News in Pathophysiology, Definition and Classification of Hepatorenal Syndrome: a step beyond the International Club of Ascites (ICA) Consensus document.

Renal dysfunction is a common, life-threatening complication occurring in patients with liver disease. Hepatorenal syndrome (HRS) has been defined as a purely "functional" type of renal failure that often occurs in patients with cirrhosis in the setting of marked abnormalities in arterial circulation, as well as overactivity of the endogenous vasoactive systems (4-5). HRS has been classified by the ICA in 2007 into two types, HRS-1 and HRS-2 (5). HRS-1 is characterized by a rapid deterioration of renal function that often occurs because of a precipitating event, while HRS-2 is a moderate and stable or slowly progressive renal dysfunction that often occurs without an obvious precipitant. Clinically, HRS-1 is characterized by acute renal failure while HRS-2 is mainly characterized by refractory ascites. Nevertheless, after these two entities were first described, new concepts, definitions, and diagnostic criteria have been developed by nephrologists for renal dysfunction in the general population and hospitalized patients. In particular, the definitions and characterization of Acute Kidney Injury (AKI), Acute Kidney Disease (AKD) and Chronic Kidney Disease (CKD) have been introduced/refined (6). Accordingly, a debate among hepatologists of the International Club of Ascites (ICA), led to a complete revision of the nomenclature and diagnosis of HRS-1, renaming it as HRS-AKI (7). Additionally, over recent years, greater granularity has also been gained regarding the pathogenesis of HRS and it is now increasingly recognized that it is not a purely "functional" entity with hemodynamic derangements but that systemic inflammation, oxidative stress and bile salt-related tubular damage may contribute significantly to its development. That is, HRS has an additional structural component that would not only make traditional diagnostic criteria less reliable but would explain the lack of response to pharmacological treatment with vasoconstrictors plus albumin that correlates with a progressive increase in inflammation. Because classification, nomenclature, diagnostic criteria and pathogenic theories have evolved over the years since the traditional classification of HRS-1 and HRS-2 was first described, it was considered that all these novel aspects be reviewed and summarized in a position paper. The aim of this position paper authored by two hepatologists (members of ICA) and two nephrologists involved in the study of renal dysfunction in cirrhosis, is to complete the re-classification of HRS initiated by the ICA in 2012 and to update the knowledge on the definition, classification, diagnosis, pathophysiology and treatment of HRS.