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Foundational Trials

RENAL

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Publication

  • Title: Intensity of continuous renal-replacement therapy in critically ill patients
  • Acronym: RENAL (Randomised Evaluation of Normal versus Augmented Level Replacement Therapy)
  • Year: 2009
  • Journal published in: The New England Journal of Medicine
  • 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.

Context & Rationale

  • Background
    • Acute kidney injury (AKI) in critical illness is common, frequently co-occurs with multi-organ failure, and is associated with high short-term mortality.
    • Continuous renal replacement therapy (CRRT) was widely used in haemodynamically unstable ICU patients, but the optimal “dose” (commonly prescribed as effluent flow, mL/kg/h) was uncertain.
    • Earlier smaller trials and centre-level practice variation suggested potential benefit from “higher dose” haemofiltration/haemodiafiltration, but estimates were imprecise and biologically plausible harms (electrolyte losses, micronutrient removal, workload, filter use) were recognised.
    • Delivered dose commonly differed from prescribed dose due to downtime (filter clotting, procedures), creating uncertainty about what intensity was actually received in routine practice.
  • Research Question/Hypothesis
    • In critically ill adults with AKI requiring CRRT, would a higher-intensity CVVHDF prescription (40 mL/kg/h) reduce 90-day all-cause mortality compared with a lower-intensity prescription (25 mL/kg/h)?
  • Why This Matters
    • Higher-intensity CRRT has major opportunity costs (fluids, nursing time, filter consumption) and plausible iatrogenic harms; an adequately powered pragmatic trial could de-implement unnecessary intensity.
    • Establishing a defensible “standard dose” has downstream implications for guideline recommendations, benchmarking (delivered vs prescribed dose), and trial design for AKI interventions.

Design & Methods

  • Research Question: Among critically ill adults with AKI treated with CVVHDF, does higher-intensity treatment (40 mL/kg/h effluent) reduce 90-day all-cause mortality compared with lower-intensity treatment (25 mL/kg/h effluent)?
  • Study Type: Multicentre, parallel-group, randomised controlled trial; open-label treatment; conducted in 35 ICUs in Australia and New Zealand; recruitment 2005–2008; investigator-initiated.
  • Population:
    • Setting: ICU patients in whom the treating team had decided CRRT was clinically indicated for AKI.
    • Key inclusion: age ≥18 years; body weight 60–100 kg; AKI with an intention to deliver CVVHDF.
    • Common triggers for initiating study CVVHDF (not mutually exclusive): oliguria; hyperkalaemia; severe metabolic acidaemia; uraemia (blood urea nitrogen threshold); rising creatinine; fluid overload/organ oedema.
    • Key exclusions: pre-existing end-stage kidney disease requiring maintenance dialysis; weight outside 60–100 kg; other exclusions per protocol (e.g., inability to obtain consent via deferred process, or contraindications to protocolised CVVHDF).
    • Consent: deferred consent was used where appropriate; if consent was declined after initiation, study data could be withdrawn.
  • Intervention:
    • Higher-intensity CVVHDF (post-dilution) prescribed at an effluent flow of 40 mL/kg/h (effluent = ultrafiltration + dialysate + replacement fluid).
    • Delivered using CVVHDF with centre-selected anticoagulation and routine ICU co-interventions.
  • Comparison:
    • Lower-intensity CVVHDF (post-dilution) prescribed at an effluent flow of 25 mL/kg/h, otherwise managed similarly (same modality; pragmatic co-interventions).
    • Intermittent haemodialysis could be used after randomisation when clinically indicated (pre-specified as allowable co-intervention).
  • Blinding: Not blinded (clinicians and bedside staff necessarily aware of prescribed intensity); primary outcome (mortality) objective and centrally analysed.
  • Statistics: Sample size 1500 planned to detect an 8.5% absolute reduction in 90-day mortality (from 60.0% to 51.5%) with 90% power at a two-sided 5% significance level; two interim analyses with Haybittle–Peto boundary (P<0.001) and final alpha 0.048; primary analysis by intention-to-treat (with exclusions where consent/data withdrawal occurred after deferred consent); pre-specified statistical approach published separately1.
  • Follow-Up Period: 90 days (primary endpoint); additional outcomes assessed at 28 days and at ICU/hospital discharge (as applicable).

