Online resources as a source of information for exercise and physical activity in solid organ transplant recipients.

Introduction: Exercise training post-transplant has been shown to improve physical function and quality of life in solid organ transplant (SOT) recipients. Online resources in the form of websites and videos are commonly used to provide education and instruction on exercise and physical activity in SOT; however, the content and quality of these online resources has not been evaluated. Methods: The first 200 websites and videos identified on Google and YouTube using the English search term "exercise and physical activity in solid organ transplantation" were analyzed. Website and video content was evaluated based on 25 key components of exercise and physical activity in SOT as described in established exercise program recommendations. Website and video quality was determined using DISCERN, Global Quality Scale (GQS), and Patient Education Materials and Assessment Tool (PEMAT; threshold for which material is deemed understandable or actionable is >70%). Parametric and non-parametric tests were used to assess website and video characteristics, content, and quality metrics. Results: Forty-nine unique SOT websites (n = 15) and videos (n = 34) were identified, with the two most common categories being foundation/advocacy organizations and scientific resources. The average reading grade level of websites was 13 ± 3. Website and video content scores varied significantly (websites 11.3 ± 6.4; videos 8.4 ± 5.3). DISCERN total score and GQS score were low (median range for DISCERN 2.5-3.0; median for GQS 2.0 for both websites and videos, out of 5). PEMAT understandability and actionability scores were also low across websites and videos (mean range 57%-67% and 47%-65%, respectively). Foundation/advocacy websites had higher content and quality scores compared to scientific organizations and news/media articles. Conclusions: To our knowledge, this is the first comprehensive assessment of online content and quality of website and video resources on physical activity and exercise in adult SOT recipients. There were a limited number of online English patient-directed resources related to physical activity in SOT, most of which only partly captured items outlined in consensus exercise program recommendations and were of low quality and understandability and actionability. This work provides important insight to the English-speaking transplant community on the current state of online exercise health information and provides future direction for resource development.

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

Background Living donor liver transplantation (LDLT) offers the opportunity to decrease waitlist time and mortality for patients with AILD; autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). We compared the survival of patients with a potential live donor (pLDLT) on the waitlist vs. no potential live donor (pDDLT), on an intention-to-treat (ITT) basis. Methods Our retrospective cohort study investigated adults with AILD listed for liver transplant at our program between 2000 and 2021. The pLDLT group comprised recipients with a potential live donor. Otherwise, they were included in the pDDLT group. ITT survival was assessed from the time of listing. Results 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 ITT survival rates were higher for pLDLT vs. 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 PSC 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]). Conclusion Our study suggests that having a potential live donor could decrease the risk of death in patients with PSC on the waitlist. Importantly, the post-transplant outcomes in this population are similar between the LDLT and DDLT groups.

What Is Hot and New in Basic and Translational Science in Liver Transplantation in 2023? Report of the Basic and Translational Research Committee of the International Liver Transplantation Society.

The 2023 Joint Annual Congress of the International Liver Transplantation Society, European Liver and Intestine Transplant Association, and Liver Intensive Care Group of Europe were held in Rotterdam, the Netherlands, from May 3 to 6, 2023. This year, all speakers were invited to attend the Congress in person for the first time since the COVID-19 pandemic. The congress was attended by 1159 registered delegates from 54 countries representing 5 continents, with the 10 countries comprising the bulk of the delegates. Of the 647 abstracts initially submitted, 542 were eventually presented at the meeting, coming from 38 countries (mainly North America, Europe, and Asia) and 85% of them (462 abstracts) came from only 10 countries. Fifty-three (9.8%) abstracts, originated from 17 countries, were submitted under the Basic/Translational Scientific Research category, a similar percentage as in 2022. Abstracts presented at the meeting were classified as (1) ischemia and reperfusion injury, (2) machine perfusion, (3) bioengineering and liver regeneration, (4) transplant oncology, (5) novel biomarkers in liver transplantation, (6) liver immunology (rejection and tolerance), and (7) artificial intelligence and machine learning. Finally, we evaluated the number of abstracts commented in the Basic and Translational Research Committee-International Liver Transplantation Society annual reports over the past 5 y that resulted in publications in peer-reviewed journals to measure their scientific impact in the field of liver transplantation.

Perioperative Cardiovascular Risk Assessment and Management in Liver Transplant Recipients: A Review of the Literature Merging Guidelines and Interventions.

