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Liver and kidney are strictly connected in a reciprocal manner, in both the physiological and pathological condition. The Italian Association for the Study of Liver, in collaboration with the Italian Society of Nephrology, with this position paper aims to provide an up-to-date overview on the principal relationships between these two important organs. A panel of well-recognized international expert hepatologists and nephrologists identified five relevant topics: 1) The diagnosis of kidney damage in patients with chronic liver disease; 2) Acute kidney injury in liver cirrhosis; 3) Association between chronic liver disease and chronic kidney disease; 4) Kidney damage according to different etiology of liver disease; 5) Polycystic kidney and liver disease. The discussion process started with a review of the literature relating to each of the five major topics and clinical questions and related statements were subsequently formulated. The quality of evidence and strength of recommendations were graded according to the GRADE system. The statements presented here highlight the importance of strong collaboration between hepatologists and nephrologists for the management of critically ill patients, such as those with combined liver and kidney impairment.

Background: Despite the dominance of respiratory disease, acute-on-chronic liver failure (ACLF) and acute decompensation (AD) have been reported in patients with COVID-19 and preexisting liver disease, in particular cirrhosis. Moreover, COVID-19 has been associated with increased mortality in patients with end-stage liver disease (ESLD). Aim our study is to evaluate the impact of SARS-CoV-2 infection in patients with ESLD listed for liver transplant (LT). Methods: Data from adults listed for LT with laboratory-confirmed SARS-CoV-2 infection were collected from 7 LT centers across Italy. Results: From March 1st to October 31st 2020, 29 patients listed for LT were tested positive for SARS-CoV-2 infection. Twenty-one patients (72%) were male, median age was 59 years (20-71). The most common indication (70%) for LT was ESLD. The mean MELD score was 18 (8-32). At diagnosis, twenty patients (69%) presented at least one symptom: 38% fever, 28% dry cough, and 31% respiratory distress. Notably, 25% of patients presented hepatic encephalopathy as first presenting symptom. The remaining 9 patients (31%) were completely asymptomatic: nasopharyngeal swab was performed according to surveillance protocols. Twenty-one patients (70%) required hospitalization for the management of COVID-19. Respiratory support was necessary in 13 patients (45%): 5 (17%) required O2-supply, 4 (14%) non-invasive ventilation and 4 (14%) mechanical ventilation. Only five patients (17%) received at least one drug for infection treatment (see table). Heparin was administrated in 7 patients (28%). No bleeding episodes were reported. Eight (%) patients died after a median time of 6 days (2-29) from Covid-19 diagnosis, with a 30-day-mortality rate of 30%. Three patients died of liver failure, while the remaining of multiple organ failures. In the univariate analysis, factors associated with 30-days mortality were respectively presence of comorbidities (0.07), severity of liver disease according to MELD score (0.05) and severity of respiratory failure (0.011). In the cox-regression analysis, only the severity of respiratory failure was significantly associated with the mortality (HR 3.13, IC 1.53-6.3). Conclusions: COVID-19 is associated with elevated mortality in LT candidates, listed for ESLD.

Long-term functional outcomes of sofosbuvir-based antiviral treatment were evaluated in a cohort study involving 16 Italian centres within the international compassionate use programme for post-transplant hepatitis C virus (HCV) recurrence. Seventy-three patients with cirrhosis (n=52) or fibrosing cholestatic hepatitis (FCH, n=21) received 24-week sofosbuvir with ribavirin±pegylated interferon or interferon-free sofosbuvir-based regimen with daclatasvir/simeprevir+ribavirin. The patients were observed for a median time of 103 (82-112) weeks. Twelve of 73 (16.4%) died (10 non-FCH, 2 FCH) and two underwent re-LT. Sustained virological response was achieved in 46 of 66 (69.7%): 31 of 47 (66%) non-FCH and 15 of 19 (79%) FCH patients. All relapsers were successfully retreated. Comparing the data of baseline with last follow-up, MELD and Child-Turcotte-Pugh scores improved both in non-FCH (15.3±6.5 vs 10.5±3.8, P

