1. ICA and KDIGO Diagnostic Criteria

Hepatorenal Syndrome (HRS) is a unique form of functional renal failure occurring in patients with advanced cirrhosis. Its diagnosis hinges on dynamic changes in serum creatinine (SCr) and the systematic exclusion of other potential causes of kidney injury. Utilizing the consensus criteria from the International Club of Ascites (ICA) and KDIGO is essential for prompt recognition and intervention.

A. Definition of Acute Kidney Injury (AKI) in Cirrhosis

The diagnosis begins with identifying AKI based on specific SCr thresholds:

• An absolute increase in SCr of ≥0.3 mg/dL within 48 hours.
• A relative increase in SCr of ≥50% from a stable baseline value within the previous 7 days.

B. Essential Exclusion Criteria

Before diagnosing HRS, other causes of AKI must be ruled out. This involves a three-pronged approach:

1. Rule out hemodynamic instability: The patient should not be in circulatory shock.
2. Remove potential insults: Discontinue all nephrotoxic medications (e.g., NSAIDs, aminoglycosides) and stop diuretic therapy.
3. Exclude structural kidney disease: There should be no signs of intrinsic renal pathology, such as significant proteinuria (>500 mg/day), hematuria (>50 RBCs/HPF), or abnormal findings on renal ultrasound.

C. The Albumin Challenge

A crucial diagnostic step is the albumin challenge to rule out pre-renal azotemia from true volume depletion. The protocol is:

• Administer intravenous albumin at a dose of 1 g/kg of body weight on day 1 (maximum 100 g).
• Continue with 20–40 g of albumin daily for the next 48 hours.
• A diagnosis of HRS is confirmed if there is no improvement in SCr after 48 hours of diuretic withdrawal and adequate volume expansion with albumin.

2. Essential Laboratory and Imaging Studies

Laboratory trends and non-invasive imaging are vital to support a functional etiology for HRS by excluding intrinsic or post-renal causes of kidney failure.

A. Serum and Urine Studies

• Serum Creatinine: As noted, SCr trends are more important than absolute values. In cases of diagnostic uncertainty, alternative GFR markers like cystatin C or a measured 24-hour creatinine clearance can provide a more accurate assessment of renal function.
• Urine Studies: HRS is a state of maximal sodium and water retention. Classic findings include a very low urine sodium concentration (<10 mmol/L) and a fractional excretion of sodium (FeNa) <1%.
• Fractional Excretion of Urea (FeUrea): If the patient has recently received diuretics, FeNa is unreliable. In this setting, FeUrea is the preferred test. A value <35% strongly suggests a pre-renal or HRS physiology.

B. Renal Ultrasound

A renal ultrasound is mandatory in the workup of AKI in cirrhosis. Its primary roles are to:

• Exclude obstruction: Rule out hydronephrosis, which would indicate a post-renal cause.
• Assess parenchyma: In HRS, the kidneys should appear normal in size and echotexture. Evidence of chronic changes, such as cortical scarring or reduced size, would point toward pre-existing chronic kidney disease.

3. Classification and Staging

The modern classification of HRS distinguishes between an acute, rapidly progressive form (HRS-AKI) and a more chronic, insidious form (HRS-CKD). This distinction, along with AKI staging, is critical for determining the urgency of therapy and prognosis.

A. HRS-AKI (Formerly Type 1 HRS)

This is an acute, life-threatening condition characterized by a rapid decline in renal function, defined by a doubling of SCr to a level ≥2.5 mg/dL in less than 2 weeks. It is staged according to the ICA-AKI criteria, which directly correlate with outcomes.

B. HRS-CKD (Formerly Type 2 HRS)

This form involves a more indolent, slower rise in creatinine to a value >1.5 mg/dL. It is not classified as AKI. HRS-CKD is typically associated with refractory ascites and has a better short-term prognosis than HRS-AKI, but it still signifies advanced liver disease.

C. Clinical Implications

• HRS-AKI is a medical emergency requiring immediate hospitalization, initiation of vasoconstrictor therapy (e.g., terlipressin) and albumin, and a search for precipitating factors like infection.
• HRS-CKD management focuses on controlling ascites and evaluating the patient for liver transplantation. These patients may be candidates for simultaneous liver-kidney transplantation (SLK) if their GFR remains <30 mL/min or they require dialysis for over 6 weeks.

4. Emerging Biomarkers and Controversies

While the diagnosis of HRS is currently based on clinical and standard laboratory criteria, research into novel urinary biomarkers aims to improve the differentiation from acute tubular necrosis (ATN), the most common and challenging differential diagnosis.

A. Urinary Biomarkers

• Neutrophil Gelatinase-Associated Lipocalin (NGAL): This is the most studied biomarker. In general, lower urinary NGAL levels (<130–150 ng/mL) are suggestive of HRS, whereas very high levels (>220 ng/mL) favor a diagnosis of ATN, which involves structural tubular injury.
• Other Markers: Interleukin-18 (IL-18), Kidney Injury Molecule-1 (KIM-1), and liver-type fatty acid-binding protein (L-FABP) are also being investigated, with similar patterns suggesting that higher levels correlate with tubular damage (ATN) rather than functional changes (HRS).

B. Limitations and Current Status

Despite promising data, several barriers prevent the routine use of these biomarkers:

• Confounding Factors: Sepsis and systemic inflammation, common in cirrhosis, can independently raise NGAL levels, leading to false-positive results for ATN.
• Lack of Standardization: There are no universally accepted cutoff values, and assay availability and cost remain significant limitations.
• Guideline Status: No major clinical practice guideline currently mandates biomarker testing for the diagnosis of HRS. They remain investigational tools.

5. Clinical Decision Algorithm

A systematic, stepwise approach is essential to streamline the diagnosis of HRS and expedite the initiation of life-saving pharmacotherapy. The following algorithm integrates the key diagnostic and management steps.