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Frontiers in Cardiovascular Medicine 2024During donation after circulatory death (DCD), cardiac grafts are exposed to potentially damaging conditions that can impact their quality and post-transplantation...
BACKGROUND
During donation after circulatory death (DCD), cardiac grafts are exposed to potentially damaging conditions that can impact their quality and post-transplantation outcomes. In a clinical DCD setting, patients have closed chests in most cases, while many experimental models have used open-chest conditions. We therefore aimed to investigate and characterize differences in open- vs. closed-chest porcine models.
METHODS
Withdrawal of life-sustaining therapy (WLST) was simulated in anesthetized juvenile male pigs by stopping mechanical ventilation following the administration of a neuromuscular block. Functional warm ischemic time (fWIT) was defined to start when systolic arterial pressure was <50 mmHg. Hemodynamic changes and blood chemistry were analyzed. Two experimental groups were compared: (i) an open-chest group with sternotomy prior to WLST and (ii) a closed-chest group with sternotomy after fWIT.
RESULTS
Hemodynamic changes during the progression from WLST to fWIT were initiated by a rapid decline in blood oxygen saturation and a subsequent cardiovascular hyperdynamic (HD) period characterized by temporary elevations in heart rates and arterial pressures in both groups. Subsequently, heart rate and systolic arterial pressure decreased until fWIT was reached. Pigs in the open-chest group displayed a more rapid transition to the HD phase after WLST, with peak heart rate and peak rate-pressure product occurring significantly earlier. Furthermore, the HD phase duration tended to be shorter and less intense (lower peak rate-pressure product) in the open-chest group than in the closed-chest group.
DISCUSSION
Progression from WLST to fWIT was more rapid, and the hemodynamic changes tended to be less pronounced in the open-chest group than in the closed-chest group. Our findings support clear differences between open- and closed-chest models of DCD. Therefore, recommendations for clinical DCD protocols based on findings in open-chest models must be interpreted with care.
PubMed: 38938649
DOI: 10.3389/fcvm.2024.1325160 -
American Journal of Physiology.... Jun 2024Ischemia-reperfusion injury (IRI) is an intrinsic risk associated with liver transplantation. hepatic machine perfusion (MP) is an emerging organ preservation technique...
Ischemia-reperfusion injury (IRI) is an intrinsic risk associated with liver transplantation. hepatic machine perfusion (MP) is an emerging organ preservation technique that can mitigate IRI, especially in livers subjected to prolonged warm ischemia time (WIT). However, a method to quantify the biological response to WIT during MP has not been established. Previous studies used physiologically-based pharmacokinetic (PBPK) modeling to demonstrate that a decrease in hepatic transport and biliary excretion of the tracer molecule sodium fluorescein (SF) could correlate with increasing WIT . Furthermore, these studies proposed intracellular sequestration of the hepatocyte canalicular membrane transporter multi-drug resistance-associated protein 2 (MRP2) leading to decreased MRP2 activity (maximal transport velocity; ) as the potential mechanism for decreased biliary SF excretion. We adapted an extant PBPK model to account for hepatic MP and fit a 6-parameter version of this model to control time course measurements of SF in MP perfusate and bile. We then identified parameters whose values were likely insensitive to changes in WIT and fixed them to generate a reduced model with only 3 unknown parameters. Finally, we fit the reduced model to each individual biological replicate SF time course with differing WIT and found the mean estimated value for each parameter and compared them using a one-way ANOVA. We demonstrated that there was a significant decrease in the estimated value of for MRP2 at 30 min WIT. These studies provide the foundation for future studies investigating real-time assessment of liver viability during MP.
PubMed: 38917324
DOI: 10.1152/ajpgi.00048.2024 -
Journal of Visualized Experiments : JoVE Jun 2024Pancreatic islet transplantation is an emerging treatment for type I diabetes; however, it is limited by donor matching and availability. Porcine islet...
