Liver Allograft Research Articles

Protocol liver biopsy predicts graft survival after liver transplantation.

The use of protocol liver biopsy to monitor liver allograft status remains controversial. There is limited data from modern transplantation populations that includes protocol biopsies to evaluate its value in predicting clinical outcomes. All protocol liver biopsies were identified from 875 patients who underwent liver transplantation at Helsinki University Hospital between 2000 and 2019. Each histologic component was analyzed for its ability to predict long-term outcomes, especially graft survival. We determined the frequency of significant biopsy findings based on the Banff working group definition. Liver function tests (LFTs) and clinical markers were evaluated for their ability to predict significant biopsy findings. In total, 867 protocol liver biopsies were analyzed. Significant findings were identified in 20.1% of the biopsies. In the first protocol biopsy, steatohepatitis (hazard ratio [HR] 3.504, p=.03) and moderate or severe congestion (HR 3.338, p=.04) predicted graft loss. The presence of cholangitis (HR 2.563, p=.04), necrosis (HR 7.635, p<.001), mild congestion (HR 4.291, p=.009), and significant biopsy finding (HR 2.540, p=.02) predicted inferior death-censored graft survival. While the degree of elevation of LFTs was positively associated with significant biopsy findings, the discrimination was poor (AUC.572-.622). Combined LFTs and clinical risk factors remained suboptimal for discriminating significant biopsy findings (AUC.696). Our findings support the use of protocol liver biopsies after liver transplantation since they frequently revealed changes associated with long-term outcomes, even when LFTs were normal.

Anti-intercellular adhesion molecule 1 monomaintenance therapy induced long-term liver allograft survival without chronic rejection

Calcineurin inhibitors (CNIs) are essential in liver transplantation (LT); however, their long-term use leads to various adverse effects. The anti–intercellular adhesion molecule (ICAM)-1 monoclonal antibody MD3 is a potential alternative to CNI. Despite its promising results with short-term therapy, overcoming the challenge of chronic rejection remains important. Thus, we aimed to investigate the outcomes of long-term MD3 therapy with monthly MD3 monomaintenance in nonhuman primate LT models. Rhesus macaques underwent major histocompatibility complex–mismatched allogeneic LT. The conventional immunosuppression group (Con-IS, n = 4) received steroid, tacrolimus, and sirolimus by 4 months posttransplantation. The induction MD3 group (IN-MD3, n = 5) received short-term MD3 therapy for 3 months with Con-IS. The maintenance MD3 group (MA-MD3, n = 4) received MD3 for 3 months, monthly doses by 2 years, and then quarterly. The MA-MD3 group exhibited stable liver function without overt infection and had significantly better liver allograft survival than the IN-MD3 group. Development of donor-specific antibody and chronic rejection were suppressed in the MA-MD3 group but not in the IN-MD3 group. Donor-specific T cell responses were attenuated in the MA-MD3 group. In conclusion, MD3 monomaintenance therapy without maintenance CNI provides long-term liver allograft survival by suppressing chronic rejection, offering a potential breakthrough for future human trials.

Banff 2022 Liver Group Meeting report: Monitoring long-term allograft health

The Banff Working Group on Liver Allograft Pathology met in September 2022. Participants included hepatologists, surgeons, pathologists, immunologists, and histocompatibility specialists. Presentations and discussions focused on the evaluation of long-term allograft health, including noninvasive and tissue monitoring, immunosuppression optimization, and long-term structural changes. Potential revision of the rejection classification scheme to better accommodate and communicate late T cell-mediated rejection patterns and related structural changes, such as nodular regenerative hyperplasia, were discussed. Improved stratification of long-term maintenance immunosuppression to match the heterogeneity of patient settings will be central to improving long-term patient survival. Such personalized therapeutics are in turn contingent on a better understanding and monitoring of allograft status within a rational decision-making approach, likely to be facilitated in implementation with emerging decision-support tools. Proposed revisions to rejection classification emerging from the meeting include the incorporation of interface hepatitis and fibrosis staging. These will be opened to online testing, modified accordingly, and subject to consensus discussion leading up to the next Banff conference.

