Tailoring allocation policies and improving access to paediatric liver transplantation over a 16-year period.

BACKGROUND & AIMS: Mortality on the paediatric liver transplantation (pLT) waiting list (WL) is still an issue. We analysed the Italian pLT WL to evaluate the intention-to-treat (ITT) success rate and to identify factors influencing success. METHODS: All children (<18 years) listed for pLT in Italy between 2002-2018 were included (Era 1 [2002-2007]: centre-based allocation; Era 2 [2008-2014]: national allocation; Era 3 [2015-2018]: national allocation+mandatory-split policy). RESULTS: A total of 1,424 patients (median age: 2.0 [IQR 1.0-9.0] years; median weight: 12.0 kg [IQR 7-27]) were listed for pLT. Median WL time was 2 days (IQR 1-5) for Status 1 and 44 days (IQR 15-120) for non-Status 1 patients; 1,302 children (91.4%) were transplanted (67.3% with split grafts), while 50 children (3.5%) dropped off the WL (2.5% death, 1.0% clinical deterioration). Predictive factors for receiving LT included Status 1 (hazard ratio [HR] 1.66, p = 0.001), Status 1B (HR 1.96, p = 0.016), Status 2A (HR 2.15, p = 0.024) and each 1-point increase in PELD/MELD score. Children with recipient's weight >25 kg, blood group O or awaiting pLT combined with other organs had less chance of being transplanted. ITT patient survival rates were 90.5% at 1 year and 87.5% at 5 years, remaining stable across eras. Risk factors for ITT survival were re-transplantation (HR 5.83, p <0.001), Status 1 (HR 2.28, p = 0.006), Status 1B (HR 2.90, p = 0.014), Status 2A (HR 9.12, p <0.001), recipient weight <6 kg (HR 4.53, p <0.001) and low-volume activity (HR 4.38, p = 0.001). CONCLUSIONS: In Italy, continuous adaption of paediatric organ allocation policies via the introduction of national allocation, paediatric prioritisation rules and a mandatory-split policy have helped maximise the use of donors for paediatric candidates and to minimise WL mortality without compromising outcomes. IMPACT AND IMPLICATIONS: Globally, paediatric liver transplant candidates still suffer from high mortality. Over recent decades, the continuous adaption of organ allocation policies in Italy has led to excellent outcomes for children awaiting liver transplantation. The mortality rate of paediatric liver transplant candidates has been minimised to almost zero, mainly using grafts from deceased donors. Paediatric prioritisation rules, national organ exchange organisation and a mandatory-split liver policy have resulted in a unique allocation model for paediatric liver transplant candidates and represent a landmark for the paediatric transplant community.

How best to combine liver transplantation and bariatric surgery?-Results from a global, web-based survey.

BACKGROUND AND AIMS: Obesity is a growing healthcare challenge worldwide and a significant risk factor for liver failure as seen with non-alcoholic steatohepatitis (NASH). Combining metabolic-bariatric surgery (MBS) with liver transplantation (LT) appears as attractive strategy to treat both, the underlying liver disease and obesity. However, there is an ongoing debate on best timing and patient selection. This survey was designed to explore the current treatment practice for patients with NASH and obesity worldwide. METHODS: A web-based survey was conducted in 2022 among bariatric and LT surgeons, and hepatologists from Europe, North and South America and Asia. RESULTS: The survey completion rate was 74% (145/196). The average respondents were 41-50 years (38%), male (82.1%) and had >20 years of clinical experience (42.1%). Centres with a high LT-caseload for NASH were mainly located in the USA and United Kingdom. Almost 30% have already performed a combination of LT with MBS and 49% plan to do it. A majority of bariatric surgeons prefer MBS before LT (77.2%), whereas most of LT surgeons (52%) would perform MBS during LT. Most respondents (n = 114; 80%) favour sleeve gastrectomy over other bariatric techniques. One third (n = 42; 29.4%) has an established protocol regarding MBS for LT candidates. CONCLUSION: The most experienced centres doing LT for NASH are in the USA and United Kingdom with growing awareness worldwide. Overall, a combination of MBS and LT has already been performed by a third of respondents. Sleeve gastrectomy is the bariatric technique of choice-preferably performed either before or during LT.

Improving outcomes of in situ split liver transplantation in Italy over the last 25 years.

