Hepatorenal syndrome: Progressive renal failure in patients with cirrhosis

Hepatorenal syndrome: Progressive renal failure


■ The main driving force behind the development of hepatorenal syndrome (HRS) is portal hypertension, and the key event is linked to splanchnic arterial vasodilation.

■ Therapy should be geared toward increasing intravascular volume, as the underlying issue appears related to depletion of effective circulating volume depletion (third space and splanchnic vasodilation).

■ Current medical options for the treatment of either type 1 or type 2 HRS serve as a means of transition to a more definitive treatment, such as a transjugular intrahepatic portosystemic shunt (TIPS) procedure or, ideally, a liver transplant.

■ Medical management primarily involves therapies that will aid in vasoconstriction.

■ TIPS is typically used in patients who are not candidates for liver transplant or who remain on the transplant waiting list and are in need of emergent intervention.

Cirrhosis of the liver is a common clinical problem encountered by both inpatient and outpatient providers. It is the 12th leading cause of overall mortality in the United States and a marker for subsequent progression of portal hypertension complications.1What may be even more disconcerting to the patient than the years lost to cirrhosis is the impact this disease has on quality of life. Many complications are a result of longstanding portal hypertension brought on by the distortive, fibrotic, and regenerative changes within the liver. In the US population, these changes are most often due to alcoholic liver disease or chronic hepatitis C virus (HCV) infection.1

Although the complications of portal hypertension are well known, one frequent complication is less noticed, more misunderstood, and underdiagnosed compared with the others. This complication is hepatorenal syndrome (HRS), which is a frequently encountered end point to portal hypertension and has an annual incidence in the range of 8% to 40% in cirrhotic patients.2 The presence of ascites increases the risk of HRS, with 20% of patients developing HRS within 1 year after the onset of ascites and 40% developing HRS by year 5.3 The frequency of this complication is further confounded by its associated high mortality.

Renal failure (RF) is common in cirrhotic patients. In part, RF can be a consequence of treatment for other entities of portal hypertension, or it can be associated with common comorbidities that lead to chronic RF (ie, hypertensive and diabetic nephropathy). HRS, however, is a different disease process. Depending on type, median survival is often cited as 1 month (type 1) and 6 months (type 2).4

Some resources also propose a type 3 and a type 4 classification. These types deal more directly with prior coexisting chronic kidney disease superimposed on HRS and acute fulminant liver failure, respectively. To date, these classifications have not been as extensively studied, and such patients have been excluded from many clinical trials because they did not meet the traditional diagnostic criteria for HRS.2 This article further identifies and defines type 1 and type 2 HRS and their management, while focusing on the basic pathophysiologic and prognostic factors that determine its outcome.


Renal failure in cirrhotic patients is a common finding in both inpatient and outpatient settings.The use of lactulose in hepatic encephalopathy, loop diuretics and large-volume paracentesis in ascites, and hemorrhage associated with esophageal varices portend intravascular depletion and put patients at increased risk for acute RF.3 These causes of RF are often treatable with effective volume replacement and are not to be confused with HRS, which is characterized by a separate disease process than other common causes of renal failure. Hepatorenal syndrome is a diagnosis of exclusion, and the condition should be definitively diagnosed only after treatments for the correctable causes of RF have failed.

To further complicate the early detection of HRS, renal function is often subject to misinterpretation because of alterations in creatinine and urea production. In liver disease, the decrease in muscle mass and albumin can lead to lower levels of creatinine and urea.5 This can skew significantly the calculation of glomerular filtration rate (GFR) by such measures as the Cockcroft-Gault formula.5 The recommendation in these patients is to evaluate RF based on the creatinine level, keeping in mind that a serum creatinine level of 0.6 to 0.8 mg/dL is often considered normal in advanced cirrhosis.2 Therefore, a creatinine level of 1.5 mg/dL is considered the threshold for early detection of HRS, regardless of type.

Because no laboratory study or imaging modality is considered definitive for HRS, diagnosis depends on the acumen of the clinician. This has led to misdiagnosis in as many as 60% to 70% of cases.2 Once other causes of renal failure have been eliminated, the principles for early and accurate detection of HRS revolve around five major criteria:5

1. The patient must have acute or chronic hepatic disease that includes advanced liver failure and portal hypertension.

2. The plasma creatinine level must have risen over days to weeks to a level greater than 1.5 mg/dL; that is, the creatinine cannot have been chronically elevated.

3. The patient must not have any other form of renal disease, such as that caused by shock, bacterial infection, or current or recent use of nephrotoxic drugs, and there can be no sign of GI or renal fluid loss.

4. Cessation of any diuretic medication and expansion of the plasma volume with IV albumin (1 g/kg of body weight up to a maximum of 100 g) does not lead to improved renal function (defined as a creatinine level of less than 1.5 mg/dL).

5. Urinary protein is less than 500 mg/dL in the absence of parenchymal renal disease (by urinalysis) or obstructive uropathy (by ultrasound).

These criteria apply only to persons who do not have preexisting/chronic renal disease.


