Background. Small children awaiting intestinal transplantation are disadvantaged because of a lack of size-compatible donors. To achieve suitable access to transplantation, using intestinal grafts from very young donors is an option. However, there is a lack of literature describing the posttransplant immunological complications associated with these grafts. Our aim was to report the outcome of intestine-containing grafts from very young donors (6 mo and younger). Methods. A single-center retrospective study of all children who received an intestine-containing allograft between January 1993 and December 2020. To investigate the effect of donor age, the participants were separated into 3 groups. These comprised early infancy (EI, donors 6 mo and younger), late infancy (LI, 7–12 mo), and an early childhood (EC, 13–36 mo). The primary outcome was clinically significant immunological complications, defined as severe rejection and/or graft versus host disease. Results. During the study period, 105 pediatric intestinal transplants were performed and 35 were from donors aged 36 mo and younger. The EI, LI, and EC donor groups comprised 5, 9, and 21 patients, respectively. The indications for transplant, recipient age (in months) (EI: 17 [15–20], LI: 18 [11–30], EC: 24 [15–47]), and maintenance immunosuppression were similar between groups. Significant immunological complications occurred more frequently in the EI group (EI: 4/5 [80%], LI: 5/9 [56%] EC: 7/21 [33%], P = 0.134), and 3 of 5 of the recipients died as a direct result of these complications. Conclusions. The findings suggest that immunological complications are more frequent with grafts from donors within the first 6 mo of life and caution should be applied with their use.

Abstract Background Normothermic machine perfusion of donor livers has become standard practice in the field of transplantation, allowing the assessment of organs and safe extension of preservation times. Alongside its clinical uses, there has been expanding interest in extended normothermic machine perfusion (eNMP) of livers as a potential vehicle for medical research. Reproducible extended normothermic machine perfusion has remained elusive due to its increased complexity and monitoring requirements. We set out to develop a reproducible protocol for the extended normothermic machine perfusion of whole human livers. Methods Human livers declined for transplantation were perfused using a blood-based perfusate at 36 °C using the Liver Assist device (XVIVO, Sweden), with continuous veno-venous haemofiltration in-parallel. We developed the protocol in a stepwise fashion. Results Perfusion techniques utilised included: targeted physiological vascular flows, phosphate replacement (to prevent hypophosphataemia), N-acetylcysteine (to prevent methaemoglobin accumulation), and the utilisation of sodium lactate as both a nutritional source and real-time measure of hepatocyte function. All five human livers perfused with the developed protocol showed preserved function with a median perfusion time of 168 h (range 120–184 h), with preserved viability throughout. Conclusions Livers can be reproducibly perfused in excess of 120 (range 121–184) hours with evidence of preserved hepatocyte and cholangiocyte function.

BACKGROUND:Liver disease is the third leading cause of premature death in the UK. Transplantation is the only successful treatment for end-stage liver disease but is limited by a shortage of suitable donor organs. As a result, up to 20% of patients on liver transplant waiting lists die before receiving a transplant. A third of donated livers are not suitable for transplant, often due to steatosis. Hepatic steatosis, which affects 33% of the UK population, is strongly associated with obesity, an increasing problem in the potential donor pool. We have recently tested defatting interventions during normothermic machine perfusion (NMP) in discarded steatotic human livers that were not transplanted. A combination of therapies including forskolin (NKH477) and L-carnitine to defat liver cells and lipoprotein apheresis filtration were investigated. These interventions resulted in functional improvement during perfusion and reduced the intrahepatocellular triglyceride (IHTG) content. We hypothesise that defatting during NMP will allow more steatotic livers to be transplanted with improved outcomes. METHODS:In the proposed multi-centre clinical trial, we will randomly assign 60 livers from donors with a high-risk of hepatic steatosis to either NMP alone or NMP with defatting interventions. We aim to test the safety and feasibility of the defatting intervention and will explore efficacy by comparing ex-situ and post-reperfusion liver function between the groups. The primary endpoint will be the proportion of livers that achieve predefined functional criteria during perfusion which indicate potential suitability for transplantation. These criteria reflect hepatic metabolism and injury and include lactate clearance, perfusate pH, glucose metabolism, bile composition, vascular flows and transaminase levels. Clinical secondary endpoints will include proportion of livers transplanted in the two arms, graft function; cell-free DNA (cfDNA) at follow-up visits; patient and graft survival; hospital and ITU stay; evidence of ischemia-reperfusion injury (IRI); non-anastomotic biliary strictures and recurrence of steatosis (determined on MRI at 6 months). DISCUSSION:This study explores ex-situ pharmacological optimisation of steatotic donor livers during NMP. If the intervention proves effective, it will allow the safe transplantation of livers that are currently very likely to be discarded, thereby reducing waiting list deaths. TRIAL REGISTRATION:ISRCTN ISRCTN14957538. Registered in October 2022.

