Hypothermic oxygenated machine perfusion influences the immunogenicity of donor livers in humans.

Hypothermic oxygenated machine perfusion (HOPE) is an organ preservation strategy shown to reduce ischemia-reperfusion-injury (IRI)-related complications following liver transplantation (LT). In animal models HOPE can also decrease alloimmune responses post-transplantation, but this remains to be evaluated in humans. Our study, involving 27 LT patients enrolled in 2 randomised controlled trials comparing static cold storage (SCS) with HOPE (14 HOPE- and 13 SCS-treated), delves into the impact of HOPE on the molecular profile of liver allografts and on the immune responses elicited post-transplantation. Following HOPE treatment, fewer intra-hepatic immune cells were observed in liver perfusates compared to SCS. Analysis of liver tissue transcriptome at reperfusion revealed an effect of HOPE on the reactive oxygen species pathway. Two weeks post-transplantation, HOPE recipients exhibited increased circulating CD4+FOXP3+CD127lo regulatory T cells (Tregs) (p<0.01), which corresponded to a higher frequency of donor specific Tregs (p<0.01) and was followed by reduced alloreactivity index of CD8+ T cells 3 months post-transplant. Our study provides novel mechanistic insight into the capacity of HOPE to influence liver IRI and to modulate effector and regulatory donor-specific T cell responses post-transplantation. These findings, which confirm observations made in animal models, help explain the decreased rejection rates reported in patients receiving HOPE-treated allografts.

Implementation and impact of an antibiotic control program and multidrug-resistant bacterial colonization in a liver transplant unit.

INTRODUCTION: infections by multidrug-resistant bacteria are a major cause of morbidity and mortality in transplant patients. OBJECTIVE: a retrospective single-center study was performed to evaluate the implementation of an Antimicrobial Treatment Optimization Program (PROA) on multidrug-resistant bacteria colonization and infection after liver transplant (LT). METHODS: colonization by multidrug-resistant bacteria and infections during the first year after a liver transplant were analyzed in a group of 76 transplanted patients in two stages, before and after PROA (2016-2019). Clinical variables related to infection, readmissions and survival one year after the liver transplant were analyzed. RESULTS: there was good adherence to the PROA. Infection was the most frequent cause for readmission during the first year after the liver transplant. Incidence of infections was similar during both periods (mean of 1.25 and 1.5 episodes of bacterial infection per patient/year, respectively) with 19 bacterial infectious episodes, six by hospital-acquired multidrug-resistant and extensively drug-resistant (MDR-XDR) bacteria in the pre-PROA stage, and 18 bacterial infectious episodes, five by MDR-XDR in the post-PROA stage. A 37 % decrease of post-TH of rectal colonization by MDR-XDR after liver transplant was observed during 2019. CONCLUSIONS: epidemiological surveillance policies and antibiotic optimization are key to control the increase of colonization and infection by multidrug-resistant bacteria in liver transplant units. Long-term studies are needed to better evaluate the impact of these programs.

Cumulative exposure to tacrolimus and incidence of cancer after liver transplantation.

Cancer is the leading cause of death after liver transplantation (LT). This multicenter case-control nested study aimed to evaluate the effect of maintenance immunosuppression on post-LT malignancy. The eligible cohort included 2495 LT patients who received tacrolimus-based immunosuppression. After 13 922 person/years follow-up, 425 patients (19.7%) developed malignancy (cases) and were matched with 425 controls by propensity score based on age, gender, smoking habit, etiology of liver disease, and hepatocellular carcinoma (HCC) before LT. The independent predictors of post-LT malignancy were older age (HR = 1.06 [95% CI 1.05-1.07]; p < .001), male sex (HR = 1.50 [95% CI 1.14-1.99]), smoking habit (HR = 1.96 [95% CI 1.42-2.66]), and alcoholic liver disease (HR = 1.53 [95% CI 1.19-1.97]). In selected cases and controls (n = 850), the immunosuppression protocol was similar (p = .51). An increased cumulative exposure to tacrolimus (CET), calculated by the area under curve of trough concentrations, was the only immunosuppression-related predictor of post-LT malignancy after controlling for clinical features and baseline HCC (CET at 3 months p = .001 and CET at 12 months p = .004). This effect was consistent for de novo malignancy (after excluding HCC recurrence) and for internal neoplasms (after excluding non-melanoma skin cancer). Therefore, tacrolimus minimization, as monitored by CET, is the key to modulate immunosuppression in order to prevent cancer after LT.

