Hyponatremia influences the outcome of patients with acute-on-chronic liver failure: an analysis of the CANONIC study

INTRODUCTION: Hyponatremia is a marker of poor prognosis in patients with cirrhosis. This analysis aimed to assess if hyponatremia also has prognostic value in patients with acute-on-chronic liver failure (ACLF), a syndrome characterized by acute decompensation of cirrhosis, organ failure(s) and high short-term mortality. METHODS: We performed an analysis of the Chronic Liver Failure Consortium CANONIC database in 1,341 consecutive patients admitted to 29 European centers with acute decompensation of cirrhosis (including ascites, gastrointestinal bleeding, hepatic encephalopathy, or bacterial infections, or any combination of these), both with and without associated ACLF (301 and 1,040 respectively). RESULTS: Of the 301 patients with ACLF, 24.3% had hyponatremia at inclusion compared to 12.3% of 1,040 patients without ACLF (P <0.001). Model for end-stage liver disease, Child-Pugh and chronic liver failure-SOFA scores were significantly higher in patients with ACLF and hyponatremia compared to those without hyponatremia. The presence of hyponatremia (at inclusion or during hospitalization) was a predictive factor of survival both in patients with and without ACLF. The presence of hyponatremia and ACLF was found to have an independent effect on 90-day survival after adjusting for the potential confounders. Hyponatremia in non-ACLF patients nearly doubled the risk (hazard ratio (HR) 1.81 (1.33 to 2.47)) of dying at 90 days. However, when considering patients with both factors (ACLF and hyponatremia) the relative risk of dying at 90 days was significantly higher (HR 6.85 (3.85 to 12.19) than for patients without both factors. Patients with hyponatremia and ACLF had a three-month transplant-free survival of only 35.8% compared to 58.7% in those with ACLF without hyponatremia (P <0.001). CONCLUSIONS: The presence of hyponatremia is an independent predictive factor of survival in patients with ACLF. In cirrhosis, outcome of patients with ACLF is dependent on its association with hyponatremia

Renal dysfunction prevalence and clinical impact in heart failure

Alberto Palazzuoli, Susanna Benincasa, Stefanie Grothgar, Pasquale Di Sipio, Giovanni Paganini, Marco Pellegrini, Ranuccio NutiDepartment of Internal Medicine and Metabolic Diseases, Cardiology Section, Le Scotte Hospital, University of Siena, ItalyAbstract: Chronic kidney disease (CKD) is associated with a significant increase in death and cardiovascular mortality. However the exact mechanism by which CKD impairs the cardiovascular outcome is not well established. Some reasons may lie in the association of CKD with several other cardiovascular and noncardiovascular disorders including accelerated systemic atherosclerosis, endothelial dysfunction, increased levels of inflammatory factors, anemic status, bone mineral dysfunction, electrolyte imbalance, and renin–angiotensin–aldosterone system (RAAS) activation. Therefore several risk factors such as hypertension, diabetes, lipid disorders, and older age are common in both conditions. In patients affected with heart failure (HF) a key role is represented by the neurohormonal activation. This condition causes fluid and sodium retention, peripheral vasoconstriction, as well as increased congestion and cardiac workload. Moreover, HF during the decompensated phases is often associated with a worsening renal function that leads to further RAAS activation, microvascular damage, and intrarenal flow redistribution. In order to clarify the interactions between these factors, several questions need to be answered: the universal definition of "worsening renal function," the identification of the best laboratory parameters to investigate renal function in terms of sensitivity and specificity, and a better definition of the comorbidities' role in the determination of the outcome, especially in patients with chronic HF. A clarification of these key points could lead to the individualization of new specific therapeutic targets and to a reduction in mortality and hospitalization in patients with HF and renal impairment.Keywords: heart failure, outcome, renal insufficiency, worsening renal functio

Plasma copeptin as biomarker of disease progression and prognosis in cirrhosis

BACKGROUND & AIMS: Research on vasopressin (AVP) in cirrhosis and its role in the assessment of prognosis has been hindered by the difficulty of measuring AVP levels accurately. Copeptin, a 39-aminoacid glycopeptide, is released from the neurohypophysis together with AVP. Copeptin could have a role as biomarker of prognosis in cirrhosis as it may reflect circulatory dysfunction. The aim of this study is to investigate the role of copeptin as biomarker of disease progression and prognosis in cirrhosis. METHODS: This prospective study is divided in 2 study protocols including 321 consecutive patients. Plasma copeptin levels were measured in all patients at study inclusion. Protocol 1: to investigate the relationship of copeptin with kidney and circulatory function (56 patients). Protocol 2: to investigate the relationship between copeptin and prognosis, as assessed by the development of complications of cirrhosis or mortality at 3months (265 patients admitted to hospital for complications of cirrhosis). RESULTS: Patients with decompensated cirrhosis showed significantly higher plasma copeptin levels compared to those of patients with compensated cirrhosis. Copeptin levels had a significant positive correlation with model for end-satge liver disease (MELD) score, AVP, endogenous vasoconstrictor systems, and kidney function parameters. Patients developing complications of cirrhosis or mortality had significantly higher plasma copeptin levels compared to those of the remaining patients. Plasma copeptin levels were an independent predictive factor of both the development of complications and mortality at 3months. This was confirmed in a validation series of 120 patients. CONCLUSIONS: Copeptin is a novel biomarker of disease progression and prognosis in cirrhosis. LAY SUMMARY: Copeptin is a fragment of the vasopressin precursor, a hormone that is known to be increased in patients with cirrhosis and that plays a role in the development of complications of the disease. Vasopressin is difficult to measure, but copeptin is a more stable molecule and is easier to measure in blood. Solà and Kerbert and colleagues have shown in a series of 361 patients that copeptin is markedly increased in patients with cirrhosis who develop complications during the following 3months, compared to those patients who do not develop complications. Moreover, copeptin correlates with prognosis

