Elsevier

The Lancet

Volume 397, Issue 10281, 3–9 April 2021, Pages 1293-1300
The Lancet

Articles
Comparison of two delayed strategies for renal replacement therapy initiation for severe acute kidney injury (AKIKI 2): a multicentre, open-label, randomised, controlled trial

https://doi.org/10.1016/S0140-6736(21)00350-0Get rights and content

Summary

Background

Delaying renal replacement therapy (RRT) for some time in critically ill patients with severe acute kidney injury and no severe complication is safe and allows optimisation of the use of medical devices. Major uncertainty remains concerning the duration for which RRT can be postponed without risk. Our aim was to test the hypothesis that a more-delayed initiation strategy would result in more RRT-free days, compared with a delayed strategy.

Methods

This was an unmasked, multicentre, prospective, open-label, randomised, controlled trial done in 39 intensive care units in France. We monitored critically ill patients with severe acute kidney injury (defined as Kidney Disease: Improving Global Outcomes stage 3) until they had oliguria for more than 72 h or a blood urea nitrogen concentration higher than 112 mg/dL. Patients were then randomly assigned (1:1) to either a strategy (delayed strategy) in which RRT was started just after randomisation or to a more-delayed strategy. With the more-delayed strategy, RRT initiation was postponed until mandatory indication (noticeable hyperkalaemia or metabolic acidosis or pulmonary oedema) or until blood urea nitrogen concentration reached 140 mg/dL. The primary outcome was the number of days alive and free of RRT between randomisation and day 28 and was done in the intention-to-treat population. The study is registered with ClinicalTrial.gov, NCT03396757 and is completed.

Findings

Between May 7, 2018, and Oct 11, 2019, of 5336 patients assessed, 278 patients underwent randomisation; 137 were assigned to the delayed strategy and 141 to the more-delayed strategy. The number of complications potentially related to acute kidney injury or to RRT were similar between groups. The median number of RRT-free days was 12 days (IQR 0–25) in the delayed strategy and 10 days (IQR 0–24) in the more-delayed strategy (p=0·93). In a multivariable analysis, the hazard ratio for death at 60 days was 1·65 (95% CI 1·09–2·50, p=0·018) with the more-delayed versus the delayed strategy. The number of complications potentially related to acute kidney injury or renal replacement therapy did not differ between groups.

Interpretation

In severe acute kidney injury patients with oliguria for more than 72 h or blood urea nitrogen concentration higher than 112 mg/dL and no severe complication that would mandate immediate RRT, longer postponing of RRT initiation did not confer additional benefit and was associated with potential harm.

Funding

Programme Hospitalier de Recherche Clinique.

Introduction

Severe acute kidney injury is frequent among critically ill patients hospitalised in intensive care units (ICUs) and is associated with high morbidity and mortality.1 Major uncertainty remains concerning the duration for which renal replacement therapy (RRT) can be postponed without risk as criteria for initiating RRT lack precision in the absence of complication. The majority of well conducted, randomised, controlled trials2, 3 including a recently issued very large one4 as well as a large individual patient data meta-analysis5 showed that an early RRT initiation strategy did not confer any survival advantage compared with a delayed strategy during severe acute kidney injury in critically ill patients when no severe complication is present.6 Moreover, early institution of this technique was associated with more complications, some being very severe.2, 4

The duration for which RRT initiation was delayed varied considerably, expanding from 25 hours to 57 h according to study.2, 3, 4 The large variation in the criteria retained for initiating RRT in the delayed group of these studies2, 3, 4 was responsible for this marked heterogeneity. The longer RRT is safely postponed, the more numerous are patients who do not receive this treatment. Severe hyperkalaemia or metabolic acidosis and pulmonary oedema unresponsive to diuretic administration are recognised criteria for RRT initiation.7, 8 In the absence of such complications, the extent to which the duration of oliguria or anuria, or the degree of uremia constitute an appropriate indication for RRT is unknown. Establishing evidence-based criteria for both pertinent and safe initiation of RRT might help rationalise the use of this costly treatment.

Research in context

Evidence before this study

In May, 2020, we published a systematic review and individual patient data meta-analysis (IPDMA) of randomised controlled trials (RCTs), published from April, 2008, to Dec, 2019, which compared a delayed versus early renal replacement therapy (RRT) initiation strategy for severe acute kidney injury. We completed the electronic search via PubMed up until July 16, 2020, by means of the same keywords. This systematic review included ten RCTs. The complementary search found one more recent RCT (STARRT-AKI trial). The IPDMA showed that RRT initiation strategy (delayed versus early) did not affect survival in critically ill patients with severe acute kidney injury who had no urgent indications and that delayed strategies were associated with less frequent usage of RRT. The STARRT-AKI trial, a large multicentre international RCT, confirmed these findings.

