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.

Revisiting the forgotten "full-right full-left" liver division: Simplified technique and new strategical considerations for clinical implementation in Italy.

BACKGROUND: Full-right/full-left liver splitting was introduced early in the 90s as part of the great wave of technical innovations that characterized that decade. One approach was to divide the liver on the right of the Cantlie's line and leave the middle hepatic vein with the left graft, with both grafts allocated to adults. Both grafts had some functional disadvantages and exposed the adult recipients to some early hepatic dysfunction, and the results were not great. An alternative approach consisted of an ex situ division of the liver, exactly along Cantlie's line, thus sharing the middle hepatic vein between the two grafts. None of these two techniques were really adopted, and there has been nearly no transplantation of this type in the last decade worldwide. METHOD AND RESULTS: The authors propose a variation of the latter technique that was used recently with success: The division of the liver is made simpler; the two grafts are prepared ex situ and need a simple vascular reconstruction (one venous patch on each graft); and the grafts can be implanted using very standard techniques. CONCLUSION: Because candidates for liver transplantation weighing 25-60 kg (old children, teenagers, and some small adults) are often at some disadvantage in getting size-matched livers (this range of weight is less represented in the donor population), implementing the latter technique would help provide adequate grafts for them. In Italy, where many livers offered for splitting are not used, there would be ample room for implementing this option within the actual donor pool and allocation system.

Combining living and deceased donation for pediatric first isolated liver transplantation: A win-win even in countries with high deceased donor donation rates.

BACKGROUND: Split and living donor liver transplantations are both key surgical strategies for development of pediatric liver transplant programs. Often, however, teams tend to prioritize only one preferentially. METHODS: In the context of a very active national split liver graft allocation program (Italy), retrospective study of 226 consecutive pediatric first isolated liver transplants performed by a single team using organs from both deceased and living donors. Clinical characterisitics and outcome were compared. RESULTS: In the context of a steadily slowly decreasing split graft offer, living donation activity steadily increased. Deceased and living donation accounted for 52.6% and 47.4% of transplantations, respectively. Both strategies were equally used for transplanting patients up to 30 kg of weight, while deceased donors were predominantly used for older recipients. Technical variants represented 86% of all transplants, with 183 conisting of left lateral segment grafts (76 split liver grafts and 107 left grafts from living donors). Outcome of both surgical strategies was similar, with excellent outcomes at early, mid-, and long-term. CONCLUSIONS: Splitting livers of deceased donors and using living donation were complementary and non-competitive strategies for developping pediatric liver transplant activity. Implementing both activities in parallell allowed to maintain stable the number of annual transplant in Italy and allowed to reach superior outcomes. This analysis provides evidence that living donation plays a role in Italy despite an existing very active "mandatory-split" national policy.

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.

Recurrent graft failure secondary to portal vein steal syndrome: a case report with an unusual indication for a third liver transplant.

BACKGROUND: Portal vein shunt is common in chronic hepatic diseases and after a liver transplant. Ensuring a satisfactory portal flow is essential to support a rapid liver recovery, of paramount importance to meet the recipient's metabolic needs. CASE PRESENTATION: We report the case of a 32-year-old female undergoing a third liver transplant due to recurrence of graft failure secondary to portosystemic shunting. The patient, affected with biliary atresia, was first transplanted in 2009 with a right split liver graft. The clinical course was complicated by biliary stenosis of the Roux-en-Y anastomosis and multiple episodes of acute rejection treated with steroid boluses, plastic dilation of the biliary anastomosis, and biliary catheter placement. Unfortunately, in 2017 a liver biopsy showed an autoimmunity with histological evidence of ANA 1:80 (granular and nucleolar pattern). This was a contributing factor of liver function impairment, leading to the need to perform a second liver transplant, complicated by an acute rejection, with only a partial response to steroid therapy. Due to the further worsening of the liver function (MELD: 40, Child-Pugh: C11), the patient was relisted for a liver transplant. After five days, she received her third liver transplant, with an entire graft of an AB0 identical group. Intraoperative exploration revealed multiple collaterals and large splenocaval shunts, with a significant alteration of the portal flow and hypertension, isolated and closed with a vascular stapler to restore the graft's regular portal vein flow. CONCLUSIONS: In patients listed for a liver transplant, portal steal syndrome should be identified prior to the transplant. Our recommendation is to consider intraoperative or perioperative closure of the portal collateral varices.

