News in pathophysiology, definition and classification of hepatorenal syndrome: A step beyond the International Club of Ascites (ICA) consensus document

Abstract

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 In 2007, the International Club of Ascites (ICA) classified HRS into types 1 and 2 (HRS-1 and HRS-2). 5 HRS-1 is characterised 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 characterised by acute renal failure while HRS-2 is mainly characterised 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 hospitalised patients. In particular, the definitions and characterisation of acute kidney injury (AKI), acute kidney disease and chronic kidney disease have been introduced/refined. 6 Accordingly, a debate among hepatologists of the ICA led to a complete revision of the nomenclature and diagnosistic criteria for HRS-1, which was renamed HRS-AKI. 7 Additionally, over recent years, greater granularity has been gained regarding the pathogenesis of HRS; it is now increasingly recognised that it is not a purely ''functional" entity with haemodynamic 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 summarised 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 provide an update on the definition, classification, diagnosis, pathophysiology and treatment of HRS.

Paradigmenwechsel im Verständnis der akuten Nierenschädigung bei chronischer Leberinsuffizienz: Von der Pathophysiologie zur Definition von Krankheitsentitäten

“…Im Rahmen der bakteriellen Translokation kommt es außerdem zu einer vermehrten Expression von tubulären Toll-like-Rezeptoren in der Niere [37], die mit einem renalen Funktionsverlust durch Schädigung und Apoptose der tubulären Zellen einhergeht [65,66]. Der dafür verantwortliche pathophysiologische Mechanismus ist derzeit noch nicht bekannt.…”

“…Sowohl DAMPs als auch PAMPs aktivieren über verschiedene Signalkaskaden eine Verminderung des mitochondrialen Stoffwechsels der proximalen Tubuluszellen in der Niere, was wiederum zu einer verminderten Aufnahme von luminal lokalisiertem Natrium (Na) und Chlorid (Cl) führt. Eine dadurch bedingte Konzentrationssteigerung von NaCl im Bereich der Macula densa des juxtaglomerulären Apparats löst eine weitere intrarenale Aktivierung des RAAS und eine damit verbundene Abnahme der GFR aus [37].…”

“…Bei Vorliegen einer strukturellen Schädigung (z. B. Tubulusnekrose) kommt es aufgrund der kompromittierten Natriumreabsorption zu einem Anstieg der FE Na auf 2-3 % [37]. Hinz et al konnten in einer kleinen klinischen Studie zeigen, dass eine verminderte FE Na mit schlechterem klinischem Outcome und einer erhöhten Mortalität korrelierte [86].…”

Transjugular Intrahepatic Portosystemic Shunts in High-Risk Patients

“…HRS carries an extremely high mortality and has been thought to be mostly related to a decrease in renal perfusion in liver disease 47 but there is now evolving evidence that it may also be caused by systemic inflammatory changes, microvascular dysfunction, and direct tubular damage. 48 Brensing et al treated 31 nontransplantable patients with both type 1 and type 2 HRS and showed that renal function did improve after TIPS placement. 49 Guevara et al studied TIPS in patients with type 1 HRS, the most severe form of acute kidney injury in liver disease, and found a significant improvement in serum creatinine, blood urea nitrogen, GFR, and renal plasma flow.…”

Lack of evidence for a continuum between hepatorenal syndrome and acute tubular necrosis

“…Overall, current published data do not support the existence of a continuum between HRS and ATN as proposed in the review article. 1 While we cannot discount the possibility that a continuum does exist, confirmation of such a hypothesis would require performing 2 kidney biopsies, 1 at diagnosis of HRS-AKI and 1 during follow-up. However, current evidence does not provide a sufficiently solid background to warrant such a study.…”