Donor Atheromatous Disease is a Risk Factor for Hepatic Artery Thrombosis After Liver Transplantation.

The increasing age of liver donors and transplant candidates, together with the growing prevalence of metabolic comorbidities, could impact the risk of vascular complications after liver transplantation. We enrolled a consecutive cohort of adult patients undergoing liver transplantation from 2012 to 2021 who had a blinded pathological assessment of atherosclerosis in the donor and recipient hepatic arteries (HA). Patients receiving partial or reduced grafts, retransplantation, or combined organ transplantation were excluded. The relationship between HA atherosclerosis and HA thrombosis after liver transplantation was evaluated using logistic regression in the whole study cohort and in a propensity score-matched subpopulation. Among 443 eligible patients, 272 had a full pathological evaluation of the donor and recipient HA and were included in the study. HA atheroma was present in 51.5% of donors and in 11.4% of recipients. HA thrombosis occurred in 16 patients (5.9%), being more likely in patients who received a donor with HA atherosclerosis than in those without (10.7% vs. 0.8%; p < 0.001). Donor HA atherosclerosis was an independent risk factor of HA thrombosis (OR = 17.79; p = 0.008), and this finding was consistent in the propensity score-matched analysis according to age, sex, complex arterial anastomosis, and alcoholic liver disease (OR = 19.29; p = 0.007). Atheromatous disease in the recipient had no influence on the risk of HA thrombosis (OR = 1.70; p = 0.55). In conclusion, patients receiving donors with HA atherosclerosis are at increased risk for HA thrombosis after liver transplantation. The evaluation of the donor graft vasculature could guide antiplatelet therapy in the postoperative period.

Hepatic artery thrombosis and use of anticoagulants and antiplatelet agents in pediatric liver transplantation.

BACKGROUND: Hepatic artery thrombosis (HAT) is a reported complication of 5%-10% of pediatric liver transplantations, rates 3-4 times that seen in adults. Early HAT (seen within 14 days after transplant) can lead to severe allograft damage and possible urgent re-transplantation. In this report, we present our analysis of HAT in pediatric liver transplant from a national clinical database and examine the association of HAT with anticoagulant or antiplatelet medication administered in the post-operative period. METHODS: Data were obtained from the Pediatric Health Information System database maintained by the Children's Hospital Association. For each liver transplant recipient identified in a 10-year period, diagnosis, demographic, and medication data were collected and analyzed. RESULTS: Our findings showed an average rate of HAT of 6.3% across 31 centers. Anticoagulant and antiplatelet medication strategies varied distinctly among and even within centers, likely due to the fact there are no consensus guidelines. Notably, in centers with similar medication usage, HAT rates continue to vary. At the patient level, use of aspirin within the first 72 h of transplantation was associated with a decreased risk of HAT, consistent with other reports in the literature. CONCLUSION: We suggest that concerted efforts to standardize anticoagulation approaches in pediatric liver transplant may be of benefit in the prevention of HAT. A prospective multi-institutional study of regimen-possibly including aspirin-following transplantation could have significant value.

Preemptive Venoarterial Extracorporeal Membrane Oxygenation for Liver Transplantation-Judicious Candidate Selection.

Portopulmonary hypertension is a relatively common pathologic condition in patients with end-stage liver disease. Traditionally, severe pulmonary hypertension is regarded as a contraindication to liver transplantation (LT) due to a high perioperative mortality rate. Recently, extracorporeal membrane oxygenation (ECMO) has been utilized for intraoperative management of LT. As venoarterial (VA) ECMO may benefit certain high-risk LT patients by reducing the ventricular workload by the equivalent of the programmed flow rate, its usage requires multidisciplinary planning with considerations of the associated complications. We highlighted two cases at our single-center institution as examples of high-risk pulmonary hypertension patients undergoing LT on planned VA ECMO. These patients both survived the intraoperative period; however, they had drastically different postoperative outcomes, generating discussions on the importance of judicious patient selection. Since ECMO has removed the barrier of intraoperative survivability, the patient selection process may need to put weight on the patient's potential for postoperative recovery and rehabilitation. Considerations on LT recipients undergoing preemptive ECMO need to expand from the ability of the patients to withstand the demands of the surgery during the immediate perioperative period to the long-term postoperative recovery course.

