Detrimental impact of early biopsy-proven rejection in liver transplantation.

Existing literature offers conflicting conclusions about whether early acute cellular rejection influences long-term outcomes in liver transplantation. We retrospectively collected donor and recipient data on all adult, first-time liver transplants performed at a single center between 2008 and 2020. We divided this population into two cohorts based on the presence of early biopsy-proven acute cellular rejection (EBPR) within the first 90 days post-transplant and compared outcomes between the groups. There were 896 liver transplants that met inclusion criteria with 112 cases (12.5%) of EBPR. Recipients who developed EBPR had higher biochemical Model for End-Stage Liver Disease scores (28 vs. 24, p < .01), but other donor and recipient characteristics were similar. Recipients with EBPR had similar overall survival compared to patients without EBPR (p = .09) but had decreased graft survival (p < .05). EBPR was also associated with decreased time to first episode of late (> 90 days post-transplant) rejection (p < .0001) and increased vulnerability to bacterial and viral infection (p < .05). In subgroup analysis of recipients with autoimmune indications for liver transplantation, EBPR had a more pronounced association with patient death (hazard ratio [HR] 3.9, p < .05) and graft loss (HR 4.0, p < .01). EBPR after liver transplant is associated with inferior graft survival, increased susceptibility to late rejections, and increased vulnerability to infection.

Normothermic Machine Perfusion of Donor Livers for Transplantation in the United States: A Randomized Controlled Trial.

OBJECTIVE: To compare conventional low-temperature storage of transplant donor livers [static cold storage (SCS)] with storage of the organs at physiological body temperature [normothermic machine perfusion (NMP)]. BACKGROUND: The high success rate of liver transplantation is constrained by the shortage of transplantable organs (eg, waiting list mortality >20% in many centers). NMP maintains the liver in a functioning state to improve preservation quality and enable testing of the organ before transplantation. This is of greatest potential value with organs from brain-dead donor organs (DBD) with risk factors (age and comorbidities), and those from donors declared dead by cardiovascular criteria (donation after circulatory death). METHODS: Three hundred eighty-three donor organs were randomized by 15 US liver transplant centers to undergo NMP (n = 192) or SCS (n = 191). Two hundred sixty-six donor livers proceeded to transplantation (NMP: n = 136; SCS: n = 130). The primary endpoint of the study was "early allograft dysfunction" (EAD), a marker of early posttransplant liver injury and function. RESULTS: The difference in the incidence of EAD did not achieve significance, with 20.6% (NMP) versus 23.7% (SCS). Using exploratory, "as-treated" rather than "intent-to-treat," subgroup analyses, there was a greater effect size in donation after circulatory death donor livers (22.8% NMP vs 44.6% SCS) and in organs in the highest risk quartile by donor risk (19.2% NMP vs 33.3% SCS). The incidence of acute cardiovascular decompensation at organ reperfusion, "postreperfusion syndrome," as a secondary outcome was reduced in the NMP arm (5.9% vs 14.6%). CONCLUSIONS: NMP did not lower EAD, perhaps related to the inclusion of lower-risk liver donors, as higher-risk donor livers seemed to benefit more. The technology is safe in standard organ recovery and seems to have the greatest benefit for marginal donors.

Post-pancreatic transplant enteric leaks: The role of the salvage operation.

Enteric drainage in pancreas transplantation is complicated by an enteric leak in 5%-8%, frequently necessitating pancreatectomy. Pancreatic salvage outcomes are not well studied. Risk factors for enteric leak were examined and outcomes of attempted graft salvage were compared to immediate pancreatectomy. Pancreas transplants performed between 1995 and 2018 were reviewed. Donor, recipient, and organ variables including demographics, donor type, ischemic time, kidney donor profile index, and pancreas donor risk index were analyzed. Among 1153 patients, 33 experienced enteric leaks (2.9%). Donors of allografts that developed leak were older (37.9y vs. 29.0y, p = .001), had higher KDPI (37% vs. 24%, p < .001), higher pancreas donor risk index (1.83 vs. 1.32, p < .001), and longer cold ischemic time (16.5 vs. 14.8 h, p = .03). Intra-abdominal abscess and higher blood loss decreased the chance of successful salvage. Enteric leak increased 6-month graft loss risk (HR 13.9[CI 8.5-22.9], p < .001). However, 50% (n = 12) of allografts undergoing attempted salvage survived long-term. After 6 months of pancreas graft survival, salvage and non-leak groups had similar 5-year graft survival (82.5% vs. 81.5%) and mortality (90.9% vs. 93.5%). Enteric leaks remain a challenging complication. Pancreatic allograft salvage can be attempted in suitable patients and accomplished in 50% of cases without significantly increased graft failure or mortality risk.

