Days Of Liver Transplantation Research Articles

Two sides to every story: Reappraising the early history of liver transplantation at Addenbrooke's Hospital, Cambridge.

Over the course of the past six decades, liver transplantation has evolved to become the treatment of choice for chronic end-stage liver disease and some cases of acute hepatic failure. Currently, more than 34,000 liver transplants are conducted worldwide per annum, and overall one year survival rates exceed 90%. However, the early years of human liver transplantation were beset by failure. Eyewitness reports from this period make for tragic, yet compelling reading. Volume 12 of The History of Anaesthesia Society Proceedings contains one such account, written by Dr Elizabeth Gibbs. This outlined the experience of single-handedly anaesthetising the recipient of the first liver transplant to be undertaken at Addenbrooke's Hospital, Cambridge, UK, in June 1967. Despite the best efforts of the team, the patient died from uncontrollable haemorrhage 19 hours after the start of the procedure. While this tragic outcome might have been expected in the early days of liver transplantation, Gibbs included an unsettling postscript in her paper. This stated that all of the patient's records had apparently been 'lost', and the date of the first Cambridge liver transplant was publicly reported as 2 May 1968, some 11 months after the events described. This article outlines the results of research aimed at critically appraising this postscript. In doing so a number of unexpected discoveries were made. These highlight some important lessons for medical historians and demonstrate that if you look hard enough, there really are two sides to every story.

Long-term follow-up of temporary abdominal closure in complex abdomens during liver transplant

BackgroundTemporary abdominal closure is commonly employed in liver transplantation when patient factors make primary fascial closure challenging. However, there is minimal data evaluating long-term survival and patient outcomes after temporary abdominal closure. MethodsA single-center, retrospective review of patients undergoing liver transplantation from January 2013 through December 2017 was performed with a 5-year follow-up. Patients were characterized as either requiring temporary abdominal closure or immediate primary fascial closure at the time of liver transplantation. ResultsOf 422 patients who underwent 436 liver transplantations, 17.2% (n = 75) required temporary abdominal closure, whereas 82.8% (n = 361) underwent primary fascial closure. Patients requiring temporary abdominal closure had higher Model for End-Stage Liver Disease scores preoperatively (27 [22–36] vs 23 [20–28], P = .0002), had higher rates of dialysis preoperatively (28.0% vs 12.5%, P = .0007), and were more likely to be hospitalized within 90 days of liver transplantation (64.0% vs 47.5%, P = .0093). On univariable analysis, survival at 1 year was different between the groups (90.9% surviving at 1 year for primary fascial closure versus 82.7% for temporary abdominal closure, P = .0356); however, there was no significant difference in survival at 5 years (83.7% vs 76.0%, P = .11). On multivariable analysis, there was no difference in survival after adjusting for multiple factors. Patients requiring temporary abdominal closure were more likely to have longer hospital stays (median 16 days [9.75–29.5] vs 8 days [6–14], P < .0001), more likely to be readmitted within 30 days (45.3% vs 32.2%, P = .03), and less likely to be discharged home (36.5% vs 74.2%, P < .0001). ConclusionsTemporary abdominal closure after liver transplantation appears safe and has similar outcomes to primary fascial closure, though it is used more commonly in complex patients.

Incidence, mortality, and risk factors associated with carbapenem-resistant Acinetobacter baumannii bacteremia within 30 days after liver transplantation.

Carbapenem-resistant Acinetobacter baumannii bacteremia (CRAB-B) is a fatal infectious complication of liver transplantation (LT). This study investigated the incidence, effects, and risk factors associated with CRAB-B during the early post-LT period. Among 1051 eligible LT recipients, 29 patients experienced CRAB-B within 30 days of LT with a cumulative incidence of 2.7%. In the patients with CRAB-B (n=29) and matched controls (n=145) by nested-case control design, the cumulative incidence of death on days 5, 10, and 30 from the index date was 58.6%, 65.5%, and 65.5%, and 2.1%, 2.8%, and 4.2%, respectively (p<.001). Pre-transplant MELD (OR 1.11, 95% confidence interval [CI] 1.04-1.19, p=.002), severe encephalopathy (OR 4.62, 95% CI 1.24-18.61, p=.025), donor body mass index (OR .57, 95% CI .41-.75, p<.001), and reoperation (OR 6.40, 95% CI 1.19-36.82, p=.032) were independent risk factors for 30-day CRAB-B. CRAB-B showed extremely high mortality within 30 days after LT, especially within 5 days after its occurrence. Therefore, assessment of risk factors and early detection of CRAB, followed by proper treatment, are necessary to control CRAB-B after LT.

