Urine cell cycle arrest biomarkers distinguish poorly between transient and persistent AKI in early septic shock: a prospective, multicenter study

Dimitri Titeca-Beauport, Delphine Daubin, Ly Van Vong, Guillaume Belliard, Cédric Bruel, Sami Alaya, Karim Chaoui, Maud Andrieu, Isabelle Rouquette-Vincenti, Frederic Godde, Michel Pascal, Momar Diouf, Christophe Vinsonneau, Kada Klouche, Julien Maizel, Dimitri Titeca-Beauport, Delphine Daubin, Ly Van Vong, Guillaume Belliard, Cédric Bruel, Sami Alaya, Karim Chaoui, Maud Andrieu, Isabelle Rouquette-Vincenti, Frederic Godde, Michel Pascal, Momar Diouf, Christophe Vinsonneau, Kada Klouche, Julien Maizel

Abstract

Background: The urine biomarkers tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) have been validated for predicting and stratifying AKI. In this study, we analyzed the utility of these biomarkers for distinguishing between transient and persistent AKI in the early phase of septic shock.

Methods: We performed a prospective, multicenter study in 11 French ICUs. Patients presenting septic shock, with the development of AKI within the first 6 h, were included. Urine [TIMP-2]*[IGFBP7] was determined at inclusion (0 h), 6 h, 12 h, and 24 h. AKI was considered transient if it resolved within 3 days. Discriminative power was evaluated by receiver operating characteristic (ROC) curve analysis.

Results: We included 184 patients, within a median [IQR] time of 1.0 [0.0-3.0] h after norepinephrine (NE) initiation; 100 (54%) patients presented transient and 84 (46%) presented persistent AKI. Median [IQR] baseline urine [TIMP-2]*[IGFBP7] was higher in the persistent AKI group (2.21 [0.81-4.90] (ng/ml)2/1000) than in the transient AKI group (0.75 [0.20-2.12] (ng/ml)2/1000; p < 0.001). Baseline urine [TIMP-2]*[IGFBP7] was poorly discriminant, with an AUROC [95% CI] of 0.67 [0.59-0.73]. The clinical prediction model combining baseline serum creatinine concentration, baseline urine output, baseline NE dose, and baseline extrarenal SOFA performed well for the prediction of persistent AKI, with an AUROC [95% CI] of 0.81 [0.74-0.86]. The addition of urine [TIMP-2]*[IGFBP7] to this model did not improve the predictive performance.

Conclusions: Urine [TIMP-2]*[IGFBP7] measurements in the early phase of septic shock discriminate poorly between transient and persistent AKI and do not improve clinical prediction over that achieved with the usual variables.

Trial registration: NCT02812784.

Keywords: Acute kidney injury; Biomarkers; Recovery; Septic shock.

Conflict of interest statement

The authors have no competing interest to declare.

Figures

Fig. 1
Fig. 1
Study flow chart. RRT, renal replacement therapy; AKI, acute kidney injury
Fig. 2
Fig. 2
a Change in AKI severity over the first 72 h. The vertical bar indicates the AKI stage at inclusion according to the KDIGO classification. Horizontal bars indicate changes in the AKI stage over 72 h according to the AKI stage at inclusion. b Change in AKI severity and mortality in the transient and persistent AKI groups, over the first 72 h. The bars indicate the AKI stage and the proportion of patients dead at inclusion, 24 h, 48 h, and 72 h of follow-up
Fig. 3
Fig. 3
Box plots of the baseline, 6 h, 12 h, and 24 h urine [TIMP-2]*[IGFBP7] values. Log-transformed data area shown. The boxes and whiskers correspond to interquartile ranges and total ranges, respectively. Each dot represents an individual value. Urine [TIMP-2]*[IGFBP7] was significantly higher in patients with persistent AKI than in those with transient AKI. At baseline (n = 184), median [IQR] value of 2.21 [0.81–4.90] vs. 0.75 [0.20–2.12] (ng/ml)2/1000 (p < 0.001); at 6 h (n = 172), median [IQR] value of 2.02 [0.54–5.43] vs. 0.37 [0.13–1.38] (ng/ml)2/1000 (p < 0.001); at 12 h (n = 165), median [IQR] value of 1.19 [0.30–3.8] vs. 0.33 [0.13–0.78] (ng/ml)2/1000 (p < 0.001); and at 24 h (n = 156), median [IQR] value of 0.69 [0.26–2.36] vs. 0.32 [0.12–0.86] (ng/ml)2/1000 (< 0.001). TIMP-2, tissue inhibitor of metalloproteinases-2; IGFBP-7, insulin-like growth factor-binding protein 7; AKI, acute kidney injury; IQR, interquartile range

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