Cross-decoration of dendritic cells by non-inherited maternal antigen-containing extracellular vesicles: Potential mechanism for PD-L1-based tolerance in cord blood and organ transplantation.

Exposure to non-inherited maternal antigens (NIMA) during the fetal period induces lifelong split tolerance to grafts expressing these allo-antigens. In adult mice, the production of extracellular vesicles (EVs) from maternal microchimeric cells causes cross-decoration (XD) of offspring dendritic cells (DC) with NIMA and upregulation of PD-L1, contributing to NIMA tolerance. To see how this may apply to humans, we tested NIMA acquisition by fetal DCS in human cord blood. The average percentage of NIMA-XD among total DCs was 2.6% for myeloid and 4.5% for Plasmacytoid DC. These cells showed higher PD-L1 expression than their non-XD counterparts (mDC: p = .0016; pDC: p = .024). We detected CD9+ EVs bearing NIMA and PD-L1 in cord blood. To determine if this immune regulatory mechanism persists beyond the pregnancy, we analyzed NIMA-expressing kidney and liver transplant recipients. We found donor antigen XD DCs in peripheral blood and graft-infiltrating DCs. As in cord blood, the pattern of donor antigen expression was punctate, and PD-L1 expression was upregulated, likely due to both protein and miRNA acquired from EV. Our findings support a mechanism for split tolerance to NIMAs that develops during pregnancy and is recapitulated in adult transplant recipients.

Coagulopathy and hemostasis management in patients undergoing liver transplantation: Defining a dynamic spectrum across phases of care.

Patients with acute and chronic liver disease present with a wide range of disease states and severity that may require liver transplantation (LT). Physiologic alterations occur that are dynamic throughout all phases of perioperative care, creating complex management scenarios that necessitate multidisciplinary clinical care. Specifically, alterations in hemostasis in liver disease can be pronounced and evolve with disease progression over time. Recent studies and society guidance address this emerging paradigm and offer recommendations to assist with hemostatic management in patients with liver disease. However, patients undergoing LT are unique and diverse, often with unstable disease that requires specialized approaches. Our aim is to provide a focused review of hemostatic management of the LT patient, distinguish unique aspects of the three main phases of care (before LT, perioperative, and after LT), and identify knowledge gaps and critical areas of future research.

Single-cell RNA sequencing distinguishes dendritic cell subsets in the rat, allowing advanced characterization of the effects of FMS-like tyrosine kinase 3 ligand.

Tissue-resident dendritic cells (DCs) are essential for immunological homeostasis and hold promise for a variety of therapeutic interventions. The rare nature of tissue-resident DCs and their suboptimal description in the lab rat model has limited their characterization. To address this limitation, FMS-like tyrosine kinase 3 ligand (FLT3L) has been utilized to expand these population in vitro and in vivo for investigative or therapeutic purposes. However, conflicting reports have suggested that FLT3L can either promote immune tolerance or enhance immunogenicity, necessitating clarification of the effects of FLT3L on DC phenotype and functionality. We first paired single-cell RNA sequencing with multicolour spectral flow cytometry to provide an updated strategy for the identification of tissue-resident classical and plasmacytoid DCs in the rat model. We then administered FLT3L to Lewis rats in vivo to investigate its effect on tissue-resident DC enumeration and phenotype in the liver, spleen, and mesenteric lymph nodes. We found that FLT3L expands classical DCs (cDCs) 1 and 2 in a dose-dependent manner and that cDC1 and cDC2 in secondary lymphoid organs had altered MHC I, MHC II, CD40, CD80, CD86, and PD-L1 cell-surface expression levels following FLT3L administration. These changes were accompanied by an increase in gene expression levels of toll-like receptors 2, 4, 7, and 9 as well as inflammatory cytokines IL-6 and TNF-α. In conclusion, FLT3L administration in vivo increases cDC enumeration in the liver, spleen, and mesenteric lymph nodes accompanied by a tissue-restricted alteration in expression of antigen presentation machinery and inflammatory mediators.

