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Identification of candidate serum biomarkers for severe septic shock-associated kidney injury via microarray.

ABSTRACT: Septic-shock-associated acute kidney injury (SSAKI) carries high morbidity in the pediatric population. Effective treatment strategies are lacking, in part due to poor detection and prediction. There is a need to identify novel candidate biomarkers of SSAKI. The objective of our study was to determine whether microarray data from children with septic shock could be used to derive a panel of candidate biomarkers for predicting SSAKI.A retrospective cohort study compared microarray data representing the first 24 hours of admission for 179 children with septic shock with those of 53 age-matched normal controls. SSAKI was defined as a >200% increase of baseline serum creatinine, persistent to 7 days after admission.Patients with SSAKI (n = 31) and patients without SSAKI (n = 148) were clinically similar, but SSAKI carried a higher mortality (45% vs. 10%). Twenty-one unique gene probes were upregulated in SSAKI patients versus patients without SSAKI. Using leave-one-out cross-validation and class prediction modeling, these probes predicted SSAKI with a sensitivity of 98% (95% confidence interval (CI) = 81 to 100) and a specificity of 80% (95% CI = 72 to 86). Serum protein levels of two specific genes showed high sensitivity for predicting SSAKI: matrix metalloproteinase-8 (89%, 95% CI = 64 to 98) and elastase-2 (83%, 95% CI = 58 to 96). Both biomarkers carried a negative predictive value of 95%. When applied to a validation cohort, although both biomarkers carried low specificity (matrix metalloproteinase-8: 41%, 95% CI = 28 to 50; and elastase-2: 49%, 95% CI = 36 to 62), they carried high sensitivity (100%, 95% CI = 68 to 100 for both).Gene probes upregulated in critically ill pediatric patients with septic shock may allow for the identification of novel candidate serum biomarkers for SSAKI prediction.

SUBMITTER: Basu RK

PROVIDER: S-EPMC3388679 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Identification of candidate serum biomarkers for severe septic shock-associated kidney injury via microarray.

Basu Rajit K RK Standage Stephen W SW Cvijanovich Natalie Z NZ Allen Geoffrey L GL Thomas Neal J NJ Freishtat Robert J RJ Anas Nick N Meyer Keith K Checchia Paul A PA Lin Richard R Shanley Thomas P TP Bigham Michael T MT Wheeler Derek S DS Devarajan Prasad P Goldstein Stuart L SL Wong Hector R HR

Critical care (London, England) 20111118 6

<h4>Introduction</h4>Septic-shock-associated acute kidney injury (SSAKI) carries high morbidity in the pediatric population. Effective treatment strategies are lacking, in part due to poor detection and prediction. There is a need to identify novel candidate biomarkers of SSAKI. The objective of our study was to determine whether microarray data from children with septic shock could be used to derive a panel of candidate biomarkers for predicting SSAKI.<h4>Methods</h4>A retrospective cohort stud ...[more]

PMID: 22098946

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Project description:Adults hospitalized with sepsis/septic shock commonly develop acute kidney injury (AKI) which imposes a significant burden on the healthcare system. The administration of early human albumin in this patient population may yield more efficient healthcare resource utilization.ObjectivesTo examine the association between early use of albumin and time to discharge in adults who develop severe AKI while hospitalized with sepsis/septic shock.DesignRetrospective cohort study using de-identified electronic health records from a national database (Cerner Health Facts; Cerner Corp., Kansas City, MO).Setting and participantsPatients (n = 2,829) hospitalized between January 2013 and April 2018 with a diagnosis of sepsis/septic shock (identified using International Classification of Diseases, 9th Revision and 10th Revision codes) who developed severe AKI (stage 3 according to Kidney Disease Improving Global Outcomes criteria) during hospitalization (n = 2,845 unique encounters).Main outcomes and measuresPatients were grouped according to timing of albumin exposure: within less than or equal to 24 hours of admission ("early albumin") or unexposed/exposed late ("nonearly albumin"). A cause-specific hazard model, censoring for death/discharge to hospice, was used to examine the association between "early albumin" and the rate of hospital discharge with clinical stability.ResultsAlbumin was administered early in 8.6% of cases. Cases with early albumin administration had a median time to discharge of 13.2 days compared with 17.0 in the nonearly group (Log-rank p < 0.0001). An adjusted analysis showed that the rate of hospital discharge with clinical stability increased by 83% in the early albumin group compared with the nonearly group (hazard ratio, 1.832; 95% CI, 1.564-2.146; p < 0.001 nonearly group.Conclusions and relevanceThe use of albumin within 24 hours of hospital admission was associated with a shorter time to discharge and a higher rate of discharge with clinical stability, suggesting an improvement in healthcare resource utilization among patients with sepsis/septic shock who developed stage 3 AKI during hospitalization.