Postoperative Atrial Fibrillation and Long-Term Risk of Stroke in Patients Undergoing Liver Transplantation.

Postoperative atrial fibrillation (POAF) is the commonest cardiovascular complication following liver transplantation (LT). This study sought to assess a possible association of POAF with subsequent thromboembolic events in patients undergoing LT. A retrospective cohort study of consecutive adults undergoing LT between 2010 and 2018 was undertaken. Patients were classified as POAF if atrial fibrillation (AF) was documented within 30 days of LT without a prior history of AF. Cases of ischemic stroke or systemic embolism were adjudicated by a panel of 2 independent physicians. Among the 461 patients included, POAF occurred in 47 (10.2%) a median of 3 days following transplantation. Independent predictors of POAF included advancing age, postoperative sepsis and left atrial enlargement. Over a median follow-up of 4.9 (interquartile range, 2.9-7.2) years, 21 cases of stroke and systemic embolism occurred. Rates of thromboembolic events were significantly higher in patients with POAF (17.0% versus 3.1%; P<0.001). After adjustment, POAF remained a strong independent predictor of thromboembolic events (hazard ratio, 8.36 [95% CI, 2.34-29.79]). Increasing CHA2DS2VASc score was also an independent predictor of thromboembolic events (hazard ratio, 1.58 [95% CI, 1.02-2.46]). A model using POAF and a CHA2DS2VASc score ≥2 alone yielded a C statistic of 0.77, with appropriate calibration for the prediction of thromboembolic events. However, POAF was not an independent predictor of long-term mortality. POAF following LT is associated with an 8-fold increased risk of thromboembolic events and the use of the CHA2DS2VASc score may facilitate risk stratification of these patients. Prospective studies are warranted to assess whether the use of oral anticoagulants can reduce the risk of thromboembolism following LT.

Alcohol Consumption the Day of Liver Transplantation for Alcohol-Associated Liver Disease Does Not Affect Long-Term Survival: A Case-Control Study.

Alcohol abstinence before liver transplantation (LT) for alcohol-associated liver disease (ALD) is required for every candidate. Some listed patients might relapse, resulting in LT for patients nonabstinent during the pretransplant period. Long-term survival outcomes of these patients have never been studied. We sought to determine whether alcohol consumption on the day of the LT influenced long-term survival after LT. We conducted a retrospective case-control study among French LT centers. Cases were defined as recipients between January 1995 and December 2007 having positive blood and/or urine alcohol levels the day of LT. Each case was paired with 2 controls corresponding to patients transplanted for ALD during the same trimester. Patients were classified into 3 categories per alcohol consumption: abstainers, occasional or transitory excessive consumers, or patients with a sustained excessive consumption (daily consumption >20-30g/day). During the study period, 3052 LTs for ALD were conducted in France. We identified 42 cases paired with 84 controls. Median blood alcohol level was 0.4g/L (range 0.1-4.1g/L) and median urine alcohol level was 0.2g/L (range 0.1-2.0g/L). Median follow-up period until death or censoring was 12.9years (CI95% = [12.3; 13.6]). Long-term survival was not different between the groups. Relapse to any alcohol consumption rate was higher in the case group (59.5%) than in the control group (38.1%, odds ratio 2.44; CI95% = [1.13; 5.27]), but sustained excessive consumption was not significantly different between the groups (33.3% versus 29.8% in case and control groups respectively, χ2 =0.68). Rates of recurrent cirrhosis and cirrhosis-related deaths were more frequent in the case group. Liver transplantation for nonabstinent patients during the immediate pretransplant period does not result in impaired long-term survival despite higher relapse and recurrent cirrhosis rates.

Early reduction of regulatory T cells is associated with acute rejection in liver transplantation under tacrolimus-based immunosuppression with basiliximab induction.

Regulatory T (Treg) cells are important in preventing acute rejection (AR) in solid organ transplantation, but the clinical relevance of the different kinetics early after liver transplantation (LT) in acute rejectors and non-rejectors is unclear. We analyzed peripheral blood samples of 128 LT recipients receiving basiliximab induction plus tacrolimus immunosuppression. Samples were obtained at pretransplant, D7, and D30 after LT. Frequency and phenotype of Tregs were analyzed by flow cytometry. The predictive value of Treg frequency at D7 was assessed for suspected acute rejection (SAR) and was validated for biopsy-proven AR (BPAR). We found that the frequencies of total and activated Tregs at D7 were significantly lower in recipients with SAR and BPAR. Treg was more reduced in BPARs by in vitro tacrolimus treatment in the presence of basiliximab. Moreover, an early reduction of Treg frequency in rejectors was associated with a greater increase in Treg apoptosis and further attenuated IL-2 signaling. D7 Treg frequency was an independent risk factor for SAR, which was also validated for BPAR. In conclusion, first-week peripheral blood Treg frequency correlates with AR after LT under tacrolimus-based immunosuppression, which needs to be proven in larger, geographically and clinically diverse populations.

