Effects of Cyclodextrin Curcumin Formulation on Ischemia-Reperfusion Injury in Porcine DCD Liver Transplantation.

BACKGROUND: Curcumin is a pleiotropic antioxidant polyphenol, which has proven to be highly protective in various models of liver injury and inflammation. We hypothesized that adding a stable aqueous curcumin formulation which comprises a water-soluble cyclodextrin curcumin formulation (CDC) complex of the water-insoluble curcumin molecule (Novobion, Espoo, Finland) to preservation solution during liver procurement may reduce ischemia-reperfusion injury and improve graft function after liver transplantation using donation after circulatory death (DCD). METHODS: In a preclinical pig model of DCD-liver transplantation, livers exposed to 15' of warm ischemia were either modulated (N = 6) with a flush of preservation solution (histidine-tryptophan-ketoglutarate) containing CDC (60 µmol/L) through the vena porta and the aorta, or not (controls, N = 6) before 4 h of cold storage. Area under the curve of log serum aspartate aminotransferase, markers of graft function (lactate, glycemia, prothrombin time, and bile production), inflammation (tumor necrosis factor-alpha), and survival were monitored. RESULTS: Area under the curve of log serum aspartate aminotransferase were similar between curcumin and control groups (22.12 [20.87-24.88] versus 25.08 [22.1-26.55]; P = 0.28). No difference in the liver function markers were observed between groups except a lower serum lactate level 3-h post-reperfusion in the curcumin group (3 [1.95-6.07] versus 8.2 [4.85-13.45] mmol/L; P = 0.05). Serum tumor necrosis factor-alpha levels were similar in each group. Recipient survival rates were found similar. CONCLUSIONS: CDC added to the preservation solution in DCD liver pig model did not improve ischemia-reperfusion injury severity, liver function, or survival. Further efforts are needed to explore this strategy, particularly with dynamic preservation, which finds its way into clinical practice.

Lung transplantation following controlled hypothermic storage with a portable lung preservation device: first multicenter European experience.

Introduction: Compared with traditional static ice storage, controlled hypothermic storage (CHS) at 4-10°C may attenuate cold-induced lung injury between procurement and implantation. In this study, we describe the first European lung transplant (LTx) experience with a portable CHS device. Methods: A prospective observational study was conducted of all consecutively performed LTx following CHS (11 November 2022 and 31 January 2024) at two European high-volume centers. The LUNGguard device was used for CHS. The preservation details, total ischemic time, and early postoperative outcomes are described. The data are presented as median (range: minimum-maximum) values. Results: A total of 36 patients underwent LTx (i.e., 33 bilateral, 2 single LTx, and 1 lobar). The median age was 61 (15-68) years; 58% of the patients were male; 28% of the transplantations had high-urgency status; and 22% were indicated as donation after circulatory death. In 47% of the patients, extracorporeal membrane oxygenation (ECMO) was used for perioperative support. The indications for using the CHS device were overnight bridging (n = 26), remote procurement (n = 4), rescue allocation (n = 2), logistics (n = 2), feasibility (n = 1), and extended-criteria donor (n = 1). The CHS temperature was 6.5°C (3.7°C-9.3°C). The preservation times were 11 h 18 (2 h 42-17 h 9) and 13 h 40 (4 h 5-19 h 36) for the first and second implanted lungs, respectively, whereas the total ischemic times were 13 h 38 (4 h 51-19 h 44) and 15 h 41 (5 h 54-22 h 48), respectively. The primary graft dysfunction grade 3 (PGD3) incidence rates were 33.3% within 72 h and 2.8% at 72 h. Intensive care unit stay was 8 (4-62) days, and the hospital stay was 28 (13-87) days. At the last follow-up [139 (7-446) days], three patients were still hospitalized. One patient died on postoperative day 7 due to ECMO failure. In-hospital Clavien-Dindo complications of 3b were observed in six (17%) patients, and 4a in seven (19%). Conclusion: CHS seems safe and feasible despite the high-risk recipient and donor profiles, as well as extended preservation times. PGD3 at 72 h was observed in 2.8% of the patients. This technology could postpone LTx to daytime working hours. Larger cohorts and longer-term outcomes are required to confirm these observations.

Anesthesia for Combined Heart-Liver Transplantation: A Narrative Review.

