Incidence of acute kidney injury and attributive mortality in acute respiratory distress syndrome randomized trials

Acute kidney injury (AKI) is a common complication of critical illness, including acute respiratory distress syndrome (ARDS) [1]. Mortality is higher in patients with ARDS who develop AKI [2, 3].

Mortality directly attributable to ARDS has been reported to be between 21% and 38% [4], suggesting an important contribution from other factors, most likely comorbidities, and extra-pulmonary organ injury. The attributable mortality from AKI in ARDS patients has however not been reported.

Strategies to prevent new episodes of AKI or improve recovery from AKI therefore carry the promise to decrease mortality in patients with ARDS [5]. Designing trials to prevent or treat ARDS-associated AKI requires a good understanding of both the incidence and attributable mortality of AKI in this population.

An accurate estimate of the attributable mortality of AKI is mandatory when calculating the effect size of an intervention targeting AKI. In other words, calculating a sample size on the overall mortality of ARDS with an intervention targeting AKI would likely overestimate the effect size of the intervention and decrease the power of the trial relative to the attributable mortality of AKI [6].

Therefore, the objective of this study is to assess the incidence of AKI and estimate the attributable mortality from AKI in the population of patients with ARDS, using prospectively collected data from clinical trials over 20 years.

This individual patient analysis among 5148 patients with ARDS, enrolled over 20 years in 10 multicenter randomized clinical trials, shows a 43.7% crude incidence of AKI. The risk of developing AKI remained stable over time across the trials, after adjusting for risk factors. The excess mortality attributable to AKI was estimated to be 15.4% at 90 days, highlighting a substantial impact on the clinical outcomes of ARDS patients. Of note, the timing of AKI onset aligns with previous studies, with AKI occurring predominantly during the first days of critical illness [29‐31].

We observed a high incidence of AKI and higher attributable mortality compared to the overall critically ill patients. In patients with ARDS, AKI may result from a combination of mechanisms [32, 33] including systemic release of pro-inflammatory mediators and biotrauma [33], as well as endothelial injury and increased capillary permeability. Furthermore, hypoxemia may reduce renal blood flow and lead to altered renal function [34]. Elevation of central venous pressure under mechanical ventilation may translate into elevated renal venous pressure and reduced renal perfusion pressure [35, 36].

We estimated the conditional risk of AKI by adjusting for multiple baseline and time-dependent covariates associated with an increased risk of kidney injury. To account for differences between the studies in individual confounders, we used the Super Learner model to compute trial-specific AKI incidences, all marginalized over the full set of observed individual confounders, with different hypothetical trial assignments. We considered the chronological order of the trials to be a corse capture of the trend over time (Fig. 1). Our observation aligns with other large studies in high-resource countries showing a stable trend in the incidence of AKI in critically ill patients [37, 38]. While critical care processes and overall prognosis of patients admitted to intensive care units have improved over the last two decades [39], this does not appear to apply to the prevention of AKI. AKI incidence was found higher in the ROSE trial. The isolated higher risk of AKI in ROSE is likely due to the sicker population enrolled in the trial (ROSE included patients with a PaO₂/FiO₂ ratio ≤ 150 mmHg) with higher severity score. This is reflected by the higher mortality in the ROSE trial (42.6% 90-day mortality in ROSE, 27.3% in SAILS, for instance). Similar findings were observed in the ACURASYS trial [40] in which RRT was needed in 33% and 36% in the patients randomized in the neuromuscular agent and placebo groups, respectively.

We also observed no improvement in renal recovery (and a trend toward increased incidence of AKD, Fig. 3). This observation is alarming as non-recovery from AKI is associated with a higher risk of adverse outcomes such as death, cardiovascular diseases, or CKD [41, 42].

In this line, the lack of interventions to prevent or treat AKI among critically ill patients has been, and continues to be, a major concern. Recent efforts have highlighted the need for changes to improve the chances of success in trials to prevent and treat AKI in the critically ill [5].

A crosstalk between the lung and kidney has long been reported, with lung injury being a risk factor for AKI, and AKI being a trigger for lung injury [43]. AKI could therefore drive mortality through remote organ injury [41]. It is believed that the occurrence of AKI in patients with lung injury contributes to a vicious circle of damage compromising the chances of recovery and survival [32]. In critically ill patients, the excess in 90-day mortality attributable to AKI has been estimated to be 8.6% (95% CI 2.6–17.6) [44]. Another prospective study estimated the excess 30-day mortality linked to early AKI in general intensive care unit (ICU) patients to be 8.1% (95% CI 4.1–12.1%) [45].

