Hepatorenal syndrome HRS is a cause of acute kidney injury AKI that can be seen in those with acute or chronic liver disease. This article explains the classification, diagnosis and management of HRS-AKI.

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Hepatorenal syndrome HRS is a multiorgan condition affecting the kidneys and the liver. Traditionally, HRS has been classified into two types.

Type 1 HRS has a more rapid onset, often precipitated by bacterial infection, gastrointestinal haemorrhage, large-volume paracentesis without albumin administration, or excessive response to diuretics, alcohol, or drugs. It can rapidly lead to decompensation, including renal and liver failure, as well as encephalopathy.

Type 2 HRS is typically spontaneous and has a slower progression, with refractory ascites as the primary clinical presentation.

In relatively recent years, the definition of HRS and the subtypes have evolved, and they have largely been classified based on acute (AKI) or chronic kidney injury (CKI).

Functional kidney injury in cirrhotic patients who do not meet the criteria of HRS-AKI is termed HRS-Non-AKI and is based on the estimated glomerular filtration rate (eGFR) rather than the serum creatinine. HRS-NAKI is further divided into two subtypes; HRS - Acute Kidney Disease (HRS-AKD) and HRS-CKD.

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Diagnosis

The following are the criteria for diagnosis of HRS-AKI

• Cirrhosis with ascites
• Diagnosis of AKI
• No response after 2 consecutive days of diuretic withdrawal and plasma volume expansion with albumin infusion (1 g/kg body weight per day)
• Absence of shock
• No current or recent use of nephrotoxic drugs (NSAIDs, aminoglycosides, or iodinated contrast media)
• No signs of structural kidney injury, as indicated by proteinuria (>500 mg per day), microhematuria (>50 red blood cells per high‐power field), and/or abnormal renal ultrasonography

Diagnosis of AKI

By convention, stable creatinine values within the previous 3 months before hospitalisation can be used as the baseline in the diagnosis of AKI. If a previous creatinine before admission is not available, a formal diagnosis of AKI can only be made if creatinine continues to rise during hospitalisation. AKI can be staged according to the criteria listed in the below table.

AKI Stage	Description
Stage 1	Increase of creatinine ≥0.3 mg/dL up to 2‐fold of baseline
Stage 2	Increase in creatinine between 2‐fold and 3‐fold of baseline
Stage 3	Increase in creatinine >3‐fold of baseline or creatinine >4 mg/dL (353.6 µmol/L) with an acute increase ≥0.3 mg/dL (26.5 µmol/L) or the initiation of RRT

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Aetiology of AKI

1. The main aetiologies for AKI in cirrhosis are prerenal AKI and acute tubular necrosis (ATN).
2. The two main causes of prerenal AKI are hypovolemia and HRS‐AKI.
3. ATN is usually due to septic or hypovolemic shock and, less commonly, nephrotoxic drugs/agents.
4. Bile cast nephropathy in patients with hyperbilirubinemia.
5. Glomerulonephritis e.g., immunoglobulin A in alcohol‐associated cirrhosis, membranous or Membranoproliferative glomerulonephritis in hepatitis B virus/hepatitis C virus cirrhosis.
6. Postrenal obstruction is a less common cause of AKI, which should be considered as part of the differential diagnosis.

Urine biomarkers of tubular damage are potentially useful for differential diagnosis of AKI in cirrhosis, including neutrophil gelatinase‐associated lipocalin (NGAL), interleukin‐18, liver fatty‐acid binding protein, and albumin. Among those, urine NGAL is the most promising biomarker. The best time to measure NGAL seems to be day 3 of diagnosis.

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Prevention of AKI

The first principle in the prevention of AKI is the treatment or prevention of possible precipitating factors, particularly gastrointestinal bleeding and bacterial infections, and avoiding large-volume paracentesis without albumin administration. In addition, there are specific circumstances for which management recommendations may be made to prevent AKI. For example, IV albumin, together with antibiotics, reduces the incidence of HRS‐AKI and improves survival in patients with SBP. By contrast, albumin in patients with cirrhosis and bacterial infections other than SBP neither prevents HRS‐AKI nor improves survival.

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Management of AKI

Management in an intensive or intermediate care unit should be considered. Diuretics should be stopped after the diagnosis of AKI. Patients with spontaneous bacterial peritonitis should be treated promptly and remain on long-term antibiotic therapy to prevent the development of HRS. Those with sepsis from other sources should also be treated promptly to limit the release of sepsis-related vasoactive mediators.

The active medical treatment of HRS is directed at splanchnic vasoconstriction which results in increased systemic vascular resistance and mean arterial pressure.

Several randomised controlled trials and meta‐analyses have shown that vasoconstrictors, either terlipressin or norepinephrine, in combination with albumin are effective in improving kidney function in patients with HRS‐AKI, with a response rate of 20%‐80% (average ~50%).

In conjunction with terlipressin, albumin is infused at a dose of 1 g/kg on day 1 of therapy followed by 40‐50 g/day, continued for the duration of therapy.

Side effects are mainly related to vasoconstrictive effects of the drugs (abdominal pain or ischemia of fingers, skin, intestines, heart, and so on) or the development of pulmonary oedema from albumin infusion.

The risk of ischemic side effects related to terlipressin may be reduced by administration of the drug in a continuous IV infusion (start dose 2 mg/day, increased every 24‐48 hours up to 12 mg/day until creatinine decreases).

Norepinephrine appears to be equally effective as terlipressin, although there is less data. Norepinephrine is given as continuous IV infusion, typically in an intensive care unit setting, starting at 0.5 mg/hour to achieve an increase in mean arterial pressure of at least 10 mm Hg or an increase in urine output of >200 mL/4 hours.

When medical management fails, surgical/interventional management involves the placement of a transjugular intrahepatic portosystemic shunt (TIPS). This type of surgical treatment is established with the insertion of an intrahepatic stent to connect the portal vein to the hepatic vein. The shunt redirects portal blood into the systemic circulation, reducing portal pressure and increasing systemic venous return. This reduces the arterial hypoperfusion and thereby down-regulates stimulation of the RAAS and SNS.

Other experimental techniques such as molecular adsorbent recirculating system, a modified dialysis technique aimed at removing substances causing vasodilation like nitric oxide, tumour necrosis factor, and cytokines have not been shown to improve overall survival.

Renal replacement therapy has been tried in patients who do not respond to the vasoconstrictors above or are poor candidates for TIPS. However, both these therapies may be considered more appropriate as a bridge to transplant.

Renal Replacement Therapy RRT

The optimal timing for initiation of RRT has not been studied in patients with cirrhosis. Initiation of RRT should be made on clinical grounds, including worsening kidney function, electrolyte disturbances such as severe acidosis, hyponatremia or hyperkalemia not improving with medical management, diuretic intolerance, or increasing volume overload. Continuous RRT is the modality preferred to intermittent dialysis in hemodynamically unstable patients.

Disclaimer- The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of M3 India.

About the author of this article: Dr Bhavin Mandowara is a practising nephrologist at Zydus Hospital, Ahmedabad.