Liver transplantation (LT) is the second most performed solid organ transplant. Coronary artery disease (CAD) is a critical consideration for LT candidacy, particularly in patients with known CAD or risk factors, including metabolic dysfunction associated with steatotic liver disease. The presence of severe CAD may exclude patients from LT; therefore, precise preoperative evaluation and interventions are necessary to achieve transplant candidacy. Cardiovascular complications represent the earliest nongraft-related cause of death post-transplantation. Timely intervention to reduce cardiovascular events depends on adequate CAD screening. Coronary disease screening in end-stage liver disease is challenging because standard noninvasive CAD screening tests have low sensitivity due to hyperdynamic state and vasodilatation. As a result, there is overuse of invasive coronary angiography to exclude severe CAD. Coronary artery calcium scoring using a computed tomography scan is a tool for the prediction of cardiovascular events, and can be used to achieve risk stratification in LT candidates. Recent literature shows that qualitative assessment on both noncontrast- and contrast-enhanced chest computed tomography can be used instead of calcium score to assess the presence of coronary calcium. With increasing prevalence, protocols to address CAD in LT candidates must be reconsidered. Percutaneous coronary intervention could allow a shorter duration of dual-antiplatelet therapy in simple lesions, with safer perioperative outcomes. Hybrid coronary revascularization is an option for high-risk LT candidates with multivessel disease nonamenable to percutaneous coronary intervention. The objective of this review is to evaluate existing methods for preoperative cardiovascular risk stratification, and to describe interventions before surgery to optimize patient outcomes and reduce cardiovascular event risk.

Outcomes of re-referrals of patients with alcohol-associated liver disease, who were previously declined for liver transplantation.

Since 2018, our program has utilized specific psychosocial criteria and a multidisciplinary approach to assess patients for liver transplant due to alcohol-associated liver disease (ALD), rather than the 6-month abstinence rule alone. If declined based on these criteria, specific recommendations are provided to patients and their providers regarding goals for re-referral to increase the potential for future transplant candidacy. Recommendations include engagement in treatment for alcohol use disorder, serial negative biomarker testing, and maintenance of abstinence from alcohol. In our current study, we evaluate the outcomes of patients with ALD, who were initially declined upon assessment and re-referred to our program. This is a retrospective cohort study that includes 98 patients with ALD, who were previously declined for liver transplantation and were subsequently re-referred for liver transplant assessment between May 1, 2018, and December 31, 2021. We assess the outcomes of patients who were re-referred including acceptance for transplantation following a second assessment. Of the 98 patients who were re-referred, 46 (46.9%) fulfilled the recommendations made and proceeded to further medical evaluation. Nine were eventually transplanted; others are listed and are waiting for transplant. The presence of a partner was independently associated with a higher rate of acceptance (OR 0.16, 95% CI: 0.03-0.97, p = 0.05). Most of the patients who did not proceed further (n = 52) were declined again due to ALD contraindications (n = 33, 63.4%), including ongoing drinking and lack of engagement in recommended addiction treatment. Others had medical contraindications (11.2%), clinically improved (6.1%), had adherence issues (5.1%), or lack of adequate support (2%). Patients with ALD previously declined for a liver transplant can be re-referred and successfully accepted for transplantation by fulfilling the recommendations made by the multidisciplinary team. Important factors including ongoing abstinence, engagement in addiction treatment, and social support are key for successful acceptance.

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.

Defining an approach for therapeutic strategies in metabolic dysfunction-associated steatotic liver disease after liver transplantation.

Occurrence of metabolic dysfunction-associated steatotic liver disease (MASLD) is common following liver transplantation (LT). MASLD can be classified as a recurrent disease when it occurs in patients receiving LT for metabolic dysfunction-associated steatohepatitis (MASH) or as de novo when it occurs in patients undergoing transplantation for non-metabolic dysfunction-associated steatohepatitis etiologies of liver disease. Fibrosis progression in patients with MASLD is accelerated, with progression to cirrhosis occurring more rapidly compared with the general (ie, non-LT) population. Moreover, the metabolic burden in LT recipients with MASLD is high and synergizes with liver disease to negatively affect the clinical course. Despite the oversized clinical burden of MASLD among LT recipients, there is currently a lack of regulatory approach and pathway for therapeutics development in this patient population. The present document, thus, provides guidance for therapeutics development that incorporates nuances of transplant care in patients with post-LT MASLD to facilitate drug development.

Clinical Deployment of Machine Learning Tools in Transplant Medicine: What Does the Future Hold?

Medical applications of machine learning (ML) have shown promise in analyzing patient data to support clinical decision-making and provide patient-specific outcomes. In transplantation, several applications of ML exist which include pretransplant: patient prioritization, donor-recipient matching, organ allocation, and posttransplant outcomes. Numerous studies have shown the development and utility of ML models, which have the potential to augment transplant medicine. Despite increasing efforts to develop robust ML models for clinical use, very few of these tools are deployed in the healthcare setting. Here, we summarize the current applications of ML in transplant and discuss a potential clinical deployment framework using examples in organ transplantation. We identified that creating an interdisciplinary team, curating a reliable dataset, addressing the barriers to implementation, and understanding current clinical evaluation models could help in deploying ML models into the transplant clinic setting.

