Recipient hepatectomy technique may affect oncological outcomes of liver transplantation for hepatocellular carcinoma.

To date, caval sparing (CS) and total caval replacement (TCR) for recipient hepatectomy in liver transplantation (LT) have been compared only in terms of surgical morbidity. Nonetheless, the CS technique is inherently associated with an increased manipulation of the native liver and later exclusion of the venous outflow, which may increase the risk of intraoperative shedding of tumor cells when LT is performed for HCC. A multicenter, retrospective study was performed to assess the impact of recipient hepatectomy (CS vs. TCR) on the risk of posttransplant HCC recurrence among 16 European transplant centers that used either TCR or CS recipient hepatectomy as an elective protocol technique. Exclusion criteria comprised cases of non-center-protocol recipient hepatectomy technique, living-donor LT, HCC diagnosis suspected on preoperative imaging but not confirmed at the pathological examination of the explanted liver, HCC in close contact with the IVC, and previous liver resection for HCC. In 2420 patients, CS and TCR approaches were used in 1452 (60%) and 968 (40%) cases, respectively. Group adjustment with inverse probability weighting was performed for high-volume center, recipient age, alcohol abuse, viral hepatitis, Child-Pugh class C, Model for End-Stage Liver Disease score, cold ischemia time, clinical HCC stage within Milan criteria, pre-LT downstaging/bridging therapies, pre-LT alphafetoprotein serum levels, number and size of tumor nodules, microvascular invasion, and complete necrosis of all tumor nodules (matched cohort, TCR, n = 938; CS, n = 935). In a multivariate cause-specific hazard model, CS was associated with a higher risk of HCC recurrence (HR: 1.536, p = 0.007). In conclusion, TCR recipient hepatectomy, compared to the CS approach, may be associated with some protective effect against post-LT tumor recurrence.

Successful clinical and virological outcomes of liver transplantation for HDV/HBV-related disease after long-term discontinuation of hepatitis B immunoglobulins.

BACKGROUND: Indefinite, long-term administration of hepatitis B immunoglobulins (HBIg), together with a third generation nucleos(t)ide analog (NA), is the currently recommended prophylactic strategy to prevent viral recurrence after liver transplantation (LT) for Hepatitis Delta virus (HDV)/Hepatitis B virus (HBV)-related disease. METHODS: We retrospectively analyzed the safety and long-term clinical and virological outcomes of a consecutive cohort of 16 patients (10 males, median age 64.5, range 41-75) transplanted for HDV/HBV-related cirrhosis at our Institution, who discontinued HBIg after a median of 24.5 months (range 15-116) after transplant. All patients continued prophylaxis with same NA used before LT. Recurrence of HDV/HBV infection was defined as reappearance of serum HDV-RNA with detectable serum HBsAg and/or HBV-DNA. RESULTS: The median follow-up after LT was 138 months (range 73-316) and 110 months (range 52-200) after HBIg withdrawal. All patients were HBsAg-positive, HBV-DNA negative, and anti-HDV positive at the time of LT and without coinfections with HCV or HIV. Patients were followed with biochemical and virological tests every 3-6 months after HBIg withdrawal. No recurrences of HDV/HBV infection or disease were observed during monoprophylaxis with NA. In addition, eight patients (50%) spontaneously developed anti-HBs titers above 10 IU/L at a median of 74 months (range 58-140) following HBIG discontinuation. CONCLUSIONS: HBIg withdrawal after LT is a safe and efficacious strategy in patients transplanted for HDV/HBV disease and is frequently associated with the spontaneous development of serological immunity against HBV. These data call for a revision of current prophylactic recommendations in this setting.

Effects of Anti-COVID-19 Vaccination and Pre-Exposure Prophylaxis with Tixagevimab-Cilgavimab in Kidney and Liver Transplant Recipients.