Neutrophil-to-lymphocyte ratio predicts early acute cellular rejection in living donor liver transplantation.

PurposeThe aim of this study was to evaluate the predictive value of neutrophil-to-lymphocyte ratio (NLR) in acute cellular rejection (ACR) after living donor liver transplantation (LDLT).MethodsAll consecutive patients who underwent ABO-compatible (ABOc) LDLT from September 2014 to December 2017 were retrospectively reviewed. NLR was calculated on 3 occasions; (1) 4 weeks prior to liver transplantation (LT), (2) the day of LT, and (3) the day before liver biopsy.ResultsAmong 66 patients who underwent ABOc LDLT, ACR was identified in 15 patients (22.7%) on protocol liver biopsy performed routinely on the postoperative day 7. There was no significant difference in NLR at 4 weeks prior to LT and the day of LT between no-ACR and ACR group (2.98 ± 1.92 vs. 2.54 ± 1.15, P = 0.433; 17.9 ± 8.31 vs. 20.5 ± 13.4, P = 0.393). However, NLR was significantly lower in ACR group compared to non-ACR group just prior to liver biopsy (5.82 ± 3.42 vs. 18.4 ± 17.2, P = 0.035). NLR tends to decrease 3.5 days before the onset of ACR. The area under the receiver operating characteristic curve for optimal cut-off value of NLR was 6.49, with sensitivity and specificity of 80.4% and 73.3% respectively.ConclusionNLR has a potential as a noninvasive predictor of early ACR in ABOc LDLT.

Impact of Rifaximin Therapy on Ischemia/Reperfusion Injury in Liver Transplantation: A Propensity Score–Matched Analysis

Intestinal microbiota is thought to play an important role in hepatic ischemia/reperfusion injury (IRI) after liver transplantation (LT). Rifaximin, a nonabsorbable antibiotic used to treat encephalopathy, exhibits antibacterial activity within the gut. We report the first study examining the impact of pre-LT rifaximin use on reducing hepatic IRI and inflammatory cell infiltration after LT. This retrospective single-center study included adult LT recipients from January 2013 through June 2016. Patients were divided into 2 groups based on duration of rifaximin use before LT: rifaximin group (≥28 days) and control group (none or <28 days). Patients receiving other antibiotics within 28 days of LT and re-LTs were excluded. Outcomes and messenger RNA (mRNA) expression in the graft were compared by 1:1 propensity score-matching and multivariate analyses. On 1:1 matching (n = 39/group), rifaximin patients had lower postoperative serum transaminase levels and lower early allograft dysfunction (EAD; 10.3% versus 33.3%; P = 0.014). Of the matched patients, 8 patients (n = 4/group) had postreperfusion liver biopsies (approximately 2 hours after reperfusion) available for mRNA analysis. Hepatic expression of CD86 (macrophage marker) and cathepsin G (neutrophil marker) was significantly lower in rifaximin patients than controls (P < 0.05). The multivariate analysis included 458 patients. Rifaximin treatment <28 days was identified as an independent risk factor EAD in all patients and those with high Model for End-Stage Liver Disease (MELD) score (MELD ≥35; n = 230). In conclusion, the propensity score-matched and multivariate analyses suggest a therapeutic role of rifaximin in reducing EAD. Pre-LT rifaximin administration exerted a protective function against early liver injury, potentially by suppressing inflammatory cell activation in the graft.

974 One, Three, and Five Years Post Transplant Outcomes in Diabetic Patients After Liver Transplant for NASH Cirrhosis: A Single Centre Study

