AKIKI

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Gaudry S, et al. "Initiation strategies for renal-replacement therapy in the intensive care unit". The New England Journal of Medicine. 2016. 375(2):122-133.
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Clinical Question

Among ICU patients with AKI, does early renal replacement therapy (RRT) reduce mortality as compared to delayed RRT?

Bottom Line

Among ICU patients with AKI, there is no mortality difference between early or delayed RRT.

Major Points

Renal replacement therapy (RRT) is a life-saving intervention among critically-ill patients with severe AKI. However, some of these patients with severe AKI spontaneously recover renal function and may not need urgent RRT. While RRT is generally well-tolerated, it is associated with procedure-related complications (eg, line infections). Conversely, early removal of uremic toxins may provide benefit among the critically-ill. As such, the timing of initiation of RRT was a matter of debate among critically-ill patients with severe AKI.

Published in 2016, the Artificial Kidney Initiation in Kidney Injury (AKIKI) trial randomized patients to received early (n=311) or delayed RRT (n=308). The primary outcome was overall survival at day 60. Early RRT did not reduce mortality as compared to delayed RRT (48.5% vs. 49.7%; P=0.79). There was a significant increase in catheter-related bloodstream infection in the early RRT group. In the delayed RRT group, 49% of patients never received RRT.

A post-hoc analysis of the timing of RRT initiation showed a higher mortality rate among those with delayed HD when compared to participants with earlier initiation or no initiation. However, those in the delayed initiation group were sicker at baseline and no mortality differences were seen when controlling for baseline characteristics. However, individuals in the delayed RRT received greater quantities of diuretics. Whether this may have contributed to worsening clinical status in these individuals is unclear. Ideally, accurate metrics predictive of renal recovery would help identify patients most likely to need RRT.[1] Until such resources are available, a watchful waiting approach seems to be safe.

In the same year, the single-centered ELAIN trial reported that early RRT significantly reduced all-cause mortality as compared to delayed initiation at 90, but not 60, days.[2] The contrasting results in these 2 recent trials have been attributed to different study designs, the threshold for initiating RRT and patient populations in each trial.[3][4] For example, ELAIN enrolled ~95% surgical ICU patients and initiated RRT at KDIGO stage 2 while AKIKI enrolled ~80% medical ICU patients and initiated RRT at KDIGO stage 3. These trials were included in a pooled analysis that did not support early being better than late RRT (early vs. delayed RRT: OR 0.74; 95% CI 0.43-1.27; I2=70.5%).[5]

Guidelines

As of August 2017, no guidelines have been published that reflect the results of this trial.

Design

Some design details are presented elsewhere.[6]

  • Multicenter, open-label, prospective, randomized trial
  • N=620
    • Early RRT (N=311)
    • Delayed RRT (N=308)
  • Setting: 31 ICU in France
  • Enrollment: 2013-2016
  • Follow-up: 60 days
  • Analysis: Intention-to-treat
  • Primary outcome: Overall survival at day 60

Population

Inclusion Criteria

  • Age ≥18 years
  • Admitted to ICU with KDIGO Stage 3 AKI that is due to ischemic or toxic acute tubular necrosis, with one of the following:
    • Serum creatinine concentration> 4 mg/dl (354 µmol/l) or >3 times the baseline level
    • Urine output ≤100 ml/day for >12 hours or <500 ml/day or <0.3 ml/kg/h for >24 hours
  • ≥1 of the following:
    • Mechanical ventilation
    • Vasopressor support with epinephrine or norepinephrine

Exclusion Criteria

  • BUN >112 mg/dL (40 mmol/L)
  • Potassium >6 mmol/L or >5.5 mmol/L despite medical treatment
  • pH <7.15 due to either pure metabolic acidosis (PaCO2 <35 mm Hg) or mixed acidosis (Paco2 ≥50 mm Hg without any capacity to increase alveolar ventilation)
  • Severe hypoxemia requiring mechanical ventilation with oxygen flow rate >5L/min to maintain SpO2 >95% or requiring a Fio2> 50% due to acute pulmonary edema despite diuretic therapy
  • Pre-existing CKD (creatinine clearance <30 ml/min)
  • Patients fulfilling the inclusion criteria who have been present for >5 hours
  • AKI due to tumor lysis syndrome, thrombotic microangiopathy, acute glomerulopathy, urinary tract or renal vessel obstruction
  • Poisoning due to an agent which is dialyzable
  • Cirrhosis (Child C)
  • Cardiac arrest with unsuccessful resuscitation
  • Life expectancy <24 hours
  • Already received RRT for the current episode of AKI
  • Extracorporeal lung or cardiovascular assistance
  • Renal transplant patients

Baseline Characteristics

From the early RRT group

  • Demographics: Age 65 years, male sex 67%
  • PMH: CKD 7%, HTN 52%, DM 26%, HF 8%, CHD 10%
  • ICU admission type: Medical 79%, emergency surgery 15%, scheduled surgery 5%
  • Labs: Serum creatinine prior to ICU admission 0.95±0.26 mg/dl, serum creatinine at randomization 3.25±1.40 mg/dl; BUN 53±24 mg/dl, potassium 4.4±0.7 mmol/l, bicarbonate 18.7±5.1 mmol/l
  • Physiological status:
    • SOFA score 11; SAPS III 73
    • Invasive mechanical ventilation 86%, vasopressor support 85%
    • Oliguria or anuria 65%
  • PMH: DM 26%, CKD 7%, hypertension 52%, heart failure 8%, IHD 10%
  • Sepsis status: Sepsis 8%, severe sepsis 5%, septic shock 67%; ARDS 34%

Interventions

  • Patients were randomized within 5 hours after confirming a stage 3 AKI to a group:
    • Early RRT - Therapy immediately after randomization (within 6 hours after confirming stage 3 AKI)
    • Delayed RRT - Therapy commenced only when meeting 1 of the laboratory abnormalities listed in the exclusion criteria, or if oliguria or anuria lasted >72 hours post-randomization
  • The method and details of RRT was decided by study site investigators
  • Discontinuation of RRT was considered if the spontaneous urine output was ≥500 mL/24 hours and highly recommended if the spontaneous urine output was ≥1000 mL/24 hours without diuretics or ≥2000 mL/24 hours with diuretics.