Elevated Plasma CXCL8 Concentrations in Significant Fibrosis but Not in Subclinical Rejection After Adult Liver Transplantation

Background. The noninvasive detection of subclinical graft injury including subclinical T cell–mediated rejection (subTCMR) is one of the unresolved challenges after liver transplantation. Recently, serum C-X-C motif chemokine ligand 8 (CXCL8) was proposed as a highly accurate marker of subTCMR in pediatric liver transplant recipients. We aimed to evaluate the accuracy of the quantification of this chemokine for predicting subTCMR in adult liver transplant recipients, as well as its capacity to classify patients who could benefit from immunosuppression reduction. Methods. Plasma CXCL8 concentrations were measured retrospectively in a prospectively collected cohort of adult liver transplant recipients with well-characterized histologic phenotypes. Results. In total, 78 patients were included. Median plasma CXCL8 concentrations did not differ (P = 0.24) between patients without histological evidence of rejection (3.6 [0.4–22.0] pg/mL), subTCMR (11.5 [0.4–41.0] pg/mL), clinical TCMR (9.4 [0.4–40.5] pg/mL), and other etiologies of graft injury (8.7 [0.4–31.2] pg/mL). Likewise, plasma CXCL8 concentrations did not discriminate between patients within and outside histologic criteria for immunosuppression reduction that were proposed by the 2016 Banff Working Group on Liver Allograft Pathology (cutoff: 10.9 pg/mL, sensitivity: 0.48, and specificity: 0.79). Furthermore, weak correlation was found between plasma CXCL8 and alanine aminotransferase and aspartate aminotransferase (Spearman ρ = 0.18 and 0.25). Patients with significant fibrosis (17.8 [0.4–40.5] pg/mL) showed higher plasma CXCL8 concentrations than patients without fibrosis (8.2 [0.4–41.0] pg/mL; P = 0.05). Conclusions. Plasma CXCL8 concentrations are not predictive of subclinical graft injury or of histological criteria for the minimization of immunosuppression in adult liver transplant recipients.

A279 WHY LIVER TRANSPLANT RECIPIENTS DIE: A QUALITY ASSURANCE REVIEW

Abstract Background Liver transplant techniques have significantly advanced over time, enhancing patient survival rates. In 2022, 99 liver transplants were performed in British Columbia (BC), ranking second in organ transplants. In BC, mortality rates for liver transplant recipients are 9.4% at one year, 15.6% at three years, 21% at five years, and 31% at ten years. However, a knowledge gap exists about the causes of post-transplant deaths in BC. This study aims to explore the primary mortality causes among these recipients over the last decade. Aims This study aims to investigate the leading causes of mortality among liver transplant recipients in British Columbia between 2013 and 2023. The objective is to identify areas for improvement and to develop strategies to decrease mortality rates. Methods We conducted a retrospective observational study including all patient deaths among liver transplant recipients in BC between January 1, 2013, to August 31, 2023. Secondary data from the BC Transplant database were used for this analysis. Results Over a ten-year period, 320 deaths were recorded in liver transplant recipients in BC. On average, patients were 53.5±12.96 years. Additionally, 60% of these individuals were male. Deaths occurred, on average, 8.6 ± 8.05 years after the patients received their transplants. Malignancy emerged as the primary cause of death, representing 24.7% of all fatalities. Together, multi-organ failure (12.5%), sepsis (11.3%), and cardiovascular issues (6.9%) made up close to one-third of the total deaths. Thirty-one patients (9.7%) died due to liver-related causes. The most common causes of graft loss were hepatitis C recurrence (6/31) and allograft rejection (8/31). Unfortunately, the cause of death was unknown in a significant proportion of patients (67/320), with nearly one-third (10/31) of all liver-related mortalities lacking a clear documented etiology. Conclusions Our study elucidated the causes of death in liver transplant recipients in British Columbia over the past decade. Cancer-related mortality, multi-organ failure, sepsis, cardiovascular events, and liver allograft failure were among the most common causes of death in this patient population. Hepatitis C recurrence and allograft rejection were common etiologies for liver-related mortality. The significant proportion of patients with undetermined or undocumented causes of death is of concern. These findings underscore the necessity for enhanced oncological surveillance, rigorous patient evaluation, and a potential re-evaluation of post-transplant care, especially in managing infections and cardiovascular health. The substantial "unknown" causes of death emphasize a need for better data capture provincially. Funding Agencies None