BACKGROUND & AIMS: Split liver transplant(ation) (SLT) is still considered a challenging procedure that is by no means widely accepted. We aimed to present data on 25-year trends in SLT in Italy, and to investigate if, and to what extent, outcomes have improved nationwide during this time. METHODS: The study included all consecutive SLTs performed from May 1993 to December 2019, divided into three consecutive periods: 1993-2005, 2006-2014, and 2015-2019, which match changes in national allocation policies. Primary outcomes were patient and graft survival, and the relative impact of each study period. RESULTS: SLT accounted for 8.9% of all liver transplants performed in Italy. A total of 1,715 in situ split liver grafts were included in the analysis: 868 left lateral segments (LLSs) and 847 extended right grafts (ERGs). A significant improvement in patient and graft survival (p <0.001) was observed with ERGs over the three periods. Predictors of graft survival were cold ischaemia time (CIT) <6 h (p = 0.009), UNOS status 2b (p <0.001), UNOS status 3 (p = 0.009), and transplant centre volumes: 25-50 cases vs. <25 cases (p = 0.003). Patient survival was significantly higher with LLS grafts in period 2 vs. period 1 (p = 0.008). No significant improvement in graft survival was seen over the three periods, where predictors of graft survival were CIT <6 h (p = 0.007), CIT <6 h vs. ≥10 h (p = 0.019), UNOS status 2b (p = 0.038), and UNOS status 3 (p = 0.009). Retransplantation was a risk factor in split liver graft recipients, with significantly worse graft and patient survival for both types of graft (p <0.001). CONCLUSIONS: Our analysis showed Italian SLT outcomes to have improved over the last 25 years. These results could help to dispel reservations regarding the use of this procedure. IMPACT AND IMPLICATIONS: Split liver transplant(ation) (SLT) is still considered a challenging procedure and is by no means widely accepted. This study included all consecutive in situ SLTs performed in Italy from May 1993 to December 2019. With more than 1,700 cases, it is one of the largest series, examining long-term national trends in in situ SLT since its introduction. The data presented indicate that the outcomes of SLT improved during this 25-year period. Improvements are probably due to better recipient selection, refinements in surgical technique, conservative graft-to-recipient matching, and the continuous, yet carefully managed, expansion of donor selection criteria under a strict mandatory split liver allocation policy. These results could help to dispel reservations regarding the use of this procedure.

Successful clinical and virological outcomes of liver transplantation for HDV/HBV-related disease after long-term discontinuation of hepatitis B immunoglobulins.

BACKGROUND: Indefinite, long-term administration of hepatitis B immunoglobulins (HBIg), together with a third generation nucleos(t)ide analog (NA), is the currently recommended prophylactic strategy to prevent viral recurrence after liver transplantation (LT) for Hepatitis Delta virus (HDV)/Hepatitis B virus (HBV)-related disease. METHODS: We retrospectively analyzed the safety and long-term clinical and virological outcomes of a consecutive cohort of 16 patients (10 males, median age 64.5, range 41-75) transplanted for HDV/HBV-related cirrhosis at our Institution, who discontinued HBIg after a median of 24.5 months (range 15-116) after transplant. All patients continued prophylaxis with same NA used before LT. Recurrence of HDV/HBV infection was defined as reappearance of serum HDV-RNA with detectable serum HBsAg and/or HBV-DNA. RESULTS: The median follow-up after LT was 138 months (range 73-316) and 110 months (range 52-200) after HBIg withdrawal. All patients were HBsAg-positive, HBV-DNA negative, and anti-HDV positive at the time of LT and without coinfections with HCV or HIV. Patients were followed with biochemical and virological tests every 3-6 months after HBIg withdrawal. No recurrences of HDV/HBV infection or disease were observed during monoprophylaxis with NA. In addition, eight patients (50%) spontaneously developed anti-HBs titers above 10 IU/L at a median of 74 months (range 58-140) following HBIG discontinuation. CONCLUSIONS: HBIg withdrawal after LT is a safe and efficacious strategy in patients transplanted for HDV/HBV disease and is frequently associated with the spontaneous development of serological immunity against HBV. These data call for a revision of current prophylactic recommendations in this setting.

Machine perfusion organ preservation: Highlights from the American Transplant Congress 2022.