Outcomes

Comparisons are early vs. delayed RRT

Primary Outcomes

All-cause mortality
Day 28: 41.6% (95% CI 35.9-46.9%) vs. 43.5% (95% CI 37.7-48.8%)
Day 60: 48.5% (95% CI 42.6-53.8%) vs. 49.7% (95% CI 43.8-55.0%); HR 1.03 95% CI 0.82–1.29; P=0.79
Adjusted analysis: HR 1.02; 95% CI 0.81-1.29; P=0.84
Stratified to center and for baseline invasive ventilation status, SAPS III score, sepsis status, vasopressor treatment, and time since admission to development of AKI

Secondary Outcomes

Receipt of RRT
98% vs. 51%; P<0.001
Median (IQR) RRT-free days between day 0-28 post-randomization
17 (2-26) vs. 19 (5-29); P<0.001
Dependence on RRT
Day 28: 12% vs. 10%; P=0.51
Day 60: 2% vs. 5%; P=0.12
Median (IQR) mechanical ventilation-free days between day 0-28 post-randomization
7 (0-22) vs. 6 (0-21); P=0.76
Median (IQR) vasopressor-free days between day 0-28 post-randomization
20 (1-26) vs. 20 (0-26); P=0.67
SOFA score
Day 3: 10±4 vs. 10±4; P=0.14
Day 7: 8±4 vs. 8±4; P=0.63
Median (IQR) duration of stay in ICU
Survivors: 13 (8-23) vs. 13 (7-23); P=0.87
Nonsurvivors: 6 (2-14) vs. 6 (2-13); P=0.92
Duration of stay in hospital
Survivors: 29 (17-51) vs. 32 (20-51); P=0.58
Nonsurvivors: 6 (2-14) vs. 6 (2-13); P=0.85
Patients with treatment limitations
Withholding or withdrawing treatment
23% vs. 24%; P=0.78
Catheter-related bloodstream infection
Patients with infection: 10% vs. 5%; P=0.03
Incidence/1000 catheter-days: 3.4 (2.3-4.6) vs. 2.1 (1.1-3.1); P=0.09
Unexplained bloodstream infection: 7% vs. 8%; P=0.43
Ventilator-associated pneumonia: 16% vs. 12%; P=0.15
Complications related to AKI or RRT
Hemorrhage: 9% vs. 12%; P=0.21
Thrombocytopenia: 55% vs. 54%; P=0.70
Thrombosis: 4% vs. 5%; P=0.31
Hypokalemia: 22% vs. 22%; P=0.95
Hyperkalemia: 5% vs. 6%; P=0.68
Hypophosphatemia: 22% vs. 15%; P=0.03
Severe cardiac rhythm disorders: 9% vs. 11%; P=0.4
Moderate cardiac rhythm disorders: 16% vs. 16%; P=0.77
Transfusion
Patients who received transfusion: 47% vs. 49%; P=0.57
Units of red cells transfused per patient: 2.4±4.1 vs. 2.4±4.3; P=0.75

Additional Analyses

Post-hoc analysis of mortality
Note: For hypothesis generation only given post-hoc nature.
Never receiving RRT: 37.1% (Lowest mortality, P<0.001. However, P=NS after adjusting for baseline illness.)
Late receipt of RRT: 61.8%
Intermediate receipt of RRT: 48.5%

Criticisms

  • Limited generalizability as ~50% of patients received intermittent HD and only 30% received continuous RRT
  • It is debatable if the trial was sufficiently powered to detect a significant difference in mortality.[7]
  • Trial results may not be applicable to patients with less severe renal disease.[7]
  • The Kt/V was not used to evaluate the dose of RRT, however, low serum urea levels were maintained during treatment.[7]

Funding

The French Ministry of Health

Further Reading

  1. Mehta RL & Renal-Replacement Therapy in the Critically Ill--Does Timing Matter?. N. Engl. J. Med. 2016. 375:175-6.
  2. Zarbock A et al. Effect of Early vs Delayed Initiation of Renal Replacement Therapy on Mortality in Critically Ill Patients With Acute Kidney Injury: The ELAIN Randomized Clinical Trial. JAMA 2016. 315:2190-9.
  3. Vinsonneau C & Monchi M Timing of Initiation of Renal Replacement Therapy in Critically Ill Patients With Acute Kidney Injury. JAMA 2016. 316:1497-1498.
  4. Zarbock A, Kellum JA. Timing of Initiation of Renal Replacement Therapy in Critically Ill Patients With Acute Kidney Injury—Reply. JAMA. 2016;316(11):1214. doi:10.1001/jama.2016.11338
  5. Bagshaw SM & Wald R Strategies for the optimal timing to start renal replacement therapy in critically ill patients with acute kidney injury. Kidney Int. 2017. 91:1022-1032.
  6. Supplementary Appendix
  7. 7.0 7.1 7.2 Gaudry S et al. Initiation Strategies for Renal-Replacement Therapy in the Intensive Care Unit. N. Engl. J. Med. 2016. 375:122-33.