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Tissue Inhibitor Metalloproteinase-2 (TIMP-2)?IGF-Binding Protein-7 (IGFBP7) Levels Are Associated with Adverse Long-Term Outcomes in Patients with AKI.

ABSTRACT: Tissue inhibitor metalloproteinase-2 (TIMP-2) and IGF-binding protein-7 (IGFBP7) have been validated for risk stratification in AKI. However, the association of urinary TIMP-2 and IGFBP7 with long-term outcomes is unknown. We evaluated the 9-month incidence of a composite end point of all-cause mortality or the need for RRT in a secondary analysis of a prospective observational international study of critically ill adults. Two predefined [TIMP-2]?[IGFBP7] cutoffs (0.3 for high sensitivity and 2.0 for high specificity) for the development of AKI were evaluated. Cox proportional hazards models were used to determine risk for the composite end point. Baseline [TIMP-2]?[IGFBP7] values were available for 692 subjects, of whom 382 (55.2%) subjects developed stage 1 AKI (defined by Kidney Disease Improving Global Outcomes guidelines) within 72 hours of enrollment and 217 (31.4%) subjects met the composite end point. Univariate analysis showed that [TIMP-2]?[IGFBP7]>2.0 was associated with increased risk of the composite end point (hazard ratio [HR], 2.11; 95% confidence interval [95% CI], 1.37 to 3.23; P<0.001). In a multivariate analysis adjusted for the clinical model, [TIMP-2]?[IGFBP7] levels>0.3 were associated with death or RRT only in subjects who developed AKI (compared with levels?0.3: HR, 1.44; 95% CI, 1.00 to 2.06 for levels>0.3 to ?2.0; P=0.05 and HR, 2.16; 95% CI, 1.32 to 3.53 for levels>2.0; P=0.002). In conclusion, [TIMP-2]?[IGFBP7] measured early in the setting of critical illness may identify patients with AKI at increased risk for mortality or receipt of RRT over the next 9 months.

SUBMITTER: Koyner JL

PROVIDER: S-EPMC4483589 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Tissue Inhibitor Metalloproteinase-2 (TIMP-2)⋅IGF-Binding Protein-7 (IGFBP7) Levels Are Associated with Adverse Long-Term Outcomes in Patients with AKI.

Koyner Jay L JL Shaw Andrew D AD Chawla Lakhmir S LS Hoste Eric A J EA Bihorac Azra A Kashani Kianoush K Haase Michael M Shi Jing J Kellum John A JA

Journal of the American Society of Nephrology : JASN 20141222 7

Tissue inhibitor metalloproteinase-2 (TIMP-2) and IGF-binding protein-7 (IGFBP7) have been validated for risk stratification in AKI. However, the association of urinary TIMP-2 and IGFBP7 with long-term outcomes is unknown. We evaluated the 9-month incidence of a composite end point of all-cause mortality or the need for RRT in a secondary analysis of a prospective observational international study of critically ill adults. Two predefined [TIMP-2]⋅[IGFBP7] cutoffs (0.3 for high sensitivity and 2. ...[more]

PMID: 25535301

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Project description:BackgroundThe G1 cell cycle inhibitors tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) have been identified as promising biomarkers for the prediction of adverse outcomes including renal replacement therapy (RRT) and mortality in critically ill adult patients who develop acute kidney injury (AKI). However, the prognostic value of urinary TIMP-2 and IGFBP7 in neonatal and pediatric AKI for adverse outcome has not been investigated yet.MethodsThe product of the urinary concentration of TIMP-2 and IGFBP7 ([TIMP-2]•[IGFBP7]) was assessed by a commercially available immunoassay (NephroCheck™) in a prospective cohort study in 133 subjects aged 0-18 years including 46 patients with established AKI according to pRIFLE criteria, 27 patients without AKI (non-AKI group I) and 60 apparently healthy neonates and children (non-AKI group II). AKI etiologies were: dehydration/hypovolemia (n = 7), hemodynamic instability (n = 7), perinatal asphyxia (n = 9), septic shock (n = 7), typical hemolytic-uremic syndrome (HUS; n = 5), interstitial nephritis (n = 5), vasculitis (n = 4), nephrotoxic injury (n = 1) and renal vein thrombosis (n = 1).ResultsWhen AKI patients were classified into pRIFLE criteria, 6/46 (13%) patients fulfilled the criteria for the category "Risk", 13/46 (28%) for "Injury", 26/46 (57%) for "Failure" and 1/46 (2%) for "Loss". Patients in the "Failure" stage had a median 3.7-fold higher urinary [TIMP-2]•[IGFBP7] compared to non-AKI subjects (P<0.001). When analyzed for AKI etiology, highest [TIMP-2]•[IGFBP7] values were found in patients with septic shock (P<0.001 vs. non-AKI I+II). Receiver operating characteristic (ROC) curve analyses in the AKI group revealed good performance of [TIMP-2]•[IGFBP7] in predicting 30-day (area under the curve (AUC) 0.79; 95% CI, 0.61-0.97) and 3-month mortality (AUC 0.84; 95% CI, 0.67-0.99) and moderate performance in predicting RRT (AUC 0.67; 95% CI, 0.50-0.84).ConclusionsThis study shows that urinary [TIMP-2]•[IGFBP7] has a good diagnostic performance in predicting adverse outcomes in neonatal and pediatric AKI of heterogeneous etiology.