In 1984, 21 years after the first liver transplantation, Thomas Starzl achieved a milestone by performing the world's first combined heart-liver transplantation. While still uncommon, the practice of combined heart-liver transplants is on the rise globally. In this review, the authors delve into the current literature on this procedure, highlighting the evolving landscape and key considerations for anesthesiologists. Over the years, there has been a remarkable increase in the number of combined heart-liver transplantations conducted worldwide. This surge is largely attributed to the growing population of adult survivors with single-ventricle physiology, palliated with a Fontan procedure, who later present with late Fontan failure and Fontan-associated liver disease. Research indicates that combined heart-liver transplantation is an effective treatment option, with reported outcomes comparable with isolated heart or liver transplants. Managing anesthesia during a combined heart-liver transplant procedure is challenging, especially in the context of underlying Fontan physiology. International experience in this field remains somewhat limited, with most techniques derived from expert opinions or experiences with single-organ heart and liver transplants. These procedures are highly complex and performed infrequently. As the number of combined heart-liver transplants continues to rise globally, there is a growing need for clear guidance on periprocedural surgical and anesthetic management. Anesthesiologists overseeing these patients must consider multiple factors, balancing various comorbidities with significant hemodynamic and metabolic shifts. An increase in (multicenter) studies focusing on specific interventions to enhance patient and organ outcomes is anticipated in the coming years.

Single-cell RNA sequencing of cystic fibrosis liver disease explants reveals endothelial complement activation.

BACKGROUND & AIMS: Cystic fibrosis (CF) is considered a multisystemic disorder in which CF-associated liver disease (CFLD) is the third most common cause of mortality. Currently, no effective treatment is available for CFLD because its pathophysiology is still unclear. Interestingly, CFLD exhibits identical vascular characteristics as non-cirrhotic portal hypertension, recently classified as porto-sinusoidal vascular disorders (PSVD). METHODS: Since endothelial cells (ECs) are an important component in PSVD, we performed single-cell RNA sequencing (scRNA-seq) on four explant livers from CFLD patients to identify differential endothelial characteristics which could contribute to the disease. We comprehensively characterized the endothelial compartment and compared it with publicly available scRNA-seq datasets from cirrhotic and healthy livers. Key gene signatures were validated ex vivo on patient tissues. RESULTS: We found that ECs from CF liver explants are more closely related to healthy than cirrhotic patients. In CF patients we also discovered a distinct population of liver sinusoidal ECs-coined CF LSECs-upregulating genes involved in the complement cascade and coagulation. Finally, our immunostainings further validated the predominant periportal location of CF LSECs. CONCLUSIONS: Our work showed novel aspects of human liver ECs at the single-cell level thereby supporting endothelial involvement in CFLD, and reinforcing the hypothesis that ECs could be a driver of PSVD. Therefore, considering the vascular compartment in CF and CFLD may help developing new therapeutic approaches for these diseases.

Abdominal Wall Closure in Intestinal and Multivisceral Transplantation: A State-Of-The-Art Review of Vascularized Abdominal Wall and Nonvascularized Rectus Fascia Transplantation.

Failure to close the abdomen after intestinal or multivisceral transplantation (Tx) remains a frequently occurring problem. Two attractive reconstruction methods, especially in large abdominal wall defects, are full-thickness abdominal wall vascularized composite allograft (AW-VCA) and nonvascularized rectus fascia (NVRF) Tx. This review compares surgical technique, immunology, integration, clinical experience, and indications of both techniques. In AW-VCA Tx, vascular anastomosis is required and the graft undergoes hypotrophy post-Tx. Furthermore, it has immunologic benefits and good clinical outcome. NVRF Tx is an easy technique without the need for vascular anastomosis. Moreover, a rapid integration and neovascularization occurs with excellent clinical outcome.

New insights in immunomodulation for intestinal transplantation.

Tolerance is the Holy Grail of solid organ transplantation (SOT) and remains its primary challenge since its inception. In this topic, the seminal contributions of Thomas Starzl at Pittsburgh University outlined foundational principles of graft acceptance and tolerance, with chimerism emerging as a pivotal factor. Immunologically, intestinal transplantation (ITx) poses a unique hurdle due to the inherent characteristics and functions of the small bowel, resulting in increased immunogenicity. This necessitates heavy immunosuppression (IS) while IS drugs side effects cause significant morbidity. In addition, current IS therapies fall short of inducing clinical tolerance and their discontinuation has been proven unattainable in most cases. This underscores the unfulfilled need for immunological modulation to safely reduce IS-related burdens. To address this challenge, the Leuven Immunomodulatory Protocol (LIP), introduced in 2000, incorporates various pro-tolerogenic interventions in both the donor to the recipient, with the aim of facilitating graft acceptance and improving outcome. This review seeks to provide an overview of the current understanding of tolerance in ITx and outline recent advances in this domain.