Renal Dysfunction in Acute Heart Failure

During treatment of acute heart failure (AHF), worsening renal function is often complicated and results in a complex clinical course. Furthermore, renal dysfunction is a strong independent predictor of long-term adverse outcomes in patients with AHF. Traditionally, the predominant cause of renal dysfunction has been attributed to impairment of cardiac output and relative underfilling of arterial perfusion. Recently, emerging data have led to the importance of venous congestion and elevated intra-abdominal pressure rather than confining it to impaired forward cardiac output as the primary driver of renal impairment. Relief of congestion is a major objective of AHF treatment but therapy is still based on the administration of loop diuretics. The results of the recently performed controlled studies for the assessment of new treatments to overcome resistance to diuretic treatment to protect kidneys from untoward effects have been mostly neutral. Better treatment of congestion in heart failure remains a major problem

Endpoints and design of clinical trials in patients with decompensated cirrhosis: Position paper of the LiverHope Consortium

Management of decompensated cirrhosis is currently geared towards the treatment of complications once they occur. To date there is no established disease-modifying therapy aimed at halting progression of the disease and preventing the development of complications that can be used for patients with decompensated cirrhosis. The design of clinical trials to investigate new therapies for patients with decompensated cirrhosis is complex. The population of patients with decompensated cirrhosis is heterogeneous (i.e., different etiologies, comorbidities, severity of the disease), leading to the inclusion of diverse populations in clinical trials. In addition, primary endpoints selected for trials that include patients with decompensated cirrhosis are not homogeneous and at times may not be appropriate endpoints. This leads to difficulties in comparing of results obtained from different trials. Against this background, the LiverHope Consortium organized a meeting of experts with the goal of making recommendations for the design of clinical trials and defining appropriate endpoints both for trials aimed at modifying the natural history and preventing progression of decompensated cirrhosis and trials aimed at investigating new therapies for the management of each complication of cirrhosis

Can we improve the treatment of congestion in heart failure?

INTRODUCTION: Dyspnoea and peripheral oedema, caused by fluid redistribution to the lungs and/or by fluid overload, are the main causes of hospitalization in patients with heart failure and are associated with poor outcomes. Treatment of fluid overload should relieve symptoms and have a neutral or favorable effect on outcomes. AREAS COVERED: We first consider the results obtained with furosemide administration, which is still the mainstay of treatment of congestion in patients with heart failure. We then discuss important shortcomings of furosemide treatment, including the development of resistance and side effects (electrolyte abnormalities, neurohormonal activation, worsening renal function), as well as the relationship of furosemide - and its doses - with patient prognosis. Finally, the results obtained with potential alternatives to furosemide treatment, including different modalities of loop diuretic administration, combined diuretic therapy, dopamine, inotropic agents, ultrafiltration, natriuretic peptides, vasopressin and adenosine antagonists, are discussed. EXPERT OPINION: Relief of congestion is a major objective of heart failure treatment but therapy remains based on the administration of furosemide, an agent that is often not effective and is associated with poor outcomes. The results of the few controlled studies aimed at the assessment of new treatments to overcome resistance to furosemide and/or to protect the kidney from its untoward effects have been mostly neutral. Better treatment of congestion in heart failure remains a major unmet need

Endpoints and design of clinical trials in patients with decompensated cirrhosis: Position paper of the LiverHope Consortium

Clinical trials; Liver transplant; Quality of lifeEnsayos clínicos; Trasplante de hígado; Calidad de vidaAssaigs clínics; Trasplantament de fetge; Qualitat de vidaManagement of decompensated cirrhosis is currently geared towards the treatment of complications once they occur. To date there is no established disease-modifying therapy aimed at halting progression of the disease and preventing the development of complications in patients with decompensated cirrhosis. The design of clinical trials to investigate new therapies for patients with decompensated cirrhosis is complex. The population of patients with decompensated cirrhosis is heterogeneous (i.e., different etiologies, comorbidities and disease severity), leading to the inclusion of diverse populations in clinical trials. In addition, primary endpoints selected for trials that include patients with decompensated cirrhosis are not homogeneous and at times may not be appropriate. This leads to difficulties in comparing results obtained from different trials. Against this background, the LiverHope Consortium organized a meeting of experts, the goal of which was to develop recommendations for the design of clinical trials and to define appropriate endpoints, both for trials aimed at modifying the natural history and preventing progression of decompensated cirrhosis, as well as for trials aimed at managing the individual complications of cirrhosis