Blood products and liver transplantation: A strategy to balance optimal preparation with effective blood stewardship.

BACKGROUND: Unanticipated transfusion requirements during liver transplantation can delay lifesaving intraoperative resuscitation and strain blood bank resources. Risk-stratified preoperative blood preparation can mitigate these deleterious outcomes. STUDY DESIGN AND METHODS: A two-tiered blood preparation protocol for liver transplantation was retrospectively evaluated. Eleven binary variables served as criteria for high-risk (HR) allocation. Primary outcomes included red blood cell (RBC), plasma (FFP), and platelet (Plt) utilization. Secondary outcomes included product under- and overpreparation. Contingency tables for transfusion requirements above the population means were generated using 15 clinical variables. Modified protocols were developed and retrospectively optimized using the study population. RESULTS: Of 225 recipients, 102 received HR preoperative orders, which correlated to higher intraoperative transfusion requirements. However, univariate analysis identified only two statistical risk factors per product: Hgb ≤7.8 g/dl (p < .001) and MELD ≥38 (p = .035) for RBCs, Hgb ≤7.8 g/dl (p = .002) and acute alcoholic hepatitis (p = 0.015) for FFP, and Hgb ≤7.8 g/dl (p = .001) and normothermic liver preservation (p = .037) for Plts. Based on these findings, we developed modified protocols for individual products, which were evaluated retrospectively for their effectiveness at reducing under-preparatory events while limiting product overpreparation. Cohort statistics were used to define the preparation strategy for each protocol. Retrospective comparative analysis demonstrated the superiority of the modified protocols by improving the under-preparation rate from 24% to <10% for each product, which required a 1.56-fold and 1.44-fold increase in RBC and FFP overpreparation, respectively. Importantly, there was no difference in Plt overpreparation. DISCUSSION: We report translatable data-driven blood bank preparation protocols for liver transplantation.

Microwave Ablation as Bridging to Liver Transplant for Patients with Hepatocellular Carcinoma: A Single-Center Retrospective Analysis.

PURPOSE: To evaluate the efficacy and safety of microwave (MW) ablation as first-line locoregional therapy (LRT) for bridging patients with hepatocellular carcinoma (HCC) to liver transplant. MATERIALS AND METHODS: This retrospective study evaluated 88 patients who received percutaneous MW ablation for 141 tumors as first-line LRT for HCC and who were listed for liver transplantation at a single medical center between 2011 and 2019. The overall survival (OS) rate statuses after liver transplant, waitlist retention, and disease progression were evaluated using the Kaplan-Meier techniques. RESULTS: Among the 88 patients (72 men and 16 women; mean age, 60 years; Model for End-Stage Liver Disease score, 11.2) who were listed for transplant, the median waitlist time was 9.4 months (interquartile range, 5.5-18.9). Seventy-one (80.7%) patients received transplant after a median waitlist time of 8.5 months. Seventeen (19.3%) patients were removed from the waitlist; of these, 4 (4.5%) were removed because of tumors outside of the Milan criteria (HCC-specific dropout). No difference in tumor size or alpha-fetoprotein was observed in the transplanted versus nontransplanted patients at the time of ablation (2.1 vs 2.1 cm and 34.4 vs 34.7 ng/mL for transplanted vs nontransplanted, respectively; P > .05). Five (5.1%) of the 88 patients experienced adverse events after ablation; however, they all recovered. There were no cases of tract seeding. The local tumor progression (LTP) rate was 7.2%. The OS status after liver transplant at 5 years was 76.7%, and the disease-specific survival after LTP was 89.6%, with a median follow-up of 61 months for all patients. CONCLUSIONS: MW ablation appears to be safe and effective for bridging patients with HCC to liver transplant without waitlist removal from seeding, adverse events, or LTP.

