In patients with advanced cirrhosis and ascites, what serum bilirubin level or rise is associated with an increased risk of hepatorenal‑syndrome acute kidney injury?

Bilirubin Levels and Risk of Hepatorenal Syndrome-AKI in Advanced Cirrhosis

In patients with advanced cirrhosis and ascites, bilirubin >3-5 mg/dL is associated with increased post-procedural complications including mortality, though no specific bilirubin threshold has been established as a definitive predictor of hepatorenal syndrome-AKI development. 1

Evidence from Guidelines on Bilirubin as a Risk Factor

The most recent EASL guidelines (2025) examining TIPS candidacy in cirrhotic patients note that a combination of high bilirubin level and low platelet count is associated with increased post-TIPS complications, including mortality, in patients with refractory ascites. 1 However, these guidelines explicitly state that no studies provide strong evidence of a specific cut-off for bilirubin above which complications should be considered inevitable. 1

The guidelines further note that patients with total bilirubin >3-5 mg/dL were included in only a limited number of prospective randomized trials, making it difficult to generate definitive conclusions about this threshold. 1

Bilirubin as Part of Multifactorial Risk Assessment

Rather than functioning as an isolated predictor, bilirubin appears to contribute to HRS-AKI risk when combined with other markers of hepatic dysfunction:

• Elevated bilirubin combined with elevated MELD score and Child-Pugh class C cirrhosis are collectively associated with increased complications and mortality in patients with refractory ascites. 1

• Recent research (2023) found that hyperbilirubinemia alone was NOT significantly correlated with increased risk of developing HRS (p=0.157), suggesting bilirubin is not an independent predictor when examined in isolation. 2

Specific Predictors Identified in Recent Research

A 2021 multicenter study of 529 cirrhotic patients with AKI identified bilirubin >2 mg/dL as one of five independent predictors of HRS development, along with history of ascites, creatinine >2.5 mg/dL, albumin <3 g/dL, and spontaneous bacterial peritonitis. 3 This lower threshold (>2 mg/dL rather than >3-5 mg/dL) suggests that even moderate hyperbilirubinemia may signal increased HRS risk when present with other decompensation features.

Clinical Context and Confounding Factors

Hyperbilirubinemia can interfere with serum creatinine assays, causing false elevation with Jaffe assays and false reduction with enzymatic assays, potentially misleading AKI assessment. 1 This technical limitation means that in patients with marked hyperbilirubinemia, creatinine measurements may not accurately reflect true kidney function, complicating both AKI diagnosis and HRS-AKI differentiation. 1

Practical Algorithm for Risk Stratification

When evaluating HRS-AKI risk in a cirrhotic patient with ascites, assess bilirubin in combination with:

1. Serum creatinine trajectory – rising creatinine ≥0.3 mg/dL within 48 hours or ≥1.5× baseline within 7 days defines AKI 1
2. Albumin level – albumin <3 g/dL increases HRS risk 3, 2
3. Presence of ascites – strongest predictor of HRS development 3
4. MELD score – elevated MELD combined with high bilirubin predicts worse outcomes 1
5. Infection markers – particularly spontaneous bacterial peritonitis 3, 2

If bilirubin >2 mg/dL is present alongside ≥2 of these factors, the patient is at substantially elevated risk for HRS-AKI and warrants intensive monitoring with serial creatinine measurements every 48 hours. 3

Common Pitfalls

• Do not rely on a single bilirubin threshold to predict or exclude HRS-AKI risk; the evidence does not support an absolute cut-off. 1

• Do not interpret creatinine values in isolation when bilirubin is markedly elevated (>5 mg/dL), as assay interference may produce spurious results. 1

• Do not wait for bilirubin to reach 3-5 mg/dL before considering HRS risk; research suggests bilirubin >2 mg/dL combined with other factors already signals increased risk. 3