Impact of a Single Dose of Alpha-1-Antitrypsin in a Rat Model of Bilateral Kidney Ischemia Reperfusion Injury.

INTRODUCTION: Renal ischemia reperfusion injury is a major cause of perioperative acute kidney injury. Alpha-1-antitrypsin (AAT), a protease inhibitor, might improve outcomes by reducing inflammation and apoptosis. We investigated the effects of a single intravenous dose of AAT immediately before ischemia in a rat bilateral renal clamping model. METHODS: Both renal pedicles of male Sprague-Dawley rats were clamped (45 min). Plasma and renal tissue were collected at 3 h, 24 h, and 7 d. Intravenous AAT (60 mg/kg) was administered 5 min before clamping. Controls received saline. Shams underwent surgery without clamping or injection. Kidney function was assessed by plasma creatinine; injury by aspartate aminotransferase, heart-type-fatty-acid-binding-protein, and histopathology. Renal gene expression of tumor necrosis factor α, interleukin (IL)-6, heat shock protein 70, Chemokine (C-X-C motif) ligand 2, cyclo-oxygenase 2, endothelin-1, IL-10, heme oxygenase 1, B-cell lymphoma 2, and bcl-2-like protein 4 were determined by quantitative reverse transcriptase polymerase chain reaction. RESULTS: None of the 3 h and 24 h end points were different between Control and AAT. In Sham, survival was 100% (6/6), 33% in Control (2/6), and 83% (5/6) in AAT (overall log-rank 0.03). At 7 d, plasma creatinine was lower with higher glomerular filtration rate in surviving AAT treated animals compared to Control (P < 0.001, P 0.03, respectively). These also had lower tumor necrosis factor α and IL-6 gene expression (P 0.001, P < 0.001, respectively). CONCLUSIONS: These data suggest that a single intravenous dose of AAT immediately before ischemia might affect proinflammatory gene expression, glomerular filtration rate and animal survival at 1 wk after reperfusion despite an absence of improvement in early renal function and injury. These findings deserve further investigating in sufficiently powered studies including both sexes.

Controlled Hypothermic Storage for Lung Preservation: Leaving the Ice Age Behind.

Controlled hypothermic storage (CHS) is a recent advance in lung transplantation (LTx) allowing preservation at temperatures higher than those achieved with traditional ice storage. The mechanisms explaining the benefits of CHS compared to conventional static ice storage (SIS) remain unclear and clinical data on safety and feasibility of lung CHS are limited. Therefore, we aimed to provide a focus review on animal experiments, molecular mechanisms, CHS devices, current clinical experience, and potential future benefits of CHS. Rabbit, canine and porcine experiments showed superior lung physiology after prolonged storage at 10°C vs. ≤4°C. In recent molecular analyses of lung CHS, better protection of mitochondrial health and higher levels of antioxidative metabolites were observed. The acquired insights into the underlying mechanisms and development of CHS devices allowed clinical application and research using CHS for lung preservation. The initial findings are promising; however, further data collection and analysis are required to draw more robust conclusions. Extended lung preservation with CHS may provide benefits to both recipients and healthcare personnel. Reduced time pressure between procurement and transplantation introduces flexibility allowing better decision-making and overnight bridging by delaying transplantation to daytime without compromising outcome.

Multilevel Analysis of the Neovascularization and Integration Process of a Nonvascularized Rectus Fascia Transplantation.

