AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Hepatorenal syndrome (HRS) is the development of renal dysfunction in patients with acute or chronic, severe liver disease in the absence of any other identifiable causes of renal pathology.

Two types of HRS are described. Type 1 HRS is mainly associated with acute liver failure or alcoholic cirrhosis, but it can also develop as a result of other forms of liver failure. It is characterized by rapid deterioration of renal function, with an increase in serum creatinine and BUN levels and a substantial decrease in the glomerular filtration rate (GFR). Hyponatremia and other electrolyte abnormalities are common findings. Type 2 HRS is characterized by a steady and progressive decline in the renal function as well as recurrent, diuretic-resistant ascites. It generally occurs more often in patients with hepatic dysfunction less severe than that observed in type 1. Both type 1 HRS and type 2 HRS are associated with a poor prognosis.

Pathophysiology

Although the exact pathophysiologic mechanisms leading to HRS are not known, decreased renal blood flow caused by severe renal arterial and arteriolar vasoconstriction plays a major role. A paradoxical interplay between local and systemic factors, which lead to both vasoconstriction and vasodilatation, appear to perpetuate severe systemic arterial hypoperfusion. Although not directly responsible for the development of HRS, lowered mean arterial pressure is frequently observed in patients with severe liver disease; this decrease is most likely secondary to release of local hepatic vasodilatory substances. This release is also accompanied by enhanced dilation of the splanchnic vascular beds due to portal hypertension, resulting in the opening of portosystemic shunts and minor arteriovenous (AV) fistulae. Renal venous pressure may also be increased because of compression of the inferior vena cava by ascites.

Dilation of the splanchnic vascular bed decreases renal perfusion pressure (mean arterial pressure - renal vein pressure) and thus decreased renal blood flow. Renal perfusion is initially maintained because of the local production of vasodilatory factors, such as prostaglandin E, prostacyclin, and nitric oxide. However, as liver disease continues to advance, splanchnic blood flow increases, and systemic perfusion reduces further. To maintain renal homeostasis and perfusion, several vasoconstrictor systems and substances are simultaneously activated. These include the renin-angiotensin-aldosterone system (RAAS), the sympathetic nervous system (SNS), and vasopressin, which lead to intense renal arterial and arteriolar vasoconstriction. As activation substantially increases, arterial and renal underfilling ensues and progresses, and HRS develops. The final result is a severely decreased GFR and renal failure inthe setting of no structural or intrinsic parenchymal renal disease.

Another theory attributes renal hypoperfusion directly to the diseased liver without any pathogenetic relationship to the hemodynamic changes. Two mechanisms support this theory: (1) decreased synthesis or release of a liver-borne factor that produces renal vasodilation and (2) the presence of a hepatorenal reflex that regulates the renal function, as demonstrated in experimental animals.

Frequency

International

The annual incidence of HRS among adults with ascites and cirrhosis is approximately 8%. In addition, among adults with cirrhosis and portal hypertension, 20% develop HRS in the first year after diagnosis, and as many as 40% of patients develop HRS by 5 years after diagnosis. Incidence data in children are scarce in the literature; therefore their incidence of HRS is essentially unknown at this time.

Mortality/Morbidity

The median survival of adults with type 1 HRS is estimated to be 2 weeks, and the hospital survival of the same patients is about 10%. In contrast, the median survival of individuals with type 2 HRS is about 6 months. Current pediatric HRS mortality and morbidity rates are not reported.

• Survival and the recovery of renal function depend on the recovery of hepatic function, which is usually accomplished with liver transplantation in a minority of patients.
• About 1-7% of patients with HRS develop end-stage renal disease and require dialysis despite liver transplantation and a recovery of hepatic function.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Patients with HRS present with symptoms of renal failure in the setting of acute or chronic liver failure with portal hypertension complicated by ascites, jaundice, hepatic encephalopathy, and coagulopathy.

• Urine volume is typically less than 500 mL/d and does not show sustained improvement after diuretic withdrawal and plasma volume expansion.
• The 1996 International Ascites Club defined 6 major criteria necessary for the diagnosis of HRS and 5 additional criteria, which are findings usually associated with HRS but not required for diagnosis.
• • The 6 required major criteria are as follows:
    1. Chronic or acute hepatic disease with advanced liver failure and portal hypertension
    2. Low GFR defined as a serum creatinine level of more than 1.5 mg/dL or 24-hour clearance of less than 40 mL/min
    3. Absence of shock, ongoing bacterial infection, fluid loss, or current or recent treatment with nephrotoxic medications
    4. No sustained improvement in renal function (serum creatinine level £1.5 mg/dL or clearance >40 mL/min) after the withdrawal of diuretics and after plasma volume expansion with 1.5 L of isotonic sodium chloride solution
    5. Proteinuria of less than 500 mg/d
    6. Absence of any evidence of obstructive uropathy or parenchymal disease, as demonstrated on ultrasonography
  • The 5 additional criteria are as follows:
    1. Urine volume of less than 500 mL/d
    2. Urine sodium concentration of less than 10 mEq/L
    3. Urine osmolality greater than plasma osmolality
    4. Urine RBC count of less than 50 per high-power field
    5. Serum sodium concentration of less than 130 mEq/L

