Hepatorenal syndrome: Clinical presentation and diagnosis

INTRODUCTION — 

Hepatorenal syndrome-acute kidney injury (HRS-AKI) is one of many potential causes of acute kidney injury in patients with cirrhosis and ascites. HRS-AKI is a diagnosis of exclusion and is associated with a poor prognosis if left untreated.

This topic will review the clinical presentation and diagnosis of HRS-AKI. The treatment and prognosis of HRS-AKI, as well as overviews of the complications of fulminant hepatic failure and cirrhosis, are presented elsewhere:

●(See "Hepatorenal syndrome: Treatment and prognosis".)

●(See "Acute liver failure in adults: Management and prognosis".)

●(See "Cirrhosis in adults: Overview of complications, general management, and prognosis".)

TERMINOLOGY — 

Hepatorenal syndrome-acute kidney injury (HRS-AKI) refers to an acute, severe form of cirrhosis-mediated kidney dysfunction (see 'Establishing the diagnosis' below). HRS-AKI is the focus of this topic review.  

Terminology varies for cirrhosis-associated decrements in glomerular filtration rate that are subacute, chronic, or less severe than those that characterize HRS-AKI. Proposed terms include HRS-nonacute kidney injury (HRS-nAKI) [1,2] or, depending on the time course, HRS-acute kidney disease (HRS-AKD; used for kidney dysfunction lasting between 7 and 90 days) or HRS-chronic kidney disease (HRS-CKD; used for kidney dysfunction lasting more than 90 days) [3].

Prior classifications of HRS, such as type 1 and type 2 HRS, are no longer used. In older studies, most patients categorized as having type 1 HRS would meet the current diagnostic criteria for HRS-AKI.

EPIDEMIOLOGY — 

Hepatorenal syndrome-acute kidney injury (HRS-AKI) is uncommon, given that it occurs only in patients with cirrhosis and ascites, and at low rates within that specific population [4-7]. The relative rarity of HRS-AKI was illustrated by a study of over 2000 patients with cirrhosis who were admitted to 11 hospital networks in the United States with AKI [4]. In this study, the etiologies of AKI were as follows:  

●Prerenal, or hemodynamic, AKI – 44.3 percent

●Acute tubular necrosis (ATN) – 30.4 percent  

●Other or unknown etiologies of AKI – 13.2 percent

●HRS-AKI – 12.1 percent

PATHOGENESIS — 

Portal hypertension-induced vasodilatation in the splanchnic circulation plays a major role in the pathogenesis of hepatorenal syndrome-acute kidney injury (HRS-AKI). Systemic inflammation also may contribute (figure 1).

●Splanchnic vasodilation – Arterial vasodilation in the splanchnic circulation is triggered by obstruction to portal flow from cirrhosis, which leads to portal hypertension, increased sheer stress on the splanchnic vessels, and the subsequent production of various vasodilators (eg, nitric oxide) [8-10]. Splanchnic vasodilation leads to the pooling of blood in the splanchnic circulation and a concomitant decrease in the effective arterial blood volume. Additionally, systemic vascular resistance falls due to the transmission of vasodilators from the splanchnic to the systemic circulation via portal-systemic shunts. The compensatory response to these changes ultimately leads to renal vasoconstriction that may become severe enough to impair kidney function [8,11,12].

The adaptive pathways that maintain systemic hemodynamic stability in patients with splanchnic vasodilation include activation of the sympathetic nervous system (via catecholamine release), the renin-angiotensin-aldosterone system, and arginine vasopressin (or anti-diuretic hormone [ADH]) [13-15]. In patients with portal hypertension, increased cardiac output is an important component of preserving hemodynamic stability [16]. Patients with advanced cirrhosis have two notable characteristics that predispose to HRS-AKI:

•The compensatory response becomes increasingly maladaptive, resulting in worsening ascites (from excessive sodium retention), hyponatremia (when free water retention exceeds solute reabsorption), and renal vasoconstriction that may eventually diminish glomerular filtration rate [11,17,18].

•The ability to maintain an increased cardiac output is lost. This condition, referred to as cirrhotic cardiomyopathy, is characterized by impaired diastolic function, a blunted response to pharmacologic, physiologic, or pathologic stress, and altered electrophysiologic signaling [19-21]. (See "Definition and classification of the cardiomyopathies", section on 'Cirrhotic cardiomyopathy'.)

●Systemic inflammation – Systemic inflammation, likely related to increased gut bacteria translocation in the setting of portal hypertension, also may contribute to HRS-AKI. Systemic inflammation may potentiate the hemodynamic pathophysiology of HRS by multiple mechanisms, including augmented vasodilation, direct damage to the kidney, and/or impairment of the integrity of the renal microcirculation [11,17,18]. In addition, HRS-AKI often occurs as a part of a multi-organ failure syndrome (eg, acute-on-chronic liver failure [ACLF]), which is characterized by multiple extrahepatic organ failures. The presence of other organ failures may enhance the inflammatory milieu, which can significantly worsen kidney function [22-26].

