on outcomes. Large registry analyses show that older donors are frequently matched to older recipients. Whether age-related risks accumulate in a synergic negative effect on outcomes because of donor-recipient age matching is poorly understood. METHODS: We investigated the impact of donor-recipient age interaction on patient and death-censored graft survival in multivariate Cox regressions in 849 transplants (January 2000 to December 2015). RESULTS: Donors 70 years or older did not affect long-term patient or graft survival. Recipient age independently increased the risk of death (hazard ratio [HR], 1.03; 95% confidence interval [CI], 1.02-1.05, P < 0.0001), but donor-recipient age interaction was noninfluential. The negative impact of recipient age on patient survival was significant as early as 6 months after transplantation (HR, 1.06; 95% CI, 1.03-1.09; P = 0.00008). The adjusted risk of death was significant for patients aged 60 to 69 years (HR, 1.995; 95% CI, 1.40-2.85; P < 0.0001) and 70 years or older (HR, 2.001; 95% CI, 1.10-2.66; P = 0.04). In contrast, the risk of graft loss was not influenced by recipient age (HR, 1.02; 95% CI, 0.996-1.04; P = 0.11) or age interaction. CONCLUSIONS: Older livers can be safely used in older recipients without jeopardizing graft and patient survival if other risk factors are minimized.

Hemodynamic changes in ALPPS influence liver regeneration and function: results from a prospective study.

BACKGROUND: Excessive increase of portal flow and pressure following extended hepatectomy have been associated to insufficient growth or function of the future liver remnant (FLR), with the risk of post-hepatectomy liver failure (PHLF). We prospectively assess the influence of liver hemodynamics on FLR regeneration and function in Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS). METHODS: Twenty-three patients underwent ALPPS; liver hemodynamics were assessed throughout the procedures. Volume and function of the FLR were evaluated by angio-CT and 99mTc-Mebrofenin-scintigraphy. RESULTS: The portal vein flow at the end of stage-1 correlated with the increase of the FLR volume (p = 0.002). Patients with portal vein pressure (PVP) < 20 mmHg and hepatic to portal vein gradients (HVPG) < 15 mmHg at the end of ALPPS-1 showed higher FLR regeneration (76.7% vs. 30.6%, p = 0.04) and function (26.7% vs. -0.13%, p = 0.02). FLR regeneration was inversely correlated with baseline FLR/Total Liver Volume (p = 0.002) and FLR/Body Weight (p = 0.02). No correlation was found between volumes and function (p = 0.13). CONCLUSION: Liver hemodynamic stress at the end of ALPPS-1 influences the increase of the FLR volume and function, which is higher with PVP < 20 and HVPG < 15 mmHg. Liver volume overestimates liver function and could be imprecise to set stage-2 timing.

Pre-operative trans-catheter arterial chemo-embolization increases hepatic artery thrombosis after liver transplantation - a retrospective study.

Little is known about nonsurgical risk factors for hepatic artery thrombosis (HAT) after liver transplantation (LT). We determined risk factors for HAT occurring within 90 days post-LT and analysed the effect of HAT on graft and patient survival. Donor and recipient demographics, surgery-related data and outcome in transplants complicated by thrombosis (HAT+) and their matched controls (HAT-) were compared. Risk factors were assessed by univariate logistic regression. Median (IQR) is given. A total of 25 HAT occurred among 1035 adult LT (1/1997-12/2014) and 50 controls were manually matched. Donor and recipient demographics were similar. Pre-LT trans-catheter arterial chemo-embolization (TACE) was more frequent in HAT+ (HAT+ 20% vs. HAT- 4%, P = 0.037). HAT+ had longer implantation [HAT+ 88 min (76-108) vs. HAT- 77 min (66-93), P = 0.028] and surgery times [HAT+ 6.25 h (5.18-7.47) vs. HAT- 5.25 h (4.33-6.5), P = 0.001]. Early graft dysfunction and sepsis were more frequent in HAT+ and hospitalization longer. TACE had the greatest odds ratio in unadjusted analysis (OR: 6, 95% CI: 1.07-33.53, P = 0.03). All but seven grafts were lost after HAT (HAT+ 72% vs. HAT- 36%, P = 0.003); however, patient survival was unaffected (HAT+ 79.8% vs. HAT- 76%, P = 0.75). LT candidates undergoing TACE are at risk of developing HAT early after transplant.

Graft inflow modulation in adult-to-adult living donor liver transplantation: A systematic review.

