Long-term outcomes after normothermic machine perfusion in liver transplantation-Experience at a single North American center.

Normothermic machine perfusion (NMP) has emerged as a valuable tool in the preservation of liver allografts before transplantation. Randomized trials have shown that replacing static cold storage (SCS) with NMP reduces allograft injury and improves graft utilization. The University of Alberta's liver transplant program was one of the early adopters of NMP in North America. Herein, we describe our 7-year experience applying NMP to extend preservation time in liver transplantation using a "back-to-base" approach. From 2015 to 2021, 79 livers were transplanted following NMP, compared with 386 after SCS only. NMP livers were preserved for a median time of minutes compared with minutes in the SCS cohort (P < .0001). Despite this, we observed significantly improved 30-day graft survival (P = .030), although there were no differences in long-term patient survival, major complications, or biliary or vascular complications. We also found that although SCS time was strongly associated with increased graft failure at 1 year in the SCS cohort (P = .006), there was no such association among NMP livers (P = .171). Our experience suggests that NMP can safely extend the total preservation time of liver allografts without increasing complications.

Immunologic benefits of maternal living donor allografts in pediatric liver transplantation: fewer rejection episodes and no evidence of de novo allosensitization.

BACKGROUND: Pediatric liver transplant (LT) recipients of maternal living liver donor (LLD) grafts have been reported to experience fewer rejection episodes. However, it is unclear whether this benefit translates to reduction in developing donor-specific antibody (DSA) among maternal-LLD recipients. The aim of this study was to compare immunologic outcomes among maternal-LLD, non-maternal-LLD, and deceased donor liver transplant (DDLT) recipients. METHODS: Children (≤18 years) who underwent LT between 1/1998 and 12/2019 at two high-volume LT centers in North America were evaluated. Patients were divided into three groups by type of graft received (maternal-LLD, non-maternal LLD, and DDLT). Clinical variables and outcomes were compared according to each graft type. RESULTS: A total of 450 pediatric primary LT were analyzed: 275 (61.1%) DDLT, 73 (16.2%) maternal-LLD, and 102 (22.6%) non-maternal-LLD. Children receiving LLD grafts were less likely to develop rejection when compared to the DDLT group (DDLT 46.9% vs. maternal-LLD 31.5% vs. non-maternal-LLD 28.4%, p = 0.001). There was no difference in rejection rates between maternal and non-maternal-LLD recipients. A higher percentage of maternal-LLD recipients were on immunosuppression monotherapy compared to non-maternal-LLD and DDLT recipients (6.7% vs. 1.2 vs. 2.4%, respectively). A subgroup of 68 patients were tested for DSA post-LT. Maternal-LLD recipients were less likely to develop de novo DSA (maternal-LLD 11.8% vs. non-maternal-LLD 19.3% vs. DDLT 43%, p = 0.018). None of the maternal-LLD recipients developed antibody-mediated rejection. CONCLUSIONS: These data support the concept of immunologic benefit of maternal-LLD in pediatric LT, with lower rates of rejection and allosensitization post-LT when compared to DDLT recipients.

Downstaging prior to liver transplantation for hepatocellular carcinoma: advisable but at the price of an increased risk of cancer recurrence - a retrospective study.

The use of downstaging prior to liver transplantation for hepatocellular carcinoma (HCC) still needs refinement. This study included patients with HCC listed for transplantation according to the Total Tumour Volume (TTV) ≤115 cm3 and alpha fetoprotein (AFP) ≤400 ng/ml criteria, with and without previous downstaging. Overall, 455 patients were listed, and 286 transplanted. Post-transplant follow-up was 38.5 ± 1.7 months. Patients downstaged to TTV115/AFP400 (n = 29) demonstrated similar disease-free survivals (DFS, 74% vs. 80% at 5 years, P = 0.949), but a trend to more recurrences (14% vs. 5.8%, P = 0.10) than those always within TTV115/AFP400 (n = 257). Similarly, patients downstaged to Milan criteria (n = 80) demonstrated similar DFS (76% vs. 86% at 5 years, P = 0.258), but more recurrences (11% vs. 1.7%, P = 0.001) than those always within Milan (n = 177). Among patients downstaged to Milan, those originally beyond TTV115/AFP400 (n = 27) had similar outcomes as those originally beyond Milan, but within TTV115/AFP400 (n = 53). However, the likelihood of being within Milan at transplant was lower for patients with more advanced original HCCs (P < 0.0001). Overall, despite an expected increase in post-transplant HCC recurrence, similar survivals can be achieved with and without downstaging, using the TTV115/AFP400 transplantation criteria, and including patients with advanced original HCCs. Downstaging should continue to be performed.

Intraoperative continuous renal replacement therapy during liver transplantation: a pilot randomized-controlled trial (INCEPTION).

