Fluid Overload Associates With Major Adverse Kidney Events in Critically Ill Patients With Acute Kidney Injury Requiring Continuous Renal Replacement Therapy Objectives: We examined the association between fluid overload and major adverse kidney events in critically ill patients requiring continuous renal replacement therapy for acute kidney injury. Design: Retrospective cohort study. Setting: ICU in a tertiary medical center. Patients: Four-hundred eighty-one critically ill adults requiring continuous renal replacement therapy for acute kidney injury. Interventions: None. Measurements and Main Results: Fluid overload was assessed as fluid balance from admission to continuous renal replacement therapy initiation, adjusted for body weight. Major adverse kidney events were defined as a composite of mortality, renal replacement therapy-dependence or inability to recover 50% of baseline estimated glomerular filtration rate (if not on renal replacement therapy) evaluated up to 90 days after discharge. Patients with fluid overload less than or equal to 10% were less likely to experience major adverse kidney events than those with fluid overload greater than 10% (71.6% vs 79.4%; p = 0.047). Multivariable logistic regression showed that fluid overload greater than 10% was associated with a 58% increased odds of major adverse kidney events (p = 0.046), even after adjusting for timing of continuous renal replacement therapy initiation. There was also a 2.7% increased odds of major adverse kidney events for every 1 day increase from ICU admission to continuous renal replacement therapy initiation (p = 0.024). Fluid overload greater than 10% was also found to be independently associated with an 82% increased odds of hospital mortality (p = 0.004) and 2.5 fewer ventilator-free days (p = 0.044), compared with fluid overload less than or equal to 10%. Conclusions: In critically ill patients with acute kidney injury requiring continuous renal replacement therapy, greater than 10% fluid overload was associated with higher risk of 90-day major adverse kidney events, including mortality and decreased renal recovery. Increased time between ICU admission and continuous renal replacement therapy initiation was also associated with decreased renal recovery. Fluid overload represents a potentially modifiable risk factor, independent of timing of continuous renal replacement therapy initiation, that should be further examined in interventional studies. Dr. Woodward designed the project, managed the database, gathered the data, prepared the figures, and wrote and submitted the article. Dr. Lambert and Ms. Li managed the database, analyzed the statistical data, and prepared the figures. Drs. Ortiz-Soriano, Bissell, Adams, Yessayan, and Morris designed the project and edited the article. Dr. Ruiz-Conejo gathered data and wrote the article. Mr. Kelly designed the project, managed the database, and extracted data. Dr. Neyra designed and supervised the project, and wrote and submitted the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Dr. Lambert received support for article research from the National Institutes of Health. Dr. Neyra is currently supported by an Early Career Pilot Grant from the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1TR001998. The remaining authors have disclosed that they do not have any potential conflicts of interest. This work was performed at the University of Kentucky, Lexington, KY. For information regarding this article, E-mail: javier.neyra@uky.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.