Hepatorenal Syndrome (HRS)

I. What every physician needs to know.

Hepatorenal syndrome (HRS) is a potentially reversible form of renal failure seen in patients with advance liver disease and occasionally in acute fulminant liver failure. HRS is a diagnosis of exclusion and it is diagnosed when all other causes of renal failure have been ruled out. It is estimated that about 40% of patients with liver cirrhosis and ascites will develop HRS during the course of disease. Approximately 20% of patients with decompensated liver cirrhosis who are hospitalized will develop acute kidney injury. Majority of these patients will have pre-renal cause of renal dysfunction and will response to volume expansion. HRS accounts for minority of patients in this group who develop renal dysfunction.

Renal failure in HRS occurs because of vasoconstriction of renal circulation accompanied by uncontrolled severe vasodilatation of peripheral circulation. That results in reduced peripheral circulation resistance and hypotension.

II. Diagnostic Confirmation: Are you sure your patient has HRS?

HRS is a form of renal insufficiency seen in patients with severe acute or chronic liver disease and portal hypertension. By definition, there must be no other identifiable cause of renal failure, and the renal insufficiency does not improve with plasma volume expansion using albumin.

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Traditionally HRS has been classified in two distinct classes, Type 1 HRS and Type 2 HRS. Type I HRS occurs rapidly with a doubling of serum creatinine to greater than 2.5 mg/dL in under two weeks. Type II HRS is more slowly progressive with creatinine values typically ranging from 1.5 to 2.5 mg/dL. These criteria have been found to be too strict to define HRS, leading to under diagnosis of renal failure in cirrhosis.

Acute kidney injury defined as increase in serum creatinine by 0.3 mg/dl in <48hours or an increase in serum creatinine >50% from base line reading within 3 months has been proposed to define renal dysfunction in patients with liver cirrhosis and type 1 HRS would be re-named as HRS-AKI. Stage 1 AKI is defined by 0.3 mg /dl serum creatinine or a 50% increase, Stage 2 as twofold increase in serum creatinine and stage 3 as threefold increase in serum creatinine from baseline.

A. History Part I: Pattern Recognition:

Patients with HRS will show signs of underlying liver disease including hepatosplenomegaly, ascites, jaundice, palmar erythema, spider angiomata, and/or muscle wasting. Once HRS develops, the patient will often exhibit arterial hypotension and reduced urine output. Jaundice and hepatic encephalopathy frequently coincide with a diagnosis of HRS.

B. History Part 2: Prevalence:

Patients with acute or chronic liver disease and portal hypertension are at risk of developing HRS. Ten percent of hospitalized patients with cirrhosis and ascites may have HRS. Those patients with underlying alcoholic liver disease are at a particularly high risk. A precipitating factor for the development of hepatorenal syndrome can be identified in approximately half of patients. These underlying factors consist of infection, including spontaneous bacterial peritonitis, gastrointestinal bleeding, and volume depletion from excessive paracentesis or the overuse of diuretics.

C. History Part 3: Competing diagnoses that can mimic HRS.

HRS can only be diagnosed after the exclusion of other forms of renal failure that can occur in patients with liver disease including plasma volume depletion, drug-induced renal failure, sepsis and other forms of acute tubular necrosis, and intrinsic renal disease arising from underlying medical conditions such as hypertension or diabetes. Obstructive or post-renal failure, glomerulonephritis, and acute interstitial nephritis should also be considered in the differential.

D. Physical Examination Findings.

Arterial hypotension is common in patients with HRS, and many of these patients will also exhibit a reflexive tachycardia in the setting of profound hypotension. Patients appear ill and frequently show signs of underlying liver disease including hepatosplenomegaly, ascites, jaundice, palmar erythema, spider angiomata, and/or muscle wasting. Jaundice and hepatic encephalopathy frequently coincide with a diagnosis of HRS. In the setting of type II HRS, chronic diuretic-resistant ascites is common.

E. What diagnostic tests should be performed?

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

A complete metabolic panel should be performed, paying particular attention to changes in serum creatinine and potassium levels. In patient with cirrhosis, an increase in serum creatinine level greater than 0.3 mg/dL or 50% from the baseline reflects a significant decline in GFR. This low threshold for diagnosing renal failure is due to the reduced muscle mass and decreased creatinine production in this population at baseline.

Monitoring for developing hyperkalemia is prudent in the setting of renal insufficiency and is particularly common in those patients receiving aldosterone antagonists such as spironolactone.