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.

A Comprehensive Review of Liver Allograft Fibrosis and Steatosis: From Cause to Diagnosis.

Despite advances in posttransplant care, long-term outcomes for liver transplant recipients remain unchanged. Approximately 25% of recipients will advance to graft cirrhosis and require retransplantation. Graft fibrosis progresses in the context of de novo or recurrent disease. Recurrent hepatitis C virus infection was previously the most important cause of graft failure but is now curable in the majority of patients. However, with an increasing prevalence of obesity and diabetes and nonalcoholic fatty liver disease as the most rapidly increasing indication for liver transplantation, metabolic dysfunction-associated liver injury is anticipated to become an important cause of graft fibrosis alongside alloimmune hepatitis and alcoholic liver disease. To better understand the landscape of the graft fibrosis literature, we summarize the associated epidemiology, cause, potential mechanisms, diagnosis, and complications. We additionally highlight the need for better noninvasive methods to ameliorate the management of graft fibrosis. Some examples include leveraging the microbiome, genetic, and machine learning methods to address these limitations. Overall, graft fibrosis is routinely seen by transplant clinicians, but it requires a better understanding of its underlying biology and contributors that can help inform diagnostic and therapeutic practices.

Development of a Radiomics-Based Model to Predict Graft Fibrosis in Liver Transplant Recipients: A Pilot Study.

Liver Transplantation is complicated by recurrent fibrosis in 40% of recipients. We evaluated the ability of clinical and radiomic features to flag patients at risk of developing future graft fibrosis. CT scans of 254 patients at 3-6 months post-liver transplant were retrospectively analyzed. Volumetric radiomic features were extracted from the portal phase using an Artificial Intelligence-based tool (PyRadiomics). The primary endpoint was clinically significant (≥F2) graft fibrosis. A 10-fold cross-validated LASSO model using clinical and radiomic features was developed. In total, 75 patients (29.5%) developed ≥F2 fibrosis by a median of 19 (4.3-121.8) months. The maximum liver attenuation at the venous phase (a radiomic feature reflecting venous perfusion), primary etiology, donor/recipient age, recurrence of disease, brain-dead donor, tacrolimus use at 3 months, and APRI score at 3 months were predictive of ≥F2 fibrosis. The combination of radiomics and the clinical features increased the AUC to 0.811 from 0.793 for the clinical-only model (p = 0.008) and from 0.664 for the radiomics-only model (p < 0.001) to predict future ≥F2 fibrosis. This pilot study exploring the role of radiomics demonstrates that the addition of radiomic features in a clinical model increased the model's performance. Further studies are required to investigate the generalizability of this experimental tool.

RNA nanomedicine in liver diseases.

The remarkable impact of RNA nanomedicine during the COVID-19 pandemic has demonstrated the expansive therapeutic potential of this field in diverse disease contexts. In recent years, RNA nanomedicine targeting the liver has been paradigm-shifting in the management of metabolic diseases such as hyperoxaluria and amyloidosis. RNA nanomedicine has significant potential in the management of liver diseases, where optimal management would benefit from targeted delivery, doses titrated to liver metabolism, and personalized therapy based on the specific site of interest. In this review, we discuss in-depth the different types of RNA and nanocarriers used for liver targeting along with their specific applications in metabolic dysfunction-associated steatotic liver disease, liver fibrosis, and liver cancers. We further highlight the strategies for cell-specific delivery and future perspectives in this field of research with the emergence of small activating RNA, circular RNA, and RNA base editing approaches.

Availability of living donor optimizes timing of liver transplant in high-risk waitlisted cirrhosis patients.

Liver transplant (LT) candidates have become older and frailer, with growing Non-alcoholic steatohepatitis (NASH) and comorbid disease burden in recent years, predisposing them for poor waitlist outcomes. We aimed to evaluate the impact of access to living donor liver transplantation (LDLT) in waitlisted patients at highest risk of dropout. We reviewed all adult patients with decompensated cirrhosis listed for LT from November 2012 to December 2018. Patients with a potential living donor (pLD) available were identified. Survival analyses with Cox Proportional Hazards models and time to LT with Competing risk models were performed followed by prediction model development. Out of 860 patients who met inclusion criteria, 360 (41.8%) had a pLD identified and 496 (57.6%) underwent LT, out of which 170 (34.2%) were LDLT. The benefit of pLD was evident for all, but patients with moderate to severe frailty at listing (interaction p = 0.03), height <160 cm (interaction p = 0.03), and Model for end stage liver disease (MELD)-Na score <20 (interaction p < 0.0001) especially benefited. Our prediction model identified patients at highest risk of dropout while waiting for deceased donor and most benefiting of pLD (time-dependent area under the receiver operating characteristic curve 0.82). Access to LDLT in a transplant program can optimize the timing of transplant for the increasingly older, frail patient population with comorbidities who are at highest risk of dropout.

