ULTRA: Early vs Late Initiation of RRT in AKI (2016)

“In critically ill patients with severe AKI, a strategy of delayed initiation of renal replacement therapy was not associated with a significant difference in 60-day mortality.”

— The AKIKI Study Group

1. Publication Details

  • Trial Title: Strategy of Renal Replacement Therapy Initiation in Acute Kidney Injury.
  • Citation: Gaudry S, Hajage D, Schortgen F, et al; for the AKIKI Study Group. 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 Illness, Timing of Initiation, Delayed Strategy.

3. The Clinical Question

In critically ill patients with severe acute kidney injury (KDIGO stage 3) (Population), does an early strategy of initiating renal replacement therapy (RRT) immediately (Intervention) compared to a delayed, watchful-waiting strategy (Comparison) reduce 60-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Acute kidney injury (AKI) is a common and life-threatening condition in the ICU. The optimal time to start renal replacement therapy (RRT) was a major area of clinical uncertainty. Some believed an “early” start could prevent complications, while others argued a “delayed” approach might allow for spontaneous kidney recovery and avoid an unnecessary invasive procedure.
  • Knowledge Gap: Previous studies on the timing of RRT initiation were small, often single-center, and had conflicting results. A large, multicenter, randomized trial was needed to provide definitive evidence.
  • Proposed Hypothesis: The authors hypothesized that an early strategy of RRT initiation would be superior to a delayed strategy in reducing 60-day mortality.

5. Study Design and Methods

  • Design: A prospective, multicenter, open-label, randomized, controlled trial.
  • Setting: 31 intensive care units (ICUs) in France.
  • Trial Period: Enrollment from September 2013 to June 2015.
  • Population:
    • Inclusion Criteria: Adult critically ill patients with AKI KDIGO stage 3, who required mechanical ventilation, catecholamine infusion, or both.
    • Exclusion Criteria: Urgent, life-threatening indications for RRT (e.g., severe hyperkalemia, severe acidosis, pulmonary edema), or pre-existing end-stage kidney disease.
  • Intervention: An “early” strategy, where RRT was initiated immediately after randomization.
  • Control: A “delayed” strategy, where RRT was initiated only if an urgent indication developed or if anuria or severe uremia persisted for more than 72 hours.
  • Management Common to Both Groups: The choice of RRT modality and all other aspects of ICU care were at the discretion of the local clinical team.
  • Power and Sample Size: The trial was powered to detect a 15% absolute difference in 60-day mortality, requiring 620 patients.
  • Outcomes:
    • Primary Outcome: All-cause mortality at 60 days.
    • Secondary Outcomes: Included RRT-free days, ventilator-free days, ICU length of stay, and incidence of catheter-related bloodstream infections.

6. Key Results

  • Enrollment and Baseline: 620 patients were randomized (311 to the early group, 309 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 60-day mortality between the early and delayed strategy groups (48.5% vs 49.7%; P=0.79).
  • Secondary Outcomes: A key finding was that 49% of patients in the delayed-strategy group recovered kidney function and never required RRT. The delayed group had significantly more RRT-free days. Catheter-related bloodstream infections were more frequent in the early group.
  • Adverse Events: The incidence of catheter-related bloodstream infections was significantly higher in the early-strategy group.