The American Transplant Congress 2022, which took place between June 4th and June 8th of 2022, was a hybrid meeting with in-person attendance in Boston-MA and a real-time virtual experience via an online platform. First, we identified abstracts discussing machine perfusion preservation for all organs, a hot topic and approach that may develop into the new gold standard of organ preservation in the near future. A total of 39 abstracts on organ machine preservation were presented at the meeting. Next, we selected abstracts which focus on advances including new approaches to organ preservation, promising biomarkers, ex-situ treatment including cellular therapies, and novel research areas. Here, we summarized the latest developments on machine perfusion preservation in both experimental and clinical studies.

The impact of center volume on the utilization and outcomes of machine perfusion technology in liver transplantation: An international survey.

INTRODUCTION: Machine perfusion (MP) was developed to expand the donor pool and improve liver transplantation (LT) outcomes. Despite optimal results in clinical trials, the real-world MP benefit in centers with low-/mid-volume activity (LVCs) is still being determined. METHODS: Online survey on MP for LT, distributed to worldwide LT-centers representatives. Variables of interest included logistics, technicalities, and outcomes. Responders were grouped into high-volume centers (HVCs) (>60 LTs/year) and LVCs and results compared. RESULTS: Sixty-seven centers were included, 36 HVCs and 31 LVCs. Significant differences in MP regarded: (I) existence of an established program (80.6% vs. 41.9%; p = 0.02), (II) presence of a dedicated perfusionist (58.3% vs. 22.6%; p = 0.006), (III) duration (>4 h: 47.2% vs. 16.1%; p = 0.01), (IV) routine use (20%-40% vs. 5%-20%; p = 0.002), (V) graft utilization (>50%: 75% vs. 51.6%; p = 0.009), (VI) 90-day patient-survival (90%-100% vs. 50%-90%; p = 0.001) and (VII) subjectively perceived benefit (always vs. only in selected ECD; p = 0.009). Concordance was found for indications, type, viability tests, graft-salvage, 90-day graft-loss, and major-complications. CONCLUSIONS: This study captured a picture of MP in real-world LT-practice. Significant disparities have surfaced between LVCs and HVCs regarding logistics, utilization, and results. To close this gap, efforts should be made to more efficiently deliver dedicated support, training and mentoring to LVC teams adopting MP technology.

Effects of Anti-COVID-19 Vaccination and Pre-Exposure Prophylaxis with Tixagevimab-Cilgavimab in Kidney and Liver Transplant Recipients.

Background and Objectives: Underpowered immune response to vaccines against SARS-CoV-2 was observed in solid organ transplant (SOT) recipients. A novel combination of monoclonal antibodies tixagevimab-cilgavimab (TGM/CGM) received authorization as pre-exposure prophylaxis (PrEP) in those with reduced response to vaccine. We aimed to evaluate the response rate to COVID-19 vaccination in kidney transplant (KT), compared to liver transplant (LT) recipients, and the efficacy and safety of PrEP with TGM/CGM. Material and Methods: Between March and November 2022, adult KT and LT recipients who had completed the vaccination schedule (3 doses) were tested for anti-SARS-CoV-2 antibodies titer. SOT recipients with anti-SARS-CoV-2 titer ≥ 100 IU/mL were considered protected against infection, while those with titer < 100 UI/mL were defined non-protected. Patients with inadequate response were invited to PrEP. Results: In total, 306 patients were enrolled [KT:197 (64.4%), LT:109 (35.6%)]. After the complete scheme of vaccination, 246 (80.3%) patients developed a protective titer, while 60 (19.6%) did not have a protective titer. KT recipients had a lower rate of protective anti-COVID-19 titer compared to LT patients [149 (75.6%) vs. 97 (89.0%), p = 0.004]. Recipients with non-protective anti-COVID-19 titer received mainly tacrolimus-based regimen associated with mycophenolate mofetil (MMF) (70%) e steroids (46.7%) as maintenance immunosuppression, while those treated with everolimus were associated with higher protective titer. Of 35 (58.3%) patients who received PrEP, within 12 months, 6 (17.1%) (all KT) developed pauci-symptomatic COVID-19 disease, while 15/25 (60%) of non-responders, who did not receive the prophylaxis, developed COVID-19 disease. After PrEP, hospitalization rate was lower (2.8% vs. 16%), and no adverse events, neither graft loss nor rejection, were observed. Conclusions: Despite complete COVID-19 vaccination, SOT recipients might be not protected from the SARS-CoV-2 infection, especially after KT. In non-protected SOT patients, the subsequent pre-exposure prophylaxis with combination of monoclonal antibodies (TGM/CGM) might be an efficacy and safe strategy to prevent COVID-19 severe disease and hospitalization.

