Deep learning-based pathway-centric approach to characterize recurrent hepatocellular carcinoma after liver transplantation.

BACKGROUND: Liver transplantation (LT) is offered as a cure for Hepatocellular carcinoma (HCC), however 15-20% develop recurrence post-transplant which tends to be aggressive. In this study, we examined the transcriptome profiles of patients with recurrent HCC to identify differentially expressed genes (DEGs), the involved pathways, biological functions, and potential gene signatures of recurrent HCC post-transplant using deep machine learning (ML) methodology. MATERIALS AND METHODS: We analyzed the transcriptomic profiles of primary and recurrent tumor samples from 7 pairs of patients who underwent LT. Following differential gene expression analysis, we performed pathway enrichment, gene ontology (GO) analyses and protein-protein interactions (PPIs) with top 10 hub gene networks. We also predicted the landscape of infiltrating immune cells using Cibersortx. We next develop pathway and GO term-based deep learning models leveraging primary tissue gene expression data from The Cancer Genome Atlas (TCGA) to identify gene signatures in recurrent HCC. RESULTS: The PI3K/Akt signaling pathway and cytokine-mediated signaling pathway were particularly activated in HCC recurrence. The recurrent tumors exhibited upregulation of an immune-escape related gene, CD274, in the top 10 hub gene analysis. Significantly higher infiltration of monocytes and lower M1 macrophages were found in recurrent HCC tumors. Our deep learning approach identified a 20-gene signature in recurrent HCC. Amongst the 20 genes, through multiple analysis, IL6 was found to be significantly associated with HCC recurrence. CONCLUSION: Our deep learning approach identified PI3K/Akt signaling as potentially regulating cytokine-mediated functions and the expression of immune escape genes, leading to alterations in the pattern of immune cell infiltration. In conclusion, IL6 was identified to play an important role in HCC recurrence.

Pursuing living donor liver transplantation improves outcomes of patients with autoimmune liver diseases: An intention-to-treat analysis.

Living donor liver transplantation (LDLT) offers the opportunity to decrease waitlist time and mortality for patients with autoimmune liver disease (AILD), autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. We compared the survival of patients with a potential living donor (pLDLT) on the waitlist versus no potential living donor (pDDLT) on an intention-to-treat basis. Our retrospective cohort study investigated adults with AILD listed for a liver transplant in our program between 2000 and 2021. The pLDLT group comprised recipients with a potential living donor. Otherwise, they were included in the pDDLT group. Intention-to-treat survival was assessed from the time of listing. Of the 533 patients included, 244 (43.8%) had a potential living donor. Waitlist dropout was higher for the pDDLT groups among all AILDs (pDDLT 85 [29.4%] vs. pLDLT 9 [3.7%], p < 0.001). The 1-, 3, and 5-year intention-to-treat survival rates were higher for pLDLT versus pDDLT among all AILDs (95.7% vs. 78.1%, 89.0% vs. 70.1%, and 87.1% vs. 65.5%, p < 0.001). After adjusting for covariates, pLDLT was associated with a 38% reduction in the risk of death among the AILD cohort (HR: 0.62, 95% CI: 0.42-0.93 [ p <0.05]), and 60% among the primary sclerosing cholangitis cohort (HR: 0.40, 95% CI: 0.22-0.74 [ p <0.05]). There were no differences in the 1-, 3, and 5-year post-transplant survival between LDLT and DDLT (AILD: 95.6% vs. 92.1%, 89.9% vs. 89.4%, and 89.1% vs. 87.1%, p =0.41). This was consistent after adjusting for covariates (HR: 0.97, 95% CI: 0.56-1.68 [ p >0.9]). Our study suggests that having a potential living donor could decrease the risk of death in patients with primary sclerosing cholangitis on the waitlist. Importantly, the post-transplant outcomes in this population are similar between the LDLT and DDLT groups.

Trajectories of patients relisted for liver transplantation.

