Approximately 5.5 million people in the United States have cirrhosis, a condition that is associated with very high morbidity, healthcare costs, and death. Kidney dysfunction is a major complication of cirrhosis, with the incidence increasing as the severity of cirrhosis progresses. The prevalence is highest in cirrhotic patients with ascites. The onset of kidney dysfunction in liver failure portends a poor prognosis. Patients with advanced liver disease and kidney failure are at increased risk for death while awaiting liver transplantation and are at a higher risk for complications and reduced survival after transplantation when compared with patients without kidney failure. Kidney dysfunction in the setting of liver failure is due mostly to conditions that lead to reduced kidney blood flow (pre-renal causes) or from problems within the kidney (intrinsic renal causes).

The pathophysiologic hallmark of cirrhosis complicated by renal dysfunction is portal hypertension. The development of portal hypertension is associated with splanchnic vasodilatation and reduction in effective blood volume, a hyperdynamic systemic circulation which is characterized by increased heart rate and cardiac output and also intense renal vasoconstriction due the activation of neurohumoral vasoconstrictor systems like the sympathetic nervous system (SNS), renin-angiotension-aldosterone-system (RAAS), and vasopressin, which is aimed at counteracting the hemodynamic effects of splanchnic vasodilatation. The foregoing establishes a tenuous background renal blood flow and makes the kidneys overly sensitive to further hemodynamic compromise occurring either spontaneously from progression of the underlying portal hypertension or as precipitated by sepsis or hypovolemia among others. These patients also have increased sensitivity to both endogenous and exogenous nephrotoxins, including intravenous contrast and nonsteroidal anti-inflammatory drugs.

The hepatorenal syndrome is one of the many potential causes of renal dysfunction in patients with chronic liver disease. It is relatively less common but is a potentially life-threatening complication. Identifying the specific cause of acute renal dysfunction is difficult in the clinical setting as the initial clinical findings and test results are usually nonspecific. The patients may also have intrinsic renal diseases that are commonly associated with chronic renal dysfunction, including diabetic nephropathy, IgA nephropathy, and glomerulonephritis from hepatitis B or hepatitis C infection.

The hepatorenal syndrome (HRS) is a severe and potentially life-threatening complication of advanced cirrhosis, alcoholic hepatitis, and fulminant acute liver failure. It is one of the many possible causes of renal dysfunction in subjects with chronic liver disease and occurs in approximately 11 % of cirrhotics with refractory ascites. HRS is characterized by significant reduction in renal blood flow due to an intense renal vasoconstriction on the background of marked systemic and splanchnic vasodilation. HRS is associated with very poor prognosis. Two subtypes (types 1 and 2) of HRS are described based on the clinical presentation and overall clinical course. There are no specific diagnostic tests and treatment options are limited. Although HRS presents clinically with a pre-renal hemodynamic picture, it is unresponsive to volume expansion. The diagnosis needs to be made as early as possible in order to initiate treatment.

The HRS represents the culmination of significant hemodynamic derangement that is initiated by portal hypertension. It is characterized by intense intrarenal vasoconstriction in association with overt splanchnic vasodilatation and a relatively insufficient cardiac output [6–10]. Increased pressure in the portal system due to worsening cirrhosis causes increased shear stress in the splanchnic vasculature. This, in addition to bacterial translocation from the bowel and the associated inflammatory response lead to the elaboration of endogenous vasodilators including nitric oxide, prostacyclins, glucagon, and carbon monoxide that contribute to splanchnic vasodilatation, pooling of blood, and reduced effective circulating blood volume [9–14]. The body compensates for the effective hypovolemia by the establishment of a hyperdynamic circulation, including increased heart rate and cardiac output. As portal hypertension progresses, the splanchnic vasodilatation and associated reduction in systemic vascular resistance worsen, and with time, the heart is unable to generate adequate output to maintain the arterial pressure. The cause of this so-called cirrhotic cardiomyopathy is unclear [13–18]. Relative adrenal insufficiency is common in patients with cirrhosis and worsens as the cirrhosis progresses. This subclinical adrenal insufficiency state could affect cardiac function and may play a role in the development of the cardiomyopathy and the circulatory dysfunction [19]. Also, with advancing cirrhosis, neurohumoral vasoconstrictor systems like the sympathetic nervous system (SNS), renin-angiotension-aldosterone-system (RAAS), and vasopressin are activated. These vasoconstrictor mechanisms while helping to achieve and maintain an adequate circulating blood volume, are associated with detrimental vasoconstriction in various organs including the kidney, brain, and liver. In the kidney, the consequences include intense vasoconstriction, reduction in blood flow, reduced GFR, and salt and water retention that causes ascites and the oligoanuric state typical of the hepatorenal syndrome [19–24].