INTRODUCTION: Beside immunosuppression, patients undergoing liver transplantation (LT) for non-alcoholic steatohepatitis (NASH) cirrhosis are at additional risk of complications due to a myriad of comorbidities that accompany the metabolic syndrome. We aimed to assess post-LT outcomes at one, three and five year intervals for patients with type-2 diabetes mellitus who underwent LT for NASH cirrhosis. METHODS: Using ICD-9 codes all type diabetics with the diagnosis of non-alcoholic fatty liver disease (NAFLD) were identified between January 2000 and Decemeber 2015. Of these, those who had biopsy-proven NAFLD and underwent LT for NASH cirrhosis were recognized and subsequently followed to assess outcomes at one-, three- and five-years. A P-value of &lt; 0.05 was considered significant. RESULTS: 60 out of 1300 patients underwent LT for NASH-cirrhosis. Mean age was 59.6 ± 7.6 years; mean BMI was 31.2 ± 6.3 kg/m2. Mean MELD score at listing was 17.9 ± 9.1 and on the day of LT was 20.1 ± 9.3. Median post-LT follow-up was 66.5 months (IQR 59.5). Follow-up was available for 57, 50 and 34 patients at 1, 3 and 5 years, respectively. Infection was the most common complication within the first year (35%). Cardiovascular (CV) events were most common overall, effecting 25.3% patients in year 1, 32 % in 3 years and 23.5 % in a 5-year period. Post-LT biliary complications were seen in 22.8%, 12.9% and 8%, respiratory complications in 4%, 2% and 0%; gastrointestinal complications in 1%, 2%, 1% and renal complications in 9%, 5%, and 1% within one, three and five years, respectively. 29.6% patients had an episode of rejection within one year of transplant, 7 % within 3 years and 3.3% in 5 years (P = 0.02). A worsening trend was seen in steatosis of the graft across the years 20%, 39.3%, 42.9 % for year 1, 3 and 5 ((P = 0.02). Rates of complications were not statistically different for patients who had normal versus those with elevated gylcated hemoglobin post LT, or for those who lost weight ( &gt;5 lbs), except at year 3 (P &lt; 0.05) (Figure 1). CONCLUSION: Patients undergoing LT for NASH-cirrhosis are at a high risk of developing post-LT infectious and cardiovascular complications. Risk of developing steatosis in the graft also increases every year. These patients need to continue dietary and lifestyle modifications to reduce the risk of future complications, even after LT.

Passenger Lymphocyte Syndrome After Pediatric Liver Transplantation

Passenger lymphocyte syndrome (PLS) is a less known etiology of acute onset anemia following ABO-compatible (ABO-c) liver transplantation (LT). Available literature on PLS after pediatric LT is limited. Therefore, we evaluated the prevalence, clinical course, and risk factors of PLS in children following ABO-c LT. A single-center retrospective review of all children who underwent LT between 2000 and 2017 was performed. PLS was defined as a drop-in hemoglobin >20 g/L within 30 days of LT, with positive direct antiglobulin test and 1 laboratory test confirming hemolysis. Chi square and student t tests compared variables between subjects with and without PLS. Amongst 333 pediatric LT performed, 51 children received an ABO-c graft. PLS was diagnosed in 7 (14%) subjects at a median of 10 days after LT. There were no significant differences in patient demographics, graft type, or immunosuppression between those who did and did not develop PLS. Recipient blood group A+ receiving a donor O+ graft was a risk factor for PLS (P = 0.015). All PLS subjects recovered with blood transfusions (median 2), and no additional interventions. Three subjects initially received recipient (instead of donor) blood group red cells. We report a 14% prevalence of PLS following pediatric ABO-c LT. Recipient blood group A+ receiving a donor O+ graft is a risk factor for PLS. Recognition of PLS as a cause of early acute anemia in pediatric ABO-c LT enables timely transfusion with donor (rather than recipient) blood group red cells.

Hepatopulmonary Syndrome in Children: A 20-Year Review of Presenting Symptoms, Clinical Progression, and Transplant Outcome.

Hepatopulmonary syndrome (HPS) in stable patients with cirrhosis can easily be overlooked. We report on the presenting symptoms, disease progression, and outcomes after liver transplantation (LT) in children with HPS. Twenty patients were diagnosed with HPS between 1996 and 2016. The etiologies were as follows: biliary atresia (n = 9); alpha-1-antitrypsin deficiency (n = 2); cryptogenic liver disease (n = 3); and others (n = 6). HPS presentations were as follows; dyspnea (n = 17) and pneumonia (n = 3). For diagnostic confirmation, the following techniques were used: technetium-99m-labeled macroaggregated albumin lung perfusion scan (n = 13) or contrast echocardiogram (n = 7). There were 16 patients listed for LT, with a median age at HPS diagnosis of 10 years and an average wait from listing to LT of 9 weeks. A marked rise in hemoglobin (Hb; median, 125-143.5 g/L) and modest decrease in oxygen saturation (SpO2 ; median 91% to 88% room air) were evident over this time. Patients' need for assisted ventilation (1 day), pediatric intensive care unit (PICU) stay (3 days), and total hospital stay (20 days) were similar to our general LT recipients-the key difference in the postoperative period was the duration of supplementary O2 requirement. Hb of ≥130 g/L on the day of LT correlated with a longer PICU stay (P value = 0.02), duration of supplementary O2 (P value = 0.005), and the need for the latter beyond 7 days after LT (P value = 0.01). Fifteen patients had resolution of their HPS after LT. The 5-, 10-, and 20-year survival rates were unchanged at 87.5%. None had a recurrence of HPS. In conclusion, HPS is a life-threatening complication of cirrhosis which usually develops insidiously. This combined with the often-stable nature of the liver disease leads to delays in diagnosis and listing for LT. Progressive polycythemia extends the need for supplementary O2 and PICU stay. We advocate screening for HPS with a combination of SpO2 and Hb monitoring to facilitate earlier recognition, timely LT, and shortened recovery periods.