Heart-liver-kidney transplantation for AL amyloidosis using normothermic recovery and storage from a donor following circulatory death: Short-term outcome in a first-in-world experience.

AL amyloidosis is a rare condition characterized by the overproduction of an unstable free light chain, protein misfolding and aggregation, and extracellular deposition that can progress to multiorgan involvement and failure. To our knowledge, this is the first worldwide report to describe triple organ transplantation for AL amyloidosis and triple organ transplantation using thoracoabdominal normothermic regional perfusion recovery with a donation from a circulatory death (DCD) donor. The recipient was a 40-year-old man with multiorgan AL amyloidosis with a terminal prognosis without multiorgan transplantation. An appropriate DCD donor was selected for sequential heart, liver, and kidney transplants via our center's thoracoabdominal normothermic regional perfusion pathway. The liver was additionally placed on an ex vivo normothermic machine perfusion, and the kidney was maintained on hypothermic machine perfusion while awaiting implantation. The heart transplant was completed first (cold ischemic time [CIT]: 131 minutes), followed by the liver transplant (CIT: 87 minutes, normothermic machine perfusion: 301 minutes). Kidney transplantation was performed the following day (CIT: 1833 minutes). He is 8 months posttransplant without evidence of heart, liver, or kidney graft dysfunction or rejection. This case highlights the feasibility of normothermic recovery and storage modalities for DCD donors, which can expand transplant opportunities for allografts previously not considered for multiorgan transplantations.

Hereditary thrombotic thrombocytopenic purpura acquired through liver transplantation: A case report.

A 62-year-old received orthotopic liver transplantation. Three weeks later, thrombotic microangiopathy developed. Testing revealed thrombotic thrombocytopenic purpura (TTP) characterized by low ADAMTS13 (A Disintegrin-like Metallopeptidase with ThromboSpondin type 1 motif 13) activity and no inhibitor of ADAMTS13 protein. Retrospective attainment of donor records revealed a TTP diagnosis, presumably hereditary TTP (hTTP), as an ADAMTS13 protein inhibitor was not mentioned. As the grafted liver does not produce ADAMTS13 protein, the recipient now functionally has hTTP and will likely need plasma transfusions indefinitely. While hTTP is extremely rare, it should be considered a contraindication to liver donation outside of exceptional circumstances. If a potential liver donor has TTP listed on medical history, attempts should be made to determine whether it is autoimmune or hereditary. An accurate medical history is critical as it is the only reliable way to identify hTTP, as outside of acute exacerbations of TTP, donors with hTTP can have normal laboratory values, including normal hemoglobin, platelets, and renal function.

Preliminary safety and efficacy of laser stricturotomy for treatment of refractory biliary anastomotic strictures following liver transplantation.

Biliary anastomotic stricture (BAS) is a frequent complication of liver transplantation and is associated with reduced graft survival and patient morbidity. Existing treatments for BAS involve dilation of the stricture though placement of 1 or more catheters for 6 to 24 months yielding limited effectiveness in transplant patients. In this case series, we present preliminary safety and efficacy of a novel percutaneous laser stricturotomy treatment in a cohort of 5 posttransplant patients with BAS refractory to long-term large bore catheterization. In all patients, holmium or thulium laser was used to excise the stricture and promote biliary re-epithelization. There were no periprocedural complications. Technical success was 100% and at mean follow-up time of 22 months, there have been no recurrences. In conclusion, percutaneous laser stricturotomy demonstrates preliminary safety and efficacy in treatment of refractory BAS following liver transplantation.

Prolonged preservation by hypothermic machine perfusion facilitates logistics in liver transplantation: A European observational cohort study.