The typical patient at risk of HRS is one with advanced, decompensated chronic liver disease. These patients usually have resistant ascites and other complications of cirrhosis, including spontaneous bacteria peritonitis (SBP), esophageal varices, and hepatic encephalopathy. HRS may also complicate fulminant liver failure and severe alcoholic hepatitis. The incidence of hepatorenal syndrome increases with advancing cirrhosis and is estimated to occur in approximately 20 % and 40 % of cirrhotics at 1 year and 5 years respectively. HRS occurs in 11 % of hospitalized patients with cirrhosis and ascites [6, 7]. Risk factors for development of HRS include orthostatic hypotension and hyponatremia. Common precipitating clinical events include SBP, gastrointestinal bleeding, and large-volume paracentesis.

For some time now, the definition of HRS has been based on the International Club of Ascites (ICA) 2007 guidelines [3]. HRS is a diagnosis of exclusion with no specific diagnostic test. In patients with advanced liver cirrhosis or fulminant acute liver failure, the diagnosis of HRS may be made if the following criteria are met:

Very recently, the ICA published new guidelines for the definition of AKI in patients with cirrhosis and also the diagnosis of HRS [45]. In the new guidelines, the definition of AKI is based on the ICA-AKI criteria which is a modification of the Kidney Disease Improving Global Outcomes (KDIGO) criteria. The major change in the diagnostic criteria of HRS noted in the 2015 guidelines compared to the 2007 criteria is that the threshold of serum creatinine ≥1.5 mg/dl has been abandoned.

The 2015 ICA definition of AKI and diagnostic criteria for HRS are as follows:

ICA-AKI criteria: Increase in serum creatinine ≥0.3 mg/dl (≥26.5 μmol/l) within 48 h; or a ≥50 % increase in serum creatinine from baseline which is known, or presumed to have occurred within the prior 7 days.

The new HRS diagnostic criteria are:

*Patients who fulfill these criteria may still have structural damage such as tubular damage. Urine biomarkers will become an important element in making a more accurate differential diagnosis between HRS and acute tubular necrosis.

Renal biopsy is not required to make the diagnosis and is usually avoided because of the significant risk of bleeding in this group of patients. HRS has long been designated as a “functional” condition because no major histological abnormalities were evident on biopsy. Also the return of renal function after liver transplantation and the ability of the affected kidney to function in a recipient without liver failure are consistent with this [25, 26]. Of note, most of the information used to identify HRS as a functional condition was based on data from several decades ago; at a time when HRS was not particularly well-defined as is true currently. It may therefore not be entirely true that HRS uniformly has normal histological findings as the biopsies might have been done in patients with renal dysfunction but who did not have HRS as per current diagnostic criteria. Also, per current knowledge, the rate of recovery of renal function following liver transplantation is rather variable in patients with a presumed diagnosis of HRS [27, 28]. Possible explanations for this are (1) inability to routinely identify when HRS progresses to ATN. (2) HRS is not as “functional” as we think [28, 29]. In a review of autopsy series, Kanel et al. noted reflux of proximal convoluted tubular epithelium into Bowman’s space in 71.4 % of cases with the hepatorenal syndrome, while this lesion was only present in 0–27.3 % of other autopsy categories [30]. They suggested that since this lesion had been previously described with experimental renal ischemic change and terminal hypotension, it is possible that it is caused in part by the decreased or altered renal blood flow known to be associated with the hepatorenal syndrome.

Clinically, two distinct subtypes of HRS are encountered based on the rate of decline in renal function and the overall prognosis. Type 1 HRS is associated with rapidly progressing renal failure with a natural course that lead to death at a median of 2 weeks. It usually develops in the presence of a precipitating event such as SBP, gastrointestinal bleeding, and large-volume paracentesis and is defined as at least a twofold increase in serum creatinine to a level greater than 2.5 mg/dl (221 μmol/l) in less than 2 weeks. In many subjects, the occurrence of the HRS is associated with deterioration of function in other organs, including the liver, heart, and brain.