Background and Objectives: Underpowered immune response to vaccines against SARS-CoV-2 was observed in solid organ transplant (SOT) recipients. A novel combination of monoclonal antibodies tixagevimab-cilgavimab (TGM/CGM) received authorization as pre-exposure prophylaxis (PrEP) in those with reduced response to vaccine. We aimed to evaluate the response rate to COVID-19 vaccination in kidney transplant (KT), compared to liver transplant (LT) recipients, and the efficacy and safety of PrEP with TGM/CGM. Material and Methods: Between March and November 2022, adult KT and LT recipients who had completed the vaccination schedule (3 doses) were tested for anti-SARS-CoV-2 antibodies titer. SOT recipients with anti-SARS-CoV-2 titer ≥ 100 IU/mL were considered protected against infection, while those with titer < 100 UI/mL were defined non-protected. Patients with inadequate response were invited to PrEP. Results: In total, 306 patients were enrolled [KT:197 (64.4%), LT:109 (35.6%)]. After the complete scheme of vaccination, 246 (80.3%) patients developed a protective titer, while 60 (19.6%) did not have a protective titer. KT recipients had a lower rate of protective anti-COVID-19 titer compared to LT patients [149 (75.6%) vs. 97 (89.0%), p = 0.004]. Recipients with non-protective anti-COVID-19 titer received mainly tacrolimus-based regimen associated with mycophenolate mofetil (MMF) (70%) e steroids (46.7%) as maintenance immunosuppression, while those treated with everolimus were associated with higher protective titer. Of 35 (58.3%) patients who received PrEP, within 12 months, 6 (17.1%) (all KT) developed pauci-symptomatic COVID-19 disease, while 15/25 (60%) of non-responders, who did not receive the prophylaxis, developed COVID-19 disease. After PrEP, hospitalization rate was lower (2.8% vs. 16%), and no adverse events, neither graft loss nor rejection, were observed. Conclusions: Despite complete COVID-19 vaccination, SOT recipients might be not protected from the SARS-CoV-2 infection, especially after KT. In non-protected SOT patients, the subsequent pre-exposure prophylaxis with combination of monoclonal antibodies (TGM/CGM) might be an efficacy and safe strategy to prevent COVID-19 severe disease and hospitalization.

Histology for nephrology, from pre-implantation to post-transplant kidney biopsy. Lesson learned from ReBIrth (Renal BIopsy for Kidney Transplantation Therapy).

A meeting entitled Renal BIopsy for Kidney Transplantation Therapy (ReBIrth) took place on May 31st, 2022 in Bologna, Italy. The meeting drew together nephrologists, surgeons, and pathologists and recognized as experts in the field of kidney transplantation in Italy. In this paper, we present our experience working with kidney transplants in the current era of immunosuppression therapy. The primary aim is to report the histopathological characteristics of failed kidney allografts after a consensus of experts reviewed the cases on a wholeslide imaging digital platform. Regardless of the cases discussed, digital pathology was reliable in identifying all the morphological and immunohistochemical features required to improve the correct use of immunosuppressive therapy to prevent graft failure and optimize patient management.

Renal Function, Adherence and Quality of Life Improvement After Conversion From Immediate to Prolonged-Release Tacrolimus in Liver Transplantation: Prospective Ten-Year Follow-Up Study.

Immunosuppression non-adherence is a major cause of graft failure after liver transplantation. The aim of this study was to evaluate practice surrounding conversion from immediate-release to prolonged-release Tacrolimus formulation and to assess patient adherence and quality of life (QoL). One hundred and seven adult liver transplant recipients, receiving immediate-release Tacrolimus for a minimum of 6 months, were converted to prolonged-release formulation, based on a dose ratio of one (1:1). The median follow-up was 120 [IQR, 120-123] months. Tacrolimus dosage and blood level, liver and renal function, lipid and glucose profiles were recorded. In addition, questionnaires were submitted to evaluate adherence and QoL following conversion. No rejection was recorded. The median serum Tacrolimus blood level decreased over 1 month (5.80, [IQR, 2.0-10.8] vs. 3.8 [IQR, 1.4-8.7]; p < 0.0005). Significant improvement in renal function was noted (median GFR was 81.7 [IQR, 43.4-128.6] vs. 73.9 [IQR, 27.1-130.2]; p = 0.0002). At the end of the follow-up, conversion resulted in an overall decrease in non-adherence of 53.3% (p = 0.0001) and an improvement in QoL was reported by 76.2% of patients. Thus, 1:1 conversion from immediate to prolonged-release Tacrolimus is safe, feasible and efficient, avoiding under-therapeutic and toxic peak concentrations, improving renal function, adherence to immunosuppression and overall patient QoL.

