Objective To assess the relationship between the change in fluid overload at 48 h after initiation of continuous renal replacement therapy (CRRT) and 28-day mortality in critically ill patients with acute kidney injury (AKI). Methods A retrospective cohort study was performed using data from the MIMIC-IV database from 2008 to 2019. Patients who received CRRT for AKI for more than 24 h within 14 d of admission to the intensive care unit were included. The exposure variable was the proportion of change of fluid overload (ΔFO%, defined as the difference between body weight normalized fluid input and output) at 48 h after CRRT initiation, and the endpoint was 28-day mortality. Generalized additive linear regression models and logistic regression models were used to determine the relationship between the exposure and endpoint. Results A total of 911 patients were included in the study, with a median (lower quartile, upper quartile) ΔFO% of −3.27% (−6.03%, 0.01%) and a 28-day mortality of 40.1%. Generalized additive linear regression model showed that the ΔFO% at 48 h after CRRT initiation was associated with a J-shaped curve with 28-day mortality. After adjusting for other variables, as compared with the second quartile of ΔFO% group, the first quartile group [odds ratio (OR)=1.23, 95% confidence interval (CI) (0.81, 1.87), P=0.338] was not associated with higher risk of 28-day mortality, while the third quartile group [OR=1.54, 95%CI (1.01, 2.35), P=0.046] and the fourth quartile group [OR=2.05, 95%CI (1.32, 3.18), P=0.001] were significantly associated with higher risk of 28-day mortality. There was no significant relationship between ΔFO% groups and 28-day mortality in the first 24-hour after CRRT initiation (P>0.05), but there was a linear relationship between ΔFO% and 28-day mortality in the second 24-hour after CRRT initiation, the larger the ΔFO%, the higher the mortality rate [OR=1.10, 95%CI (1.04 1.16), P<0.001 for per 1% increase]. ConclusionIn critically ill patients with AKI, the ΔFO% greater than −3.27% within 48 h after CRRT initiation is independently associated with an increased risk of 28-day mortality, and the goals of CRRT fluid management may be dynamical.