Renal replacement therapy (RRT) is increasingly used for organ support among hospitalized patients with severe AKI, particularly those in intensive care unit (ICU) settings.1 RRT can play an important role in achieving and maintaining fluid, electrolyte, acid-base, and uremic solute homeostasis and, in selected circumstances, and facilitate additional therapeutic interventions (e.g., nutrition, medications, transfusions). RRT can also prevent the occurrence or worsening of life-threatening complications commonly provoked by AKI, such as hyperkalemia, acidemia, and pulmonary edema. In critical illness, RRT may also represent an important platform of multi-organ support by potentially limiting worsening non-renal organ dysfunction that may be exacerbated by AKI. A longstanding and fundamental question about the application of RRT in AKI is: When is the optimal time to start therapy?
Definition of “timing” unclear
One challenge for clinicians when interpreting the literature on this issue is that there has been no consensus on how best to define “timing” related to RRT initiation in AKI. Published studies have been heterogeneous in their definitions for “early” or “delayed” start to RRT.2,3 Definitions have incorporated physiologic measures (e.g., urine output), biochemical measures (e.g., creatinine, urea), time relative to AKI onset, time relative to hospital or ICU admission, and time relative to the development of complications attributable to AKI. However, the terms “early” and “delayed” are generally relative. As such, “early” RRT in one clinical context may be “delayed” in another. Many studies have also failed to include outcome comparisons among patients who received early RRT with those who did not receive RRT, recognizing that selected patients will survive and recover kidney function without the need for RRT.4,5 Such heterogeneity in definitions for timing and strategies for comparing groups, in particular from observational data (often with variable designs and methodological quality), has generated challenges to provide clear guidance for health care professionals on this issue.
In severe AKI, particularly in ICU settings, there is a biologic rationale to support earlier initiation of RRT, even in the absence of so-called classic indications. In this context, earlier RRT will not only prevent the occurrence of overt life-threatening complications, but may translate into more rapid correction of acid-base, metabolic and fluid balance derangements. Observational data support this concept by showing that pre-emptive start of RRT prior to the development of conventional indications in critically ill patients with AKI was associated with reduced mortality.6,7
Conservative or delayed RRT
Alternatively, earlier RRT may confer risk for RRT-related complications, increased bedside workload and health care costs.8 For example, patients will require dedicated central venous access for RRT, be exposed to an extracorporeal circuit, and may receive anticoagulation. During treatment, ultrafiltration or rapid shifts in serum osmolarity may prompt intradialytic hypotension and contribute to iatrogenic delays in kidney recovery.9,10 As such, there is also rationale to adopt a watchful waiting approach in selected patients with severe AKI, and only start RRT in response to the development of AKI-related complications refractory to medical management.4
Several organizations have published guidelines that include statements on the timing of RRT initiation in AKI.11-13 Each of these guidelines provided relatively uncontroversial recommendations to start RRT urgently when confronted with potentially life-threatening complications of AKI related to fluid overload or severe electrolyte, metabolic, or acid-base disturbances. These guidelines further provide practical recommendations for health care professionals to weigh the broad clinical context, the patient’s illness trajectory, and the presence of conditions for which RRT will be likely to modify the course when considering the initiation of RRT. In the end, however, these guidelines all generally acknowledge the limitations of the existing literature, and each recommend additional high-quality studies be performed to inform practice.
Recent randomized trials
Prior systematic reviews, derived largely from observational studies and containing relatively few randomized trials, have had discordant conclusions about whether early compared with delayed strategies to starting RRT may improve outcomes in AKI.2,3,14 This is not unexpected given that a significant proportion of studies included in these reviews were susceptible to bias and confounding (i.e., retrospective, small sample size, variable definitions for timing, exclusion of patients with AKI not receiving RRT) or had limited generalizability (i.e., focused on selected populations, such as cardiac surgery patients).