Liver transplantation performed in a SARS-CoV-2 positive hospitalized recipient using a SARS-CoV-2 infected donor.

The coronavirus disease 2019 (COVID-19) is a novel infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 currently affected more than 108 million people worldwide with a fatality rate of 2.2%. Herein, we report the first case of liver transplantation (LT) performed with a liver procured from a SARS-CoV-2 positive donor. The recipient was a 35-year-old SARS-CoV-2 positive female patient affected by severe end-stage HBV-HDV-related liver disease (model of end-stage liver disease = 32) who had neutralizing SARS-CoV-2 antibodies (titers 1:320) at time of LT. The LT was successful, and the graft is functioning two months after surgery. The recipient cleared the SARS-CoV-2 infection 1 month after LT. The current case shows that the prompt use of SARS-CoV-2 infected liver donors offers an invaluable life-saving opportunity for SARS-CoV-2 positive wait-listed patients who developed neutralizing SARS-CoV-2 antibodies.

Hepatocellular carcinoma and the risk of de novo malignancies after liver transplantation - a multicenter cohort study.

Patients with hepatocellular carcinoma (HCC) are at high risk of second primary malignancies. As HCC has become the leading indication of liver transplant (LT), the aim of this study was to investigate whether the presence of HCC before LT could influence the onset of de novo malignancies (DNM). A cohort study was conducted on 2653 LT recipients. Hazard ratios (HR) of DNM development for patients transplanted for HCC (HCC patients) were compared with those of patients without any previous malignancy (non-HCC patients). All models were adjusted for sex, age, calendar year at transplant, and liver disease etiology. Throughout 17 903 person-years, 6.6% of HCC patients and 7.4% of non-HCC patients developed DNM (202 cases). The median time from LT to first DNM diagnosis was shorter for solid tumors in HCC patients (2.7 vs 4.5 years for HCC and non-HCC patients, respectively, P < 0.01). HCC patients were at a higher risk of bladder cancer and skin melanoma. There were no differences in cumulative DNM-specific mortality by HCC status. This study suggests that primary HCC could be a risk factor for DNM in LT recipients, allowing for risk stratification and screening individualization.

The hamletic dilemma of patients waiting for kidney transplantation during the COVID-19 pandemic: To accept or not to accept (an organ offer)?

The outbreak of COVID-19 led to a reduction in the number of organ transplant interventions in most Countries. In April 2020, at the Tor Vergata University in Rome, Italy, two patients on the waiting list for kidney transplantation (KT) declined a deceased donor's kidney offer. Therefore, between April 20 and 25, 2020, we conducted a telephone survey among our 247 KT waitlist patients. Our aim was to explore: (a) the COVID-19 diffusion among them and (b) their current willingness to be transplanted in case of a kidney offer from a deceased donor. Two hundred and forty-three patients participated in a phone interview. One patient had died from COVID-19. Eighty-five (35%) KT candidates would decline any kidney offer, in most cases until the end of the COVID-19 pandemic. Upon a multivariate analysis, female gender (OR = 2.25, 95% CI = 1.26-4.03, P = .006), high cardiovascular risk (OR = 2.33, 95% CI = 1.06-5.08, P = .034), a waiting list time <3 years (OR = 0.375, 95% CI = 0.15-0.95, P = .04), and the need to be transferred to another hospital for HD (OR = 2.56, 95% CI = 1.10-5.9, P = .03) were associated with such refusal. The COVID-19 pandemic led to a fear of transplantation in a third of the KT candidates. Proactive educational webinars could be a useful tool to remove, or at least lessen, any doubts on the part of KT candidates and to avoid losing the opportunity to quit dialysis.

The Management of Immunosuppression in Kidney Transplant Recipients with COVID-19 Disease: An Update and Systematic Review of the Literature.

