ELAIN: Early vs. Late Initiation of RRT in Critical Illness (2016)

“Among critically ill patients with acute kidney injury, early initiation of renal replacement therapy was associated with a significant reduction in 90-day mortality.”

  • The ELAIN Investigators

1. Publication Details

  • Trial Title: 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
  • Citation: 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(20):2190-2199. DOI: 10.1001/jama.2016.5828
  • Published: May 24, 2016, in The Journal of the American Medical Association (JAMA)
  • Author: Alexander Zarbock, M.D.
  • Funding: German Research Foundation; and others.

2. Keywords

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

3. The Clinical Question

  • In critically ill adult patients with acute kidney injury (AKI) stage 2 and a plasma NGAL level >150 ng/mL (Population), does an early strategy of initiating renal-replacement therapy (RRT) (Intervention) compared to a delayed strategy (Comparison) reduce 90-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The optimal time to initiate renal-replacement therapy (RRT) for acute kidney injury (AKI) in critically ill patients 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 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, particularly in a well-defined, high-risk population.
  • Proposed Hypothesis: The authors hypothesized that an early strategy for initiating RRT would be superior to a delayed strategy in reducing 90-day mortality in critically ill patients with AKI.

5. Study Design and Methods

  • Design: A single-center, prospective, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: A single tertiary care university hospital in Germany.
  • Trial Period: Enrollment ran from August 2012 to June 2015.
  • Population:
    • Inclusion Criteria: Adult patients (18-90 years) admitted to the ICU with AKI KDIGO stage 2 (e.g., creatinine 2-2.9 times baseline or oliguria <0.5 mL/kg/h for 12 hours) who also had a plasma neutrophil gelatinase–associated lipocalin (NGAL) level >150 ng/mL. The majority of patients were post-cardiac surgery.
    • Exclusion Criteria: Included pre-existing end-stage renal disease, and contraindications to RRT.
  • Intervention: An “early” strategy, where RRT was initiated within 8 hours of the patient meeting criteria for KDIGO stage 2 AKI.
  • Control: A “delayed” strategy, where RRT was initiated only after the patient progressed to KDIGO stage 3 AKI, or if an urgent indication developed.
  • Management Common to Both Groups: All patients who received RRT were treated with continuous venovenous hemodiafiltration (CVVHDF). 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 230 patients would be required to have 80% power to detect a 15% absolute risk reduction in 90-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 90 days.
    • Secondary Outcomes: Included recovery of kidney function, duration of organ support, and length of hospital stay.

6. Key Results

  • Enrollment and Baseline: 231 patients were randomized (112 to the early group and 119 to the delayed group). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: 90-day mortality was significantly lower in the early-RRT group: 44 of 112 patients (39.3%) died, compared with 65 of 119 patients (54.6%) in the delayed-RRT group (p=0.03).
  • Secondary Outcomes: Patients in the early-RRT group had a shorter duration of mechanical ventilation and a shorter length of hospital stay.
  • Adverse Events: The incidence of adverse events was similar in both 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 0.03 for the primary outcome is below the 0.05 threshold, indicating that the observed difference in mortality is statistically significant and unlikely to be 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 = 54.6% – 39.3% = 15.3%.
      • Clinical Meaning: For every 100 patients treated with early RRT, about 15 additional deaths were prevented at 90 days.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.153 = 6.5, which is rounded down to 6.
      • Clinical Meaning: You would need to treat only 6 patients with an early RRT strategy to prevent one additional death.
  • Subgroup Analyses: The benefit of early RRT was consistent across subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The randomized, controlled design provided a high level of evidence. The use of a biomarker (NGAL) to enrich the study population with high-risk patients was a novel and important strength.
  • Patient-Centered Outcomes: The primary outcome of 90-day mortality is a robust and patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label (unblinded), which introduces a risk of performance bias.
  • External Validity (Generalizability): The single-center design is a major limitation, as the results may not be applicable to other centers. The study population was also very specific (predominantly post-cardiac surgery patients selected with a biomarker), which further limits the generalizability of the findings to a broad ICU population with AKI from other causes (like sepsis).
  • Other: The mortality rate in the delayed-RRT group (54.6%) was very high, which may have exaggerated the benefit of the early intervention.

10. Conclusion of the Authors

  • The authors concluded that among critically ill patients with AKI, early initiation of RRT was associated with a significant reduction in 90-day mortality.

11. To Summarize

  • Impact on Current Practice: This trial was highly influential but also controversial. Its positive finding for early RRT initiation directly contradicted the neutral findings of the larger, multicenter AKIKI trial, which was published at the same time. This created significant clinical uncertainty.
  • Specific Recommendations:
    • Patient Selection: The results are most applicable to the specific population studied: post-cardiac surgery patients with KDIGO stage 2 AKI and an elevated NGAL.
    • Actionable Intervention: In this specific high-risk population, the results support the initiation of RRT at KDIGO stage 2.
  • What This Trial Does NOT Mean: This trial does NOT mean that all patients with AKI should receive early RRT. Its findings are limited by the single-center design and the highly selected patient population.
  • Implementation Caveats: The use of NGAL to guide RRT initiation is not a widespread practice.

12. Context and Related Studies

  • Building on Previous Evidence: The ELAIN trial (2016) was one of the first major RCTs to provide evidence on the timing of RRT.
  • Influence on Subsequent Research: The conflicting results between the single-center ELAIN trial (positive) and the multicenter AKIKI trial (2016) (neutral) spurred further research and debate. This ultimately led to the very large STARRT-AKI trial (2020), which enrolled a broad population of critically ill patients and definitively found no benefit for an accelerated RRT strategy, supporting the conclusions of AKIKI over ELAIN.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The key unresolved question from this trial was whether its positive finding was a true effect specific to its high-risk population or a false-positive result due to its single-center design and other limitations.
  • Future Directions: The subsequent, larger STARRT-AKI trial has largely answered this question for the general ICU population. Future research is focused on identifying specific patient phenotypes that might still benefit from earlier RRT initiation.

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.
  • Methods: The RCT design was appropriate. However, the single-center, open-label design and the highly selected patient population are major methodological limitations that significantly reduce the external validity of the findings. The use of a biomarker to enrich the population is a novel approach.
  • Results: The study reported a large and statistically significant mortality benefit (NNT of 6). However, this finding from a single-center trial must be interpreted with caution.
  • Conclusions and Applicability: The authors’ conclusion is a fair reflection of their data, but the applicability of the findings is highly questionable due to the study’s significant limitations. The subsequent, larger, and more robust STARRT-AKI trial, which found no benefit for early RRT, is generally considered to be the more definitive evidence on this topic for the general ICU 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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