Pancreatic islet transplantation is an emerging treatment for type I diabetes; however, it is limited by donor matching and availability. Porcine islet xenotransplantation offers a promising alternative to allotransplantation, with the potential for large-scale production of on-demand, functional islets. The yield and viability of isolated islets is highly susceptible to the quality of the donor pancreas and the method of procurement, particularly the duration of warm-ischemia time. To improve organ preservation and subsequent islet yield and viability, we have developed a protocol for surgical perfusion and resection of the porcine pancreas. This protocol employs direct infrarenal aortic cannulation and organ perfusion to both minimize warm-ischemia time and simplify the procedure for operators who do not have extensive surgical expertise. Subsequent arterial perfusion of the pancreas via the aorta flushes stagnant blood from the microvasculature, thereby reducing thrombosis and oxidative damage to the tissue. This manuscript provides a detailed protocol for surgical perfusion and resection of the porcine pancreas, followed by islet isolation and purification.
Topics: Animals; Swine; Islets of Langerhans; Islets of Langerhans Transplantation; Perfusion; Pancreas; Transplantation, Heterologous
PubMed: 38912778
DOI: 10.3791/66350 -
Hepatobiliary Surgery and Nutrition Jun 2024Liver retransplant is the only option to save a patient with liver graft failure. However, it is controversial due to its poor survival outcome compared to primary...
BACKGROUND
Liver retransplant is the only option to save a patient with liver graft failure. However, it is controversial due to its poor survival outcome compared to primary transplantation. Insufficient deceased organ donation in Taiwan leads to high waitlist mortality. Hence, living-donor grafts offer a valuable alternative for retransplantation. This study aims to analyze the single center's outcome in living donor liver retransplantation (re-LDLT) and deceased donor liver retransplantation (re-DDLT) as well as the survival related confounding risk factors.
METHODS
This is a single center retrospective study including 32 adults who underwent liver retransplantation (re-LT) from June 2002 to April 2020. The cohort was divided into a re-LDLT and a re-DDLT group and survival outcomes were analyzed. Patient outcomes over different periods, the effect of timing on survival, and multivariate analysis for risk factors were also demonstrated.
RESULTS
Of the 32 retransplantations, the re-LDLT group (n=11) received grafts from younger donors (31.3 43.75 years, P=0.016), with lower graft weights (688 1,457.2 g, P<0.001) and shorter cold ischemia time (CIT) (45 313 min, P<0.001). The 5-year survival was significantly better in the re-LDLT group than in the re-DDLT group (100% 70.8%, P=0.02). This difference was adjusted when only retransplantation after 2010 was analyzed. Further analysis showed that the timing of retransplantation (early late) did not affect patient survival. Multivariate analysis revealed that prolonged warm ischemia time (WIT) and intraoperative blood transfusion were related to poor long-term survival.
CONCLUSIONS
Retransplantation with living donor graft demonstrated good long-term outcomes with acceptable complications to both recipient and donor. It may serve as a choice in areas lacking deceased donors. The timing of retransplantation did not affect the long-term survival. Further effort should be made to reduce WIT and massive blood transfusion as they contributed to poor survival after retransplantation.
PubMed: 38911194
DOI: 10.21037/hbsn-23-178 -
Transplantation Jun 2024Curcumin is a pleiotropic antioxidant polyphenol, which has proven to be highly protective in various models of liver injury and inflammation. We hypothesized that...
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.
PubMed: 38902859
DOI: 10.1097/TP.0000000000005117 -
Scandinavian Journal of Urology Jun 2024Surgical video review is an emerging tool for assessing patient outcomes, especially in complex surgeries such as robot-assisted partial nephrectomy (RAPN). Assessing...
INTRODUCTION
Surgical video review is an emerging tool for assessing patient outcomes, especially in complex surgeries such as robot-assisted partial nephrectomy (RAPN). Assessing and measuring warm ischaemia time (WIT) during RAPN by dividing it into the time used for tumour excision time (ExcT), time used for kidney reconstruction time (RecT) and intermediate time (IntT) has not been performed before. This study aimed to analyse the factors that can influence all surgical times and assess their impact on positive surgical margins (PSMs) and complication rates.
METHODS
We evaluated 32 surgical video recordings from patients undergoing RAPN and measured WIT, ExcT, RecT and IntT with a stopwatch. Factors such as tumour characteristics and surgeon experience were also recorded. SPSS software was used to identify the predictors for all surgical times and to correlate ExcT with PSM and RecT with complication rate.