Background and Objectives: In the era of the coronavirus disease 2019 (COVID-19) pandemic, the management of immunosuppressive (IS) therapy in kidney transplant (KT) recipients affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires attention. It is not yet understood whether IS therapy may protect from the cytokine storm induced by SARS-CoV-2 infection or a temporary adjustment/withdrawal of IS therapy to restore the immune system may be necessary. We performed a systematic literature review to investigate the current management of IS therapy in KT recipients with COVID-1. Materials and Methods: Out of 71 articles published from 1 February 2020 until 30 October 2020, 554 KT recipients with SARS-CoV-2 infection were identified. Results: Modifications of IS therapy were based on the clinical conditions. For asymptomatic patients or those with mild COVID-19 symptoms, a "wait and see approach" was mostly used; a suspension of antimetabolites drugs (347/461, 75.27%) or mTOR inhibitors (38/48, 79.2%) was adopted in the majority of patients with symptomatic COVID-19 infections. For CNIs, the most frequent attitude was their maintenance (243/502, 48.4%) or dose-reduction (99/502, 19.72%) in patients asymptomatic or with mild COVID-19 symptoms, while drug withdrawal was the preferred choice in severely symptomatic patients (160/450, 31.87%). A discontinuation of all IS drugs was used only in severely symptomatic COVID-19 patients on invasive mechanical ventilation. Renal function remained stable in 422(76.17%) recipients, while 49(8.84%) patients experienced graft loss. Eight (1.44%) patients experienced a worsening of renal function. The overall mortality was 21.84%, and 53(9.56%) patients died with functioning grafts. Conclusion: A tailored approach to the patient has been the preferred strategy for the management of IS therapy in KT recipients, taking into account the clinical conditions of patients and the potential interactions between IS and antiviral drugs, in the attempt to balance the risks of COVID-19-related complications and those due to rejection or graft loss.

Machine Perfusions in Liver Transplantation: The Evidence-Based Position Paper of the Italian Society of Organ and Tissue Transplantation.

The use of machine perfusion (MP) in liver transplantation (LT) is spreading worldwide. However, its efficacy has not been demonstrated, and its proper clinical use has far to go to be widely implemented. The Società Italiana Trapianti d'Organo (SITO) promoted the development of an evidence-based position paper. A 3-step approach has been adopted to develop this position paper. First, SITO appointed a chair and a cochair who then assembled a working group with specific experience of MP in LT. The Guideline Development Group framed the clinical questions into a patient, intervention, control, and outcome (PICO) format, extracted and analyzed the available literature, ranked the quality of the evidence, and prepared and graded the recommendations. Recommendations were then discussed by all the members of the SITO and were voted on via the Delphi method by an institutional review board. Finally, they were evaluated and scored by a panel of external reviewers. All available literature was analyzed, and its quality was ranked. A total of 18 recommendations regarding the use and the efficacy of ex situ hypothermic and normothermic machine perfusion and sequential normothermic regional perfusion and ex situ MP were prepared and graded according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method. A critical and scientific approach is required for the safe implementation of this new technology.

Survival after the diagnosis of de novo malignancy in liver transplant recipients.

In the setting of liver transplant (LT), the survival after the diagnosis of de novo malignancies (DNMs) has been poorly investigated. In this study, we assessed the impact of DNMs on survival of LT recipients as compared to corresponding LT recipients without DNM. A nested case-control study was conducted in a cohort of 2,818 LT recipients enrolled in nine Italian centres between 1985 and 2014. Cases were 244 LT recipients who developed DNMs after LT. For each case, two controls matched for gender, age, and year at transplant were selected by incidence density sampling among cohort members without DNM. The survival probabilities were estimated using the Kaplan-Meier method. Hazard ratios (HRs) of death and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models. The all-cancer 10-year survival was 43% in cases versus 70% in controls (HR = 4.66; 95% CI: 3.17-6.85). Survival was impaired in cases for all the most frequent cancer types, including lung (HR = 37.13; 95% CI: 4.98-276.74), non-Hodgkin lymphoma (HR = 6.57; 95% CI: 2.15-20.01), head and neck (HR = 4.65; 95% CI: 1.81-11.95), and colon-rectum (HR = 3.61; 95% CI: 1.08-12.07). The survival gap was observed for both early and late mortality, although the effect was more pronounced in the first year after cancer diagnosis. No significant differences in survival emerged for Kaposi's sarcoma and nonmelanoma skin cancers. The survival gap herein quantified included a broad range of malignancies following LT and prompts close monitoring during the post-transplant follow-up to ensure early cancer diagnosis and to improve survival.

