Flow competition between hepatic arterial and portal venous flow during hypothermic machine perfusion preservation of porcine livers

Hypothermic machine perfusion (HMP) is regarded as a better preservation method for donor livers than cold storage. During HMP, livers are perfused through the inlet blood vessels, namely the hepatic artery (HA) and the portal vein (PO. In previous HMP feasibility studies of porcine and human livers, we observed that the PV flow decreased while the HA flow increased. This flow competition restored either spontaneously or by lowering the HA pressure (P-HA). Since this phenomenon had never been observed before and because it affects the HMP stability, it is essential to gain more insight into the determinants of flow competition. To this end, we investigated the influence of the HMP boundary conditions on liver flows during controlled experiments. This paper presents the flow effects induced by increasing P-HA and by obstructing the outlet blood vessel, which is the vena cava inferior (VCI). Flow competition was evoked by increasing P-HA to 55-70 mmHg, as well as by obstructing the VCI. Remarkably, a severe obstruction resulted in a repetitive and alternating tradeoff between the HA and PV flows. These phenomena could be related to intra-sinusoidal pressure alterations. Consequently, a higher P-HA is most likely transmitted to the sinusoidal level. This increased sinusoidal pressure reduces the pressure drop between the PV and the sinusoids, leading to a decreased PV perfusion. Flow competition has not been encountered or evoked under physiological conditions and should be taken into account for the design of liver HMP protocols. Nevertheless, more research is necessary to determine the optimal parameters for stable HMP

Case report: Immediate revascularization for symptomatic hepatic artery pseudoaneurysm after orthotopic liver transplantation? A case series and literature review

IntroductionHepatic artery pseudoaneurysm (HAPA), a rare vascular complication that can develop after liver transplantation, is associated with a high mortality rate and graft loss. To salvage the liver graft, immediate revascularization, either through surgical or endovascular intervention, is required. However, currently there is no consensus on the optimal strategy. Here, we report three cases of liver transplant recipients diagnosed with HAPA and treated with immediate revascularization. In addition, we present an overview of HAPA cases described in the literature and make recommendations on how to treat this rare complication.MethodsAll adults transplanted in our center between 2005 and 2021 were retrospectively reviewed. Literature search was done in PubMed for original studies between 1980 and 2021 reporting early hepatic artery (pseudo) aneurysm after liver transplantation requiring either surgical or endovascular intervention.ResultsFrom a total of 1,172, 3 liver transplant patients were identified with a symptomatic HAPA and treated with immediate revascularization. HAPA occurred 73, 27, and 8 days after liver transplantation and was treated with immediate revascularization (two surgical and one endovascular intervention). Literature review identified 127 cases of HAPA. HAPA was managed with endovascular therapy in 20 cases and by surgical intervention in 89 cases. Overall reported mortality rate was 39.6%, whereas overall graft survival was 45.2%.ConclusionImmediate surgical or radiological interventional excision and prompt revascularization to salvage liver grafts is feasible but still associated with a high mortality

Orlistat treatment is safe in overweight and obese liver transplant recipients: a prospective, open label trial

Obesity is a frequent complication following liver transplantation and is insufficiently responsive to dietary and life style advice. We studied the safety of orlistat treatment in obese and overweight liver transplant recipients (n = 15) on a stable tacrolimus-based immunosuppressive regimen. For safety reasons, the treatment period was restricted (6 months 120 mg t.i.d., 3 months 120 mg daily). Three patients dropped out, tacrolimus dose was adjusted in six of 12 remaining patients (dose reduction in 4, increase in 2, P = N.S.). All dose adjustments occurred during the 6 months of orlistat 120 mg t.i.d. therapy. No drug intolerance, adverse events or episodes of rejection occurred during the study. Efficacy of orlistat treatment in this population could not be shown, because a formal control population was not included in this safety trial. Moreover, only a significant decrease of waist circumference (P < 0.01 versus start of the study), but not of weight or body mass index, was achieved in the treated group. Orlistat treatment is well tolerated in liver transplant recipients and can be started safely, provided immunosuppressive drug levels and dietary adherence are closely monitored

Role of PEG35, Mitochondrial ALDH2, and Glutathione in Cold Fatty Liver Graft Preservation: An IGL-2 Approach.