Summary Background There remains a lack of consensus on how to assess functional exercise capacity and physical frailty in patients with advanced chronic liver disease (CLD) being assessed for liver transplantation (LT). Aim To investigate prospectively the utility of the Duke Activity Status Index (DASI) and Liver Frailty Index (LFI) in ambulatory patients with CLD. Aim To investigate prospectively the utility of the Duke Activity Status Index (DASI) and Liver Frailty Index (LFI) in ambulatory patients with CLD. Methods We recruited patients from outpatient clinics at University Hospitals Birmingham, UK (2018–2019). We prospectively collated the DASI and LFI to identify the prevalence of, respectively, functional capacity and physical frailty, and to evaluate their accuracy in predicting overall and pre‐LT mortality. Results We studied 307 patients (57% male; median age 54 years; UKELD 52). Median DASI score was 28.7 (IQR 16.2–50.2), mean LFI was 3.82 (SD = 0.72), and 81% were defined either ‘pre‐frail’ or ‘frail’. Female sex and hyponatraemia were significant independent predictors of both DASI and LFI. Age and encephalopathy were significant independent predictors of LFI, while BMI significantly predicted DASI. DASI and LFI were significantly related to overall (HR 0.97, p = 0.001 [DASI], HR 2.04, p = 0.001 [LFI]) and pre‐LT mortality (HR 0.96, p = 0.02 [DASI], HR 1.94, p = 0.04 [LFI]). Conclusions Poor functional exercise capacity and physical frailty are highly prevalent among ambulatory patients with CLD who are being assessed for LT. The DASI and LFI are simple, low‐cost tools that predict overall and pre‐LT mortality. Implementation of both should be considered in all outpatients with CLD to highlight those who may benefit from targeted nutritional and exercise interventions.

Background: Biomarkers with strong predictive capacity towards transplantation outcome for livers undergoing normothermic machine perfusion (NMP) are needed. We investigated lactate clearing capacity as a basic function of liver viability during the first 6 h of NMP. Methods: A trial conducted in 6 high-volume transplant centres in Europe. All centres applied a back-to-base NMP approach with the OrganOx metra system. Perfusate lactate levels at start, 1, 2, 4 and 6 h of NMP were assessed individually and as area under the curve (AUC) and correlated with EAD (early allograft dysfunction), MEAF (model for early allograft function) and modified L-GrAFT (liver graft assessment following transplantation) scores. Results: A total of 509 livers underwent >= 6 h of NMP before transplantation in 6 centres in the UK, Germany and Austria. The donor age was 53 (40-63) years (median, i.q.r.). The total NMP time was 10.8 (7.9-15.7) h. EAD occurred in 26%, MEAF was 4.72 (3.54-6.05) and L-GrAFT(10) -0.96 (-1.52--0.32). Lactate at 1, 2 and 6 h correlated with increasing robustness with MEAF. Rather than a binary assessment with a cut-off value at 2 h, the actual 2 h lactate level correlated with the MEAF (P = 0.0306 versus P = 0.0002, Pearson r = 0.01087 versus r = 0.1734). The absolute lactate concentration at 6 h, the AUC of 0-6 h and 1-6 h (P < 0.0001, r = 0.3176) were the strongest predictors of MEAF. Conclusion: Lactate measured 1-6 h and lactate levels at 6 h correlate strongly with risk of liver allograft dysfunction upon transplantation. The robustness of predicting MEAF by lactate increases with perfusion duration. Monitoring lactate levels should be extended to at least 6 h of NMP routinely to improve clinical outcome.