Risk of virus and non-virus related malignancies following immunosuppression in a cohort of liver transplant recipients. Italy, 1985-2014.

This cohort study assessed, in Italy, the overall pattern of risk of de novo malignancies following liver transplantation (LT). The study group included 2,832 individuals who underwent LT between 1985 and 2014 in nine centers all over Italy. Person-years (PYs) at cancer risk were computed from 30 days after LT to the date of cancer diagnosis, to the date of death or to the end of follow-up. Excess cancer risk, as compared to the general population, was estimated using standardized incidence ratios (SIRs) and 95% confidence intervals (CIs). During 18,642 PYs, 246 LT recipients developed 266 de novo malignancies, corresponding to a 1.8-fold higher cancer risk (95% CI: 1.6-2.0). SIRs were particularly elevated for virus-related malignancies, including Kaposi's sarcoma (SIR = 53.6, 95% CI: 30.0-88.5), non-Hodgkin lymphomas (SIR = 7.1, 95% CI: 4.8-10.1) and cervix uteri (SIR = 5.4, 95% CI: 1.1-15.8). Among virus-unrelated malignancies, elevated risks emerged for head and neck (SIR = 4.4, 95% CI: 3.1-6.2), esophagus (SIR = 6.7, 95% CI: 2.9-13.3) and adrenal gland (SIR = 22.9, 95% CI: 2.8-82.7). Borderline statistically significant elevated risks were found for lung cancer (SIR = 1.4, 95% CI: 1.0-2.1) and skin melanoma (SIR = 2.6, 95% CI: 1.0-5.3). A reduced risk emerged for prostate cancer (SIR = 0.1, 95% CI: 0.0-0.5). These findings underline the need of preventive interventions and early detection of malignancies, specifically tailored to LT recipients.

Vagally mediated gastric effects of brain stem α2-adrenoceptor activation in stressed rats.

Chronic stress exerts vagally dependent effects to disrupt gastric motility; previous studies have shown that, among other nuclei, A2 neurons are involved in mediating these effects. Several studies have also shown robust in vitro and in vivo effects of α2-adrenoceptor agonists on vagal motoneurons. We have demonstrated previously that brainstem vagal neurocircuits undergo remodeling following acute stress; however, the effects following brief periods of chronic stress have not been investigated. Our aim, therefore, was to test the hypothesis that different types of chronic stress influence gastric tone and motility by inducing plasticity in the response of vagal neurocircuits to α2-adrenoreceptor agonists. In rats that underwent 5 days of either homotypic or heterotypic stress loading, we applied the α2-adrenoceptor agonist, UK14304, either by in vitro brainstem perfusion to examine its ability to modulate GABAergic synaptic inputs to vagal motoneurons or in vivo brainstem microinjection to observe actions to modulate antral tone and motility. In neurons from naïve rats, GABAergic currents were unresponsive to exogenous application of UK14304. In contrast, GABAergic currents were inhibited by UK14304 in all neurons from homotypic and, in a subpopulation of neurons, heterotypic stressed rats. In control rats, UK14304 microinjection inhibited gastric tone and motility via withdrawal of vagal cholinergic tone; in heterotypic stressed rats, the larger inhibition of antrum tone was due to a concomitant activation of peripheral nonadrenergic, noncholinergic pathways. These data suggest that stress induces plasticity in brainstem vagal neurocircuits, leading to an upregulation of α2-mediated responses. NEW & NOTEWORTHY Catecholaminergic neurons of the A2 area play a relevant role in stress-related dysfunction of the gastric antrum. Brief periods of chronic stress load induce plastic changes in the actions of adrenoceptors on vagal brainstem neurocircuits.

A Nigro-Vagal Pathway Controls Gastric Motility and Is Affected in a Rat Model of Parkinsonism.

