ATN

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Palevsky PM, et al. "Intensity of renal support in critically ill patients with acute kidney injury". The New England Journal of Medicine. 2008. 359(1):7-20.
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Clinical Question

In critically ill patients with acute tubular necrosis, does more intensive renal replacement therapy decrease the risk of death at 60 days compared to conventional less-intensive renal replacement therapy?

Bottom Line

In critically ill patients with acute tubular necrosis, more intensive renal replacement therapy does not improve all-cause mortality at 60 days compared to conventional less-intensive therapy. In the ATN study, intensive RRT did not improve renal function or nonrenal organ dysfunction, although it was associated with more frequent hypotensive episodes.

Major Points

Acute tubular necrosis (ATN) occurs in a significant minority (5-10%) of medical and surgical ICU patients and is associated with a mortality of ≥50%. While the standard of care for severe ATN includes renal replacement therapy (RRT), the optimal intensity of therapy has been controversial. Several single-center studies had suggested that mortality was improved with more intensive RRT programs, but this was not consistently seen.[1][2] A large, prospective randomized study was needed.

Published in 2008 under the auspices of the VA Cooperative Study Group and the National Institutes of Health, the Acute Renal Failure Trial Network Study (ATN) studied 1,124 ICU patients with ATN. Patients were randomized to intensive or conventional (less intensive) RRT strategies which incorporated intermittent hemodialysis (IHD), continuous venovenous hemodiafiltration (CVVHDF), and sustained low-efficiency hemodialysis, with the exact strategy modified based on hemodynamic and organ function parameters. At 60 days, the primary endpoint of all-cause mortality was no different in the intensive and conventional groups (53.6% vs. 51.5%; P=0.47). Similar results were seen for the secondary outcomes of in-hospital mortality (51.2% vs. 48.0%; P=0.27), discharge to home off dialysis (15.7% vs. 16.4%; P=0.75), and RRT-free days through day 28 (6 vs. 7; P=0.07). Adverse event rates were similar between groups, although more serious episodes of hypotension occurred in the group assigned to intensive RRT.

Although the delivery of RRT in the ATN study mirrored what is often seen in the United States, investigators abroad raised concerns that the results of ATN could not necessarily be extrapolated to non-US centers. This concern prompted the RENAL study, which evaluated the role of intensive (prescribed effluent 40 ml/kg/h) versus less-intensive (25 ml/kg/h) CVVHDF in critically ill patients with acute renal failure.[3] In RENAL, the primary outcome of 90-day mortality was similar between intensive and non-intensive groups (44.7% in each arm), with higher rates of adverse events in the intensive group. The lack of survival benefit with intensive RRT in this patient group has been demonstrated in a 2010 meta-analysis as well.[4]

Does the ATN study guide the use of RRT in sepsis? Although ATN included a large proportion of patients with sepsis (63%), the study did not aim to specifically address the role of optimal RRT intensity in septic patients with acute renal injury. Nevertheless, in a subgroup analysis of septic patients in the ATN study, there was a trend towards increased 60-day mortality in the group receiving intensive RRT (OR 1.19; 95% CI 0.88-1.62; P=0.36). A 2013 Cochrane review identified 3 studies specifically addressing RRT intensity in septic patients; the review concluded that only very weak evidence supports intensive RRT in this patient population.[5]

Current guidelines have not been updated to reflect the results of this trial, and therefore recommendations are scant. Based on the results of ATN and similar studies, three-times weekly IHD (with target Kt/Vurea of 1.2-1.4) or CVVHDF (prescribed effluent rate of 20 ml/kg/h) should probably remain the standard of care for treating most ICU patients with severe ATN requiring RRT.

Guidelines

As of March 2015, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, open-label, parallel-group, randomized, controlled trial
  • N=1,124 patients with critical illness and ATN
    • Intensive renal replacement therapy (n=563)
    • Conventional low-intensity renal replacement therapy (n=561)
  • Setting: 31 centers in the United States
  • Enrollment: 2003-2007
  • Follow-up: 60 days
  • Analysis: Intention-to-treat
  • Primary outcome: All-cause mortality at 60 days

Population

Inclusion Criteria

  • Age ≥18 years
  • Admitted to ICU
  • Acute tubular necrosis, defined by:
    • Clinically apparent ischemia or nephrotoxic injury and
    • One or more of oliguria (average urine output < 20 ml/hr for >24 hours), or increased serum creatinine ongoing for less than 4 days (increased to >177 umol/L [2 mg/dl] for men and >133 umol/L [1.5 mg/dl] for women)
  • Investigator must have been planning to initiate renal replacement therapy
  • Failure of one or more non-renal organs (SOFA score ≥2) or sepsis

Exclusion Criteria

  • Elevated baseline serum creatinine (>177 umol/L [2 mg/dl] for men and >133 umol/L [1.5 mg/dl] for women)
  • Etiology of AKI other than ATN
  • More than 72 hours has passed since meeting AKI definition AND having a BUN of > 35.7 mmol/L [100 mg/dl]
  • More than 24 hours has passed since starting CRRT
  • More than 1 hemodialysis treatment has already been given
  • Previous renal transplant
  • Pregnancy
  • Prisoner
  • Weight >128.5 kg
  • Moribund state
  • Patient unlikely to survive 28 days

Baseline Characteristics

From the intensive therapy group.