Alternative forms of portal vein revascularization in liver transplant recipients with complex portal vein thrombosisJournal of HepatologyVol. 78Issue 4PreviewComplex portal vein thrombosis (PVT) is a challenge in liver transplantation (LT). Extra-anatomical approaches to portal revascularization, including renoportal (RPA), left gastric vein (LGA), pericholedochal vein (PCA), and cavoportal (CPA) anastomoses, have been described in case reports and series. The RP4LT Collaborative was created to record cases of alternative portal revascularization performed for complex PVT. Full-Text PDF Reply to: “Reconstruction for complex portal vein thrombosis – Anatomical if possible”Journal of HepatologyVol. 79Issue 3PreviewWe thank Duran et al. for their commentary regarding our publication1, and for sharing their experience managing portal vein thrombosis (PVT) in liver transplant (LT) candidates.2 They question the use of extra-anatomical portal vein (PV) reconstructions for non-complex PVT and describe their own cases of anatomical PV reconstructions performed both with and without venous interposition grafts in the context of complex and non-complex PVT. This commentary is constructive to the degree that it highlights the essential role anatomical PV reconstructions play in managing LT recipients, including those with PVT. Full-Text PDF We read the recent article by Fundora et al. with great interest, and these authors should be commended on collating multicentre data that addresses a question very pertinent to liver transplant surgeons.[1]Fundora Y. Hessheimer A.J. Del Prete L. Maroni L. Lanari J. Barrios O. et al.Alternative forms of portal vein revascularization in liver transplant recipients with complex portal vein thrombosis.J Hepatol. 2023; 78Abstract Full Text Full Text PDF Scopus (3) Google Scholar The number of complex portal vein thrombosis (PVT) cases included is impressive and reflects a growing challenge in the contemporary era, with diffuse PVT still being viewed as a contraindication for liver transplantation in many centres and only taken on by a few.[2]Harding D.J. Perera M.T. Chen F. Olliff S. Tripathi D. Portal vein thrombosis in cirrhosis: controversies and latest developments.World J Gastroenterol. 2015; 21: 6769-6784Crossref PubMed Scopus (73) Google Scholar,[3]Bhangui P. Lim C. Levesque E. Salloum C. Lahat E. Feray C. et al.Novel classification of non-malignant portal vein thrombosis: a guide to surgical decision-making during liver transplantation.J Hepatol. 2019; 71: 1038-1050Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar The prevalence of PVT increases with the severity of cirrhosis,[4]Senzolo M. Garcia-Tsao G. García-Pagán J.C. Current knowledge and management of portal vein thrombosis in cirrhosis.J Hepatol. 2021; 75: 442-453Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar and liver transplant surgeons need to be informed regarding optimal management. Severe portal hypertension, an associated portal cavernoma and competitive flow via spontaneous shunts all make these cases a surgical challenge.[3]Bhangui P. Lim C. Levesque E. Salloum C. Lahat E. Feray C. et al.Novel classification of non-malignant portal vein thrombosis: a guide to surgical decision-making during liver transplantation.J Hepatol. 2019; 71: 1038-1050Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar The study re-affirms the concept that was proposed by Starzl and colleagues 50 years ago, which is that the liver is better off when it receives splanchnic blood.[5]Starzl T.E. Francavilla A. Halgrimson C.G. Francavilla F.R. Porter K.A. Brown T.H. et al.The origin, hormonal nature, and action of hepatotrophic substances in portal venous blood.Surg Gynecol Obstet. 1973; 137: 179-199PubMed Google Scholar Although the data emanates from operations over a 25-year period, the authors show that the majority of cases are from the last decade (Fig. 2 in their paper) and therefore applicable to modern practice. In Birmingham, we have also strived to give patients with complex PVT the transplant opportunity and agree with the emphasis that surgical planning and graft selection are of paramount importance. However, a finding described by Fundora et al. that caught our interest was that 23% (n = 32) of this cohort with extra-anatomical portal venous (PV) reconstruction had Yerdel grade III thrombosis. On first assessment, this strategy seems excessive as by definition a grade III thrombus extends only to the proximal superior mesenteric vein (SMV). Therefore, if a complete thrombectomy cannot be achieved, the distal SMV can be used as a landing for an interposition graft or anastomosed directly to the donor portal vein as per the original series describing this classification.[6]Yerdel M.A. Gunson B. Mirza D. Karayalçin K. Olliff S. Buckels J. et al.Portal vein thrombosis in adults undergoing liver transplantation: risk factors, screening, management, and outcome.Transplantation. 2000; 69: 1873-1881Crossref PubMed Scopus (542) Google Scholar As the data reported by Fundora et al. only included cases of extra-anatomical PV reconstruction, the important number missing is the denominator with grade III thrombosis; we believe the majority would have been amenable to a more straightforward anatomical reconstruction technique. In a review of our recent (2010-2021) experience in Birmingham during which 2,022 transplants were performed, grade III thrombosis was encountered on 52 and grade IV thrombosis on 15 occasions. This gives an overall incidence of 3.3% (67/2022) for complex PVT (Grade III or IV). In the group with grade III thrombosis, only 38/52 (73%) were amenable to thrombectomy alone with direct porto-portal anastomosis if the length and vein wall integrity permitted. In the remaining 14/52 (27%), a vein interposition graft was used. Therefore, in our series of recent grade III PVT, no extra-anatomical reconstructions were required. In patients with grade IV thrombosis, only 2/15 required extra-anatomical reconstruction (one cavoportal anastomosis [CPA] and one renoportal anastomosis [RPA]). The remainder have been managed with thrombectomy and/or a jump graft from the distal SMV or inferior mesenteric vein, thus creating physiological PV inflow to the graft.[7]Durán M. Hann A. Lembach H. Nutu A. Clarke G. Patel I. et al.Normothermic machine perfusion as a tool for safe transplantation of high-risk recipients.Transplantology. 2022; 3: 169-183Crossref Scopus (2) Google Scholar Graft survival curves of our series are shown in Fig. 1. The extent of PVT (Fig. 1A) and the use of a vein graft (Fig. 1B) did not impact survival. We also found the post-operative complications reported by Fundora et al. interesting. Although there was a high rate of re-operation, this should not be viewed as a failure in this undoubtedly complex cohort and surgical re-exploration is often the safest option in complex liver transplant surgery. It would have been a worthwhile addition to the manuscript to include the indication for reintervention and laparotomy findings, or the need for further invasive interventions. Fundora et al. quite clearly demonstrate that both RPA or CPA fail to decompress the portal system and post-transplant oesophageal varices remain problematic at 8.6% and 25%, respectively. Portal hypertension-related problems have also been reported by other authors recently with RPA.[8]Azoulay D. Quintini C. Rayar M. Salloum C. Llado L. Diago T. et al.Renoportal anastomosis during liver transplantation in patients with portal vein thrombosis: first long-term results from a multicenter study.Ann Surg. 2022; 276: e825-e833Crossref PubMed Scopus (10) Google Scholar In addition to the fact that recipients in the non-physiological group do not have PV (or rather splanchnic) decompression, the act of opening the abdominal wall and explanting the native liver will result in ligation of many spontaneous collaterals, a factor that may further accentuate the already existing portal hypertension. Another comment about the data is that information about other portosystemic shunts, apart from spleno-renal shuts, and their management is not described. We believe large spontaneous portosystemic shunts are common among those with complex PVT, and PV flow mitigation is a mandatory step in the surgical strategy.[9]Centonze L. Gorga G. De Carlis R. Bernasconi D. Lauterio A. Carbonaro L. et al.Clinical impact of spontaneous portosystemic shunts in liver transplantation: a comprehensive assessment through total shunt area measurement.Transplantation. 2022; 107: 913-924Crossref Scopus (2) Google Scholar,[10]Mueller A.R. Platz K.P. Kremer B. Early postoperative complications following liver transplantation.Best Pract Res Clin Gastroenterol. 2004; 18: 881-900Crossref PubMed Scopus (0) Google Scholar Despite these minor criticisms, we feel that this is a valuable contribution to the literature on the subject. The authors should be commended on this collaboration and the initiative to investigate a fascinating surgical topic. The authors received no financial support to produce this manuscript. The authors declare no conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details. Study concept and design; MD, MTPRP. Acquisition of data; JA and AH. Analysis and interpretation of data; AH, MD, JA, MTPRP. Drafting of the manuscript; AH, MD MTPRP. Critical revision of the manuscript: AH, MD, JA MTPRT. The following are the supplementary data to this article: Download .pdf (.34 MB) Help with pdf files Multimedia component 1

