Artificial Kidney Initiation in Kidney Injury (AKIKI) STUDY

 

Gaudry S, Hajage D, Schortgen F, Martin‐Lefevre L, Pons B, Boulet E, Boyer A, Chevrel G, Lerolle N, Carpentier D, de Pros N, Lautrette A et al. Initiation Strategies for Renal-Replacement Therapy in the Intensive Care Unit. For the Artificial Kidney Initiation in Kidney Injury (AKIKI) Study Group. N Engl J Med. DOI: 10.1056/NEJMoa1603017.

 

BACKGROUND

Renal replacement therapy has been the cornerstone for immediate management of life threating complications of Acute kidney injury (AKI). The timing for initiation of RRT for non-life-threatening complications of AKI has been a topic of debate since long time.

Clinical question

Investigators of this studied tried to find out, whether early initiation of RRT for nonlife threating complications of AKI can lead to better out come?

 

STUDY DESIGN

This was an unblinded, prospective, multicenter, open-label, two-group randomized trial conducted in 31 intensive care units in France over approximately 28 months.

 

Inclusion Criteria

 

1. Age (18 years of age or older).

 

1. Admitted to the intensive care unit with acute kidney injury that was compatible with a diagnosis of acute tubular necrosis in the context of injury due to  ischemia or toxin.

 

1. Receiving invasive mechanical ventilation, catecholamine infusion (epinephrine or norepinephrine) or both.

 

1. Kidney Disease: Improving Global Outcomes [KDIGO] classification stage 3 AKI (serum creatinine, 3.0 times the baseline level or ≥4.0 mg per deciliter [≥354 μmol per liter]; urine output, <0.3 ml per kilogram of body weight per hour for 24 or more hours or anuria for ≥12 hours)

 

 

Exclusion criteria

 

1. Blood urea nitrogen level higher than 112 mg per deciliter.

2. Serum potassium concentration greater than 6 mmol per liter (or greater than 5.5 mmol per liter despite medical treatment)

3. pH < 7.15

4. Acute pulmonary edema (requiring an oxygen flow rate > 5 liters per minute to maintain a peripheral capillary oxygen saturation (Spo2) greater than 95% or requiring a fraction of inspired oxygen (Fio2) greater than 50% in patients receiving mechanical ventilation and despite diuretic therapy)

 

Randomization

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Patients were randomized with in 5 hours of decision in 1:1 ratio and RRT started with in 6 hours in early initiation group.

Groups & Interventions

 

Initiation of RRT

 

Early-strategy group- RRT was initiated within 6 hours.

Delayed-strategy group- RRT was initiated if the patient developed one of the laboratory abnormalities defined in the initial exclusion criteria, or if oliguria or anuria persisted for more than 72 hours after randomization.

Choice of the method of RRT was left to the clinician decision and local guidelines.

 

Cessation of RRT

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1. If spontaneous urine output was 500 ml or higher per 24 hours, or

2. If spontaneous urine output >1000 ml per 24 hours in the absence of diuretic therapy, or

3. if urine output was > 2000 ml per 24 hours in patients with diuretic therapy.

 

Resumption of RRT

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1. If diuresis is insufficient to cause a spontaneous decrease in creatinine level, or

2. if urine output <1000ml/24 hours (or <2000ml/24 hours in patients receiving diuretics)

 

Outcomes

 

Primary outcome

1. Mortality at 60 days

 

Secondary outcome

1. Mortality at 28 days

2. Received renal replacement therapy 

3. Median length of ICU stay

4. Median length of hospital stay

5. Patients with catheter related nosocomial infection 

6. Dependency on RRT

7. Sepsis-related Organ Failure Assessment (SOFA) score at day 3 and day 7

 

RESULTS

Primary outcome 

 

mortality at 60 days – no significant difference

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Secondary outcomes

 

Mortality at 28 days, median length of ICU stay, median vasopressor-free days, median mechanical ventilation–free days  – no significant difference.

Received renal replacement therapy (98% early vs. 51% delayed , p<0.001) &  patients with catheter related nosocomial infection ((10% early vs 5% delayed,p-0.03) were significantly higher in early group.