PURPOSE: To evaluate the feasibility of intraoperative continuous renal replacement therapy (IoCRRT) during liver transplantation (LT), in terms of recruitment, protocol adherence, and ascertainment of follow-up. METHODS: In this pilot randomized open-label controlled trial in adults receiving LT with a Model for End-Stage Liver Disease (MELD) score ≥ 25 and preoperative acute kidney injury (RIFLE - RISK or higher) and/or estimated glomerular filtration rate < 60 mL·min-1·1.73 m-2, patients were randomized to receive IoCRRT or standard of care (SOC). Primary endpoints were feasibility and adverse events. Primary analysis was intention-to-treat (n = 32) and secondary analysis was per-protocol (n = 28). RESULTS: The trial was stopped early because of slow patient accrual and inadequate funding. Sixty patients were enrolled and 32 (53%) were randomized (n = 15 IoCRRT; n = 17 SOC). Mean (standard deviation) MELD was 36 (8), 81% (n = 26) had cirrhosis; 69% (n = 22) received preoperative RRT; 66% (n = 21) received LT from the intensive care unit. Four patients (n = 2 IoCRRT, n = 2 SOC) did not receive LT post-randomization. Seven patients (41%) allocated to SOC crossed over intraoperatively to IoCRRT. Three patients were lost to follow-up at one year. No adverse events occurred related to IoCRRT. There were no differences in survival at one year (IoCRRT, 71% [n = 10/14] vs SOC, 93% [n = 14/15]; risk ratio, 0.77; 95% confidence interval, 0.54 to 1.1). In the per-protocol analysis (n = 28 received IoCRRT after randomization - n = 20 IoCRRT, n = 8 SOC), one-year survival was 92% and perioperative complications were similar between groups. Only one patient was receiving dialysis one year after LT. CONCLUSION: In this pilot randomized trial, IoCRRT was feasible and safe with no difference in complications. Crossover rates were high. Despite high preoperative severity of illness, one-year survival was excellent. These data can inform the design of a larger multicentre trial. TRIAL REGISTRATION: www.clinicalTrials.gov (NCT01575015); registered 12 April, 2012.

RéSUMé: OBJECTIF: Notre but était d'évaluer la faisabilité d'un traitement substitutif peropératoire continu de l'insuffisance rénale pendant une greffe hépatique, notamment en matière de recrutement, d'adhésion au protocole, et de suivi. MéTHODE: Dans cette étude randomisée contrôlée non aveugle pilote réalisée auprès d'adultes recevant une greffe hépatique avec un score MELD (Model for End-Stage Liver Disease) ≥ 25 et une insuffisance rénale aiguë préopératoire (RIFLE - RISQUÉ ou plus élevé) et/ou un taux de filtration glomérulaire estimé < 60 mL·min−1·1,73 m−2, les patients ont été randomisés à recevoir un traitement substitutif peropératoire continu de l'insuffisance rénale (le traitement) ou les soins habituels (la norme). Les critères d'évaluation principaux étaient la faisabilité et les événements indésirables. L'analyse principale était l'analyse du projet thérapeutique (intention-to-treat; n = 32) et l'analyse secondaire était l'analyse selon le protocole (n = 28). RéSULTATS: L'étude a été précocement interrompue en raison du recrutement lent de patients et du manque de fonds. Soixante patients ont été recrutés et 32 (53 %) ont été randomisés (n = 15 traitement; n = 17 norme). Le score MELD moyen (écart type) était de 36 (8), 81 % (n = 26) des patients souffraient de cirrhose; 69 % (n = 22) ont reçu un traitement substitutif de l'insuffisance rénale préopératoire; 66 % (n = 21) ont reçu une greffe hépatique à partir de l'unité de soins intensifs. Quatre patients (n = 2 traitement, n = 2 norme) n'ont pas reçu de greffe hépatique après la randomisation. Sept patients (41 %) alloués au groupe norme sont passés dans le groupe traitement en période peropératoire. Trois patients ont été perdus au suivi au cours de la première année. Aucun événement indésirable n'est survenu en association au traitement substitutif peropératoire continu de l'insuffisance rénale. Aucune différence en matière de survie à un an n'a été observée (traitement, 71 % [n = 10/14] vs norme, 93 % [n = 14/15]; risque relatif, 0,77; intervalle de confiance 95 %, 0,54 à 1,1). Dans l'analyse selon le protocole (n = 28 ont reçu un traitement après la randomisation - n = 20 traitement, n = 8 norme), la survie à un an était de 92 % et les complications périopératoires étaient semblables dans les deux groupes. Un seul patient recevait de la dialyse un an après la greffe hépatique. CONCLUSION: Dans cette étude randomisée pilote, le traitement substitutif peropératoire continu de l'insuffisance rénale s'est avéré faisable et sécuritaire, et aucune différence en matière de complications n'a été observée. Les taux de transfert d'un groupe à l'autre étaient élevés. Malgré une sévérité préopératoire élevée de la maladie, la survie à un an était excellente. Ces données peuvent être utiles pour concevoir une étude multicentrique plus importante. ENREGISTREMENT DE L'éTUDE: www.clinicalTrials.gov (NCT01575015); enregistrée le 12 avril 2012.