Background: Failure to close the abdominal wall after intestinal transplantation (ITx) or multivisceral Tx remains a surgical challenge. An attractive method is the use of nonvascularized rectus fascia (NVRF) in which both layers of the donor abdominal rectus fascia are used as an inlay patch without vascular anastomosis. How this graft integrates over time remains unknown. The study aims to provide a multilevel analysis of the neovascularization and integration process of the NVRF. Methods: Three NVRF-Tx were performed after ITx. Clinical, radiological, histological, and immunological data were analyzed to get insights into the neovascularization and integration process of the NVRF. Moreover, cryogenic contrast-enhanced microfocus computed tomography (microCT) analysis was used for detailed reconstruction of the vasculature in and around the NVRF (3-dimensional histology). Results: Two men (31- and 51-y-old) and 1 woman (49-y-old) underwent 2 multivisceral Tx and 1 combined liver-ITx, respectively. A CT scan showed contrast enhancement around the fascia graft at 5 days post-Tx. At 6 weeks, newly formed blood vessels were visualized around the graft with Doppler ultrasound. Biopsies at 2 weeks post-Tx revealed inflammation around the NVRF and early fibrosis. At 6 months, classical 2-dimensional histological analysis of a biopsy confirmed integration of the fascia graft with strong fibrotic reaction without signs of rejection. A cryogenic contrast-enhanced microCT scan of the same biopsy revealed the presence of microvasculature, enveloping and penetrating the donor fascia. Conclusions: We showed clinical, histological, and microCT evidence of the neovascularization and integration process of the NVRF after Tx.

Bariatric surgery post-liver transplantation: A Belgian nationwide study.

Weight gain poses a rising concern post-liver transplantation (LT), and metabolic dysfunction-associated steatotic liver disease might impair graft health. The timing is crucial when considering bariatric surgery (BS) in a population with liver disease or transplantation. BS can be considered for post-LT weight gain, although the evidence is limited and the long-term outcome still uncertain. We conducted a national retrospective analysis in 5 Belgian transplant centers and included 25 patients with an LT followed by a bariatric procedure. A total of 187 LT patients without BS were included for comparison. Clinical, biochemical, and outcome data were retrospectively retrieved. In our nationwide cohort, 25 patients had undergone BS post-LT, at a median 3.5 years after LT. Twenty-one (84.0%) patients received a sleeve gastrectomy (SG). Patients were predominantly male (72.0%), with a lower age at time of transplantation compared with the non-BS population (54.5 vs. 60.6, p <0.001). Weight loss was significant and sustained, with a decrease in body mass index from 41.0±4.5 pre-BS to 32.6±5.8 1-3 years post-BS ( p <0.001) and 31.1±5.8 3-5 years post-BS ( p <0.001). Three pre-BS (12.0%) patients presented with recurrent and one (4.0%) de novo metabolic dysfunction-associated steatotic liver disease after LT, with 100% resolution post-BS ( p =0.016). Notable reductions were observed in alanine transaminase levels (40.5±28.5 U/L to 27.1±25.1 U/L post-BS, p =0.05) and HbA1c levels (6.9±1.6 to 6.0±1.4 post-BS, p <0.001). Three patients were re-transplanted, and eight patients died, of which five (20.0%) due to a nonhepatic malignancy and one (4.0%) due to liver failure. SG is the favored BS post-LT and has proven to be safe and feasible in a post-LT setting with favorable metabolic consequences. SG post-LT is a valid treatment for de novo and recurrent metabolic dysfunction-associated steatotic liver disease post-LT. Although we report on the largest cohort to date, there is still a need for larger cohorts to examine the effect of BS on patient and graft survival.

Tacrolimus Drug Exposure Level and Smoking Are Modifiable Risk Factors for Early De Novo Malignancy After Liver Transplantation for Alcohol-Related Liver Disease.

De novo malignancy (DNM) is the primary cause of mortality after liver transplantation (LT) for alcohol-related liver disease (ALD). However, data on risk factors for DNM development after LT are limited, specifically in patients with ALD. Therefore, we retrospectively analyzed all patients transplanted for ALD at our center before October 2016. Patients with a post-LT follow-up of <12 months, DNM within 12 months after LT, patients not on tacrolimus in the 1st year post-LT, and unknown smoking habits were excluded. Tacrolimus drug exposure level (TDEL) was calculated by area under the curve of trough levels in the 1st year post-LT. 174 patients received tacrolimus of which 19 (10.9%) patients developed a DNM between 12 and 60 months post-LT. Multivariate cox regression analysis identified TDEL [HR: 1.710 (1.211-2.414); p = 0.002], age [1.158 (1.076-1.246); p < 0.001], number of pack years pre-LT [HR: 1.021 (1.004-1.038); p = 0.014] and active smoking at LT [HR: 3.056 (1.072-8.715); p = 0.037] as independent risk factors for DNM. Tacrolimus dose minimization in the 1st year after LT and smoking cessation before LT might lower DNM risk in patients transplanted for ALD.