Is Cardiac Surgery Safe in Patients with Previous Liver Transplantation? A Narrative Review

Background Liver transplant patients have increased risk of developing cardiovascular disease and the outcome of these patients following cardiac surgery has been reported in small series of patients. The aim of this review was to examine and report safety outcomes of liver transplant patients undergoing cardiac surgery. Methods Literature review was conducted using three databases from inception to June 2023. Multiple search terms were used and limited to English language. Nine relevant articles were included. Outcomes of interest were short-term mortality, long-term survival, liver graft failure, major morbidity and infection in liver transplant recipients undergoing cardiac surgery. Results Cardiac risk factors (diabetes mellitus, hypertension, hyperlipidemia) were prevalent in liver transplant patients. 30-days mortality ranged across the studies from zero to 23.8%. 1-year survival ranged from 74-91% and 5-years survival ranged from 33-69%. Commonest causes of death were cardiac and sepsis. Predictors of mortality were preoperative encephalopathy, pulmonary hypertension, blood transfusion and postoperative increase in creatinine and bilirubin levels. Liver allograft rejection ranged from zero to 4.7% with no predictors reported. Liver dysfunction was seen in 33-46% of patients, and all were transient with recovery at the time of hospital discharge. Major morbidities were commonly reported and included respiratory and renal failure. Infection rates ranged from zero to 38% and the most common reported sites were pneumonia, sepsis, and surgical site infections. Conclusion Cardiac surgery can be performed in liver transplant patients with good short- and long-term results and acceptable morbidities.

Mesenchymal Stem Cell Extracellular Vesicles as a New Treatment Paradigm in Solid Abdominal Organ Transplantation: A Case Series.

Solid abdominal organ transplantation is fraught with variable rates of rejection and graft versus host disease (GVHD). We sought to determine the safety and efficacy of an advanced extracellular vesicle (EV) investigational product (IP) derived from mesenchymal stem cells (MSC) in the transplant patient population. Seven separate emergency investigational new drug (eNIDs) were filed with the Food and Drug Administration (FDA) for the emergency treatment of rejection of an isolated intestinal graft (n = 2), liver allograft graft (n = 2), modified multivisceral graft (n = 3), and GVHD in isolated intestinal transplant patients (n = 2). Fifteen milliliters of IP was administered intravenously on Day 0, 2, 4, and this treatment cycle was repeated up to four times in each patient depending on the treatment protocol allowed by the FDA. Safety (adverse event reporting) and efficacy (clinical status, serologies, and histopathology) were evaluated. There were no adverse events related to IP. All patients had improvement in clinical symptoms within 24 h, improved serologic laboratory evaluation, improved pulmonary symptoms and dermatologic manifestations of GVHD, and complete histologic resolution of graft inflammation/rejection within 7 days of IP administration. Systemic use of a MSC-derived EV IP was successful in achieving histological clearance of intestinal, liver, and multivisceral graft inflammation, and skin and pulmonary manifestations of GVHD.

Immunosuppressive enzyme-responsive nanoparticles for enhanced accumulation in liver allograft to overcome acute rejection

Acute rejection is a life-threatening complication after liver transplantation. Immunosuppressants such as tacrolimus are used to inhibit acute rejection of liver grafts in clinic. However, inefficient intragraft accumulation may reduce the therapeutic outcomes of tacrolimus. Here, an enzyme-responsive nanoparticle is developed to selectively enhance the accumulation of tacrolimus in liver allograft through enzyme-induced aggregation to refine immunotherapeutic efficacy of tacrolimus. The nanoparticles are composed of amphiphilic tacrolimus prodrugs synthesized by covalently conjugating tacrolimus and matrix metalloproteinase 9 (MMP9)-cleavable peptide-containing methoxy poly (ethylene glycol) to poly (l-glutamic acid). Upon exposure to MMP9, which is overexpressed in rejected liver allografts, the nanoparticles undergo a morphological transition from spherical micellar nanoparticles to microscale aggregate-like scaffolds. Intravenous administration of MMP9-responsive nanoparticles into a rat model of acute liver graft rejection results in enhanced nanoparticle accumulation in allograft as compared to nonresponsive nanoparticles. Consequently, the MMP9-responsive nanoparticles significantly inhibit intragraft inflammatory cell infiltration and proliferation, maintain intragraft immunosuppressive environment, alleviate graft damage, improve liver allograft function, abate weight loss and prolong recipient survival. This work proves that morphology-switchable enzyme-responsive nanoparticles represent an innovative strategy for selectively enhancing intragraft accumulation of immunosuppressive agents to improve treatment of liver allograft rejection.