Key Results

This trial was not stopped early. Recruitment reached the planned sample size (1508 randomised), with interim monitoring not triggering early stopping.

Outcome Higher-intensity (40 mL/kg/h) Lower-intensity (25 mL/kg/h) Effect p value / 95% CI Notes
Death from any cause by day 90 (primary) 322/721 (44.7%) 332/743 (44.7%) OR 1.00 95% CI 0.81 to 1.23; P=0.99 No mortality difference despite substantial separation in delivered dose.
Death from any cause by day 28 247/721 (34.3%) 251/743 (33.8%) OR 1.02 95% CI 0.80 to 1.30; P=0.88 Early mortality unchanged.
Death in ICU 220/721 (30.5%) 233/743 (31.4%) OR 0.96 95% CI 0.75 to 1.23; P=0.74 Objective outcome; no signal of benefit.
Cessation of renal-replacement therapy (by day 90) 630/721 (87.4%) 648/743 (87.2%) HR 1.01 95% CI 0.93 to 1.10; P=0.74 Higher intensity did not accelerate liberation from RRT.
Alive and receiving dialysis at day 90 27/399 (6.8%) 18/411 (4.4%) OR 1.59 95% CI 0.86 to 2.92; P=0.14 Numerically higher dialysis-dependence with higher intensity; not statistically significant.
ICU length of stay (days) 12.2 ± 10.2 12.6 ± 11.2 Not reported P=0.51 No reduction in ICU resource use.
Hospital length of stay (days) 35.4 ± 31.9 35.5 ± 29.9 Not reported P=0.97 No difference in total hospital stay.
Mechanical ventilation duration (days) 12.1 ± 13.9 13.0 ± 15.6 Not reported P=0.20 No evidence of faster organ support resolution.
Hypophosphataemia (complication) 461/708 (65.1%) 396/733 (54.0%) Not reported P<0.0001 More frequent with higher intensity; episodes 1495 vs 1059 (P<0.0001).
Serious adverse events judged related to study treatment 7 patients 5 patients Not reported Not reported Types included dysrhythmia, hypoxaemia/hypotension, venous air embolus, and peritoneal haemorrhage/bleeding.
  • 90-day mortality was identical: 44.7% in both groups (OR 1.00; 95% CI 0.81 to 1.23; P=0.99).
  • Higher intensity achieved better biochemical control (e.g., lower urea/creatinine) but did not improve clinical endpoints (liberation from RRT, ICU/hospital LOS).
  • Higher intensity increased electrolyte complications, most notably hypophosphataemia (65.1% vs 54.0%; P<0.0001).