INTRODUCTION: Small-for-size syndrome (SFSS) has an incidence between 0 and 43% in small-for-size graft (SFSG) adult living donor liver transplantation (LDLT). Portal hypertension following reperfusion and the hyperdynamic splanchnic state are reported as the major triggering factors of SFSS. Intra- and postoperative strategies to prevent or to reduce its onset are still under debate. We analyzed graft inflow modulation (GIM) during adult LDLT considering the indications, efficacy of the available techniques, changes in hemodynamics and outcomes. MATERIALS AND METHODS: A systematic literature search was performed using PubMed, EMBASE, Scopus and the Cochrane Library Central. Treatment outcomes including in-hospital mortality and morbidity, re-transplantation rate, 1-, 3-, and 5-year patient overall survival and 1-, 3-, and 5-year graft survival rates, hepatic artery and portal vein flows and pressures before and after inflow modulation were analyzed. RESULTS: From 563 articles, 12 studies dated between 2003 and 2014 fulfilled the selection criteria and were therefore included in the study. These comprised a total of 449 adult patients who underwent inflow modulation during adult-to-adult LDLT. Types of GIM described were splenic artery ligation, splenectomy, meso-caval shunt, spleno-renal shunt, portocaval shunt, and splenic artery embolization. Mortality and morbidity ranged between 0 and 33% and 17% and 70%, respectively. Re-transplantation rates ranged between 0% and 25%. GIM was associated with good survival for both graft and recipients, reaching an 84% actuarial rate at 5 years. Through the use of GIM, irrespective of the technique, a statistically significant reduction of PVF and PVP was obtained. CONCLUSIONS: GIM is a safe and efficient technique to avoid or limit portal hyperperfusion, especially in cases of SFSG, decreasing overall morbidity and improving outcomes.

Living donor liver transplantation in Europe.

Living donor liver transplantation (LDLT) sparked significant interest in Europe when the first reports of its success from USA and Asia were made public. Many transplant programs initiated LDLT and some of them especially in Germany and Belgium became a point of reference for many patients and important contributors to the advancement of the field. After the initial enthusiasm, most of the European programs stopped performing LDLT and today the overall European activity is concentrated in a few centers and the number of living donor liver transplants is only a single digit fraction of the overall number of liver transplants performed. In this paper we analyse the present European activities and highlight the European contribution to the advancement of the field of LDLT.

A multicentre, randomized clinical trial comparing the Veriset™ haemostatic patch with fibrin sealant for the management of bleeding during hepatic surgery.

BACKGROUND: Bleeding during hepatic surgery is associated with prolonged hospitalization and increased morbidity and mortality. The Veriset™ haemostatic patch is a topical haemostat comprised of an absorbable backing made of oxidized cellulose and self-adhesive hydrogel components. It is designed to achieve haemostasis quickly and adhere to tissues without fixation. METHODS: A prospective, randomized, multicentre, single-blinded study (n = 50) was performed to compare the use of a Veriset™ haemostatic patch with a fibrin sealant patch (TachoSil(®) ) (control) in the management of diffuse bleeding after hepatic surgery. Patients were randomized following the confirmation of diffuse bleeding requiring the use of a topical haemostat. Time to haemostasis was assessed at preset intervals until haemostasis was achieved. RESULTS: Both groups were similar in comorbidities and procedural techniques. The median time to haemostasis in the group using the Veriset™ haemostatic patch was 1.0 min compared with 3.0 min in the control group (P < 0.001; 3-min minimum application time for the control patch). This result was independent of bleeding severity and surface area. Both products had similar safety profiles and no statistical differences were observed in the occurrence of adverse or device-related events. CONCLUSIONS: Regardless of bleeding severity or surface area, the Veriset™ haemostatic patch achieved haemostasis in this setting significantly faster than the control device in patients undergoing hepatic resection. It was safe and easy to handle in open hepatic surgery.

Flow competition between hepatic arterial and portal venous flow during hypothermic machine perfusion preservation of porcine livers.

Hypothermic machine perfusion (HMP) is regarded as a better preservation method for donor livers than cold storage. During HMP, livers are perfused through the inlet blood vessels, namely the hepatic artery (HA) and the portal vein (PV). In previous HMP feasibility studies of porcine and human livers, we observed that the PV flow decreased while the HA flow increased. This flow competition restored either spontaneously or by lowering the HA pressure (PHA). Since this phenomenon had never been observed before and because it affects the HMP stability, it is essential to gain more insight into the determinants of flow competition. To this end, we investigated the influence of the HMP boundary conditions on liver flows during controlled experiments. This paper presents the flow effects induced by increasing PHA and by obstructing the outlet blood vessel, which is the vena cava inferior (VCI). Flow competition was evoked by increasing PHA to 55-70 mmHg, as well as by obstructing the VCI. Remarkably, a severe obstruction resulted in a repetitive and alternating tradeoff between the HA and PV flows. These phenomena could be related to intra-sinusoidal pressure alterations. Consequently, a higher PHA is most likely transmitted to the sinusoidal level. This increased sinusoidal pressure reduces the pressure drop between the PV and the sinusoids, leading to a decreased PV perfusion. Flow competition has not been encountered or evoked under physiological conditions and should be taken into account for the design of liver HMP protocols. Nevertheless, more research is necessary to determine the optimal parameters for stable HMP.