Background. Primary nonfunction (PNF) is a life-threatening complication of liver transplantation (LT), but in the early postoperative period, it can be difficult to differentiate from early allograft dysfunction (EAD). The aim of this study was to determine if serum biomarkers can distinguish PNF from EAD in the initial 48 h following LT. Materials and Methods. A retrospective study of adult patients that underwent LT between January 2010 and April 2020 was performed. Clinical parameters, absolute values and trends of C-reactive protein (CRP), blood urea, creatinine, liver function tests, platelets, and international normalized ratio in the initial 48 h after LT were compared between the EAD and PNF groups. Results. There were 1937 eligible LTs, with PNF and EAD occurring in 38 (2%) and 503 (26%) patients, respectively. A low serum CRP and urea were associated with PNF. CRP was able to differentiate between the PNF and EAD on postoperative day (POD)1 (20 versus 43 mg/L; P < 0.001) and POD2 (24 versus 77; P < 0.001). The area under the receiver operating characteristic curve (AUROC) of POD2 CRP was 0.770 (95% confidence interval [CI] 0.645-0.895). The urea value on POD2 (5.05 versus 9.0 mmol/L; P = 0.002) and trend of POD2:1 ratio (0.71 versus 1.32 mmol/L; P < 0.001) were significantly different between the groups. The AUROC of the change in urea from POD1 to 2 was 0.765 (95% CI 0.645-0.885). Aspartate transaminase was significantly different between the groups, with an AUROC of 0.884 (95% CI 0.753-1.00) on POD2. Discussion. The biochemical profile immediately following LT can distinguish PNF from EAD; CRP, urea, and aspartate transaminase are more effective than ALT and bilirubin in distinguishing PNF from EAD in the initial postoperative 48 h. Clinicians should consider the values of these markers when making treatment decisions.

