Timing of Dialysis Initiation in Acute Kidney Injury and Acute-On-Chronic Renal Failure Etienne Macedo,* and Ravindra L Mehta† *Division of Nephrology, University of S ~ ao Paulo, S ~ ao Paulo, Brazil, and †Division of Nephrology, School of Medicine, University of California, San Diego, California ABSTRACT The decision to provide dialytic support and choosing the ideal moment to initiate therapy are common impasses for physicians treating patients with acute kidney injury (AKI). Although renal replacement therapy (RRT) has been extensively used in clinical practice for more than 30 years, there is a paucity of evidence to guide clinicians on the optimal utilization of RRT in AKI. In the absence of traditional or urgent indications, there is no consensus on whether dialysis should be offered and when it should be started. The lack of agreed-upon parameters to guide the decision, the fear of the risk of the procedure, and the possible contribution to worse prognosis with RRT have resulted in a considerable variation in practice among physicians and centers. In this review, we summarize the evidence evaluating time of initiation of RRT and discuss possible approaches for future trials in addressing this issue. Patients with acute kidney injury (AKI) often require dialysis support to compensate for the declining renal function and to allow time for renal recovery. In clinical practice, there is no parameter to accurately distinguish an AKI patient who will need renal replacement therapy (RRT) support from those who will recover without dialysis. More- over, some recent studies have suggested that RRT initiation could be associated with worse outcomes in AKI patients compared with those presenting with similar severity of illness who are not submit- ted to RRT. Although it has been proposed as a main issue in AKI treatment, timing of RRT initia- tion has not been included as a controlled factor in any of the large, randomized controlled trials in this area. A few studies have suggested an association between early RRT and favorable clinical outcomes in patients with AKI, but currently there are no powered randomized clinical trials to guide clini- cians. This is largely because the parameters to define timing of initiation and the thresholds for the decision to initiate RRT “early” are not yet agreed upon. Furthermore, there is no agreement as to whether an early RRT initiation would benefit patient outcomes by the metabolic control of uremic toxins or by the prevention of volume overload. Finally, whether the benefits of the procedure are potentially greater than the risks associated with it is still an open question. In this review, we discuss the criteria usually applied for initiation of RRT, highlight the wide variation in clinical practice, review the evidence to guide decisions to initiate dialysis, and provide a framework for future studies in this field. Factors Influencing Decisions for Initiating RRT in AKI Many factors, including logistics, resource avail- ability, physician experience, and patient-related fac- tors, are involved in the decision of when to start RRT for AKI patients (Table 1). The patient- related factors include the trend of serum creatinine and blood urea nitrogen (BUN), severity of nonkid- ney organ dysfunction, fluid accumulation, and oli- guria (1). Most clinicians rely on the traditional indications, including severe hyperkalemia, severe acidosis, pulmonary edema, and uremic complica- tions, to guide the decision to initiate dialysis (1–5). In general, these indications favor initiating RRT only when there is clear evidence of renal functional deterioration to a point where the kidney is unlikely to recover quickly enough to avoid the deleterious consequences of altered kidney function. In recent years, experimental and clinical studies have shown that before detection of decreased glomerular filtra- tion rate (GFR), the inflammatory response associ- ated with kidney injury determines distant organ injury (6). Consequently, AKI may be regarded as a Address correspondence to: Ravindra L. Mehta, M.D., Division of Nephrology, School of Medicine, University of California, 200 West Arbor Drive, Mail Code 8342, San Diego, CA 92103, Tel.: +619 543 7310, Fax: +619 543 7420, or e-mail: rmehta@ucsd.edu Seminars in Dialysis—2013 DOI: 10.1111/sdi.12128 © 2013 Wiley Periodicals, Inc. 1 TRANSITION TO DIALYSIS: CONTROVERSIES IN ITS TIMING AND MODALITY