INTRODUCTION AND OBJECTIVES: Recurrent cirrhosis complicates 10-30% of Liver transplants (LT) and can lead to consideration for re-transplantation. We evaluated the trajectories of relisted versus primary listed patients on the waitlist using a competing risk framework. MATERIALS AND METHODS: We retrospectively examined 1,912 patients listed for LT at our centre between from 2012 to 2020. Cox proportional hazard models were used to assess overall survival (OS) by listing type and competing risk analysis Fine-Gray models were used to assess cumulative incidence of transplant by listing type. RESULTS: 1,731 patients were included (104 relisted). 44.2% of relisted patients received exception points vs. 19.8% of primary listed patients (p<0.001). Patients relisted without exceptions, representing those with graft cirrhosis, had the worst OS (HR: 4.17, 95%CI 2.63 - 6.67, p=<0.0001) and lowest instantaneous rate of transplant (HR: 0.56, 95%CI 0.38 - 0.83, p=0.006) than primary listed with exception points. On multivariate analysis listing type, height, bilirubin and INR were associated with cumulative incidence of transplant, while listing type, bilirubin, INR, sodium, creatinine were associated with OS. Within relisted patients, there was a trend towards higher mortality (HR: 1.79, 95%CI 0.91 - 3.52, p=0.08) and low transplant incidence (HR: 0.51, 95%CI 0.22 - 1.15, p=0.07) for graft cirrhosis vs other relisting indications. CONCLUSIONS: Patients relisted for LT are carefully curated and comprise a minority of the waitlist population. Despite their younger age, they have worse liver/kidney function, poor waitlist survival, and decreased transplant incidence suggesting the need for early relisting, while considering standardized exception points.

Impact of early surgical complications on kidney transplant outcomes.

BACKGROUND: Kidney transplantation (KT) improves clinical outcomes of patients with end stage renal disease. Little has been reported on the impact of early post-operative surgical complications (SC) on long-term clinical outcomes following KT. We sought to determine the impact of vascular complications, urological complications, surgical site complications, and peri-graft collections within 30 days of transplantation on patient survival, graft function, and hospital readmissions. METHODS: We conducted a single-centre, observational cohort study examining adult patients (≥ 18 years) who received a kidney transplant from living and deceased donors between January 1st, 2005 and December 31st, 2015 with follow-up until December 31st, 2016 (n = 1,334). Univariable and multivariable analyses were performed with Cox proportional hazards models to analyze the outcomes of SC in the early post-operative period after KT. RESULTS: The cumulative probability of SC within 30 days of transplant was 25%, the most common SC being peri-graft collections (66.8%). Multivariable analyses showed significant relationships between Clavien Grade 1 SC and death with graft function (HR 1.78 [95% CI: 1.11, 2.86]), and between Clavien Grades 3 to 4 and hospital readmissions (HR 1.95 [95% CI: 1.37, 2.77]). CONCLUSIONS: Early SC following KT are common and have a significant influence on long-term patient outcomes.

Medical Assistance in Dying (MAiD) as a Source of Liver Grafts: Honouring the Ultimate Gift.

OBJECTIVE: To report the clinical outcomes of liver transplants from donors after medical assistance in dying (MAiD) versus donors after cardiac death (DCD) and deceased brain death (DBD). SUMMARY BACKGROUND DATA: In North America, the number of patients needing liver transplants exceeds the number of available donors. In 2016, MAiD was legalized in Canada. METHODS: All patients undergoing deceased donor liver transplantation at Toronto General Hospital between 2016 and 2021 were included in the study. Recipient perioperative and postoperative variables and donor physiological variables were compared among 3 groups. RESULTS: Eight hundred seven patients underwent deceased donor liver transplantation during the study period, including DBD (n=719; 89%), DCD (n=77; 9.5%), and MAiD (n=11; 1.4%). The overall incidence of biliary complications was 6.9% (n=56), the most common being strictures (n=55;6.8%), highest among the MAiD recipients [5.8% (DBD) vs. 14.2% (DCD) vs. 18.2% (MAiD); P =0.008]. There was no significant difference in 1 year (98.4% vs. 96.4% vs. 100%) and 3-year (89.3% vs. 88.7% vs. 100%) ( P =0.56) patient survival among the 3 groups. The 1- and 3- year graft survival rates were comparable (96.2% vs. 95.2% vs. 100% and 92.5% vs. 91% vs. 100%; P =0.37). CONCLUSION: With expected physiological hemodynamic challenges among MAiD and DCD compared with DBD donors, a higher rate of biliary complications was observed in MAiD donors, with no significant difference noted in short-and long-term graft outcomes among the 3 groups. While ethical challenges persist, good initial results suggest that MAiD donors can be safely used in liver transplantation, with results comparable with other established forms of donation.

