The polymorphic variant of SerpinB3 (SerpinB3-PD) is associated with faster cirrhosis decompensation.

BACKGROUND: SerpinB3 is a cysteine protease inhibitor involved in liver disease progression due to its proinflammatory and profibrogenic properties. The polymorphic variant SerpinB3-PD (SB3-PD), presents a substitution in its reactive centre loop, determining the gain of function. AIMS: To disclose the clinical characteristics of a cohort of patients with cirrhosis in relation to the presence of SB3-PD and to assess the effect of this genetic variant on fibrogenic and inflammatory cytokines in vitro. METHODS: We assessed SB3 polymorphism in 90 patients with cirrhosis, prospectively followed up in our referral centre. We used HepG2 and HuH-7 cells transfected to overexpress either wild-type SB3 (SB3-WT) or SB3-PD to assess their endogenous effect, while LX2 and THP-1 cells were treated with exogenous SB3-WT or SB3-PD proteins. RESULTS: Patients carrying SB3-PD had more severe portal hypertension and higher MELD scores, than patients carrying SB3-WT. In multivariate analysis, SB3-PD was an independent predictor of cirrhosis complications. Patients with SB3-PD polymorphism presented with more severe liver fibrosis and inflammatory features. Hepatoma cells overexpressing SB3-PD showed higher TGF-ß1 expression than controls. The addition of recombinant SB3-PD induced an up-regulation of TGF-ß1 in LX2 cells and a more prominent inflammatory profile in THP-1 cells, compared to the effect of SB3-WT protein. CONCLUSIONS: The polymorphic variant SB3-PD is highly effective in determining activation of TGF-ß1 and inflammation in vitro. Patients with cirrhosis who carry SB3-PD polymorphism may be more prone to develop severe liver disease progression. However, further validation studies are warranted to support the in vivo relevance of this polymorphism.

A new clinical and prognostic characterization of the patterns of decompensation of cirrhosis.

BACKGROUND & AIMS: The prognostic impact of acute decompensation (AD), i.e. the development of complications that require hospitalization, has recently been assessed. However, complications of cirrhosis do not necessarily require hospitalization and can develop progressively, as in the recently defined non-acute decompensation (NAD). Nevertheless, there is no data regarding the incidence and prognostic impact of NAD. The aim of the study was to evaluate the incidence and the prognostic impact of NAD and AD in outpatients with cirrhosis. METHODS: A total of 617 outpatients with cirrhosis from two Italian tertiary centers (Padua and Milan) were enrolled from January 2003 to June 2021 and followed prospectively until the end of the study, death or liver transplantation. The complications registered during follow-up were considered as AD if they required hospitalization, or NAD if managed at the outpatient clinic. RESULTS: During follow-up, 154 patients (25.0% of total patients) developed complications, 69 patients (44.8%) developed NAD and 85 (55.2%) developed AD, while 29 patients with NAD (42.0%) developed a further episode of AD during follow-up. Sixty-month survival was significantly higher in patients with no decompensation than in patients with NAD or AD. On multivariable analysis, AD (hazard ratio [HR] 21.07, p <0.001), NAD (HR 7.13, p <0.001), the etiological cure of cirrhosis (HR 0.38, p <0.001) and model for end-stage liver disease score (HR 1.12, p = 0.003) were found to be independent predictors of mortality. CONCLUSIONS: The first decompensation is non-acute in almost 50% of outpatients, though such events are still associated with decreased survival compared to no decompensation. Patients who develop NAD must be treated with extreme care and monitored closely to prevent the development of AD. IMPACT AND IMPLICATIONS: This multicenter study is the first to investigate the role of non-acute decompensation (NAD) in patients with cirrhosis. In fact, while the unfavorable impact of acute decompensation is well known, there is currently a dearth of evidence on NAD, despite it being a common occurrence in clinical practice. Our data show that almost half of decompensations in patients with cirrhosis can be considered NAD and that such events are associated with a higher risk of mortality than no decompensation. This study has important clinical implications because it highlights the need to carefully consider patients who develop NAD, in order to prevent further decompensation and reduce mortality.