Histology for nephrology, from pre-implantation to post-transplant kidney biopsy. Lesson learned from ReBIrth (Renal BIopsy for Kidney Transplantation Therapy).

A meeting entitled Renal BIopsy for Kidney Transplantation Therapy (ReBIrth) took place on May 31st, 2022 in Bologna, Italy. The meeting drew together nephrologists, surgeons, and pathologists and recognized as experts in the field of kidney transplantation in Italy. In this paper, we present our experience working with kidney transplants in the current era of immunosuppression therapy. The primary aim is to report the histopathological characteristics of failed kidney allografts after a consensus of experts reviewed the cases on a wholeslide imaging digital platform. Regardless of the cases discussed, digital pathology was reliable in identifying all the morphological and immunohistochemical features required to improve the correct use of immunosuppressive therapy to prevent graft failure and optimize patient management.

Electronic Outpatient Referral System for Liver Transplant Improves Appropriateness and Allows First Visit Triage.

BACKGROUND & AIMS: Missed or inappropriate referrals of potential candidates for liver transplantation (LT) are common and traditional referral methods (tRs) do not allow for efficient triage. We investigated the effects of a website developed for electronic outpatient referral to LT (eRW-LT) on these issues. METHODS: We prospectively collected data on all consecutive outpatient referrals to 2 Italian LT centers from January 2015 to December 2019. In the second half of the study, starting from July 2017, referring physicians had the option of using eRW-LT, quickly obtaining the judgment on the appropriateness and urgency of the visit from a transplant hepatologist. RESULTS: In the second half of the study, there were 99 eRW-LTs and 96 traditional referrals (new tRs), representing a 17.4% increase over the 161 traditional referrals (old tRs) of the first half. With eRW-LT, 11.1% of referrals were judged inappropriate online without booking a visit. Appropriateness, judged at the time of the first visit, was 59.6%, 56.2%, and 94.3% with old tRs, new tRs, and eRW-LT, respectively. Considering the appropriate visits, the median waiting time in days between referral date and first visit appointment was significantly shorter for urgent visits referred with eRW-LT (5.0; 95% CI, 4.8-9.3) compared with nonurgent visits sent with the same system (17.0; 95% CI, 11.5-25.0; P < .0001), those referred with old tRs (14.0; 95% CI, 8.0-23.0; P < .001) and with new tRs (16.0; 95% CI, 10.0-23.0; P < .001). CONCLUSIONS: eRW-LT allows an increase in the number of referrals for LT, ensuring effective triage and better appropriateness of visits.

Allograft Fibrosis After Pediatric Liver Transplantation: Incidence, Risk Factors, and Evolution.

Allograft fibrosis (AF) after pediatric liver transplantation (pLT) is frequent, but its dynamics are unclear. Our aim was to assess the evolution and risk factors of AF after pLT. A retrospective single-center analysis of pLT patients with a follow-up of ≥5 years who underwent protocol liver biopsies at 6 months, 1 year, 2 years, 5 years, and 10 years was performed. Fibrosis was assessed using the METAVIR and Ishak systems and the liver allograft fibrosis score (LAFs). Of 219 pLTs performed from 2008 to 2018, 80 (36.5%) pLTs were included, and 320 biopsies were reviewed. At 6 months after pLT, fibrosis was found in 54 (67.5%) patients by the METAVIR/Ishak systems and in 59 (73.8%) by the LAFs (P = 0.65). By 5 years, AF was detected in 67 (83.8%), 69 (86.3%), and 72 (90%) specimens using the METAVIR, Ishak, and LAFs systems, respectively (P = 0.54); mild (METAVIR, 51 [63.8%]; Ishak, 60 [75%]; LAFs, 65 [81.2%]) and moderate (METAVIR, 16 [20%]; Ishak, 9 [11.9%]; LAFs, 7 [8.8%]) stages were detected, but severe fibrosis was not found (P = 0.09). In the LAFs, fibrosis involved the portal (85%), sinusoidal (15%), and centrolobular (12%) areas. Of 18 patients with 10-year protocol biopsies, AF was present in 16 (90%), including 1 (5.5%) with severe fibrosis. In all systems, 36.3% of patients showed fibrosis progression from 2 years to 5 years after LT, but they remained stable at the 10-year biopsies without clinical implications. In multivariate analysis, only donor age >40 years was a risk factor for moderate AF at 5 years after LT (odds ratio, 8.3; 95% confidence interval, 1.6-42.1, P = 0.01). Cold ischemia time (CIT) >8 hours was associated with portal (P < 0.001)/sinusoidal fibrosis (P = 0.04), donor age >40 years was associated with sinusoidal (P = 0.01)/centrilobular (P = 0.04) fibrosis, and low tacrolimus trough level within 1 year after LT was associated with centrilobular fibrosis (P = 0.02). AF has a high incidence after pLT, occurring early after transplantation. In most cases, AF is mild or moderate and remains stable in the long run without clinical implications. Donor selection, short CIT, and immunosuppression adherence are crucial to reducing the risk of advanced AF.