Project description:BackgroundSepsis and septic shock are life-threatening diseases with high mortality rate in intensive care unit (ICU). Acute kidney injury (AKI) is a common complication of sepsis, and its occurrence is a poor prognostic sign to septic patients. We analyzed co-differentially expressed genes (co-DEGs) to explore relationships between septic shock and AKI and reveal potential biomarkers and therapeutic targets of septic-shock-associated AKI (SSAKI).MethodsTwo gene expression datasets (GSE30718 and GSE57065) were downloaded from the Gene Expression Omnibus (GEO). The GSE57065 dataset included 28 septic shock patients and 25 healthy volunteers and blood samples were collected within 0.5, 24 and 48 h after shock. Specimens of GSE30718 were collected from 26 patients with AKI and 11 control patents. AKI-DEGs and septic-shock-DEGs were identified using the two datasets. Subsequently, Gene Ontology (GO) functional analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and protein-protein interaction (PPI) network analysis were performed to elucidate molecular mechanisms of DEGs. We also evaluated co-DEGs and corresponding predicted miRNAs involved in septic shock and AKI.ResultsWe identified 62 DEGs in AKI specimens and 888, 870, and 717 DEGs in septic shock blood samples within 0.5, 24 and 48 h, respectively. The hub genes of EGF and OLFM4 may be involved in AKI and QPCT, CKAP4, PRKCQ, PLAC8, PRC1, BCL9L, ATP11B, KLHL2, LDLRAP1, NDUFAF1, IFIT2, CSF1R, HGF, NRN1, GZMB, and STAT4 may be associated with septic shock. Besides, co-DEGs of VMP1, SLPI, PTX3, TIMP1, OLFM4, LCN2, and S100A9 coupled with corresponding predicted miRNAs, especially miR-29b-3p, miR-152-3p, and miR-223-3p may be regarded as promising targets for the diagnosis and treatment of SSAKI in the future.ConclusionsSeptic shock and AKI are related and VMP1, SLPI, PTX3, TIMP1, OLFM4, LCN2, and S100A9 genes are significantly associated with novel biomarkers involved in the occurrence and development of SSAKI.

Project description:ObjectivesAcute kidney injury is common in critically ill children; however, the frequency of septic shock-associated acute kidney injury and impact on functional status are unknown. We evaluated functional outcomes of children with septic shock-associated acute kidney injury.DesignSecondary analysis of patients with septic shock from the prospective Life after Pediatric Sepsis Evaluation study. We defined acute kidney injury using Kidney Disease Improving Global Outcomes criteria, comparing patients with absent/Stage 1 acute kidney injury to those with Stage 2/3 acute kidney injury (severe acute kidney injury). Our primary outcome was a composite of mortality or new functional morbidity at day 28 of hospitalization or discharge. We also assessed poor long-term outcome, defined as mortality or a persistent, serious deterioration in health-related quality of life at 3 months.SettingTwelve academic PICUs in the United States.PatientsCritically ill children, 1 month to 18 years, with community-acquired septic shock requiring vasoactive-inotropic support.InterventionsNone.Measurements and main resultsMore than 50% of patients (176/348) developed severe acute kidney injury; of those, 21.6% (38/176) required renal replacement therapy. Twice as many patients with severe acute kidney injury died or developed new substantive functional morbidity (38.6 vs 16.3%; p < 0.001). After adjustment for age, malignancy, and initial illness severity, severe acute kidney injury was independently associated with mortality or new substantive morbidity (adjusted odds ratio, 2.78; 95% CI, 1.63-4.81; p < 0.001). Children with severe acute kidney injury had poorer health-related quality of life at 3 months (adjusted effect size 2.46; 95% CI, 1.44-4.20; p = 0.002). Children with severe acute kidney injury required longer duration of mechanical ventilation (11.0 vs 7.0 d; p < 0.001) and PICU stay (11.7 vs 7.1 d; p < 0.001).ConclusionsAmong children with septic shock, severe acute kidney injury was independently associated with increased risk of death or new substantive functional morbidity. Survivors of sepsis with severe acute kidney injury were more likely to have persistent, serious health-related quality of life deterioration at 3 months.

Project description:Rationale: Urinary TIMP-2 (tissue inhibitor of metalloproteinases-2) and IGFBP7 (insulin-like growth factor-binding protein 7) can predict acute kidney injury (AKI) in patients with sepsis.Objectives: To address critical questions about whether biomarkers can inform the response to treatment and whether they might be used to guide therapy, as most sepsis patients present with AKI.Methods: We measured [TIMP-2] · [IGFBP7] before and after a 6-hour resuscitation in 688 patients with septic shock enrolled in the ProCESS (Protocol-based Care for Early Septic Shock) trial. Our primary endpoint was stage 3 AKI, renal replacement therapy, or death within 7 days.Measurements and Main Results: The endpoint was reached in 113 patients (16.4%). In patients with negative [TIMP-2] · [IGFBP7] at baseline, those who became positive (>0.3 U) after resuscitation had three-times higher risk compared with those who remained negative (21.8% vs. 8.5%; P = 0.01; odds ratio [OR], 3.0; 95% confidence interval [CI], 1.31-6.87). Conversely, compared with patients with a positive biomarker at baseline that were still positive at Hour 6, risk was reduced for patients who became negative (23.8% vs. 9.8%; P = 0.01; OR, 2.15; 95% CI, 1.17-3.95). A positive [TIMP-2] · [IGFBP7] after resuscitation was associated with worse outcomes in both patients with and without AKI at that time point. The clinical response to resuscitation, as judged by the Acute Physiology and Chronic Health Evaluation II score, was weakly predictive of the endpoint (area under the curve, 0.68; 95% CI, 0.62-0.73) and improved with addition of [TIMP-2] · [IGFBP7] (0.72; 95% CI, 0.66-0.77; P = 0.03). Different resuscitation protocols did not alter biomarker trajectories, nor did they alter outcomes in biomarker-positive or biomarker-negative patients. However, biomarker trajectories were associated with outcomes.Conclusions: Changes in urinary [TIMP-2] · [IGFBP7] after initial fluid resuscitation identify patients with sepsis who have differing risk for progression of AKI.Clinical trial registered with www.clinicaltrials.gov (NCT00510835).

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Identification of candidate serum biomarkers for severe septic shock-associated kidney injury via microarray.

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Identification of candidate serum biomarkers for severe septic shock-associated kidney injury via microarray.

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