Novel prognostic biomarkers in decompensated cirrhosis: a systematic review and meta-analysis.

BACKGROUND: Patients with decompensated cirrhosis experience high mortality rates. Current prognostic scores, including the model for end-stage liver disease (MELD), may underperform in settings other than in those they were initially developed. Novel biomarkers have been proposed to improve prognostication accuracy and even to predict development of complications. METHODS: We performed a systematic review and meta-analysis on novel urine and blood biomarkers and their ability to predict 90-day mortality in patients with decompensated cirrhosis. Secondary outcomes included 28-day and 1-year mortality, and development of acute-on-chronic liver failure, acute kidney injury and other complications. To overcome differences in units, temporal changes in assays and reporting heterogeneity, we used the ratio of means (RoM) as measure of association for assessing strength in predicting outcomes. An RoM>1 implies that the mean biomarker level is higher in those that develop the outcome than in those that do not. RESULTS: Of 6629 unique references, 103 were included, reporting on 29 different biomarkers, with a total of 31 362 biomarker patients. Most studies were prospective cohorts of hospitalised patients (median Child-Pugh-Turcotte score of 9 and MELD score of 18). The pooled 90-day mortality rate was 0.27 (95% CI 0.24 to 0.29). The RoM for predicting 90-day mortality was highest for interleukin 6 (IL-6) (2.56, 95% CI 2.39 to 2.74), followed by urinary neutrophil gelatinase-associated lipocalin (uNGAL) (2.42, 95% CI 2.20 to 2.66) and copeptin (2.33, 95% CI 2.17 to 2.50). These RoMs were all higher than for MELD (1.44, 95% CI 1.42 to 1.46). CONCLUSION: Novel biomarkers, including IL-6, uNGAL and copeptin, can probably improve prognostication of patients with decompensated cirrhosis compared with MELD alone.

Mechanisms and treatment approaches for ACLF.

Acute-on-chronic liver failure (ACLF) is a life-threatening syndrome characterized by decompensation of cirrhosis, severe systemic inflammation and organ failures. ACLF is frequently triggered by intra- and/or extrahepatic insults, such as bacterial infections, alcohol-related hepatitis or flares of hepatic viruses. The imbalance between systemic inflammation and immune tolerance causes organ failures through the following mechanisms: (i) direct damage of immune cells/mediators; (ii) worsening of circulatory dysfunction resulting in organ hypoperfusion and (iii) metabolic alterations with prioritization of energetic substrates for inflammation and peripheral organ 'energetic crisis'. Currently, the management of ACLF includes the support of organ failures, the identification and treatment of precipitating factors and expedited assessment for liver transplantation (LT). Early LT should be considered in patients with ACLF grade 3, who are unlikely to recover with the available treatments and have a mortality rate > 70% at 28 days. However, the selection of transplant candidates and their prioritization on the LT waiting list need standardization. Future challenges in the ACLF field include a better understanding of pathophysiological mechanisms leading to inflammation and organ failures, the development of specific treatments for the disease and personalized treatment approaches. Herein, we reviewed the current knowledge and future perspectives on mechanisms and treatment of ACLF.

Development, validation, and prognostic evaluation of a risk score for long-term liver-related outcomes in the general population: a multicohort study.

