This document summarizes a key clinical trial called the Acute Renal Failure Trial Network Study (ATN) that compared intensive versus conventional renal replacement therapy (RRT) in critically ill patients with acute kidney injury (AKI) from acute tubular necrosis (ATN). The trial found that intensive RRT, with either 6 hemodialysis treatments per week or higher effluent flow rates with continuous RRT, did not decrease mortality at 60 days compared to conventional RRT with 3 hemodialysis treatments per week or lower effluent flow rates. Intensive RRT also did not improve renal function or other organ dysfunction, though it was associated with more hypotensive episodes. The trial provided evidence that a more

1. ATN
OVMC LANDMARK TRIALS SERIES
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.

2. Acute Renal Failure Trial Network Study (ATN)

3. BACKGROUND
SOME FACTS:
 Acute tubular necrosis (ATN) is associated with a
mortality of >50% in critically ill patients
 ATN involves the death of tubular epithelial cells of
the renal tubules of the kidneys. Common causes
include low BP and use of nephrotoxic drugs
PRIOR TO TRIAL:
 Prior to the ATN trial, the intensity of renal
replacement therapy (RRT) has not been well
established.
 Many single center trials showed that intensive RRT
programs led improved mortality

4. 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?
Photo Credit: Pathology Department of James Cook University

5. DESIGN
 Analysis: Intention-to-treat
 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
 Primary outcome: All-cause mortality at 60 days

6. 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 >2 in men or >1.5 in women
 Failure of one or more non-renal organs (SOFA
score ≥2) or sepsis
Exclusion Criteria
 Elevated baseline serum creatinine >2 mg/dl
for men and >1.5 mg/dl for women)
 Etiology of AKI other than ATN
 Hemodialysis already given
 Previous renal transplant
 Pregnancy
 Prisoner
 Weight >128.5 kg
 Patient unlikely to survive 28 days

7. INTERVENTIONS
 Randomization:
 Intensive RRT
 Conventional less intensive RRT
 Sequential Organ Failure Assessment (SOFA) Score determined intermittent versus continuous therapy. There
were different modalities that were used, but study only examined treatment intensity
 Intensive renal replacement therapy:
 Intermittent hemodialysis or sustained low-efficiency dialysis: 6 treatments per week
 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
 Continuous venovenous hemodiafiltration (CVVHDF): Prescribed total effluent flow rate of 20 ml/kg/hour

8. CRITICISMS
 Timing of RRT initiation was not standardized
 Many patients in study had dynamically changing disease severity, BUT a dynamic dosing regimen
was not used
 Possible biased outcomes due to prolonged ICU stay, differences in fluid balance, high rate of
treatment with CRRT before randomization
 It is unclear why the renal recovery rate was so low
 Generalizability limited because:
 Men were overrepresented in the study (25% from VA centers)
 Excluded patients with baseline advanced CKD

9. 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.
Intensive RRT DID NOT improve renal
function or nonrenal organ dysfunction,
although it was associated with more
frequent hypotensive episodes.

10. DISCUSSION QUESTIONS
 What did the ATN show in terms of intensive RRT and renal function?
 What type of patients were studied in the ATN trial?
 Possible controversy: how should unstable patients with acute kidney injury be treated?

11. DISCUSSION QUESTIONS/ANSWERS
 What did the ATN show in terms of intensive RRT and renal function?
 ANSWER: RRT did not improve renal function or nonrenal organ dysfunction, although it was
associated with more frequent hypotensive episodes.
 What type of patients were studied in the ATN trial?
 ANSWER: ICU patients with apparent nephrotoxic injury and evidence of kidney injury
 Defined as oliguria (average urine output < 20 ml/hr for >24 hours), OR increased serum
creatinine >2 in men or >1.5 in women

12. MKSAP NEPHROLOGY QUESTION #32
A 47-year-old man is admitted to the medical ICU with
severe sepsis, multi-lobar pneumonia, and acute
respiratory distress syndrome. He developed oliguric
acute kidney injury on hospital day 3; he has produced
only 240 mL of urine over the past 24 hours despite
adequate intravenous hydration. He is mechanically
ventilated and requires 80% FIO2. Medical history is
unremarkable, and current medications are
piperacillin/tazobactam, vancomycin, norepinephrine,
vasopressin and propofol infusions, and a proton pump
inhibitor.
On physical examination the patient is intubated and
sedated. Temperature is 38.5 °C (101.3 °F), blood pressure
is 95/60 mm Hg, and pulse rate is 130/min. Estimated
central venous pressure is 14 cm H2O. There is no rash.
Generalized anasarca is noted. Examination of the chest
reveals coarse breath sounds and inspiratory crackles
throughout both lungs.
(ADAPTED from MKSAP 17)
Which of the following is the most appropriate treatment
for this patient's kidney failure?
A. Initiate continuous renal replacement therapy
B. Initiate intermittent hemodialysis
C. Initiate slow continuous ultrafiltration
D. Start laxis IV

13. ANSWER UP FOR DISCUSSION
Educational Objective:
Treat acute kidney injury with continuous renal
replacement therapy.
Key Point:
- Continuous renal replacement therapy is
preferred for critically ill, unstable patients
with acute kidney injury because it provides a
slower rate of solute and fluid removal per
unit of time, resulting in better hemodynamic
tolerance.
- Tolwani A. Continuous renal replacement
therapy for AKI. N Engl J Med. 2012 Dec
27;367(26):2505-14.
ANSWER
Which of the following is the most
appropriate treatment for this patient's
kidney failure?
A. Initiate continuous renal replacement
therapy
B. Initiate intermittent hemodialysis
C. Initiate slow continuous ultrafiltration
D. Start laxis IV