More recently, a number of randomized trials have been reported that focused on timing strategies for initiation of RRT in critically ill patients with AKI.4,5,15-17 The ELAIN (Early Versus Late Initiation of Renal Replacement Therapy In Critically Ill Patients With Acute Kidney Injury) trial15 was a single-center trial in Germany that randomized 231 mostly post-surgical critically ill adults with AKI to 2 thresholds for starting RRT: early RRT, which involved starting RRT within 8 hours of fulfilling criteria for KDIGO (Kidney Disease: Improving Global Outcomes) stage 2 AKI, or delayed RRT, defined as starting RRT within 12 hours of developing KDIGO stage 3 AKI or the development of conventional indications. In this trial, all participants in the early RRT arm and 91% of participants in the delayed RRT arm received RRT (median 21 hour difference in starting RRT). ELAIN found that early compared with delayed RRT reduced the 90-day mortality rate (39.3% vs 54.7%; HR 0.66, 95% CI, 0.45-0.97). Early RRT also conferred shorter durations of RRT dependence (18 fewer days), mechanical ventilation, and hospitalization (37 fewer days).
The AKIKI (Artificial Kidney Initiation in Kidney Injury) trial was a multicenter randomized trial from France that compared 2 strategies for starting RRT among 620 critically ill adults with KDIGO Stage 3 AKI.4 The early RRT strategy started participants on RRT within 6 hours of fulfilling KDIGO stage 3 AKI, while the delayed RRT strategy deferred RRT until 1 or more conventional indications developed. Notably, only about 50% of patients randomized to the delayed RRT strategy commenced RRT. Investigators found no significant difference in 60-day mortality between strategies (48.5% for early vs 49.7% for delayed, P = 0.79).
The ideal time to start RRT in AKI has been a longstanding evidence care gap.18 The recent publication of several similarly-themed trials focused on this issue is clearly a welcome addition. The discrepant findings across trials may sustain the clinical uncertainty and practice variation regarding when to start RRT in AKI; however, there are fundamental differences in design, populations, and interventions across trials that warrant context-specific interpretation.
The AKIKI findings should caution those health care professionals who strongly advocate an early start to RRT, certainly in the absence of any conventional indication. Some patients may never need RRT because of early kidney recovery or changes in philosophy of care or death. Large randomized trials are the best opportunity to understand the natural history of such patients and fully describe the relative benefits and/or harms associated with RRT timing strategies and RRT use.19 One challenge for health care professionals when confronted with patients with AKI is reliably predicting who is going to worsen and ideally benefit most from starting RRT. At present, there are no clearly validated clinical or laboratory tools to clearly discriminate those who will progress to require RRT from those whose recovery is imminent. Near real-time estimates of glomerular filtration rate in the non-steady state conditions of AKI that inform about trajectory of kidney function would present useful tools for bedside professionals considering whether RRT should be started.20,21 Similarly, a recent small single-center prospective cohort study found the implementation of a clinical-decision support algorithm for starting RRT may be associated with improved outcomes in AKI, likely driven by greater reliability of care among those with lower illness severity.22 While promising, such adjuvants to clinical decision-making require further validation.
A key question is whether the additional data offered from these recent trials provide definitive guidance for when to ideally start RRT among critically ill patients with AKI. While the prevailing findings may suggest a more conservative strategy of watchful waiting to starting RRT in AKI may be acceptable in selected circumstances, AKI, particularly in the context of critical illness, remains a massively heterogeneous and complex syndrome. As such, recent studies have greatly extended our knowledge, but have not resolved this dilemma, and practice is likely to continue to vary widely. We believe that ongoing randomized trials remain essential to shed further light on this vexing question.
Sean M. Bagshaw, MD, MSc, is in the Department of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada. Ron Wald, MDCM, MPH, is in the Division of Nephrology, St. Michael’s Hospital and University of Toronto, Toronto, Canada, and is affiliated with the Li Ka Shing Knowledge Institute of St. Michael’s Hospital.
- Wald R, McArthur E, Adhikari NK, et al. Changing incidence and outcomes following dialysis-requiring acute kidney injury among critically ill adults: a population-based cohort study. Am J Kidney Dis 2015;65:870-877.
- Karvellas CJ, Farhat MR, Sajjad I, et al. A comparison of early versus late initiation of renal replacement therapy in critically ill patients with acute kidney injury: a systematic review and meta-analysis. Crit Care 2011;15:R72.