Background Active tuberculosis (TB) is commonly considered a contraindication for liver transplantation (LT). However, in patients with TB who develop acute liver failure (ALF) due to toxicity induced by anti-tubercular treatment (ATT), LT could be the only opportunity for treatment. The aim of this study was to evaluate the feasibility of LT in this scenario. Methods We described 2 cases and comprehensively reviewed the literature finding 26 cases of LT performed in patients having a concomitant active TB and liver failure secondary to ATT toxicity. Results TB was classified as pulmonary in 18/26 (69%), nodal in 3/26 (11%) TB cases, while the remaining 5/26 cases included disseminated, pleural, renal, ovarian, and vertebral TB localization (1 case each). ATT following LT consisted mainly of isoniazid or rifampin (RIF)-sparing regimens and included primarily fluoroquinolones and ethambutol. Rejection episodes and liver toxicity were reported in 19% and 8% of patients respectively. Graft rejection was more frequent among patients treated with RIF-containing regimens (P

Introduction: The availability of interferon-sparing therapy with direct acting antivirals (DAAs) has expanded the pool of patients eligible for treatment. Despite this, data on the efficacy and safety of these treatments in elderly are lacking. Aim: To evaluate the efficacy and safety of the treatment with DAA-based regimens in HCV patients aged ≥65 years with advanced fibrosis/cirrhosis in a real life clinical setting. Methods: Retrospective data of elderly patients treated with DAAs from January to November 2015 in 7 tertiary referral center of Emilia-Romagna Region (Italy) were collected. Patients received: sofosbuvir (SOF) [n = 35], SOF + simeprevir (SMV) [n = 78], SOF + daclatasvir (DCV) [n = 21], SOF + ledipasvir [n = 17], SMV + DCV [n = 4], ombitasvir/paritaprevir/ritonavir only [n = 3] or with dasasbuvir [n = 42]. Ribavirin was added at the physician's discretion according weight. The primary efficacy endpoint was sustained virological response 12 weeks after the last dose of study drug (SVR12). Results: Overall, 200 consecutive elderly patients were treated. The median age was 74 years (range: 65-85) and 90 (45%) aged ≥75 years; 49% were male, 50.5% were treatment experienced and 85% had cirrhosis. The majority (76%) had genotype (GT) 1b. To date, 155 patients completed treatment. Two cirrhotics died during the therapy and were excluded from final analysis because the cause of death was unrelated to the treatment. Overall, 94 have reached week 12 of post-treatment and the SVR12 was 91.5% (86/94). According to GT, the SVR12 was achieved in 69/73 (94.5%) with GT1, in 16/18 (88.9%) with GT2 and in 1/3 (33.4%) with GT4 infection. Relapse occurred more commonly in cirrhotic patients. No serious adverse events have been reported until now. Complete safety data for the cohort and updated SVR data will be presented. Conclusions: This preliminary data indicate that DAA-based regimen have a similar efficacy compared to registrative studies and without significant side effects in HCV elderly patients in a real-world setting.

Introduction: Non-interferon-based therapy with direct acting antiviral agents (DAA) have become an integral component of treatment for HCV infection but little is known about their real-world effectiveness. Aim: To evaluate the efficacy and safety of the treatment with DAA-based regimen in HCV patients with advanced fibrosis/cirrhosis in a real life clinical setting. Methods: Retrospective data of patients treated with DAA from January to November 2015 in 7 tertiary referral centers in the Emilia-Romagna Region (Italy) were collected. Patients on the waiting list for orthotopic liver transplantation and with HIV co-infection were excluded. Patients received: sofosbuvir (SOF) [n = 74], SOF + simeprevir (SMV) [n = 149], SOF + daclatasvir (DCV) [n = 69], SOF + ledipasvir [n = 43], SMV + DCV [n = 4], ombitasvir/paritaprevir/ritonavir only [n = 11] or with dasasbuvir [n = 84]. Ribavirin was added at the physician's discretion according to weight. The primary efficacy endpoint was sustained virological response 12 weeks after the last dose of study drug (SVR12). Results: Overall, 435 consecutive patients were treated. The median age was 63 years (range: 29–85); 60% were male, 55.2% were treatment experienced and 81.1% had cirrhosis. The majority (56.6%) had genotype (GT) 1b, 12.4% GT1a, 11.3% GT2, 12.6% GT3 and 7.1% GT4. To date, 347 patients completed treatment and 179 the week 12 of post-treatment follow-up. Three cirrhotics died during treatment and were excluded from analysis. Overall, the SVR12 was 88.8% (159/179). According to GT, the SVR12 was achieved in 17/19 (89.5%) GT1a, in 100/111 (90.1%) GT1b, in 24/26 (92.3%) GT2, in 9/11 (81.8%) GT3 and in 9/12 (75%) GT4. Patients with cirrhosis had a lower response rate than those with advanced fibrosis (86.7% vs 97.2%; p = 0.082). Complete safety data for the entire cohort, updated SVR12 will be presented. Conclusions: The DAA-based regimen was efficacious with low relapse rates in HCV patients in a real-world setting. Patients with cirrhosis seems to respond less well to the different regimens used.