Total tumor volume and alpha-fetoprotein for selection of transplant candidates with hepatocellular carcinoma: A prospective validation.

UNLABELLED: The selection of liver transplantation (LT) candidates with hepatocellular carcinoma (HCC) is currently validated based on Milan criteria. The use of extended criteria has remained a matter of debate, mainly because of the absence of prospective validation. The present prospective study recruited patients according to the previously proposed total tumor volume (TTV; ≤115 cm(3) )/alpha-fetoprotein (AFP; ≤400 ng/mL) score. Patients with AFP >400 ng/mL were excluded, and, as such, the Milan group was modified to include only patients with AFP <400 ng/mL; these patients were compared to patients beyond Milan, but within TTV/AFP. From January 2007 to March 2013, 233 patients with HCC were listed for LT. Of them, 195 patients were within Milan and 38 beyond Milan, but within TTV/AFP. The average follow-up from listing was 33.9 ± 24.9 months. Risk of dropout was higher for patients beyond Milan, but within TTV/AFP (16 of 38; 42.1%), than for those within Milan (49 of 195 [25.1%]; P = 0.033). In parallel, intent-to-treat survival from listing was lower in patients beyond Milan (53.8% vs. 71.6% at 4 years; P < 0.001). After a median waiting time of 8 months, 166 patients were transplanted, 134 within Milan criteria, and 32 beyond Milan but within TTV/AFP. They demonstrated acceptable and similar recurrence rates (4.5% vs. 9.4%; P = 0.138) and post-transplant survivals (78.7% vs. 74.6% at 4 years; P = 0.932). CONCLUSION: Based on the present prospective study, HCC LT candidate selection could be expanded to the TTV (≤115 cm(3) )/AFP (≤400 ng/mL) criteria in centers with at least 8-month waiting time. An increased risk of dropout on the waiting list can be expected, but with equivalent and satisfactory post-transplant survival.

Comorbidities have a limited impact on post-transplant survival in carefully selected cirrhotic patients: a population-based cohort study.

BACKGROUND: Improving estimation of long-term survival of patients with end-stage liver disease after orthotopic liver transplantation (OLT) would optimize decisions on eligibility for transplant. We aimed to externally validate previously derived Charlson Comorbity Index for OLT (CCI-OLT); subsequently, we developed a new model to predict 5-year mortality after transplant. MATERIAL AND METHODS: This single center retrospective cohort study included 524 consecutive adult cirrhotic patients who underwent OLT in 2002-2012. External validation of CCI-OLT used Kaplan-Meier method. Derivation of the new predictive model used Cox proportional hazards regression. RESULTS: One-, 3-, and 5-year cumulative survival after OLT was 89%, 80%, and 73%, respectively. CCI-OLT was not associated with 5-year mortality after transplant (P = 0.34). We derived and internally validated a new predictive model of 5-year mortality after OLT based on six pre-transplant characteristics of patients: age, body mass index, hepatitis C, hepatic encephalopathy, intensive care unit stay at transplant, and live donor (C-index = 0.64). We further developed a nomogram to estimate individual probability of 1-, 3-, and 5-year survival after OLT. CONCLUSIONS: In our cohort, CCI-OLT was not associated with survival following transplant. The new predictive model discriminative capacity was only modest, suggesting that pre-transplant characteristics are of limited value in predicting post-transplant outcomes in thoroughly selected patients.

Serum sodium shift in hyponatremic patients undergoing liver transplantation: a retrospective cohort study.

