Hepatorenal Syndrome

© Springer International Publishing Switzerland 2017
Kia Saeian and Reza Shaker (eds.)Liver Disordershttps://doi.org/10.1007/978-3-319-30103-7_32

32. Hepatorenal Syndrome

Michael M. Yeboah 

Division of Nephrology, Medical College of Wisconsin, Milwaukee, WI, USA



Michael M. Yeboah

Hepatorenal syndromeKidney failureCirrhosisLiver transplantationDialysis

Patient Questions and Answers

  1. 1.

    What is hepatorenal syndrome?

    The hepatorenal syndrome is a potentially life-threatening but reversible kidney disease which usually develops in patients with advanced liver disease. It occurs when the worsening liver disease leads to constriction of the blood vessels in the kidney and causes diversion of blood supply away from the kidneys. Generally, correction of the liver problem leads to resolution of the kidney problem. The condition therefore emphasizes the close relationship between the liver and the kidney in the body.


  2. 2.

    What are the symptoms of hepatorenal syndrome?

    There are 2 types of hepatorenal syndrome. The first one is called type 1 hepatorenal syndrome. Type 1 hepatorenal syndrome tends to progress very rapidly and may lead to death within 2–3 weeks if no treatment is given. Patients with this type of hepatorenal syndrome have nonspecific symptoms including general malaise and will usually notice reduction in their urine volume. These patients are often very sick overall and will need to be admitted to the hospital if they are not already hospitalized. The diagnosis is then made by the doctor after full assessment, including the results of urine and blood tests. The second type, called type 2 hepatorenal syndrome is relatively less aggressive and progresses rather slowly over weeks to several months. Type 2 hepatorenal syndrome usually does not cause specific symptoms apart from some reduction in urine volume and increasing swelling of the belly. Patients with type 2 hepatorenal syndrome are usually well enough to stay at home and are followed-up in the clinic from time to time.


  3. 3.

    How is hepatorenal syndrome treated?

    Patients with type 1 hepatorenal syndrome are usually very sick and need to be admitted to hospital immediately for treatment. The most effective and ideal treatment option is liver transplantation. This helps to reverse the liver failure and leads to resolution of the hepatorenal syndrome, and more importantly prevents death in most people with hepatorenal syndrome.

    In situations where the person cannot have liver transplantation for whatever reason, maximum medical management will be given that includes medicines that help the body to redirect more blood flow to the kidneys. Also some of these patients will undergo some form of dialysis where a machine helps in doing the work of the kidney by removing toxins from the blood, at least temporarily. This is especially the case when the patient is awaiting liver transplantation. The dialysis on its own will neither cure the liver nor the kidney problem.

    Patients with type 2 hepatorenal syndrome may remain overall well for several months. In some of them, however, the kidney condition worsens over time and may switch to become type 1 hepatorenal syndrome and will need to be treated as above. Treatment options for type 2 hepatorenal syndrome include attempts at improving the liver function by treating underlying viral hepatitis, stopping alcohol use, or addressing any other reversible cause of the liver problem. If improvement in liver function cannot be achieved through such means, liver transplantation will be necessary in suitable patients. Some patients who have had hepatorenal syndrome for several weeks will ultimately develop chronic kidney failure and will need long-term dialysis treatment or combined liver and kidney transplantation.


  4. 4.

    Does one need to take specific medications daily?

    Patients with the type 1 hepatorenal syndrome are usually very sick and are admitted to the hospital for treatment. For those who have resolution of the hepatorenal syndrome (either through medical treatment or after liver transplantation), no specific ongoing medications will be necessary; however, the patient may be on medications for other reasons. For instance those who undergo liver transplantation will need to take regular medications to prevent rejection of the liver. Patients with type 2 hepatorenal syndrome are usually at home and are followed in the outpatient clinic periodically. Those with very low blood pressure may be given a particular medicine to help improve their blood pressure but most of them will not need any specific medications.


  5. 5.

    What is the prognosis for hepatorenal syndrome?

    Unfortunately, the prognosis for persons with the hepatorenal syndrome is generally poor. Most of those who develop the type 1 hepatorenal syndrome die within a couple weeks unless they respond to medical treatment their liver condition resolves in a timely manner or if they receive a liver transplantation urgently. Patients with the type 2 hepatorenal syndrome tend to be relatively well for several weeks to months but will ultimately need liver transplantation to stay alive unless the liver failure resolves one way or the other. Some of these patients will also need kidney transplantation or will require long-term dialysis because the hepatorenal syndrome would have progressed to chronic kidney failure over time. Persons with the hepatorenal syndrome have to abstain from alcohol ingestion and avoid any medications that could affect the function of the liver or kidney.



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.

Introduction: Hepatorenal Syndrome

The occurrence of kidney failure in the setting of advanced liver failure has been known for over 150 years [1]. The modern description of the hepatorenal syndrome which laid down the foundation for our present understanding of its pathophysiology is attributed to Sherlock and Hecker [2]. Over the years, most of their original findings have been confirmed, including the underlying hemodynamic disturbances. Considerable effort has also gone into clearly defining the hepatorenal syndrome in order to distinguish patients with the hepatorenal syndrome from other patients who have renal dysfunction from causes other than the hepatorenal syndrome. This is important as the treatment and clinical course is very different. To this end the diagnostic criteria for the hepatorenal syndrome has undergone some modifications over this period [3]. Current medical treatment of the hepatorenal syndrome is based on an attempt to correct the systemic and splanchnic vasodilatation and to improve the circulating blood volume. However, despite the advances made over the last 2–3 decades, only about 40 % of patients respond to the available treatments which generally speaking are only seen as bridge therapy pending liver transplantation [4, 5].


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 [610]. 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 [914]. 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 [1318]. 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 [1924].


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.

Current Diagnostic Criteria and Clinical Subtypes

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:

  • Serum creatinine >1.5 mg/dl

  • No improvement of serum creatinine (decrease to a level of ≤1.5 mg/dl) after at least 2 days with diuretic withdrawal and volume expansion with albumin

  • No signs of shock

  • No recent use of nephrotoxic drugs

  • Absence of parenchymal kidney disease as indicated by proteinuria >500 mg/day, microhematuria (>50 red blood cells per high power field)

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:

  • Diagnosis of cirrhosis and ascites

  • Diagnosis of AKI according to ICA-AKI criteria

  • No response after 2 consecutive days of diuretic withdrawal and plasma volume expansion with albumin 1 g/kg body weight

  • Absence of shock

  • No current or recent use of nephrotoxic drugs (NSAIDs, aminoglycosides, iodinated contrast media etc.)

  • No macroscopic signs of structural kidney injury*, defined as:

    • absence of proteinuria (>500 mg/day)

    • absence of microhaematuria (>50 RBCs per high power field)

    • normal findings on renal ultrasonography

*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.

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Nov 20, 2017 | Posted by in GASTROENTEROLOGY | Comments Off on Hepatorenal Syndrome

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