  • Demographics: Age 60 years, female sex 27%
    • Race/ethnicity: White 74%, black 16%, Hispanic 8%
  • Health data: 84 kg, Charlson comorbidity index 4.3
  • Pre-injury kidney measurements:
    • Creatinine 1.1 mg/dL
    • eGFR (mL/min/1.73 m2):
      • ≥60: 65%
      • 45-59: 23%
      • 30-44: 12%
  • AKI data: BUN onset of RRT 66 mg/dL, oliguria 78%
    • Cause: Ischemia 82%, nephrotoxins 28%, sepsis 57%, multiple 59%
    • Sustained low-efficiency dialysis (SLED), intermittent hemodialysis (IHD), or <24 hours of CRRT before randomization: 64%
  • Primary service: Medical 48%, surgical 41%, other 11%
  • Hospitalization duration before randomization: Hospital 11 days, ICU 7 days
  • ICU data: Mechanical ventilation 81%, APACHE II score 27, Cleveland Clinic ICU Acute Renal Failure score 12
    • SOFA score:
      • Respiratory: 2.4
      • Coagulation: 1.4
      • Liver: 1.5
      • CV: 2.3
      • CNS: 2.5
      • Total: 14.7

Interventions

Patients were randomized to intensive or conventional less intensive renal replacement therapy. Within each group, the ATN protocol defined when to use an intermittent therapy (IHD) or a continuous therapy (CVVHDF or SLED) based on the SOFA score. Patients with a SOFA score of ≤2 were treated with intermittent hemodialysis. Those with SOFA scores of 3-4 were treated with one of the continuous therapies. The choice between the two continuous therapy options was left to local clinicians. Therefore, although different modalities were used in ATN, this study only examined the effect of treatment intensity.

Intensive renal replacement therapy
  • Intermittent hemodialysis or sustained low-efficiency dialysis: 6 treatments per week with goal Kt/Vurea of 1.2-1.4 per session
  • Continuous venovenous hemodiafiltration (CVVHDF): Prescribed total effluent flow rate of 35 ml/kg/hour
Conventional renal replacement therapy
  • Intermittent hemodialysis or sustained low-efficiency dialysis: 3 treatments per week with goal Kt/Vurea of 1.2-1.4 per session
  • Continuous venovenous hemodiafiltration (CVVHDF): Prescribed total effluent flow rate of 20 ml/kg/hour

Outcomes

Comparisons are intensive therapy vs. conventional therapy. OR is odds ratio.

Primary Outcomes

All-cause mortality by day 60
53.6% vs. 51.5% (OR 1.09; 95% CI 0.86-1.40; P=0.47)

Secondary Outcomes

In-hospital mortality
51.2% vs. 48.0% (OR 1.15; 95% CI 0.90-1.47; P=0.27)
Discharged home and off dialysis within 60 days
15.7% vs. 16.4% (OR 0.95; 95% CI 0.68-1.32; P=0.75)
Recovery of renal function
Complete: 15.4% vs. 18.4%
Partial: 8.9% vs. 9.0%
None: 75.8% vs. 72.6%

Additional Analyses

RRT-free days through day 28
6.0 vs. 7.0 days (P=0.07)
Hospital-free days through day 60
11.0 vs. 13.0 days (mean difference -1.9; 95% CI -3.9 to 0.0; P=0.053)
ICU-free days through day 60
18.7 vs. 20.1 days (P=0.25)

Subgroup Analysis

There was no differences in the incidence of the primary outcome when analyzed by SOFA score, oliguria, sex, and sepsis. There was a trend observed among septic patients towards a benefit with conventional RRT. This is contrary to previous opinion which has held that patients suffering from sepsis would be the most likely to benefit from intensive RRT[6][7]

Adverse Events

Hypotension requiring cessation of dialysis
9.8% vs. 8.7% (P=0.55)
Need for vasopressor support
14.4% vs. 10.0% (P=0.02)
Need for other hypotension interventions
37.7% vs. 29.9% (P=0.006)
Hypophosphatemia
17.6% vs. 10.9% (P=0.001)
Hypokalemia
7.5% vs. 4.5% (P=0.03)

Criticisms

  • Timing of RRT initiation was not standardized[8]
  • A dynamic dosing approach may have been more appropriate for these individuals with a disease that dynamically changes in severity[8]
  • The outcomes may be biased because of the prolonged duration from ICU admission to enrollment, lack of consideration of fluid balance, and high rate of treatment with CRRT before randomization[8]
  • It is unclear why the renal recovery rate was so low[8]
  • Men were overrepresented in the study, likely attributable to the fact that 25% of patients enrolled were from VA centers
  • Generalizability also limited by exclusion of patients with baseline advanced CKD

Funding

  • Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • Multiple authors received support from manufacturers of dialysis equipment and disposables (Gambro, Baxter, Fresenius)
  • Gambro provided IHD, SLED and CVVHDF solutions at discounted prices for the purposes of this study

Further Reading

  1. Ronco C, et al. "Effects of different doses in continuous ven-venous haemofiltration on outcomes of acute renal failure: A prospective randomised trial." The Lancet. 2000;356(9223):26-30
  2. 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.
  3. Bellomo R, et al. Intensity of continuous renal-replacement therapy in critically ill patients. N Engl J Med. 2009 Oct 22;361(17):1627-38.
  4. Van Wert R, et al. High-dose renal replacement therapy for acute kidney injury: Systematic review and meta-analysis. Crit Care Med. 2010 May;38(5):1360-9.
  5. Borthwick EM, et al. "High-volume haemofiltration for sepsis." Cochrane Database of Systematic Reviews. 2013;1:CD008075.
  6. Tetta C, et al. "Do circulating cytokines really matter in sepsis?" Kidney International. 2003;May(84):s69-s71.
  7. Joannes-Boyau O, et al. "Hemofiltration: The case for removal of sepsis mediators from where they do harm." Critical Care Medicine.' 2006;34(8):2244-2246.
  8. 8.0 8.1 8.2 8.3 Multiple authors. "Correspondence: Renal support in critically ill patients with acute kidney injury." The New England Journal of Medicine. 2008;359:1959-1962.