INTRODUCTION: We aimed to describe the pre-operative incidence of hyponatremia in patients undergoing liver transplantation (LTx), as well as the rate and consequences of rapid peri-operative sodium rises in these patients. METHODS: This was a retrospective before and after observational study performed at a University-affiliated LTx center between January 2007 and June 2013. The primary exposure was pre-operative hyponatremia, defined as a serum sodium (SNa) <133 mmol/L. The primary outcome was occurrence of a rapid SNa shift, defined as ≥10 mmol/L in the first 24 h following LTx. The rates of rapid peri-operative SNa shift were compared before and after a focused quality assurance (QA) initiative performed in July 2009. RESULTS: Of 366 LTx, 69 (18.9%) had pre-operative hyponatremia, 6 (8.7%) of whom had a rapid rise in serum sodium (SNa). Rapid rise was associated with a greater intra-operative positive fluid balance (p < 0.001) and use of intra-operative continuous renal replacement therapy (CRRT) (p = 0.017). A rapid rise in SNa was associated with more neurological investigations in the post-transplant period (brain computed tomography, electroencephalogram, swallow studies), increased neurological deficits (p = 0.006), more abnormal swallowing assessments (p = 0.003), a tendency for more neurology consultations (p = 0.058), increased discharge to a rehabilitation or long-term care facility (p < 0.001), and increased 6-month mortality (p < 0.001). Following a QA initiative, rapid peri-operative rises in SNa among hyponatremic patients was significantly reduced (20% vs. 0%, p < 0.003). CONCLUSION: Pre-operative hyponatremia and rapid peri-operative SNa shifts are associated with a more complicated post-operative course and worse outcomes following LTx. Increased education and awareness, along with process changes, such as standardizing CRRT prescription, can reduce iatrogenic rapid peri-operative shifts in SNa.

Patients with cirrhosis and denied liver transplants rarely receive adequate palliative care or appropriate management.

BACKGROUND & AIMS: Patients with cirrhosis who are receiving palliative care and are not eligible for liver transplantation (LT) are often hospitalized multiple times, with lack of expectations or understanding of death and dying. We evaluated how frequently these patients received appropriate and palliative care. METHODS: We performed a retrospective study of 102 consecutive adult patients (67% men; mean age, 55 years) who were removed from the list for or declined LT from January 2005 through December 2010 at the University of Alberta, Canada. Patients' medical records were reviewed to determine their access to palliative care and relief of symptoms, the appropriateness of the goals for their care, and their requirements for acute care services. RESULTS: The patients' median Model for End-stage Liver Disease score was 20, and median time from denial of LT to death was 52 days (range, 10-332 days). The most common reasons that patients were removed from the transplant wait list were noncompliance or substance abuse (26%) and severe illness or organ dysfunction (25%). After patients were removed from the list, 17% received renal replacement therapy, and 48% were subsequently admitted to the intensive care unit. Patients spent a median of 14 days (range, 6-33 days) in the hospital after they were removed from the transplant wait list. On the basis of the Edmonton Symptom Assessment System, 65% of patients had evidence of pain, 58% had evidence of nausea, 10% had depression, 36% had anxiety, 48% had dyspnea, and 49% had symptoms of anorexia. Twenty-eight percent of all the patients had documentation of do not resuscitate status on their charts, and only 11% were referred for palliative care. CONCLUSIONS: Patients with cirrhosis who have been removed from the wait list for LT are infrequently referred for palliative care (∼ 10% of cases), although a high percentage have pain or nausea. Goals of care and do not resuscitate status are rarely discussed. Improved planning of goals of care and access to palliative services are required for these patients.

Severe muscle depletion predicts postoperative length of stay but is not associated with survival after liver transplantation.

Muscle depletion or sarcopenia is associated with increased mortality in patients with cirrhosis; how it affects mortality after liver transplantation requires further study. In this study, we aimed to establish whether sarcopenia predicts increased morbidity or mortality after liver transplantation. We analyzed 248 patients with cirrhosis who had a computed tomography (CT) scan including the third lumbar vertebra before liver transplantation. Data were recovered from medical charts, the skeletal muscle cross-sectional area was measured with CT, and sarcopenia was defined with previously published sex- and body mass index-specific cutoffs. One hundred sixty-nine patients (68%) were male, and the mean age at transplantation was 55 ± 1 years. The etiologies of cirrhosis were hepatitis C virus (51%), alcohol (19%), autoimmune liver diseases (15%), hepatitis B virus (8%), and other etiologies (7%). Sarcopenia was present in 112 patients (45%), and it was more frequent in males (P = 0.002), patients with ascites (P = 0.02), and patients with higher bilirubin levels (P = 0.05), creatinine levels (P = 0.02), international normalized ratios (P = 0.04), Child-Pugh scores (P = 0.002), and Model for End-Stage Liver Disease scores (P = 0.002). The median survival period after liver transplantation was 117 ± 17 months for sarcopenic patients and 146 ± 20 months for nonsarcopenic patients (P = 0.4). Sarcopenic patients had longer hospital stays (40 ± 4 versus 25 ± 3 days; P = 0.005) and a higher frequency of bacterial infections within the first 90 days after liver transplantation (26% versus 15%, P = 0.04) in comparison with nonsarcopenic patients. In conclusion, sarcopenia is one of the most common complications in patients with cirrhosis and is predictive of longer hospital stays and a higher risk of perioperative bacterial infections after liver transplantation, but it is not associated with increased mortality.

Validation of the five-variable Model for End-stage Liver Disease (5vMELD) for prediction of mortality on the liver transplant waiting list.

