Summary
Biliary tract complications (BTCs) still burden liver transplantation (LT). The wide reporting variability highlights the absence of systematic screening. From 2000 to 2009, simultaneous ...liver biopsy and direct biliary visualization were prospectively performed in 242 recipients at 3 and 6 months (n = 212, 87.6%) or earlier when indicated (n = 30, 12.4%). Median follow‐up was 148 (107–182) months. Seven patients (2.9%) experienced postprocedural morbidity. BTCs were initially diagnosed in 76 (31.4%) patients; 32 (42.1%) had neither clinical nor biological abnormalities. Acute cellular rejection (ACR) was present in 27 (11.2%) patients and in 6 (22.2%) BTC patients. Nine (3.7%) patients with normal initial cholangiography developed BTCs after 60 (30–135) months post‐LT. BTCs directly lead to 7 (2.9%) re‐transplantations and 14 (5.8%) deaths resulting in 18 (7.4%) allograft losses. Bile duct proliferation at 12‐month biopsy proved an independent risk factor for graft loss (P = 0.005). Systematic biliary tract and allograft evaluation allows the incidence and extent of biliary lesions to be documented more precisely and to avoid erroneous treatment of ACR. The combination ‘abnormal biliary tract‐canalicular proliferation’ is an indicator of worse graft outcome. BTCs are responsible for important delayed allograft and patient losses. These results underline the importance of life‐long follow‐up and appropriate timing for re‐transplantation.
Premature senescence occurs in adult hepatobiliary diseases and worsens the prognosis through deleterious liver remodeling and hepatic dysfunction. Senescence might also arises in biliary atresia ...(BA), the first cause of pediatric liver transplantation. Since alternatives to transplantation are needed, our aim was to investigate premature senescence in BA and to assess senotherapies in a preclinical model of biliary cirrhosis.
BA liver tissues were prospectively obtained at hepatoportoenterostomy (n=5) and liver transplantation (n=30) and compared to controls (n=10). Senescence was investigated through spatial whole transcriptome analysis, SA-β-gal activity, p16 and p21 expression, γ-H2AX and senescence-associated secretory phenotype (SASP). Human allogenic liver-derived progenitor cells (HALPC) or dasatinib and quercetin (D+Q) were administrated to two-month-old Wistar rats after bile duct ligation (BDL).
Advanced premature senescence was evidenced in BA livers from early stage and continued to progress until liver transplantation. Senescence and SASP were predominant in cholangiocytes, but also present in surrounding hepatocytes. HALPC but not D+Q reduced the early marker of senescence p21 in BDL rats and improved biliary injury (serum γGT and
expression) and hepatocytes mass loss (
).
BA livers displayed advanced cellular senescence at diagnosis that continued to progress until liver transplantation. HALPC reduced early senescence and improved liver disease in a preclinical model of BA, providing encouraging preliminary results regarding the use of senotherapies in pediatric biliary cirrhosis.
OBJECTIVE:The aim of the study is to evaluate whether intra-operative induction with anti-lymphocytic serum (ALS) is superior to no induction in adult liver transplantation (LT).
BACKGROUND:The ...efficacy of ALS induction remains inconclusive in LT, because of poorly designed trials.
METHODS:A randomized controlled trial was conducted, including 206 adults (>15 years) and comparing tacrolimus monotherapy (TAC, n = 109) and tacrolimus plus a single, intraoperative, high-dose (9 mg/kg), rabbit anti-T-lymphocyte globulins (ATLG; n = 97). All patients had similar follow-up, including Banff-scored biopsies. Rejection was considered clinically relevant and treated if pathologic and biochemical changes were concordant. The primary endpoint was immunosuppression minimization to monotherapy; secondary endpoints were biopsy-proven rejection, clinical rejection, patient (PS) and graft (GS) survival.
RESULTS:At 1 year, 79/81 (96.3%) ATLG and 101/102 (99.0%) TAC patients were steroid-free (P = 0.585); 28 (34.6%) ATLG, and 31 (30.4%) TAC patients were on double-drug immunosuppression (P = 0.633). One-year PS and GS of ATLG and TAC patients were 84% and 92% (P = 0.260) and 76% and 90% (P = 0.054).Despite significantly a fewer day-7 moderate-to-severe acute cellular rejections (ACR) in ATLG group (10.0% vs 24.0% in TAC group, P = 0.019), cumulative proportion of patients experiencing steroid-sensitive (11.3% ATLG vs 14.7% TAC, P = 0.539), steroid-resistant (2.1% ATLG vs 3.7% TAC, P = 0.686) and chronic rejection (1.0% ATLG vs 0.9% TAC, P = 1.000) were similar. ATLG administration brought about greater hemodynamic instability and blood products use (P = 0.001).
CONCLUSIONS:At 1 year from LT, ATLG induction did not significantly affect immunosuppressive load, treated rejection, patient, and graft survival. The observed adverse events justify a modification of dosing and timing of ATLG infusion. Long-term results are required to judge the ATLG possible benefits on immunosuppressive load and tolerance induction.