Case report: Trans-papillary free stenting of the cystic duct and of the common bile duct in a double biliary ducts anastomoses of a right lobe living donor transplantation.

BACKGROUND: One of the major issues related to the living donor liver transplantation recipient outcome is still the high rate of biliary complication, especially when multiple biliary ducts are present and multiple anastomoses have to be performed. CASE PRESENTATION AND CONCLUSION: We report a case of adult-to-adult right lobe living donor liver transplantation performed for a recipient affected by alcohol-related cirrhosis with MELD score of 17. End-stage liver disease was complicated by refractory ascites, portal hypertension, small esophageal varices and portal gastropathy, hypersplenism, and abundant right pleural effusion. Here in the attached video we described the adult-to-adult LDLT procedures, where a right lobe with two biliary ducts draining respectively the right anterior and the right posterior segments has been transplanted. LDLT required a biliary reconstruction using the native cystic and common bile ducts stented trans-papillary with two 5- French 6 cm long soft silastic catheter. None major complications were detected during post-operative clinical courses. Actually, the donor and the recipient are alive and well. The technique we describe in the video, allow to keep the biliary anastomoses protected and patent without having the risk of creating cholestasis and the need of invasive additional procedure. No living donor right lobe transplantation should be refused because of the presence of multiple biliary ducts.

Adult to Adult Living Donor Liver Transplantation in Recipients with Low MELD: A Strategy Intended to Overcome Donor Shortage.

Recent series have demonstrated advantages of living donor over deceased donor liver transplantation, with particular benefit for those with low model for end-stage liver disease score. The logic underlying the transplantation of patients before they become too sick is intuitive. It reduces mortality and drop outs from the waiting list and makes transplant surgery less demanding. Those principles have to be balanced with donor safety and transplant benefit for the recipient avoiding early, futile transplantation. The authors report a case of adult to adult right lobe living donor liver transplantation performed for a recipient affected by primary biliary cirrhosis with MELD score of 15, in a transplant center located in an area of Europe characterized by chronic organ shortage.

The addition of simvastatin administration to cold storage solution of explanted whole liver grafts for facing ischemia/reperfusion injury in an area with a low rate of deceased donation: a monocentric randomized controlled double-blinded phase 2 study.

BACKGROUND: Liver transplantation is the best treatment for end-stage liver disease. The interruption of the blood supply to the donor liver during cold storage damages the liver, affecting how well the liver will function after transplant. The drug Simvastatin may help to protect donor livers against this damage and improve outcomes for transplant recipients. The aim of this study is to evaluate the benefits of treating the donor liver with Simvastatin compared with the standard transplant procedure. PATIENT AND METHODS: We propose a prospective, double-blinded, randomized phase 2 study of 2 parallel groups of eligible adult patients. We will compare 3-month, 6-month, and 12-month graft survival after LT, in order to identify a significant relation between the two homogenous groups of LT patients. The two groups only differ by the Simvastatin or placebo administration regimen while following the same procedure, with identical surgical instruments, and medical and nursing skilled staff. To reach these goals, we determined that we needed to recruit 106 patients. This sample size achieves 90% power to detect a difference of 14.6% between the two groups survival using a one-sided binomial test. DISCUSSION: This trial is designed to confirm the effectiveness of Simvastatin to protect healthy and steatotic livers undergoing cold storage and warm reperfusion before transplantation and to evaluate if the addition of Simvastatin translates into improved graft outcomes. TRIAL REGISTRATION: ISRCTN27083228 .