- Wierstra BT, Kadri S, Alomar S, et al. The impact of “early” versus “late” initiation of renal replacement therapy in critical care patients with acute kidney injury: a systematic review and evidence synthesis. Crit Care 2016;20:122.
- Gaudry S, Hajage D, Schortgen F, et al. Initiation strategies for renal-replacement therapy in the intensive care unit. N Engl J Med. 2016;375:122-133.
- Wald R, Adhikari NK, Smith OM, et al. Comparison of standard and accelerated initiation of renal replacement therapy in acute kidney injury. Kidney Int 2015;88:897-904.
- Liborio AB, Leite TT, Neves FM, et al. AKI complications in critically ill patients: association with mortality rates and RRT. Clin J Am Soc Nephrol 2015;10:21-28.
- Vaara ST, Reinikainen M, Wald R, et al. Timing of RRT based on the presence of conventional indications. Clin J Am Soc Nephrol 2014;9:1577-1585.
- Clark EG, Hiremath S. Progressively earlier initiation of renal replacement therapy for acute kidney injury is unwarranted and potentially harmful. Blood Purif 2016;41(1-3):159-165.
- Augustine JJ, Sandy D, Seifert TH, Paganini EP. A randomized controlled trial comparing intermittent with continuous dialysis in patients with ARF. Am J Kidney Dis 2004;44:1000-1007.
- Clark EG, Bagshaw SM. Unnecessary renal replacement therapy for acute kidney injury is harmful for renal recovery. Semin Dial. 2015;28:6-11.
- Kidney Disease Improving Global Outcome. KDIGO Clinical Practice Guideline for Acute Kidney Injury. 2012. http://kdigo.org/home/guidelines/acute-kidney-injury/. Accessed May 26, 2016.
- National Institute for Health and Care Excellence (NICE). Acute kidney injury: prevention, detection and management. 2013. https://www.nice.org.uk/guidance/cg169/.
- Vinsonneau C, Allain-Launay E, Blayau C, et al. Renal replacement therapy in adult and pediatric intensive care : Recommendations by an expert panel from the French Intensive Care Society (SRLF) with the French Society of Anesthesia Intensive Care (SFAR) French Group for Pediatric Intensive Care Emergencies (GFRUP) the French Dialysis Society (SFD). Ann Intensive Care 2015;5:58.
- Wang X, Jie Yuan W. Timing of initiation of renal replacement therapy in acute kidney injury: a systematic review and meta-analysis. Ren Fail 2012;34:396-402.
- Zarbock A, Kellum JA, Schmidt C, et al. Effect of early vs delayed initiation of renal replacement therapy on mortality in critically ill patients with acute kidney injury: The ELAIN randomized clinical trial. JAMA 2016;315:2190-2199.
- Combes A, Brechot N, Amour J, et al. Early high-volume hemofiltration versus standard care for post-cardiac surgery shock. The HEROICS Study. Am J Respir Crit Care Med 2015;192:1179-1190.
- Jamale TE, Hase NK, Kulkarni M, et al. Earlier-start versus usual-start dialysis in patients with community-acquired acute kidney injury: a randomized controlled trial. Am J Kidney Dis 2013;62:1116-1121.
- Wald R, Gallagher M, Bagshaw SM. Shedding new light on an old dilemma: Two trials examining the timing of renal replacement therapy initiation in acute kidney injury. Am J Kidney Dis 2017;69:14-17.
- Liu KD, Palevsky PM. RRT in AKI: Start early or wait? Clin J Am Soc Nephrol 2016.
- Mellas J. The description of a method for accurately estimating creatinine clearance in acute kidney injury. Math Biosci 2016;275:107-114.
- Seelhammer TG, Maile MD, Heung M, et al. Kinetic estimated glomerular filtration rate and acute kidney injury in cardiac surgery patients. J Crit Care 2016;31:249-254.
- Mendu ML, Ciociolo GR, Jr., McLaughlin SR, et al. A decision-making algorithm for initiation and discontinuation of RRT in severe AKI. Clin J Am Soc Nephrol 2017;12:228-236.