ATN: Intensity of Renal Support in Acute Kidney Injury (2008)

“Intensive renal support in critically ill patients with acute kidney injury did not decrease mortality, improve recovery of kidney function, or reduce the rate of nonrenal organ failure as compared with less-intensive therapy.”

  • The VA/NIH Acute Renal Failure Trial Network

1. Publication Details

  • Trial Title: Intensity of Renal Support in Critically Ill Patients with Acute Kidney Injury
  • Citation: The VA/NIH Acute Renal Failure Trial Network. Intensity of Renal Support in Critically Ill Patients with Acute Kidney Injury. N Engl J Med. 2008;359(1):7-20. DOI: 10.1056/NEJMoa0802639
  • Published: July 3, 2008, in The New England Journal of Medicine
  • Author: The VA/NIH Acute Renal Failure Trial Network
  • Funding: National Institutes of Health (NIH) and the Department of Veterans Affairs (VA).

2. Keywords

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

3. The Clinical Question

  • In critically ill adult patients with acute kidney injury (AKI) requiring renal-replacement therapy (RRT) (Population), does an intensive RRT strategy (Intervention) compared to a less-intensive strategy (Comparison) reduce 60-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The optimal “dose” or intensity of RRT for critically ill patients with AKI was a major area of clinical uncertainty. Previous observational studies had suggested that a higher dose of RRT might be associated with improved survival, leading many clinicians to adopt more intensive strategies.
  • Knowledge Gap: There was no high-quality evidence from a large, multicenter randomized controlled trial to confirm whether this “more is better” approach was truly beneficial or if it exposed patients to unnecessary risks and costs.
  • Proposed Hypothesis: The authors hypothesized that an intensive renal-support strategy would be superior to a less-intensive strategy in reducing 60-day mortality.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: 27 Veterans Affairs and university-affiliated medical centers in the United States.
  • Trial Period: Enrollment ran from November 2003 to July 2007.
  • Population:
    • Inclusion Criteria: Critically ill adult patients with AKI (defined by high creatinine or low urine output) and failure of at least one other nonrenal organ system, who required RRT.
    • Exclusion Criteria: Included pre-existing end-stage renal disease, weight <40 kg, and contraindications to any of the RRT modalities.
  • Intervention: An intensive RRT strategy, defined as intermittent hemodialysis (IHD) and slow low-efficiency dialysis (SLED) 6 times per week, or continuous venovenous hemodiafiltration (CVVHDF) at a rate of 35 ml/kg/hr.
  • Control: A less-intensive RRT strategy, defined as IHD and SLED 3 times per week, or CVVHDF at a rate of 20 ml/kg/hr.
  • Management Common to Both Groups: The choice of RRT modality (intermittent vs. continuous) was determined by the clinical team at each site before randomization. All other aspects of ICU care were standardized where possible.
  • Power and Sample Size: The authors calculated that a sample size of 1100 patients would provide 90% power to detect an 8% absolute risk reduction in 60-day mortality. (Power is a study’s ability to find a real difference between treatments if one truly exists; 90% power means the study had a 90% chance of detecting the specified effect, which is considered very high).
  • Outcomes:
    • Primary Outcome: All-cause mortality at day 60.
    • Secondary Outcomes: Included recovery of kidney function, duration of RRT, and nonrenal organ-failure-free days.

6. Key Results

  • Enrollment and Baseline: 1124 patients were randomized (563 to the intensive group and 561 to the less-intensive 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. 303 of 563 patients (53.6%) in the intensive-therapy group died, compared with 289 of 561 patients (51.5%) in the less-intensive-therapy group (p=0.77).
  • Secondary Outcomes: There were no significant differences between the groups in the rate of recovery of kidney function or in the number of organ-failure-free days.
  • Adverse Events: The study monitored for complications related to RRT. Hypotension during RRT was significantly more common in the intensive-therapy group.