Artificial Intelligence in the Detection of Fatty Liver Disease

Background: The current gold standard for quantification of the fat content of the liver (i.e., nonalcoholic fatty liver disease, NAFLD) is the visual microscopic inspection of liver biopsies by pathologists. Percentage of macrosteatosis (%MaS), used in determining NAFLD diagnosis, is vital in determining the transplant suitability of a donor liver. A major limitation of this method is inevitable human error which causes interobserver variability and overestimation of %MaS which could cause a potential discard of donor livers. We hypothesize that artificial intelligence (AI) can assist pathologists in providing a more objective and accurate measure of %MaS.&#x0D; Methods: Our literature review identified HALO (image analysis) and U-Net (deep-learning) as AI programs currently available for high-accuracy %MaS calculation in liver biopsies. We compared the pathologist-reported %MaS from de-novo liver transplant (LT) biopsy samples taken 2h post-reperfusion to the %MaS calculated by HALO and/or U-Net (Fig. 1). 250 patients had undergone de novo LT at Indiana University between 2019-2020, and 211 of these patients had sufficient data (liver enzyme tests, biopsy results) to be included. Each biopsy sample was digitized into 5 random non-overlapping tiles at 20x magnification using a Leica microscope. Early allograft dysfunction (EAD) is defined by the presence of at least one of the following: (i) INR &gt;1.6 on postoperative day (POD) 7, (ii) total bilirubin &gt;10 mg/dL on POD7, or (iii) AST/ALT &gt;2000 IU/L within the first 7 days following LT.&#x0D; Results: Our literature review identified that both HALO and U-Net estimated the %MaS in liver allograft biopsies significantly lower than pathologists' estimation (Fig.1). Of 211 included patients, 46 (21.8%) had EAD. In this ongoing project, we found U-Net to have a 97.3% training accuracy with eight epochs (2000 biopsy images each). Tiles from the first ten patients are being analyzed by HALO and/or U-Net to calculate an average %MaS for each patient. These calculations will be compared to the %MaS estimation made by pathologists.&#x0D; Conclusions: The rapidly evolving field of AI is emerging as a promising method in the quantification of the fat content of the liver with increased accuracy. AI will therefore help pathologists and transplant surgeons to determine liver transplant viability and better predict EAD in transplant patients.

Liver transplant recipients with polycystic liver disease have longer waiting times but better long-term clinical outcomes than those with liver disease due to other causes: A retrospective cross-sectional study.

Liver transplantation is the only curative option for patients with polycystic liver disease (PLD). In the United Kingdom, these patients are listed on the variant syndrome list due to their preserved liver function reflected in the United Kingdom End-stage Liver Disease (UKELD) score. The transplantation and survival rates for this patient group in the UK have not been previously reported. A retrospective cross-sectional analysis of patients receiving liver transplantation between 2010 and 2017 was performed using the NHS blood and transplantation database. This database contains the demographic, clinical parameters, indication for transplantation and follow-up of all patients in UK-based transplant centres. Basic statistics was performed using SPSS version 27. 5412 recipients received elective liver allografts in the study period. 1.6% (100) of recipients had PLD as their primary indication for transplantation with 60 receiving liver only allografts and 40 receiving combined liver-kidney allografts. PLD patients had a >3-fold longer mean waiting time for transplantation compared to non-PLD patients, 508 days v 154 days respectively. PLD patients receiving combined liver-kidney allografts had a longer waiting time than those receiving a liver only allograft, 610 days v 438 days respectively. There were comparable patient survival rates for people with PLD and non-PLD primary indications at 30 days (94.0% vs 97.6%) and 1 year (92.0% vs 93.2%) but improved survival rates at 5 years (81.3% vs 76.5%). There were also comparable allograft survival rates for people with PLD and non-PLD primary indications at 30 days (93.9% vs 95.3%) and 1 year (91.9% vs 91.2%) but improved survival rates at 5 years (82.5% vs 77.3%). Transplant centre-level analysis identified variation in the proportion of liver transplantations for people with PLD as their primary listed indication. Patients with PLD wait significantly longer for liver transplantation compared to other indications. However, transplanted PLD patients demonstrate better longer-term patient and liver allograft survival rates compared to transplanted non-PLD patients. The unexpected variation between individual UK centres transplanting for PLD deserves further study.