Physical

• Ascites is almost always present in patients with advanced hepatic failure and cirrhosis. The mechanism of ascites formation in these patients is likely a combination of increased sinusoidal pressure and hepatic insufficiency, as well as decreased renal function.
• Jaundice, hepatic encephalopathy, and clinically significant coagulopathy may all be present to some degree as part of the hepatic failure, especially in patients with type 1 HRS.
• Resting low arterial blood pressure is a frequent finding in patients with HRS despite increased plasma volume, high cardiac output, the presence of potent vasoconstrictors (eg, renin, angiotensin II, vasopressin), and an activated sympathetic nervous system. The systemic hypotension is attributed to a marked splanchnic vasodilation secondary to portal hypertension and local hepatic vasodilators.

Causes

• HRS may complicate any form of severe liver disease.
• • Many liver transplantations are performed in children with chronic liver disease secondary to biliary atresia.
  • In children, 50% of all cases of acute hepatic failure are secondary to acute viral hepatitis. Other etiologies include acetaminophen toxicity, Wilson disease, liver malignancy, and autoimmune hepatitis.
• Several findings are often seen in patients who develop HRS and include the following:
• • Previous episodes of ascites
  • Absence of hepatomegaly
  • Poor nutritional status
  • Moderately increased BUN and creatinine secondary to the lack of endogenous production and low muscle mass
  • Severely decreased GFR
  • Low serum sodium value, ie, dilutional hyponatremia
  • Moderately elevated serum potassium levels
  • Low urinary sodium excretion
  • High plasma renin activity
  • Low arterial blood pressure
  • Increased plasma norepinephrine level
  • Clinically significant esophageal varices
• Among adults with cirrhosis and portal hypertension, several precipitating factors have been implicated in the progression to HRS. These factors include spontaneous bacterial peritonitis, large volume paracentesis without simultaneous or subsequent plasma expansion, and GI or variceal bleeding.
• Patients with hepatic failure and ascites are prone to develop spontaneous bacterial peritonitis. In approximately 20% of adults with advanced liver disease and spontaneous bacterial peritonitis, their condition progresses to HRS.
• Large-volume paracentesis without plasma volume replacement is associated with the development of HRS in up to 15% of patients with ascites. Renal failure is attributed to a circulatory dysfunction after paracentesis and is preventable by administering an isotonic solution, or preferably intravenous (IV) albumin, during or soon after the procedure.
• HRS develops in as many as 10% of adults after a clinically significant upper or lower GI bleed. Care must be taken to rule out acute tubular necrosis from volume depletion as the etiology of the renal failure after a GI bleed, as HRS is a diagnosis of exclusion.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Drug-induced renal failure
Glomerulonephritis
Severe volume depletion

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• General laboratory study: No specific tests help in definitively diagnosing HRS. HRS is a diagnosis of exclusion.
• Serum creatinine measurement
• • This test usually has good specificity for low GFR. However, it is least useful in patients with hepatic failure and ascites because their creatinine levels may be in the reference range or only slightly elevated despite a severely decreased GFR secondary to low endogenous production of creatinine, poor nutrition, and decreased muscle mass.
  • A creatinine level of more than 1.5 mg/mL and a creatinine clearance of less than 40 mL/min are criteria the 1996 International Ascites Club used to define HRS. A 24-hour urine collection or a specific measure of the GFR may be required for accurate measurement.
• BUN measurement: The BUN level is not reliable for assessing for low GFR in the clinical settings of HRS. The level may be abnormally low because of reduced hepatic synthesis or low protein intake. Causes other than a low GFR, such as GI bleeding, may contribute to an elevated BUN level.
• Sodium measurement: Dilutional hyponatremia may be seen in patients with HRS. This condition is secondary to impaired renal capacity to excrete solute-free water, as well as increased vasopressin release in response to the severe arterial underfilling.
• Urinalysis: No urinary findings are consistently associated with the diagnosis of HRS. Clinically significant proteinuria (>500 mg/dL) usually indicates renal failure secondary to tubular or glomerular damage and not HRS. Microscopic hematuria makes the diagnosis of HRS unlikely and suggests a glomerular pathology. Tubular cells or muddy, brown casts suggest that acute tubular necrosis as the etiology of renal failure.
• Test of urine osmolarity: The concentrating capacity of the kidney is preserved in HRS, and urine osmolality is typically higher than the plasma osmolality. In some patients, osmolality may decrease as renal failure progresses.
• Urine electrolytes measurement: The reabsorption capacity of the tubule is maintained in patients with HRS, as it is only functional renal failure. Therefore, the urinary sodium concentration is usually less than 10 mEq/L. However, some patients have high urinary sodium excretion. Therefore, this marker is not reliable in the diagnosis of HRS.