Minimally invasive hepatopancreatic and biliary surgery in children: a large centre experience and review of the literature.

BACKGROUND: Minimally invasive surgery (MIS) for hepatopancreatic and biliary (HPB) diseases has been widely used in adults, while in children, its application is limited due to its complexity. Herein, we report the experience of MIS for paediatric HPB diseases and literature review. METHODS: All children (≤18 years-old) undergoing major HPB operations by MIS during January 2017-June 2020 in our institution were prospectively enrolled. RESULTS: Out of 139 children operated on for HPB diseases with MIS, 26 (18.7%) patients (age: 11 (1-17) years-old; weight: 41.9 (10.7-75.5) kg) underwent major HPB surgery, including 11 pancreatic resections and 15 liver resections, all performed by a full-laparoscopic-technique. Four (15.3%) surgeries were electively converted to an open-technique for safer operative management. None required a blood transfusion. The median hospital admission was 6 days. Post-operatively, all patients had early mobilization and good recovery. Two (7.7%) patients experienced post-operative complications requiring radiological intervention. Oncological radical resection (R0) was achieved in all tumours, and after 2 years, all children were free of tumour recurrence. CONCLUSION: MIS for HPB surgery is safe and feasible in children, with less surgical trauma, short hospital-stay and better aesthetic results. An adequate learning curve in specialized centres is essential for good outcomes.

Liver transplantation performed in a SARS-CoV-2 positive hospitalized recipient using a SARS-CoV-2 infected donor.

The coronavirus disease 2019 (COVID-19) is a novel infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 currently affected more than 108 million people worldwide with a fatality rate of 2.2%. Herein, we report the first case of liver transplantation (LT) performed with a liver procured from a SARS-CoV-2 positive donor. The recipient was a 35-year-old SARS-CoV-2 positive female patient affected by severe end-stage HBV-HDV-related liver disease (model of end-stage liver disease = 32) who had neutralizing SARS-CoV-2 antibodies (titers 1:320) at time of LT. The LT was successful, and the graft is functioning two months after surgery. The recipient cleared the SARS-CoV-2 infection 1 month after LT. The current case shows that the prompt use of SARS-CoV-2 infected liver donors offers an invaluable life-saving opportunity for SARS-CoV-2 positive wait-listed patients who developed neutralizing SARS-CoV-2 antibodies.

COVID-19, liver transplant, and immunosuppression: Allies or foes?

Liver transplant (LT) recipients are considered at a particularly high risk for developing critical COVID-19 infection. To date, available data are heterogeneous and scarce and mortality in LT recipients seems to be higher compared to normal population, but whether this is caused by altered immunological status, immunosuppression (IS), or underlying comorbidities has not yet been fully clarified. Some evidences show that IS might play a role in the pathophysiology of this new disease. We searched all available data regarding LT recipients infected by COVID-19, focusing on the role of IS. To date, 244 LT recipients have been reported as COVID-19-positive. Trends among transplant physicians are to reduce overall IS, especially antimetabolite drugs, but the current available observations are still not enough to build strong evidences for recommendation and IS should be meticulously tailored case by case.

The hamletic dilemma of patients waiting for kidney transplantation during the COVID-19 pandemic: To accept or not to accept (an organ offer)?