The epidemiology of early deep vein thrombosis in kidney transplant recipients.

BACKGROUND: Because kidney transplant recipients may be at increased risk for deep vein thrombosis (DVT) following transplantation, we investigated the incidence, risk factors, treatments and outcomes of early DVT among kidney transplant recipients. METHODS: An observational, single-centre cohort study was conducted among adult kidney transplant recipients from Jan. 1, 2005, to Dec. 31, 2016 with 1-year followup. Time to DVT was assessed using the Kaplan-Meier method. Cox proportional hazards and linear regression models were used to analyze risk factors for and outcomes of DVT. RESULTS: The cumulative incidence of DVT was 4.25% at 3 months after transplant. In multivariable analysis, the use of depleting induction agents (hazard ratio [HR] 2.13, 95% confidence interval [CI] 1.05-4.35]), white recipient race (HR 1.84. 95% CI 1.08-3.12), the use of kidneys from expanded criteria donors (HR 2.13, 95% CI 1.05-4.32) and lower recipient body mass index (HR 0.95, 95% CI 0.91-1.00) increased the risk for early DVT. Peritransplant DVT prophylaxis was not associated with early DVT. Early DVT was not associated with reduced graft function, death, graft failure or first hospital readmission. CONCLUSION: Risk factors for early DVT in our cohort of kidney transplant recipients included white recipient race, use of depleting agents, lower recipient body mass index and use of expanded criteria donors. As practice patterns of donor and recipient selection in kidney transplantation evolve, the results of this study may aid in perioperative risk assessments and decision-making about the use of DVT prophylaxis.

Should advanced donor age be a deterrent in the utilization of grafts from donation after cardiac death in deceased donor liver transplantation? The Toronto experience.

BACKGROUND: Advanced donor age paired with donation after cardiac death (DCD) increases the risk of transplantation, precluding widespread use of grafts from such donors worldwide. Our aim was to analyze outcomes of liver transplantation using grafts from older DCD donors and donation after brain death (DBD) donors. METHODS: Patients who underwent liver transplantation using grafts from deceased donors between January 2016 and December 2021 were included in the study. Short-and long-term outcomes were analyzed for 4 groups of patients: those who received DCD and DBD grafts from younger (< 50 yr) and older (≥ 50 yr) donors. RESULTS: Of the 807 patients included in the analysis, 44.7% (n = 361) of grafts were received from older donors, with grafts for older DCD donors comprising 4.7% of the total cohort (n = 38). Patients who received grafts from older donors had a lower incidence of biliary strictures than those who received grafts from younger donors (7.9% v. 20.0% for DCD donation, p = 0.14, and 4.9% v. 6.8% for DBD donation, p = 0.34), with a significantly lower incidence of ischemic-type biliary strictures in patients who received grafts from older versus younger DCD donors (2.6% v. 18.0%, p = 0.04). There was no difference in 1- and 3-year graft survival rates among patients who received grafts from older and younger DCD donors (92.1% v. 90.8% and 80.2% v. 80.9%, respectively) and those who received grafts from older and younger DBD donors (90.1% v. 93.2% and 85.3% v. 84.4%, respectively) (p = 0.85). Pretransplantation admission to the intensive care unit (hazard ratio [HR] 9.041, p < 0.001) and nonalcoholic steatohepatitis (HR 2.197, p = 0.02) were found to significantly affect survival of grafts from older donors. CONCLUSION: Donor age alone should not be the criterion to determine the acceptability of grafts in liver transplantation. With careful selection criteria, older DCD donors could make a valuable contribution to expanding the liver donor pool, with grafts that produce comparable results to those obtained with standard-criteria grafts.

Low utilization of adult-to-adult LDLT in Western countries despite excellent outcomes: International multicenter analysis of the US, the UK, and Canada.

