Abstract
Sepsis-induced acute kidney injury (AKI) is a frequent complication of critically ill patients and leads to high mortality rates. The specificity of currently available urinary biomarkers for AKI in the context of sepsis is questioned. This study aimed to discover urinary biomarkers for septic AKI by contemporary shotgun proteomics in a mouse model for sepsis and to validate these in individual urine samples of mice and human septic patients with and without AKI. At 48 h after uterine ligation and inoculation of Escherichia coli, aged mice (48 weeks) became septic. A subgroup developed AKI, defined by serum creatinine, blood urea nitrogen, and renal histology. Separate pools of urine from septic mice with and without AKI mice were collected during 12 h before and between 36-48 h after infection, and their proteome compositions were quantitatively compared. Candidate biomarkers were validated by Western blot analysis of urine, plasma, and renal tissue homogenates from individual mice, and a limited number of urine samples from human septic patients with and without AKI. Urinary neutrophil gelatinase-associated lipocalin, thioredoxin, gelsolin, chitinase 3-like protein 1 and -3 (CHI3L3) and acidic mammalian chitinase were the most distinctive candidate biomarkers selected for septic AKI. Both neutrophil gelatinase-associated lipocalin and thioredoxin were detected in urine of septic mice and increased with severity of AKI. Acidic mammalian chitinase was only present in urine of septic mice with AKI. Both urinary chitinase 3-like protein 1 and -3 were only detected in septic mice with severe AKI. The human homologue chitinase 3-like protein 1 was found to be more excreted in urine from septic patients with AKI than without. In summary, urinary chitinase 3-like protein 1 and -3 and acidic mammalian chitinase discriminated sepsis from sepsis-induced AKI in mice. Further studies of human chitinase proteins are likely to lead to additional insights in septic AKI.
Highlights
From the ‡Department of Pharmacology, Toxicology and Biochemistry, Ghent University, Belgium; §Department of Medical Protein Research, VIB, Ghent, Belgium; ¶Department of Biochemistry, Ghent University, Belgium; ʈDepartment of Internal Medicine, Renal Division, Ghent University Hospital, Belgium
Our results indicate that chitinase-3 like proteins 1 and 3 (CHI3L1, -3) and acidic mammalian chitinase (CHIA) are candidate biomarkers for sepsis-induced Acute kidney injury (AKI) in mice and that CHI3L1 and CHIA hold promise as biomarkers or key proteins involved in human septic AKI
Approach 1, which consists of three filter components, filter 1 only considered proteins with a ratio Ͼ 9.3 in the SϩAKI T1/T0 differential analysis (n ϭ 79/133)
Summary
From the ‡Department of Pharmacology, Toxicology and Biochemistry, Ghent University, Belgium; §Department of Medical Protein Research, VIB, Ghent, Belgium; ¶Department of Biochemistry, Ghent University, Belgium; ʈDepartment of Internal Medicine, Renal Division, Ghent University Hospital, Belgium. Several biomarkers for AKI have been detected in urine such as neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), IL-18, sodium/hydrogen exchanger 3, and cystatin C. These have been associated with earlier diagnostic potential than serum creatinine (sCr), the standard surrogate marker for kidney function [9, 10]. With regards to the proteome analysis of sepsis-induced AKI, to the best of our knowledge, only one study has been reported on the discovery of urinary biomarkers [23]. A two-dimensional DIGE of urine was used in a rat sepsis model, but again only detected a small number of differentially expressed proteins
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