The underlying mechanisms associated with HRS result in one of two distinct disease processes, which can develop rapidly or slowly, depending on specific precipitating factors. Whichever disease process occurs, the main driving force behind the development of hepatorenal syndrome is portal hypertension, and the key event is linked to splanchnic arterial vasodilation.5 Briefly, portal hypertension stimulates the production of endogenous vasodilators secondary to vascular congestion and inflammation in the portal system.2,4,5

The vasodilator most understood in splanchnic vasodilation is nitric oxide; however, numerous other agents appear to be involved as well.5 Ultimately, the vasodilation leads to decreases in systemic resistance and effective circulating intravascular volume. The decreased circulating volume and portal hypertension trigger two responses.

First, there is an increase in the innate sympathetic nervous system (SNS) response, such that the heart rate increases in an attempt to maintain cardiac output. A secondary effect of the SNS activation is renal vasoconstriction.5 This vasoconstriction is further augmented by the second main component of the two-fold process, the renin-angiotensin-aldosterone system (RAAS). Poor renal perfusion and intravascular hypovolemia activate the RAAS, and the net result is renal retention of sodium and water along with an enhanced renal vasoconstriction.2 This imbalance in systemic vasodilation and renal vasoconstriction is thought to be the primary cause of progressive renal failure.


There are classically two distinct types of HRS. Type 1 HRS involves a rapid clinical deterioration, typically within 2 weeks. Serum creatinine level rises more than 2.5 mg/dL and is often associated with specific precipitating factors.3 Often, these factors are either consequences of persistent portal hypertension or causes of acute hepatitis, such as spontaneous bacterial peritonitis (SBP), variceal hemorrhage/GI hemorrhage, or acute alcoholic hepatitis.

Type 2 HRS manifests in a comparatively more insidious fashion, typically over weeks to months. Precipitating factors are not usually noted.2 Clinically, the reason for determining the type of HRS is related to prognosis: Patients with type 1 HRS have a higher mortality rate, and the need for prompt treatment is therefore much greater.


Time is of the essence when diagnosing and treating HRS. The necessity for early diagnosis is complicated by the need to exclude other more common causes of acute renal failure. As previously noted, other common consequences and treatment modalities for portal hypertension often lead to acute renal failure. In general, diuretics and other nephrotoxic agents should be stopped, at least temporarily. Therapy should be geared toward increasing intravascular volume, as the underlying issue appears related to depletion of effective circulating volume (third space and splanchnic vasodilation).2

All potential precipitating factors should be treated, especially in patients with type 1 HRS. Third-generation cephalosporins traditionally provide adequate coverage of aerobic gram-negative organisms that are often found in SBP. GI hemorrhage warrants upper endoscopy. Last, if tense ascites is present and large-volume paracentesis is needed, the addition of albumin replacement is recommended to avoid further worsening of intravascular depletion.2

Medical options

At best, current medical options for the treatment of either type 1 or type 2 HRS serve as a means of transition to a more definitive treatment, such as a trans­jugular intrahepatic portosystemic shunt (TIPS) procedure or, ideally, a liver transplant (Figure 1). Medical management primarily involves therapies that will aid in vasoconstriction. Theoretical renal vasodilators, ie, dopamine, have been ineffective in the reversal of HRS even though renal vasoconstriction appears to be involved in the physiologic process.2 Although most studies have incorporated only type 1 HRS in the evaluation of the effectiveness of specific therapeutics, the general principles of management are the same for type 1 and type 2 HRS. Typically, a combination of multiple medications is employed; however, the overall prognosis of patients remains variable and HRS frequently reoccurs once these agents are stopped.4

Vasoconstrictors are typically given with albumin infusions to help support effective circulatory volume. Normal saline infusion has a limited role. Before starting vasoconstricting agents, make certain that there are no contraindications. These include coronary artery disease, cardiomyopathy, cardiac arrhythmias, cardiac or respiratory failure, arterial hypertension, cerebrovascular disease, peripheral vascular disease, bronchospasm/asthma, terminal liver disease, advanced hepatocellular carcinoma, and age older than 70 years.2

One specific combination therapy often considered is midodrine (Orvaten, Proamatine, generics) and octreotide (Sandostatin, generics) in addition to an albumin infusion. This dual vasoconstrictor therapy (along with albumin) promotes both vasoconstriction via stimulation of alpha-1 receptors and inhibition of endogenous vasodilator release. One 2007 study evaluating the efficacy of octreotide/midodrine therapy found that this combination of vasoconstrictors significantly reduced 30-day mortality in patients with type 1 HRS.6 This study included the evaluation of 81 patients, 60 of whom were treated with octreotide/midodrine and 21 patients who received no treatment.