Decreased Long-Term Severe Acute Respiratory Syndrome Coronavirus 2-Specific Humoral Immunity in Liver Transplantation Recipients 12 Months After Coronavirus Disease 2019.

Long-term humoral immunity and its protective role in liver transplantation (LT) patients have not been elucidated. We performed a prospective multicenter study to assess the persistence of immunoglobulin G (IgG) antibodies in LT recipients 12 months after coronavirus disease 2019 (COVID-19). A total of 65 LT recipients were matched with 65 nontransplanted patients by a propensity score including variables with recognized impact on COVID-19. LT recipients showed a lower prevalence of anti-nucleocapsid (27.7% versus 49.2%; P = 0.02) and anti-spike IgG antibodies (88.2% versus 100.0%; P = 0.02) at 12 months. Lower index values of anti-nucleocapsid IgG antibodies were also observed in transplantation patients 1 year after COVID-19 (median, 0.49 [interquartile range, 0.15-1.40] versus 1.36 [interquartile range, 0.53-2.91]; P < 0.001). Vaccinated LT recipients showed higher antibody levels compared with unvaccinated patients (P < 0.001); antibody levels reached after vaccination were comparable to those observed in nontransplanted individuals (P = 0.70). In LT patients, a longer interval since transplantation (odds ratio, 1.10; 95% confidence interval, 1.01-1.20) was independently associated with persistence of anti-nucleocapsid IgG antibodies 1 year after infection. In conclusion, compared with nontransplanted patients, LT recipients show a lower long-term persistence of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies. However, SARS-CoV-2 vaccination after COVID-19 in LT patients achieves a significant increase in antibody levels, comparable to that of nontransplanted patients.

Changes in humoral immune response after SARS-CoV-2 infection in liver transplant recipients compared to immunocompetent patients.

The protective capacity and duration of humoral immunity after SARS-CoV-2 infection are not yet understood in solid organ transplant recipients. A prospective multicenter study was performed to evaluate the persistence of anti-nucleocapsid IgG antibodies in liver transplant recipients 6 months after coronavirus disease 2019 (COVID-19) resolution. A total of 71 liver transplant recipients were matched with 71 immunocompetent controls by a propensity score including variables with a well-known prognostic impact in COVID-19. Paired case-control serological data were also available in 62 liver transplant patients and 62 controls at month 3 after COVID-19. Liver transplant recipients showed a lower incidence of anti-nucleocapsid IgG antibodies at 3 months (77.4% vs. 100%, p < .001) and at 6 months (63.4% vs. 90.1%, p < .001). Lower levels of antibodies were also observed in liver transplant patients at 3 (p = .001) and 6 months (p < .001) after COVID-19. In transplant patients, female gender (OR = 13.49, 95% CI: 2.17-83.8), a longer interval since transplantation (OR = 1.19, 95% CI: 1.03-1.36), and therapy with renin-angiotensin-aldosterone system inhibitors (OR = 7.11, 95% CI: 1.47-34.50) were independently associated with persistence of antibodies beyond 6 months after COVID-19. Therefore, as compared with immunocompetent patients, liver transplant recipients show a lower prevalence of anti-SARS-CoV-2 antibodies and more pronounced antibody levels decline.

HCV eradication in recurrent hepatitis C after liver transplantation normalizes enhanced endothelial activation.