Donor safety in living donor liver donation: An Italian multicenter survey.

Major concerns about donor morbidity and mortality still limit the use of living donor liver transplantation (LDLT) to overcome the organ shortage. The present study assessed donor safety in LDLT in Italy reporting donor postoperative outcomes in 246 living donation procedures performed by 7 transplant centers. Outcomes were evaluated over 2 time periods using the validated Clavien 5-tier grading system, and several clinical variables were analyzed to determine the risk factors for donor morbidity. Different grafts were obtained from the 246 donor procedures (220 right lobe, 10 left lobe, and 16 left lateral segments). The median follow-up after donation was 112 months. There was no donor mortality. One or more complications occurred in 82 (33.3%) donors, and 3 of them had intraoperative complications (1.2%). Regardless of graft type, the rate of major complications (grade ≥ 3) was 12.6% (31/246). The overall donor morbidity and the rate of major complications did not differ significantly over time: 26 (10.6%) donors required hospital readmission throughout the follow-up period, whereas 5 (2.0%) donors required reoperation. Prolonged operative time (>400 minutes), intraoperative hypotension (systolic < 100 mm Hg), vascular abnormalities, and intraoperative blood loss (>300 mL) were multivariate risk factors for postoperative donor complications. In conclusion, from the standpoint of living donor surgery, a meticulous and well-standardized technique that reduces operative time and prevents blood loss and intraoperative hypotension may reduce the incidence of donor complications. Transparency in reporting results after LDLT is mandatory, and we should continue to strive for zero donor mortality. Liver Transplantation 23 184-193 2017 AASLD.

Liver Transplantation for Hemoperitoneum Secondary to Huge Multiple Hemangiomatosis: A Case Report of a Tele-intensive Care Unit in Deceased-Donor Management.

BACKGROUND: Patients with growing and nonresectable liver hemangiomas should be followed up by a transplant center with extensive experience in complex liver disease. They could be treated on an emergency basis with orthotopic liver transplantation, with an expectation of good long-term results. MATERIALS AND METHODS: We describe the case of a 37-year-old woman with liver hemangiomatosis followed up for 8 years, who presented with bleeding requiring transfusions and developed hemodynamic instability. We listed her for emergency transplant before her sister's living donor work-up could be completed. A liver from a cadaveric donor became available at a small local hospital with no experience in organ donation. Tele-intensive care unit (tele-ICU) technology was used for providing clinical data electronically to physicians, nurses, and other critical care specialists, creating medication orders, and communicating with on-site caregivers to implement changes in donor care. RESULTS: The recipient was transplanted on an emergency basis with a specific customization and application of the telemedicine system in the management of the organ procurement by the recipient team. Tele-ICU technology was used for providing an effective intensive care unit service, managing and stabilizing the deceased donor and allowing the procurement to be carried out uneventfully. CONCLUSIONS: Tele-ICU technology could be a promising resource for emergency transplantation, reducing the urgent need for a living donation and allowing prompt recipient team management of the deceased donor. Our first tele-ICU case offers early confirmation of the feasibility of the telemedicine system in deceased-donor management.

Continuous Erector Spinae Plane Block for Pain Management in a Pediatric Kidney Transplant Recipient: A Case Report and Review of the Current Literature.

Pain management in patients undergoing kidney transplantation requires careful consideration due to their altered physiology, and potential risks associated with certain analgesic options. In recent years, personalized and multimodal approaches have proven to be pivotal in perioperative pain management, as well as in children. Implementing regional analgesia methods offers a valuable solution in many pediatric surgical settings and the erector spinae plane block (ESPB) could represent a possible analgesic strategy in pediatric patients undergoing renal transplantation. Here, we report the case of a 13-year-old child who underwent living-donor kidney transplantation (LDKx) and received continuous erector spinae plane block (ESPB) for perioperative pain management. This multimodal approach with continuous ESPB resulted in optimal pain control without the need for opioids, allowing for early mobilization and for an optimal postoperative course.