BACKGROUND: Modifications to the Model for End-Stage Liver Disease (MELD) have been proposed to improve prioritization of liver transplant (LT) candidates. Using a U.S. database, we derived a revised MELD including sodium and albumin [5-variable MELD (5vMELD)] that improved prediction of waiting list mortality. Our objectives were to confirm the association between hypoalbuminaemia and mortality and to externally validate 5vMELD in Canadian LT candidates. METHODS: Among adults registered on the LT waiting list at the University of Alberta (01/2000-10/2009), Cox regression determined the association between albumin and 1-year waiting list mortality. The discrimination of MELD, MELDNa and 5vMELD for predicting 1-year mortality were compared using c-statistics. RESULTS: Among 677 patients, 17% died and 51% underwent LT within 1 year of listing. Median serum albumin was 3.1 g/dl (IQR 2.6-3.6) and 70% of patients were hypoalbuminaemic (albumin <3.5 g/dl). One-year mortality in patients with normal serum albumin and hypoalbuminaemia were 14% and 29% respectively (P = 0.004). For patients with serum albumin between 2.0 and 4.0 g/dl, an approximately linear, inverse relationship was observed between albumin and 1-year mortality [adjusted hazard ratio (HR) 1.45; 95% CI 1.03-2.03; P = 0.03]. For this outcome, the c-statistic of 5vMELD (0.778) was superior to those of MELD (0.754) and MELDNa (0.765) (both P ≤ 0.05). CONCLUSIONS: Hypoalbuminaemia is an independent predictor of mortality on the LT waiting list. Compared with MELD and MELDNa, 5vMELD improves prediction of mortality suggesting that modification of these scores to include serum albumin should be considered as a means of prioritizing LT candidates.

Identifying risk factors for central pontine and extrapontine myelinolysis after liver transplantation: a case-control study.

BACKGROUND: Central pontine and extrapontine myelinolysis (CPEPM) is a rare but potentially fatal complication after orthotopic liver transplantation (OLT). The aim of this study was to identify risk factors for development of CPEPM after OLT and to assess patient outcome. METHODS: We reviewed the clinical data of 1,378 patients who underwent OLT between 1987 and 2009 in Geneva, Switzerland and Edmonton, Canada. Nineteen patients (1.4 %) developed CPEPM. We compared their characteristics with control patients, matched by age, gender, date of OLT, and MELD score. RESULTS: The 19 patients with CPEPM (7F, mean age 52.1 ± 2 years) had a mean MELD score of 26 ± 2.2. Before OLT, patients who develop CPEPM presented more frequently low (<130 mmol/l; p < 0.04) and very low (<125 mmol/l; p < 0.009) sodium than controls. In patients developing CPEPM, the number of platelet units and fresh frozen plasma transfused during surgery was higher (p = 0.05 and 0.047), hemorrhagic complications were more frequent after OLT (p = 0.049), and variations of sodium before and after OLT were higher (p = 0.023). The association of >2 of these conditions were strongly associated with CPEPM (p = 0.00015). Mortality at 1 year of patients developing CPEPM was higher (63 vs. 13 %, p < 0.0001). CONCLUSIONS: High MELD score patients undergoing OLT, receiving massive perfusions of Na-rich products, experiencing surgery-related hemorrhagic complication and important fluctuations of Na are at risk of developing CPEPM. Therefore careful monitoring of natremia in the perioperative period and use of water-free perfusion in case of massive blood-products transfusion are critical points of this patient management.

Cardiac work-up protocol for liver transplant candidates: experience from a single liver transplant centre.

BACKGROUND: Ischemic cardiac events can cause significant morbidity and mortality postliver transplantation; however, no validated protocols to screen patients before transplantation exist. OBJECTIVES: To report the introduction of a noninvasive cardiac screening protocol used at the Liver Unit, University of Calgary (Calgary, Alberta); to determine whether the protocol decreases use of coronary angiograms; and to compare cardiac outcomes using the new protocol with an appropriately matched historical control group. METHODS: A new cardiac screening protocol was introduced into the program in 2005, which uses perfusion scintigraphy to screen high-risk cardiac patients, reserving coronary angiograms for abnormal results. Transplanted patients screened using this protocol were compared with matched historical controls. Electronic charts were reviewed for cardiac outcomes intra- and postliver transplantation. RESULTS: A total of 396 patients were screened between April 2005 and February 2009. Eighty-two were transplanted by February 2009 and included in the study. Eighty-one patients were successfully matched according to age, sex, cardiac history and presence of diabetes. Twelve of 82 (14.6%) and 11 of 81 (13.6%) in the study and control groups, respectively, underwent coronary angiograms (P=0.85). Coronary artery disease was found in six of 12 (50.0%) study patients and three of 11 (27.3%) control patients who underwent coronary angiography (P=0.27). The mean (± SD) length of the follow-up period was 1.87±0.91 years and 4.45±1.89 years in the study and control groups, respectively. One of 81 in the control group and zero of 82 in the study group experienced an acute coronary syndrome event postoperatively. CONCLUSIONS: Coronary events are infrequent in liver transplant recipients. The described protocol is an effective method of coronary artery disease screening before liver transplant but does not reduce the number of cardiac investigations performed.

