Anti-complement 5 antibody ameliorates antibody-mediated rejection after liver transplantation in rats

Antibody-mediated rejection (AMR) remains a refractory rejection after donor-specific antibody (DSA)-positive or blood-type incompatible liver transplantation (LT), even in the era of pre-transplant rituximab desensitization. This is due to the lack of not only effective post-transplant treatments but also robust animal models to develop/validate new interventions. Orthotopic LT from male Dark Agouti (DA) to male Lewis (LEW) rats was used to develop a rat LT-AMR model. LEW were pre-sensitized by a preceding skin transplantation from DA 4–6 weeks before LT (Group-PS), while sham procedure was performed in non-sensitized controls (Group-NS). Tacrolimus was daily administered until post-transplant day (PTD)-7 or sacrifice to suppress cellular rejections. Using this model, we validated the efficacy of anti-C5 antibody (Anti-C5) for LT-AMR. Group-PS+Anti-C5 received Anti-C5 intravenously on PTD-0 and -3. Group-PS showed increased anti-donor (DA) antibody-titers (P <0.001) and more C4d deposition in transplanted livers than in Group-NS (P <0.001). Alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bile acid (TBA), and total bilirubin (T-Bil) were all significantly higher in Group-PS than in Group-NS (all P <0.01). Thrombocytopenia (P <0.01), coagulopathies (PT-INR, P =0.04), and histopathological deterioration (C4d+h-score, P <0.001) were also confirmed in Group-PS. Anti-C5 administration significantly lowered anti-DA IgG (P <0.05), resulting in decreased ALP, TBA, and T-Bil on PTD-7 than in Group-PS (all P <0.01). Histopathological improvement was also confirmed on PTD-1, -3, and -7 (all P <0.001). Of the 9,543 genes analyzed by RNA sequencing, 575 genes were upregulated in LT-AMR (Group-PS vs. Group-NS). Of these, 6 were directly associated with the complement cascades. In particular, Ptx3, Tfpi2, and C1qtnf6 were specific to the classical pathway. Volcano plot analysis identified 22 genes that were downregulated by Anti-C5 treatment (Group-PS+Anti-C5 vs. Group-PS). Of these, Anti-C5 significantly down-regulated Nfkb2, Ripk2, Birc3, and Map3k1, the key genes that were amplified in LT-AMR. Notably, just two doses of Anti-C5 only on PTD-0 and -3 significantly improved biliary injury and liver fibrosis up to PTD-100, leading to better long-term animal survival (P =0.02). We newly developed a rat model of LT-AMR that meets all the Banff diagnostic criteria and demonstrated the efficacy of Anti-C5 antibody for LT-AMR

Worldwide variations in COVID-19 vaccination policies and practices in liver transplant settings: results of a multi-society global survey

BackgroundDespite the WHO's report of 24 available SARS-CoV-2 vaccines, limited data exist regarding vaccination policies for liver transplant (LT) patients. To address this, we conducted a global multi-society survey (EASL-ESOT-ELITA-ILTS) in LT centers.MethodsA digital questionnaire assessing vaccine policies, safety, efficacy, and center data was administered online to LT centers.ResultsOut of 168 responding centers, 46.4%, 28%, 13.1%, 10.7%, and 1.8% were from European, American, Western Pacific, Southeast Asian, and Eastern Mediterranean Regions. Most LT centers prioritized COVID-19 vaccine access for LT patients (76%) and healthcare workers (86%), while other categories had lower priority (30%). One-third of responders recommended mRNA vaccine exclusively, while booster doses were widely recommended (81%). One-third conducted post-vaccine liver function tests post COVID-19 vaccine. Only 16% of centers modified immunosuppression, and mycophenolate discontinuation or modification was the main approach. Side effects were seen in 1 in 1,000 vaccinated patients, with thromboembolism, acute rejection, and allergic reaction being the most severe. mRNA showed fewer side effects (−3.1, p = 0.002).ConclusionCOVID-19 vaccines and booster doses were widely used among LT recipients and healthcare workers, without a specific vaccine preference. Preventative immunosuppression adjustment post-vaccination was uncommon. mRNA vaccines demonstrated a favorable safety profile in this population