A Multicenter Study on Clinical Outcomes of Infections within 200 Days of Liver Transplantation among Recipients Age 65 Years and Older

BackgroundLiver transplantation is increasingly performed in patients aged ≥65 years. Per the United Network for Organ Sharing data, infections are the leading primary and contributory cause of death in older liver transplant (LT) recipients. This study aims to describe the epidemiology and outcomes of infections within the first 200 days of LT in older adults.MethodsWe performed a retrospective, observational multi-center study of patients aged ≥65 years who underwent primary LT from January 1, 2010 to June 30, 2015. Data collection included patient demographics, co-morbidities, transplant data, infection event in 200 days of LT and death. Severe infection was defined as the presence of sepsis, septic shock, or sepsis with multi-organ failure.ResultsA total of 255 patients met inclusion criteria with median follow-up of 690 days (range 1– 2095). The mean age was 67.6 years (SD 2.4). Majority were male (67%) and white (85%). Frequent indications of LT were hepatocellular carcinoma (46%) and hepatitis C (32%). The median MELD score at the time of LT was 22 (range 6–47). Only 3% of recipients received thymoglobulin for induction. Acute rejection within 200 days of LT occurred in 31 (12%); graft failure in 8 (3%); and re-transplantation in 5 (2%). One hundred twenty-seven patients (50%) developed 274 infections; 63 (25%) had 1 infection and 64 (25%) had ≥ 2 infections. Median time to first infection after LT was 26 days [IQR 9–72]. Out of 274 infections, 182 (66%) occurred in <90 days. Severe infection occurred in 40/127 (31%). Cystitis (16%), colitis (12%), and pneumonia (11%) were common. Bacterial, viral, and fungal infections were 61%, 22%, and 7%, respectively. Common bacterial pathogens were Enterococcus sp. (15%), Clostridium difficile (12%) and E. coli (8%). Thirty-five (13%) opportunistic infections (OI) occurred due to Cytomegalovirus [CMV] (26), Candida (4), Cryptococcus (3), HHV-8 (1), and Aspergillus (1). Mortality due to infection was 3%, while all-cause mortality was 12%. Frequency of discharge to sub-acute or extended care facility after infection was 23%.ConclusionInfections are common in this older LT cohort and occurred mainly in the early post-LT period. OIs were infrequent except for CMV. Despite concerns for immunosuppression and immunosenescence, the outcome of infection within the 200 days of LT was overall favorable.Disclosures All authors: No reported disclosures.

Negativization of viremia prior to liver transplant reduces early allograft dysfunction in hepatitis C-positive recipients.

Although early allograft dysfunction (EAD) negatively impacts survival from the first months following liver transplantation (LT), direct-acting antiviral agents (DAAs) have revolutionized hepatitis C virus (HCV) therapy. We investigated the EAD definition best predicting 90-day graft loss and identified EAD risk factors in HCV-positive recipients. From November 2002 to June 2016, 603 HCV-positive patients (hepatocellular carcinoma, 53.4%) underwent a first LT with HCV-negative donors. The median recipient Model for End-Stage Liver Disease (MELD) score was 15, and the median donor age was 63 years. At LT, 77 (12.8%) patients were HCV RNA negative; negativization was achieved and maintained by pre-LT antiviral therapy (61 patients) or pre-LT plus a pre-emptive post-LT course (16 patients); 60 (77.9%) patients received DAAs and 17 (22.1%) interferon. We compared 3 different EAD definitions: (1) bilirubin ≥ 10 mg/dL or international normalized ratio ≥ 1.6 on day 7 after LT or aspartate aminotransferase or alanine aminotransferase > 2000 IU/L within 7 days of LT; (2) bilirubin > 10 mg/dL on days 2-7 after LT; and (3) MELD ≥ 19 on day 5 after LT. EAD defined by MELD ≥ 19 on day 5 after LT had the lowest negative (0.1) and the highest positive (1.9) likelihood ratio to predict 90-day graft loss. At 90 days after LT, 9.2% of recipients with EAD lost their graft as opposed to 0.7% of those without EAD (P < 0.001). At multivariate analysis, considering variables available at LT, MELD at LT of >25 (OR = 7.4) or 15-25 (OR = 3.2), graft macrovesicular steatosis ≥ 30% (OR = 6.7), HCV RNA positive at LT (OR = 2.7), donor age > 70 years (OR = 2.0), earlier LT era (OR = 1.8), and cold ischemia time ≥ 8 hours (OR = 1.8) were significant risk factors for EAD. In conclusion, in HCV-positive patients, MELD ≥ 19 on day 5 after LT best predicts 90-day graft loss. Preventing graft infection by pre-/peri-LT antiviral therapy reduces EAD incidence and could be most beneficial in high-MELD patients and recipients of suboptimal grafts. Liver Transplantation 23 915-924 2017 AASLD.