The 30-day mortality in these groups was 43% and 71%, respectively. Patients in the treatment arm were more likely to experience serum creatinine reduction (40-10%, respectively, P < .05).6 Additional data support the utilization of octreotide, midodrine, and albumin for improvement of short-term survival and renal function in patients with type 2 HRS. In one controlled study that involved 162 individuals with type 1 (n = 102) or type 2 HRS (n = 60), 75 participants were given triple therapy (midodrine, octreotide, and albumin) and compared with an historical cohort that received no therapy.7 Those in the treatment arm experienced significant improvement in renal function at 1 month (GFR 48 mL/min versus 34 mL/min), had longer transplant-free survival (median survival of 101 days versus only 18 days in the untreated group), and a transplantation rate of 45% versus only 26% in the untreated group with HRS type 2.7

Another agent that can be considered for use with albumin is terlipressin. This synthetic vasopressin derivative theo­retically has a greater effect on vascular receptors compared with renal vasopressin receptors.2 However, terlipressin has
a tendency to cause side effects that may prompt its early termination or the need to lower the prior effective dosage. Side effects include abdominal pain, cardiac arrhythmias (which resolve on their own), necrosis of the skin, ischemia of the fingers, bronchospasm, and diarrhea.2 One meta-analysis of five randomized controlled trials evaluating the efficacy and safety of terlipressin in patients with HRS concluded that terlipressin significantly increased the chances of HRS reversal based on improvement of RF. Although ischemic events and side effects are of concern with terlipressin, no statistically significant impact on outcome has been found.8

Noradrenaline (with albumin) is typically used when other agents are not readily available; it carries limitations on a par with commonly used agents. The efficacy of noradrenaline is similar to that of terlipressin, but noradrenaline therapy is 15-fold less expensive. As with terlipressin, use of noradrenaline has been associated with ischemic events, and close observation/monitoring is needed.2

Thus comparatively, the safety profile of midodrine/octreotide therapy has some added advantages over nor­adrenaline; however, either therapy with IV albumin is sufficient. If noradrenaline is chosen, then ICU monitoring is warranted given its potential to result in ischemia.5 Terlipressin has not yet been FDA approved.

Generally speaking, the previously noted vasoconstrictor medications and albumin are reasonable starting therapies, with the caveat that if hemodialysis is needed, it should be initiated quickly.4 Standard principles guiding the implementation of hemodialysis remain vital in directing therapy and the treatment regimen for HRS.

Surgical options

The poor outcome of HRS (especially HRS type 1) and the shortcomings of medical management alone over the long term must be stressed. The ultimate therapy for HRS is either a TIPS procedure or liver transplantation. These can be difficult to perform in patients with advanced liver disease. TIPS is typically used in patients who are not candidates for liver transplant or who remain on the transplant waiting list and are in need of emergent intervention. Frequently cited adverse effects of TIPS involve complications from the procedure (carotid artery puncture, peritoneal hemorrhage), worsening hepatic encephalopathy, and worsening hepatic failure.9

Patients with HRS are often not candidates for TIPS placement because of the other comorbidities and complications found in cirrhotic patients. According to the American Association for the Study of Liver Diseases, the TIPS placement is contraindicated in patients undergoing primary prevention of variceal bleeding and in those who have heart failure, multiple hepatic cysts, uncontrolled systemic infections or sepsis, unrelieved biliary obstruction, or severe pulmonary hypertension. Severe coagulopathy (international normalized ratio greater than 5.0) and thrombocytopenia (platelet count less than 20,000/µL) are considered relative contraindications.9

The risks and benefits of TIPS in HRS must be weighed alongside the likelihood that the patient will survive to receive a liver transplant. One predictive model is the Model for End-Stage Liver Disease (MELD). A score greater than 18 has been associated with a median survival of 3 months in postprocedure follow up.5 A secondary tool often employed for prognostic value and disease severity is the Child-Turcotte-Pugh Score.

In HRS, liver transplant is still the ideal, definitive treatment. There are few true contraindications to liver transplantation; however, these contraindications are often ongoing problems in the HRS patient population. Continuing substance abuse and poor adherence to medical therapy are two main barriers to liver transplantation.10 Other less problematic contraindications are related to advanced cardiopulmonary disease, extrahepatic malignancy, untreated sepsis, and any anatomic abnormality precluding transplantation.10 Hepatitis C virus infection is not by itself a contraindication for liver transplantation.


Advanced liver disease and cirrhosis are common problems encountered in the inpatient and outpatient setting, oftentimes presenting perplexing clinical scenarios for clinicians. Not only can the diagnosis of the underlying etiology be a challenge, but the systemic consequences of prolonged disease frequently create life-threatening situations. HRS is a common complication associated with cirrhosis and portal hypertension and is difficult to diagnose given the need to exclude other more common causes of renal failure.

The mortality associated with HRS warrants the serious clinical investigation of any renal insufficiency seen in cirrhotic patients. Although treatment options are limited and revolve around intravascular expansion and vasoconstricting agents, early recognition of both type 1 and 2 HRS can lead to earlier, more definitive therapies. Patient education and early reversal of precipitating factors are lifesaving and a significant reminder of how important primary prevention is for correctable causes of liver disease. jaapa

Matthew Dameron practices internal medicine with the Hospitalist Group at Carilion Roanoke Memorial Hospital in Roanoke, Virginia. The author has indicated no relationships to disclose relating to the content of this article.


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