In the last US national conference on liver transplantation for hepatocellular carcinoma (HCC), a continuous priority score, that incorporates model for end-stage liver disease (MELD), alpha-fetoprotein and tumor size, was recommended to ensure a more equitable liver allocation. However, prioritizing highest alpha-fetoprotein levels or largest tumors may select lesions at a higher risk for recurrence; similarly, patients with higher degree of liver failure could have lower postoperative survival. Data from 300 adult HCC recipients were reviewed and the proposed HCC-MELD equation was applied to verify if it can predict post-transplantation survival. The 5-year survival and recurrence rates after transplantation were 72.8 and 13.5%, respectively. Cox regression analysis confirmed HCC-MELD as predictive of both postoperative survival and recurrence (p < 0.001). The 5-year predicted survival and recurrence rates were plotted against the HCC-MELD-based dropout probability: the higher the dropout probability while on waiting list, the lower the predicted survival after transplantation, that is worsened by hepatitis C positivity; similarly, the higher the predicted HCC recurrence rate after transplantation. The HCC priority score could predict the postoperative survival of HCC recipients and could be useful in selecting patients with greater possibilities of survival, resulting in higher post-transplantation survival rates of HCC populations.

In liver transplant, during anti-viral therapy for hepatitis C virus (HCV) recurrence, the immunosuppressant levels should be monitored to prevent both toxicity and rejection. Sofosbuvir (SOF) has been used within compassionate programs for HCV recurrence and, according to pharmacokinetic analyses, is not supposed to have significant pharmacological interactions with tacrolimus (Tac) or ciclosporin.1 This was reported in the review article by Koff recently published.2 We treated eight transplant recipients with SOF/ribavirin (RBV) for a severe HCV recurrence, and observed unexpected Tac/ciclosporin reduction during SOF.

Background and aim: Sorafenib is a multikinase inhibitor approved for the treatment of advanced hepatocellular carcinoma (HCC). However, the predictive factors of outcome among treated patients have not been fully investigated. Aim of this study was to identify factors predictive for tumor control among patients with advanced HCC treated with sorafenib. Material and methods: All consecutive HCC patients treated with sorafenib at our Unit from October 2008 to October 2010 were evaluated. All patients received 800 mg/day of sorafenib until progression or unacceptable toxicities. Overall survival (OS) and time to progression (TTP) were estimated by using Kaplan-Meier curves. TTP was considered as a marker of tumor control. Univariate analysis included age, gender, etiology, AFP, Child-Pugh class, MELD, alanine aminotransferase (ALT), alkaline phosphatase, bilirubin, albumin, ascites, metastasis, portal vein thrombosis, oesophageal varices, effects related to VEGF inhibition: rash, arterial hypertension, bleeding, and hand-foot syndrome (HFS). To detect factors independently related to TTP, multivariate analysis by Cox’s model was done. Results: We treated 101 patients (median age 67 years; 81 males; 98 cirrhotics; Child A/B: 79/19; 55 macrovascular invasion; 39 extrahepatic spread). Median therapy duration was 4 (range 1-16) months. Median OS was 10 (95% CI 4.5-15.5) months. TTP was 9 (95%CI 3.7-14.3) months. Complete/partial response occurred in 21% of patients and stable disease in 19%. At univariate analysis, the variables significantly related to TTP were: female sex (14 months vs 6 months, p=.05), no portal thrombosis (13 months vs 6 months, p=.04), ALT =60UI (15 months vs 6 months, p=.02), no ascites (11 months vs 2 months, p=.003), and occurrence of HFS (16 months vs 5 months, p

427 TREATMENT OF HEPATITIS C RECURRENCE AFTER LIVER TRANSPLANTATION: GENDER ISSUE ON THERAPY OUTCOME V. Giannelli, C. Lucidi, M. Giusto, F.R. Ponziani, M. Pompili, R. Vigano, R.M. Iemmolo, F.M. Donato, M. Rendina, P. Toniutto, L. Pasulo, S. Fagiuoli, M.C. Morelli, E. de Martin, L. Miglioresi, D. di Paolo, M. Merli, RECOLT-C. Sapienza University of Rome, Cattolica Sacro Cuore, Niguarda Ca’Granda Hospital, Rome, Modena University, Modena, Maggiore Hospital, Milan, Bari University, Bari, Udine University, Udine, Bergamo University, Bergamo, Sant’Orsola Malpighi Hospital, Bologna, Padua University Hospital, Padua, San Camillo-Spallanzani Hospital, Tor Vergata University Hospital, Rome, Italy E-mail: mr_valegiann84@hotmail.it