The total damage inflicted on the liver before transplantation is associated with severalsurgical manipulations, such as organ recovery, washout of the graft, cold conservation in organpreservation solutions (UW, Celsior, HTK, IGL-1), and rinsing of the organ before implantation.Polyethylene glycol 35 (PEG35) is the oncotic agent present in the IGL-1 solution, which is an alterna-tive to UW and Celsior solutions in liver clinical transplantation. In a model of cold preservation inrats (4◦C; 24 h), we evaluated the effects induced by PEG35 on detoxifying enzymes and nitric oxide,comparing IGL-1 to IGL-0 (which is the same as IGL-1 without PEG). The benefits were also assessedin a new IGL-2 solution characterized by increased concentrations of PEG35 (from 1 g/L to 5 g/L)and glutathione (from 3 mmol/L to 9 mmol/L) compared to IGL-1. We demonstrated that PEG35promoted the mitochondrial enzyme ALDH2, and in combination with glutathione, prevented theformation of toxic aldehyde adducts (measured as 4-hydroxynonenal) and oxidized proteins (AOPP).In addition, PEG35 promoted the vasodilator factor nitric oxide, which may improve the microcircu-latory disturbances in steatotic grafts during preservation and revascularization. All of these resultslead to a reduction in damage inflicted on the fatty liver graft during the cold storage preservation.In this communication, we report on the benefits of IGL-2 in hypothermic static preservation, whichhas already been proved to confer benefits in hypothermic oxygenated dynamic preservation. Hence,the data reported here reinforce the fact that IGL-2 is a suitable alternative to be used as a uniquesolution/perfusate when hypothermic static and preservation strategies are used, either separately orcombined, easing the logistics and avoiding the mixture of different solutions/perfusates, especiallywhen fatty liver grafts are used. Further research regarding new therapeutic and pharmacologicalinsights is needed to explore the underlying mitochondrial mechanisms exerted by PEG35 in staticand dynamic graft preservation strategies for clinical liver transplantation purpos

Portal hypertension after combined liver and intestinal transplantation, a diagnostic and therapeutic challenge?

A widely accepted technique to transplant the liver-bowel bloc is first to perform a piggyback anastomosis of the donor suprahepatic vena cava to the recipient vena cava; second to restore the arterial blood supply through an aortic interposition graft; and third to ensure venous drainage of the native foregut. The venous drainage of the native foregut can be restored through an end-to-end portocaval anastomosis between the donor infrahepatic vena cava and the recipient portal vein. Stenosis of this anastomosis can lead to portal hypertension presenting with upper GI congestion, bleeding, and hypersplenism. We report the successful treatment of this complication using an e-PTFE-covered stent inserted following balloon angioplasty

Paneth Cell Alterations During Ischemia-reperfusion, Follow-up, and Graft Rejection After Intestinal Transplantation

BACKGROUND Ischemia-reperfusion (IR) injury is inevitable during intestinal transplantation (ITx) and executes a key role in the evolution towards rejection. Paneth cells (PC) are crucial for epithelial immune defense and highly vulnerable to IR injury. We investigated the effect of ITx on PC after reperfusion (T0), during follow-up, and rejection. Moreover, we investigated whether PC loss was associated with impaired graft homeostasis. METHODS Endoscopic biopsies, collected according to center-protocol and at rejection episodes, were retrospectively included (n=28 ITx, n=119 biopsies) Biopsies were immunohistochemically co-stained for PC (lysozyme) and apoptosis, and PC/crypt and lysozyme intensity were scored. RESULTS We observed a decrease in PC/crypt and lysozyme intensity in the first week after ITx (W1) compared to T0. There was a tendency towards a larger decline in PC/crypt (p=0.08) and lysozyme intensity (p=0.08) in W1 in patients who later developed rejection compared to patients without rejection. Follow-up biopsies showed that the PC number recovered, whereas lysozyme intensity remained reduced. This persisting innate immune defect may contribute to the well-known vulnerability of the intestine to infection. There was no clear evidence that PC were affected throughout rejection. CONCLUSION This study revealed a transient fall in PC numbers in the early post-ITx period, but a permanent reduction in lysozyme intensity following ITx. Further research is needed to determine the potential clinical impact of PC impairment after ITx