The Dynamic Nature of Renal Failure in Acute-on-Chronic Liver Failure: Sequence Matters

Acute-on-chronic liver failure (ACLF) is an acute deterioration of chronic liver disease or cirrhosis with high short-term mortality and frequent extrahepatic organ failure.^1-6 The study by Chang et al.⁷ in this issue of Gut and Liver offers an important refinement to our understanding of ACLF. Using a large Korean multicenter cohort, the authors demonstrate that the sequence of organ failure and not simply the number of organs involved, critically determines short-term prognosis. In this study, hepatic failure was associated with poorer survival irrespective of its presence at admission or later development. While renal failure that developed during hospitalization predicted lower survival, renal failure present at admission showed outcomes similar to those without renal failure. In sequence analyses, the most favorable prognosis was observed in patients who presented with isolated renal failure, and the worst outcomes occurred when organ failures accumulated sequentially, regardless of order.

The recent Acute Disease Quality Initiative and International Club of Ascites joint multidisciplinary consensus on acute kidney injury (AKI) in cirrhosis provides a valuable interpretive framework.⁸ It emphasizes that kidney dysfunction in cirrhosis encompasses a spectrum ranging from purely functional hepatorenal syndrome-AKI to mixed forms with structural tubular injury. This spectrum of reversibility may explain why “initial renal failure” in ACLF, often functional and rapidly correctable, carries a more favorable prognosis than hepatic failure, which reflects irreversible hepatocellular injury and drives systemic inflammation. In contrast, the development of secondary renal failure during hospitalization likely represents maladaptive repair and systemic collapse, consistent with the poor survival reported by Chang et al.⁷

In this study, the creatinine-based thresholds used to define renal failure (≥2.0 mg/dL, with a lower threshold of ≥1.5 mg/dL) can include patients with stable pre-existing chronic kidney disease who meet the criteria without acute deterioration, which likely contributed to the relatively favorable prognosis among those presenting with isolated renal failure. In addition, within the European Association for the Study of the Liver–Chronic Liver Failure (EASL-CLIF) framework, the renal failure definition is relatively permissive, whereas the hepatic failure threshold is comparatively strict at bilirubin ≥12.0 mg/dL. In a comparative analysis of EASL and Asian Pacific Association for the Study of the Liver definitions, among 5,653 patients who met either definition, 76% fulfilled only the EASL criteria, with renal failure as the most common organ failure and hepatic failure as the least common. The relatively low creatinine thresholds in this study may have contributed to the more favorable outcomes among patients classified as having renal failure at admission.

Compared with AKI in acute decompensation, AKI in ACLF tends to involve more severe structural kidney injury, follow a more progressive course, and more often require dialysis. The mortality risk with AKI also increases with higher AKI stage and higher ACLF grade.^8,9 Thus, the prognostic significance of AKI in ACLF should not be underestimated, even among patients who survive the initial hepatic insult. The integration of these insights suggests that dynamic organ crosstalk such as the liver–kidney axis is central to ACLF outcomes. Preventing secondary organ failure should be prioritized over managing established multi-organ dysfunction. This study underscores that early recognition and intervention, especially for renal dysfunction, may shift the trajectory of ACLF from irreversible decline to potential recovery. Future risk models for ACLF should incorporate not only the presence but also the sequence and reversibility of organ failure.