BACKGROUND: Liver cirrhosis is a major cause of death worldwide. Cirrhosis develops after a long asymptomatic period of fibrosis progression, with the diagnosis frequently occurring late, when major complications or cancer develop. Few reliable tools exist for timely identification of individuals at risk of cirrhosis to allow for early intervention. We aimed to develop a novel score to identify individuals at risk for future liver-related outcomes. METHODS: We derived the LiverRisk score from an international prospective cohort of individuals from six countries without known liver disease from the general population, who underwent liver fibrosis assessment by transient elastography. The score included age, sex, and six standard laboratory variables. We created four groups: minimal risk, low risk, medium risk, and high risk according to selected cutoff values of the LiverRisk score (6, 10, and 15). The model's discriminatory accuracy and calibration were externally validated in two prospective cohorts from the general population. Moreover, we ascertained the prognostic value of the score in the prediction of liver-related outcomes in participants without known liver disease with median follow-up of 12 years (UK Biobank cohort). FINDINGS: We included 14 726 participants: 6357 (43·2%) in the derivation cohort, 4370 (29·7%) in the first external validation cohort, and 3999 (27·2%) in the second external validation cohort. The score accurately predicted liver stiffness in the development and external validation cohorts, and was superior to conventional serum biomarkers of fibrosis, as measured by area under the receiver-operating characteristics curve (AUC; 0·83 [95% CI [0·78-0·89]) versus the fibrosis-4 index (FIB-4; 0·68 [0·61-0·75] at 10 kPa). The score was effective in identifying individuals at risk of liver-related mortality, liver-related hospitalisation, and liver cancer, thereby allowing stratification to different risk groups for liver-related outcomes. The hazard ratio for liver-related mortality in the high-risk group was 471 (95% CI 347-641) compared with the minimal risk group, and the overall AUC of the score in predicting 10-year liver-related mortality was 0·90 (0·88-0·91) versus 0.84 (0·82-0·86) for FIB-4. INTERPRETATION: The LiverRisk score, based on simple parameters, predicted liver fibrosis and future development of liver-related outcomes in the general population. The score might allow for stratification of individuals according to liver risk and thus guide preventive care. FUNDING: European Commission under the H20/20 programme; Fondo de Investigación Sanitaria de Salud; Instituto de Salud Carlos III; Spanish Ministry of Economy, Industry, and Competitiveness; the European Regional Development Fund; and the German Ministry of Education and Research (BMBF).

Impact of bacterial infections prior to liver transplantation on post-transplant outcomes in patients with cirrhosis.

Background & Aims: Bacterial infections are frequent in patients with cirrhosis and increase the risk of death and drop-out from liver transplant (LT) waiting list. In patients with bacterial infections, LT is frequently delayed because of the fear of poor outcomes. We evaluated the impact of pre-LT infections on post-LT complications and survival. Methods: From 2012 to 2018, consecutive patients transplanted at the Hospital of Padua were identified and classified in two groups: patients surviving an episode of bacterial infection within 3 months before LT (study group) and patients without infections before LT (control group). Post-LT outcomes (complications, new infections, survival) were collected. Results: A total of 466 LT recipients were identified (study group n = 108; control group n = 358). After LT, the study group had a higher incidence of new bacterial (57% vs. 20%, p <0.001) and fungal infections (14% vs. 5%, p = 0.001) and of septic shock (8% vs. 2%, p = 0.004) than the control group. Along with the model for end-stage liver disease (MELD) score and alcohol-related cirrhosis, bacterial infection pre-LT was an independent predictor of post-LT infections (odds ratio = 3.92; p <0.001). Nevertheless, no significant difference was found in 1-year (88% vs. 89%, p = 0.579) and 5-year survival rates (76% vs. 75%, p = 0.829) between the study group and control group. Within the study group, no association was found between the time elapsed from infection improvement/resolution to LT and post-LT outcomes. Conclusions: Patients with pre-LT infections have a higher risk of new bacterial and fungal infections and of septic shock after LT. However, post-LT survival is excellent. Therefore, as soon as the bacterial infection is improving/resolving, transplant should not be delayed, but patients with pre-transplant bacterial infections require active surveillance for infections after LT. Impact and Implications: Bacterial infections increase mortality and delay transplant in patients with cirrhosis awaiting liver transplantation (LT). Little is known about the impact of adequately treated infections before LT on post-transplant complications and outcomes. The study highlights that pre-LT infections increase the risk of post-LT infections, but post-LT survival rates are excellent despite the risk. These findings suggest that physicians should not delay LT because of concerns about pre-LT infections, but instead should actively monitor these patients for infections after surgery.