RESULTS
We recorded a median WIT of 1,048 s (17 min and 28 s). The median of ExcT, RecT and IntT was 398 s (37.1% of WIT), 518 s (46.7% of WIT) and 180 s (16.2% of WIT), respectively. We found a significant correlation (P < 0.001) between R.E.N.A.L. score and all surgical times. No correlation was found between ExcT and PSM (P = 0.488) and between RecT and the probability of developing complications (P = 0.544).
CONCLUSION
Tumour morphology influences all surgical times, and surgeon experience influences only ExcT. We observed a short RecT during RAPN though at the cost of increased ExcT, and we believe that improving surgical experience, especially for the excision of more complex tumours, can reduce WIT during RAPN.
Topics: Humans; Nephrectomy; Robotic Surgical Procedures; Warm Ischemia; Kidney Neoplasms; Operative Time; Middle Aged; Male; Female; Aged; Video Recording; Kidney; Margins of Excision; Adult; Postoperative Complications; Plastic Surgery Procedures
PubMed: 38896070
DOI: 10.2340/sju.v59.40397 -
European Review For Medical and... Jun 2024End-stage liver disease is commonly associated with portal vein thrombosis (PVT). Lastly, PVT is no longer an absolute contraindication for liver transplantation, and...
OBJECTIVE
End-stage liver disease is commonly associated with portal vein thrombosis (PVT). Lastly, PVT is no longer an absolute contraindication for liver transplantation, and many centers adopt portal vein thrombectomy. PVT imposes special technical difficulties during living donor liver transplantation (LDLT). In this research, the experience with PVT cases during LDLT in a high-volume center is introduced.
PATIENTS AND METHODS
Between January 2018 and July 2023, 312 patients underwent LDLT. After 88 cases were excluded, 224 cases were included, and their incidence of pre-transplant PVT was 16.5% (37/224). Demographic and clinical features, perioperative variables, and post-transplant outcomes of patients with PVT (PVT group, n=37) were compared to patients who had no PVT (non-PVT group, n=187).
RESULTS
According to Yerdel classification, 16, 16, 2, and 3 patients had PVT grade I, II, III, and IV, respectively. Complete venous thrombectomy was accomplished in 34 patients, while for three patients, thrombectomy was not feasible, and graft inflow was established by interposition vascular graft. For portal flow modulation, splenectomy and splenic artery ligation were performed in 7 and 4 patients, respectively, while two patients underwent post-transplant splenic artery embolization. The PVT group had longer operation time (p<0.001), longer warm ischemia time (p=0.031), longer anhepatic phase (p<0.001), and intraoperatively required more than 3 packed RBCs units (p=0.029) and ≥1 platelet unit transfusion (p=0.021) than the non-PVT group. No statistically significant difference was found between groups in terms of re-exploration (p=0.954), post-transplant PVT (p=0.375), biliary (p=0.253) and arterial complications (p=0.593), ICU stay (p=0.633), hospital stay (p=896), and 30-day mortality (p=1.000). Survival analysis showed no statistically significant difference regarding 1-year survival (p=0.176) between both groups.
CONCLUSIONS
This study showed that patients with different stages of PVT can successfully undergo LDLT in experienced centers and that they do not differ from patients without PVT in terms of post-transplant complications.
Topics: Humans; Liver Transplantation; Portal Vein; Female; Male; Venous Thrombosis; Living Donors; Middle Aged; Adult; Thrombectomy; Retrospective Studies; End Stage Liver Disease
PubMed: 38884510
DOI: 10.26355/eurrev_202406_36380 -
Scientific Reports Jun 2024Intestinal preservation for transplantation is accompanied by hypoperfusion with long periods of ischemia with total blood cessation and absolute withdrawal of oxygen...
Intestinal preservation for transplantation is accompanied by hypoperfusion with long periods of ischemia with total blood cessation and absolute withdrawal of oxygen leading to structural damage. The application of intraluminal oxygen has been successfully tested in small-animal series during storage and transport of the organ but have been so far clinically unrelatable. In this study, we tested whether a simple and clinically approachable method of intraluminal oxygen application could prevent ischemic damage in a large animal model, during warm ischemia time. We utilised a local no-flow ischemia model of the small intestine in pigs. A low-flow and high-pressure intraluminal oxygen deliverance system was applied in 6 pigs and 6 pigs served as a control group. Mucosal histopathology, hypoxia and barrier markers were evaluated after two hours of no-flow conditions, in both treatment and sham groups, and in healthy tissue. Macro- and microscopically, the luminal oxygen delivered treatment group showed preserved small bowel's appearance, viability, and mucosal integrity. A gradual deterioration of histopathology and barrier markers and increase in hypoxia-inducible factor 1-α expression towards the sites most distant from the oxygen application was observed. Intraluminal low-flow, high oxygen delivery can preserve the intestinal mucosa during total ischemia of the small intestine. This finding can be incorporated in methods to overcome small bowel ischemia and improve intestinal preservation for transplantation.