BACKGROUND & AIMS: Adult-to-adult living donor liver transplantation (LDLT) offers an opportunity to decrease the liver transplant waitlist and reduce waitlist mortality. We sought to compare donor and recipient characteristics and post-transplant outcomes after LDLT in the US, the UK, and Canada. METHODS: This is a retrospective multicenter cohort-study of adults (≥18-years) who underwent primary LDLT between Jan-2008 and Dec-2018 from three national liver transplantation registries: United Network for Organ Sharing (US), National Health Service Blood and Transplantation (UK), and the Canadian Organ Replacement Registry (Canada). Patients undergoing retransplantation or multi-organ transplantation were excluded. Post-transplant survival was evaluated using the Kaplan-Meier method, and multivariable adjustments were performed using Cox proportional-hazards models with mixed-effect modeling. RESULTS: A total of 2,954 living donor liver transplants were performed (US: n = 2,328; Canada: n = 529; UK: n = 97). Canada has maintained the highest proportion of LDLT utilization over time (proportion of LDLT in 2008 - US: 3.3%; Canada: 19.5%; UK: 1.7%; p <0.001 - in 2018 - US: 5.0%; Canada: 13.6%; UK: 0.4%; p <0.001). The 1-, 5-, and 10-year patient survival was 92.6%, 82.8%, and 70.0% in the US vs. 96.1%, 89.9%, and 82.2% in Canada vs. 91.4%, 85.4%, and 66.7% in the UK. After adjustment for characteristics of donors, recipients, transplant year, and treating transplant center as a random effect, all countries had a non-statistically significantly different mortality hazard post-LDLT (Ref US: Canada hazard ratio 0.53, 95% CI 0.28-1.01, p = 0.05; UK hazard ratio 1.09, 95% CI 0.59-2.02, p = 0.78). CONCLUSIONS: The use of LDLT has remained low in the US, the UK and Canada. Despite this, long-term survival is excellent. Continued efforts to increase LDLT utilization in these countries may be warranted due to the growing waitlist and differences in allocation that may disadvantage patients currently awaiting liver transplantation. LAY SUMMARY: This multicenter international comparative analysis of living donor liver transplantation in the United States, the United Kingdom, and Canada demonstrates that despite low use of the procedure, the long-term outcomes are excellent. In addition, the mortality risk is not statistically significantly different between the evaluated countries. However, the incidence and risk of retransplantation differs between the countries, being the highest in the United Kingdom and lowest in the United States.

Results of Early Transplantation for Alcohol-Related Cirrhosis: Integrated Addiction Treatment With Low Rate of Relapse.

BACKGROUND & AIMS: In 2018, our team initiated a prospective pilot program to challenge the paradigm of the "6-month rule" of abstinence for patients with alcohol-related liver disease (ALD) requiring transplant. Our pilot involved an in-depth examination of patients' alcohol use, social support, and psychiatric comorbidity, as well as the provision of pre- and post-transplantation addiction treatment. METHODS: Patients with ALD were assessed for inclusion in the pilot by a multidisciplinary team. Relapse prevention therapy was provided directly to all patients deemed to meet the program's inclusion criteria. Random biomarker testing for alcohol was used pre and post transplantation. RESULTS: We received 703 referrals from May 1, 2018 to October 31, 2020. After fulfilling the program's criteria, 101 patients (14%) were listed for transplantation and 44 (6.2%) received transplants. There were no significant differences in survival rates between those receiving transplants through the pilot program compared with a control group with more than 6 months of abstinence (P = .07). Three patients returned to alcohol use during an average post-transplantation follow-up period of 339 days. In a multivariate analysis, younger age and lower Model for End-Stage Liver Disease scores at listing were associated with an increased likelihood of a return to alcohol use (P < .05); length of abstinence was not a predictor. CONCLUSIONS: Our prospective program provided direct monitoring and relapse prevention treatment for patients with ALD and with less than 6 months of abstinence and resulted in a reduction of post-transplantation return to drinking. This pilot study provides a framework for the future of more equitable transplant care.

Superior Long-Term Outcomes of Adult Living Donor Liver Transplantation: A Cumulative Single-Center Cohort Study With 20 Years of Follow-Up.

Living donor liver transplantation (LDLT) is an attractive alternative to deceased donor liver transplantation (DDLT). Although both modalities have similar short-term outcomes, long-term outcomes are not well studied. We compared the 20-year outcomes of 668 adults who received LDLT with1596 DDLTs at the largest liver transplantation (LT) program in Canada. Recipients of LDLT were significantly younger and more often male than DDLT recipients (P < 0.001). Autoimmune diseases were more frequent in LDLT, whereas viral hepatitis and alcohol-related liver disease were more frequent in DDLT. LDLT recipients had lower Model for End-Stage Liver Disease scores (P = 0.008), spent less time on the waiting list (P < 0.001), and were less often inpatients at the time of LT (P < 0.001). In a nonadjusted analysis, 1-year, 10-year, and 20-year patient survival rates were significantly higher in LDLT (93%, 74%, and 56%, respectively) versus DDLT (91%, 67%, and 46%, respectively; log-rank P = 0.02) as were graft survival rates LDLT (91%, 67%, and 50%, respectively) versus (90%, 65%, and 44.3%, respectively, for DDLT; log-rank P = 0.31). After multivariable adjustment, LDLT and DDLT were associated with a similar hazard of patient and graft survival. Our data of 20 years of follow-up of LDLT from a single, large Western center demonstrates excellent long-term outcomes for recipients of LDLT.