Histopathological Spectrum of Liver Allograft Biopsies and Association with Clinical and Pathological Parameters in Transplant Patients: A Cross-sectional Study

Introduction: Transplantation is vital for acute and terminal irreversible liver conditions. While imaging and functional measurements are valuable for evaluating post-transplant hepatocellular or biliary issues, liver allograft biopsies are used to determine the underlying causes of these changes. Long-term Immunosuppression (IMS), complex clinical circumstances, and de novo complications present challenges in transplant pathology, necessitating a multidisciplinary approach. Aim: To conduct a histopathological assessment of allograft liver biopsies for differential diagnosis, timing (postoperative day), and prevalence of post-transplantation complications, including identifying the causes of graft damage. Materials and Methods: This retrospective cross-sectional study was conducted between January 2019 and June 2022 at Vayalil Parambath Shamsheer (VPS) Lakeshore Hospital, Kochi, Kerala, India. A total of 45 post-transplant needle biopsy samples were analysed, examining histological characteristics and clinical data extracted from hospital records. Over 3.5 years, 45 post-liver transplant biopsies were performed. All clinical records and biopsy findings were examined using staining, and immunohistochemical analysis was performed. The Banff Working Group’s criteria were used to grade rejection based on a semiquantitative index, the Rejection Activity Index (RAI), into indeterminate (Score 1, 2); mild (Score 3, 4); moderate (Score 5, 6); and severe (&gt;6). The classic histologic findings are characterised by predominant portal-based lesions, including a classical triad of mixed inflammatory cell infiltrates, venous endothelial inflammation, and inflammatory infiltration of bile ducts. Results: Among 38 patients, a total of 45 needle biopsies were performed. The first specimen was collected within a few hours of transplantation, and the final specimen was collected after 770 days. Notably, T-Cell-Mediated Rejection (TCMR) was diagnosed in 9 out of 45 (20.00%) specimens. Other complications included Intrahepatic Cholestasis (IHC) in 11 out of 45 (24.44%) cases, biliary obstruction in 5 out of 45 (11.11%) patients, Herpes Simplex Virus (HSV) hepatitis in 3 out of 45 (6.67%) specimens, Plasma Cell-Rich Rejection (PCRR) in 2 out of 45 (4.44%), and Isolated Central Perivenulitis (ICP), Dengue Haemorrhagic Fever (DHF), and veno-occlusive-like disease in 2 out of 45 (4.44% each) specimens. One patient had ethanolinduced liver injury (1 out of 45, 2.22%). Conclusion: Post-transplant liver biopsies are essential for accurate and timely diagnosis of rejection and other complications, guiding therapeutic interventions. This study offers insights into the types, prevalence, and timing of critical complications following liver transplantation (LTx).

Risk Factors for Surgical-site Infections After Liver Transplant: Does Perioperative Antibiotic Regimen Matter?

Surgical-site infections (SSIs) are common in liver transplant recipients. The optimal SSI antimicrobial prophylaxis agent and duration are not established. We aimed to explore risk factors for SSIs after transplant, with a particular interest in the impact of perioperative antibiotic regimen on the development of SSIs. Retrospective study of adults undergoing liver transplant across 3 transplant programs between January 1, 2020, and June 01, 2021. Of 557 patients included in the study, 32 (5.7%) were infected or colonized with a multidrug-resistant organism (MDRO) within 1 y before liver transplant. Narrow-spectrum SSI prophylaxis with ceftriaxone or cefazolin alone was administered in 488 of 577 patients (87.6%); the remaining 69 patients (12.4%) received broad-spectrum prophylaxis with vancomycin and aztreonam (n = 40), piperacillin-tazobactam (n = 11), carbapenems (n = 8), ceftriaxone and another antibiotic (n = 7), and others. Patients with pretransplant MDRO were more likely to receive broad-spectrum coverage than those without pretransplant MDROs (28.1% versus 11.4%, P = 0.005). SSIs were identified in 40 patients (7.2%); 25 (62.5%) were organ-space infections, 3 (7.5%) were deep incisional infections, and 12 (30.0%) were superficial incisional infections. The median time from liver transplant to SSIs was 14 d (interquartile range, 10-20.2). MDROs were identified in 12 SSIs (30%). Multivariable analysis revealed no significant association between antimicrobial spectrum and risk of SSIs ( P = 0.5), whereas surgical leak ( P <0.001) and reoperation ( P = 0.017) were independently associated with increased risk of SSIs. SSIs were not significantly associated with composite risk of death or liver allograft failure. The spectrum of antimicrobial prophylaxis did not impact the development of SSIs in liver transplant recipients.