Outcome of Liver Transplant Recipients With Revascularized Coronary Artery Disease: A Comparative Analysis With and Without Cardiovascular Risk Factors.

Coronary artery disease (CAD) is a significant problem during evaluation for liver transplantation (LT). We aim to assess survival in LT recipients based on presence, severity, extent of CAD, and cardiac events within 90 days of LT. Eighty-seven LT recipients with history of pre-LT angiogram (December 2005 to December 2012) were compared with 2 control groups without prior angiogram, 72 LT recipients matched for cardiovascular risk factors (control group I), and 119 consecutive LT recipients without any CV risk factors (control group II). CAD was assessed by (1) vessel score (≥50% reduction in luminal diameter), and (2) Extent score (Reardon scoring system). Of the 87 LT recipients (study group), 58 (66.7%) had none or less than 50% stenosis, 29 (33.3%) had obstructive CAD (≥50% stenosis), 7 (8%) with single-vessel disease, and 22 (25.3%) with multivessel disease. In the study group, irrespective of prerevascularization severity of CAD (P = 0.357), number of segments involved (0, 1-2, > 2 segments, P = 0.304) and extent of CAD based on Reardon score (0, 1-9, >10, P = 0.224), comparable posttransplant survival was noted. Overall, patient survival in the revascularized CAD group was comparable to angiogram group without obstructive CAD, and both control group I and control group II (P = 0.184, Log Rank). Postoperative cardiac events within 90 days of LT predicted poor survival in study group as well as control groups. Severity or extent of CAD does not impact post-LT survival, if appropriately revascularized. Early postoperative cardiac events are associated with inferior survival in LT recipients, irrespective of underlying CAD.

Effects of therapeutic plasma exchange on early allograft dysfunction after liver transplantation.

Early allograft dysfunction (EAD) is a serious complication of liver transplantation (LT) and is associated with graft failure, which can result in patient mortality. Due to the shortage of organs for retransplantation, only a small proportion of EAD patients undergo retransplantation. Thus, liver support is needed for most patients with EAD. We evaluated the effects of therapeutic plasma exchange (TPE) in EAD patients. EAD was defined as a sustained hyperbilirubinemia (≥10 mg/dL) within 30 days of LT without concurrent biliary complications. In a 13-year period, 107 EAD patients underwent TPE while 36 EAD patients did not. We investigated the laboratory and clinical outcomes of TPE and non-TPE groups. The TPE group showed 1-month and 1-year survival rates of 82.2% and 53.8%, respectively, whereas the non-TPE group showed 58.3% and 22.2%, respectively. In TPE group, statistically significant decreases (P < 0.05) in total bilirubin (15.2 ± 5.2 to 13.1 ± 5.4 mg/dL), and INR (1.72 ± 1.04 to 1.38 ± 1.14), were seen after the final TPE session. TPE responder groups with age <51 years, total bilirubin <11.1 mg/dL, or INR <1.15 after final TPE showed better prognosis. TPE decreased the hazard risk of death in EAD patients whereas older age, male gender, and higher INR on the day of EAD onset increased the risk. TPE effectively removed plasma bilirubin and improved coagulation function in EAD patients, with higher survival in the TPE group than in the non-TPE group. TPE may be an effective liver support for EAD patients. J. Clin. Apheresis 32:147-153, 2017. © 2016 Wiley Periodicals, Inc.

The impact of donor liver graft quality on postoperative outcome in liver transplant recipients. A single centre experience.

