AKIKI: Timing of Renal-Replacement Therapy in AKI (2016)

“In a critically ill patient with severe acute kidney injury, a delayed strategy for initiating renal-replacement therapy was not associated with a significant difference in 60-day mortality, as compared with an early strategy.”

  • The AKIKI Study Group

1. Publication Details

  • Trial Title: Timing of Renal-Replacement Therapy in Patients with Acute Kidney Injury and Sepsis
  • Citation: Gaudry S, Hajage D, Schortgen F, et al. Timing of Renal-Replacement Therapy in Patients with Acute Kidney Injury and Sepsis. N Engl J Med. 2016;375(2):122-133. DOI: 10.1056/NEJMoa1603017
  • Published: July 14, 2016, in The New England Journal of Medicine
  • Author: Stéphane Gaudry, M.D., Ph.D.
  • Funding: French Ministry of Health

2. Keywords

  • Acute Kidney Injury (AKI), Renal Replacement Therapy (RRT), Sepsis, Critical Care, Randomized Controlled Trial

3. The Clinical Question

  • In critically ill patients with severe acute kidney injury (Population), does a delayed strategy for initiating renal-replacement therapy (RRT) (Intervention) compared to an early strategy (Comparison) affect 60-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Acute kidney injury (AKI) is a common and serious complication in critically ill patients, and the optimal time to initiate renal-replacement therapy (RRT) was a major area of clinical uncertainty. While RRT is life-saving for severe AKI, starting it too early could expose patients to unnecessary risks (e.g., catheter-related infections, hemodynamic instability) and costs.
  • Knowledge Gap: Previous studies on the timing of RRT were mostly small, observational, and had conflicting results. There was no high-quality evidence from a large randomized trial to guide this common clinical decision.
  • Proposed Hypothesis: The authors hypothesized that a delayed strategy for initiating RRT would not be inferior to an early strategy with respect to 60-day mortality.

5. Study Design and Methods

  • Design: A multicenter, prospective, open-label, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: 31 intensive care units (ICUs) in France.
  • Trial Period: Enrollment ran from September 2013 to June 2015.
  • Population:
    • Inclusion Criteria: Critically ill patients with severe AKI (KDIGO stage 3), receiving mechanical ventilation, catecholamine infusions, or both.
    • Exclusion Criteria: Included life-threatening complications mandating immediate RRT (e.g., severe hyperkalemia, metabolic acidosis, or pulmonary edema), end-stage renal disease, or a decision to withhold life-sustaining treatment.
  • Intervention: A “delayed” strategy, where RRT was initiated only if one of the urgent criteria developed or if the AKI did not resolve after a period of watchful waiting.
  • Control: An “early” strategy, where RRT was initiated immediately after randomization.
  • Management Common to Both Groups: All other aspects of ICU care, including the modality of RRT (intermittent or continuous), were at the discretion of the treating clinicians.
  • Power and Sample Size: The authors calculated that a sample of 620 patients would provide 80% power to detect a 10% absolute difference in 60-day mortality. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80% is the standard accepted level for clinical trials).
  • Outcomes:
    • Primary Outcome: All-cause mortality at day 60.
    • Secondary Outcomes: Included the proportion of patients who received RRT, ventilator-free days, and the incidence of catheter-related bloodstream infections.

6. Key Results

  • Enrollment and Baseline: 620 patients were randomized (312 to the early group and 308 to the delayed group). The baseline characteristics were well-matched.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in 60-day mortality between the groups. 153 of 312 patients (48.5%) in the early-strategy group died, compared with 155 of 308 patients (50.3%) in the delayed-strategy group (p=0.79).
  • Secondary Outcomes: A key finding was that in the delayed-strategy group, 151 patients (49%) recovered kidney function and never required RRT. The delayed-strategy group had significantly fewer catheter-related bloodstream infections.
  • Adverse Events: The incidence of complications like hyperkalemia was not significantly different between the groups.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of death between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute mortality rates and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.79 is much higher than the 0.05 threshold, indicating that the small difference in mortality between the groups was not statistically significant and was very likely due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures: As the trial was neutral, ARR and NNT are not applicable.
  • Subgroup Analyses: No significant differences were found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, controlled design provided high-quality evidence on a critical clinical question.
  • Generalizability: The pragmatic design and inclusion of 31 diverse ICUs make the findings highly generalizable to real-world practice.
  • Statistical Power: The study was adequately powered for its primary outcome.
  • Patient-Centered Outcomes: The primary outcome of 60-day mortality is a robust and patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label (unblinded), which is a significant limitation. Clinicians’ knowledge of the group assignment could have influenced their decisions about other aspects of care (performance bias).
  • External Validity (Generalizability): The study population consisted of patients with a high severity of illness, and the results may not apply to less sick patients with AKI.
  • Other: The criteria for initiating RRT in the “delayed” group were based on the development of urgent complications, which may not represent all clinical scenarios for delayed initiation.

10. Conclusion of the Authors

  • In critically ill patients with severe acute kidney injury, there was no significant difference in 60-day mortality between an early and a delayed strategy for the initiation of renal-replacement therapy.

11. To Summarize

  • Impact on Current Practice: This trial provided strong evidence that a “watchful waiting” or delayed strategy for initiating RRT is a safe and acceptable approach in critically ill patients with severe AKI, as it did not lead to worse mortality.
  • Specific Recommendations:
    • Patient Selection: For critically ill patients with severe AKI (KDIGO stage 3) who do not have an immediate life-threatening indication for RRT.
    • Actionable Intervention: It is reasonable to adopt a delayed strategy, closely monitoring the patient for the development of urgent indications for RRT.
    • Expected Benefit: This strategy may allow nearly half of patients to recover kidney function without ever needing RRT, thereby avoiding the risks and costs associated with the procedure.
  • What This Trial Does NOT Mean: This trial does NOT mean that RRT should be withheld from patients who develop clear, life-threatening indications (e.g., severe hyperkalemia, severe acidosis, or severe fluid overload).
  • Implementation Caveats: A delayed strategy requires diligent and active monitoring to ensure that RRT is initiated promptly if and when an urgent indication arises.

12. Context and Related Studies

  • Building on Previous Evidence: The AKIKI trial (2016) was one of the first large, high-quality RCTs to address the timing of RRT. Its findings were in contrast to the single-center ELAIN trial (2016), published at the same time, which suggested a benefit for early RRT in a population of post-surgical patients.
  • Influence on Subsequent Research: The conflicting results between AKIKI and ELAIN spurred further research, including the very large STARRT-AKI trial (2020), which ultimately confirmed the findings of AKIKI, showing no benefit for an accelerated RRT strategy in a broad population of critically ill patients.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The optimal timing of RRT in specific subgroups of patients (e.g., those with less severe AKI or different underlying causes) remains an area of investigation.
  • Future Directions: Future research is focused on identifying biomarkers that could help predict which patients will recover kidney function and which will progress to needing RRT, allowing for a more personalized approach to timing.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a very common and important clinical dilemma in the ICU for which there was no clear evidence-based guidance.
  • Methods: The multicenter RCT design was appropriate. The main methodological weakness is the open-label (unblinded) design, which introduces a risk of performance bias. The primary outcome of mortality was objective and patient-centered.
  • Results: The study reported a clear neutral finding for its primary outcome. A key secondary finding was that a delayed strategy allowed a large proportion of patients to avoid RRT altogether without an increase in harm.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The high external validity of this pragmatic trial means its findings are broadly applicable to the care of general ICU patients with severe AKI. The trial provides strong support for a “watchful waiting” approach in patients without urgent indications for dialysis.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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