BACKGROUND & AIMS: In most patients with Parkinson's disease, gastrointestinal (GI) dysfunctions, such as gastroparesis and constipation, are prodromal to the cardinal motor symptoms of the disease. Sporadic Parkinson's disease has been proposed to develop after ingestion of neurotoxicants that affect the brain-gut axis via the vagus nerve, and then travel to higher centers, compromising the substantia nigra pars compacta (SNpc) and, later, the cerebral cortex. We aimed to identify the pathway that connects the brainstem vagal nuclei and the SNpc, and to determine whether this pathway is compromised in a rat model of Parkinsonism. METHODS: To study this neural pathway in rats, we placed tracers in the dorsal vagal complex or SNpc; brainstem and midbrain were examined for tracer distribution and neuronal neurochemical phenotype. Rats were given injections of paraquat once weekly for 3 weeks to induce features of Parkinsonism, or vehicle (control). Gastric tone and motility were recorded after N-methyl-d-aspartate microinjection in the SNpc and/or optogenetic stimulation of nigro-vagal terminals in the dorsal vagal complex. RESULTS: Stimulation of the SNpc increased gastric tone and motility via activation of dopamine 1 receptors in the dorsal vagal complex. In the paraquat-induced model of Parkinsonism, this nigro-vagal pathway was compromised during the early stages of motor deficit development. CONCLUSIONS: We identified and characterized a nigro-vagal monosynaptic pathway in rats that controls gastric tone and motility. This pathway might be involved in the prodromal gastric dysmotility observed in patients with early-stage Parkinson's disease.

Longterm Survival and Cost-Effectiveness of Immunosuppression Withdrawal After Liver Transplantation.

Lifelong immunosuppression (IS) after liver transplantation is associated with severe adverse effects and increased recipients' morbidity and mortality. Clinical operational tolerance has been reported in up to 40% in very well-selected recipients. Longterm survival and cost savings within the Italian national health system in operational tolerant recipients is reported. Seventy-five liver recipients were enrolled for IS withdrawal at our institution during the period from April 1998 to December 2015. The study population comprised 32 (42.7%) tolerant patients; 41 (54.7%) nontolerant patients needing uptake of IS after clinical or biopsy-proven rejection; and 2 (2.7%) immediate nontolerant patients who developed early rejection after the first drug reduction. The primary endpoint of the study was to assess the longterm patients and graft outcome; the secondary endpoint was the assessment of cost savings in the context of IS withdrawal. The follow-up was 95.0 months (interquartile range, 22.5-108.5 months). IS withdrawal did not result in patient nor graft loss and resulted in a major cost savings reaching about €630,000. In conclusion, longterm IS withdrawal represents a remarkable cost savings in the health care of liver recipients without exposing them to graft loss.

Complete hepatitis B virus prophylaxis withdrawal in hepatitis B surface antigen-positive liver transplant recipients after longterm minimal immunosuppression.

Tailored approaches have been attempted to prevent hepatitis B virus (HBV) reinfection in antibodies against hepatitis B surface antigen (HBsAg)-positive liver transplantation (LT) recipients in order to minimize the use of hepatitis B immune globulin (HBIG) and nucleoside analogues (NAs). We report the results of complete HBV prophylaxis withdrawal after a follow-up of at least 6 years in LT recipients with undetectable serum HBV DNA and intrahepatic total HBV DNA and covalently closed circular DNA at LT. We included 30 HBsAg positive, hepatitis B e antigen-negative recipients, 6 with hepatitis C virus and 7 with hepatitis D virus coinfection, who had received HBIG plus NA for at least 5 years after LT. Stepwise HBIG and NA withdrawal was performed in two 6-month periods under strict monitoring of HBV virology. All patients underwent a clinical, biochemical, and virological follow-up at 3-6 month intervals. HBV recurrence (HBsAg seroreversion ± detectable HBV DNA) occurred in 6 patients: in 1 patient after HBIG interruption and in 5 after both HBIG and NA cessation. Only 3 patients required reinstitution of HBV prophylaxis because of persistent HBV replication, and all achieved optimal control of HBV infection and did not experience clinical events. The other who recurred showed only short-lasting HBsAg positivity, with undetectable HBV DNA, followed by spontaneous anti-HBs seroconversion. An additional 15 patients mounted an anti-HBs titer, without previous serum HBsAg detectability. At the end of follow-up, 90% of patients were still prophylaxis-free, 93.3% were HBsAg negative, and 100% were HBV DNA negative; 60% had anti-HBs titers >10 IU/L (median, 143; range, 13-1000). This small series shows that complete prophylaxis withdrawal is safe in patients transplanted for HBV-related disease at low risk of recurrence and is often followed by spontaneous anti-HBs seroconversion. Further studies are needed to confirm this finding. Liver Transplantation 22 1205-1213 2016 AASLD.