The Donor Risk Index (DRI) has become a universal score for organ allocation in liver transplantation (LT) worldwide. The aim of this study was to evaluate the impact of liver graft quality measured by DRI, CIT, WIT and donor age on intraoperative hemodynamics (reperfusion syndrome) and early postoperative outcome, defined as initial graft poor function (within 3 days of LT), of deceased donor liver transplant (DDLT) recipients. Secondary end-points were the assessment of the impact of graft quality on the intraoperative and postoperative day 1 hemostasis (evaluated using ROTEM assay). We retrospectively analyzed 135 patients who underwent deceased-donor LT between January 2013 and December 2014. Patient demographic data (age, sex, cause of End-Stage Liver Disease), preoperative paraclinical data (total bilirubin, creatinine, serum sodium), severity of liver disease scores (Model for End-Stage Liver Disease - MELD and MELD-sodium), intraoperative blood loss and blood products transfusion, incidence of post reperfusion syndrome, postoperative biochemical data (including total bilirubin, hepatic transaminases, lactate levels) and outcome (initial graft poor function diagnosis) were noted. Donor characteristics including DRI, CIT, WIT and donor age were noted. Coagulation was assessed by rotational thromboelastometry (ROTEM) after reperfusion of the graft and on postoperative day 1 in order to determine the effects of liver graft quality on hemostasis. Donor age has significantly correlated with decreased derived ROTEM parameters time to the maximum velocity of clot formation - MaxVt (p = 0.000), area under the curve (AUC) (p = 0.008) and maximum clot elasticity (MCE) (p = 0.018) although no difference in transfusion requirements has been observed. A longer CIT was associated with an increase in AST and ALT observed during the early postoperative period: day 1 ALT (p = 0.032) and AST (p = 0.008), day 2 ALT (p = 0.001) and AST (p = 0.001) and day 3 AST (p = 0.010) and ALT (p = 0.001). Higher DRI correlated with higher bilirubin levels measured on postoperative day 1 (p = 0.027) and 2 (p = 0.001). Patients who developed initial graft poor function received liver grafts from older donors (p = 0.05) with a higher DRI (p = 0.002). Our results suggest a significant impact of donor age and DRI on perioperative coagulation kinetics that may be a result of initial graft poor function. Although CIT and DRI correlated with a more severe cholestasis and hepatocitolysis during the early postoperative period these seems to be short-lived.

Risk of Reoperation Within 90 Days of Liver Transplantation: A Necessary Evil?

The rate and consequences of reoperation after liver transplantation (LT) are unknown in the United States. Adult patients (n= 10,295; 45% of all LT) undergoing LT from 2009 through 2012 were examined using a linkage of the University HealthSystem Consortium and Scientific Registry of Transplant Recipients databases providing recipient, donor, center, hospitalization, and survival details. Median follow-up was 2 years. Reoperations were identified within 90 days after LT. Overall 90-day reoperation rate after LT was 29.3%. Risk factors for 90-day reoperation included recipients with a history of hemodialysis, severely ill functional status, government insurance, increasing Model for End-Stage Liver Disease score, and increasing donor risk index. Reoperation within 90 days was found to be an independent predictor of adjusted 1-year mortality (odds ratio= 1.8; 95% CI, 1.5-2.1), as was government-provided insurance and increasing donor risk index. Additionally, patients undergoing delayed reoperative intervention (after 30 days) were found to have increased risk of 1-year mortality compared with those undergoing early reoperative intervention (odds ratio= 1.96; 95% CI, 1.4-2.7; p < 0.01). This is the first national study reporting that nearly one-third of transplant recipients undergo reoperation within 90 days of LT. Although necessary at times, reoperation is associated with increased risk of death at 1 year; however, it appears that the timing of these interventions can be critical, due to the type of intervention required. Early reoperative intervention does not appear to influence long-term outcomes, and delayed intervention (after 30 days) is strongly associated with decreased survival.

Predictors of Early Hospitalization After Deceased Donor Liver Transplantation.