A short period (1-2 h) of hypothermic oxygenated machine perfusion (HOPE) after static cold storage is safe and reduces ischemia-reperfusion injury-related complications after liver transplantation. Machine perfusion time is occasionally prolonged for logistical reasons, but it is unknown if prolonged HOPE is safe and compromises outcomes. We conducted a multicenter, observational cohort study of patients transplanted with a liver preserved by prolonged (≥4 h) HOPE. Postoperative biochemistry, complications, and survival were evaluated. The cohort included 93 recipients from 12 European transplant centers between 2014-2021. The most common reason to prolong HOPE was the lack of an available operating room to start the transplant procedure. Grafts underwent HOPE for a median (range) of 4:42 h (4:00-8:35 h) with a total preservation time of 10:50 h (5:50-20:50 h). Postoperative peak ALT was 675 IU/L (interquartile range 419-1378 IU/L). The incidence of postoperative complications was low, and 1-year graft and patient survival were 94% and 88%, respectively. To conclude, good outcomes are achieved after transplantation of donor livers preserved with prolonged (median 4:42 h) HOPE, leading to a total preservation time of almost 21 h. These results suggest that simple, end-ischemic HOPE may be utilized for safe extension of the preservation time to ease transplantation logistics.

Patisiran treatment in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy after liver transplantation.

Hereditary transthyretin-mediated (hATTR) amyloidosis, or ATTRv amyloidosis, is a progressive disease, for which liver transplantation (LT) has been a long-standing treatment. However, disease progression continues post-LT. This Phase 3b, open-label trial evaluated efficacy and safety of patisiran in patients with ATTRv amyloidosis with polyneuropathy progression post-LT. Primary endpoint was median transthyretin (TTR) reduction from baseline. Twenty-three patients received patisiran for 12 months alongside immunosuppression regimens. Patisiran elicited a rapid, sustained TTR reduction (median reduction [Months 6 and 12 average], 91.0%; 95% CI: 86.1%-92.3%); improved neuropathy, quality of life, and autonomic symptoms from baseline to Month 12 (mean change [SEM], Neuropathy Impairment Score, -3.7 [2.7]; Norfolk Quality of Life-Diabetic Neuropathy questionnaire, -6.5 [4.9]; least-squares mean [SEM], Composite Autonomic Symptom Score-31, -5.0 [2.6]); and stabilized disability (Rasch-built Overall Disability Scale) and nutritional status (modified body mass index). Adverse events were mild or moderate; five patients experienced ≥1 serious adverse event. Most patients had normal liver function tests. One patient experienced transplant rejection consistent with inadequate immunosuppression, remained on patisiran, and completed the study. In conclusion, patisiran reduced serum TTR, was well tolerated, and improved or stabilized key disease impairment measures in patients with ATTRv amyloidosis with polyneuropathy progression post-LT (www.clinicaltrials.gov NCT03862807).

Liver transplantation for hepatocellular carcinoma following checkpoint inhibitor therapy with nivolumab.

Limited case series describe conflicting results regarding the safety of checkpoint inhibitors (CPI) prior to liver transplantation (LT). We reviewed single-center data on all consecutive patients who underwent LT for hepatocellular carcinoma treated with CPI between January 1, 2018, and January 30, 2021. Time from CPI to LT, immunosuppression, biopsy-proven acute cellular rejection (BPACR), graft loss and death were evaluated. Five patients with a mean age 65 (range 61-71) years underwent LT after CPI with nivolumab. Time from last CPI to LT ranged from 0.3 to 11 months. Two patients with <3 months from the last dose of CPI to LT developed BPACR and severe hepatic necrosis, one of whom required retransplantation with recurrent BPACR but without recurrent graft loss over 38 months of follow up. None of the patients who underwent LT >3 months from the last dose of CPI had BPACR. In conclusion, pretransplant use of CPIs, particularly within 90 days of LT, was associated with BPACR and immune-mediated hepatic necrosis. Future multicenter studies should consider a sufficient interval from the last dose of CPI to LT to mitigate the risk for adverse immune-mediated outcomes and graft loss.