Internal Validity

  • Randomisation and Allocation:
    • Central randomisation with allocation concealment before assignment; 1:1 allocation across 35 ICUs.
    • Pragmatic implementation with protocolised dose targets and standardised reporting of delivered CRRT parameters.
  • Drop out or exclusions (post-randomisation):
    • Randomised: 1508 total; analysed for primary outcome: 721 (higher intensity) and 743 (lower intensity).
    • Post-randomisation exclusions occurred due to deferred-consent processes/data withdrawal (not evenly balanced: 26 vs 18), introducing a small but real risk of attrition bias if refusals correlated with prognosis.
    • Follow-up for vital status at 90 days was near-complete (one patient lost to follow-up reported).
  • Performance/Detection Bias:
    • Open-label treatment could influence co-interventions; however, major outcomes were objective (mortality, RRT status), and co-interventions were broadly similar.
    • Use of intermittent haemodialysis after randomisation was similar (7.6% vs 7.0%), reducing concern for systematic rescue imbalance.
  • Protocol Adherence:
    • Delivered effluent flow (mean ± SD): 33.4 ± 12.8 mL/kg/h vs 22.0 ± 17.8 mL/kg/h, demonstrating meaningful separation of intensity despite real-world interruptions.
    • Dialysis circuit utilisation differed, reflecting higher intensity workload: filters used per day 1.06 ± 0.49 vs 0.84 ± 0.42 (P<0.001).
  • Baseline Characteristics:
    • Groups were well balanced: age 64.7 ± 15.1 vs 64.4 ± 15.0 years; severe sepsis 49.9% vs 48.9%; APACHE III score 102.5 ± 27.0 vs 102.3 ± 26.1.
    • Renal dysfunction at baseline was substantial and similar: serum creatinine 338 ± 192 vs 330 ± 197 μmol/L; blood urea nitrogen 24.2 ± 13.3 vs 22.8 ± 12.2 mmol/L.
  • Heterogeneity:
    • Multicentre design increases clinical heterogeneity, but the intervention was tightly defined (effluent targets within a single modality: post-dilution CVVHDF).
    • Primary effect was consistent across pre-specified subgroup comparisons in the main report (interaction estimates not numerically reported in text).
  • Timing:
    • Randomisation occurred when clinicians had decided to start CVVHDF; mean time in ICU before randomisation: 48.4 ± 72.5 vs 54.5 ± 78.2 hours.
    • This trial addressed “dose once CRRT is started”, not the timing of initiation; thus any benefit (or harm) attributable to earlier/later start is not evaluable here.
  • Dose:
    • Prescribed effluent: 40 vs 25 mL/kg/h; delivered biochemical separation supports biological plausibility of a true “dose test”.
    • Higher intensity achieved lower steady-state solute concentrations (e.g., serum creatinine during treatment 139 ± 92 vs 180 ± 107 μmol/L; blood urea nitrogen 15.2 ± 7.4 vs 18.1 ± 7.9 mmol/L).
  • Separation of the Variable of Interest:
    • Delivered effluent (mL/kg/h): 33.4 ± 12.8 vs 22.0 ± 17.8.
    • During-treatment laboratory separation (means ± SD): phosphate 1.5 ± 0.5 vs 1.8 ± 0.6 mmol/L; bicarbonate 25.1 ± 3.5 vs 25.4 ± 3.4 mmol/L.
  • Key Delivery Aspects:
    • Because the control dose (25 mL/kg/h prescribed) was already within contemporary “adequate” ranges, the trial principally tested whether escalation beyond an adequate standard improves outcomes.
    • The intervention was delivered within a pragmatic ICU environment, improving credibility of “real-world deliverability”.
  • Outcome Assessment:
    • Primary outcome (90-day mortality) was objective and clinically meaningful.
    • RRT dependence at day 90 was clinically relevant but depends on ascertainment and post-discharge care pathways; nevertheless, denominators were reported among survivors.
  • Statistical Rigor:
    • Sample size target achieved; pre-specified interim analysis boundary and adjusted final alpha (0.048) reduce multiplicity-driven false positives.
    • Primary effect estimate presented as an odds ratio with 95% CI; secondary outcomes largely consistent with null.

Conclusion on Internal Validity: Overall, internal validity appears strong given concealed randomisation, large sample size, objective primary outcome, and clear separation in delivered CRRT intensity; limitations include open-label delivery and modest post-randomisation data withdrawal due to deferred-consent processes.

External Validity

  • Population Representativeness:
    • Represents adult ICU patients with AKI for whom clinicians chose CVVHDF, including a high proportion with severe sepsis (~50%) and substantial severity of illness (APACHE III ~102).
    • Important exclusions limit representativeness: body weight restricted to 60–100 kg; patients requiring alternative modalities (or with established end-stage kidney disease) were excluded.
  • Applicability:
    • Findings generalise best to high-resource ICUs using CVVHDF with capacity to deliver prescribed effluent rates and monitor electrolytes closely.
    • Applicability is less certain for extremes of body size, centres routinely delivering substantially lower doses (e.g., <20 mL/kg/h delivered), or settings where CVVHDF is not standard.

Conclusion on External Validity: Overall generalisability is moderate: the trial is highly applicable to many modern ICUs using CVVHDF, but weight restrictions and the specific “control” dose constrain extrapolation to all real-world CRRT practices.