A urinalysis should be performed to rule out the presence of urinary casts and/or hematuria which may indicate another underlying cause of the renal failure. Urine electrolyte evaluation and calculation of the renal indices may be helpful in patients who have not recently received diuretic therapy. Typically, the FeNa will be less than 1% in HRS.

However, it should be noted that patients with advanced cirrhosis might be on high doses of diuretics due to ascites and edema, which can effect sodium excretion. Also in advance cirrhosis, patients will also retain sodium due to hyperactive renin-agiotensin-aldosteron system (RAAS) and the FeNa may be lower than expected, even in the setting of acute tubular necrosis. Therefore, the FeNa is not diagnostic for HRS. FeUrea may be used as alternative.

The complete blood count is useful to evaluate for the presence of underlying precipitating factors in the development of HRS. For example, worsening anemia may reflect ongoing gastrointestinal bleeding while an elevated white blood cell count may indicate bacterial infection.

For all patients with ascites, a diagnostic paracentesis should be performed to rule out spontaneous bacterial peritonitis, as this is frequently a precipitating factor in the development of type I HRS. In general, therapeutic paracentesis and aggressive diuresis should be avoided as these are risk factors for the development of type I HRS.

The exception is in patients with elevated serum creatinine and tense ascites. In this sub-group of patients, careful paracentesis to reduce intra-abdominal pressure performed with intravascular fluid replacement with intravenous albumin may improve renal indices.

Plasma aldosterone levels and plasma renin activity are elevated in the setting of hepatorenal syndrome, but, due to high cost and limited clinical availability of these assays, these tests are not routinely recommended.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Renal ultrasound is useful to rule out other causes of renal insufficiency, including post-renal obstruction or intrinsic kidney disease. According to the diagnostic criteria, standard renal ultrasonography is normal in HRS. Estimations of renal vasoconstriction obtained by renal Doppler may be useful in determining those patients most at risk for developing HRS even before serum creatinine rises; however, this has little clinical utility once the diagnosis is established.

Several Biomarkers have emerged as potentially useful in determining the cause of renal failure. Panel of renal tubular damage markers including urinary neutrophil gelatinase-associated lipocalin (NGAL) levels, IL 18, kidney injury molecule-1 and liver type fatty acid binding protein will be increased indicating diagnosis of tubular damage and presence of acute tubular necrosis. Despite their apparent advantages, biomarkers for renal tubular damage are still investigational and a research tool and their validity in patients with cirrhosis has not been tested in large clinical trials.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

III. Default Management.

As HRS is likely a functional renal disorder resulting due to generalized vasodilation and decreased total peripheral resistance coupled by localized renal vessels vasoconstriction, volume expansion of intravascular volume with intravenous albumin should be initiated in all patients upon the diagnosis of HRS. All patients should be monitored closely, preferably in intensive care unit. Nephrotoxic drugs including diuretics and NSAIDS should be held as they can potentiate renal vasoconstriction and worsen kidney injury. Patients with severe liver dysfunction should receive a reduced sodium and fluid-restricted diet. In addition, low potassium and low phosphorus diets should be implemented as renal failure progresses.

A. Immediate management.

Volume expansion with intravenous albumin should be used to treat the arterial hypotension associated with HRS. This will increase preload and subsequently improve cardiac output. Using 20% human albumin solution, a general dosing regimen begins with 1 gm/kg body weight over 24 hours on day 1, followed by 20-40 gm IV daily with a goal central venous pressure (CVP) of 10-15 cm H20.

In combination with intravenous albumin, treatment with systemic vasoconstrictors is the mainstay of medical therapy. Therapy with intravenous vasoconstrictors is aimed at reversing the physiology of HRS and has been shown to improve renal function and reduce mortality.

Vasopressin analogues have shown the most promise. Terlipressin, the most widely studied vasopressin analogue in HRS, is currently not FDA approved. Terlipressin 0.5 2.0 mg intravenously every 4-6 hours has shown higher reversal rate of HRS as compared to placebo. As terlipressin is yet not available in US, other systemic vasoconstrictors such as midodrine plus octreotide or norepinephrine may be used. Patients in intensive care units should be treated with norepinephrine along with albumin and patients on general medical floor should be treated with octreotide 100-200 microgram subcutaneously three times a day plus midodrine 7.5-12.5 mg orally three times a day along with albumin.

Therapy with vasoactive medications should begin as soon as possible. Data suggests that beginning therapy early when serum creatinine is less than 5 mg/dL leads to improved outcomes.