Can the Multidimensional Prognostic Index (MPI) be a predictive instrument for mortality in older adult liver transplant candidates?

PURPOSE: The most recent guidelines recommend that selection of liver transplant recipient patients be guided by a multidimensional approach that includes frailty assessment. Different scales have been developed to identify frail patients and determine their prognosis, but the data on older adult candidates are still inconclusive. The aim of this study was to compare the accuracy of the Liver Frailty Index (LFI) and the Multidimensional Prognostic Index (MPI) as predictors of mortality in a cohort of older people patients being evaluated for liver transplantation. METHODS: This retrospective study was conducted on 68 patients > 70 years being followed at the University Hospital of Padua in 2018. Clinical information on each patient, Model For End-Stage Liver Disease (MELD), Body Mass Index (BMI), Activities of Daily Living (ADL), Mini Nutritional Assessment (MNA), LFI, MPI, and date-of-death, were recorded. The observational period was 3 years. RESULTS: We studied 68 individuals (25 women), with a mean age 72.21 ± 1.64 years. Twenty-five (36.2%) patients died during the observational period. ROC curve analysis showed both MPI and LFI to be good predictors of mortality (AUC 0.7, p = 0.007, and AUC 0.689, p = 0.015, respectively). MELD (HR 1.99, p = 0.001), BMI (HR 2.34, p = 0.001), and poor ADL (HR 3.34, p = 0.04) were risk factors for mortality in these patients, while male sex (HR 0.1, p = 0.01) and high MNA scores (HR 0.57, p = 0.01) were protective factors. CONCLUSION: Our study confirmed the prognostic value of MPI in older adult patients awaiting liver transplantation. In this cohort, good nutritional status and male sex were protective factors, while high MELD and BMI scores and poor functional status were risk factors.

Etiological cure prevents further decompensation and mortality in patients with cirrhosis with ascites as the single first decompensating event.

BACKGROUND AND AIMS: Removal/suppression of the primary etiological factor reduces the risk of decompensation and mortality in compensated cirrhosis. However, in decompensated cirrhosis, the impact of etiologic treatment is less predictable. We aimed to evaluate the impact of etiological treatment in patients with cirrhosis who developed ascites as single index decompensating event. APPROACH AND RESULTS: Patients with cirrhosis and ascites as single first decompensation event were included and followed until death, liver transplantation, or Q3/2021. The etiology was considered "cured" (alcohol abstinence, hepatitis C cure, and hepatitis B suppression) versus "controlled" (partial removal of etiologic factors) versus "uncontrolled." A total of 622 patients were included in the study. Etiology was "cured" in 146 patients (24%), "controlled" in 170 (27%), and "uncontrolled" in 306 (49%). During follow-up, 350 patients (56%) developed further decompensation. In multivariable analysis (adjusted for age, sex, varices, etiology, Child-Pugh class, creatinine, sodium, and era of decompensation), etiological cure was independently associated with a lower risk of further decompensation (HR: 0.46; p = 0.001). During follow-up, 250 patients (40.2%) died, while 104 (16.7%) underwent LT. In multivariable analysis, etiological cure was independently associated with a lower mortality risk (HR: 0.35, p < 0.001). CONCLUSIONS: In patients with cirrhosis and ascites as single first decompensating event, the cure of liver disease etiology represents a main treatment goal since this translates into considerably lower risks of further decompensation and mortality.

Cirrhosis and Portal Hypertension: How Do We Deal with Ascites and Its Consequences.

Ascites is the most common complication of cirrhosis, with 5-year mortality reaching 30%. Complications of ascites (ie, spontaneous bacterial peritonitis, hepatorenal syndrome, recurrent/refractory ascites, and hepatic hydrothorax) further worsen survival. The development of ascites is driven by portal hypertension, systemic inflammation, and splanchnic arterial vasodilation. Etiologic treatment and nonselective beta-blockers can prevent ascites in compensated cirrhosis. The treatment of ascites is currently based on the management of fluid overload (eg, diuretics, sodium restriction, and/or paracenteses). In selected patients, long-term albumin use, norfloxacin prophylaxis, and transjugular intrahepatic portosystemic shunt reduce the risk of further decompensation and improve survival.