Early regeneration of the remnant liver volume after right hepatectomy for living donation: a multiple regression analysis.

Early liver regeneration was studied in a series of 70 patients who underwent right hepatectomy for living donation between November 2004 and January 2010. Liver regeneration was evaluated with multidetector computed tomography (MDCT) at a mean of 61.07 days after surgery. Presurgical variables [eg, age, weight, height, body mass index (BMI), liver function tests, creatinine levels, platelet counts, international normalized ratio, and glucose levels] and variables detected with preoperative MDCT imaging [eg, main portal vein diameter, steatosis, original liver volume, and spleen volume (SV)] were investigated as potential predictors of liver regeneration. The future remnant liver volume (FRLV) was preoperatively calculated with a virtual surgical cut. Liver function tests and creatinine levels were recorded on the 30th postoperative day. In addition, the onset of postoperative complications occurring within 90 days of surgery was analyzed, and the complications were codified according to the 5 tiers of the Clavien-Dindo classification. In 26 of the 70 patients (37.14%), 100% or greater hepatic regeneration had occurred at 2 months. There was no association between the clinical outcome and the liver regeneration rate. A stepwise multiple regression analysis showed that a higher BMI (coefficient = 0.035, P < 0.0001) and preoperative parameters such as a smaller FRLV (coefficient = -0.002, P < 0.0001) and a greater SV/FRLV ratio (coefficient = 1.196, P < 0.0001) were predictors of greater liver regeneration.

Efficient human fetal liver cell isolation protocol based on vascular perfusion for liver cell-based therapy and case report on cell transplantation.

Although hepatic cell transplantation (CT) holds the promise of bridging patients with end-stage chronic liver failure to whole liver transplantation, suitable cell populations are under debate. In addition to hepatic cells, mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) are being considered as alternative cell sources for initial clinical cell work. Fetal liver (FL) tissue contains potential progenitors for all these cell lineages. Based on the collagenase incubation of tissue fragments, traditional isolation techniques yield only a fraction of the number of available cells. We report a 5-step method in which a portal vein in situ perfusion technique is used for tissue from the late second trimester. This method results in the high viabilities known for adult liver vascular perfusion, addresses the low cell yields of conventional digestion methods, and reduces the exposure of the tissue to collagenase 4-fold. We used donated tissue from gestational weeks 18 to 22, which yielded 1.8 ± 0.7 × 10(9) cells with an average viability of 78%. Because HSC transplantation and MSC transplantation are of interest for the treatment of hepatic failure, we phenotypically confirmed that in addition to hepatic progenitors, the resulting cell preparation contained cells expressing typical MSC and HSC markers. The percentage of FL cells expressing proliferation markers was 45 times greater than the percentage of adult hepatocytes expressing these markers and was comparable to the percentage of immortalized HepG2 liver hepatocellular carcinoma cells; this indicated the strong proliferative capacity of fetal cells. We report a case of human FL CT with the described liver cell population for clinical end-stage chronic liver failure. The patient's Model for End-Stage Liver Disease (MELD) score improved from 15 to 10 within the first 18 months of observation. In conclusion, this human FL cell isolation protocol may be of interest for further clinical translation work on the development of liver cell-based therapies.

How important is the role of iterative liver direct surgery in patients with hepatocellular carcinoma for a transplant center located in an area with a low rate of deceased donation?