Plasticity in the brainstem vagal circuits controlling gastric motor function triggered by corticotropin releasing factor.

Stress impairs gastric emptying, reduces stomach compliance and induces early satiety via vagal actions. We have shown recently that the ability of the anti-stress neuropeptide oxytocin (OXT) to modulate vagal brainstem circuits undergoes short-term plasticity via alterations in cAMP levels subsequent to vagal afferent fibre-dependent activation of metabotropic glutamate receptors. The aim of the present study was to test the hypothesis that the OXT-induced gastric response undergoes plastic changes in the presence of the prototypical stress hormone, corticotropin releasing factor (CRF). Whole cell patch clamp recordings showed that CRF increased inhibitory GABAergic synaptic transmission to identified corpus-projecting dorsal motor nucleus of the vagus (DMV) neurones. In naive brainstem slices, OXT perfusion had no effect on inhibitory synaptic transmission; following exposure to CRF (and recovery from its actions), however, re-application of OXT inhibited GABAergic transmission in the majority of neurones tested. This uncovering of the OXT response was antagonized by pretreatment with protein kinase A or adenylate cyclase inhibitors, H89 and di-deoxyadenosine, respectively, indicating a cAMP-mediated mechanism. In naive animals, OXT microinjection in the dorsal vagal complex induced a NO-mediated corpus relaxation. Following CRF pretreatment, however, microinjection of OXT attenuated or, at times reversed, the gastric relaxation which was insensitive to l-NAME but was antagonized by pretreatment with a VIP antagonist. Immunohistochemical analyses of vagal motoneurones showed an increased number of oxytocin receptors present on GABAergic terminals of CRF-treated or stressed vs. naive rats. These results indicate that CRF alters vagal inhibitory circuits that uncover the ability of OXT to modulate GABAergic currents and modifies the gastric corpus motility response to OXT.

Gastric dysregulation induced by microinjection of 6-OHDA in the substantia nigra pars compacta of rats is determined by alterations in the brain-gut axis.

Idiopathic Parkinson's disease (PD) is a late-onset, chronic, and progressive motor dysfunction attributable to loss of nigrostriatal dopamine neurons. Patients with PD experience significant gastrointestinal (GI) issues, including gastroparesis. We aimed to evaluate whether 6-hydroxy-dopamine (6-OHDA)-induced degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) induces gastric dysmotility via dysfunctions of the brain-gut axis. 6-OHDA microinjection into the SNpc induced a >90% decrease in tyrosine hydroxylase-immunoreactivity (IR) on the injection site. The [13C]-octanoic acid breath test showed a delayed gastric emptying 4 wk after the 6-OHDA treatment. In control rats, microinjection of the indirect sympathomimetic, tyramine, in the dorsal vagal complex (DVC) decreased gastric tone and motility; this inhibition was prevented by the fourth ventricular application of either a combination of α1- and α2- or a combination of D1 and D2 receptor antagonists. Conversely, in 6-OHDA-treated rats, whereas DVC microinjection of tyramine had reduced effects on gastric tone or motility, DVC microinjection of thyrotropin-releasing hormone induced a similar increase in motility as in control rats. In 6-OHDA-treated rats, there was a decreased expression of choline acetyl transferase (ChAT)-IR and neuronal nitric oxide synthase (NOS)-IR in DVC neurons but an increase in dopamine-ß-hydroxylase-IR in the A2 area. Within the myenteric plexus of the esophagus, stomach, and duodenum, there were no changes in the total number of neurons; however, the percentage of NOS-IR neurons increased, whereas that of ChAT-IR decreased. Our data suggest that the delayed gastric emptying in a 6-OHDA rat model of PD may be caused by neurochemical and neurophysiological alterations in the brain-gut axis.