Diagnostic and prognostic performance of urinary neutrophil gelatinase-associated lipocalin in patients with cirrhosis and acute kidney injury.

BACKGROUND AND AIMS: Acute kidney injury (AKI) commonly occurs in patients with decompensated cirrhosis. Urinary neutrophil gelatinase-associated lipocalin (uNGAL) could help discriminate between different etiologies of AKI. The aim of this study was to investigate the use of uNGAL in (1) the differential diagnosis of AKI, (2) predicting the response to terlipressin and albumin in patients with hepatorenal syndrome-AKI (HRS-AKI), and (3) predicting in-hospital mortality in patients with AKI. APPROACH AND RESULTS: One hundred sixty-two consecutive patients with cirrhosis and AKI were included from 2015 to 2020 and followed until transplant, death, or 90 days. Standard urinary markers and uNGAL were measured. Data on treatment, type, and resolution of AKI were collected. Thirty-five patients (21.6%) had prerenal AKI, 64 (39.5%) HRS-AKI, 27 (16.7%) acute tubular necrosis-AKI (ATN-AKI), and 36 (22.2%) a mixed form of AKI. Mean values of uNGAL were significantly higher in ATN-AKI than in other types of AKI (1162 ng/ml [95% CI 423-2105 ng/ml] vs. 109 ng/ml [95% CI 52-192 ng/ml]; p  < 0.001). uNGAL showed a high discrimination ability in predicting ATN-AKI (area under the receiver operating characteristic curve, 0.854; 95% CI 0.767-0.941; p  < 0.001). The best-performing threshold was found to be 220 ng/ml (sensitivity, 89%; specificity, 78%). The same threshold was independently associated with a higher risk of nonresponse (adjusted OR [aOR], 6.17; 95% CI 1.41-27.03; p  = 0.016). In multivariable analysis (adjusted for age, Model for End-Stage Liver Disease, acute-on-chronic liver failure, leukocytes, and type of AKI), uNGAL was an independent predictor of in-hospital mortality (aOR, 1.74; 95% CI 1.26-2.38; p  = 0.001). CONCLUSIONS: uNGAL is an adequate biomarker for making a differential diagnosis of AKI in cirrhosis and predicting the response to terlipressin and albumin in patients with HRS-AKI. In addition, it is an independent predictor of in-hospital mortality.

Risk of further decompensation/mortality in patients with cirrhosis and ascites as the first single decompensation event.