The outbreak of COVID-19 led to a reduction in the number of organ transplant interventions in most Countries. In April 2020, at the Tor Vergata University in Rome, Italy, two patients on the waiting list for kidney transplantation (KT) declined a deceased donor's kidney offer. Therefore, between April 20 and 25, 2020, we conducted a telephone survey among our 247 KT waitlist patients. Our aim was to explore: (a) the COVID-19 diffusion among them and (b) their current willingness to be transplanted in case of a kidney offer from a deceased donor. Two hundred and forty-three patients participated in a phone interview. One patient had died from COVID-19. Eighty-five (35%) KT candidates would decline any kidney offer, in most cases until the end of the COVID-19 pandemic. Upon a multivariate analysis, female gender (OR = 2.25, 95% CI = 1.26-4.03, P = .006), high cardiovascular risk (OR = 2.33, 95% CI = 1.06-5.08, P = .034), a waiting list time <3 years (OR = 0.375, 95% CI = 0.15-0.95, P = .04), and the need to be transferred to another hospital for HD (OR = 2.56, 95% CI = 1.10-5.9, P = .03) were associated with such refusal. The COVID-19 pandemic led to a fear of transplantation in a third of the KT candidates. Proactive educational webinars could be a useful tool to remove, or at least lessen, any doubts on the part of KT candidates and to avoid losing the opportunity to quit dialysis.

The Management of Immunosuppression in Kidney Transplant Recipients with COVID-19 Disease: An Update and Systematic Review of the Literature.

Background and Objectives: In the era of the coronavirus disease 2019 (COVID-19) pandemic, the management of immunosuppressive (IS) therapy in kidney transplant (KT) recipients affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires attention. It is not yet understood whether IS therapy may protect from the cytokine storm induced by SARS-CoV-2 infection or a temporary adjustment/withdrawal of IS therapy to restore the immune system may be necessary. We performed a systematic literature review to investigate the current management of IS therapy in KT recipients with COVID-1. Materials and Methods: Out of 71 articles published from 1 February 2020 until 30 October 2020, 554 KT recipients with SARS-CoV-2 infection were identified. Results: Modifications of IS therapy were based on the clinical conditions. For asymptomatic patients or those with mild COVID-19 symptoms, a "wait and see approach" was mostly used; a suspension of antimetabolites drugs (347/461, 75.27%) or mTOR inhibitors (38/48, 79.2%) was adopted in the majority of patients with symptomatic COVID-19 infections. For CNIs, the most frequent attitude was their maintenance (243/502, 48.4%) or dose-reduction (99/502, 19.72%) in patients asymptomatic or with mild COVID-19 symptoms, while drug withdrawal was the preferred choice in severely symptomatic patients (160/450, 31.87%). A discontinuation of all IS drugs was used only in severely symptomatic COVID-19 patients on invasive mechanical ventilation. Renal function remained stable in 422(76.17%) recipients, while 49(8.84%) patients experienced graft loss. Eight (1.44%) patients experienced a worsening of renal function. The overall mortality was 21.84%, and 53(9.56%) patients died with functioning grafts. Conclusion: A tailored approach to the patient has been the preferred strategy for the management of IS therapy in KT recipients, taking into account the clinical conditions of patients and the potential interactions between IS and antiviral drugs, in the attempt to balance the risks of COVID-19-related complications and those due to rejection or graft loss.

The COVID-19 outbreak in Italy: Initial implications for organ transplantation programs.

The spread of Coronavirus Disease 2019 (COVID-19) has already reached a pandemic dimension within a few weeks. Italy has been one of the first countries dealing with the outbreak of COVID-19, and severe measures have been adopted to limit viral transmission. The spread of COVID-19 may have several implications in organ transplant activity that physicians should be aware of. The initial experience gained during the COVID-19 outbreak shows that around 10% of infected patients in Italy need intensive care management to overcome the acute respiratory distress syndrome. Due to the exponential rise of infected patients we are now facing an actual risk of saturation of intensive care unit (ICU) beds. A restriction in the number of ICU beds available for both donors and transplant recipients may unfavorably influence the overall donation activity, and eventually lead to a reduced number of transplants. Preliminary Italian data show that a 25% reduction of procured organs has already occurred during the first 4 weeks of COVID-19 outbreak. This underlines the need to closely monitor what will be further happening in ICUs due to the COVID-19 spread in the attempt to preserve transplant activity, especially in Western countries where deceased donors represent the major organ resource.

An international multicenter study of protocols for liver transplantation during a pandemic: A case for quadripartite equipoise.