Risk factors for high level cytomegalovirus viremia in liver transplant recipients and associated outcomes.

PURPOSE: To evaluate epidemiology, risk-factors, and outcomes of high-level (HL) cytomegalovirus (CMV) viremia in liver transplant recipients. METHODS: Adult patients receiving a liver transplant between 1/1/2017 and 9/30/2020 were evaluated. Viral loads at University of Wisconsin Health Clinical Laboratories were required to allow for numerical comparison. Primary objective was incidence and outcomes of HL CMV viremia (viral-load > 100 000 IU/ml). Secondary objective was to elucidate risk factors to allow targeted interventions. RESULTS: Two hundred nine patients met inclusion criteria; 175 kept their graft for at least 240 days. Of these nine patients developed HL CMV, 28 developed low-level (LL CMV, viral-load 250-100 000 IU/ml), and 138 did not develop CMV viremia. When comparing these three groups via classic statistical methods time from transplant to viremia was similar (HL 158 ± 77 days, LL 150 ± 76 days). Clinical factors were also similar with the exception of donor seropositivity (HL 87.5%, LL 70.4%, No CMV 49.6%, p = 0.025). HL CMV was significantly associated with graft loss (p < 0.0001) on Kaplan-Meier analysis; graft loss in the LL CMV group did not differ from the no CMV group (p = 0.96). To allow valid assessment of risk factors in the total study population (n = 209), models of time-varying covariates were used, and Cox proportional hazards ratios were calculated. In this analysis, HL CMV was associated with a significantly increased risk of graft loss (HR 5.6, p = 0.0016). When investigating risk factors associated with HL CMV, donor seropositivity significantly increased risk (HR 8.85, 95% CI 1.13-71.43, p = 0.038). Pretransplant total bilirubin (HR 1.04, 95% CI 0.998-1.07, p = 0.06) trended toward significance. Recipient seronegativity, liver disease, clinical and allocation model for end-stage liver disease (MELD), transplant surgery duration, age, sex, induction immunosuppression, and maintenance immunosuppression were not significantly associated with development of HL CMV. CONCLUSION: HL CMV after liver transplant is uncommon but is associated with a significantly increased risk of graft loss that is not present in those patients who develop LL CMV or do not develop CMV viremia. Given these negative graft effects, CMV stewardship interventions targeting recipients of CMV seropositive allografts are warranted. Future larger scale studies evaluating the potential role of other factors in risk stratification are needed.

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.

Pretransplant solid organ malignancy and organ transplant candidacy: A consensus expert opinion statement.

Patients undergoing evaluation for solid organ transplantation (SOT) often have a history of malignancy. Although the cancer has been treated in these patients, the benefits of transplantation need to be balanced against the risk of tumor recurrence, especially in the setting of immunosuppression. Prior guidelines of when to transplant patients with a prior treated malignancy do not take in to account current staging, disease biology, or advances in cancer treatments. To develop contemporary recommendations, the American Society of Transplantation held a consensus workshop to perform a comprehensive review of current literature regarding cancer therapies, cancer stage-specific prognosis, the kinetics of cancer recurrence, and the limited data on the effects of immunosuppression on cancer-specific outcomes. This document contains prognosis based on contemporary treatment and transplant recommendations for breast, colorectal, anal, urological, gynecological, and nonsmall cell lung cancers. This conference and consensus documents aim to provide recommendations to assist in the evaluation of patients for SOT given a history of a pretransplant malignancy.

Preexisting melanoma and hematological malignancies, prognosis, and timing to solid organ transplantation: A consensus expert opinion statement.