Hospitalizations after solid organ transplantation may affect patient outcomes. Identification of the factors attributed to them may decrease hospitalization rates, reduce overall cost, and improve post-transplant outcomes. We examined the risk factors for early hospitalization within 30 and 90 days after liver transplantation (LT). Data on all deceased donor LT recipients (age ≥18 years) transplanted between 2/28/2002-2/27/2007 and discharged alive from the index hospitalization within 30 days of LT were collected (N = 267). Patients were followed up until December 31, 2013. Logistic regression was used to identify the predictors of 30-day hospitalization, and linear regression was used to identify the factors associated with number of days hospitalized during 30- and 90-day hospitalization after LT. Renal risk index (RRI), a recently developed and validated risk score that accurately predicts the post-LT ESRD based upon recipient factors at LT, was computed using RRI calculator ( http://rri.med.umich.edu ). One-third and more than half of the patients had at least one 30- and 90-day hospitalization, respectively. RRI decile (OR 1.12, P = 0.02) and serum sodium at LT (OR 0.90, P < 0.001) were independently associated with 30-day hospitalization after adjusting for MELD score. Serum creatinine at LT (β = 4.34, P = 0.001) and pre-LT admission days (β = 0.15, P = 0.027) affected the number of days hospitalized for 90-day hospitalization. RRI was also an independent predictor of post-LT mortality. Early hospitalizations within 30 and 90 days after deceased donor LT are common. While all post-LT hospitalization cannot be prevented, efforts should be directed toward risk-based post-discharge care, and coordination of effective transitional care through ambulatory clinics. Implementation of such processes may attenuate early post-LT hospitalization and resource utilization and improve quality.

Telaprevir-containing regimen for treatment of hepatitis C virus infection in patients with hepatocellular carcinoma awaiting liver transplantation: a case series.

In patients who undergo liver transplantation (LT), allograft failure secondary to hepatitis C virus (HCV) recurrence after LT accounts for two-thirds of graft failures and deaths. Achievement of sustained virologic response before LT eliminates the risk of HCV recurrence. Only a limited number of studies have evaluated the role of antiviral treatment before LT. No published data are available regarding the use of HCV protease inhibitors before LT. We report our experience using the combination of telaprevir, pegylated interferon alfa-2a (PegIFN alfa-2a), and ribavirin in three patients with HCV-associated hepatocellular carcinoma (HCC) awaiting LT. Two patients had not received, and one had had a partial response to HCV therapy (PegIFN alfa-2a plus ribavirin). All three patients had genotype 1b and were started on telaprevir and full doses of PegIFN alfa-2a and ribavirin. Treatment was planned to be continued until the day of LT or 48 weeks total, whichever came first. One patient still had detectable HCV RNA after 24 weeks of antivirals and was, therefore, excluded from further analysis. The other two patients had undetectable HCV RNA at the end of antiviral therapy. In one of these patients, HCV RNA remained undetectable after LT; the other patient experienced viral relapse. HCV therapy was tolerated by all patients; no patient required permanent discontinuation of therapy because of toxic effects. All three patients experienced hematologic toxic effects. Only one patient required treatment discontinuation, due to progression of HCC. The use of telaprevir-containing regimens appears to be safe in selected patients with HCV-associated HCC awaiting LT, but more studies are warranted to evaluate the safety and efficacy of this treatment combination to prevent post-LT viral recurrence.

Dynamic Inflammatory Gene Expression Profiles Among Patients With and Without Acute Cellular Rejection (ACR) During the First Post-Transplant Year.

Early acute cellular rejection (ACR) often occurs within 90 days of liver transplantation. Diagnosis of ACR requires a liver biopsy with associated risk and expenses. We hypothesized that the longitudinal inflammatory gene expression profiles in blood may serve as proxy of the graft status and have utility as a non-invasive diagnostic measure of ACR. Methods: A prospective observational cohort study involving 87 recipients was performed in the CTOT03 Study (NIAID Clinical Trials in Organ Transplantation), collecting blood samples at defined intervals post transplant: within 2 hours of reperfusion, at 1 and 6 weeks, 3, 6, and 12 months. Expression of 102 genes involving in inflammatory and immune responses was profiled in all samples. Samples and genes meeting quality control measures (82 genes in 443 samples) were subjected to: 1) mixed models to examine their association with ACR and interactions with time since transplant; 2) general linear models to test their associations with ACR using a nested case-control study design; and 3) qualitatively profile their changes during the 1st year post-transplant. Results: Widely ranging dynamic changes were observed in inflammatory genes surveyed during the first year. During the study period, 9 patients developed biopsy proven ACR. Mixed model analyses revealed nominally significant associations of inflammatory gene expression with ACR status, time since transplant, and interactions of ACR and time since transplant. In a nested case-control study that included 7 samples collected at ACR diagnosis and 21 non-ACR samples frequency-matched to ACR samples on early allograft dysfunction, age, and time since transplant, TNF, CD40LG, FOSB, and MSRA were found to be nominally significant. Prediction analyses identified a multi-marker model consisting of CAT, CTSB, and GPX4 that may potentially serve as a predictive signature for ACR. Conclusion: Dynamic changes in inflammatory gene profiles during the first year may be the reflection of changes in immunosuppressant dosage, as well as a process during which the grafts were adopted by the recipients. With the precaution of small sample size, our results suggest that multi-marker signature has the potential for the diagnosis/prediction of ACR.