CLINICAL PRESENTATION

Clinical features — In addition to an abrupt decrease in kidney function in a patient with cirrhosis and ascites, hepatorenal syndrome-acute kidney injury (HRS-AKI) is usually characterized by the following features [11]:

●The absence of systemic hypertension

●An often normal urine sediment

●No or minimal proteinuria

●Very low urine sodium levels (eg, <10 to 20 mmol/L)

However, the clinical features of HRS-AKI vary substantially according to individual patient characteristics. For example, the urine sediment may show a variety of abnormalities, such as hematuria due to bladder catheterization or bilirubin-stained granular casts. Patients with underlying chronic kidney disease (eg, diabetic nephropathy) may have substantial amounts of proteinuria, and individuals treated with diuretics may have higher urine sodium concentrations.

Precipitants — For many episodes of HRS-AKI, a precipitating event cannot be identified. However, common precipitants of HRS-AKI are as follows [27]:

●Infection (often spontaneous bacterial peritonitis [28])

●Gastrointestinal bleeding

●Aggressive diuresis

●Excessive diarrhea due to overzealous lactulose administration

●Large volume paracentesis without adequate volume expansion

●Alcoholic hepatitis

Problems with estimating kidney function — Because many patients with cirrhosis have sarcopenia [29], the kidney dysfunction in HRS-AKI may be substantially more severe than suggested by serum creatinine level, particularly in females [30-33]. However, serum creatinine is a reliable prognostic metric in patients with cirrhosis. Creatinine is a key component of the Model for End Stage Liver Disease (MELD) score [34], and relative changes in serum creatinine correlate well with short-term prognosis among patients with AKI and cirrhosis [4,35].

To address the limitations of creatinine-based estimates of glomerular filtration rate (GFR), serum cystatin C has been increasingly incorporated into estimated GFR (eGFR) formulas and clinical practice (see "Assessment of kidney function") [36,37]. Although several studies have demonstrated that either cystatin C-based eGFR or cirrhosis-specific eGFR formulas (such as the GRAIL formula) may better estimate kidney function and survival in cirrhosis [38-43], these eGFR formulas were derived in patients with stable kidney function and may not be applicable in patients with AKI. Additionally, cystatin C does not have an established AKI staging schemata, in contrast to creatinine. (See "Definition and staging criteria of acute kidney injury in adults".)

DIAGNOSIS — 

Hepatorenal syndrome-acute kidney injury (HRS-AKI) is a diagnosis of exclusion. There is no one specific test that can establish the diagnosis.

When to suspect hepatorenal syndrome — HRS-AKI should be suspected in any patient with cirrhosis and ascites who develops AKI, especially if no other cause of AKI is readily apparent.

Diagnostic evaluation — Because AKI in patients with advanced liver disease is often not due to HRS-AKI, patients should be evaluated thoroughly for other causes of AKI using a similar approach as that for patients without hepatic impairment. (See "Evaluation of acute kidney injury among hospitalized adult patients".)

In addition, patients with suspected HRS-AKI should be evaluated thoroughly for potential sources of infection that may have precipitated HRS-AKI (see 'Precipitants' above). We perform a diagnostic paracentesis to assess for spontaneous bacterial peritonitis, even in asymptomatic patients. (See "Spontaneous bacterial peritonitis in adults: Diagnosis".)

Establishing the diagnosis — HRS-AKI is a clinical diagnosis. The diagnostic criteria for HRS-AKI and the rationale for using intravenous (IV) albumin as a diagnostic criterion are discussed below.

●Diagnostic criteria – Our approach to the diagnosis of HRS-AKI is broadly consistent with the 2015 International Club of Ascites guidelines [44] as well as guidelines proposed by other expert panels [2,45]. We diagnose HRS-AKI in patients who meet all of the following criteria:

•Cirrhosis and ascites.

•AKI, defined as an increase in serum creatinine by ≥0.3 mg/dL (≥26.5 micromol/L) within 48 hours, or an increase in serum creatinine to ≥1.5 times baseline, which is known or presumed to have occurred within the prior seven days [44]. This definition is consistent with the Kidney Disease: Improving Global Outcomes (KDIGO) creatinine criteria for AKI (see "Definition and staging criteria of acute kidney injury in adults"). We do not use urine output criteria for AKI because baseline urine volume is often low in patients with cirrhosis and ascites [44,46].

•The absence of strong evidence for an alternative cause of AKI [3]. This criterion includes the following:

-Absence of shock.