The widespread uptake of different machine perfusion (MP) strategies for liver transplant has been driven by an effort to minimize graft injury. Damage to the cholangiocytes during the liver donation, preservation, or early posttransplant period may result in stricturing of the biliary tree and inadequate biliary drainage. This problem continues to trouble clinicians, and may have catastrophic consequences for the graft and patient. Ischemic injury, as a result of compromised hepatic artery flow, is a well-known cause of biliary strictures, sepsis, and graft failure. However, very similar lesions can appear with a patent hepatic artery and these are known as ischemic type biliary lesions (ITBL) that are attributed to microcirculatory dysfunction rather than main hepatic arterial compromise. Both the warm and cold ischemic period duration appear to influence the onset of ITBL. All of the commonly used MP techniques deliver oxygen to the graft cells, and therefore may minimize the cholangiocyte injury and subsequently reduce the incidence of ITBL. As clinical experience and published evidence grows for these modalities, the impact they have on ITBL rates is important to consider. In this review, the evidence for the three commonly used MP strategies (abdominal normothermic regional perfusion [A-NRP], hypothermic oxygenated perfusion [HOPE], and normothermic machine perfusion [NMP] for ITBL prevention has been critically reviewed. Inconsistencies with ITBL definitions used in trials, coupled with variations in techniques of MP, make interpretation challenging. Overall, the evidence suggests that both HOPE and A-NRP prevent ITBL in donated after circulatory death grafts compared to cold storage. The evidence for ITBL prevention in donor after brain death grafts with any MP technique is weak.