NRF2 assessment in discarded liver allografts: A role in allograft function and salvage.

Antioxidant defence mechanisms, such as the nuclear factor-erythroid 2-related-factor-2 (NRF2) axis, are integral to oxidative stress responses and ischemic injury. Hepatic antioxidant capacity is contingent on parenchymal quality, and there is a need to develop new insights into key molecular mechanisms in marginal liver allografts that might provide therapeutic targets. This study examines the clinical relevance of NRF2 in donor livers and its response to normothermic machine perfusion (NMP). Discarded donor livers (n = 40) were stratified into a high NRF2 and low NRF2 group by quantifying NRF2 expression. High NRF2 livers had significantly lower transaminase levels, hepatic vascular inflammation and peri-portal CD3+ T cell infiltration. Human liver allografts (n = 8) were then exposed to 6-h of NMP and high NRF2 livers had significantly reduced liver enzyme alterations and improved lactate clearance. To investigate these findings further, we used a rat fatty-liver model, treating livers with an NRF2 agonist during NMP. Treated livers had increased NRF2 expression and reduced transaminase derangements following NMP compared to vehicle control. These results support the association of elevated NRF2 expression with improved liver function. Targeting this axis could have a rationale in future studies and NRF2 agonists may represent a supplemental treatment strategy for rescuing marginal donor livers.

Donor-derived cell-free DNA levels predict graft injury in liver transplant recipients.

Donor-derived cell-free DNA (dd-cfDNA) has been evaluated as a rejection marker in organ transplantation. This study sought to assess the utility of dd-cfDNA to diagnose graft injury in liver transplant recipients (LTR) and as a predictive biomarker prior to different causes of graft dysfunction. Plasma from single and multicenter LTR cohorts was analyzed for dd-cfDNA. Phenotypes of treated biopsy-proven acute rejection (AR, N = 57), normal function (TX, N = 94), and acute dysfunction no rejection (ADNR; N = 68) were divided into training and test sets. In the training set, dd-cfDNA was significantly different between AR versus TX (AUC 0.95, 5.3% cutoff) and AR versus ADNR (AUC 0.71, 20.4% cutoff). Using these cutoffs in the test set, the accuracy and NPV were 87% and 100% (AR vs. TX) and 66.7% and 87.8% (AR vs. ADNR). Blood samples collected serially from LTR demonstrated incremental elevations in dd-cfDNA prior to the onset of graft dysfunction (AR > ADNR), but not in TX. Dd-cfDNA also decreased following treatment of rejection. In conclusion, the serial elevation of dd-cfDNA identifies pre-clinical graft injury in the context of normal liver function tests and is greatest in rejection. This biomarker may help detect early signs of graft injury and rejection to inform LTR management strategies.

Outcome and safety of a surveillance biopsy guided personalized immunosuppression program after liver transplantation.

Graft survival beyond year 1 has not changed after orthotopic liver transplantation (OLT) over the last decades. Likewise, OLT causes comorbidities such as infection, renal impairment and cancer. We evaluated our single-center real-world individualized immunosuppression program after OLT, based on 211 baseline surveillance biopsies (svLbx) without any procedural complications. Patients were classified as low, intermediate and high rejection risk based on graft injury in svLbx and anti-HLA donor-specific antibodies. While 32% of patients had minimal histological inflammation, 57% showed histological inflammation and 23% advanced fibrosis (>F2), which was not predicted by lab parameters. IS was modified in 79% of patients after svLbx. After immunosuppression reduction in 69 patients, only 5 patients showed ALT elevations and three of these patients had a biopsy-proven acute rejection, two of them related to lethal comorbidities. The rate of liver enzyme elevation including rejection was not significantly increased compared to a svLbx control cohort prior to the initiation of our structured program. Immunosuppression reduction led to significantly better kidney function compared to this control cohort. In conclusion, a biopsy guided personalized immunosuppression protocol after OLT can identify patients requiring lower immunosuppression or patients with graft injury in which IS should not be further reduced.

