Dataset Information

Analysis of Spatiotemporal Urine Protein Dynamics to Identify New Biomarkers for Sepsis-Induced Acute Kidney Injury.

ABSTRACT: Acute kidney injury (AKI) is a frequent complication of sepsis and contributes to increased mortality. Discovery of reliable biomarkers could enable identification of individuals with high AKI risk as well as early AKI detection and AKI progression monitoring. However, the current methods are insensitive and non-specific. This study aimed to identify new biomarkers through label-free mass spectrometry (MS) analysis of a sepsis model induced by cecal ligation and puncture (CLP). Urine samples were collected from septic rats at 0, 3, 6, 12, 24, and 48 h. Protein isolated from urine was subjected to MS. Immunoregulatory biological processes, including immunoglobin production and wounding and defense responses, were upregulated at early time points. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses identified 77 significantly changed pathways. We further examined the consistently differentially expressed proteins to seek biomarkers that can be used for early diagnosis. Notably, the expression of PARK7 and CDH16 were changed in a continuous manner and related to the level of Scr in urine from patients. Therefore, PARK7 and CDH16 were confirmed to be novel biomarkers after validation in sepsis human patients. In summary, our study analyzed the proteomics of AKI at multiple time points, elucidated the related biological processes, and identified novel biomarkers for early diagnosis of sepsis-induced AKI, and our findings provide a theoretical basis for further research on the molecular mechanisms.

SUBMITTER: Li Y

PROVIDER: S-EPMC7063463 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Analysis of Spatiotemporal Urine Protein Dynamics to Identify New Biomarkers for Sepsis-Induced Acute Kidney Injury.

Li Yiming Y Long Junke J Chen Jiaquan J Zhang Jing J Qin Yi Y Zhong Yanjun Y Liu Fen F Peng Zhiyong Z

Frontiers in physiology 20200303

Acute kidney injury (AKI) is a frequent complication of sepsis and contributes to increased mortality. Discovery of reliable biomarkers could enable identification of individuals with high AKI risk as well as early AKI detection and AKI progression monitoring. However, the current methods are insensitive and non-specific. This study aimed to identify new biomarkers through label-free mass spectrometry (MS) analysis of a sepsis model induced by cecal ligation and puncture (CLP). Urine samples wer ...[more]

PMID: 32194432

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Project description:BackgroundThe study of novel urinary biomarkers of acute kidney injury has expanded exponentially. Effective interpretation of data and meaningful comparisons between studies require awareness of factors that can adversely affect measurement. We examined how variations in short-term storage and processing might affect the measurement of urine biomarkers.Study designCross-sectional prospective.Setting & participantsHospitalized patients from 2 sites: Yale New Haven Hospital (n=50) and University of California, San Francisco Medical Center (n=36).PredictorsWe tested the impact of 3 urine processing conditions on these biomarkers: (1) centrifugation and storage at 4°C for 48 hours before freezing at -80°C, (2) centrifugation and storage at 25°C for 48 hours before freezing at -80°C, and (3) uncentrifuged samples immediately frozen at -80°C.OutcomesUrine concentrations of 5 biomarkers: neutrophil gelatinase-associated lipocalin (NGAL), interleukin 18 (IL-18), kidney injury molecule 1 (KIM-1), liver-type fatty acid-binding protein (L-FABP), and cystatin C.MeasurementsWe measured urine biomarkers by established enzyme-linked immunosorbent assay methods. Biomarker values were log-transformed, and agreement with a reference standard of immediate centrifugation and storage at -80°C was compared using concordance correlation coefficients (CCCs).ResultsNeither storing samples at 4°C for 48 hours nor centrifugation had a significant effect on measured levels, with CCCs higher than 0.9 for all biomarkers tested. For samples stored at 25°C for 48 hours, excellent CCC values (>0.9) also were noted between the test sample and the reference standard for NGAL, cystatin C, L-FABP and KIM-1. However, the CCC for IL-18 between samples stored at 25°C for 48 hours and the reference standard was 0.81 (95% CI, 0.66-0.96).LimitationsNo comparisons to fresh, unfrozen samples; no evaluation of the effect of protease inhibitors.ConclusionsAll candidate markers tested using the specified assays showed high stability with both short-term storage at 4°C and without centrifugation prior to freezing. For optimal fidelity, urine for IL-18 measurement should not be stored at 25°C before long-term storage or analysis.

Project description: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.

Project description:The interaction between baseline kidney function and the performance of biomarkers of acute kidney injury (AKI) on the development of AKI is unclear.Post hoc analysis of prospective cohort study.The 1,219 TRIBE-AKI Consortium adult cardiac surgery cohort participants.Unadjusted postoperative urinary biomarkers of AKI measured within 6 hours of surgery.AKI was defined as AKI Network stage 1 (any AKI) or higher, as well as a doubling of serum creatinine level from the preoperative value or the need for post-operative dialysis (severe AKI).Stratified analyses by preoperative estimated glomerular filtration rate (eGFR) ? 60 versus > 60mL/min/1.73m(2).180 (42%) patients with preoperative eGFRs?60mL/min/1.73m(2) developed clinical AKI compared with 246 (31%) of those with eGFRs>60mL/min/1.73m(2) (P<0.001). For log2-transformed biomarker concentrations, there was a significant interaction between any AKI and baseline eGFR for interleukin 18 (P=0.007) and borderline significance for liver-type fatty acid binding protein (P=0.06). For all biomarkers, the adjusted relative risk (RR) point estimates for the risk for any AKI were higher in those with elevated baseline eGFRs compared with those with eGFRs?60mL/min/1.73m(2). However, the difference in magnitude of these risks was low (adjusted RRs were 1.04 [95% CI, 0.99-1.09] and 1.11 [95% CI, 1.07-1.15] for those with preoperative eGFRs?60mL/min/1.73m(2) and those with higher eGFRs, respectively). Although no biomarker displayed an interaction for baseline eGFR and severe AKI, log2-transformed interleukin 18 and kidney injury molecule 1 had significant adjusted RRs for severe AKI in those with and without baseline eGFRs?60mL/min/1.73m(2).Limited numbers of patients with severe AKI and post-operative dialysis.The association between early postoperative AKI urinary biomarkers and AKI is modified by preoperative eGFR. The degree of this modification and its impact on the biomarker-AKI association is small across biomarkers. Our findings suggest that distinct biomarker cutoffs for those with and without a preoperative eGFR?60mL/min/1.73m(2) is not necessary.

Dataset Information

Analysis of Spatiotemporal Urine Protein Dynamics to Identify New Biomarkers for Sepsis-Induced Acute Kidney Injury.

Publications

Analysis of Spatiotemporal Urine Protein Dynamics to Identify New Biomarkers for Sepsis-Induced Acute Kidney Injury.

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