The effect of perioperative packed red blood cells transfusion on patient outcomes after liver transplant for hepatocellular carcinoma.

BACKGROUND: The impact of packed Red Blood Cell (pRBC) transfusion on oncological outcomes after liver transplantation (LT) for Hepatocellular Carcinoma (HCC) remains controversial. We evaluated the impact of pRBC transfusion on HCC recurrence and overall survival (OS) after LT for HCC. METHODS: Patients with HCC transplanted between 2000 and 2018 were included and stratified by receipt of pRBC transfusion. Outcomes were HCC recurrence and OS. Propensity score matching was performed to account for confounders. RESULTS: Of the 795 patients, 234 (29.4%) did not receive pRBC transfusion. After matching the 1-, 3-, and 5-year cumulative incidence of recurrence was 6.6%, 12.5% and 14.8% for no-pRBC transfusion, and 8.6%, 18.8% and 21.3% (p = 0.61) for pRBC transfusion. The OS at 1-, 3-, 5-year was 93.0%, 84.6% and 75.8% vs 92.0%, 79.7% and 73.5% (p = 0.83) for no-pRBC transfusion and pRBC transfusion, respectively. There were no differences in recurrence (HR 1.13, 95%CI 0.71-1.78, p = 0.61) or OS (HR 1.04, 95%CI 0.71-1.54, p = 0.83). CONCLUSION: Perioperative administration of pRBC in liver transplant recipients for HCC resulted in a nonsignificant increase of HCC recurrence and death after accounting for confounder. Surgeons should continue to exercise cation and optimize patients iron stores medically preoperatively.

Living donor liver paired exchange: A North American first.

Paired organ exchange can be used to circumvent living donor-recipient ABO incompatibilities. Herein, we present the first case of successful liver paired exchange in North America. This 2-way swap required 4 simultaneous operations: 2 living donor hepatectomies and 2 living donor liver transplants. A nondirected anonymous living donor gift initiated this domino exchange, alleviating an ABO incompatibility in the other donor-recipient pair. With careful attention to ethical and logistical issues, paired liver exchange is a feasible option to expand the donor pool for incompatible living liver donor-recipient pairs.

Standardized Feeding Protocol Improves Delivery and Acceptance of Enteral Nutrition in Children Immediately After Liver Transplantation.

Delivery of adequate nutrition after liver transplantation (LT) surgery is an important goal of postoperative care. Existing guidelines recommend early enteral nutrition after abdominal surgery and in the child who is critically ill but data on nutritional interventions after LT in children are sparse. We evaluated the impact of a standardized postoperative feeding protocol on enteral nutrition delivery in children after LT. Data from 49 children (ages 0-18 years) who received a LT prior to feeding protocol implementation were compared with data for 32 children undergoing LT after protocol implementation. The 2 groups did not differ with respect to baseline demographic data. After protocol implementation, enteral nutrition was started earlier (2 versus 3 days after transplant; P = 0.005) and advanced faster when a feeding tube was used (4 versus 8 days; P = 0.03). Protocol implementation was also associated with reduced parenteral nutrition use rates (47% versus 75%; P = 0.01). No adverse events occurred after protocol implementation. Hospital length of stay and readmission rates were not different between the 2 groups. In conclusion, implementation of a postoperative nutrition protocol in children after LT led to optimized nutrient delivery and reduced variability of care.

Combined proteomic/transcriptomic signature of recurrence post-liver transplantation for hepatocellular carcinoma beyond Milan.