Topics: Animals; Intestinal Mucosa; Intestine, Small; Oxygen; Swine; Ischemia; Disease Models, Animal; Organ Preservation; Hypoxia-Inducible Factor 1, alpha Subunit
PubMed: 38877069
DOI: 10.1038/s41598-024-64660-x -
Transplantation Jun 2024This study examined 1071 adult primary kidney transplants from the French-controlled donation after the circulatory determination of death (cDCD) program, which uses...
BACKGROUND
This study examined 1071 adult primary kidney transplants from the French-controlled donation after the circulatory determination of death (cDCD) program, which uses normothermic regional perfusion (NRP), and involves short cold ischemia times (CIT) and constrained asystole times differing by donor age.
METHODS
Logistic regression identified risk factors for primary nonfunction (PNF), delayed graft function (DGF), and graft failure.
RESULTS
Risk factors for PNF included donor hypertension, admission for ischemic vascular stroke, and HLA DR mismatches. Risk factors for DGF included functional warm ischemia time >40 min, dialysis >2 y, recipient body mass index of 30 kg/m2 or higher, recipient diabetes, and CIT >10 h. Risk factors for 1-y graft failure included donor hypertension, donor lung recovery, ostial calcification, recipient cardiovascular comorbidities, and HLA DR mismatches. A high donor estimated glomerular filtration rate protected against DGF and graft failure at 1-y. After adjustment restricted to recipient and graft factors and donor age, the risks of PNF, DGF, and graft failure increased with donor age up to 65 y and then remained stable.
CONCLUSIONS
The study suggests that cDCD kidney transplants are highly successful, but also that its outcomes are influenced by lung recovery, poor HLA DR matching, and warm ischemia times differing with donor age. Our study identified several risk factors for kidney transplantation failure after cDCD with systematic use of NRP and some of them seem as modifiable variables associated with cDCD transplant outcome.
PubMed: 38872246
DOI: 10.1097/TP.0000000000005102 -
American Journal of Physiology. Renal... Jun 2024Kidneys from donors with prolonged warm and cold ischemia are prone to post-transplant T cell-mediated rejection (TCMR) due to ischemia-reperfusion injury (IRI)....
Kidneys from donors with prolonged warm and cold ischemia are prone to post-transplant T cell-mediated rejection (TCMR) due to ischemia-reperfusion injury (IRI). However, the precise mechanisms still remain obscure. Renal tubular epithelial cells (TECs) are the main target during IRI. Meanwhile, we reported previously that murine double minute 2 (MDM2) actively participates in TEC homeostasis during IRI. In this study, we established a murine model of renal IRI and a cell model of hypoxia/reoxygenation by culturing immortalized rat renal proximal tubule cells (NRK-52E) in a hypoxic environment for different time points followed by 24 hours of reoxygenation or incubating NRK-52E cells in a chemical anoxia/recovery environment. We found that during renal IRI, MDM2 expression increased on the membrane of TECs and aggregated mainly on the basolateral side. This process was accompanied by a reduction of a transmembrane protein programmed death-ligand 1 (PD-L1), a co-inhibitory second signal for T cells in TECs. By using mutant plasmids of MDM2 to anchor MDM2 on the cell membrane or nuclei, we found that the upregulation of membrane MDM2 could promote the ubiquitination of PD-L1 and lead to its ubiquitination-proteasome degradation. Lastly, we set up a co-culture system of TECs and CD4+ T cells in vitro; our results revealed that the immunogenicity of TECs was enhanced during IRI. In conclusion, our findings suggest that the increased immunogenicity of TECs during IRI may be related to ubiquitinated degradation of PD-L1 by increased MDM2 on the cell membrane, which consequently results in T cell activation and TCMR.
PubMed: 38867673
DOI: 10.1152/ajprenal.00200.2023