Introduction: Hepatocellular carcinoma (HCC) accounts for nearly 90% of primary liver cancers, with estimates of over 1 million people affected by 2025. We aimed to explore the impacting role of an iterative surgical treatment approach in a cohort of HCC patients within the Milan criteria, associated with clinical risk factors for tumor recurrence (RHCC) after liver transplant (LT) and loco-regional therapies (LRT), as well as liver resection (LR) and/or microwave thermal ablation (MWTA). Methods: We retrospectively analyzed our experience performed during an 8-year period between January 2013 and December 2021 in patients treated for HCC, focusing on describing the impact on preoperative end-stage liver disease severity, oncologic staging, tumor characteristics, and surgical treatments. The Cox model was used to evaluate variables that could predict relapse risks. Relapse risk curves were calculated according to the Kaplan-Meier method, and the log-rank test was used to compare them. Results: There were 557 HCC patients treated with a first-line approach of LR and/or LRTs (n = 335) or LT (n = 222). The median age at initial transplantation was 59 versus 68 for those whose first surgical approach was LR and/or LRT. In univariate analysis with the Cox model, nodule size was the single predictor of recurrence of HCC in the posttreatment setting (HR: 1.61, 95% CI: 1.05-2.47, p = 0.030). For the LRT group, we have enlightened the following clinical characteristics as significantly associated with RHCC: hepatitis B virus infection (which has a protective role with HR: 0.34, 95% CI: 0.13-0.94, p = 0.038), number of HCC nodules (HR: 1.54, 95% CI: 1.22-1.94, p < 0.001), size of the largest nodule (HR: 1.06, 95% CI: 1.01-1.12, p = 0.023), serum bilirubin (HR: 1.57, 95% CI: 1.03-2.40, p = 0.038), and international normalized ratio (HR: 16.40, 95% CI: 2.30-118.0, p = 0.006). Among the overall 111 patients with RHCC in the LRT group, 33 were iteratively treated with further curative treatment (12 were treated with LR, two with MWTA, three with a combined LR-MWTA treatment, and 16 underwent LT). Only one of 18 recurrent patients previously treated with LT underwent LR. For these RHCC patients, multivariable analysis showed the protective roles of LT for primary RHCC after IDLS (HR: 0.06, 95% CI: 0.01-0.36, p = 0.002), of the time relapsed between the first and second IDLS treatments (HR: 0.97, 95% CI: 0.94-0.99, p = 0.044), and the impact of previous minimally invasive treatment (HR: 0.28, 95% CI: 0.08-1.00, p = 0.051). Conclusion: The coexistence of RHCC with underlying cirrhosis increases the complexity of assessing the net health benefit of ILDS before LT. Minimally invasive surgical therapies and time to HCC relapse should be considered an outcome in randomized clinical trials because they have a relevant impact on tumor-free survival.

Donor Simvastatin Treatment Is Safe and Might Improve Outcomes After Liver Transplantation: A Randomized Clinical Trial.

BACKGROUND: The current curative approaches for ischemia/reperfusion injury on liver transplantation are still under debate for their safety and efficacy in patients with end-stage liver disease. We present the SIMVA statin donor treatment before Liver Transplants study. METHODS: SIMVA statin donor treatment before Liver Transplants is a monocentric, double-blind, randomized, prospective tial aiming to compare the safety and efficacy of preoperative brain-dead donors' treatment with the intragastric administration of 80 mg of simvastatin on liver transplant recipient outcomes in a real-life setting. Primary aim was incidence of patient and graft survival at 90 and 180 d posttransplant; secondary end-points were severe complications. RESULTS: The trial enrolled 58 adult patients (18-65 y old). The minimum follow-up was 6 mo. No patient or graft was lost at 90 or 180 d in the experimental group (n = 28), whereas patient/graft survival were 93.1% ( P = 0.016) and 89.66% ( P = 0.080) at 90 d and 86.21% ( P = 0.041) and 86.2% ( P = 0.041) at 180 d in the control group (n = 29). The percentage of patients with severe complications (Clavien-Dindo ≥IIIb) was higher in the control group, 55.2% versus 25.0% in the experimental group ( P = 0.0307). The only significant difference in liver tests was a significantly higher gamma-glutamyl transferase and alkaline phosphatase at 15 d ( P = 0.017), ( P = 0.015) in the simvastatin group. CONCLUSIONS: Donor simvastatin treatment is safe, and may significantly improve early graft and patient survival after liver transplantation, although further research is mandatory.