We observed an excess in 90-day mortality attributable to AKI of 15.4%, which increased to 20.3% when considering severe AKI (Fig. 2). The excess in 90 days mortality appeared to decrease after the ALVEOLI trial (i.e. lower or higher PEEP levels) and remained stable since then. Nonetheless, the multivariable logistic regression model used for sensitivity analysis showed that ALTA, SAILS, and EDEN trials were associated with a significantly lower risk of mortality when compared to ARMA. The reduction of mortality attributable to AKI after the implementation of the first interventions introduced by the ARDS network might be due to the use of protective ventilation, mediated by a reduction in venous congestion or systemic inflammation [46] (Fig. 2). The differences in AKI incidence between the intervention and control groups in the FACTT trial could be related to chance or to the intervention itself. The FACTT trial investigated the impact of a restrictive versus liberal fluid strategy in patients with ARDS. This resulted in more negative fluid balance in the intervention group. The intervention group also showed a higher incidence of AKI. This could be explained by hypovolemia or hemoconcentration in the intervention group. After adjustment of creatinine for fluid balance, Liu et al. reported that the incidence of AKI was greater in those managed with the liberal fluid protocol (66 versus 58%, P = 0.007) [1]. Cumulative fluid balance at 72 h after enrollment was mostly similar between the intervention and control groups in other trials.

The overall stable attributable mortality highlights the needs for developing preventive and curative interventions for AKI in ARDS patients.

The results of our study have several strengths and implications. We used Super Learner for AKI incidence estimation, accounting for variations in AKI rates between trials, across treatment groups and individual characteristics, which minimized the contribution of coufounding factors.

Furthermore, we introduced factors previously linked to mortality in patients with AKI and adjusted for them in a time-dependent analysis to account for covariates trajectories effect on the development of AKI. Death and ICU discharge within the first 7 days were treated as competing risks to avoid immortal time bias.

Finally we integrated the Super Learner with the IPTW analysis to estimate the attributable mortality during ARDS management.

The estimated attributable mortality will serve to design future trials with mortality as the primary endpoint. The observed attributable mortality of AKI could guide calculating the appropriate sample size with the effect size in future trials. Unrealistic effect size estimations are one of the reasons for the multiple so-called “negative trials” in critically ill patients [6, 47].

Our study has several limitations. First, we included only patients enrolled in randomized trials performed in the United States which may limit the generalizability of our findings, as the accessible population may not be representative of the broader population of ARDS patients. Of note, the trials included in the study were not originally designed for the purpose of evaluating the incidence and attributable mortality of AKI in ARDS patients. The limited amount of data available influenced the development of the most effective model for testing our hypothesis. The definition of ARDS varied during the timeline in which the trials we included were performed, supplementary Table 1. Nonetheless, all of them used the American-European Consensus Conference on ARDS (1994) [48], except for SAILS, which included only patients having sepsis-related ARDS, and ROSE, which only included patients with a PaO₂/FiO₂ ratio ≤ 150 mmHg.

However, this cohort is likely to be very close to the population eligible for many future trials in ARDS, although the New Global Definition of ARDS recommends including patients who are being treated with high flow nasal oxygen or continuous positive airway pressure [21].

Second, some unmeasured confounders (e.g. chronic cardiovascular, respiratory, and metabolic conditions) persist in the estimation of the risk of AKI and the attributable mortality to AKI. Inflammatory, immunologic, or genetic factors, measures of venous congestion (e.g. central venous pressure), and other surrogate markers of renal function (e.g. cystatin C) were not included in the models and should be considered for future studies.

The study did not explore the mechanisms of AKI in ARDS patients. AKI in ARDS is multifactorial, including inflammation, hemodynamic factors, hypoxia, drug toxicity or strategies of mechanical ventilation and it is likely that some episodes of AKI were not directly caused by ARDS. The cause of death was not available for the observations included in our original dataset. A direct cause of death is most often difficult to identify in ICU patients as several contributing factors are at play (e.g. cardiovascular dysfunction, sepsis), and respiratory failure is rarely the sole or primary contributor [49, 50].

AKI was defined by an increase in serum creatinine from baseline, as all positive delta in serum creatinine reflects a change in GFR and meets the definition of AKI. Therefore, patients who had an elevation of serum creatinine prior to admission and a decline before randomization were not considered to have developed AKI during their ICU stay for ARDS. Unavailability of serum creatinine prior to admission may have misclassified patients with underlying CKD or patients who had AKI with peak serum creatinine before admission and did not recover. We consider this scenario unlikely for the majority of patients. Then, we estimated potential CKD upon baseline serum creatinine levels and excluded patients with chronic dialysis. Nonetheless, using the acute variation of serum creatinine from baseline would identify patients with AKI, regardless of their CKD status, including de novo and acute-on-chronic injury [51]. Furthermore, we provided results of a sensitivity analysis on Severe AKI, to reduce the risk of misclassification.

Finally, urine output was unavailable in most trials. The specificity of urine output as a sole biomarker of AKI (i.e. without elevation of serum creatinine) has however been challenged given the multiple factors affecting urine output in mechanically ventilated patients.

In conclusion, the incidence of AKI appears to be stable over time in the population of patients with ARDS enrolled in randomized trials in the United States, and the development of AKI is a significant contributing factor to mortality. These findings can be used to inform the design of future clinical trials of AKI prevention or treatment in this high-risk subpopulation.