The Effects of Sustained Immunosuppression Withdrawal After Liver Transplantation on Metabolic Syndrome.

BACKGROUND: Liver transplant (LT) recipients often experience adverse effects of immunosuppressive (IS) drugs, especially on metabolic profiles. Selected LT recipients can achieve successful IS withdrawal; however, its effects on metabolic syndrome (MS) are unknown. METHODS: This is a retrospective single-center study investigating the incidence and/or regression of MS in 75 selected LT recipients who were previously enrolled in prospective IS withdrawal trials between 1999 and 2017. Patients who were transplanted due to nonalcoholic steatohepatitis/metabolic-associated fatty liver disease were excluded, as well as those with a follow-up <3 y after IS weaning. RESULTS: Forty-four patients (58.7%) achieved sustained withdrawal or minimization of immunosuppression (WMIS) and 31 patients (41.3%) required reintroduction of immunosuppression (no-WMIS). Among LT recipients who were metabolically healthy (n = 52, 69.3%) before the start of IS weaning, there was a significantly lower rate of de novo MS in WMIS patients compared with no-WMIS patients after 5 y (8.3% and 47.8%, respectively, P = 0.034). Of 23 LT recipients (30.7%) who had MS at the time of commencing IS withdrawal, complete regression of MS was observed in 47.1% of WMIS patients and in none (0%) of the no-WMIS patients after 5 y (P = 0.054). Furthermore, individual components of MS were better controlled in IS-weaned patients, such as arterial hypertension and abnormal serum lipids. CONCLUSIONS: Achievement of sustained IS withdrawal reduces the incidence of de novo MS development in metabolically healthy patients and increases the likelihood of MS regression in patients with established MS. The foreseeable long-term beneficial effects of these favorable metabolic changes on morbidity and mortality of LT recipients require further investigation.

Portal vein thrombosis and liver transplantation: management, matching, and outcomes. A retrospective multicenter cohort study.

BACKGROUND AND AIMS: Besides the increased risk of perioperative morbidity, graft failure, and mortality, the majority of PVT are diagnosed at liver transplantation (LT). Improving preoperative management and patient selection may lead to better short-term and long-term outcomes and reduce the risk of a futile LT. The authors aimed to identify predictors of adverse outcomes after LT in patients with nonmalignant portal vein thrombosis (PVT) and improve donor to recipient matching by analyzing the results of the Italian cohort of LT recipients. METHODS: Adult patients who underwent LT in Italy between January 2000 and February 2020 diagnosed with PVT pre-LT or at time of LT were considered eligible for inclusion. Based on a survey encompassing all 26 surgeons participating in the study, a binary composite outcome was defined. Patients were classified as having the composite event if at least one of these conditions occurred: operative time more than 600 min, estimated blood loss greater than 5000 ml, more than 20 ICU days, 90 days mortality, 90 days retransplant. RESULTS: Seven hundred fourteen patients were screened and 698 met the inclusion criteria. The analysis reports the results of 568 patients that fulfilled the criteria to enter the composite outcome analysis.Overall, 156 patients (27.5%) developed the composite outcome. PVT stage 3/4 at transplant and need for any surgical correction of PVT are independent predictors of the composite outcome occurrence. When stratified by PVT grade, overall survival at 1-year ranges from 89.0% with PVT grade 0/1 to 67.4% in patients with PVT grade 3/4 at LT ( P <0.001). Nevertheless, patients with severe PVT can improve their survival when identified risk factors are not present. CONCLUSIONS: Potential LT candidates affected by PVT have a benefit from LT that should be adequately balanced on liver function and type of inflow reconstruction needed to mitigate the incidence of adverse events. Nonetheless, the absence of specific risk factors may improve the outcomes even in patients with PVT grades 3-4.