BACKGROUND AND AIMS: Liver transplantation (LT) can be offered to patients with Hepatocellular carcinoma (HCC) beyond Milan criteria. However, there are currently limited molecular markers on HCC explant histology to predict recurrence, which arises in up to 20% of LT recipients. The goal of our study was to derive a combined proteomic/transcriptomic signature on HCC explant predictive of recurrence post-transplant using unbiased, high-throughput approaches. METHODS: Patients who received a LT for HCC beyond Milan criteria in the context of hepatitis B cirrhosis were identified. Tumor explants from patients with post-transplant HCC recurrence (N = 7) versus those without recurrence (N = 4) were analyzed by mass spectrometry and gene expression array. Univariate analysis was used to generate a combined proteomic/transcriptomic signature linked to recurrence. Significantly predictive genes and proteins were verified and internally validated by immunoblotting and immunohistochemistry. RESULTS: Seventy-nine proteins and 636 genes were significantly differentially expressed in HCC tumors with subsequent recurrence (p < 0.05). Univariate survival analysis identified Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1) gene (HR = 0.084, 95%CI 0.01-0.68, p = 0.0152), ALDH1A1 protein (HR = 0.039, 95%CI 0.16-0.91, p = 0.03), Galectin 3 Binding Protein (LGALS3BP) gene (HR = 7.14, 95%CI 1.20-432.96, p = 0.03), LGALS3BP protein (HR = 2.6, 95%CI 1.1-6.1, p = 0.036), Galectin 3 (LGALS3) gene (HR = 2.89, 95%CI 1.01-8.3, p = 0.049) and LGALS3 protein (HR = 2.6, 95%CI 1.2-5.5, p = 0.015) as key dysregulated analytes in recurrent HCC. In concordance with our proteome findings, HCC recurrence was linked to decreased ALDH1A1 and increased LGALS3 protein expression by Western Blot. LGALS3BP protein expression was validated in 29 independent HCC samples. CONCLUSIONS: Significantly increased LGALS3 and LGALS3BP gene and protein expression on explant were associated with post-transplant recurrence, whereas increased ALDH1A1 was associated with absence of recurrence in patients transplanted for HCC beyond Milan criteria. This combined proteomic/transcriptomic signature could help in predicting HCC recurrence risk and guide post-transplant surveillance.

Lymphoceles: impact on kidney transplant recipients, graft, and healthcare system.

INTRODUCTION: Following kidney transplantation, lymphoceles can impact patient and graft outcomes, while resulting in significant hospital resource utilization. We aimed to characterize the incidence, risk factors, outcomes, and clinical management of lymphoceles among kidney transplant recipients and review impact on health system utilization at a high-volume center. MATERIALS AND METHODS: We conducted a single-center, observational cohort study on adults transplanted between January 1, 2005 and December 31, 2017. Incidence, risk factors, and clinical outcomes were assessed using the Kaplan-Meier product-limit method, multivariable logistic regression model, and Cox proportional hazards model, respectively. RESULTS: Lymphoceles developed in 72 of 1881 patients (3.8%). Multivariate analysis demonstrated that a longer time on dialysis before transplant [HR 1.09 (95% CI: 1.02, 1.17)], laparoscopic donor nephrectomy [HR 2.31 (95% CI: 1.04, 5.12)], and depleting induction therapy [HR 0.39 (95% CI: 0.18, 0.87)] were significant risk factors for lymphocele development. Lymphoceles independently increased the likelihood of hospital readmission [HR 3.96 (95% CI: 2.99, 5.25)] but had no significant effect on the likelihood of graft failure or death with graft function. Of 72 cases, 44 received a radiological or surgical intervention. Fifteen of 44 lymphoceles required further intervention due to re-accumulation or complications. CONCLUSION: Patients with longer dialysis times, kidneys from laparoscopic donor nephrectomy, and depleting induction therapy were associated with an increased risk for developing symptomatic lymphoceles. Our center's treatment for symptomatic lymphoceles did not result in significant graft dysfunction, but significantly higher healthcare resource utilization was noted.

Surgical site complications in kidney transplant recipients: incidence, risk factors and outcomes in the modern era.