7. Medical Statistics

  • Analysis Principle: An intention-to-treat analysis was performed.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The proportion of deaths at day 60 was compared between the two groups.
  • Key Statistic(s) Reported: Hazard Ratio (HR) for death at 60 days with the early strategy: 1.03 (95% CI, 0.82 to 1.30).
  • Interpretation of Key Statistic(s):
    • Hazard Ratio (HR):
      • Formula: Conceptually, HR represents the instantaneous risk of death in the intervention group relative to the control group.
      • Calculation: The paper reports the HR as 1.03.
      • Clinical Meaning: An HR of 1.03 means there was a 3% higher hazard of death at any given time in the early strategy group compared to the delayed strategy group, a difference that is not statistically significant.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The reported 95% CI was 0.82 to 1.30.
      • Clinical Meaning: Since this confidence interval widely crosses the line of no effect (1.0), it indicates that there is no significant difference between the two strategies. The true effect is likely somewhere between an 18% benefit and a 30% harm.
    • P-value:
      • Calculation: The reported p-value for the primary outcome was 0.79.
      • Clinical Meaning: The p-value of 0.79 is far above the 0.05 threshold, confirming that the observed result is very likely due to chance. A result is conventionally considered statistically significant if the p-value is less than 0.05.
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group).
      • Calculation: ARR = 49.7% – 48.5% = 1.2%.
      • Clinical Meaning: The early strategy was associated with a non-significant 1.2% absolute reduction in the risk of death at 60 days.
    • Number Needed to Treat (NNT): Not applicable, as the intervention showed no benefit.
  • Subgroup Analyses: No significant benefit was found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: This was a large, multicenter, randomized trial that provided a robust answer to a critical clinical question.
  • Generalizability: The pragmatic design and inclusion of 31 diverse ICUs in France increase the applicability of the findings.
  • Patient-Centered Outcomes: The primary outcome of 60-day mortality is a strong, patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label (unblinded), which could introduce performance bias, though the primary outcome of mortality is objective.
  • External Validity (Generalizability): The results apply to a mixed population of critically ill patients with severe AKI and may not be generalizable to all specific causes of AKI.
  • Other: The criteria for initiating RRT in the delayed group were based on clinical judgment and were not strictly protocolized, which could introduce variability.

10. Conclusion of the Authors

“In this trial, there was no significant difference in 60-day mortality between a strategy of early initiation of renal-replacement therapy and a watchful-waiting strategy in patients in the intensive care unit who had acute kidney injury and were receiving mechanical ventilation or catecholamine infusions.”

11. To Summarize

  • Impact on Current Practice: The AKIKI trial was a landmark study that provided strong evidence to support a more conservative, watchful-waiting approach to the initiation of RRT. It demonstrated that an early, routine start to RRT does not improve survival and exposes patients to the risks of an invasive procedure that nearly half of them may not need.
  • Specific Recommendations:
    • Patient Selection: For critically ill adult patients with severe AKI (KDIGO stage 3) who do not have an urgent, life-threatening indication for RRT.
    • Actionable Intervention: A delayed, watchful-waiting strategy is the preferred approach. Initiate RRT only if urgent indications develop or if kidney function fails to recover.
    • Expected Benefit: No difference in mortality compared to an early strategy. A delayed strategy avoids RRT altogether in about half of patients and is associated with a lower risk of catheter-related infections.
  • What This Trial Does NOT Mean: This trial does not mean RRT should be unduly delayed when clear, life-threatening indications are present. The “delayed” arm still involved prompt initiation of RRT when it became necessary.
  • Implementation Caveats: A watchful-waiting strategy requires careful and frequent monitoring of the patient for the development of urgent indications for RRT.

12. Context and Related Studies

  • Building on Previous Evidence: AKIKI was one of the first large, multicenter RCTs to robustly address the timing of RRT initiation. Its findings were in contrast to the ELAIN trial (2016), a smaller single-center trial that favored early RRT, but were consistent with the subsequent, even larger STARRT-AKI trial (2020).
  • Influence on Subsequent Research: The results of AKIKI, largely confirmed by STARRT-AKI, have solidified the evidence base in favor of a more conservative approach to RRT initiation and have heavily influenced international guidelines.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: Are there specific subgroups of patients with AKI (e.g., based on biomarkers or etiology) who might still benefit from an earlier approach?
  • Future Directions: Future research is focused on developing better predictive tools to identify which patients will ultimately require RRT, thereby allowing for a more personalized approach to timing.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was of fundamental importance in critical care nephrology, addressing a common, high-stakes clinical decision.
  • Methods: The large, multicenter, randomized design was methodologically strong and provided a high level of evidence.
  • Results: The trial had a clear and convincing neutral result for its primary outcome. The secondary finding that nearly half of the patients in the delayed group avoided RRT was a critical, practice-changing piece of information.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The results are highly applicable to the global ICU community and provide a clear directive to favor a standard, watchful-waiting approach to RRT initiation in the absence of urgent indications.

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.

Scroll to Top