Imaging Studies

• Renal ultrasonography is useful in eliminating structural causes of renal failure, such as obstructive uropathy and intrinsic parenchymal renal disease, especially in the setting of an abnormal urinary sediment.
• Doppler sonography is performed to determine the intrarenal arteriolar vascular resistance, defined as the resistive index (RI). The reference range for RI is 0.7 or lower. The RI can be a more sensitive parameter than the creatinine clearance.

Procedures

• Renal biopsy is indicated for patients with abnormal urinary sediment, proteinuria or hematuria, or renal ultrasonographic findings suggestive of organic causes of renal failure.
• Patients with HRS are usually too ill to tolerate renal biopsy. However, if performed, biopsy reveals normal histology because HRS is only functional renal failure.

Histologic Findings

In patients with HRS, renal histology is preserved. After the patient undergoes liver transplantation, renal recovery is usually good.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Medical therapy is used as a temporizing measure to improve renal function while the patient awaits liver transplantation.
• Vasoconstrictors, such as the vasopressin analogs ornipressin and terlipressin, and the alpha1-adrenergic agonists, norepinephrine and midodrine, were recently studied and have shown promising results in adult patients. In 1 study, octreotide, a potent splanchnic vasoconstrictor was not beneficial as single therapy.
• • The vasopressin analogs both act on V1 vasopressin receptors in the vascular smooth muscle cells to cause splanchnic vasoconstriction and thus increase systemic and renal perfusion.
  • Ornipressin is an effective vasoconstrictive agent but has severe ischemic adverse effects in 30-50% of adult patients. Therefore, it is not currently recommended as treatment for HRS.
  • Terlipressin is used frequently internationally, and it is currently in phase III trials in the United States. Patients given terlipressin had a 50-75% response rate defined as an improved GFR to more than 40 mL/min. GFR typically remains below normal, but this therapy provides a bridge to liver transplantation and improves the prognosis after transplantation. Most studies demonstrated an improved response rate with the addition of an albumin infusion to the terlipressin infusion. About 15% of patients have a recurrence after the drug is withdrawn. However mostpatients respond to retreatment. Terlipressin is administered in an IV bolus every 4 hours for up to 15 days. Ischemic adverse effects are rare (5-10%) and milder than those of ornipressin. However, this drug is costly and has somewhat limited availability.
  • Alpha1-adrenergic agonists are alternatives to the vasopressin analogs and offer the advantage current availability in the United States.
  • The authors know of no studies to compare the vasopressin analogs and norepinephrine or midodrine, but the latter agents appear to be effective alternatives in patients with HRS. They have been most extensively studied in patients with type 2 HRS, whereas terlipressin has been evaluated more extensively in type 1 HRS.
• Hemodialysis (HD), continuous renal replacement therapy (CRRT), and albumin dialysis are possible treatment options for patients with HRS.
• • These options have not been reported sufficiently in the literature to support their consistent use.
  • Patients with HRS historically do not tolerate HD, and deaths during dialysis have been reported.
  • At present, HD is recommended for medically resistant hyperkalemia or severe fluid overload.
  • CRRT remains a potential option for certain patients with HRS; however, the literature is limited to only case reports.
  • Data regarding the use of albumin dialysis in this patient population are lacking.

Surgical Care

Surgical options for patients with HRS include the transjugular intrahepatic portosystemic shunt (TIPS) procedure and liver transplantation. Peritoneovenous shunting and portosystemic shunting have been attempted in HRS, but their effectiveness in the treatment of HRS has not been demonstrated.