BACKGROUND: Surgical site complications (SSCs) are an important source of morbidity after kidney transplantation. We assessed the incidence, risk factors, outcomes and economic impact of SSCs in a large, diverse population of kidney transplant recipients. METHODS: We conducted a single-centre, observational cohort study of adult (age ≥ 18 yr) patients who underwent kidney transplantation between Jan. 1, 2005, and Dec. 31, 2015, with a minimum of 1 year of follow-up. Cases of SSC, including infections and wound dehiscence, were determined from patient records. Inpatient and outpatient hospital costs were determined 6 and 12 months after transplantation. We used the Kaplan-Meier product-limit method to determine the cumulative probability of SSCs and other outcomes. We evaluated risk factors and clinical outcomes using Cox proportional hazard ratios. Linear regression models were used to study the effect of SSCs on graft function. RESULTS: The incidence rate of SSCs within 30 days after transplantation was 4.19 per 100 person-months. The cumulative probability of developing an SSC within 30 days after transplantation was 4.13% (95% confidence interval [CI] 3.23%-5.28%). Increased recipient body mass index (BMI) (hazard ratio [HR] 1.07, 95% CI 1.02-1.11), longer cold ischemic time (HR 1.05, 95% CI 1.01-1.09) and transplantation in 2010-2012 versus 2005-2009 (HR 2.20, 95% CI 1.19-4.04) were risk factors for SSC development. In multivariable stepwise Cox proportional hazard models, SSC was a significant risk factor for death-censored graft failure (HR 3.08, 95% CI 1.60-5.90) and total graft failure (HR 2.09, 95% CI 1.32-3.32). Cumulative median hospital costs were $2238.46 greater for patients with an SSC than for those without. CONCLUSION: Increased BMI, longer cold ischemic time and the 2010-2012 transplantation period predisposed to SSCs. The development of SSCs was associated with a higher risk of graft failure. Strategies to minimize SSCs may improve outcomes after kidney transplantation and reduce costs.

Novel biomarker for hepatocellular carcinoma: high tumoral PLK-4 expression is associated with better prognosis in patients without microvascular invasion.

BACKGROUND: Hepatocellular carcinoma (HCC) recurrence after liver resection (LR) adversely affects prognosis but is difficult to predict. Aberrant expression of Polo-Like Kinase 4 (PLK-4) is implicated in several adult malignancies. We sought to evaluate the prognostic value of PLK-4 expression in HCC after curative-intent LR. METHODS: Patients undergoing LR for HCC between July-2015 and November-2017 at our centre were retrospectively identified. PLK-4 expression was measured in tumour and adjacent non-tumour liver tissue using quantitative RT-PCR. Disease-free survival (DFS) was evaluated by Kaplan-Meier and Cox proportional hazard models. RESULTS: A total of 145 patients were identified. Patients were divided according to PLK-4 expression (high: n = 58, low: n = 87) by generating a receiver operating characteristic curve for recurrence with an area under the curve of 0.72 (95% CI: 0.6-0.8). Recurrence and death rates were similar between groups. In patients without mVI, low PLK-4 expression was associated with worse actuarial DFS (low 1-, 3-, 5-year 83%, 60%, 47% vs. high 91%, 81%, 81%; p = 0.02). In patients without mVI, high PLK-4 expression was an independent predictor of survival (HR 0.3, 95% CI: 0.1-1.0; p = 0.04). CONCLUSION: PLK-4 represents a biomarker for good prognosis in patients with HCC who do not have mVI. This could aid clinical decision making for adjuvant clinical trials.

Pediatric living donor liver transplantation with large-for-size left lateral segment grafts.

Usage of "large-for-size" left lateral segment (LLS) liver grafts in children with high graft to recipient weight ratio (GRWR) is controversial due to concerns about increased recipient complications. During the study period, 77 pediatric living donor liver transplantations (LDLTs) with LLS grafts were performed. We compared recipients with GRWR ≥2.5% (GR-High = 50) vs GRWR <2.5% (GR-Low = 27). Median age was higher in the GR-Low group (40 vs 8 months, P> .0001). Graft (GR-High: 98%, 98%, 98% vs GR-Low: 96%, 93%, 93%) and patient (GR-High: 98%, 98%, 98% vs GR-Low: 100%, 96%, 96%) survival at 1, 3, and 5 years was similar between groups (P = NS). Overall complications were also similar (34% vs 30%; P = .8). Hepatic artery and portal vein thrombosis following transplantation was not different (P = NS). Delayed abdominal fascia closure was more common in GR-High patients (17 vs 1; P = .002). Subgroup analysis comparing recipients with GRWR ≥4% (GR-XL = 20) to GRWR <2.5% (GRWR-Low = 27) revealed that delayed abdominal fascia closure was more common in the GR-XL group, but postoperative complications and graft and patient survival were similar. We conclude that pediatric LDLT with large-for-size LLS grafts is associated with excellent clinical outcomes. There is an increased need for delayed abdominal closure with no compromise of long-term outcomes. The use of high GRWR expands the donor pool and improves timely access to the benefits of transplantation without extra risks.