Global impact of the first wave of COVID-19 on liver transplant centers: A multi-society survey (EASL-ESOT/ELITA-ILTS)

Background and Aims: The global impact of SARS-CoV-2 on liver transplantation (LT) practices across the world is unknown. The goal of this survey was to assess the impact of the pandemic on global LT practices. Method: A prospective web-based survey (available online from 7th September 2020 to 31st December 2020) was proposed to the active members of the EASL-ESOT/ELITA-ILTS in the Americas (including North, Central, and South America) (R1), Europe (R2), and the rest of the world (R3). The survey comprised 4 parts concerning transplant processes, therapy, living donors, and organ procurement. Results: Of the 470 transplant centers reached, 128 answered each part of the survey, 29 centers (23%), 64 centers (50%), and 35 centers (27%) from R1, R2, and R3, respectively. When we compared the practices during the first 6 months of the pandemic in 2020 with those a year earlier in 2019, statistically significant differences were found in the number of patients added to the waiting list (WL), WL mortality, and the number of LTs performed. At the regional level, we found that in R2 the number of LTs was significantly higher in 2019 (p <0.01), while R3 had more patients listed, higher WL mortality, and more LTs performed before the pandemic. Countries severely affected by the pandemic (“hit” countries) had a lower number of WL patients (p = 0.009) and LTs (p = 0.002) during the pandemic. Interestingly, WL mortality was still higher in the “non-hit” countries in 2020 compared to 2019 (p = 0.022). Conclusion: The first wave of the pandemic differentially impacted LT practices across the world, especially with detrimental effects on the “hit” countries. Modifications to the policies of recipient and donor selection, organ retrieval, and postoperative recipient management were adopted at a regional or national level. Lay summary: The health emergency caused by the coronavirus pandemic has dramatically changed clinical practice during the pandemic. The first wave of the pandemic impacted liver transplantation differently across the world, with particularly detrimental effects on the countries badly hit by the virus. The resilience of the entire transplant network has enabled continued organ donation and transplantation, ultimately improving the lives of patients with end-stage liver disease

The impact of using an intraoperative goal directed fluid therapy protocol on clinical outcomes in patients undergoing total pancreatectomy and islet cell autotransplantation.

BACKGROUND: Patients undergoing total pancreatectomy and islet cell autotransplant (TPIAT) for treatment of pancreatitis are at risk for complications of over and under resuscitation. We hypothesized that using a goal directed fluid therapy (GDFT) protocol might impact clinical outcomes. MATERIALS AND METHODS: A consecutive series of adult patients undergoing TPIAT were managed intraoperatively using either standard fluid therapy (SFT, n = 44) or GDFT (n = 23) as part of a pilot study between January 2013 and May 2015. Patient characteristics, intraoperative, and postoperative data were recorded prospectively, then retrospectively analyzed for differences between the groups. RESULTS: The GDFT group had lower total fluid resuscitation (3,240 cc vs 5,173 cc, p \u3c 0.0001) and transfusion requirements (1.0 cc/kg vs 3.3 cc/kg, p = 0.050) compared to the SFT group. The pre to postop nadir hemoglobin change was significantly less for GDFT (4.2 vs 5.1 gm/dl, p = 0.021) despite less transfusion. CONCLUSIONS: Compared to SFT, using an intraoperative GDFT protocol in TPIAT patients was associated with significantly decreased intraoperative fluid resuscitation, blood transfusion and less postoperative dilutional anemia, without any difference in complications of underresuscitation. This pilot study suggests that GDFT is likely safe and further investigation is warranted

Use of HBsAg-positive donors in liver transplantation: An ILTS-EASL-AASLD multisociety survey

