Evaluation of the Natural History of Combined Hepatorenal Syndrome in Patients With Signs of Chronic Renal Disease

Liver cirrhosis is a major cause of global health burden, accounting for 31 million disability adjusted life years and 1 million deaths worldwide in 2010. In the natural history of liver disease, there are two clearly distinct clinical phases. During the compensated phase, patients remain asymptomatic or oligosymptomatic. Although these patients may exhibit signs of cirrhosis, such as varices, spider naevi, or abnormalities in blood tests, they do not experience overt symptoms of the disease. The median survival rate for these patients is approximately 15 years 2. During the course of liver cirrhosis, patients may develop ascites, variceal bleeding or hepatic encephalopathy, which marks the transition to the decompensated phase of the disease. Thus, decompensation is associated with a significant reduction in survival, with a median of approximately 2 years, and ascites is the most frequent decompensating event. Clinically significant portal hypertension, as determined by the hepatic venous pressure gradient, is a main driver for the development of decompensation. In the decompensated phase, one can differentiate between patients who have a sole event as a decompensating event (typically ascites or variceal bleeding) and those who develop more than one decompensating event (further decompensation). These patients are at risk of dying due to their liver disease.

Hepatorenal syndrome refers to a "functional" renal dysfunction that occurs in patients with cirrhosis and ascites due to reduced renal perfusion secondary to hemodynamic alterations in the arterial circulation and activation of endogenous vasoactive system. Traditionally, one distinguished between hepatorenal syndrome type 1, which was a rapidly progressive renal failure (increase of serum creatinine (SCr) to greater than 2.5 mg/dL within two weeks) or hepatorenal syndrome type 2, which has a less rapid course, with a progressive increase of SCr to greater than 1.5 mg/dL. Typically, hepatorenal syndrome type 1 takes place in the context of an acute event, whereas hepatorenal syndrome type 2 takes place in end-stage refractory ascites.

In 2015, the International Club of Ascites (ICA) adopted a new classification of renal dysfunction in cirrhosis.

The decision was motivated by increasing evidence suggesting that serum creatinine could underestimate the real renal function in cirrhosis due to muscle wasting, increased tubular secretion of creatinine, increased volume of distribution potentially diluting creatinine and interference with bilirubin. Furthermore, the use of thresholds does not allow the flexibility that is required to confront a dynamic situation like hepatorenal syndrome type 1. To address these concerns, the ICA proposed to adopt criteria from The Kidney Disease: Improving Global Out-comes (KDIGO) guidelines, which define AKI as any of the following: 1) increase in SCr by ≥ 0.3 mg/dl (≥ 26.5 µmol/L) within 48 h; or 2) increase in SCr to ≥ 1.5x baseline, which is known or presumed to have occurred within the prior 7 days; or 3) urine volume < 0.5 ml/kg/h for 6 h. In the specific context of cirrhosis, the ICA proposed a modification by using only the first three KDIGO criteria, given the fact that urine output frequently does not properly reflect the renal function as patients with cirrhosis often are oliguric due to avid sodium retention or have a falsely high urine output due to the use of diuretics. Furthermore, ICA proposed that if a baseline value within the previous 7 days is unavailable, a SCr within the last 3 months before admission can be used.

According to the relative increase in creatinine, various stages of AKI can be identified. Noticeably, AKI can occur even when renal function remains within the given normal range. Within AKI Stage I, a differentiation can be made between individuals who achieve a peak over SCr ≥ 1.5 mg/dL (Stage Ib) and those who achieve a peak below this threshold (Stage Ia), the latter of which may have a similar survival as those without AKI and in whom the AKI is more frequently reversible.