Mortality and host response aberrations associated with transient and persistent acute kidney injury in critically ill patients with sepsis: a prospective cohort study

Abstract

Purpose: Sepsis is the most frequent cause of acute kidney injury (AKI). The "Acute Disease Quality Initiative Workgroup" recently proposed new definitions for AKI, classifying it as transient or persistent. We investigated the incidence, mortality, and host response aberrations associated with transient and persistent AKI in sepsis patients.

Methods: A total of 1545 patients admitted with sepsis to 2 intensive care units in the Netherlands were stratified according to the presence (defined by any urine or creatinine RIFLE criterion within the first 48 h) and evolution of AKI (with persistent defined as remaining > 48 h). We determined 30-day mortality by logistic regression adjusting for confounding variables and analyzed 16 plasma biomarkers reflecting pathways involved in sepsis pathogenesis (n = 866) and blood leukocyte transcriptomes (n = 392).

Results: AKI occurred in 37.7% of patients, of which 18.4% was transient and 81.6% persistent. On admission, patients with persistent AKI had higher disease severity scores and more frequently had severe (injury or failure) RIFLE AKI stages than transient AKI patients. Persistent AKI, but not transient AKI, was associated with increased mortality by day 30 and up to 1 year. Persistent AKI was associated with enhanced and sustained inflammatory and procoagulant responses during the first 4 days, and a more severe loss of vascular integrity compared with transient AKI. Baseline blood gene expression showed minimal differences with respect to the presence or evolution of AKI.

Conclusion: Persistent AKI is independently associated with sepsis mortality, as well as with sustained inflammatory and procoagulant responses, and loss of vascular integrity as compared with transient AKI.

Trial registration: ClinicalTrials.gov NCT01905033.

Keywords: Acute kidney injury; Host response; Intensive care unit; Mortality; Sepsis.

Conflict of interest statement

The authors disclose that they do not have any potential conflicts of interest.

Figures

Fig. 1

Evolution of acute kidney injury in patients with sepsis. a Chord diagrams depicting the relationship between the severity of AKI upon ICU-admission and the subsequent presence and evolution of AKI over the first 48 hours. The bottom part of the diagram represents patients ranked by initial RIFLE score calculated upon ICU admission, and the top part represents the same patients ranked according to the presence and evolution of AKI over the first 48 h (no AKI, transient or persistent AKI). Ribbons show for every patient the connection between the initial RIFLE score and the subsequent evolution of AKI. The first diagram (a) represents all patients combined. The diagrams below (b–e), highlight each individual RIFLE severity score separately. Admission RIFLE score was “none” for all (n = 968) patients without AKI. Of patients with transient AKI, 13 (12.3%), 60 (56.6), 24 (22.6), and 9 (8.5%) had an admission RIFLE score of “none,” “at risk,” “injury,” or “failure,” respectively. Of patients who developed persistent AKI, 39 (8.3%), 110 (23.4%), 147 (31.2%), and 175 (37.2%) had an admission RIFLE score of “none”, “at risk”, “injury”, or “failure”, respectively. f Plasma creatinine over time stratified according to the evolution of AKI after admission to the intensive care unit (ICU). Data are presented as mean and standard error of the mean. Numbers below axes indicate the number of patients still present in the ICU for each group. Note: mean creatinine levels showed small increases at day 8 and day 20 in the transient AKI group due to the occurrence of ICU-acquired AKI in 4 patients in whom renal function initially recovered after the initial episode of AKI

Fig. 2

Host response biomarkers in patients with sepsis during the first 4 days of ICU stay stratified according to the evolution of acute kidney injury after admission. Biological parameters are classified as a inflammatory responses, b endothelial cell activation, and c coagulation activation biomarkers. Data are presented as box and whiskers, as specified by Tukey. Dotted lines represent median values obtained in 27 healthy age-matched healthy subjects. Overall P values were derived from the linear mixed model in which the group, or the interaction of time x group (i.e. the trajectory) were defined as fixed effects, and patient-specific intercept and slopes were defined as random effects. Comparisons between groups at specific days were performed using the Kruskal–Wallis test followed by Dunn's post hoc tests of multiple comparisons using rank sums. *P < .05, **P < .01, ***P < .001, ****P < .0001. AKI, acute kidney injury; ANG, angiopoietin; aPTT, activated partial thromboplastin time; IL, interleukin; MMP, matrix metalloproteinase; PT, prothrombin time; sE-Selectin, soluble E-selectin; sICAM, soluble intercellular adhesion molecule

Fig. 3

Leukocyte genomic responses upon admission in sepsis patients without, transient, or persistent acute kidney injury. a Volcano plots illustrating the differences in leukocyte genomic responses (integrating log2 fold changes and multiple-test adjusted probabilities) between sepsis patients without acute kidney injury (AKI) on admission and healthy subjects (left), between patients with transient AKI and healthy subjects (center), and between patients with persistent AKI and healthy subjects (right). Considering adjusted P < .05, 9037, 8303 and 9467 genes were identified as differentially expressed in patients without AKI, patients with transient AKI and patients with persistent AKI on admission vs healthy subjects, respectively. Blue dots represent significantly underexpressed genes (adjusted P < .05, fold expression < −1.5), whereas red dots represent significantly overexpressed genes (adjusted P < .05, fold expression > 1.5) in patients relative to healthy controls. Horizontal dotted line indicates multiple-test adjusted Benjamini–Hochberg (BH) P < .05 threshold. Within plots, pie charts show the extent of gene expression changes: Blue slices show significantly underexpressed genes (adjusted P < .05 and expression more than 1.5-times decreased compared with healthy controls), red slices show significantly overexpressed genes (adjusted P < .05 and expression more than 1.5-time increased compared with healthy controls), and grey slices show significantly different gene expression (adjusted P < .05 and expression less than 1.5-time increased or decreased compared with healthy controls). b Venn–Euler representation of differentially expressed genes on admission in sepsis patients without, transient or persistent AKI vs healthy subjects (adjusted P < .05). Red arrows denote overexpressed genes; blue arrows denote underexpressed genes. c Dot plot depicting the common response (log2 fold changes) of patients without, transient, or persistent AKI as compared with healthy subjects. Rho, Spearman’s correlation coefficient. d Volcano plot illustrating the differences in leukocyte genomic responses on admission between patients with transient AKI relative to patients without AKI (left), between patients with persistent AKI relative to patients without AKI (center), and between patients with persistent AKI relative to patients with transient AKI (right). Considering adjusted P < .05, no gene was differentially expressed in patients with transient AKI versus no AKI and in patients with persistent AKI vs transient AKI, and 2466 genes were differentially expressed between patients with persistent AKI vs patients without AKI. Within plots, pie charts show the extent of gene expression changes compared to the control group