Identification of liver transplant biopsy phenotypes associated with distinct liver biological markers and allograft survival

The intricate association between histologic lesions and circulating antihuman leucocyte antigen donor-specific antibodies (DSA) in liver transplantation (LT) requires further clarification. We conducted a probabilistic, unsupervised approach in a comprehensively well-annotated LT cohort to identify clinically relevant archetypes. We evaluated 490 pairs of LT biopsies with DSA testing from 325 recipients transplanted between 2010 and 2020 across 3 French centers and an external cohort of 202 biopsies from 128 recipients. Unsupervised archetypal analysis integrated all clinico-immuno-histologic parameters of each biopsy to identify biopsy archetypes. The median time after LT was 1.17 (interquartile range, 0.38-2.38) years. We identified 7 archetypes distinguished by clinico-immuno-histologic parameters: archetype #1: severe T cell-mediated rejection (15.9%); #2: chronic rejection with ductopenia (1.8%); #3: architectural and microvascular damages (3.5%); #4: (sub)normal (55.9%); #5: mild T cell-mediated rejection (4.9%); #6: acute antibody-mediated rejection (6.5%); and #7: chronic rejection with DSA (11.4%). Cell infiltrates vary in the archetype. These archetypes were associated with distinct liver biological markers and allograft outcomes. These findings remained consistent when stratified using the patient’s age or indications for LT, with good performance in the external cohort (mean highest probability assignment = 0.58, standard deviation ± 0.17). In conclusion, we have identified clinically meaningful archetypes, providing valuable insights into the intricate DSA-histology association, which may help standardize liver allograft pathology classification.

Liver transplant outcomes using late allocation grafts.

Post-cross clamp late allocation (LA) liver allografts are at increased risk for discard for many reasons including logistical complexity. Nearest neighbor propensity score matching was used to match 2 standard allocation (SA) offers to every 1 LA liver offer performed at our center between 2015 and 2021. Propensity scores were based on a logistic regression model including recipient age, recipient sex, graft type (donation after circulatory death vs. donation after brain death), Model for End-stage Liver Disease (MELD), and DRI score. During this time, 101 liver transplants (LT) were performed at our center using LA offers. In comparing LA and SA offers, there were no differences in recipient characteristics including indication for transplant ( p = 0.29), presence of PVT ( p = 0.19), TIPS ( p = 0.83), and HCC status ( p = 0.24). LA grafts came from younger donors (mean age 43.6 vs. 48.9y, p = 0.009) and were more likely to come from regional or national Organ Procurement Organizations (OPOs) ( p < 0.001). Cold ischemia time was longer for LA grafts (median 8.5 vs 6.3h, p < 0.001). Following LT, there were no differences between the 2 groups in intensive care unit ( p = 0.22) and hospital ( p = 0.49) lengths of stay, need for endoscopic interventions ( p = 0.55), or biliary strictures ( p = 0.21). Patient (HR 1.0, 95% CI, 0.47-2.15, p = 0.99) and graft (HR 1.23, 95% CI, 0.43-3.50, p = 0.70) survival did not vary between the LA and SA cohorts. One-year LA and SA patient survival was 95.1% and 95.0%; 1-year graft survival was 93.1% and 92.1%, respectively. Despite the additional logistical complexity and longer cold ischemia time, LT outcomes utilizing LA grafts are similar to those allocated by means of SA. Improving allocation policies specific to LA offers, as well as the sharing of best practices between transplant centers and OPOs, are opportunities to further help minimize unnecessary discards.