Patients undergoing evaluation for solid organ transplantation (SOT) frequently have a history of malignancy. Only patients with treated cancer are considered for SOT but the benefits of transplantation need to be balanced against the risk of tumor recurrence, taking into consideration the potential effects of immunosuppression. Prior guidelines on timing to transplant in patients with a prior treated malignancy do not account for current staging, disease biology, or advances in cancer treatments. To update these recommendations, the American Society of Transplantation (AST) facilitated a consensus workshop to comprehensively review contemporary literature regarding cancer therapies, cancer stage specific prognosis, the kinetics of cancer recurrence, as well as the limited data on the effects of immunosuppression on cancer-specific outcomes. This document contains prognosis, treatment, and transplant recommendations for melanoma and hematological malignancies. Given the limited data regarding the risk of cancer recurrence in transplant recipients, the goal of the AST-sponsored conference and the consensus documents produced are to provide expert opinion recommendations that help in the evaluation of patients with a history of a pretransplant malignancy for transplant candidacy.

Interleukin-10 and Transforming Growth Factor-ß Cytokines Decrease Immune Activation During Normothermic Ex Vivo Machine Perfusion of the Rat Liver.

Normothermic ex vivo liver perfusion (NEVLP) is a novel system for organ preservation that may improve over static cold storage clinically and offers the chance for graft modification prior to transplantation. Although recent studies have shown the presence of inflammatory molecules during perfusion, none have yet shown the effects of NEVLP on liver-resident immune cell activation. We investigated the effects of NEVLP on liver-resident immune cell activation and assessed the ability of anti-inflammatory cytokines interleukin 10 (IL10) and transforming growth factor ß (TGF-ß) to improve organ function and reduce immune activation during perfusion. Rat livers were perfused for 4 hours at 37°C with or without the addition of 20 ng/mL of each IL10 and TGF-ß (n = 7). Naïve and cold storage (4 hours at 4°C) livers served as controls (n = 4). Following preservation, gene expression profiles were assessed through single-cell RNA sequencing; dendritic cell and macrophage activation was measured by flow cytometry; and cytokine production was assessed by enzyme-linked immunosorbent assay. NEVLP induced a global inflammatory gene expression signature, most notably in liver-resident macrophages and dendritic cells, which was accompanied by an increase in cell-surface levels of major histocompatibility complex (MHC) II, CD40, and CD86. Immune activation was partially ameliorated by IL10 and TGF-ß treatment, but no changes were observed in inflammatory cytokine production. Overall levels of liver damage and cellular apoptosis from perfusion were low, and liver function was improved with IL10 and TGF-ß treatment. This is the first study to demonstrate that liver-resident immune cells gain an activated phenotype during NEVLP on both the gene and protein level and that this activation can be reduced through therapeutic intervention with IL10 and TGF-ß.

A review of the immune response stimulated by xenogenic tissue heart valves.

Valvular heart disease continues to afflict millions of people around the world. In many cases, the only corrective treatment for valvular heart disease is valve replacement. Valve replacement options are currently limited, and the most common construct utilized are xenogenic tissue heart valves. The main limitation with the use of this valve type is the development of valvular deterioration. Valve deterioration results in intrinsic permanent changes in the valve structure, often leading to hemodynamic compromise and clinical symptoms of valve re-stenosis. A significant amount of research has been performed regarding the incidence of valve deterioration and determination of significant risk factors for its development. As a result, many believe that the underlying driver of valve deterioration is a chronic immune-mediated rejection process of the foreign xenogenic-derived tissue. The underlying mechanisms of how this occurs are an area of ongoing research and active debate. In this review, we provide an overview of the important components of the immune system and how they respond to xenografts. A review of the proposed mechanisms of xenogenic heart valve deterioration is provided including the immune response to xenografts. Finally, we discuss the role of strategies to combat valve degeneration such as preservation protocols, epitope modification and decellularization.

Defining postoperative transfusion thresholds in liver transplant recipients: A novel retrospective approach.