Background & Aims: Although ascites is the most frequent first decompensating event in cirrhosis, the clinical course after ascites as the single index decompensation is not well defined. The aim of this multicentre study was thus to systematically investigate the incidence and type of further decompensation after ascites as the first decompensating event and to assess risk factors for mortality. Methods: A total of 622 patients with cirrhosis presenting with grade 2/3 ascites as the single index decompensating event at 2 university hospitals (Padova and Vienna) between 2003 and 2021 were included. Events of further decompensation, liver transplantation, and death were recorded. Results: The mean age was 57 ± 11 years, and most patients were male (n = 423, 68%) with alcohol-related (n = 366, 59%) and viral (n = 200,32%) liver disease as the main aetiologies. In total, 323 (52%) patients presented with grade 2 and 299 (48%) with grade 3 ascites. The median Child-Pugh score at presentation was 8 (IQR 7-9), and the mean model for end-stage liver disease (MELD) was 15 ± 6. During a median follow-up period of 49 months, 350 (56%) patients experienced further decompensation: refractory ascites (n = 130, 21%), hepatic encephalopathy (n = 112, 18%), spontaneous bacterial peritonitis (n = 32, 5%), hepatorenal syndrome-acute kidney injury (n = 29, 5%). Variceal bleeding as an isolated further decompensation event was rare (n = 18, 3%), whereas non-bleeding further decompensation (n = 161, 26%) and ≥2 concomitant further decompensation events (n = 171, 27%) were frequent. Transjugular intrahepatic portosystemic shunt was used in only 81 (13%) patients. In patients presenting with grade 2 ascites, MELD ≥15 indicated a considerable risk for further decompensation (subdistribution hazard ratio [SHR] 2.18; p <0.001; 1-year incidences: <10: 10% vs. 10-14: 13% vs. ≥15: 28%) and of mortality (SHR 1.89; p = 0.004; 1-year incidences: <10: 3% vs. 10-14: 6% vs. ≥15: 14%). Importantly, mortality was similarly high throughout MELD strata in grade 3 ascites (p = n.s. for different MELD strata; 1-year incidences: <10: 14% vs. 10-14: 15% vs. ≥15: 20%). Conclusions: Further decompensation is frequent in patients with ascites as a single index decompensation event and only rarely owing to bleeding. Although patients with grade 2 ascites and MELD <15 seem to have a favourable prognosis, those with grade 3 ascites are at a high risk of mortality across all MELD strata. Lay summary: Decompensation (the development of symptoms as a result of worsening liver function) marks a turning point in the disease course for patients with cirrhosis. Ascites (i.e. , the accumulation of fluid in the abdomen) is the most common first decompensating event, yet little is known about the clinical course of patients who develop ascites as a single first decompensating event. Herein, we show that the severity of ascites is associated with mortality and that in patients with moderate ascites, the widely used prognostic MELD score can predict patient outcomes.

Treatment With Simvastatin and Rifaximin Restores the Plasma Metabolomic Profile in Patients With Decompensated Cirrhosis.

Patients with decompensated cirrhosis, particularly those with acute-on-chronic liver failure (ACLF), show profound alterations in plasma metabolomics. The aim of this study was to investigate the effect of treatment with simvastatin and rifaximin on plasma metabolites of patients with decompensated cirrhosis, specifically on compounds characteristic of the ACLF plasma metabolomic profile. Two cohorts of patients were investigated. The first was a descriptive cohort of patients with decompensated cirrhosis (n = 42), with and without ACLF. The second was an intervention cohort from the LIVERHOPE-SAFETY randomized, double-blind, placebo-controlled trial treated with simvastatin 20 mg/day plus rifaximin 1,200 mg/day (n = 12) or matching placebo (n = 13) for 3 months. Plasma samples were analyzed using ultrahigh performance liquid chromatography-tandem mass spectroscopy for plasma metabolomics characterization. ACLF was characterized by intense proteolysis and lipid alterations, specifically in pathways associated with inflammation and mitochondrial dysfunction, such as the tryptophan-kynurenine and carnitine beta-oxidation pathways. An ACLF-specific signature was identified. Treatment with simvastatin and rifaximin was associated with changes in 161 of 985 metabolites in comparison to treatment with placebo. A remarkable reduction in levels of metabolites from the tryptophan-kynurenine and carnitine pathways was found. Notably, 18 of the 32 metabolites of the ACLF signature were affected by the treatment. Conclusion: Treatment with simvastatin and rifaximin modulates some of the pathways that appear to be key in ACLF development. This study unveils some of the mechanisms involved in the effects of treatment with simvastatin and rifaximin in decompensated cirrhosis and sets the stage for the use of metabolomics to investigate new targeted therapies in cirrhosis to prevent ACLF development.

Comparison of Fondaparinux and Low-Molecular-Weight Heparin in the Treatment of Portal Vein Thrombosis in Cirrhosis.