The increased risk of cardiovascular disease (CVD) conferred by hepatitis C virus (HCV) is especially relevant after liver transplantation (LT), but its mechanism is still not well defined. This study aimed to evaluate the influence of HCV eradication in inflammatory and endothelial activation markers after LT. We evaluated inflammatory (TNF-alfa, IL-6, IL-8, and MCP-1) and endothelial activation (E-selectin, ICAM-1, VCAM-1, and MMP-9) markers before and after eradication in 45 LT recipients with HCV infection (LT+/HCV+) and 44 non-transplanted HCV-infected patients (LT-/HCV+). We also considered an additional group of 40 LT recipients without HCV infection (LT+/HCV-). LT+/HCV+ patients presented a higher endothelial activation status before eradication compared with LT+/HCV- patients. However, levels of E-selectin, ICAM-1, VCAM-1, and MMP-9 were comparable between LT+/HCV+ and LT-/HCV+ patients before eradication. HCV eradication decreased ICAM-1 (5466.55 pg/ml vs. 3354.88 pg/ml, P < 0.001) and VCAM-1 (10456.52 pg/ml vs. 6658.85 pg/ml, P < 0.001) levels in LT+/HCV+ and LT-/HCV+ patients. Remarkably, HCV eradication restored levels of endothelial activation markers of LT+/HCV+ patients compared with that of LT+/HCV- patients. HCV plays a major role in endothelial dysfunction after LT. Furthermore, HCV eradication restores endothelial activation despite the exposure to immunosuppressive therapy.

Long-term outcomes and clinical impact of anti-HLA donor-specific antibodies (DSA) after liver transplantation: a prospective study in a pilot cohort.

INTRODUCTION: the presence of donor-specific antibodies (DSA) is thought to affect survival of the allograft and patient after liver transplantation (LT). However, their significance is not well understood. PATIENTS AND METHODS: a prospective study was performed of 32 adult patients who underwent LT in 2011 to analyze the existence of DSA, associated risk factors and medium-term impact. Immunological determinations were performed immediately before LT and at three, six, 12 months and five years after LT. RESULTS: eight patients (24.2 %) presented pre-formed DSA. However, titers were negative in all patients five years after LT and there were no associated events. Eight out of 24 patients (33.3 %) developed de novo DSA. After five years, only two remained positive; both were class II with high mean fluorescence intensity (MFI) values at diagnosis (over 15,000). No association was found between the development of DSA and the risk of rejection, graft loss or death. However, an increase in liver stiffness values was observed in patients with persistent DSA, and focal sinusoidal deposition of C4d and moderate liver fibrosis were reported. CONCLUSION: the incidence of DSA is high after LT. In addition, the persistence of de novo DSA could be associated with silent liver fibrosis with a potential impact on graft outcomes.

Endoscopically placed stents: a useful alternative for the management of refractory benign cervical esophageal stenosis.

INTRODUCTION: Benign esophageal strictures are relatively frequent and can severely affect the quality of life of a patient. Stenting has been proposed for the treatment of refractory cases. Lesions affecting the cervical esophagus are more difficult to treat, and the placement of stents in this location has traditionally been restricted due to potential adverse events. The aim of this study was to describe the efficacy and safety of endoscopic stenting in the management of refractory benign cervical esophageal strictures (RBCES) in a single-center cohort study. METHODS: We analyzed 12 patients with RBCES (Kochman's criteria) and severe dysphagia. We recorded previous endoscopic treatments, stricture characteristics and demographic data. The two types of stents used were fully covered self-expandable metallic stents (FCSEMS) and uncovered biodegradable stents (BDS). FCSEMS were removed eight weeks after placement, and BDS were followed-up until degradation. We assessed technical and clinical success, rate of stricture recurrence and adverse events. RESULTS: The mean age of participants was 64 years (range 30-85). A total of 23 stents (13 FCSEMS and 10 BDS) were placed in 12 patients (median 1.92, range 1-4). The technical success rate was 96% (22/23 stents). Eight patients (66.6%) maintained adequate oral intake at the end of follow-up (median 33.3 months, range 3-84 months). Migration was recorded in 7/23 stents (30.4%) and epithelial hyperplasia in 4/23 stents (17.4%). No severe adverse events were noted. All patients complained of minor cervical pain after placement that was well controlled with mild analgesia. CONCLUSIONS: Endoscopic stent therapy seems to be effective and safe in the management of RBCES.

