1. What is hepatorenal syndrome?
The current definition of hepatorenal syndrome (HRS) updated in 2007 by the International Ascites Club (IAC) states that it is “a potentially reversible syndrome that occurs in patients with cirrhosis, ascites and liver failure, consisting of impaired kidney function, marked abnormalities in cardiovascular function, and intense over-activity of the endogenous vasoactive systems.” It can appear spontaneously or follow a precipitating event. It is important to emphasize that HRS is a form of prerenal acute kidney injury (AKI) not associated with structural changes; a kidney biopsy usually reveals normal histology.
2. What is the incidence and prevalence of HRS?
In 1993, the annual incidence of HRS in patients with cirrhosis and ascites was reported as 8% and the probability of developing HRS was 18% at 1 year and 39% at 5 years. However, in 2006 a similar study showed a significantly lower prevalence of disease, with only 7.6% of cirrhotic patients developing HRS during the study period (40 ± 3 months) and a 5-year probability of developing HRS of 11.4%. These reductions are largely due to the increased recognition of the condition, the advances in the medical management of cirrhosis, and the availability of prophylactic antibiotics for spontaneous bacterial peritonitis (SBP).
3. What is the pathophysiology of HRS? ( fig. 8.1 )
Reduction in the effective arterial blood volume : Hemodynamic changes of significant arterial vasodilatation occur in advanced cirrhosis, which preferentially localizes in the splanchnic circulation. The pooling of blood in the splanchnic circulation, splanchnic steal syndrome , results in insufficient blood volume in other vascular compartments, including the systemic circulation, reducing the effective arterial blood volume .
Excess renal vasoconstriction : The reduction in effective arterial blood volume activates the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system, and stimulates the nonosmostically induced release of vasopressin. The vasoconstrictors decrease renal blood flow and, consequently, the glomerular filtration rate (GFR).
Abnormal renal autoregulation in advanced cirrhosis : In cirrhosis, the renal autoregulation curve, which describes the relationship of mean arterial pressure and renal blood flow, is shifted to the right. This means that for any given arterial pressure, there is less renal blood flow than in a healthy individual. The decreased renal blood flow may be due to excess sympathetic drive seen in cirrhosis. The decreased renal blood flow makes patients with advanced cirrhosis more susceptible to AKI.
Portal hypertension : Independent of splanchnic vasodilatation and systemic hemodynamic changes, increased portal pressure reduces renal blood flow. This is mediated by increased sympathetic nervous activity and is called the hepatorenal reflex. Insertion of a transjugular intrahepatic portosystemic shunt (TIPS) eliminates portal hypertension and increases renal blood flow.
Abnormal cardiac function in cirrhosis : The presence of systemic arterial vasodilatation in advanced cirrhosis leads to a hyperdynamic circulation with tachycardia, high cardiac output, and low systemic vascular resistance. The presence of cirrhotic cardiomyopathy, consisting of myocardial thickening, diastolic dysfunction at rest, and systolic dysfunction under conditions of stress, means that the heart is unable to further increase cardiac output in periods of stress (e.g., sepsis). This lack of a cardiac reserve predisposes to the development of HRS.
4. What is the clinical presentation of HRS?
HRS is a form of kidney injury, so patients present with increased serum creatinine and low urine output. Clinically, there are two types of HRS.
Acute or type 1 HRS is characterized by a rapidly progressive kidney failure in a cirrhotic patient with ascites. It usually develops following a precipitating event but can occur spontaneously. Patients are usually very ill, with severe jaundice, coagulopathy, and liver failure. Type 1 HRS is now renamed as AKI-HRS.
Chronic or type 2 HRS is characterized by moderate kidney failure, with a serum creatinine between 1.5 and 2.5 mg/dL. It evolves slowly over weeks to months in patients with ascites refractory to diuretics. Patients with type 2 HRS are usually less ill than those with type 1 HRS, with a milder degree of jaundice and coagulopathy.
5. What factors can precipitate the development of HRS?
Any condition that causes a further reduction of the effective arterial blood volume can precipitate HRS (see Fig. 8.1 ). These include over-diuresis, large-volume paracentesis (≥5 liters) without intravascular colloid replacement in patients with refractory ascites, and gastrointestinal bleeding. Other triggers are conditions that worsen the arterial vasodilatation, such as sepsis (especially SBP) or jaundice due to obstruction in the biliary tree (bile acids are vasodilators).