BACKGROUND: Portal vein thrombosis is the most common thrombotic complication in cirrhosis. About 60% of anticoagulated patients can achieve recanalization. Despite fondaparinux (FPX) theoretical advantages, data are lacking about safety and efficacy for treatment of portal vein thrombosis in cirrhosis. METHODS: Cirrhotic patients with portal vein thrombosis treated with FPX or low-molecular-weight heparin (LMWH) were retrospectively included. The extension of thrombosis at baseline and its evolution during anticoagulant treatment were evaluated. Patients were treated with LMWH or FPX at therapeutic dosage and reduction was considered in selected cases. RESULTS: There were 124 patients included. Main portal vein branch, splenic, and superior mesenteric veins were involved in 84%, 13%, and 36% of cases, respectively. Forty-one patients (33%) were treated with FPX and 83 (67%) with LMWH. The probability of resolution of thrombosis at 36 months was significantly higher in patients treated with FPX than in those treated with LMWH (77% vs 51%; P = .001), particularly when prescribed at reduced dose. With multivariate analysis, the treatment with FPX (hazard ratio 2.38; P = .002) and use of a full dose (hazard ratio 1.78; P = .035) were independent predictors of portal vein full recanalization. Bleeding rate was higher in patients treated with FPX than in those treated with LMWH (27% vs 13%; P = .06). CONCLUSIONS: FPX appears to be more effective than LMWH in the treatment of portal vein thrombosis when used at reduced dose, also in complete thrombosis. FPX should be considered among possible treatments for portal vein thrombosis in cirrhosis.

Changes in the epidemiology and management of bacterial infections in cirrhosis.

Patients with cirrhosis are susceptible to develop infections because of immune dysfunction, changes in microbiome and increase in bacterial translocation from the gut to systemic circulation. Bacterial infections can worse the clinical course of the disease, triggering the development of complications such as acute kidney injury, hepatic encephalopathy, organ failures and acute on chronic liver failure. In recent years, the spread of multi drug resistant bacteria made more challenging the management of infections in patients with cirrhosis. Hence, the mortality rate associated to sepsis is increasing in these patients. Therefore, the optimization of the management of infections has a high priority in cirrhosis. Herein we reviewed the recent changes in the epidemiology and the management of bacterial infections in patients with liver cirrhosis.

Natural history of acute kidney disease in patients with cirrhosis.

BACKGROUND & AIMS: In 2012, the KDIGO group proposed new definitions for acute kidney injury (AKI), acute kidney disease (AKD) and chronic kidney disease (CKD). According to the definition adapted by the International Club of Ascites, AKI has been extensively investigated in patients with cirrhosis. On the contrary, there are currently no data on the epidemiology and clinical outcomes associated with AKD. The aim of the study was to assess the prevalence and the impact of AKD on the clinical course and survival of patients with cirrhosis. METHODS: A total of 272 consecutive patients with cirrhosis attending our outpatient clinic were included in the study. Clinical and laboratory data were collected at inclusion. Patients were followed-up until death, liver transplant or the end of follow-up. RESULTS: During follow-up, 80 patients developed AKD (29.4%). Forty-two (52.5%) recovered from the first episode of AKD and 26 maintained a normal renal function up to the end of follow-up. Sixteen patients developed a second episode of AKD. Globally, 36 patients (45.0%) died with AKD. Finally, AKD progressed to CKD in 11 patients (13.8%). The 5-year survival rate was significantly lower in patients who developed AKD than in those who did not (34.8% vs. 88.8%, p <0.001). The 5-year rates of complications of cirrhosis and of hospitalizations were also higher in patients with AKD than in those without AKD. CONCLUSIONS: AKD is frequent in patients with cirrhosis. It can be reversible, but it may recur and progress to CKD. AKD has a very negative impact on morbidity and mortality in patients with cirrhosis. LAY SUMMARY: Renal impairment has a very negative impact on patients with cirrhosis. Renal impairment seems to be characterized by a very dynamic course, which is defined according to renal function and length of the impairment as acute kidney injury, acute kidney disease and chronic kidney disease. The role of acute kidney disease is currently unknown. Our study shows for the first time that acute kidney disease is frequent in patients with cirrhosis and has a very negative impact on survival.