Recent outcomes of liver transplantation for Budd-Chiari syndrome: A study of the European Liver Transplant Registry (ELTR) and affiliated centers.

BACKGROUND AND AIMS: Management of Budd-Chiari syndrome (BCS) has improved over the last decades. The main aim was to evaluate the contemporary post-liver transplant (post-LT) outcomes in Europe. APPROACH AND RESULTS: Data from all patients who underwent transplantation from 1976 to 2020 was obtained from the European Liver Transplant Registry (ELTR). Patients < 16 years, with secondary BCS or HCC were excluded. Patient survival (PS) and graft survival (GS) before and after 2000 were compared. Multivariate Cox regression analysis identified predictors of PS and GS after 2000. Supplemental data was requested from all ELTR-affiliated centers and received from 44. In all, 808 patients underwent transplantation between 2000 and 2020. One-, 5- and 10-year PS was 84%, 77%, and 68%, and GS was 79%, 70%, and 62%, respectively. Both significantly improved compared to outcomes before 2000 ( p < 0.001). Median follow-up was 50 months and retransplantation rate was 12%. Recipient age (aHR:1.04,95%CI:1.02-1.06) and MELD score (aHR:1.04,95%CI:1.01-1.06), especially above 30, were associated with worse PS, while male sex had better outcomes (aHR:0.63,95%CI:0.41-0.96). Donor age was associated with worse PS (aHR:1.01,95%CI:1.00-1.03) and GS (aHR:1.02,95%CI:1.01-1.03). In 353 patients (44%) with supplemental data, 33% had myeloproliferative neoplasm, 20% underwent TIPS pre-LT, and 85% used anticoagulation post-LT. Post-LT anticoagulation was associated with improved PS (aHR:0.29,95%CI:0.16-0.54) and GS (aHR:0.48,95%CI:0.29-0.81). Hepatic artery thrombosis and portal vein thrombosis (PVT) occurred in 9% and 7%, while recurrent BCS was rare (3%). CONCLUSIONS: LT for BCS results in excellent patient- and graft-survival. Older recipient or donor age and higher MELD are associated with poorer outcomes, while long-term anticoagulation improves both patient and graft outcomes.

The dynamics of cytokine release during 24 hours continuous normothermic machine perfusion liver preservation: An explorative porcine study.

BACKGROUND: Normothermic machine perfusion (NMP) has been proposed to preserve liver grafts in a less pro-inflammatory environment. However, the effect of NMP on liver inflammation remains unclear. Therefore, we aimed at characterizing the inflammatory response during continuous NMP with a comprehensive investigation of cytokine release during perfusion. METHODS: Ten porcine livers underwent either 24 h NMP or whole blood-based NMP (WB-NMP) immediately after procurement. WB-NMP was used as a positive control to mimic early post-reperfusion inflammation. High mobility group box-1 (HMGB1), interleukin 1-beta (IL-1beta), tumor necrosis factor-alpha (TNFalpha), interleukin 6 (IL-6), 8 (IL-8), and 10 (IL-10), transforming growth factor-beta (TGFbeta), aspartate transferase (AST), and hyaluronic acid were measured in the perfusate. The area under the curve (AUC) of their perfusate concentration was compared between groups. Median (IQR) is given. RESULTS: The AUC of HMGB1 and IL-1beta was similar between groups. Compared to WB-NMP, NMP inhibited the release of TNFalpha [NMP: 20275 (18402-32 152), WB-NMP: 242100 (203511-244 238); p = 0.01], IL-6 [NMP: 1206 (338.9-1686), WB-NMP: 8444 (7359-10 087); p = 0.03], and IL-8 [NMP: 1635 (106.90-2130), WB-NMP: 3951 (3090-4116); p = 0.008]. The release of TGFbeta remained unchanged but IL-10 release was lower in NMP [1612 (1313-1916), WB-NMP: 5591 (4312-6421); p = 0.01]. The ratios TGFbeta:TNFalpha and IL-10:TNFalpha were significantly higher in the NMP than in the WB-NMP group. Importantly, the AUC of AST was significantly lower during NMP [1960 (1950-2893)] than WB-NMP [6812 (6370-7916); p = 0.02]. CONCLUSIONS: Continuous NMP leads to the release of detectable levels of cytokines with a slow, linear increase over time and a shift toward anti-inflammatory signaling.