HRS in absence of pre-renal azotemia or acute tubular necrosis is an indication for liver transplantation due to associated high mortality despite specific treatment. Vasoconstrictors including terlipressin, midodrine, norepinephrine plus albumin, TIPS and extracorporeal albumin dialysis can be used to “bridge” a patient for transplant.

B. Physical Examination Tips to Guide Management.

Frequent monitoring of vital signs, in particular heart rate and blood pressure, is required in patients with HRS. In those patients receiving vasoconstrictor therapy, telemetry monitoring is appropriate to monitor for the development of arrhythmias or ischemic changes. The clinician should pay close attention to the circulatory examination, noting any signs of intravascular volume overload including elevated jugular venous pressure or the development of pulmonary edema that may accompany albumin therapy.

In those patients receiving vasoconstrictor therapy, close monitoring of the extremities and peripheral pulses and monitoring for arrhythmias is warranted. In addition, a careful abdominal examination may convey the development of tense ascites which may develop in association with volume expansion. If this develops with an associated increased intra-abdominal pressure, therapeutic paracentesis may be indicated.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Frequent monitoring of serum creatinine and serum potassium is indicated in HRS. For most patients, these values may be assessed once or twice daily; however, more frequent monitoring is indicated if the patient’s condition deteriorates. If intestinal or peripheral ischemia is suspected during the course of vasoconstrictor treatment, serum lactate levels and arterial blood gas may be considered. Reductions in plasma aldosterone levels and plasma renin activity may be seen as the disease improves; however, significant cost and limited local availability of these tests limit their clinical utility.

D. Long-term management.

There is limited data on the prolonged use of vasoconstrictors in HRS; however, small studies suggest that these medications may be used long-term as a bridge to liver transplantation.

Although traditional hemodialysis does not reverse HRS it may be initiated as a bridge to liver transplantation and has been shown to improve survival in the short-term. Indications for hemodialysis include uncontrolled volume overload, hyperkalemia not responsive to medical therapy, symptomatic uremia, and acidosis.

Early referral to a liver transplant team is imperative, as liver transplant gives the best possibility of recovery. Complete resolution of HRS is expected in 60% of patients who undergo orthotopic liver transplantation, and less than a quarter of patients undergoing liver transplantation require long-term hemodialysis. Recent studies have shown similar rates of renal function recovery in patients with HRS undergoing liver transplants as those patients without HRS undergoing liver transplants. Concomitant kidney transplantation is not recommended as there is no survival benefit.

Transjugular intrahepatic portosystemic shunt (TIPS) may be used in patients with HRS who are not eligible for transplantation. Three and twelve month survival rates approach 81% and 48%, respectively.

E. Common Pitfalls and Side-Effects of Management

Patients treated with intravenous albumin are at risk for circulatory overload and congestive heart failure, especially in the setting of reduced cardiac output seen in advanced cirrhosis. Monitoring in an intermediate or intensive care setting may be warranted. Diarrhea or abdominal cramping has also been reported in association with the use of terlipressin.

Patients treated with vasopressin analogues or other vasoconstrictors should be closely monitored for cardiovascular complications. Although patients with known vascular disease were excluded from most of the clinical trials using terlipressin, approximately 15% of patients treated with this drug experienced an ischemic event.

Reported side effects of this therapy include myocardial infarction, intestinal ischemia, hypertension, bronchoconstriction, and cardiac arrhythmias.

IV. Management with Co-Morbidities

A. Renal Insufficiency.

No change in standard management.

B. Liver Insufficiency.

No change in standard management.

C. Systolic and Diastolic Heart Failure

Close monitoring for circulatory overload should be undertaken when using intravenous albumin in the setting of concomitant heart failure. In addition, the decreased cardiac output seen in patients with HRS may predispose to symptomatic congestive heart failure even in patients without known systolic or diastolic dysfunction in the setting of volume expansion and increased preload.

The use of vasoconstrictors in treatment of HRS may also lead to worsening of heart failure by increasing peripheral vascular resistance and increasing afterload. The pro-arrhythmic side effects of vasoconstrictors may be exacerbated in patients with dilated cardiomyopathy who are at risk for arrhythmia at baseline. These medications should only be used in a closely monitored setting and dosing should be titrated slowly.

Uncontrolled heart failure is a relative contraindication to liver transplantation.

D. Coronary Artery Disease or Peripheral Vascular Disease

Precaution should be taken when using vasoconstrictors in patients with underlying coronary artery disease and atherosclerosis. Myocardial infarction, intestinal ischemia, and limb ischemia have been reported with the use of terlipressin. Terlipressin and other vasoconstrictors should be titrated slowly and the minimal effective dose should be used. Discontinue use for reports of chest pain, severe abdominal pain, or decreases in peripheral perfusion.