The impact of sirolimus on hepatitis C recurrence after liver transplantation.

BACKGROUND: While some immunosuppression strategies may accelerate hepatitis C virus (HCV) recurrence after liver transplantation (LT), the impact of sirolimus (SRL) is not known. OBJECTIVE: To assess the risk of biopsy-proven HCV recurrence and patient survival using known and suspected risk factors for HCV recurrence as covariates. METHODS: A retrospective analysis of 141 consecutive patients, including 88 who received de novo SRL therapy, who had undergone a first LT for HCV cirrhosis was conducted. Known and suspected risk factor covariates including transplant era, donor and recipient age, Model for End-stage Liver Disease score, cold ischemia time, immunosuppressive drugs and steroid treatment rejection rates were used in the assessment. RESULTS: Overall, 72.3% of the cohort developed biopsy-proven HCV recurrence. The incidence of HCV recurrence was not significantly different for patients treated with SRL (75% versus 69.8%; P=0.5). There was no difference found for time to recurrence, nor did mean activity or fibrosis scores differ at the time of initial recurrence. However, on follow-up using serial biopsies in patients with recurrence, the mean activity and fibrosis scores were significantly lower in the SRL group. Donor age and acute rejection episodes were the only factors affecting the HCV recurrence rate (expB 1.02 [95% CI 1.01 to 1.03]); P=0.03; and expB 2.8 [95% CI 1.8 to 4.3]; P<0.01], respectively). SRL treatment did not alter patient survival rates. Among patients treated with SRL-based immunosuppression, higher drug area under the curve levels were associated with a trend to lower disease activity and fibrosis at diagnosis; however, higher SRL levels were associated with shorter recurrence-free survival (P=0.038). CONCLUSION: Results of the present analysis suggest that de novo SRL-based immunosuppression can be safely used in patients undergoing LT for HCV-associated liver disease; however, SRL-based immunosuppression did not significantly affect the timing or severity of post-transplant HCV recurrence. HCV recurrence in SRL-treated patients had lower progressive activity and fibrosis levels on serial biopsy.

An evaluation of intraoperative renal support during liver transplantation: a matched cohort study.

BACKGROUND: Intraoperative continuous renal replacement therapy (CRRT) has been utilized during liver transplantation (LT). Our objective was to assess intraoperative CRRT for metabolic control, postoperative complications and outcomes. METHODS: Retrospective matched cohort study. Cases were LT patients receiving intraoperative CRRT. Controls were matched for demographics and Model for End-Stage Liver Disease (MELD) score. Data were extracted on physiology, course and outcomes. RESULTS: 72 patients were included. Despite effort to match by MELD, cases had higher scores (35.4 vs. 29.9, p = 0.01) compared to controls. Preoperatively, cases received more vasopressors (p = 0.006), and more RRT (94.4 vs. 25.7%, p < 0.0001). There was no difference in complications (p = 0.35) or ICU re-admission rate (p = 0.29). Cases were more likely to require postoperative RRT (p < 0.0001). There was no difference in hospital mortality (p = 0.61). CONCLUSIONS: LT patients selected for intraoperative CRRT more commonly have hemodynamic instability and preoperative acute kidney injury requiring RRT. Despite higher illness severity for cases, there were no differences in complications or mortality.

Living Donor Versus Deceased Donor Pediatric Liver Transplantation: A Systematic Review and Meta-analysis.

Reduced-size deceased donors and living donor liver transplantation (LDLT) can address the organ shortage for pediatric liver transplant candidates, but concerns regarding technical challenges and the risk of complications using these grafts have been raised. The aim of this study was to compare outcomes for pediatric LDLT and deceased donor liver transplantation (DDLT) via systematic review. METHODS: A systematic literature search was performed to identify studies reporting outcomes of pediatric (<18 y) LDLT and DDLT published between 2005 and 2019. A meta-analysis was conducted to examine peri- and postoperative outcomes using fixed- and random-effects models. RESULTS: Overall, 2518 abstracts were screened, and 10 studies met criteria for inclusion. In total, 1622 LDLT and 6326 DDLT pediatric patients from 4 continents were examined. LDLT resulted in superior patient survival when compared with DDLT at 1, 3, and 5 y post-LT (1-y hazard ratio: 0.58, 95% confidence interval [CI] 0.47-0.73, P < 0.0001). Similarly, LDLT resulted in superior graft survival at all time points post-LT when compared with DDLT (1-y hazard ratio: 0.56 [95% CI 0.46-0.68], P < 0.0001]. The OR for vascular complications was 0.73 (95% CI 0.39-1.39) and 1.31 (95% CI 0.92-1.86) for biliary complications in LDLT compared with DDLT, whereas LDLT was associated with lower rates of rejection (OR: 0.66 [95% CI 0.45-0.96], P = 0.03). CONCLUSIONS: This meta-analysis demonstrates that LDLT may offer many advantages when compared with DDLT in children and suggests that LDLT should continue to be expanded to optimize outcomes for pediatric LT candidates.