Living donor liver transplantation can address disparities in transplant access for patients with primary sclerosing cholangitis.

BACKGROUND: Liver transplantation (LT) is frequently lifesaving for people living with primary sclerosing cholangitis (PSC). However, patients are waitlisted for LT according to the model for end-stage liver disease-sodium (MELD-Na) score, which may not accurately reflect the burden of living with PSC. We sought to describe and analyze the clinical trajectory for patients with PSC referred for LT, in a mixed deceased donor/living donor transplant program. METHODS: This was a retrospective cohort study from November 2012 to December 2019, including all patients with PSC referred for assessment at the University Health Network Liver Transplant Clinic. Patients who required multiorgan transplant or retransplantation were excluded. Liver symptoms, hepatobiliary malignancy, MELD-Na progression, and death were abstracted from chart review. Competing risk analysis was used for timing of LT, transplant type, and death. RESULTS: Of 172 PSC patients assessed, 84% (n = 144) were listed of whom 74% were transplanted. Mean age was 47.6 years, and 66% were male. Overall mortality was 18.2% at 2 years. During the follow-up, 16% (n = 23) were removed from the waitlist for infection, clinical deterioration, liver-related mortality or new cancer; 3 had clinical improvement. At listing, 82% (n = 118) had a potential living donor (pLD). Patients with pLD had significantly lower waitlist and liver-related waitlist mortality (HR 0.20, p<0.001 and HR 0.17, p<0.001, respectively), and higher rates of transplantation (HR 1.83, p = 0.05). Exception points were granted to 13/172 (7.5%) patients. CONCLUSIONS: In a high-volume North American LT center, most patients with PSC assessed for transplant were listed and subsequently transplanted. However, this was a consequence of patients engaging in living donor transplantation. Our findings support the concern from patients with PSC that MELD-Na allocation does not adequately address their needs.

Exception points for liver transplantation: A Canadian review.

Background: Exception points for liver transplant (LT) allocation are used to account for mortality risk not reflected by scoring systems such as the Model for End-Stage Liver Disease with sodium (MELD-Na). Currently, there is no formal policy regarding exception points in Canada, and differences across the country are not well understood. As such, a review of the criteria and exception points granted throughout the country for LT was conducted. Methods: Seven LT centres in five provinces were surveyed (Vancouver, Edmonton, London, Toronto, Montréal, Halifax) regarding the indications and criteria for exception points granted, the number of points granted, how points would be accrued, and the maximum points granted. Results: Programs in British Columbia and Nova Scotia grant variable exception points based on the median MELD-Na score with modifications; Alberta, Ontario, and Quebec grant exception points using specific values based on the indication. Overall, there was significant heterogeneity regarding exception points granted nationally with agreement only for awarding exception points for hepatopulmonary syndrome and polycystic liver disease. The second most common agreed-upon indications for exception points were portopulmonary hypertension and recurrent cholangitis offered by four provinces. Quebec had the most formal criteria for non-cirrhosis-based conditions. Conclusions: There is substantial variance across the country regarding the indications for granting exception points as well as the number of points granted. Future work on developing a national consensus will be important for the development of equity in LT across Canada.

Automated fatty liver disease detection in point-of-care ultrasound B-mode images.

Purpose: Non-alcoholic fatty liver disease (NAFLD) is an increasing global health concern, with a prevalence of 25% worldwide. The rising incidence of NAFLD, an asymptomatic condition, reinforces the need for systematic screening strategies in primary care. We present the use of non-expert acquired point-of-care ultrasound (POCUS) B-mode images for the development of an automated steatosis classification algorithm. Approach: We obtained a Health Insurance Portability and Accountability Act compliant dataset consisting of 478 patients [body mass index 23.60±3.55, age 40.97±10.61], imaged with POCUS by non-expert health care personnel. A U-Net deep learning (DL) model was used for liver segmentation in the POCUS B-mode images, followed by 224×224 patch extraction of liver parenchyma. Several DL models including VGG-16, ResNet-50, Inception V3, and DenseNet-121 were trained for binary classification of steatosis. All layers of each tested model were unfrozen, and the final layer was replaced with a custom classifier. Majority voting was applied for patient-level results. Results: On a hold-out test set of 81 patients, the final DenseNet-121 model yielded an area under the receiver operator characteristic curve of 90.1%, sensitivity of 95.0%, and specificity of 85.2% for the detection of liver steatosis. Average cross-validation performance in models using patches of liver parenchyma as input outperformed methods using complete B-mode frames. Conclusions: Despite minimal POCUS acquisition training, and low-quality B-mode images, it is possible to detect steatosis using DL algorithms. Implementation of this algorithm in POCUS software may offer an accessible, low-cost steatosis screening technology, for use by non-expert health care personnel.