Severe coronary artery disease is generally a contraindication for liver transplantation.

E. Diabetes or other Endocrine issues

The use of octreotide may cause hypoglycemia, or, more commonly, hyperglycemia, due to the suppression of glucagon and insulin, respectively. Frequent monitoring of blood glucose and coverage with sliding scale insulin is suggested.

F. Malignancy

Patients with extrahepatic malignancies other than some skin cancers are not eligible for liver transplantation. Patients with early stage hepatocellular carcinoma or cholangiocarcinoma confined to the liver and gallbladder may be amenable to transplantation depending on the transplant center’s criteria.

G. Immunosuppression (HIV, chronic steroids, etc).

No change in standard management.

H. Primary Lung Disease (COPD, Asthma, ILD)

Caution should be used when using terlipressin in patients with underlying COPD or asthma as this drug may induce bronchoconstriction and exacerbate underlying lung disease.

I. Gastrointestinal or Nutrition Issues

Side effects of terlipressin include diarrhea and abdominal cramping.

J. Hematologic or Coagulation Issues

No change in standard management.

K. Dementia or Psychiatric Illness/Treatment

Uncontrolled psychiatric disease and active substance abuse are generally contraindicated for liver transplantation. Otherwise, there is no change in standard management.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

If circulatory overload develops, hold intravenous albumin and administer high dose furosemide. For complaints of chest pain or abdominal pain, hold intravenous vasoconstrictor therapy until ischemic side effects have been ruled out.

If the patient is a transplant candidate and requires transfusion, administer leukoreduced or washed blood products to minimize the formation of antibodies. CMV-negative blood products should also be used if the patient’s CMV status is undetermined.

B. Anticipated Length of Stay.

Many patients with HRS have a protracted hospital course that often requires care in the intensive care unit. Of those who are discharged, patients with HRS who are maintained on chronic hemodialysis have an average of 2.2 admissions per month, spending an average of 11.2 days per month hospitalized.

C. When is the Patient Ready for Discharge.

The patient may be eligible for discharge if the serum creatinine is stabilized at a level less than 1.5 mg/dL and if the patient can maintain a sufficient blood pressure without requiring vasoactive medications. Certain patients may be eligible for treatment at home with oral midodrine and subcutaneous octreotide once the creatinine level is stabilized. Discharge planning should occur in consultation with the liver transplant service to facilitate appropriate outpatient follow-up.

D. Arranging for Clinic Follow-up

1. When should clinic follow up be arranged and with whom.

The patient should have close follow-up with a hepatologist and liver transplant team. Although there is no standard recommendation in regards to follow-up, it would be prudent for the patient to be seen within one week of discharge for follow-up and repeat lab work including measurement of serum creatinine and potassium levels.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

Consult with the liver transplant team to determine if any pre-transplant testing is required prior to the patient being eligible for listing for organ transplant. These criteria vary among institutions.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

Regular monitoring of serum creatinine and electrolytes should be performed in patients with HRS. A complete metabolic panel should be obtained prior to the first outpatient clinic visit.

E. Placement Considerations.

Patients with HRS, particularly those who are not eligible for liver transplantation, should receive education about hospice given the grim prognosis of the disease process. Of those who survive, due to the prolonged hospital course and the chronic nature of the underlying disease, many will require placement for rehabilitation after discharge. Physical therapy and occupational therapy evaluations should be requested as the patient nears discharge to determine the level of care required.

F. Prognosis and Patient Counseling.

Prognosis is poor once HRS develops. Patients with type I disease have worse outcomes than those patients diagnosed with type II HRS with a median survival of one month and 6.7 months, respectively. Additionally, a higher Model for End-stage Liver Disease (MELD) score predicts a worse prognosis in patients with HRS. Those patients with underlying alcoholic hepatitis have a two-fold increased risk of death from type I HRS.

In a Cochrane review of terlipressin in the treatment of HRS, mortality was reduced by 34% when this therapy was utilized. One year survival for patients with HRS who receive orthotopic liver transplantation is approximately 86%.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.


B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

The use of compression device is appropriate for inpatient prophylaxis against deep venous thrombosis. Additionally, stress ulcer prophylaxis with a H2 blocker or proton pump inhibitor is indicated if the patient has an underlying coagulopathy.

The development of bacterial infections increases the risk of developing HRS. Patients with ascites should receive prophylaxis against spontaneous bacterial peritonitis with an oral antibiotic such as norfloxacin 400 mg daily.

VII. What's the evidence?

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