AKIKI2: RRT Timing in Less Severe AKI (2021)

“Among critically ill patients with severe AKI (KDIGO stage 2 or 3) and a high risk of progression, a more-delayed strategy for initiating RRT did not result in a significant difference in the number of days alive and free of RRT by day 28, as compared with a delayed strategy.”

  • The AKIKI2 Trial Investigators

1. Publication Details

  • Trial Title: A More-Delayed versus Delayed Strategy for Initiating Renal Replacement Therapy for Severe Acute Kidney Injury: A Multicenter Randomized Clinical Trial
  • Citation: Gaudry S, Hajage D, Martin-Lefevre L, et al. A More-Delayed versus Delayed Strategy for Initiating Renal Replacement Therapy for Severe Acute Kidney Injury: A Multicenter Randomized Clinical Trial. Am J Respir Crit Care Med. 2021;204(12):1393-1402. DOI: 10.1164/rccm.202101-0063OC
  • Published: December 15, 2021, in The American Journal of Respiratory and Critical Care 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 AKI (KDIGO stage 2 or 3) at high risk of progression but without an urgent indication for RRT (Population), does a “more-delayed” strategy for initiating RRT (Intervention) compared to a “delayed” strategy (Comparison) increase the number of days alive and free of RRT (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The AKIKI trial (2016) and the STARRT-AKI trial (2020) had established that a “delayed” or “watchful waiting” strategy for initiating RRT was safe and allowed many patients to avoid RRT altogether compared to an “early” strategy.
  • Knowledge Gap: While a delayed strategy was proven safe, it was unknown if the window for watchful waiting could be extended even further. The question remained whether a “more-delayed” strategy could spare even more patients from needing RRT without causing harm.
  • Proposed Hypothesis: The authors hypothesized that a “more-delayed” strategy would be superior to a “delayed” strategy in increasing the number of days alive and free of RRT.

5. Study Design and Methods

  • Design: A multicenter, prospective, open-label, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: 39 intensive care units (ICUs) in France.
  • Trial Period: Enrollment ran from May 2018 to October 2019.
  • Population:
    • Inclusion Criteria: Critically ill patients with severe AKI (KDIGO stage 2 or 3) who had oliguria or anuria for >72 hours or a serum urea concentration >40 mmol/L, and who were at high risk of needing RRT.
    • Exclusion Criteria: Included life-threatening complications mandating immediate RRT (e.g., severe hyperkalemia, metabolic acidosis, or pulmonary edema).
  • Intervention: A “more-delayed” strategy, where RRT was initiated only if an urgent indication developed or if oliguria/anuria persisted for >120 hours or serum urea reached >50 mmol/L.
  • Control: A “delayed” strategy (based on the successful arm of the original AKIKI trial), where RRT was initiated if an urgent indication developed or if oliguria/anuria persisted for >96 hours or serum urea reached >40 mmol/L.
  • Management Common to Both Groups: All other aspects of ICU care were at the discretion of the treating clinicians.
  • Power and Sample Size: The authors calculated that a sample size of 278 patients would provide 80% power to detect a 3-day difference in the primary outcome. (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: The number of days alive and free of RRT between randomization and day 28.
    • Secondary Outcomes: Included 60-day mortality and the proportion of patients who received RRT.

6. Key Results

  • Enrollment and Baseline: 278 patients were randomized (137 to the more-delayed group and 141 to the delayed group). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in the primary outcome. The median number of days alive and free of RRT was 12 in the more-delayed group and 10 in the delayed group (p=0.93).
  • Secondary Outcomes: There was no significant difference in 60-day mortality (44% in the more-delayed group vs. 38% in the delayed group). There was also no significant difference in the proportion of patients who ultimately received RRT.
  • Adverse Events: There were no significant differences in the rates of complications 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 Wilcoxon rank-sum test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the median number of days alive and free of RRT between the two groups.
  • Key Statistic(s) Reported: The key statistics were the median values for the primary outcome and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.93 is much higher than the 0.05 threshold, indicating that the small difference in the primary outcome 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 subgroup analyses were reported.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, controlled design provided high-quality evidence on a very specific clinical question.
  • Generalizability: The pragmatic design across 39 ICUs increases the applicability of the findings.
  • Statistical Power: The study was adequately powered for its primary outcome.
  • Patient-Centered Outcomes: The primary outcome of days alive and free of RRT is a robust and patient-centered composite outcome.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label (unblinded), which introduces a risk of performance bias, as clinicians’ knowledge of the group assignment could have influenced their decisions about other aspects of care.
  • External Validity (Generalizability): The study population consisted of patients with a high severity of illness who were already in the “delayed” window. The results may not apply to all patients with AKI.
  • Other: The separation between the two strategies was ultimately small, as many patients in the “delayed” group did not meet criteria for RRT initiation until later, blurring the distinction between the groups.

10. Conclusion of the Authors

  • In critically ill patients with severe AKI at high risk for RRT, a strategy of further delaying RRT initiation did not increase the number of days alive and free of RRT compared with a delayed strategy.

11. To Summarize

  • Impact on Current Practice: This trial helps to define the safe limits of the “watchful waiting” approach for initiating RRT. It suggests that while a delayed strategy is good, a “more-delayed” strategy offers no additional benefit and may not be necessary.
  • Specific Recommendations:
    • Patient Selection: For critically ill patients with severe AKI who do not have an immediate life-threatening indication for RRT.
    • Actionable Intervention: A “delayed” strategy (similar to the control arm of this trial and the delayed arm of the original AKIKI trial) remains a safe and appropriate standard of care.
  • What This Trial Does NOT Mean: This trial does NOT mean that RRT should be initiated early. It reinforces the safety of a delayed approach but suggests there is no benefit to pushing the delay even further.
  • 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 AKIKI2 trial (2021) was a direct follow-up to the original AKIKI trial (2016) and the STARRT-AKI trial (2020), which had established the safety of a delayed RRT initiation strategy.
  • Influence on Subsequent Research: This trial helps to refine the “delayed” strategy, suggesting that there is a limit to how long one can safely wait.

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 a logical and important follow-up to previous major trials, seeking to refine the “delayed” RRT strategy.
  • Methods: The multicenter RCT design was appropriate. The main methodological weakness is the open-label (unblinded) design, which introduces a risk of performance bias.
  • Results: The study reported a clear neutral finding for its primary outcome. The lack of difference in both benefit (RRT-free days) and harm (mortality) is a key finding.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The trial provides strong evidence that there is no advantage to a “more-delayed” over a “delayed” strategy for initiating RRT in this patient population.

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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