Demographic Trends in Liver Transplant Survivors After 3 Decades of Program Implementation: The Impact of Cohort and Period Effects on Life Expectancy.

Background: Demographic analyses may reveal current patterns of change in the outcomes of rapidly developing medical procedures because they incorporate the period perspective. Methods: We analyzed the changes in size, age structure, and hospitalizations in the population of liver transplantation (LT) survivors in our center during the last 30 y (n = 1114 patients) and generated projections, including life expectancy (LE), considering cohort and period effects. Life tables were used to project the complete LE (overall 1990-2020 experience), the cohort LE (according to the decade of surgery: 1990-2000, 2000-2010, and 2010-2020), and the period LE (current 2015-2020 experience). Results: The population of LT recipients in follow-up continued to experience progressive growth and aging since 1990 (492 patients [41.9% >65 y] in 2020), and the magnitude of these phenomena may double in the next 30 y. However, the number of admissions and days of admission has been decreasing. The complete LE at LT was 12.4 y, whereas the period LE was 15.8 y. The cohort LE (limited to 10 y) was 5.3, 6.3, and 7.3 y for the 1990-2000, 2000-2010, and 2010-2020 cohorts, respectively. Conclusions: The target population of our medical care after LT is growing and aging. The prevalence of both of these phenomena is expected to increase in the coming years and is associated with a current improvement in LE. However, the hospitalization burden associated with LT survivors is declining. The period effect should be considered for generating up-to-date information on these current trends, which are crucial when designing health policies for LT survivors.

Long term SARS-CoV-2-specific cellular immunity after COVID-19 in liver transplant recipients.

PURPOSE: Long-term immunity after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in immunosuppressed patients is not well characterized. We aimed to explore the long-term natural immunity against SARS-CoV-2 in liver transplant (LT) recipients compared to the non-transplanted population (control group). METHODS: Fifteen LT recipients and 15 controls matched according to variables associated with disease severity were included at 12 months following the coronavirus disease 2019 (COVID-19) onset. Peripheral blood mononuclear cells were stimulated with peptide pools covering spike (S), nucleocapside (N), and membrane (M) proteins. Reactive CD4+ and CD8+ T cells were identified using flow cytometry, and cytokine production was evaluated in the culture supernatants using cytometric bead array. Serum anti-N and anti-S IgG antibodies were detected with chemiluminescence. RESULTS: The percentage of patients with a positive response in both CD4+ and CD8+ T cells against each viral protein and IL2, IL10, TNF-α, and IFN-γ levels was similar between LT recipients and controls. IFN-γ levels were positively correlated with the percentage of reactive CD4+ (p = 0.022) and CD8+ (p = 0.043) T cells to a mixture of M + N + S peptide pools. The prevalence and levels of anti-N and anti-S IgG antibodies were slightly lower in the LT recipients, but the difference was not statistically significant. CONCLUSION: LT recipients exhibited a similar T cell response compared to non-transplanted individuals one year after COVID-19 diagnosis.

Metabolic bone disease in patients diagnosed with inflammatory bowel disease from Spain.

BACKGROUND: The objective of this study was to analyse the prevalence of metabolic bone disease (MBD) in a cohort of Southern European patients with inflammatory bowel disease (IBD) and to identify associated risk factors in this population. METHODS: We conducted a retrospective, both cross-sectional and longitudinal study of MBD, assessed by dual energy X-ray absorptiometry (DXA), among patients diagnosed with IBD and previously recognized risk factors for this complication from two referral Spanish institutions. RESULTS: A total of 612 patients (58.6% diagnosed with Crohn's disease) were included. Mean (SD) age was 44.9 (14.7) years; 71.7% of patients received at least one tapered dosage of corticosteroids before first DXA. MBD and osteoporosis were diagnosed in 66.4% and 21.4% of patients, respectively. At baseline, male gender, menopause and ulcerative colitis were found as independent risks factors for osteoporosis, whereas age, more than three IBD-related hospitalizations and previous steroid treatment were found as independent risks factors for MBD. A total of 261 patients had at least a second DXA and were included in the longitudinal study; median follow up was 56.4 months. Logistic regression model identified menopause, ulcerative colitis and baseline lumbar DXA T-score value, but not steroid treatment, as risk factors for worsening ⩾1 SD in follow-up DXA T-score. According to guidelines, all patients under treatment with corticosteroids received calcium and vitamin D supplements. CONCLUSION: MBD is a frequent complication in south-European IBD patients. Routine evaluation of bone density when risk factors are present, as well as calcium plus D vitamin prophylaxis in patients under corticosteroid treatment should be recommended.