Modern glucose-lowering drugs in liver transplant recipients: improvement in weight, glycemic control, and potentially allograft steatosis.

Recurrent allograft steatosis occurs in one-third of transplanted livers. Antidiabetic agents like glucagon-like peptide-1 receptor agonists (GLP1RA) and sodium-glucose cotransporter type-2 (SGLT2) inhibitors are effective in the management of obesity and hepatic steatosis in the general population; however, there is limited evidence supporting their use in allograft steatosis. We aimed to evaluate their effects on steatosis, body weight, and glycemic control in liver transplant recipients at our institution. In this single-center retrospective cohort study of liver transplant recipients currently on a GLP1RA or SGLT2 inhibitor (transplanted 2015-2022), we compared clinical and radiological data before medication use and at follow-up. Differences were compared using Wilcoxon signed-rank test. Thirty-seven liver transplant recipients were taking the agents. Diabetes was the most common indication (n = 33) followed by obesity (n = 4). Median follow up was 427 days (301,798). Among those with documented steatosis (n = 21), steatosis improved in 5, worsened in 4, remained unchanged in 1, and change could not be evaluated in 11 due to lack of comparable pre and post imaging. Average weight loss was 3.2 kg (p < 0.001) and BMI decreased by 1.2 kg/m2 (p < 0.001). Hemoglobin A1c decreased by 0.6 mmol/mol (p = 0.0014), insulin requirement reduced by 7 units/day (p = 0.02), and there was no change in additional antidiabetic medications. GLP1RA and SGLT-2 inhibitors are tolerated in transplant patients and result in weight loss and better glycemic control. They are promising agents to treat recurrent or de-novo liver allograft steatosis, but further research is needed to evaluate long-term outcomes in liver transplant recipients.

Improved assessment of donor liver steatosis using Banff consensus recommendations and deep learning algorithms

The Banff Liver Working Group recently published consensus recommendations for steatosis assessment in donor liver biopsy, but few studies reported their use and no automated deep-learning algorithms based on the proposed criteria have been developed so far. We evaluated Banff recommendations on a large monocentric series of donor liver needle biopsies by comparing pathologists' scores with those generated by convolutional neural networks (CNNs) we specifically developed for automated steatosis assessment. We retrospectively retrieved 292 allograft liver needle biopsies collected between January 2016 and January 2020 and performed steatosis assessment using a former intra-institution method (pre-Banff method) and the newly introduced Banff recommendations. Scores provided by pathologists and CNN models were then compared, and the degree of agreement was measured with the intraclass correlation coefficient (ICC). Regarding the pre-Banff method, poor agreement was observed between the pathologist and CNN models for small droplet macrovesicular steatosis (ICC: 0.38), large droplet macrovesicular steatosis (ICC: 0.08), and the final combined score (ICC: 0.16) evaluation, but none of these reached statistically significance. Interestingly, significantly improved agreement was observed using the Banff approach: ICC was 0.93 for the low-power score (p <0.001), 0.89 for the high-power score (p <0.001), and 0.93 for the final score (p <0.001). Comparing the pre-Banff method with the Banff approach on the same biopsy, pathologist and CNN model assessment showed a mean (±SD) percentage of discrepancy of 26.89 (±22.16) and 1.20 (±5.58), respectively. Our findings support the use of Banff recommendations in daily practice and highlight the need for a granular analysis of their effect on liver transplantation outcomes. We developed and validated the first automated deep-learning algorithms for standardized steatosis assessment based on the Banff Liver Working Group consensus recommendations. Our algorithm provides an unbiased automated evaluation of steatosis, which will lay the groundwork for granular analysis of steatosis's short- and long-term effects on organ viability, enabling the identification of clinically relevant steatosis cut-offs for donor organ acceptance. Implementing our algorithm in daily clinical practice will allow for a more efficient and safe allocation of donor organs, improving the post-transplant outcomes of patients.