6. How is HRS diagnosed?
The diagnostic criteria for HRS were updated by the IAC in 2015. This followed the adaptation of a set of uniform nomenclature and diagnostic criteria for AKI. Table 8.1 outlines the diagnosis, staging, and definitions of progression/regression of AKI as proposed by the IAC. Using these criteria, AKI is defined as an increase in serum creatinine by 0.3 mg/dL in less than 48 hours, or a 50% increase in serum creatinine presumed to have occurred in the past 7 days from baseline. Type 1 HRS or AKI-HRS is a special type of AKI that is not responsive to volume replacement. The new diagnostic criteria of AKI-HRS as set out in 2015 modified the previous criteria set by the IAC in 2007. There has to be at least a doubling of serum creatinine without setting an absolute creatinine level (i.e., 2.5 mg/dL) for the diagnosis. The current proposed diagnostic criteria for AKI-HRS are:
Cirrhosis and ascites
Diagnosis of AKI according to the IAC-AKI criteria
No reduction in serum creatinine after at least 48 hours of diuretic withdrawal and volume expansion with albumin. The recommended dose of albumin is 1 g/kg body weight/day up to a maximum of 100 g/day.
Absence of shock
No current or recent treatment with nephrotoxic drugs
No evidence of structural kidney injury defined as:
Absence of proteinuria (>500 mg/day)
Absence of hematuria (>50 red blood cells/high power field)
Normal kidney ultrasonography
|Baseline SCr||Stable SCr in ≤ 3 months |
If not available, a stable SCr closest to the current one
If no previous SCr at all, use admission SCr
|Definition of AKI||↑ in SCr ≥ 0.3 mg/dL (26.4 µmol/L) ≤ 48 h, or ↑ 50% from baseline|
|Staging||Stage 1: ↑ SCr ≥ 0.3 mg/dL (26.4 µmol/L) or ↑ SCr ≥ 1.5–2.0 X from baseline |
Stage 2: ↑ SCr > 2.0–3.0 X from baseline
Stage 3: ↑ SCr > 3.0 X from baseline, or SCr ≥ 4.0 mg/dL (352 µmol/L) with an acute ↑ of ≥ 0.3 mg/dL (26.4 µmol/L), or initiation of renal replacement therapy
|Progression||Progression of AKI to a higher stage, or need for renal replacement therapy|
|Regression||Regression of AKI to lower stage|
|Response to treatment||None: No regression of AKI |
Partial: Regression of AKI stage with a ↓ in SCr to a value ≥ 0.3 mg/ dL (26.4 µmol/L) above baseline
Complete: ↓ SCr < 0.3 mg/dL (26.4 µmol/L) from baseline
It is possible that patients who fulfill these criteria may still have structural damage, such as acute tubular necrosis (ATN). Urine biomarkers will become an important element in making a more accurate differential diagnosis between HRS and ATN.
Urinary electrolyte criteria are not required for the diagnosis of AKI-HRS, and the presence of infection does not preclude its diagnosis.
7. Why was an absolute creatinine level removed from the diagnostic criteria for AKI-HRS?
The current diagnostic criteria for AKI-HRS do not specify an absolute creatinine level. Serum creatinine is not an accurate measurement in patients with cirrhosis. In cirrhosis, low protein intake, loss of muscle mass, diminished hepatic synthesis of creatine, and an enlarged volume of distribution, all lower the serum creatinine irrespective of kidney function. This can delay the recognition of kidney dysfunction and have a negative impact on patient outcomes. Using a change in serum creatinine allows an earlier diagnosis of AKI and more timely intervention. This may lead to improved outcomes.
8. What is the diagnostic work-up and initial management of the patient with cirrhosis and AKI?
A trial of diuretic withdrawal, together with intravascular volume replacement should be done, as this can replenish the effective arterial blood volume. The intravascular volume replacement can be blood if the patient is anemic or albumin at the dose of 1 g/kg of body weight up to a maximum of 100 g/day.
The work-up should consist of a full work-up, including blood cultures, chest x-ray, urine and sputum cultures, a diagnostic paracentesis to exclude SBP, and the swabbing of any possible skin sources of infection. The threshold for starting antibiotics should be low. In order to exclude parenchymal kidney disease, the urine should be examined for the presence of protein, blood, and casts. An abdominal ultrasound should be performed to exclude small kidneys—indicative of parenchymal kidney disease—or structural abnormalities in the kidneys. Postrenal obstruction is an extremely uncommon cause of AKI in cirrhosis, and bladder catheterization is usually not done to avoid instrumentation-induced infections.