The gap between organ supply and demand in liver transplantation remains large in most parts of the world. One strategy to increase the donor pool is to use grafts infected with HCV, HBV, and/or HIV viruses. We aimed to explore the current use of HBsAg-positive liver grafts worldwide. A prospective cross-sectional web-based survey was designed, with a total of 28 queries, assessing national and local regulations, center experience, and center-specific experience related to the topic, and sent to all members of International Liver Transplantation Society, European Association for the Study of the Liver, and American Association for the Study of the Liver, and promoted on social media. A total of 135 liver transplant centers answered the survey: 38% from WHO European Regions, 39% from American regions, and 9.7% from South-East Asian regions. Most of the participating centers (67.3%) had been performing liver transplantation for over 15 years, with a mean of 66.5 liver transplants per year, and 54% also performed living-donor liver transplants. HBV-related disease was the indication for liver transplantation in an average of 15% of all liver transplantation cases. Regarding national and/or regional regulations, 40% of the centers reported that the use of HBsAg-positive donors was permitted, and an additional 20% could use them under special circumstances. Thirty-two centers (31%) had previously used HBsAg-positive donors. Among these centers, 62.5% conducted living-donor liver transplants and showed an increased inclination towards the use of HBsAg-positive grafts in centers with elevated waitlist mortality. HBsAg-positive donors are underutilized worldwide. The use of HBsAg-positive liver grafts could help to increase the donor pool, particularly in highly endemic areas.The gap between organ supply and demand in liver transplantation remains large in most parts of the world. One strategy to increase the donor pool is to use grafts infected with HCV, HBV, and/or HIV viruses. We aimed to explore the current use of HBsAg-positive liver grafts worldwide. A prospective cross-sectional web-based survey was designed, with a total of 28 queries, assessing national and local regulations, center experience, and center-specific experience related to the topic, and sent to all members of International Liver Transplantation Society, European Association for the Study of the Liver, and American Association for the Study of the Liver, and promoted on social media. A total of 135 liver transplant centers answered the survey: 38% from WHO European Regions, 39% from American regions, and 9.7% from South-East Asian regions. Most of the participating centers (67.3%) had been performing liver transplantation for over 15 years, with a mean of 66.5 liver transplants per year, and 54% also performed living-donor liver transplants. HBV-related disease was the indication for liver transplantation in an average of 15% of all liver transplantation cases. Regarding national and/or regional regulations, 40% of the centers reported that the use of HBsAg-positive donors was permitted, and an additional 20% could use them under special circumstances. Thirty-two centers (31%) had previously used HBsAg-positive donors. Among these centers, 62.5% conducted living-donor liver transplants and showed an increased inclination towards the use of HBsAg-positive grafts in centers with elevated waitlist mortality. HBsAg-positive donors are underutilized worldwide. The use of HBsAg-positive liver grafts could help to increase the donor pool, particularly in highly endemic areas

Datasheet2_Worldwide variations in COVID-19 vaccination policies and practices in liver transplant settings: results of a multi-society global survey.pdf

BackgroundDespite the WHO's report of 24 available SARS-CoV-2 vaccines, limited data exist regarding vaccination policies for liver transplant (LT) patients. To address this, we conducted a global multi-society survey (EASL-ESOT-ELITA-ILTS) in LT centers.MethodsA digital questionnaire assessing vaccine policies, safety, efficacy, and center data was administered online to LT centers.ResultsOut of 168 responding centers, 46.4%, 28%, 13.1%, 10.7%, and 1.8% were from European, American, Western Pacific, Southeast Asian, and Eastern Mediterranean Regions. Most LT centers prioritized COVID-19 vaccine access for LT patients (76%) and healthcare workers (86%), while other categories had lower priority (30%). One-third of responders recommended mRNA vaccine exclusively, while booster doses were widely recommended (81%). One-third conducted post-vaccine liver function tests post COVID-19 vaccine. Only 16% of centers modified immunosuppression, and mycophenolate discontinuation or modification was the main approach. Side effects were seen in 1 in 1,000 vaccinated patients, with thromboembolism, acute rejection, and allergic reaction being the most severe. mRNA showed fewer side effects (−3.1, p = 0.002).ConclusionCOVID-19 vaccines and booster doses were widely used among LT recipients and healthcare workers, without a specific vaccine preference. Preventative immunosuppression adjustment post-vaccination was uncommon. mRNA vaccines demonstrated a favorable safety profile in this population.</p

Datasheet3_Worldwide variations in COVID-19 vaccination policies and practices in liver transplant settings: results of a multi-society global survey.docx