Pediatric living donor liver transplantation from adult allograft liver after resection of focal nodular hyperplasia: a case series study

Pediatric living donor liver transplantation from adult allograft liver after resection of focal nodular hyperplasia: a case series study

Comparison of the effects of normothermic machine perfusion and cold storage preservation on porcine intestinal allograft regenerative potential and viability

Intestinal transplantation (IT) is the final treatment option for intestinal failure. Static cold storage (CS) is the standard preservation method used for intestinal allografts. However, CS and subsequent transplantation induce ischemia-reperfusion injury (IRI). Severe IRI impairs epithelial barrier function, including loss of intestinal stem cells (ISC), critical to epithelial regeneration. Normothermic machine perfusion (NMP) preservation of kidney and liver allografts minimizes CS-associated IRI; however, it has not been used clinically for IT. We hypothesized that intestine NMP would induce less epithelial injury and better protect the intestine’s regenerative ability when compared with CS. Full-length porcine jejunum and ileum were procured, stored at 4 °C, or perfused at 34 °C for 6 hours (T6), and transplanted. Histology was assessed following procurement (T0), T6, and 1 hour after reperfusion. Real-time quantitative reverse transcription polymerase chain reaction, immunofluorescence, and crypt culture measured ISC viability and proliferative potential. A greater number of NMP-preserved intestine recipients survived posttransplant, which correlated with significantly decreased tissue injury following 1-hour reperfusion in NMP compared with CS samples. Additionally, ISC gene expression, spheroid area, and cellular proliferation were significantly increased in NMP-T6 compared with CS-T6 intestine. NMP appears to reduce IRI and improve graft regeneration with improved ISC viability and proliferation.

Modern-Day Practice of DCD Liver Transplantation: Controversies, Innovations, and Future Directions.

Over the past decade, donation after circulatory death (DCD) liver transplantation has expanded in the United States due to improved surgical experience and perioperative management. Despite these advances, there remains a reluctance towards broader utilization of DCD liver allografts due to lack of standardized donation process, concern for inferior graft survival, and risk of ischemic cholangiopathy associated with temporary lack of oxygenated perfusion during withdrawal of life-supporting treatment during procurement. New perfusion technologies offer potential therapeutic options to mitigate biliary complications and expand utilization of marginal DCD grafts. As these modalities enter routine clinical practice, DCD utilization will continue to increase, and liver allocation policies in turn will evolve to reflect this growing practice. This review describes recent progress in DCD LT, current challenges with utilization of DCD liver allografts, and how novel technologies and policies could impact the future of the field.

Preserved 2-y Liver Transplant Outcomes Following Simultaneous Thoracoabdominal DCD Organ Procurement Despite Effects on Liver Utilization Rate.

Current techniques for donation after circulatory determination of death (DCD) heart procurement, through either direct procurement and machine perfusion or thoracoabdominal normothermic regional perfusion (NRP), have demonstrated excellent heart transplant outcomes. However, the impact of thoracoabdominal DCD (TA-DCD) heart procurement on liver allograft outcomes and utilization is poorly understood. One hundred sixty simultaneous heart and liver DCD donors were identified using the United Network for Organ Sharing/Organ Procurement and Transplantation Network database between December 2019 and July 2021. Liver outcomes from TA-DCD donors were stratified by heart procurement technique and evaluated for organ utilization, graft survival, and patient survival. Results were compared with abdominal-only DCD (A-DCD; n = 1332) and donation after brain death (DBD; n = 12 891) liver transplants during the study interval. Kaplan-Meier methods with log-rank testing were used to evaluate patient and graft survival. One hundred thirty-three of 160 livers procured from TA-DCD donors proceeded to transplant. TA-DCD donors were younger (mean 28.26 y; P < 0.0001) with lower body mass index (mean 26.61; P < 0.0001) than A-DCD and DBD donors. TA-DCD livers had equivalent patient survival ( P = 0.893) and superior graft survival (P = 0.009) compared with A-DCD. TA-DCD livers had higher rates of organ discard for long warm ischemia time (37.0%) than A-DCD (20.5%) and DBD (0.5%; P < 0.0001), with direct procurement and machine perfusion procurements leading to a higher discard rate (18.5%) than NRP procurements (7.4%). Liver transplants after TA-DCD donation demonstrated equivalent patient outcomes and excellent graft outcomes. NRP procurements resulted in the lowest rate of organ discard after DCD donation and may represent an optimal strategy to maximize organ utilization.