Renal Dysfunction After Liver Transplantation: Effect of Donor Type.

Recipients of donation after circulatory death (DCD) grafts are reportedly at higher risk of developing renal dysfunction after liver transplantation (LT). We compared the development of acute kidney injury (AKI) and chronic kidney disease (CKD) after LT in recipients of DCD versus donation after brain death (DBD) or living donor liver transplantation (LDLT) livers. Adult recipients of DBD, LDLT, and DCD between 2012 and 2016 at Toronto General Hospital were included. AKI was defined as a post-LT increase of serum creatinine (sCr) ≥26.5 µmol/L within 48 hours or a ≥50% increase from baseline, and CKD was defined as an estimated glomerular filtration rate <60 mL/minute for >3 months. A total of 681 patients (DCD, n = 57; DBD, n = 446; and LDLT, n = 178) with similar baseline comorbidities were included. Perioperative AKI (within the first 7 postoperative days) was observed more frequently in the DCD group (61%; DBD, 40%; and LDLT, 44%; P = 0.01) and was associated with significantly higher peak AST levels (P < 0.001). Additionally, patients in the DCD group had a significantly higher peak sCr (P < 0.001) and a trend toward higher rates of AKI stage 3 (DCD, 33%; DBD, 21%; LDLT, 21%; P = 0.11). The proportions of recovery from AKI (DCD, 77%; DBD, 72%; LDLT, 78%; P = 0.45) and patients developing CKD (DCD, 33%; DBD, 32%; LDLT, 32%; P = 0.99) were similar. Nevertheless, patients who received DCD or DBD LT and required perioperative renal replacement therapy showed significantly lower patient survival in multivariate analysis (hazard ratio, 7.90; 95% confidence interval, 4.51-13.83; P < 0.001). In conclusion, recipients of DCD liver grafts experience higher rates of short-term post-LT renal dysfunction compared with DBD or LDLT. Additional risk factors for the development of severe kidney injury, such as high Model for End-Stage Liver Disease score, massive transfusions, or donor age ≥60 years should be avoided.

Donor outcomes in anonymous live liver donation.

BACKGROUND & AIMS: Death rates on liver transplant waiting lists range from 5%-25%. Herein, we report a unique experience with 50 anonymous individuals who volunteered to address this gap by offering to donate part of their liver to a recipient with whom they had no biological connection or prior relationship, so called anonymous live liver donation (A-LLD). METHODS: Candidates were screened to confirm excellent physical, mental, social, and financial health. Demographics and surgical outcomes were analyzed. Qualitative interviews after donation examined motivation and experiences. Validated self-reported questionnaires assessed personality traits and psychological impact. RESULTS: A total of 50 A-LLD liver transplants were performed between 2005 and 2017. Most donors had a university education, a middle-class income, and a history of prior altruism. Half were women. Median age was 38.5 years (range 20-59). Thirty-three (70%) learned about this opportunity through public or social media. Saving a life, helping others, generativity, and reciprocity for past generosity were motivators. Social, financial, healthcare, and legal support in Canada were identified as facilitators. A-LLD identified most with the personality traits of agreeableness and conscientiousness. The median hospital stay was 6 days. One donor experienced a Dindo-Clavien Grade 3 complication that completely resolved. One-year recipient survival was 91% in 22 adults and 97% in 28 children. No A-LLD reported regretting their decision. CONCLUSIONS: This is the first and only report of the characteristics, motivations and facilitators of A-LLD in a large cohort. With rigorous protocols, outcomes are excellent. A-LLD has significant potential to reduce the gap between transplant organ demand and availability. LAY SUMMARY: We report a unique experience with 50 living donors who volunteered to donate to a recipient with whom they had no biological connection or prior relationship (anonymous living donors). This report is the first to discuss motivations, strategies and facilitators that may mitigate physical, social and ethical risk factors in this patient population. With rigorous protocols, anonymous liver donation and recipient outcomes are excellent; with appropriate clinical expertise and system facilitators in place, our experience suggests that other centers may consider the procedure for its significant potential to reduce the gap between transplant organ demand and availability.