Galectin-3 in septic acute kidney injury: a translational study

Abstract

Background: Galectin-3 (Gal-3) is a pleiotropic glycan-binding protein shown to be involved in sepsis and acute kidney injury (AKI). However, its role has never been elucidated in sepsis-associated AKI (S-AKI). We aimed to explore Gal-3's role and its potential utility as a therapeutic target in S-AKI.

Methods: In 57 patients admitted to the intensive care unit (ICU) with sepsis, serum Gal-3 was examined as a predictor of ICU mortality and development of AKI. In a rat model of S-AKI induced by cecal ligation and puncture (CLP), 7-day mortality and serum Gal-3, Interleukin-6 (IL-6), and creatinine were examined at 2, 8, and 24 hours (h) post-CLP. Two experimental groups received the Gal-3 inhibitor modified citrus pectin (P-MCP) at 400 mg/kg/day and 1200 mg/kg/day, while the control group received water only (n = 18 in each group).

Results: Among 57 patients, 27 developed AKI and 8 died in the ICU. Serum Gal-3 was an independent predictor of AKI (OR = 1.2 [95% CI 1.1-1.4], p = 0.01) and ICU mortality (OR = 1.4 [95% CI 1.1-2.2], p = 0.04) before and after controlling for age, AKI, and acute physiology and chronic health evaluation (APACHE II) score. In the CLP rat experiment, serum Gal-3 peaked earlier than IL-6. Serum Gal-3 was significantly lower in both P-MCP groups compared to control at 2 h post-CLP (400 mg: p = 0.003; 1200 mg: p = 0.002), and IL-6 was significantly lower in both P-MCP groups at all time points with a maximum difference at 24 h post-CLP (400 mg: p = 0.015; 1200 mg: p = 0.02). In the Gal-3 inhibitor groups, 7-day mortality was significantly reduced from 61% in the control group to 28% (400 mg P-MCP: p = 0.03) and 22% (1200 mg P-MCP: p = 0.001). Rates of AKI per RIFLE criteria were significantly reduced from 89% in the control group to 44% in both P-MCP groups (400 mg: p = 0.007; 1200 mg: p = 0.007).

Conclusions: This translational study demonstrates the importance of Gal-3 in the pathogenesis of S-AKI, and its potential utility as a therapeutic target.

Keywords: Acute kidney injury; Galectin-3; Sepsis.

Fig. 1

CLP experimental strategy. All rats underwent CLP. Control group (n = 18) received normal drinking water, while two intervention groups received a Gal-3 inhibitor, PMCP, at 400 mg/kg/d and 1200 mg/kg/d 7 d prior to CLP. Following CLP, blood was drawn at baseline, 2, 8, and 24 h post-CLP for serum biochemical measurements

Fig. 2

Serum galectin-3 levels at ICU admission predict subsequent acute kidney injury and ICU mortality among patients. Means are shown by the gray horizontal bars and displayed numerically above the corresponding columns. a Serum galectin-3 levels in AKI vs non-AKI groups following ICU admission (11.2 ± 1.6 ng/ml vs. 5.3 ± 0.5 ng/ml, p = 0.002). Red dots represent data from non-survivors, while black dots represent data from survivors. b Serum galectin-3 levels in survivor vs non-survivor groups following ICU admission (18.7 ± 3.6 ng/ml vs. 6.4 ± 0.6 ng/ml, p = 0.0002). c Area under the receiver operating characteristic curves for serum galectin-3 in survival (green curve) and galectin-3 in AKI (blue curve)

Fig. 3

Serum galectin-3 levels with and without P-MCP pretreatment at baseline, 2 h, 8 h, and 24 h post-CLP in a rat CLP model. * indicates p < 0.05 for comparison between control group and P-MCP-treatment group. # indicates p < 0.05 for within group comparison to baseline value

Fig. 4

Serum galectin-3 and IL-6 predict AKI and death in a rat CLP model. a Area under the receiver operating characteristic curve for serum galectin-3 in AKI (yellow curve) and mortality (blue curve). b Area under the receiver operating characteristic curve for IL-6 in AKI (yellow curve) and mortality (blue curve)

Fig. 5

Serum IL-6 levels with and without P-MCP pretreatment in a rat CLP model. IL-6 concentrations were significantly lower in the P-MCP 400 mg and P-MCP 1200 mg group vs. the control group. * indicates p < 0.05 for comparison between control group and P-MCP-treatment group. # indicates p < 0.05 for within group comparison to baseline value

Fig. 6

Serum creatinine levels with and without P-MCP pretreatment in a rat CLP model. * indicates p < 0.05 for comparison between control group and P-MCP-treatment group. # indicates p < 0.05 for within group comparison to baseline value

Fig. 7

Acute kidney injury occurrence with and without P-MCP pretreatment in a rat CLP model. Percent AKI with or without P-MCP pretreatment per RIFLE criteria. Within the control group, 16 (89%) rats developed AKI. In each P-MCP group (400 mg and 1200 mg), 8 (44%) rats developed AKI

Fig. 8

Survival curves with and without P-MCP pretreatment in a rat CLP model. Each group started with 18 rats prior to CLP procedure. By day 7, 11 (61%) rats had died in the control group, compared to only 5 (28%) rats in the 400 mg P-MCP group (p = 0.03) and 4 (22%) rats in the 1200 mg P-MCP group (p = 0.001)