Introduction: The metabolic syndrome is frequently associated with liver disease; the presence of obesity and diabetes boost progression to liver cirrhosis. These conditions make lifestyle changes aiming weight loss, crucial for prevention and treatment. The Mediterranean Diet (MD) has proved to be the most useful tool for losing and maintaining weight, protecting from cardiovascular mortality. Aim: To evaluate calorie intake (CI) and adherence to MD in patients affected by liver disease, cared for in the setting of a Metabolic Unit, in relation to BMI and basal metabolic rate (BMR). Materials and Methods: We studied all patients referred to the Unit from October 2019 to March 2020 (n=60), 24% had a viral etiology, 74% dismetabolic and 2% other etiologies. For the stage of disease, 50.7% had hepatitis, 34% had a diagnosis of cirrhosis and 15.3% were transplanted. CI was determined by means of an in-house developed questionnaire ("QuantoMangioVeramente"-QMV), measuring the CI on the basis of 20 items; the Mediterranean Diet Score (MDS) was used for evaluating adherence to MD; BMR and body composition were assessed by bioimpedance analysis. Results: Males (66%), mean age 61.5 years (±8.9), 71% had diabetes, weight 84.6 kg (±18.5), BMI 30.9 kg/m2(±5.7), lean mass 58.2 kg (±10), total body water 48.7% (±5.4), fat mass 31.1% (±8.5), BMR 1607Kcal (±251), CI from QMV 1808Kcal (±589), 1331Kcal (±438) in females vs. 2020Kcal (±523) in males (p

Background: The achievement of high rates of sustained virological response (SVR) with direct-acting antivirals (DAAs) in hepatitis C virus (HCV) infected patients will reduce decompensating terminal events. Aims: To investigate whether hepatocellular carcinoma (HCC) occurrence could change due to the DAA-induced increase in life-expectancy. Methods: A Markov model was built on clinical data of 494 cirrhotic patients and available literature to estimate probabilities of “death before HCC” and of “HCC occurrence” without and with DAA. Results: In comparison to untreated patients, DAA therapy reduced the 20-year mortality before HCC by 21.9% in patients without varices and by 21.5% in those with varices, considering an SVR of 95% and no direct effect on hepatocarcinogenesis. Tumour occurrence increased by 5%–8.2% and the proportion of HCCs diagnosed in compensated stages increased to >98%. If we consider DAA as having “anti-tumoral” effects, the benefit becomes greater, achieving a 20-year survival of 81.5% in patients without varices, and 52.2% in patients with varices. Instead, if we consider DAA as having a “pro-tumoral” effect, then, the increased incidence of HCC nullifies the survival benefits. Conclusion: DAAs drastically reduce the mortality caused by the liver function worsening, increasing the proportion of HCCs diagnosed in compensated stages. Knowledge of the DAA effect on hepatocarcinogenesis remains pivotal. © 2017 Editrice Gastroenterologica Italiana S.r.l.

Background The recurrence of hepatitis C viral infection is common after liver transplant, and achieving a sustained virological response to antiviral treatment is desirable for reducing the risk of graft loss and improving patients’ survival. Aim To investigate the long-term maintenance of sustained virological response in liver transplant recipients with hepatitis C recurrence. Methods 436 Liver transplant recipients (74.1% genotype 1) who underwent combined antiviral therapy for hepatitis C recurrence were retrospectively evaluated. Results The overall sustained virological response rate was 40% (173/436 patients), and the mean follow-up after liver transplantation was 11 ± 3.5 years (range, 5–24). Patients with a sustained virological response demonstrated a 5-year survival rate of 97% and a 10-year survival rate of 93%; all but 6 (3%) patients remained hepatitis C virus RNA-negative during follow-up. Genotype non-1 (p = 0.007), treatment duration >80% of the scheduled period (p = 0.027), and early virological response (p = 0.002), were associated with the maintenance of sustained virological response as indicated by univariate analysis. Early virological response was the only independent predictor of sustained virological response maintenance (p = 0.008). Conclusions Sustained virological response achieved after combined antiviral treatment is maintained in liver transplant patients with recurrent hepatitis C and is associated with an excellent 5-year survival.