Augmenter of liver regeneration-mediated mitophagy protects against hepatic ischemia/reperfusion injury.

Augmenter of liver regeneration (ALR) is an anti-apoptotic protein found mainly in mitochondria. It protects hepatocytes from ischemia-reperfusion (I/R) injury, but the underlying mechanism is not clear. We found that in rats, delivery of the ALR gene alleviated hepatic I/R injury during orthotopic liver transplantation as evidenced by reduced serum aminotransferase, oxidative stress and apoptosis, and increased expression of autophagy markers. In an in vitro hypoxia/reoxygenation (H/R) model, overexpression of the ALR gene activated autophagy and relieved defective mitophagy via the PINK1/Parkin pathway. Mechanistically, ALR transfection induced the expression of mitofusin 2 (Mfn2) in the H/R model, which led to PINK1 accumulation and mitochondrial translocation of Parkin. Deletion of Mfn2 abolished mitophagy activation induced by ALR transfection, promoted mitochondrial dysfunction, and eventually increased cell apoptosis. Mfn2 administration prevented the inhibition of mitophagy in ALR-knockout (KO) cells, thus attenuated mitochondrial dysfunction and cell apoptosis. In heterozygous ALR-knockout mice treated with a warm I/R injury, marked aggravation of liver injury was associated with mitophagy inhibition and reduction in Mfn2 expression. Taken together, our results confirm that ALR accelerated Parkin translocation and mitophagy via Mfn2, and protected hepatocytes from I/R-induced injury. Our findings provide a novel rationale for the treatment of hepatic I/R injury.

Normothermic with or without hypothermic oxygenated perfusion for DCD before liver transplantation: European multicentric experience.

Grafts from donors with cardiac death (DCD) are subject to warm ischemia time (WIT) due to the no-touch-period (20 min in Italy and 5 min in France). These livers (LT) have higher rates of early allograft dysfunction (EAD), primary non-function (PNF), and ischemic cholangiopathy (IC) compared to LT from brain dead donors (DBD). Normothermic regional perfusion (NRP) is a beneficial strategy to mitigate organ damage; a further approach is the application of ex vivo hypothermic oxygenated perfusion (HOPE) after cold storage (CS). We retrospectively analyzed LTs performed from 2016 to 2019 at three transplant centers using NRP-DCD grafts: Bologna and Milan treated with HOPE (group A), Rennes preserved using CS (group B). No-flow period, total and functional WIT were significantly higher in group A than in group B (30.5±7.7 vs. 20.5±4.1; 56.5±20.4 vs. 39.1±21.6; 41.9±12.5 vs. 25.5±3.7; respectively, P < .05), without differences in the postoperative course. In particular, the two groups had similar rates of EAD (21.1% vs. 25.0%), PNF (5.3% vs. 6.3%), IC (0% vs. 12.5%, P = .112), and non-IC biliary complications (0% vs. 6.3%, P = .457), re-LT (10.5% vs.12.5%). This occurred despite a high rate of UK DCD risk score > 10 (63.2% A vs. 17.6% B, P = .000), which theoretically would make a large number of these transplants "futile." In conclusion, Italian and French groups had similar post-LT outcomes, probably related to the use of HOPE after CS in the case of long WIT.

Developing simultaneous liver-kidney transplant medical eligibility criteria while providing a safety net: A 2-year review of the OPTN's allocation policy.