The Transition to Microsurgical Technique for Hepatic Artery Reconstruction in Pediatric Liver Transplantation.

BACKGROUND: Hepatic artery thrombosis represents a potentially fatal complication following liver transplantation. Rates of hepatic artery thrombosis are significantly higher in children, with mortality reported up to 80 percent. Microsurgical anastomosis has been shown to decrease the rate of hepatic artery thrombosis and now represents the standard of care at the authors' institution. In this article, the authors present the largest study of its type directly comparing rates of hepatic artery thrombosis with and without microsurgical reconstruction of the hepatic artery. METHODS: All pediatric patients who underwent primary orthotopic liver transplantation between 1989 and 2018 were included. Patients were divided into two cohorts: standard anastomosis with loupes, and microsurgical anastomosis under the operating microscope. The authors' primary outcome was the rate of hepatic artery thrombosis. Secondary outcomes were graft survival, patient survival, retransplantation rate, requirement for intraoperative blood products, and length of stay. RESULTS: Two hundred thirty-one children met criteria for inclusion. One hundred eighty cases were performed with loupe magnification and 51 cases were performed under the microscope. The hepatic artery thrombosis rate was lower, but not significantly so (p = 0.114), in the microsurgical group [n = 1 (2.0 percent)] compared with the standard cohort [n = 15 (8.3 percent)]. Survival analysis revealed a significant increase in graft survival with microsurgical anastomosis (p = 0.020), but not patient survival (p = 0.196). The retransplantation rate was significantly lower with microsurgical anastomosis (p = 0.021). CONCLUSIONS: Microsurgical anastomosis was associated with a clinically important decrease in hepatic artery thrombosis compared with standard loupe anastomosis. The graft survival rate was significantly higher in the microsurgical cohort, with a reduced retransplantation rate at 1 year. On this basis, the authors recommend microsurgical hepatic artery anastomosis in cases of pediatric liver transplantation. . CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Alcohol use while on the liver transplant waiting list: a single-center experience.

Alcoholic liver disease (ALD) is a leading indication for liver transplantation. Our center has randomly checked blood alcohol levels (BALs) in ALD patients on the waiting list since 2004. We aimed to identify the incidence and predictors of inactivation on the transplant list due to alcohol use and to determine the utility of BAL-screening in this process. We conducted a retrospective review of patients with ALD listed for liver transplantation with at least 3 months of postlisting follow-up. Alcohol use while on the transplant list was defined as a positive BAL, an admission of alcohol use, or refusal to perform screening within 12 hours of request. Cox proportional hazards regression was used to estimate risk ratios (RRs). Of 134 patients meeting eligibility criteria, 78% were male, and mean age was 52 years. Alcohol use was documented in 23 patients (17%). Of these, 12 refused to have a random screen, 8 had detectable serum ethanol levels, and 3 had self-reported alcohol use. On multivariable analysis, a higher number of random BAL-checks [RR = 0.63(0.52, 0.76), P = 0.001] and a longer duration of prelisting abstinence [RR = 0.88(0.83, 0.94), P = 0.001] independently reduced the risk of alcohol use by patients while on the waiting list. None of the patients with >24 months of prelisting abstinence had a positive screen. In conclusion, this study supports random BAL-screening before transplantation and reinforces the importance of abstinence duration as a predictor of relapse. For patients with <24 months of prelisting abstinence, our center will increase the frequency of random BAL screening and increase the rehabilitation requirements to include an intensive 3-week rehabilitation program. We hope that these measures will reduce the rate of relapse to alcohol use post-transplantation.

Multicentric outcome analysis of sirolimus-based immunosuppression in 252 liver transplant recipients.