BACKGROUND: The optimal transfusion threshold for most patient populations has been defined as hematocrit (HCT) <21%. However, some specific patient populations are known to benefit from higher transfusion thresholds. To date, the optimal postoperative transfusion threshold for patients undergoing liver transplant has not been determined. To define the ideal transfusion threshold for liver transplant patients, we designed a retrospective study of 496 liver transplant recipients. METHODS: Using HCT prior to discharge as a surrogate marker for transfusion thresholds we grouped patients into three groups of transfusion thresholds (HCT <21%, <24%, and >30%). Transfusion rates (intra- and postoperative), graft and patient survival, and complications requiring readmission were compared between groups. RESULTS: Ninety-two percent of patients were transfused during their hospital stay. Graft survival, patient survival, and rates of readmission within 30 days of discharge were no different between the three discharge HCT groups. Patients discharged with HCT >30% were less likely to be readmitted with infectious complications; however, this group also had the lowest model of end-stage liver (MELD) score at time of transplantation and were less likely to have received a transfusion during their hospital stay. CONCLUSION: Transfusion thresholds of HCT <24%, and potentially as low as 21% are acceptable in postoperative liver transplant recipients. The conduct of a randomized clinical trial, as supported by these data, will be necessary to support the use of lower thresholds.

Analysis of malignant melanoma risk and outcomes in solid organ transplant recipients: Assessment of transplant candidacy and the potential role of checkpoint inhibitors.

Malignant melanoma (MM) causes tremendous morbidity and mortality in the solid organ transplant population and may arise in three different clinical scenarios: (1) pretransplant melanoma; (2) de novo melanoma post transplantation and (3) donor-derived melanoma. This manuscript primarily addresses the first two scenarios with respect to the evaluation and management of pretransplant MM, consideration of transplant candidacy and the occurrence and management of de novo MM post transplantation. The authors outline current evidence describing risks associated with pre-transplant melanoma to support recently established expert opinion for transplant candidacy.

Clinician and patient attitudes toward use of organs from hepatitis C viremic donors and their impact on acceptance: A contemporary review.

BACKGROUND: The use of Hepatitis C (HCV) NAT positive allografts remains unusual and is clustered at few centers. We conducted a contemporary literature review to assess whether patient and clinician attitudes toward viremic organs impact acceptance. METHODS: Databases including PubMed, MEDLINE, and SCOPUS databases were reviewed to identify studies focused on evaluating patient and provider perceptions of HCV NAT positive organ use within the DAA era (January 2015-April 2021). Search included MeSH terms related to Hepatitis C, transplantation, and patient and clinician attitudes. Two investigators extracted study characteristics including information on willingness to accept viremic organs, HCV-specific outcomes knowledge, HCV-specific concerns, and factors that contributed to acceptance or non-acceptance. RESULTS: Eight studies met all inclusion criteria. These included three pretransplant patient-directed studies, two post-transplant patient-directed studies, one pre- and post-transplant patient-directed study, and two clinician-directed studies. Common themes identified were concerns regarding HCV cure rates, viremic organ quality, DAA cost, stigma, and the possibility of HCV transmission to household members. The perception of decreased waitlist time was associated with viremic organ acceptance. Physician trust played a mixed role in acceptance patterns. CONCLUSIONS: Knowledge of high cure rates, shorter waitlist times, and higher organ quality appear to have the highest impact on organ acceptance.

Pre-transplant bariatric surgery is associated with increased fungal infection after liver transplant.

