A new look at renal dysfunction in the cirrhotic patient

Hepatorenal syndrome (HRS) is a pre-renal azotemia-like acute renal failure occurring in patients with end-stage cirrhosis. HRS results from arteriolar vasodilatation, arteriolar underfilling, and intense renal vasoconstriction. By definition, it is not responsive to volume expansion, and the prognosis is especially poor even with the use of terlipressin or albumin dialysis or both. It may be difficult, on the basis of the current criteria, to clearly differentiate HRS from other causes of acute renal failure in cirrhosis. In addition, patients with HRS frequently have underlying chronic kidney changes that may not be reversible after transplantation. In the previous issue of Critical Care, a group of experts proposed a new classification of acute, acute-on-chronic, or chronic renal impairment in cirrhosis on the basis of the RIFLE (Risk, Injury, Failure, Loss, and End-stage kidney disease) criteria. The group proposed the term 'hepatorenal disorder' to define patients with advanced cirrhosis and kidney dysfunction at an earlier stage, regardless of the mechanisms. As stated by the authors, more data are needed to clearly identify, by non-invasive means, those with a potential for improvement with liver transplantation and those who can undergo a combined liver and kidney transplantation.

arteriolar vasodilatation is no longer compensated by an increase in cardiac output, resulting in a state of arterial underfi lling [2,3]. Arterial underfi lling, in turn, results in the activation of vasoconstrictor systems, which causes intense intrarenal vasoconstriction and a marked decrease in glomerular fi ltration rate (GFR) and eventually leads to hepatorenal syndrome (HRS). Th e increase in creatinine can be abrupt (type I HRS) or follow a more progressive course (type II HRS) [4].
A fi rst set of criteria had been proposed in the mid-'90s to better diff erentiate HRS from other causes of acute renal failure in cirrhosis, the absence of improvement with volume expansion being central in the defi nition of HRS [5]. However, these criteria proved to be too restrictive. For instance, ongoing bacterial infection was considered an exclusion criterion although experience shows that HRS frequently is triggered by infections [3]. Th e diagnostic criteria were revisited in 2007 in order to be less restrictive [6]. However, these criteria still have some limitations. Firstly, it has been shown that a substantial proportion of patients who are undergoing transjugular renal biopsy and who have a clinical diagnosis of HRS do have intrinsic kidney changes, especially tubulointerstitial injury resulting from either comorbidities or chronic ischemia [7]. Secondly, the limit of a creatinine level of more than 1.5 mg/dL to defi ne HRS may be inappropriate. Indeed, owing to muscle wasting, some cirrhotic patients with a serum creatinine level of below 1 mg/dL may already have a marked decrease in true GFR [8,9].
In the previous issue of Critical Care, a group of experts, including not only hepatologists but also nephrologists and intensivists, reported the results of a workshop aimed at reviewing current knowledge in the fi eld of HRS and proposing new classifi cations, based on the widely used RIFLE (Risk, Injury, Failure, Loss, and Endstage kidney disease) criteria, of all forms of renal impairment in cirrhosis [1,10]. Th e group proposed the term 'hepatorenal disorder' to defi ne any kind of kidney disease that is functional or structural in nature in patients with cirrhosis [1]. Accordingly, HRS belongs to the 'hepatorenal disorders' . Acute kidney injury is

Abstract
Hepatorenal syndrome (HRS) is a pre-renal azotemialike acute renal failure occurring in patients with end-stage cirrhosis. HRS results from arteriolar vasodilatation, arteriolar underfi lling, and intense renal vasoconstriction. By defi nition, it is not responsive to volume expansion, and the prognosis is especially poor even with the use of terlipressin or albumin dialysis or both. It may be diffi cult, on the basis of the current criteria, to clearly diff erentiate HRS from other causes of acute renal failure in cirrhosis. In addition, patients with HRS frequently have underlying chronic kidney changes that may not be reversible after transplantation. In the previous issue of Critical Care, a group of experts proposed a new classifi cation of acute, acute-on-chronic, or chronic renal impairment in cirrhosis on the basis of the RIFLE (Risk, Injury, Failure, Loss, and End-stage kidney disease) criteria. The group proposed the term 'hepatorenal disorder' to defi ne patients with advanced cirrhosis and kidney dysfunction at an earlier stage, regardless of the mechanisms. As stated by the authors, more data are needed to clearly identify, by non-invasive means, those with a potential for improvement with liver transplantation and those who can undergo a combined liver and kidney transplantation.
con sidered at an earlier stage in patients with a creatinine increase of at least 0.3 mg/dL within 48 hours and/or a 1.5 or more increase in creatinine from baseline. Th is new classifi cation may help initiate specifi c therapy at an earlier stage and increase the chance for recovery. Th is classifi cation is also more appropriate to identify any kind of kidney injury within a wide spectrum of causes of acute, chronic, and acute-on-chronic kidney diseases in cirrhosis. However, even if the patients are identifi ed at an earlier stage, the revised classifi cation does not clearly diff erentiate those who may benefi t from medical therapies of HRS (that is, terlipressin or noradrenaline) [11] from those who may not. In addition, this classifi cation does not help address the important issue of reversibility after liver transplantation.
In most Western countries, the Model for End-Stage Liver Disease (MELD) score determines priority for allocation in liver transplantation. Th e higher the MELD score, the faster the access to transplantation. Since creatinine is one of the three components of the MELD score (along with bilirubin and international normalized ratio) [12], the proportion of patients undergoing liver transplantation with renal insuffi ciency has signifi cantly increased in the MELD era [13]. Th e rate of posttransplant chronic renal failure has also increased with a 5-year cumulative incidence that may exceed 20% [14]. Decrease in post-transplant GFR is an independent predic tor of mortality [14]. Finally, the number of combined liver and kidney transplantations has also increased with declining outcomes, raising the issue of overuse and misuse in combined transplantation [15].
Overall, circulatory changes in cirrhosis necessarily have a deleterious impact on the course of any chronic kidney disease, regardless of the cause and mechanisms. A challenging issue is to determine more accurately the potential for improvement with liver transplantation alone, by reversing hyperkinetic state, in order to better identify those who need a combined liver and kidney transplantation and those who do not. In theory, HRS is a functional disorder that is fully reversible with liver trans plantation. However, as discussed above, a number of patients with HRS have intrinsic kidney changes that may not improve after transplantation. Th erefore, another issue is to better identify the subgroup of HRS patients who are likely to rapidly develop end-stage renal failure after transplantation. Th ese patients may justify combined transplantation. As stated by Nadim and colleagues [1], more studies are needed to clarify these points. Unfortunately, in patients who have end-stage cirrhosis complicated by HRS and who are not candidates for transplantation, therapies such as terlipressin or albumin dialysis provide only a modest survival benefi t [11]. In the majority, HRS remains a terminal event in advanced cirrhosis.