Outcomes of liver transplantation for hepatopulmonary syndrome in patients with concomitant respiratory disease.

BACKGROUND & AIMS: Concomitant respiratory disease is a common finding in patients with hepatopulmonary syndrome (HPS). Among patients who underwent liver transplantation (LT) for HPS, we compared characteristics and outcome of patients with versus without concomitant respiratory disease. METHODS: This single center retrospective observational study included patients with HPS who underwent LT between 1999 and 2020. RESULTS: During the study period, 32 patients with HPS received a LT; nine (28%) with concomitant respiratory disease of whom one required a combined lung-liver transplantation. Patients with concomitant respiratory disease had higher PaCO2 (38 vs. 33 mm Hg, p = .031). The 30-day postoperative mortality was comparable, but the estimated cumulative probability of resolution of oxygen therapy after LT in HPS patients with versus those without concomitant respiratory disease was lower: 63% versus 91% at 12 months and 63% versus 100% at 18 months (HR 95% CI .140-.995, p = .040). In addition to the presence of concomitant respiratory disease (p = .040), history of smoking (p = .012), and high baseline 99mTcMAA shunt fraction (≥20%) (p = .050) were significantly associated with persistent need of oxygen therapy. The 5-year estimated cumulative probability of mortality in patients with concomitant respiratory disease was worse: 50% versus 23% (HR 95% CI .416-6.867, p = .463). CONCLUSIONS: The presence of a concomitant respiratory disease did not increase the short-term postoperative mortality after LT in patients with HPS. However, it resulted in a longer need for oxygen therapy.

Simultaneous Lung-abdominal Organ Procurement From Donation After Circulatory Death Donors Reduces Donor Hepatectomy Time.

BACKGROUND: Prolonged organ procurement time impairs the outcome of donation after circulatory death (DCD) and liver transplantation (LiT). Our transplant team developed a simultaneous, rather than sequential, lung-abdominal organ explantation strategy for DCD donation to prioritize liver procurement. We evaluated whether this change in strategy effectively reduced donor hepatectomy time (dHT), without affecting donor pneumonectomy time (dPT), and influenced LiT and lung transplantation outcome. METHODS: All lung-abdominal and abdominal-only transplant procedures between 2010 and 2020 were analyzed in this retrospective cohort study. Relationships were assessed between the year of transplant and dHT and dPT (univariate linear regression), 1-y patient and graft survival, primary graft dysfunction, and nonanastomotic biliary strictures (univariate logistic regression). RESULTS: Fifty-two lung-abdominal and 110 abdominal-only DCD procedures were analyzed. A significant decrease in dHT was noted in lung-abdominal (slope -1.14 [-2.14; -0.15], P = 0.026) but not in abdominal-only procedures; dPT did not increase. There were no significant associations between the year of transplant and nonanastomotic biliary strictures frequency, primary graft dysfunction incidence, 1-y patient, and graft survival. CONCLUSIONS: Simultaneous organ procurement in multiorgan lung-abdominal DCD procedures is feasible, and effectively shortened dHT without affecting lung transplantation outcome. No impact on LiT outcome was observed; however, larger multicenter studies are needed.

Organ Repair and Regeneration During Ex Situ Dynamic Preservation: The Future is Nano.

Organ preservation and assessment with machine perfusion (MP) has provided transplant physicians with the ability to evaluate and select grafts suitable for transplantation. Nevertheless, the discard of organs considered too damaged still sustains the imbalance between donor organs supply and demands. Therefore, there is the pressing clinical need for strategies to repair and/or regenerate organs before transplantation, and MP is uniquely positioned to satisfy this need. The systemic administration of mesenchymal stromal cells (MSC) was shown to reduce ischemia-reperfusion injury in pre-clinical organ transplant models but could not be reproduced in clinical transplantation, largely because of inefficient cell delivery. The administration of MSC during MP is one strategy that recently gained much attention as an alternative delivery method to target MSC directly to the donor organ. However, careful reinterpretation of preliminary results reveals that this approach is equally limited by a suboptimal delivery of short-lived MSC to the target organ. In contrast, the use of MSC secretome and/or extracellular vesicles therapy during MP seems to be more efficient in harnessing MSC properties during MP. In this mini review we speculate on the future of the novel niche of ex situ organ repair and regeneration before transplantation.