Journal Article Emergency retransplant for primary non-function of liver allograft Get access James M Halle-Smith, James M Halle-Smith Liver Unit, Queen Elizabeth Hospital, Birmingham, UKCentre for Liver and Gastrointestinal Research, University of Birmingham, Edgbaston, UK Search for other works by this author on: Oxford Academic Google Scholar Lewis A Hall, Lewis A Hall Centre for Liver and Gastrointestinal Research, University of Birmingham, Edgbaston, UK Search for other works by this author on: Oxford Academic Google Scholar Angus Hann, Angus Hann Liver Unit, Queen Elizabeth Hospital, Birmingham, UKCentre for Liver and Gastrointestinal Research, University of Birmingham, Edgbaston, UK Search for other works by this author on: Oxford Academic Google Scholar John L Isaac, John L Isaac Department of Anaesthesia and Critical care, Queen Elizabeth Hospital, Birmingham, UK Search for other works by this author on: Oxford Academic Google Scholar Nick Murphy, Nick Murphy Department of Anaesthesia and Critical care, Queen Elizabeth Hospital, Birmingham, UK Search for other works by this author on: Oxford Academic Google Scholar Keith J Roberts, Keith J Roberts Liver Unit, Queen Elizabeth Hospital, Birmingham, UKCentre for Liver and Gastrointestinal Research, University of Birmingham, Edgbaston, UK https://orcid.org/0000-0003-1799-9829 Search for other works by this author on: Oxford Academic Google Scholar Neil Rajoriya, Neil Rajoriya Liver Unit, Queen Elizabeth Hospital, Birmingham, UKCentre for Liver and Gastrointestinal Research, University of Birmingham, Edgbaston, UK Search for other works by this author on: Oxford Academic Google Scholar M Thamara P R Perera M Thamara P R Perera Liver Unit, Queen Elizabeth Hospital, Birmingham, UKCentre for Liver and Gastrointestinal Research, University of Birmingham, Edgbaston, UK Correspondence to: Thamara P. R. Perera, The Liver Unit, 3rd Floor Nuffield House, Queen Elizabeth Hospital, Birmingham B15 2TH, UK (e-mail: thamara.perera@uhb.nhs.uk) Search for other works by this author on: Oxford Academic Google Scholar British Journal of Surgery, znad110, https://doi.org/10.1093/bjs/znad110 Published: 03 May 2023 Article history Received: 05 March 2023 Accepted: 06 April 2023 Published: 03 May 2023

The British Transplantation Society (BTS) 'Guideline on transplantation from deceased donors after circulatory death' has recently been updated and this manuscript summarises the relevant recommendations in abdominal organ transplantation from Donation after Circulatory Death (DCD) donors, encompassing the chapters on liver, kidney, pancreas and islet cell transplantation.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death, and its incidence is rising. Mortality from HCC is predicted to increase by 140% by 2035. Surveillance of high-risk patients with cirrhosis or chronic liver disease may be one means of reducing HCC mortality, but the level of supporting evidence for international guidelines is low/moderate. This study explores the real-world experience of HCC surveillance at a tertiary referral centre. Electronic patient records for all new HCCs diagnosed between August 2012 and December 2021 were retrospectively reviewed. Patient and tumour characteristics were evaluated, including the co-existence of chronic liver disease, cancer treatment and survival, and categorised according to HCC diagnosis within or outside a surveillance programme. Patients with HCC who presented through surveillance had smaller tumours diagnosed at an earlier stage, but this did not translate into improved overall survival. All patients in surveillance had chronic liver disease, including 91% (n = 101) with cirrhosis, compared to 45% (n = 29) in the non-surveillance cohort. We propose that the immune dysfunction associated with cirrhosis predisposes patients to a more aggressive tumour biology than the largely non-cirrhotic population in the non-surveillance group.

