Development and patterns of acute-on-chronic liver failure in patients with cirrhosis and acute kidney injury.

Background & Aims: The prevalence and evolution of acute-on-chronic liver failure (ACLF), particularly extrarenal organ failures, in patients with cirrhosis and acute kidney injury (AKI) are not well characterized. This study investigated the development and progression of ACLF in patients with cirrhosis who develop AKI, aiming to improve understanding of disease course during the critical period following AKI onset. Methods: We conducted a retrospective cohort study of hospitalized patients with cirrhosis and AKI at two tertiary centers between 2010 and 2023. Data on AKI etiology, treatment, ACLF development and progression, and survival were collected. Multivariable regression models were used to assess associations between baseline and AKI-related characteristics, ACLF outcomes, and mortality. Results: A total of 672 patients (71% male) were included. AKI progression or non-response to therapy occurred in 47% of patients. ACLF was present at the time of AKI diagnosis in 406 patients (60%); among these, 106 (26%) experienced ACLF progression, predominantly involving renal, respiratory, and circulatory failure. Of the 266 patients without ACLF at AKI diagnosis (40%), 101 (38%) subsequently developed ACLF, most commonly with renal, respiratory, and liver failure. In multivariable analysis, patients with hepatorenal syndrome-AKI (HRS-AKI) or other/mixed AKI etiologies had a higher risk of ACLF development compared to those with pre-renal AKI (odds ratio [OR] 9.67, 95% CI 3.96-23.57; OR 4.98, 95% CI 1.78-12.95, respectively). HRS-AKI and AKI stage 2 were independently associated with ACLF progression after adjustment for MELD score and relevant clinical risk factors (OR 2.31, 95% CI 1.08-4.95; OR 2.35, 95% CI 1.03-5.36). The cumulative incidence of death was 47% at 90 days after AKI diagnosis (95% CI 44-51). Conclusions: Patients with cirrhosis who develop AKI are at high risk of ACLF development and mortality. Respiratory failure is the most frequent extrarenal organ failure among patients who develop ACLF or experience ACLF progression. Impact and implications: This study highlights the significant risk of acute-on-chronic liver failure development in patients with cirrhosis and acute kidney injury (AKI), particularly in those with hepatorenal syndrome-AKI or other/mixed types of AKI. Given the high short-term mortality observed, early recognition and risk stratification of AKI in cirrhosis are crucial. These findings are particularly relevant for hepatologists, nephrologists, and intensivists, as they underscore the need for improved therapeutic strategies targeting AKI non-responders. Future prospective studies should not only explore targeted interventions to improve outcomes in this high-risk population but also aim to elucidate the underlying pathophysiology driving AKI progression and acute-on-chronic liver failure development in patients with cirrhosis and AKI.