INT-767-A Dual Farnesoid-X Receptor (FXR) and Takeda G Protein-Coupled Receptor-5 (TGR5) Agonist Improves Survival in Rats and Attenuates Intestinal Ischemia Reperfusion Injury.

Intestinal ischemia is a potentially catastrophic emergency, with a high rate of morbidity and mortality. Currently, no specific pharmacological treatments are available. Previous work demonstrated that pre-treatment with obeticholic acid (OCA) protected against ischemia reperfusion injury (IRI). Recently, a more potent and water-soluble version has been synthesized: Intercept 767 (INT-767). The aim of this study was to investigate if intravenous treatment with INT-767 can improve outcomes after IRI. In a validated rat model of IRI (60 min ischemia + 60 min reperfusion), three groups were investigated (n = 6/group): (i) sham: surgery without ischemia; (ii) IRI + vehicle; and (iii) IRI + INT-767. The vehicle (0.9% NaCl) or INT-767 (10 mg/kg) were administered intravenously 15 min after start of ischemia. Endpoints were 7-day survival, serum injury markers (L-lactate and I-FABP), histology (Park-Chiu and villus length), permeability (transepithelial electrical resistance and endotoxin translocation), and cytokine expression. Untreated, IRI was uniformly lethal by provoking severe inflammation and structural damage, leading to translocation and sepsis. INT-767 treatment significantly improved survival by reducing inflammation and preserving intestinal structural integrity. This study demonstrates that treatment with INT-767 15 min after onset of intestinal ischemia significantly decreases IRI and improves survival. The ability to administer INT-767 intravenously greatly enhances its clinical potential.

Intestinal Donation and Utilization: Single-Center Analysis Within Eurotransplant.

Intestinal donor criteria are classically kept strict, thereby limiting donor supply. Indications for intestinal transplantation (ITx) are rare, but improved outcome and new emerging indications lead to increased demand and relaxing donor criteria should be considered. We sought to compare the donor criteria of intestines transplanted at our center with predefined (per protocol) criteria, and to determine how relaxing donor criteria could impact the potential donor pool. Donor criteria used in 22 consecutive ITx at our center between 2000 and 2020 were compared with predefined criteria. Next, multiorgan donors effectively offered by our Donor Network to Eurotransplant between 2014 and 2020 were retrospectively screened, according to predefined and effectively used intestinal donation criteria. Finally, utilization rate of offered intestines was calculated. In our ITx series, the effectively used donor criteria were less strict than those initially predefined. With these relaxed criteria, a favorable 5-year graft/patient survival of 75% and 95%, respectively was reached. Applying these relaxed criteria would lead to a 127% increase in intestinal offers. Paradoxically, 70% of offered intestines were not used. In conclusion, a significant increase in intestinal donation could be obtained by relaxing donor criteria, while still achieving excellent outcome. Offered intestines are underutilized.

The Distinct Innate Immune Response of Warm Ischemic Injured Livers during Continuous Normothermic Machine Perfusion.

Although normothermic machine perfusion (NMP) provides superior preservation of liver grafts compared to static cold storage and allows for viability testing of high-risk grafts, its effect on the liver immune compartment remains unclear. We investigated the innate immune response during 6 h of continuous NMP (cNMP) of livers that were directly procured (DP, n = 5) or procured after 60 min warm ischemia (WI, n = 5), followed by 12 h of whole blood (WB) reperfusion. WI livers showed elevated transaminase levels during cNMP but not after WB reperfusion. Perfusate concentrations of TNF-α were lower in WI livers during cNMP and WB reperfusion, whereas IL-8 concentrations did not differ significantly. TGF-ß concentrations were higher in WI livers during NMP but not after WB reperfusion, whereas IL-10 concentrations were similar. Endoplasmic stress and apoptotic signaling were increased in WI livers during cNMP but not after WB reperfusion. Additionally, neutrophil mobilization increased to a significantly lesser extent in WI livers at the end of NMP. In conclusion, WI livers exhibit a distinct innate immune response during cNMP compared to DP livers. The cytokine profile shifted towards an anti-inflammatory phenotype during cNMP and WB reperfusion, and pro-apoptotic signaling was stronger during cNMP. During WB reperfusion, livers exhibited a blunted cytokine release, regardless of ischemic damage, supporting the potential reconditioning effect of cNMP.