-No current or recent use of nephrotoxic drugs.

-Normal findings on kidney ultrasonography in patients without preexisting chronic kidney disease.

-No urinary findings of acute glomerular disease, such as proteinuria (eg, >500 mg/day) in patients without a preexisting protein-losing nephropathy (eg, diabetic kidney disease), or hematuria in patients without bladder catheterization or a history of microscopic hematuria.

•For patients without intravascular fluid overload, lack of improvement in kidney function after two days of volume expansion with IV 25 percent albumin (1 g/kg of body weight per day up to 100 g/day), and withdrawal of diuretics for at least two days. Albumin may be administered once daily or twice daily in divided doses.

Kidney biopsy is not required to diagnose HRS-AKI. Due to high rates of major bleeding in this coagulopathic population [47], we typically do not perform kidney biopsy in patients with cirrhosis and AKI unless there is a strong suspicion of an active glomerulonephritis or acute interstitial nephritis that may benefit from treatment. (See "Evaluation of acute kidney injury among hospitalized adult patients".)

●Rationale for IV albumin – A volume challenge has been a longstanding criterion for the diagnosis of HRS-AKI since lack of response to volume administration effectively eliminates prerenal AKI from the differential diagnosis (see 'Differential diagnosis' below) [44,48-50]. No trial data support the use of IV albumin rather than IV crystalloid (eg, normal saline) for this purpose, and some experts use crystalloid [3]. However, several points support the use of IV albumin in this setting:

•Many patients with cirrhosis are hypoalbuminemic due to impaired synthetic liver function. Thus, IV albumin may restore oncotic pressure while avoiding large volumes of crystalloid that are prone to third-spacing as ascites.

•IV albumin administration reduces the risk of kidney injury in a subset of patients with spontaneous bacterial peritonitis [28] and in patients receiving large-volume paracentesis [51,52].

•Albumin may have pleiotropic, anti-inflammatory effects that address the inflammatory component of HRS physiology [15].

Some experts also endorse a one-day rather than a two-day volume challenge [3] to avoid delays in implementing vasoconstrictor therapy for HRS-AKI (see "Hepatorenal syndrome: Treatment and prognosis"). However, a period of volume administration limited to one day may result in overdiagnosis of HRS-AKI. For example, in a study that included 46 patients with cirrhosis and AKI whose kidney function improved after 48 hours of IV albumin, only 28 patients (61 percent) responded to albumin at 24 hours; the other 18 patients (39 percent) required 48 hours to respond [53].

Differential diagnosis — The diagnosis of hepatorenal syndrome-acute kidney injury (HRS-AKI) is one of exclusion, made only after other potential causes of acute kidney injury have been ruled out [5,45]. For example, both glomerulonephritis and vasculitis can occur in patients with liver disease and should be suspected in patients with an active urine sediment containing red cells and/or red cell casts. (See "IgA nephropathy: Clinical features and diagnosis" and "Overview of kidney disease associated with hepatitis C virus infection" and "Kidney disease associated with hepatitis B virus infection".)

Patients with cirrhosis and AKI often have prerenal AKI or acute tubular necrosis (ATN) (see 'Epidemiology' above); these two diagnoses are discussed below:

●Prerenal disease – Patients with cirrhosis may have prerenal, or hemodynamic, AKI due to gastrointestinal fluid losses, bleeding, or diuretic or lactulose therapy. In some patients with prerenal AKI, the cause(s) of volume loss may not be obvious. Patients with cirrhosis and a history of medically treated hypertension may be particularly susceptible to prerenal AKI. Because of cirrhosis-mediated systemic vasodilation, many such patients require down-titration or cessation of their anti-hypertensive regimen to avoid hypotension as liver function worsens.

Prerenal AKI is distinguished from HRS-AKI by gauging the response to volume expansion (see 'Establishing the diagnosis' above). In contrast to HRS-AKI, prerenal AKI corrects with the administration of volume and/or treatment of hypotension.

●ATN – Patients with cirrhosis may develop ATN after exposure to a nephrotoxin or after an episode of septic or hemorrhagic shock [8]. A clinical diagnosis of ATN is usually made when the history and physical examination demonstrate a clear precipitant.

Some of the traditional laboratory methods used to distinguish ATN from patients who have impaired kidney perfusion without structural kidney damage (eg, prerenal AKI or HRS-AKI) may not be helpful in patients with hepatic disease. Although ATN is usually associated with a fractional excretion of sodium above 2 percent, the fractional excretion of sodium may remain below 1 percent in patients with cirrhosis who develop ATN (see "Etiology and diagnosis of prerenal disease and acute tubular necrosis in acute kidney injury in adults" and "Fractional excretion of sodium, urea, and other molecules in acute kidney injury"). The urinalysis may also be misleading in patients with cirrhosis and hyperbilirubinemia since fine granular casts stained with bilirubin appear similar to the muddy brown granular casts of ATN.