Implantación e impacto de un programa de control antibiótico y colonización por bacterias multirresistentes en una unidad de trasplante hepático / Implementation and impact of an antibiotic control program and multidrug-resistant bacterial colonization in a liver transplant unit

Introducción: las infecciones por bacterias multirresistentes constituyen una importante causa de morbimortalidad pre coz en los pacientes trasplantados.Propósito: se presenta un estudio unicéntrico, retrospectivo, con objetivo de evaluar la implantación de un programa de optimización del uso de antibióticos y de control epidemio lógico (PROA) en la colonización e infección por bacterias multirresistentes tras el trasplante hepático (TH).Métodos: se analizaron la colonización por bacterias multi rresistentes y las infecciones en el primer año postrasplante hepático (post-TH) en un grupo de 76 pacientes trasplanta dos en dos etapas, anterior y posterior al PROA, entre los años 2016 y 2019. Se analizaron variables clínicas relacio nadas con infección, reingresos y supervivencia a un año.Resultados: se produjo una buena adherencia al PROA. Las infecciones en el primer año post-TH fueron la causa más fre cuente de reingreso. La incidencia de infecciones fue similar en ambos periodos, con una media de 1,25 y 1,5 episodios de infección bacteriana por paciente/año con 19 episodios infecciosos bacterianos, seis por bacterias multirresistentes y de resistencia extendida (MDR-XDR) en la etapa pre-PROA y 18 episodios infecciosos bacterianos, cinco por MDR-XDR. en la etapa posterior. Se objetivó un descenso del 37 % post TH de colonización rectal por MDR-XDR durante el año 2019.Conclusión: las políticas de vigilancia epidemiológica y optimización de antibióticos son necesarias como estrategia de control del incremento de colonización e infección por bac terias multirresistentes en unidades de trasplante hepático. Son necesarios estudios a largo plazo para evaluar mejor el impacto de estos programas (AU)

Endoscopically placed stents: a useful alternative for the management of refractory benign cervical esophageal stenosis

Introduction: Benign esophageal strictures are relatively frequent and can severely affect the quality of life of a patient. Stenting has been proposed for the treatment of refractory cases. Lesions affecting the cervical esophagus are more difficult to treat, and the placement of stents in this location has traditionally been restricted due to potential adverse events. The aim of this study was to describe the efficacy and safety of endoscopic stenting in the management of refractory benign cervical esophageal strictures (RBCES) in a single-center cohort study. Methods: We analyzed 12 patients with RBCES (Kochman’s criteria) and severe dysphagia. We recorded previous endoscopic treatments, stricture characteristics and demographic data. The two types of stents used were fully covered self-expandable metallic stents (FCSEMS) and uncovered biodegradable stents (BDS). FCSEMS were removed eight weeks after placement, and BDS were followed-up until degradation. We assessed technical and clinical success, rate of stricture recurrence and adverse events. Results: The mean age of participants was 64 years (range 30-85). A total of 23 stents (13 FCSEMS and 10 BDS) were placed in 12 patients (median 1.92, range 1-4). The technical success rate was 96% (22/23 stents). Eight patients (66.6%) maintained adequate oral intake at the end of follow-up (median 33.3 months, range 3-84 months). Migration was recorded in 7/23 stents (30.4%) and epithelial hyperplasia in 4/23 stents (17.4%). No severe adverse events were noted. All patients complained of minor cervical pain after placement that was well controlled with mild analgesia. Conclusions: Endoscopic stent therapy seems to be effective and safe in the management of RBCES (AU)

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