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: Odds Ratio (OR) for death at 60 days: 1.09 (95% CI, 0.86 to 1.38).
  • Interpretation of Key Statistic(s):
    • Odds Ratio (OR):
      • Formula: Conceptually, OR = (Odds of Death in Intervention Group) / (Odds of Death in Control Group).
      • Calculation: The paper reports the result as 1.09.
      • Clinical Meaning: An OR of 1.09 suggests a non-significant 9% higher odds of death in the intensive-therapy group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 0.86 to 1.38.
      • Clinical Meaning: Since this range crosses the line of no effect (1.0), it confirms that the result is not statistically significant. Clinically, this means the true effect could range from a 14% benefit to a 38% harm.
    • P-value: The p-value of 0.77 is much higher than the 0.05 threshold, indicating the result is not statistically significant and 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, including patients with sepsis or those on different RRT modalities.

8. Strengths of the Study

  • Study Design and Conduct: The large, multicenter, randomized controlled design provided high-quality evidence and minimized bias.
  • Generalizability: The pragmatic design, including multiple RRT modalities across 27 diverse medical centers, increases the external validity of the findings.
  • Statistical Power: The study was large and adequately powered to confidently rule out a modest but clinically important mortality benefit.
  • Patient-Centered Outcomes: The study focused on mortality and recovery of kidney function, which are robust and patient-centered endpoints.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded, which introduces a risk of performance bias.
  • External Validity (Generalizability): The findings apply to the intensity of RRT once it has been initiated and do not address the optimal timing of RRT initiation.
  • Other: A potential limitation is that many patients died before receiving the full prescribed “dose” of RRT over the 60-day period, which could have diluted the difference between the groups.

10. Conclusion of the Authors

  • Intensive renal support in critically ill patients with acute kidney injury did not decrease mortality, improve recovery of kidney function, or reduce the rate of nonrenal organ failure as compared with less-intensive therapy.

11. To Summarize

  • Impact on Current Practice: This was a landmark, practice-changing trial that provided strong evidence to refute the “more is better” hypothesis for RRT dosing. It led to the widespread adoption of less-intensive, standard-dose RRT as the standard of care.
  • Specific Recommendations:
    • Patient Selection: For the general population of critically ill adult patients with AKI who require RRT.
    • Actionable Intervention: The results do not support the routine use of high-intensity RRT regimens. A less-intensive, standard-dose strategy is a safe and effective approach.
  • What This Trial Does NOT Mean: This trial does NOT mean that RRT is not beneficial for AKI. It only addresses the intensity of the therapy once the decision to start has been made.
  • Implementation Caveats: A standard-dose RRT strategy (e.g., intermittent dialysis 3 times per week or CVVHDF at ~20-25 ml/kg/hr) should be the default approach.

12. Context and Related Studies

  • Building on Previous Evidence: The ATN trial (2008) was designed to provide a definitive answer to a question that had been raised by smaller, conflicting observational studies.
  • Influence on Subsequent Research: The definitive neutral result of this trial, along with the concurrent RENAL trial (2009), solidified the standard of care for RRT dosing. This allowed the focus of AKI research to shift to other important questions, such as the optimal timing of RRT initiation, which was later addressed by the AKIKI (2016) and STARRT-AKI (2020) trials.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial did not address the optimal timing of RRT initiation or the potential superiority of one RRT modality (intermittent vs. continuous) over another.
  • Future Directions: The results of this trial helped to close the book on the “intensity” question, allowing research to focus on the more nuanced questions of “when” and “how” to best deliver RRT.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a common, expensive, and resource-intensive intervention for which the optimal dose was unknown.
  • Methods: The multicenter RCT design was appropriate and robust. The pragmatic approach of allowing clinicians to choose the RRT modality before randomization increased the generalizability of the findings to real-world practice.
  • Results: The study reported a clear neutral finding for its primary outcome and all major secondary outcomes. The finding of increased hypotension in the intensive-therapy group suggested a potential for harm without any demonstrable benefit.
  • 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 most ICUs. This is a classic example of a high-quality “negative” trial that was profoundly practice-changing by providing strong evidence to de-adopt a more intensive and expensive therapy.

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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