BackgroundDespite the WHO's report of 24 available SARS-CoV-2 vaccines, limited data exist regarding vaccination policies for liver transplant (LT) patients. To address this, we conducted a global multi-society survey (EASL-ESOT-ELITA-ILTS) in LT centers.MethodsA digital questionnaire assessing vaccine policies, safety, efficacy, and center data was administered online to LT centers.ResultsOut of 168 responding centers, 46.4%, 28%, 13.1%, 10.7%, and 1.8% were from European, American, Western Pacific, Southeast Asian, and Eastern Mediterranean Regions. Most LT centers prioritized COVID-19 vaccine access for LT patients (76%) and healthcare workers (86%), while other categories had lower priority (30%). One-third of responders recommended mRNA vaccine exclusively, while booster doses were widely recommended (81%). One-third conducted post-vaccine liver function tests post COVID-19 vaccine. Only 16% of centers modified immunosuppression, and mycophenolate discontinuation or modification was the main approach. Side effects were seen in 1 in 1,000 vaccinated patients, with thromboembolism, acute rejection, and allergic reaction being the most severe. mRNA showed fewer side effects (−3.1, p = 0.002).ConclusionCOVID-19 vaccines and booster doses were widely used among LT recipients and healthcare workers, without a specific vaccine preference. Preventative immunosuppression adjustment post-vaccination was uncommon. mRNA vaccines demonstrated a favorable safety profile in this population.</p

Datasheet1_Worldwide variations in COVID-19 vaccination policies and practices in liver transplant settings: results of a multi-society global survey.pdf

BackgroundDespite the WHO's report of 24 available SARS-CoV-2 vaccines, limited data exist regarding vaccination policies for liver transplant (LT) patients. To address this, we conducted a global multi-society survey (EASL-ESOT-ELITA-ILTS) in LT centers.MethodsA digital questionnaire assessing vaccine policies, safety, efficacy, and center data was administered online to LT centers.ResultsOut of 168 responding centers, 46.4%, 28%, 13.1%, 10.7%, and 1.8% were from European, American, Western Pacific, Southeast Asian, and Eastern Mediterranean Regions. Most LT centers prioritized COVID-19 vaccine access for LT patients (76%) and healthcare workers (86%), while other categories had lower priority (30%). One-third of responders recommended mRNA vaccine exclusively, while booster doses were widely recommended (81%). One-third conducted post-vaccine liver function tests post COVID-19 vaccine. Only 16% of centers modified immunosuppression, and mycophenolate discontinuation or modification was the main approach. Side effects were seen in 1 in 1,000 vaccinated patients, with thromboembolism, acute rejection, and allergic reaction being the most severe. mRNA showed fewer side effects (−3.1, p = 0.002).ConclusionCOVID-19 vaccines and booster doses were widely used among LT recipients and healthcare workers, without a specific vaccine preference. Preventative immunosuppression adjustment post-vaccination was uncommon. mRNA vaccines demonstrated a favorable safety profile in this population.</p

Management of Established Small-for-size Syndrome in Post Living Donor Liver Transplantation:Medical, Radiological, and Surgical Interventions: Guidelines From the ILTS-iLDLT-LTSI Consensus Conference

Small-for-size syndrome (SFSS) following living donor liver transplantation is a complication that can lead to devastating outcomes such as prolonged poor graft function and possibly graft loss. Because of the concern about the syndrome, some transplants of mismatched grafts may not be performed. Portal hyperperfusion of a small graft and hyperdynamic splanchnic circulation are recognized as main pathogenic factors for the syndrome. Management of established SFSS is guided by the severity of the presentation with the initial focus on pharmacological therapy to modulate portal flow and provide supportive care to the patient with the goal of facilitating graft regeneration and recovery. When medical management fails or condition progresses with impending dysfunction or even liver failure, interventional radiology (IR) and/or surgical interventions to reduce portal overperfusion should be considered. Although most patients have good outcomes with medical, IR, and/or surgical management that allow graft regeneration, the risk of graft loss increases dramatically in the setting of bilirubin &gt;10 mg/dL and INR&gt;1.6 on postoperative day 7 or isolated bilirubin &gt;20 mg/dL on postoperative day 14. Retransplantation should be considered based on the overall clinical situation and the above postoperative laboratory parameters. The following recommendations focus on medical and IR/surgical management of SFSS as well as considerations and timing of retransplantation when other therapies fail.</p