RENAL

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Bellomo R, et al. "Intensity of continuous renal-replacement therapy in critically ill patients". The New England Journal of Medicine. 2009. 361(17):1627-1638.
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Clinical Question

In critically ill patients with acute kidney injury requiring continuous renal replacement therapy, does a more intensive prescription reduce the risk of death?

Bottom Line

Among critically ill patients with AKI requiring continuous renal replacement therapy, a higher intensity of CRRT did not reduce all-cause mortality at 90 days.

Major Points

An early trial conducted by members of the RENAL investigative team showed improved survival among critically ill patients with acute kidney injury who were treated with higher doses of continuous renal replacement therapy.[1] However, subsequent studies failed to consistently corroborate this finding.[2][3] A multicenter trial was needed to further evaluate this therapy.

Published in 2009, the Randomized Evaluation of Normal versus Augmented Level (RENAL) Replacement Therapy Study randomized 747 ICU patients with AKI to CRRT dosed at either a higher-intensity or a more conventional intensity. There was no difference between the groups in all-cause mortality at 90 days (44.7% vs. 44.7%; P=0.99).

RENAL confirmed the findings of the latter trials and the large NIH/VA-funded ATN trial, all of which showed no improvement in outcomes with more intensive renal replacement therapy.

Guidelines

Design

  • Multicenter, open-label, parallel-group, randomized, controlled trial
  • N=1465
    • Intensive (n=722)
    • Conventional (n=743)
  • Setting: 35 centers in Australia and New Zealand
  • Enrollment: December 2005 to November 2008
  • Mean follow-up: 90 days
  • Analysis: Intention-to-treat
  • Primary outcome: All cause mortality at 90 days

Population

Inclusion Criteria

  • Adults (>18 years old) admitted to intensive care units
  • Acute kidney injury requiring CRRT, defined as:
    • The need for CRRT as determined by the treating physician, AND
    • One or more of the following: oliguria (urine output < 100 ml/hr for 6 hours unresponsive to fluid), OR serum potassium > 6.5 mmol/L, OR severe acidosis with pH <7.2, OR blood urea nitrogen > 25 mmol/L, OR serum creatinine > 300 umol/L, OR any organ edema.

Exclusion Criteria

  • Death expected within 24 hours
  • Previously treated with CRRT or dialysis during this admission
  • Previously receiving chronic dialysis
  • Body weight < 60 kg or > 100 kg

Baseline Characteristics

  • Mean age: 65 years
  • Renal function:
    • Preadmission eGFR: 56 ml/min
    • CKD stage IIIa: 18%
    • CKD stage IIIb: 19%
    • CKD stage IV – V: 20%
  • Severe sepsis: 49%
  • Mechanical ventilation: 74%
  • Admission diagnosis:
    • Cardiovascular: 51%
    • Gastrointestinal: 23%
    • Trauma: 5%
    • Other: 6%
  • Mean APACHE III score: 102

Interventions

  • Intensive CRRT:
    • Continuous venovenous hemodiafiltration (CVVHDF): Total effluent flow rate of 40 ml/kg/hour
  • Conventional CRRT:
    • Continuous venovenous hemodiafiltration (CVVHDF): Total effluent flow rate of 25 ml/kg/hour

In both groups the CVVHDF prescription used blood flow rates greater than 150 ml/min, post-filter replacement fluid and AN69 membranes.

Outcomes

Comparisons are intensive CRRT vs. conventional CRRT.

Separation Between Groups

  • Intensive CRRT (targeted 40 ml/kg/hour): 33.4 ml/kg/hour
  • Conventional CRRT (targeted 25 ml/kg/hour): 22.0 ml/kg/hour

Primary Outcomes

All-cause mortality at 90 days
44.7% vs. 44.7% (OR 1.00; 95% CI 0.81-1.23; P=0.99)

Secondary Outcomes

All-cause mortality at 28 days
38.5% vs. 36.9% (OR 1.07; 95% CI 0.87-1.32; P=0.52)
Place of death
ICU: 34.8% vs. 34.2% (OR 1.03; 95% CI 0.83-1.27; P=0.81)
Ward: 9.4% vs. 10.2% (OR 0.913; 95% CI 0.65-1.29; P=0.60)
Post-discharge: 0.4% vs. 0.3% (OR 1.55; 95% CI 0.26-9.28; P=0.63)
RRT-dependence (survivors)
At day 28: 14.4% vs. 12.2% (OR 1.22; 95% CI 0.83-1.79; P=0.31)
At day 90: 6.8% vs. 4.4% (OR 1.59; 95% CI 0.86-2.92; P=0.14)
Days of treatment
RRT by day 90: 13.0 vs. 11.5 days (P=0.14)
ICU: 11.8 vs. 11.8 days (P=0.95)
Hospitalization: 26.0 vs. 25.7 days (P=0.79)
Mechanical ventilation: 7.3 vs. 7.4 days (P=0.79)

No significant differences were found for any secondary outcome. The closest any outcome came to achieving statistical significance was the need for ongoing renal replacement therapy. At 90 days, 6.8% of surviving intensive CRRT patients still required dialysis compared to 4.4% of the conventional CRRT group.

Risk of ongoing need for dialysis at 90 days
OR 1.59; 95% CI 0.86-2.92; P=0.14

Adverse Events

A number of dialysis-related adverse outcomes were assessed including dialysis disequilibrium, arrhythmia, hypokalemia, and hypophosphatemia. Only hypophosphatemia was found to have occurred more frequently in patients receiving intensive CRRT.

Proportion of patients with at least one episode of hypophosphatemia
65.1% vs. 54.0%, P<0.001

Subgroup Analyses

There were no significant differences found within the three pre-defined subgroups (patients with sepsis, patients with cardiovascular dysfunction, patients with failure of at least one non-renal organ).

Criticisms

  • RENAL was not powered to assess outcomes in patients with more than three failed organ systems. The number of failed organ systems predicts mortality in critically ill patients with acute kidney injury and it remains unclear if more intensive treatment could improve mortality in this particularly ill population.[4]
  • Despite their assiduous attention to CRRT dose delivery, the actual delivered dose fell short of the prescribed dose in both the intensive and conventional arms. Clinicians should exercise caution in reducing CRRT dosing based on the results of RENAL because in usual practice CRRT interruptions can substantially reduce the delivered dose.[2][5]
  • The criteria for nonrenal organ failure was not specified[5]
  • This study was not powered for subgroup analysis with ≥3 organs failing[5]

Funding

  • National Health and Medical Research Council of Australia
  • Health Research Council of New Zealand

Further Reading

  1. Ronco C, et al. "Effects of different doses in continuous veno-venous haemofiltration on outcomes of acute renal failure: a prospective randomized trial." The Lancet. 2000;356(9223):26-30
  2. 2.0 2.1 Saudan P, Niederberger M, De Saudan, P et al. "Adding a dialysis dose to continuous hemofiltration increases survival in patients with acute renal failure." Kidney International. 2006;70(7):1312-1317.
  3. Bouman CS, et al. "Effects of early high-volume continuous venovenous hemofiltration on survival and recovery of renal function in intensive care patients with acute renal failure: A prospective, randomized trial." Critical Care Medicine. 2002;30(10):2205-2211.
  4. Ostermann M and Chang RW. "Correlation between parameters at initiation of renal replacement therapy and outcome in patients with acute kidney injury." Critical Care. 2009;13(6):R175-R175
  5. 5.0 5.1 5.2 Multiple authors. "Correspondence: Intensity of continuous renal-replacement therapy." The New England Journal of Medicine. 2010;362:466-468.