Ischemia-reperfusion injury (IRI) is an inflammatory process inherent in organ transplantation procedures. It is associated with tissue damage and, depending on its intensity, can impact early graft ...function. In liver transplantation (LT), strategies to alleviate IRI are essential in order to increase the use of extended criteria donor (ECD) grafts, which are more susceptible to IRI, as well as to improve postoperative graft and patient outcomes. Sevoflurane, a commonly used volatile anesthetic, has been shown to reduce IRI. This scoping review aims to give a comprehensive overview of the existing experimental and clinical data regarding the potential benefits of sevoflurane for hepatic IRI (HIRI) and to identify any gaps in knowledge to guide further research. We searched Medline and Embase for relevant articles. A total of 380 articles were identified, 45 of which were included in this review. In most experimental studies, the use of sevoflurane was associated with a significant decrease in biomarkers of acute liver damage and oxidative stress. Administration of sevoflurane before hepatic ischemia (preconditioning) or after reperfusion (postconditioning) appears to be protective. However, in the clinical setting, results are conflicting. While some studies showed a reduction of postoperative markers of liver injury, the benefit of sevoflurane on clinical outcomes and graft survival remains unclear. Further prospective clinical trials remain necessary to assess the clinical relevance of the use of sevoflurane as a protective factor against HIRI.
Although machine perfusion (MP) is being increasingly adopted in liver transplantation, indications, timing, and modality are debated. To investigate current indications for MP a web‐based Google ...Forms survey was launched in January 2021 and addressed to 127 experts in the field, identified among first and corresponding Authors of MP literature in the last 10 years. The survey presented 10 real‐life cases of donor–recipient matching, asking whether the liver would be accepted (Q1), whether MP would be used in that particular setting (Q2) and, if so, by which MP modality (Q3) and at what timing during preservation (Q4). Respondents could also comment on each case. The agreement was evaluated using Krippendorff's alpha coefficient. Answers from 39 (30.1%) participants disclosed significant heterogeneity in graft acceptance, MP indications, technique, and timing. Agreement between respondents was generally poor (Q1, α = 0.11; Q2, α = 0.14; Q3, α = 0.12, Q4, α = 0.11). Overall, respondents preferred hypothermic MP and an end‐ischemic approach in 56.3% and 81.1% of cases, respectively. A total of 18 (46.2%) participants considered only one MP approach, whereas 17 (43.6%) and 3 (7.7%) considered using alternatively 2 or 3 different techniques. Of 38 comments, 17 (44.7%) were about the use of MP for graft viability assessment before implantation. This survey shows considerable variability in MP indications, emphasizing the need to identify scenarios of optimal utilization for each technique. Viability assessment emerges as a fundamental need of transplant professionals when considering the use of MP.
In this survey, experts in the field of machine perfusion and liver transplantation were confronted to ten real‐world cases of donor‐recipient matching. Respondents were asked whether they would accept the offer and, if so, whether, how and when they would use machine perfusion for each case. The picture, which depicts each respondent answers, highlight significant heterogeneity with regards to graft acceptance and machine perfusion practice.
Following organ transplantation, lifelong immunosuppressive therapy is required to prevent the host immune system from destroying the allograft. This can cause severe side effects and increased ...recipient morbidity and mortality. Complete cessation of immunosuppressive drugs has been successfully accomplished in selected transplant recipients, providing proof of principle that operational allograft tolerance is attainable in clinical transplantation. The intra-graft molecular pathways associated with successful drug withdrawal, however, are not well defined. In this study, we analyzed sequential blood and liver tissue samples collected from liver transplant recipients enrolled in a prospective multicenter immunosuppressive drug withdrawal clinical trial. Before initiation of drug withdrawal, operationally tolerant and non-tolerant recipients differed in the intra-graft expression of genes involved in the regulation of iron homeostasis. Furthermore, as compared with non-tolerant recipients, operationally tolerant patients exhibited higher serum levels of hepcidin and ferritin and increased hepatocyte iron deposition. Finally, liver tissue gene expression measurements accurately predicted the outcome of immunosuppressive withdrawal in an independent set of patients. These results point to a critical role for iron metabolism in the regulation of intra-graft alloimmune responses in humans and provide a set of biomarkers to conduct drug-weaning trials in liver transplantation.
Large field of view CZT SPECT cameras with a ring geometry are available for some years now. Thanks to their good sensitivity and high temporal resolution, general dynamic SPECT imaging may be ...performed more easily, without resorting to dedicated systems. To evaluate the dynamic SPECT imaging by such cameras, we have performed an in vivo pilot study to analyze the kidney function of a pig and compare the results to standard dynamic planar imaging by a conventional gamma camera.
A 7-week-old (12 kg) female Landrace pig was injected with
TcTc-MAG3 and a 30 min dynamic SPECT acquisition of the kidneys was performed on a CZT ring camera. A fast SPECT/CT was acquired with the same camera immediately after the dynamic SPECT, without moving the pig, and used for attenuation correction and drawing regions of interest. The next day the same pig underwent a dynamic planar imaging of the kidneys by a conventional 2-head gamma camera. The dynamic SPECT acquisition was reconstructed using a MLEM algorithm with up to 20 iterations, with and without attenuation correction. Time-activity curves of the total counts of each kidney were extracted from 2D and 3D dynamic images. An adapted 2-compartment model was derived to fit the data points and extract physiological parameters. Comparison of these parameters was performed between the different reconstructions and acquisitions.
Time-activity curves were nicely fitted with the 2-compartment model taking into account the anesthesia and bladder filling. Kidney physiological parameters were found in agreement with literature values. Good agreement of these parameters was obtained for the right kidney between dynamic SPECT and planar imaging. Regional analysis of the kidneys can be performed in the case of the dynamic SPECT imaging and provided good agreement with the whole kidney results.
Dynamic SPECT imaging is feasible with CZT swiveling-detector ring cameras and provides results in agreement with dynamic planar imaging by conventional gamma cameras. Regional analysis of organs uptake and clearance becomes possible. Further studies are required regarding the optimization of acquisition and reconstruction parameters to improve image quality and enable absolute quantification.
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