Effect of balanced crystalloids versus saline on urinary biomarkers of acute kidney injury in critically ill adults

Blake E Funke, Karen E Jackson, Wesley H Self, Sean P Collins, Christina T Saunders, Li Wang, Jeffrey D Blume, Nancy Wickersham, Ryan M Brown, Jonathan D Casey, Gordon R Bernard, Todd W Rice, Edward D Siew, Matthew W Semler, SMART Investigators, Pragmatic Critical Care Research Group, Gordon R Bernard, Ryan M Brown, Jonathan D Casey, Todd W Rice, Matthew W Semler, Christopher J Lindsell, Li Wang, Jonathan P Wanderer, Wesley H Self, Edward D Siew, Joanna L Stollings, Blake E Funke, Karen E Jackson, Wesley H Self, Sean P Collins, Christina T Saunders, Li Wang, Jeffrey D Blume, Nancy Wickersham, Ryan M Brown, Jonathan D Casey, Gordon R Bernard, Todd W Rice, Edward D Siew, Matthew W Semler, SMART Investigators, Pragmatic Critical Care Research Group, Gordon R Bernard, Ryan M Brown, Jonathan D Casey, Todd W Rice, Matthew W Semler, Christopher J Lindsell, Li Wang, Jonathan P Wanderer, Wesley H Self, Edward D Siew, Joanna L Stollings

Abstract

Background: Recent trials have suggested use of balanced crystalloids may decrease the incidence of major adverse kidney events compared to saline in critically ill adults. The effect of crystalloid composition on biomarkers of early acute kidney injury remains unknown.

Methods: From February 15 to July 15, 2016, we conducted an ancillary study to the Isotonic Solutions and Major Adverse Renal Events Trial (SMART) comparing the effect of balanced crystalloids versus saline on urinary levels of neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) among 261 consecutively-enrolled critically ill adults admitted from the emergency department to the medical ICU. After informed consent, we collected urine 36 ± 12 h after hospital admission and measured NGAL and KIM-1 levels using commercially available ELISAs. Levels of NGAL and KIM-1 at 36 ± 12 h were compared between patients assigned to balanced crystalloids versus saline using a Mann-Whitney U test.

Results: The 131 patients (50.2%) assigned to the balanced crystalloid group and the 130 patients (49.8%) assigned to the saline group were similar at baseline. Urinary NGAL levels were significantly lower in the balanced crystalloid group (median, 39.4 ng/mg [IQR 9.9 to 133.2]) compared with the saline group (median, 64.4 ng/mg [IQR 27.6 to 339.9]) (P < 0.001). Urinary KIM-1 levels did not significantly differ between the balanced crystalloid group (median, 2.7 ng/mg [IQR 1.5 to 4.9]) and the saline group (median, 2.4 ng/mg [IQR 1.3 to 5.0]) (P = 0.36).

Conclusions: In this ancillary analysis of a clinical trial comparing balanced crystalloids to saline among critically ill adults, balanced crystalloids were associated with lower urinary concentrations of NGAL and similar urinary concentrations of KIM-1, compared with saline. These results suggest only a modest reduction in early biomarkers of acute kidney injury with use of balanced crystalloids compared with saline.

Trial registration: ClinicalTrials.gov number: NCT02444988 . Date registered: May 15, 2015.

Keywords: Critical care; Dialysis; Renal insufficiency; Resuscitation; Sepsis; Sodium chloride.

Conflict of interest statement

W.H.S. reported personal fees from Baxter during the conduct of this study. T.W.R. reported personal fees from Cumberland Pharmaceuticals, Inc. and Avisa Pharma, LLC outside the submitted work. The remaining authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Urinary biomarker levels on day 2 by study group. Urinary NGAL and KIM-1 concentration levels scaled to urinary creatinine concentration are displayed for patients in the balanced crystalloid group (green) and saline group (yellow). From top to bottom, the three horizontal lines on each colored box show the upper quartile, median, and lower quartile, and the vertical dashed lines extend to 1.5 times the interquartile range. Each boxplot is overlaid with on dot for each patient’s observed biomarker values
Fig. 2
Fig. 2
Subgroup analyses. The effects of balanced crystalloids versus saline on day 2 urinary NGAL and KIM-1 concentrations are displayed for patients in each pre-specified subgroup. Scores on the Acute Physiology and Chronic Health Evaluation (APACHE) II range from 0 to 71, with higher scores indicating a greater severity of illness [23]. Acute kidney injury (AKI) of stage 2 or higher is defined according to the Kidney Disease: Improving Global Outcomes creatinine criteria [19]
Fig. 3
Fig. 3
Change in urinary biomarker levels from day 0 to day 2 by study group. The change in urinary NGAL and KIM-1 concentration from emergency department presentation to day 2 of hospital admission scaled to urinary creatinine concentration is displayed for patients in the balanced crystalloid group (green) and saline group (yellow), among the 111 patients with urine available at both time points. From top to bottom, the three horizontal lines on each colored box show the upper quartile, median, and lower quartile, and the vertical dashed lines extend to 1.5 times the interquartile range

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