Elevated levels of urinary neutrophil gelatinase-associated lipocalin (NGAL) may suggest ATN rather than HRS-AKI [54,55]. However, a specific cutoff value of urinary NGAL that distinguishes ATN from HRS-AKI or prerenal AKI has not been established, and the use of NGAL in this setting remains investigational. (See "Investigational biomarkers and the evaluation of acute kidney injury", section on 'Neutrophil gelatinase-associated lipocalin (NGAL)'.)

Of note, AKI in patients with cirrhosis may be multifactorial. For example, a patient with HRS-AKI may incur superimposed ATN because of exposure to a nephrotoxin. Additionally, high abdominal compartment pressures, obstructive bilirubin casts, or potentially nephrotoxic levels of bile acids may further impair kidney function in patients with cirrhosis and AKI [56-58].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Fluid and electrolyte disorders in adults".)

SUMMARY AND RECOMMENDATIONS

●Overview – Hepatorenal syndrome-acute kidney injury (HRS-AKI) refers to an acute, severe form of cirrhosis-mediated kidney dysfunction. HRS-AKI is uncommon, given that it occurs only in patients with cirrhosis and ascites, and at low rates within that specific population. Portal hypertension-induced vasodilatation in the splanchnic circulation plays a major role in the pathogenesis of HRS-AKI. (See 'Terminology' above and 'Epidemiology' above and 'Pathogenesis' above.)

●Clinical presentation

•Clinical features – In addition to an abrupt decrease in kidney function in a patient with cirrhosis and ascites, hepatorenal syndrome-acute kidney injury (HRS-AKI) is usually characterized by the following features (see 'Clinical features' above):

-The absence of systemic hypertension

-An often normal urine sediment

-No or minimal proteinuria

-Very low urine sodium levels (eg, <10 to 20 mmol/L)

However, the clinical features of HRS-AKI vary substantially according to individual patient characteristics.

•Precipitants – For many episodes of HRS-AKI, a precipitating event cannot be identified. However, common precipitants of HRS-AKI are as follows (see 'Precipitants' above):

-Infection (often spontaneous bacterial peritonitis)

-Gastrointestinal bleeding

-Aggressive diuresis

-Excessive diarrhea due to overzealous lactulose administration

-Large volume paracentesis without adequate volume expansion

-Alcoholic hepatitis

●Diagnosis – HRS-AKI should be suspected in any patient with cirrhosis and ascites who develops AKI, especially if no other cause of AKI is readily apparent.

•Diagnostic evaluation – Because AKI in patients with advanced liver disease is often not due to HRS-AKI, patients should be evaluated thoroughly for other causes of AKI using a similar approach as that for patients without hepatic impairment. (See "Evaluation of acute kidney injury among hospitalized adult patients".)

In addition, patients with suspected HRS-AKI should be evaluated thoroughly for potential sources of infection that may have precipitated HRS-AKI (see 'Precipitants' above). We perform a diagnostic paracentesis to assess for spontaneous bacterial peritonitis, even in asymptomatic patients. (See "Spontaneous bacterial peritonitis in adults: Diagnosis".)

•Establishing the diagnosis – We diagnose HRS-AKI in patients who meet all of the following criteria (see 'Establishing the diagnosis' above):

-Cirrhosis and ascites.

-AKI, defined as an increase in serum creatinine by ≥0.3 mg/dL (≥26.5 micromol/L) within 48 hours, or an increase in serum creatinine to ≥1.5 times baseline, which is known or presumed to have occurred within the prior seven days. This definition is consistent with the Kidney Disease: Improving Global Outcomes (KDIGO) creatinine criteria for AKI.

-The absence of strong evidence for an alternative cause of AKI. This criterion includes the absence of shock, no current or recent use of nephrotoxic drugs, normal findings on kidney ultrasonography in patients without preexisting chronic kidney disease, and no urinary findings suggestive of acute glomerular disease.

-For patients without intravascular fluid overload, lack of improvement in kidney function after two days of volume expansion with IV 25 percent albumin (1 g/kg of body weight per day up to 100 g/day), and withdrawal of diuretics for at least two days.

•Differential diagnosis – The diagnosis of HRS-AKI is one of exclusion, made only after other potential causes of acute kidney injury have been ruled out. Alternate etiologies of AKI in patients with cirrhosis include, but are not limited to, glomerulonephritis, prerenal disease, and ATN. (See 'Differential diagnosis' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Bruce Runyon, MD, FAASLD, who contributed to an earlier version of this topic review.