The timing of early RRT initiation was roughly the same in nearly all RCTs. On the contrary, there was wide heterogeneity in the definition of delayed RRT that encompassed a delay extending from 25 to 57 h according to study. The longer the duration of delay of therapy initiation, the greater the percentage of patients who did not receive RRT. In the AKIKI trial, indications to initiate RRT in the delayed strategy were the conventional urgent indications (life-threatening metabolic complications) or oliguria for more than 72 h or a blood urea nitrogen concentration higher than 112 mg/dL. Compared with the other RCTs, this delayed strategy was associated with longer median delay (57 h) and a lower percentage of RRT initiation (51% of patients assigned to the delayed strategy).

Added value of this study

To do the present randomised trial, we considered the delayed strategy of the AKIKI trial as the standard strategy and we assessed the potential benefits of a more-delayed strategy for RRT initiation. With this new strategy the duration of oliguria was no longer an indication for RRT and the concentration of blood urea nitrogen that mandated initiation was set to higher values (140 mg/dL). The more-delayed strategy, although resulting in fewer patients receiving RRT, was not associated however with more RRT-free days which was the primary goal. Survival did not differ between groups but a prespecified multivariable analysis revealed that 60-day mortality was higher with the more-delayed strategy.

Implications of all the available evidence

This trial informs on the limit to which RRT can be safely postponed in critically ill patients with severe acute kidney injury. The more-delayed strategy was actually not associated with benefit regarding RRT-free days and was associated with higher 60-day mortality. These findings give crucial information for future guidelines which must allow maximisation of general profit by not wasting treatments and by restricting their use to the situations that really require it.

In patients with acute kidney injury stage 3 with oliguria for more than 72 h or blood urea nitrogen concentration higher than 112 mg/dL and no severe complication that would mandate immediate RRT, a longer postponing of RRT initiation does not confer additional benefit and is associated with potential harm.

The AKIKI 2 (Artificial Kidney Initiation for Kidney Injury 2) trial was a non-blinded multicentre, randomised, controlled trial that compared two delayed strategies for RRT initiation. One was exactly the same as the one used in our previous study.2 In this previous study, the delayed strategy proved safe and resulted in the longest reported delay between the onset of severe acute kidney injury and RRT initiation in randomised, controlled trials.2, 3, 4, 9 The second strategy tested in the present study was more delayed as it allowed further postponing of RRT initiation in the absence of the abovementioned complications. The aim of the study was to test the hypothesis that this more-delayed initiation strategy would result in more RRT-free days, a composite outcome of duration of RRT and survival10 compared with the delayed strategy.

Section snippets

Study design

The AKIKI 2 study was an institutionally sponsored unmasked, multicentre, open-label, two-arm, randomised, controlled trial done in 39 intensive care units in France. A complete list of participating sites is provided in the appendix (pp 2–4). The study protocol (previously published11) was approved by the competent French legal authority (Comité de Protection des Personnes de Sud-Est V) for all participating centres. All analyses were done in accordance with the International Conference on

Results

Between May 7, 2018, and Oct 11, 2019, of 5336 patients assessed, 767 patients with KDIGIO stage 3 acute kidney injury were monitored for occurrence of randomisation criteria. Ten were excluded for erroneous inclusion. Among 757 remaining patients, 278 (37%) underwent random assignment (figure). The characteristics and outcomes of the 479 patients who were not randomly assigned are presented in the appendix (p 12). Patient characteristics at the time of KDIGO stage 3 acute kidney injury and on

Discussion

This study compared two delayed strategies for RRT initiation in critically ill patients with severe acute kidney injury. The first was similar to the strategy that allowed for important and safe reduction of the number of patients receiving this treatment in our previous study.2 The second tested the possibility to further increase this number by postponing RRT initiation for an even longer period. This was achieved by two specifications of the protocol: the duration of oliguria or anuria was

Data sharing

Anonymous participant data is available under specific conditions. Proposals will be reviewed and approved by the sponsor, scientific committee, and staff on the basis of scientific merit and absence of competing interests. Once the proposal has been approved, data can be transferred through a secure online platform after the signing of a data access agreement and a confidentiality agreement.

Declaration of interests

The authors declare no competing interests. The AKIKI 2 trial was promoted by the Assistance Publique—Hôpitaux de Paris and funded by a grant of the French Ministry of Health (Programme Hospitalier de Recherche Clinique 2016; AOM16278).

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