Project description:Over expression of Tissue Inhibitor of Metalloproteinases-3 (TIMP-3) in vascular smooth muscle cells (VSMCs) induces apoptosis and reduces neointima formation occurring after saphenous vein interposition grafting or coronary stenting. In studies to address the mechanism of TIMP-3-driven apoptosis in human VSMCs we find that TIMP-3 increased activation of caspase-8 and apoptosis was inhibited by expression of Cytokine response modifier A (CrmA) and dominant negative FAS-Associated protein with Death Domain (FADD). TIMP-3 induced apoptosis did not cause mitochondrial depolarisation, increase activation of caspase-9 and was not inhibited by over-expression of B-cell Lymphoma 2 (Bcl2), indicating a mitochondrial independent/type-I death receptor pathway. TIMP-3 increased levels of the First Apoptosis Signal receptor (FAS) and depletion of FAS with shRNA showed TIMP-3-induced apoptosis was FAS dependent. TIMP-3 induced formation of the Death-Inducing Signalling Complex (DISC), as detected by immunoprecipitation and by immunofluorescence. Cellular-FADD-like IL-1 converting enzyme-Like Inhibitory Protein (c-FLIP) localised with FAS at the cell periphery in the absence of TIMP-3 and this localisation was lost on TIMP-3 expression with c-FLIP adopting a perinuclear localisation. Although TIMP-3 inhibited FAS shedding, this did not increase total surface levels of FAS but instead increased FAS levels within localised regions at the cell surface. A Disintegrin And Metalloproteinase 17 (ADAM17) is inhibited by TIMP-3 and depletion of ADAM17 with shRNA significantly decreased FAS shedding. However ADAM17 depletion did not induce apoptosis or replicate the effects of TIMP-3 by increasing localised clustering of cell surface FAS. ADAM17-depleted cells could activate caspase-3 when expressing levels of TIMP-3 that were otherwise sub-apoptotic, suggesting a partial role for ADAM17 mediated ectodomain shedding in TIMP-3 mediated apoptosis. We conclude that TIMP-3 induced apoptosis in VSMCs is highly dependent on FAS and is associated with changes in FAS and c-FLIP localisation, but is not solely dependent on shedding of the FAS ectodomain.

Project description:BackgroundTissue inhibitor of metalloproteinase 1 (TIMP-1) has recently been shown to be dependent on or independent of Matrix metalloproteinases (MMPs) in its roles in tumorigenesis and progression. This appreciation has prompted various studies assessing the prognostic value of TIMP-1 in patients with gastrointestinal cancer, however, the conclusions were still inconsistent. The aim of this study was to assess the prognostic value of TIMP-1-immunohistochemistry (IHC) staining and pretreatment serum/plasma TIMP-1 level in gastrointestinal cancer survival as well as the association between TIMP-1 and clinicopathologic features.MethodsThe meta-analysis was registered in the International Prospective Register of Systematic Reviews (PROSPERO; Registration NO. CRD42020185407) and followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. A highly sensitive literature search was performed in electronic databases including PubMed, EMBASE and the Cochrane Library. Heterogeneity analysis was conducted using both chi-square-based Q statistics and the I2 test. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to assess the prognostic value of TIMP-1 using the fixed-effects model. Odds ratios (ORs) with 95% CIs were calculated to evaluate the associations between TIMP-1 and clinicopathological characteristics. The meta-analysis was conducted using STATA 12.0 software.ResultsA total of 3,958 patients from twenty-two studies were included in the meta-analysis. Elevated TIMP-1 levels were significantly associated with poor survival in gastrointestinal cancer (TIMP-1-IHC staining: HR = 2.04, 95% CI [1.59-2.61], I 2 = 35.7%, P Q = 0.156; pretreatment serum/plasma TIMP-1 levels: HR = 2.02, 95% CI [1.80-2.28], I 2 = 0%, P Q = 0.630). Moreover, clinicopathological parameter data analysis showed that elevated TIMP-1 levels were significantly associated with lymph node metastasis (N1/N2/N3 vs N0: OR = 2.92, 95% CI [1.95-4.38]) and higher TNM stages (III/IV vs I/II: OR = 2.73, 95% CI [1.23-6.04]).ConclusionBoth TIMP-1-positive IHC staining and high serum/plasma TIMP-1 levels are poor prognostic factors for the survival of gastrointestinal cancer. In addition, TIMP-1 overexpression was correlated with more advanced clinicopathological features.

Dataset Information

Tissue Inhibitor Metalloproteinase-2 (TIMP-2)?IGF-Binding Protein-7 (IGFBP7) Levels Are Associated with Adverse Long-Term Outcomes in Patients with AKI.

Publications

Tissue Inhibitor Metalloproteinase-2 (TIMP-2)⋅IGF-Binding Protein-7 (IGFBP7) Levels Are Associated with Adverse Long-Term Outcomes in Patients with AKI.

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