The OPTN's simultaneous liver-kidney (SLK) allocation policy, implemented August 10, 2017, established medical eligibility criteria for adult SLK candidates and created Safety Net kidney allocation priority for liver-alone recipients with new/continued renal impairment. OPTN SLK and kidney after liver (KAL) data were analyzed (registrations as of December 31, 2019, transplants pre-policy [March 20, 2015-August 9, 2017] vs. post-policy [August 10, 2017-December 31, 2019]). Ninety-four percent of SLK registrations met eligibility criteria (99% CKD: 50% dialysis, 50% eGFR). SLK transplant volume decreased from a record 740 (2017) to 676 (2018, -9%), with a subsequent increase to 728 (2019, 1.6% below 2017 volume). For KAL listings within 1 year of liver transplant, waitlist mortality rates declined post-policy versus pre-policy (27 [95% CI = 20.6-34.7] vs. 16 [11.7-20.5]) while transplant rates increased fourfold (46 [32.2-60.0] vs. 197 [171.6-224.7]). There were 234 KAL transplants post-policy (94% Safety Net priority eligible), and no significant difference in 1-year patient/graft survival vs. kidney-alone (patient: 95.9% KAL, 97.0% kidney-alone [p = .39]; graft: 94.2% KAL, 94.6% kidney-alone [p = .81]). From pre- to post-policy, the proportion of all deceased donor kidney and liver transplants that were SLK decreased (kidney: 5.1% to 4.3%; liver: 9.7% to 8.7%). SLK policy implementation interrupted the longstanding rise in SLK transplants, while Safety Net priority directed kidneys to liver recipients in need with thus far minimal impact to posttransplant outcomes.

Sinusoidal obstruction syndrome as a manifestation of acute antibody-mediated rejection after liver transplantation.

Antibody-mediated rejection (AMR) after liver transplantation is uncommon but, when present, manifests as graft dysfunction. We report the case of a 54-year-old woman who developed portal hypertension with pleural effusion and ascites secondary to sinusoidal obstruction syndrome (SOS) due to acute AMR following an ABO-matched liver transplantation for autoimmune cirrhosis and hepatocellular carcinoma. Initial immunosuppression comprised basiliximab, decreasing prednisone, tacrolimus, and mycophenolate mofetil. After 1 month, she presented with the massive pleural effusion, slight ascites, and normal liver tests. After excluding common causes of pleural effusion, we performed a liver biopsy that showed atypical rejection with the involvement of large centrilobular veins partially occluded by marked endotheliitis and lax fibrosis suggestive of SOS. Direct immunofluorescence study of C4d showed diffuse endothelial sinusoidal staining, and de novo donor-specific anti-human leukocyte antigen antibodies were detected in his blood. Thus, we diagnosed AMR focused on centrilobular veins and initiated treatment with defibrotide, steroid pulses, and diuretics. However, this was ineffective, and the pleural effusion only resolved when plasmapheresis and intravenous immunoglobulin were started. This case shows that AMR can cause SOS with portal hypertension and present with a pleural effusion, and as such, it should be suspected after excluding other more common causes of effusion.

Clinical parameters and biomarkers predicting spontaneous operational tolerance after liver transplantation: A scoping review.

Indefinite allograft acceptance after immunosuppression withdrawal (ISW), also known as operational tolerance (OT), can occur spontaneously after liver transplantation (LT), but reliable and reproducible prognosis of OT versus non-OT outcomes remains elusive. To prime this, systematic extraction of OT-predictive factors from the literature is crucial. We provide the first comprehensive identification and synthesis of clinical parameters and biomarkers predicting spontaneous OT in non-autoimmune/non-replicative viral LT recipients selected for ISW. We searched Embase, Medline, the Cochrane Central Register of Controlled Trials, clinicaltrials.gov, and the World Health Organization International Clinical Trials Registry Platform for articles, conference abstracts, and ongoing trials. We contacted principal investigators of stand-alone abstracts and ongoing trials for unpublished data and screened citations and references of eligible articles. Twenty-three articles reporting on 11 completed ISW studies, 13 abstracts, and five trial registry entries were included. Longer time between LT and ISW was the only clinical parameter that may increase the incidence of OT. Prognostic biomarkers conspicuously differed between pediatric and adult ISW candidates. These included allograft gene expression patterns and peripheral blood immune exhaustion markers for adults, and histological allograft scores for children. Our results will foster cross-validation efforts to facilitate safe and harmonized candidate selection for successful ISW.