AIM: The impact of pre-transplant (pre-TXP) bariatric surgery (BS) on outcomes after liver transplant (LTX) has not been completely elucidated. Roux-en Y gastric bypass (RYGB) is one of the most common BS procedures. The primary objective of this study was to identify the risk of infection in LTX recipients with pre-TXP RYGB. METHODS: Adult patients with LTX between 1/1/2001 and 9/30/2018 at our center were screened for pre-TXP RYGB; patients with gastrectomy via sleeve or banding were excluded. Patients with no history of BS pre- or post-transplant were placed in a comparator group, matched 2:1 via incidence density sampling on age epoch. RESULTS: There were 16 LTX recipients with pre-TXP RYGB matched to 32 controls. Median time from RYGB to transplant was 11.7 years. Mean weight loss was 66 ± 19 kg. There were significantly more women with pre-TXP RYGB than in the matched control (RYGB:68.8% vs control:25%, P = .009). Demographics were otherwise similar between groups. Pre-TXP RYGB did not significantly increase hospital or ICU length of stay (P = .5, P = .3) but was associated with a significantly increased rate of fungal infection at 1 year (RYGB:33.4% vs control:9.7%, P = .01), and a numerical trend to increased bacterial infection (RYGB:56.2% vs control:32.2%, P = .09). CONCLUSION: Despite the substantial weight loss attributed to BS, patients with pre-TXP RYGB demonstrated increased rates of fungal infection after transplant and trended toward increased bacterial infection. While the anatomical complexity associated with LTX surgery after RYGB did not appear to significantly affect ICU or hospital length of stay, it may have contributed to overall infectious risk, and possibly to impaired survival. Additionally, bypass of the host natural barrier defenses of the stomach could also have contributed to infectious risk. Our findings highlight the complexity of this patient population. Future prospective studies are needed to investigate risk of infection after LTX in the setting of pre-Txp BS. Potential modification in fungal prophylaxis protocols to include pre-TXP RYGB may be warranted.

Extracellular Vesicles as a Novel Therapeutic Option in Liver Transplantation.

Longterm liver graft dysfunction and immunological rejection remain common adverse events, in part due to early acute rejection episodes initiated by ischemia/reperfusion injury (IRI) immediately following transplantation. Novel treatment methods are therefore required to ameliorate liver IRI and to promote longterm allograft acceptance. Extracellular vesicles (EVs) derived from tolerogenic phenotype cells may serve as a novel therapeutic option in liver transplantation due to their immunomodulatory and proregenerative effects. Studies of hepatic IRI along with animal liver allograft models have demonstrated that EVs isolated from mesenchymal stem/stromal cells, immature dendritic cells, and hepatocytes can reduce graft injury through mechanisms including enhancement of mitochondrial autophagy, inhibition of immune response, and promotion of tissue regeneration. These preclinical models may soon move translationally into clinical practice, necessitating the generation of robust methods to generate clinical-grade EVs. These methods must address issues of reproducibility and ability to scale up the tolerogenic cell cultivation, EV isolation, and EV characterization. Once generated, the efficient delivery of EVs to the donor organ prior to transplantation remains an issue that could be resolved through the novel organ storage method ex vivo machine perfusion (EVMP). In this review, we summarize studies that have used tolerogenic cell-derived EVs to ameliorate hepatic IRI and promote liver allograft acceptance, discuss the steps toward generation of clinical-grade EVs, and introduce EVMP as a novel method to efficiently deliver EVs.

Microsteatosis in Livers From Donation After Circulatory Death Donors Is Associated With Inferior Outcomes Following Liver Transplantation.

The acceptable threshold remains unknown for the percentage of macrosteatosis (MaS) and microsteatosis (MiS) to yield optimal outcomes after donation after circulatory death (DCD) liver transplantation (LT). The purpose of this analysis was to determine the impact of donor liver MaS and MiS on DCD LT outcomes. Using the Organ Procurement and Transplantation Network database, we analyzed pretransplant biopsy results from adult, solitary, DCD livers transplanted between January 1, 2006, and December 31, 2017. Kaplan-Meier analysis was used to assess graft and patient survival based on MaS and MiS severity. MiS was divided into the groups MiS ≤10% and >10%. MaS was divided into the groups MaS ≤15% and >15%. Of 7757 recovered DCD livers, 11.4% (n = 885) were biopsied and transplanted. Patients who received DCD livers with MaS >15% had significantly worse patient survival (P < 0.04), and those with MiS >10% demonstrated inferior graft and patient survival (P < 0.02). In multivariate analyses including known risk factors, both MaS >15% and MiS >10% were associated with increased risk of graft failure and patient mortality (P < 0.03). Recipient and donor age >60 years were also associated with increased risk of graft failure and patient death. This analysis demonstrates that MaS >15% and MiS >10% are additional risk factors for graft loss and patient mortality in DCD LT.