Strengths & Limitations

  • Strengths:
    • Large multicentre randomised trial with planned sample size achieved (1508 randomised).
    • Pragmatic delivery within routine ICU care, improving ecological validity.
    • Clear separation in delivered dose (33.4 vs 22.0 mL/kg/h) and robust reporting of delivery metrics (filter use, delivered/achieved clearances).
    • Clinically meaningful primary endpoint (90-day mortality) with near-complete follow-up.
  • Limitations:
    • Open-label design could influence discretionary co-interventions, although primary outcome was objective.
    • Post-randomisation exclusions due to deferred consent/data withdrawal (imbalanced, though numerically modest) create potential attrition bias.
    • Weight restriction (60–100 kg) limits generalisability, especially for obesity and underweight populations.
    • Intervention tested a “higher vs already adequate” intensity comparison; it does not address whether very low doses are inferior.
    • Higher intensity increased hypophosphataemia and filter consumption, highlighting a harm/resource trade-off.

Interpretation & Why It Matters

  • Clinical practice
    • Escalating CVVHDF intensity from 25 to 40 mL/kg/h did not improve survival or renal recovery, despite lower urea/creatinine during therapy.
    • Given higher rates of hypophosphataemia (65.1% vs 54.0%) and greater filter use (1.06 vs 0.84 filters/day), routine “high-intensity” prescriptions are difficult to justify when the goal is outcome improvement.
  • Trial design implications
    • RENAL established a pragmatic benchmark for “adequate” CRRT intensity and highlighted the importance of reporting delivered dose, not just prescription.
    • For subsequent AKI trials, the key methodological lesson is that robust separation of the physiological target does not guarantee benefit on patient-centred endpoints.

Controversies & Subsequent Evidence

  • Editorial synthesis contemporaneous with RENAL emphasised that higher CRRT intensity did not improve outcomes and argued against “more is better” approaches for dose escalation in AKI, shifting focus towards reliable delivery and avoidance of iatrogenic complications2.
  • Published correspondence raised concerns about generalisability and the interpretation of “dose” versus “delivered clearance” in routine practice, underscoring the methodological point that interruptions and filter performance can decouple prescription from true solute clearance3.
  • Systematic reviews and meta-analyses incorporating RENAL (and similar RRT intensity trials) have not demonstrated a mortality benefit of higher-intensity regimens in critically ill patients with AKI, reinforcing a plateau effect beyond an adequate delivered dose45.
  • Guidelines after RENAL have generally recommended targeting a delivered CRRT dose around 20–25 mL/kg/h and prescribing higher to compensate for downtime, while explicitly recognising the risk of electrolyte depletion with higher clearances6.

Summary

  • RENAL randomised 1508 ICU patients with AKI to higher-intensity vs lower-intensity CVVHDF (40 vs 25 mL/kg/h effluent).
  • There was no difference in 90-day mortality: 44.7% vs 44.7% (OR 1.00; 95% CI 0.81 to 1.23; P=0.99).
  • Higher intensity improved biochemical control (lower urea/creatinine) but did not improve liberation from RRT, ICU/hospital LOS, or ventilation duration.
  • Higher intensity increased complications and resource use, notably hypophosphataemia (65.1% vs 54.0%; P<0.0001) and greater filter consumption (1.06 vs 0.84 filters/day; P<0.001).
  • The trial materially influenced modern practice by supporting an “adequate, deliverable dose” paradigm rather than routine escalation.

Further Reading

Other Trials

Systematic Review & Meta Analysis

Observational Studies

Guidelines

Notes

  • Further Reading entries above prioritise sources with verified DOI landing pages available during preparation; where a specific RCT/meta-analysis DOI could not be verified from the available sources in this workspace, it is not listed to avoid inaccuracy.

Overall Takeaway

RENAL showed that increasing CVVHDF intensity from 25 to 40 mL/kg/h (delivered 22.0 vs 33.4 mL/kg/h) did not improve 90-day survival or renal recovery in critically ill patients with AKI, despite improved biochemical control. The trial redirected practice away from routine “high-dose” CRRT towards reliably delivering an adequate dose while actively mitigating electrolyte depletion and resource burden.

Overall Summary

  • Higher-intensity CVVHDF (40 mL/kg/h) did not reduce 90-day mortality compared with 25 mL/kg/h (44.7% vs 44.7%).
  • Delivered dose separation was substantial (33.4 vs 22.0 mL/kg/h), supporting a true negative result for outcome benefit.
  • Higher intensity increased hypophosphataemia and filter consumption, emphasising harm/resource trade-offs.

Bibliography