 

CONCLUSION

 

In critically ill patients with severe acute kidney injury, an early compared with a delayed initiation of renal replacement therapy showed no difference in mortality. Early initiation lead to significantly higher rates of RRT episodes and catheter related infections.

 

Strength

1. Multi-center study.

2. Randomized control trial.

3. Adequate powered.

Weakness

1. Non blinded.

2. Most of the patients the initial modality was intermittent RRT despite the fact that about 85% of patients require vasopressors support upon initiation of RRT.

3. In the delayed group RRT was started 72 hours after enrollment, which may be detrimental for the patient. Moreover, this time period was utilized by the treating physician to add diuretics, optimize the patients and identify the patients who did not need RRT. It was reported that the patients who required RRT in delayed group had more severe disease (higher SAPS 3) and  required more vasopressor.

4. The parameters which were taken as surrogate markers for return of kidney function i.e. diuresis and requirement of RRT can’t correctly predict renal recovery.

 

Take home message

 

In critically ill patients with acute kidney injury, initiating RRT early did not provide a mortality benefit as compared to delayed initiation of RRT. A significant increase in catheter related blood stream infections occurred in early RRT group. So if clinical condition permits (non-life threatening complications) initiation of RRT should be a delayed option.

 

 

Further reading

1. Ravindra L. Mehta. Renal-Replacement Therapy in the Critically Ill — Does Timing Matter? (Editorial) May 15, 2016DOI: 10.1056/NEJMe1606125

 

Literature before this study

An initial paper by Gibney N et al (1) raised this question effectively and proposed need for further clinical studies. Following this, another study in the successive year by Bagshaw SM et al (2) mentioned that late dialysis (as counted by days from hospital admission) was associated with longer duration and dependence on RRT, longer hospital-stay and higher mortality. However, the same study found that dialysis started at a higher creatinine level had a better outcome than when started at a lower creatinine level. A more recent study by Vaara ST et al (3) concluded that preemptive dialysis lead to a better survival profile.

On the other hand, an observational study by Schneider AG et al (4) concluded that late dialysis therapy for RIFLE-F criteria lead to shorter median ICU stay, less requirement for invasive ventilation and a lower APACHE III score. Elseviers MM et al (5) in another observational study concluded that late RRT lead to better survival out come and less ICU and hospital stay.

A recent single center trial involving 231 patients showed reduced ICU mortality at 90 days compared to delayed RRT. The early group included (KDIGO) stage 2 disease state and plasma neutrophil gelatinase-associated lipocalin (NGAL) level higher than 150 ng/mL and the late group included patients with KDIGO stage 3. RRT started within 8 hours in early group and within 12 hours in late group. (6)

 

1. Gibney N, Hoste E, Burdmann EA, et al. Timing of initiation and discontinua- tion of renal replacement therapy in AKI: unanswered key questions. Clin J Am Soc Nephrol 2008;3:876-80.

2. Bagshaw SM, Uchino S, Bellomo R, et al. Timing of renal replacement therapy and clinical outcomes in critically ill pa- tients with severe acute kidney injury. J Crit Care 2009;24:129-40.

3. Vaara ST, Reinikainen M, Wald R, Bagshaw SM, Pettilä V. Timing of RRT based on the presence of conventional in- dications. Clin J Am Soc Nephrol 2014;9: 1577-85.

4. Schneider AG, Uchino S, Bellomo R. Severe acute kidney injury not treated with renal replacement therapy: charac- teristics and outcome. Nephrol Dial Transplant 2012;27:947-52.

5. Elseviers MM, Lins RL, Van der Niepen P, et al. Renal replacement therapy is an independent risk factor for mortality in critically ill patients with acute kidney injury. Crit Care 2010;14(6):R221.

6. Zarbock A et al. Effect of Early vs Delayed Initiation of Renal Replacement Therapy on Mortality in Critically Ill Patients With Acute Kidney InjuryThe ELAIN Randomized Clinical Trial. JAMA. 2016;315(20):2190-2199. doi:10.1001/jama.2016.5828.

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DR Biswabikash Mohanty

MD, FNB

DR Sananta K Dash

MD, FNB, FCCP,EDIC