BACKGROUND & AIMS: The outbreak of COVID-19 has vastly increased the operational burden on healthcare systems worldwide. For patients with end-stage liver failure, liver transplantation is the only option. However, the strain on intensive care facilities caused by the pandemic is a major concern. There is an urgent need for ethical frameworks to balance the need for liver transplantation against the availability of national resources. METHODS: We performed an international multicenter study of transplant centers to understand the evolution of policies for transplant prioritization in response to the pandemic in March 2020. To describe the ethical tension arising in this setting, we propose a novel ethical framework, the quadripartite equipoise (QE) score, that is applicable to liver transplantation in the context of limited national resources. RESULTS: Seventeen large- and medium-sized liver transplant centers from 12 countries across 4 continents participated. Ten centers opted to limit transplant activity in response to the pandemic, favoring a "sickest-first" approach. Conversely, some larger centers opted to continue routine transplant activity in order to balance waiting list mortality. To model these and other ethical tensions, we computed a QE score using 4 factors - recipient outcome, donor/graft safety, waiting list mortality and healthcare resources - for 7 countries. The fluctuation of the QE score over time accurately reflects the dynamic changes in the ethical tensions surrounding transplant activity in a pandemic. CONCLUSIONS: This four-dimensional model of quadripartite equipoise addresses the ethical tensions in the current pandemic. It serves as a universally applicable framework to guide regulation of transplant activity in response to the increasing burden on healthcare systems. LAY SUMMARY: There is an urgent need for ethical frameworks to balance the need for liver transplantation against the availability of national resources during the COVID-19 pandemic. We describe a four-dimensional model of quadripartite equipoise that models these ethical tensions and can guide the regulation of transplant activity in response to the increasing burden on healthcare systems.

A national mandatory-split liver policy: A report from the Italian experience.

To implement split liver transplantation (SLT) a mandatory-split policy has been adopted in Italy since August 2015: donors aged 18-50 years at standard risk are offered for SLT, resulting in a left-lateral segment (LLS) graft for children and an extended-right graft (ERG) for adults. We aim to analyze the impact of the new mandatory-split policy on liver transplantation (LT)-waiting list and SLT outcomes, compared to old allocation policy. Between August 2015 and December 2016 out of 413 potentially "splittable" donors, 252 (61%) were proposed for SLT, of whom 53 (21%) donors were accepted for SLT whereas 101 (40.1%) were excluded because of donor characteristics and 98 (38.9%) for absence of suitable pediatric recipients. The SLT rate augmented from 6% to 8.4%. Children undergoing SLT increased from 49.3% to 65.8% (P = .009) and the pediatric LT-waiting list time dropped (229 [10-2121] vs 80 [12-2503] days [P = .045]). The pediatric (4.5% vs 2.5% [P = .398]) and adult (9.7% to 5.2% [P < .001]) LT-waiting list mortality reduced; SLT outcomes remained stable. Retransplantation (HR = 2.641, P = .035) and recipient weight >20 kg (HR = 5.113, P = .048) in LLS, and ischemic time >8 hours (HR = 2.475, P = .048) in ERG were identified as predictors of graft failure. A national mandatory-split policy maximizes the SLT donor resources, whose selection criteria can be safely expanded, providing favorable impact on the pediatric LT-waiting list and priority for adult sick LT candidates.

Longterm Survival and Cost-Effectiveness of Immunosuppression Withdrawal After Liver Transplantation.

Lifelong immunosuppression (IS) after liver transplantation is associated with severe adverse effects and increased recipients' morbidity and mortality. Clinical operational tolerance has been reported in up to 40% in very well-selected recipients. Longterm survival and cost savings within the Italian national health system in operational tolerant recipients is reported. Seventy-five liver recipients were enrolled for IS withdrawal at our institution during the period from April 1998 to December 2015. The study population comprised 32 (42.7%) tolerant patients; 41 (54.7%) nontolerant patients needing uptake of IS after clinical or biopsy-proven rejection; and 2 (2.7%) immediate nontolerant patients who developed early rejection after the first drug reduction. The primary endpoint of the study was to assess the longterm patients and graft outcome; the secondary endpoint was the assessment of cost savings in the context of IS withdrawal. The follow-up was 95.0 months (interquartile range, 22.5-108.5 months). IS withdrawal did not result in patient nor graft loss and resulted in a major cost savings reaching about €630,000. In conclusion, longterm IS withdrawal represents a remarkable cost savings in the health care of liver recipients without exposing them to graft loss.