RENAL: Intensity of Continuous Renal-Replacement Therapy in Critical Illness (2009)

“In this multicenter, randomized trial, we found no significant difference in 90-day mortality between critically ill patients with acute kidney injury who were treated with high-intensity or less-intensive continuous renal-replacement therapy.”

  • The RENAL Replacement Therapy Study Investigators

1. Publication Details

  • Trial Title: Intensity of Continuous Renal-Replacement Therapy in Critically Ill Patients
  • Citation: The RENAL Replacement Therapy Study Investigators. Intensity of continuous renal-replacement therapy in critically ill patients. N Engl J Med. 2009;361(17):1627-1638. DOI: 10.1056/NEJMoa0902413
  • Published: October 22, 2009, in The New England Journal of Medicine
  • Author: The RENAL Replacement Therapy Study Investigators
  • Funding: The Australian and New Zealand National Health and Medical Research Council; and others.

2. Keywords

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

3. The Clinical Question

  • In critically ill adult patients with acute kidney injury (AKI) requiring continuous renal-replacement therapy (CRRT) (Population), does a strategy of high-intensity CRRT (Intervention) compared to a less-intensive, standard-dose strategy (Comparison) reduce 90-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The optimal “dose” or intensity of CRRT for critically ill patients with AKI was a major area of clinical uncertainty. Previous observational studies and smaller trials had suggested that a higher dose of RRT might be associated with improved survival by providing better clearance of uremic toxins and inflammatory mediators.
  • Knowledge Gap: The concurrent ATN trial (2008) had shown no benefit of intensive intermittent dialysis. However, a large, definitive, multicenter trial was still needed to specifically evaluate the effect of intensity in patients receiving continuous therapy (CRRT), which was becoming an increasingly common modality.
  • Proposed Hypothesis: The authors hypothesized that a high-intensity CRRT strategy would be superior to a less-intensive strategy in reducing 90-day mortality.

5. Study Design and Methods

  • Design: A large, multicenter, prospective, randomized, open-label, controlled trial (used to test the effectiveness of interventions).
  • Setting: 35 intensive care units (ICUs) in Australia and New Zealand.
  • Trial Period: Enrollment ran from December 2005 to August 2008.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) admitted to the ICU who were judged by their treating clinician to require CRRT for AKI.
    • Exclusion Criteria: Included pre-existing end-stage renal disease, weight <40 kg, and moribund status.
  • Intervention: A high-intensity CRRT strategy, with a prescribed effluent flow rate of 40 ml per kilogram of body weight per hour.
  • Control: A less-intensive (standard-dose) CRRT strategy, with a prescribed effluent flow rate of 25 ml per kilogram of body weight per hour.
  • Management Common to Both Groups: All patients 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 1500 patients would provide 80% power to detect a 6.5% 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 after randomization.
    • Secondary Outcomes: Included recovery of kidney function among survivors and the duration of organ support.

6. Key Results

  • Enrollment and Baseline: 1508 patients were randomized (747 to high-intensity and 761 to less-intensive therapy). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in 90-day mortality. 332 of 747 patients (44.5%) in the high-intensity group died, compared with 333 of 761 patients (43.8%) in the less-intensive 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 ventilator-free days.
  • Adverse Events: The incidence of adverse events was similar in both groups, although hypophosphatemia was more common in the high-intensity 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: The key statistics were the absolute mortality rates and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.77 for the primary outcome is much higher than the 0.05 threshold, indicating that the result was 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.

8. Strengths of the Study

  • Study Design and Conduct: The very large, multicenter, randomized controlled design provided high-quality evidence on a critical clinical question.
  • Generalizability: The pragmatic design and inclusion of a very large, heterogeneous population of ICU patients make the findings highly generalizable to real-world practice in similar healthcare systems.
  • Statistical Power: The very large sample size provided definitive power to confidently rule out a modest but clinically important mortality difference.
  • 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 findings are highly generalizable to the broad population of critically ill patients with AKI requiring CRRT.
  • Other: A key point for interpretation is that the “less-intensive” control arm (25 ml/kg/hr) already represented a robust and adequate dose of RRT according to most guidelines at the time.

10. Conclusion of the Authors

  • The authors concluded that in critically ill patients with acute kidney injury, treatment with high-intensity continuous renal-replacement therapy did not reduce 90-day mortality as compared with less-intensive therapy.

11. To Summarize

  • Impact on Current Practice: This was a landmark “negative” trial that, along with the ATN trial, provided definitive evidence to refute the “more is better” hypothesis for RRT dosing. It established standard-dose CRRT as the evidence-based standard of care.
  • Specific Recommendations:
    • Patient Selection: For the broad population of adult ICU patients with AKI who require CRRT.
    • Actionable Intervention: The results do not support the routine use of high-intensity CRRT regimens. A standard-dose strategy (e.g., 20-25 ml/kg/hr) is the appropriate standard of care.
  • 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: The key takeaway is that a more aggressive and expensive strategy is not superior to a well-delivered standard of care.

12. Context and Related Studies

  • Building on Previous Evidence: The RENAL trial (2009) was designed to provide a definitive answer for CRRT, complementing the findings of the ATN trial (2008) which had studied intermittent therapies.
  • Influence on Subsequent Research: The definitive neutral result of this trial, along with the ATN trial, has solidified the standard of care for RRT dosing. This has 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 definitively answered its primary question with a clear neutral result.
  • 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 very common, expensive, and resource-intensive intervention for which the optimal dose was unknown.
  • Methods: The very large, multicenter, pragmatic RCT design was appropriate and robust. The main methodological weakness is the open-label design, but the primary outcome of mortality is objective and unlikely to be biased.
  • Results: The study reported a clear neutral finding for its primary outcome, with a narrow confidence interval centered on the null value. This provides strong evidence against a meaningful clinical benefit of high-intensity CRRT in this population.
  • 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. This is a classic example of a high-quality “negative” trial that was profoundly practice-changing by providing strong evidence that a more aggressive and expensive intervention is not superior to a well-executed standard of care.

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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