• Peritoneovenous shunt placement: A peritoneovenous shunt allows ascitic fluid to pass from the peritoneal cavity back into the systemic circulation. This passage may increase cardiac output and expand the intravascular compartment, decreasing vasoconstrictor activity in patients with HRS. Improvement in renal blood flow and increased GFR follows. No controlled studies have shown improved survival with this procedure, though isolated reports have shown a reversal of HRS.
• Portosystemic shunts placement: Portacaval anastomosis is not the standard of care for patients with HRS because of the high morbidity and mortality risks associated with these procedures.
• TIPS procedure
• • The TIPS procedure is used as an alternative in treating patients with bleeding esophageal varices that do not respond to standard therapy and in patients with refractory ascites.
  • TIPS can be used as a bridge to prolong the survival of patients with type 2 HRS until liver transplantation can be performed. This procedure may decrease portal pressure, which decreases the systemic and renal vasoconstrictor systems. It increases the GFR in 60% of patients with HRS. However, median survival after TIPS is only 2-4 months.
  • Contraindications are severe liver failure and severe hepatic encephalopathy because the procedure can lead to irreversible liver failure and chronic, disabling hepatic encephalopathy.
  • TIPS is currently recommended for patients who appear to be eligible for liver transplantation but in whom vasoconstrictor medical therapy fails. TIPS should not be considered as monotherapy in HRS.
• Liver transplantation
• • Liver transplantation is the treatment of choice for patients with HRS because it cures the underlying liver disease and thus allows renal function to recover secondary to improved perfusion after transplantation.
  • Most patients with HRS do not survive long enough or are not candidates for liver transplantation.
  • Most centers advocate vasoconstrictor therapy before the transplantation since this decreases posttransplantation morbidity and mortality.
  • Combined liver and kidney transplantation is rarely recommended because the renal failure is of only functional.
  • Renal function may further deteriorate after transplantation, and more than one third of patients require dialysis.
  • Because renal impairment is secondary to the increased nephrotoxic effect of cyclosporine, cyclosporine should be used 48-72 hours after transplantation, when renal function is expected to improve.

Consultations

• Nephrologist
• Gastroenterologist
• Transplant surgeon
• Vascular surgeon

Diet

A low-sodium diet is generally useful for all patients with HRS, as is fluid restriction because of the renal impairment. Decreased sodium intake can reduce the severity of the ascites in some patients and can lower the incidence of dilutional hyponatremia.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Vasoconstrictor agents, such as vasopressin analogs (eg, ornipressin, terlipressin) or alpha1-adrenergic agonists (eg, norepinephrine, midodrine) have been used in combination or alone to reverse the peripheral arterial vasodilatation and renal vasoconstriction that is impairing renal function. However, none of these drugs sustain improvement in renal function or reverse HRS without liver transplantation. See Medical Care for more details regarding these medications.

Drug Category: Vasoconstrictive agents

These agents induce vasoconstriction of the splanchnic vascular bed, which improves systemic and renal perfusion.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Close inpatient monitoring of patients may be needed.
• Continue medical management, especially vasoconstrictor therapy, while the patient awaits liver transplantation, if the patient is an appropriate candidate.
• Medical management of coagulopathy may be required.
• Administer medical or surgical therapy for variceal disease if necessary.
• Monitor for adverse effects of vasoconstrictor therapies.
• Promptly start antibiotic therapy if bacterial sepsis or spontaneous bacterial peritonitis is suspected.

Further Outpatient Care

• For patients with type 2 HRS, schedule regular visits for paracentesis with volume expansion related to the diuretic-resistant recurrent ascites.
• Promptly assess the patient's eligibility for liver transplantation after HRS is diagnosed because of the short median life expectancy without transplantation for individuals with type 1 or type 2 HRS.

In/Out Patient Meds

• As appropriate, provide plasma volume expansion with albumin for recurrent, diuretic-resistant ascites.
• Administer antibiotics to prevent or treat spontaneous bacterial peritonitis.

Transfer

• Transfer to a tertiary care center specializing in liver transplantation may be required to manage this complex disease.

Deterrence/Prevention

• Avoid large-volume paracentesis without proper plasma volume expansion either during or after the procedure.
• Rapidly assess and treat any signs of infection in patients with severe hepatic failure, portal hypertension, and ascites because these conditions may precipitate HRS.

Complications

• Irreversible liver failure
• Chronic, disabling hepatic encephalopathy
• Death
• End-stage renal disease
• Recurrent, diuretic-resistant ascites

Prognosis

• For adults with type 1 HRS, median survival is 2 weeks, and the hospital survival rate is 10%.
• For patients with type 2 HRS, median survival is 6 months.
• For patients undergoing a TIPS procedure, median survival is 2-4 months after the procedure.
• End-stage renal disease requiring dialysis develops in 1-7% of patients with HRS who undergo liver transplantation.
• The long-term survival rate for patients with HRS is 60% at 3 years after transplantation. This is only slightly less than the survival rate for patients with liver failure and no HRS, which is 70-80% after 3 years.

Patient Education

• Refer the patient and his or her family for psychosocial counseling.
• For excellent patient education resources, visit eMedicine's Liver, Gallbladder, and Pancreas Center and Hepatitis Center. Also, see eMedicine's patient education article, Cirrhosis.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to recognize predictive factors and conditions known to precipitate the development of HRS
• Failure to recognize other causes of renal failure, because HRS is a diagnosis of exclusion

Special Concerns

• Use of nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided in this patient population because this can cause a rapid and profound decrease in renal blood flow and GFR secondary to local renal prostaglandin blockade.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Sep 21, 2006