<p>A potential interaction between citrate and lactate metabolism may exist in critically ill patients receiving continuous renal replacement therapy (CRRT) with regional citrate anticoagulation (RCA). Although prior studies have investigated the relationships of initial lactate levels and lactate kinetics with citrate accumulation and clinical outcomes, the prognostic significance of lactate kinetics during RCA-CRRT remains inadequately defined. Critically ill patients undergoing CRRT (CRRT cohort) and those receiving RCA (Lactate Kinetics cohort) were identified from the MIMIC-Ⅳ (v3.1) database, as well as from the MIMIC-Ⅲ (v1.4) database (Lactate Kinetics Validation cohort). Propensity score matching, Kaplan-Meier survival curves, and Cox regression models were employed to assess the association between RCA use and 7-day and 28-day all-cause mortality. Latent growth mixture models, receiver operating characteristic curves, and restricted cubic splines were applied to identify lactate kinetics during RCA-CRRT. The association between lactate kinetics and mortality was evaluated using Kaplan-Meier survival curves and Cox regression models. LASSO-logistic regression analysis was applied to identify clinical characteristics associated with lactate kinetics. A total of 1,952, 1,064, and 209 patients were included in the CRRT cohort, Lactate Kinetics cohort, and Lactate Kinetics Validation cohort, respectively. The adjusted 7-day all-cause mortality risk was lower in patients who received RCA compared to those who did not, whereas no significant association was observed for 28-day mortality risk. Four distinct lactate trajectories during RCA-CRRT were identified: Class 1, low lactate with a stable trend; Class 2, high lactate with an improving trend; Classes 3–4, moderate lactate with gradually or rapidly worsening trends. Patients in Classes 3–4 exhibited significantly higher 7-day and 28-day mortality risks compared with Class 1, whereas Classes 2 showed no significant difference. SOFA score, respiratory failure, baseline lactate level, and mean daily citrate consumption were associated with an increased risk of lactate worsening, whereas pH and total carbon dioxide levels were associated with a decreased risk of lactate worsening. Patients with an increase in lactate greater than 1 mmol/L had significantly higher 7-day and 28-day mortality risks compared to those with an increase of less than or equal to 1 mmol/L. Although RCA may not increase overall mortality risk in critically ill patients, lactate worsening during RCA-CRRT has been observed and is strongly associated with adverse outcomes in certain patient populations. Timely clinical evaluation and individualized treatment adjustments are appropriate for these patients.</p>