SUMMARY: The use of sirolimus (SRL) in orthotopic liver transplantation (OLT) has been controversial after experimental data suggested an increased risk of hepatic artery thrombosis (HAT). To assess the safety and efficacy of SRL as de novo immunosuppression in OLT recipients. Outcomes of 252 OLT patients who received SRL were compared with outcomes of 291 OLT recipients who received calcineurin inhibitor in a retrospective study. Primary outcomes of this study were: patient- and graft survivals, vascular, biliary, wound complications and rejection rates. Secondary outcomes were: postoperative infection rate, bone marrow and renal function and changes of lipid levels. Patient- and graft survivals, rejection and infection rates were similar. In the SRL group, HAT occurred in 1.2%, biliary complications in 19.4%, and incisional hernias in 9.1%. In the control group the incidence of HAT was 5.8% (P = 0.004), biliary complications 18.5% (P = NS) and incisional hernias 7.2% (P = NS). Patients on SRL experienced significantly higher levels of serum triglycerides but fewer acute cellular rejections. Bone marrow and renal functions were similar in both the groups. Our findings would suggest that SRL is safe and effective for very selected OLT recipients. Randomized controlled trials are necessary to confirm our results.

A shorter duration of pre-transplant abstinence predicts problem drinking after liver transplantation.

OBJECTIVES: Liver transplantation for alcoholic liver disease (ALD) can be complicated by abusive or "problem" drinking (PD) after transplant. There are limited data for evaluating the effect of pre-transplant abstinence on post-transplant PD. Few existing studies have included a substantial number of patients with co-existing causes of hepatic dysfunction, and the effect of PD on survival in recent European studies has been controversial. We hypothesized that a longer duration of pre-transplant abstinence would lead to less PD after transplantation. Accordingly, the objectives of this study are to analyze a North American cohort of patients with ALD with or without a secondary diagnosis of liver disease to estimate (i) the incidence of PD and its predictors, as well as (ii) the effect of PD on patient survival. METHODS: We conducted a retrospective review of all patients transplanted for ALD surviving for more than 3 months after transplant. PD was defined as either any drinking (AD) to the point of intoxication or drinking above the toxic threshold (>20 g/day in women and >40 g/day in men) on at least two separate occasions. We used Cox's proportional hazards regression to estimate risk ratios and Kaplan-Meier curves with log-rank analysis to compare survival. RESULTS: Of 213 eligible transplant patients, 42 were excluded. Of the 171 remaining patients, 78% were male; mean age was 52 years. Overall 53% of patients had co-existing causes of liver dysfunction. The mean follow-up was 64.8 months. The median pre-transplant abstinence was 19 months. In all patients, the risk of AD was 24% and PD 13%. Pre-transplant abstinence duration was the only independent predictor of PD after transplant. For every 1-month increment in pre-transplant abstinence, there was a 5% decrease in the adjusted relapse rate. There was no survival difference noted between problem drinkers and non-drinkers. CONCLUSIONS: The risk of PD decreased with increasing pre-transplant abstinence. Our data support pre-transplant abstinence as an important predictor of post-transplant recidivism; however, the optimal period of abstinence remains unclear. Patients with <18 months of abstinence may benefit from more intensive follow-up and rehabilitation after transplant.

HCV Eradication with Direct-Acting Antivirals Does Not Impact HCC Progression on the Waiting List or HCC Recurrence after Liver Transplantation.

Background: The introduction of direct-acting antivirals (DAA) for HCV has led to high rates of HCV eradication. Treatment of patients awaiting liver transplantation (LT) has been controversial. Recent data suggests that DAA treatment may accelerate recurrent HCC. The impact of DAA on delisting for HCC progression or recurrent HCC post-LT has not been well characterized. Methods: A retrospective review of both waitlist patients and LT recipients at a single institution was performed. Patient demographics, HCV treatment, HCC features and treatments, biopsy results, and graft and patient survival were evaluated. Patients on the LT waitlist or who were transplanted between January 2014 and December 2015 were included. Data was collected through December 2017 to have a minimum of two years of follow-up. Results: In the study period, 128 adult LT were performed. 44 patients were HCV+, and 68.2% (N=30) also had HCC. 38.6% (N=17) of HCV+ patients received DAA pre-LT, and 94.1% (N=16/17) achieved sustained virologic response (SVR) pre-LT. Among untreated HCV+ patients who underwent LT, 81.5% (N=22/27) received DAA post-LT, with 82.6% achieving SVR post-LT (N=18/22). 82.1% (N=23/28) of untreated post-LT patients underwent liver biopsy prior to therapy, and 52.2% had at least F1 METAVIR fibrosis. 87.5% (N=14/16) of active waitlist patients received DAA and achieved SVR. HCV eradication did not result in higher rates of delisting for HCC progression. Due to local HCC listing criteria of total tumor volume and AFP, 60% (N=18/30) of HCV+/HCC patients were beyond Milan criteria at the time of LT. Despite this, there was no difference in HCC recurrence rates post-LT, whether patients achieved SVR pre- or post-LT. Conclusions: These data suggest that HCV eradication pre-LT does not significantly impact waitlist time for HCV+ patients with HCC. HCV eradication does not impact rates of delisting for HCC progression or rates of HCC recurrence post-LT.