Background: Bench liver reduction, with or without intestinal length reduction (LR) (coupled with delayed closure and abdominal wall prostheses), has been a strategy adopted by our program for small children due to the limited availability of size-matched donors. This report describes the short, medium, and long-term outcomes of this graft reduction strategy.Methods: A single-center, retrospective analysis of children that underwent intestinal transplantation (April 1993 to December 2020) was performed. Patients were grouped according to whether they received an intestinal graft of full length (FL) or following LR.Results: Overall, 105 intestinal transplants were performed. The LR group (n = 10) was younger (14.5 months vs. 40.0 months, p = .012) and smaller (8.7 kg vs. 13.0 kg, p = .032) compared to the FL group (n = 95). Similar abdominal closure rates were achieved after LR, without any increase in abdominal compartment syndrome (1/10 vs. 7/95, p = .806). The 90-day graft and patient survival were similar (9/10, 90% vs. 83/95, 86%; p = .810). Medium and long-term graft survival at 1 year (8/10, 80% vs. 65/90, 71%; p = .599), and 5 years (5/10, 50% vs. 42/84, 50%; p = 1.00) was similar.Conclusion: LR of intestinal grafts appears to be a safe strategy for infants and small children requiring intestinal transplantation. This technique should be considered in the situation of significant size mismatch of intestine containing grafts.

Extended duration of normothermic machine perfusion (NMP) provides opportunities to resuscitate suboptimal donor livers. This intervention requires adequate oxygen delivery typically provided by a blood-based perfusion solution. Methaemoglobin (MetHb) results from the oxidation of iron within haemoglobin and represents a serious problem in perfusions lasting > 24 h. We explored the effects of anti-oxidant, N -acetylcysteine (NAC) on the accumulation of methaemoglobin. NMP was performed on nine human donor livers declined for transplantation: three were perfused without NAC (no-NAC group), and six organs perfused with an initial NAC bolus, followed by continuous infusion (NAC group), with hourly methaemoglobin perfusate measurements. In-vitro experiments examined the impact of NAC (3 mg) on red cells (30 ml) in the absence of liver tissue. The no-NAC group sustained perfusions for an average of 96 (range 87–102) h, universally developing methaemoglobinaemia (≥ 2%) observed after an average of 45 h, with subsequent steep rise. The NAC group was perfused for an average of 148 (range 90–184) h. Only 2 livers developed methaemoglobinaemia (peak MetHb of 6%), with an average onset of 116.5 h. Addition of NAC efficiently limits formation and accumulation of methaemoglobin during NMP, and allows the significant extension of perfusion duration.

Normothermic machine perfusion (NMP) enables pretransplant assessment of high-risk donor livers. The VITTAL trial demonstrated that 71% of the currently discarded organs could be transplanted with 100% 90-day patient and graft survivals. Here, we report secondary end points and 5-year outcomes of this prospective, open-label, phase 2 adaptive single-arm study. The patient and graft survivals at 60 months were 82% and 72%, respectively. Four patients lost their graft due to nonanastomotic biliary strictures, one caused by hepatic artery thrombosis in a liver donated following brain death, and 3 in elderly livers donated after circulatory death (DCD), which all clinically manifested within 6 months after transplantation. There were no late graft losses for other reasons. All the 4 patients who died during the study follow-up had functioning grafts. Nonanastomotic biliary strictures developed in donated after circulatory death livers that failed to produce bile with pH >7.65 and bicarbonate levels >25 mmol/L. Histological assessment in these livers revealed high bile duct injury scores characterized by arterial medial necrosis. The quality of life at 6 months significantly improved in all but 4 patients suffering from nonanastomotic biliary strictures. This first report of long-term outcomes of high-risk livers assessed by normothermic machine perfusion demonstrated excellent 5-year survival without adverse effects in all organs functioning beyond 1 year (ClinicalTrials.gov number NCT02740608).

1Department of Cellular Pathology, Queen Elizabeth Hospital Birmingham, Birmingham, UK 2Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK 3Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, UK Financial support and sponsorship: none Abbreviations: NMP normothermic machine perfusion Correspondence Prof Desley Neil, Department of Cellular Pathology, Level -1, Queen Elizabeth Hospital Birmingham, Birmingham, UK. B15 2GW. Email: [email protected]