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Clinical use of [TIMP-2]•[IGFBP7] biomarker testing to assess risk of acute kidney injury in critical care: guidance from an expert panel.

ABSTRACT: BACKGROUND:The first FDA-approved test to assess risk for acute kidney injury (AKI), [TIMP-2]•[IGFBP7], is clinically available in many parts of the world, including the USA and Europe. We sought to understand how the test is currently being used clinically. METHODS:We invited a group of experts knowledgeable on the utility of this test for kidney injury to a panel discussion regarding the appropriate use of the test. Specifically, we wanted to identify which patients would be appropriate for testing, how the results are interpreted, and what actions would be taken based on the results of the test. We used a modified Delphi method to prioritize specific populations for testing and actions based on biomarker test results. No attempt was made to evaluate the evidence in support of various actions however. RESULTS:Our results indicate that clinical experts have developed similar practice patterns for use of the [TIMP-2]•[IGFBP7] test in Europe and North America. Patients undergoing major surgery (both cardiac and non-cardiac), those who were hemodynamically unstable, or those with sepsis appear to be priority patient populations for testing kidney stress. It was agreed that, in patients who tested positive, management of potentially nephrotoxic drugs and fluids would be a priority. Patients who tested negative may be candidates for "fast-track" protocols. CONCLUSION:In the experience of our expert panel, biomarker testing has been a priority after major surgery, hemodynamic instability, or sepsis. Our panel members reported that a positive test prompts management of nephrotoxic drugs as well as fluids, while patients with negative results are considered to be excellent candidates for "fast-track" protocols.

SUBMITTER: Guzzi LM

PROVIDER: S-EPMC6585126 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Clinical use of [TIMP-2]•[IGFBP7] biomarker testing to assess risk of acute kidney injury in critical care: guidance from an expert panel.

Guzzi Louis M LM Bergler Tobias T Binnall Brian B Engelman Daniel T DT Forni Lui L Germain Michael J MJ Gluck Eric E Göcze Ivan I Joannidis Michael M Koyner Jay L JL Reddy V Seenu VS Rimmelé Thomas T Ronco Claudio C Textoris Julien J Zarbock Alexander A Kellum John A JA

Critical care (London, England) 20190620 1

<h4>Background</h4>The first FDA-approved test to assess risk for acute kidney injury (AKI), [TIMP-2]•[IGFBP7], is clinically available in many parts of the world, including the USA and Europe. We sought to understand how the test is currently being used clinically.<h4>Methods</h4>We invited a group of experts knowledgeable on the utility of this test for kidney injury to a panel discussion regarding the appropriate use of the test. Specifically, we wanted to identify which patients would be app ...[more]

PMID: 31221200

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Project description:BackgroundAcute kidney injury (AKI) is frequently observed in serious infections, following nephrotoxic medication, surgery and trauma. Here we tested whether the detection of two recently identified biomarkers for AKI, Tissue Inhibitor of Metalloproteinase-2 (TIMP-2) and Insulin-Like Growth Factor Binding Protein 7 (IGFBP7), depends on the expression of these proteins in cells of the urinary sediment.MethodWe collected urine samples of 33 kidney transplant recipients and 14 non-transplanted patients who all had AKI (stages 1-3 according to KDIGO), and measured [IGFBP7]x[TIMP-2] using the NephroCheck® Astute1 40 ™ meter. Concomitantly, we analyzed IGFBP7 and TIMP-2 mRNA expression by quantitative polymerase chain reaction (qPCR) from urinary sediment of the same patients, and correlated the results with [IGFBP7]x[TIMP-2] (protein), by linear regression analysis. We also determined the association between [IGFBP7]x[TIMP-2] and estimated glomerular filtration rate (eGFR), and between IGFBP7 and TIMP-2 mRNA expression and markers of inflammation. Light microscopy and confocal immunofluorescence served to illustrate changes in the urinary sediment over the time course of renal function improvement.ResultsOf the 47 analyzed AKI patients, 14 presented with ascending urinary tract infection. Serum creatinine (sCr), blood urea nitrogen (BUN) and eGFR in all patients were 3.9±2.28 mg/dL, 47.59±23.1 mg/dL and 22.88±16.0 mL/min/1.73m2, respectively, on average ±standard deviation. [IGFBP7]x[TIMP-2] was 2.33±9.95 (ng/ml)2/1000, and did not associate with IGFBP7 and TIMP-2 gene expression (r = -0.0220, p = 0.4216; respectively r = 0.0972, p = 0.1909). [IGFBP7]x[TIMP-2] did not associate with eGFR; IGFBP7 and TIMP-2 mRNA expression. Improvement of renal function went along with disappearance of casts, decrease in aquaporin1 positive renal epithelial cells and leukocytes from the urinary sediment.ConclusionThe gene expression pattern of IGFBP7 and TIMP-2 from urinary sediment, which contains desquamated renal tubular epithelial cells, did not correlate with [IGFBP7]x[TIMP-2] protein, indicating that IGFBP7 and TIMP-2 measured in the NephroCheck® test originated predominantly from intact but stressed cells of the kidney itself.

Project description:BackgroundBiomarkers can play a critical role by facilitating diagnosis and stratification of disease, as well as assessment or prediction of disease severity. Urinary tissue inhibitor of metalloproteinase-2 and insulin-like growth factor binding protein 7 product ([TIMP-2]?×?[IGFBP7]) predict the development and progression of AKI and recently procalcitonin (PCT), a widely used biomarker for sepsis diagnosis and management, has been associated with AKI occurrence in ICU patients. To assess combinations of [TIMP-2]?×?[IGFBP7] and PCT results for prediction and risk stratification of short-term outcomes in septic and non-septic patients, a retrospective cohort analysis of critically ill patients was performed in a multidisciplinary ICU. ROC curve analysis was used in order to evaluate predictive performance of combined results of [TIMP-2]?×?[IGFBP7] and PCT at the time of admission for AKI development. To verify the utility of adding [TIMP-2]?×?[IGFBP7] and PCT results for risk assessment, we evaluated the predictive value of having a single-marker positivity compared to a double-marker positivity using the widely used cut-off of 0.3 (ng/mL)2/1000 for [TIMP-2]?×?[IGFBP7] and 0.5 ?g/L for PCT. Risk assessment for AKI occurrence within 48 h, acute kidney disease (AKD) and mortality at 7 days was performed by logistic/Cox regression analysis.Results433 patients were analysed, of whom 168 had AKI within 48 h (93 septic and 65 non-septic patients). Combination of [TIMP-2]?×?[IGFBP7] and PCT showed a good predictive ability for AKI occurrence (AUC 0.81, 95% CI 0.77-0.86, p?<?0.001, Sens 78%, Spec 73%). Combinations of biomarkers increased the odd ratios (OR) considerably. A single-marker positivity showed a fourfold risk increase, while the double-marker positivity a 26-fold risk increase for AKI occurrence. Moreover, the double-marker positivity showed an elevated risk for AKD at 7 days in non-septic patients (OR 15.9, 95% CI 3,21-73,57, p?<?0.001) and for mortality within 7 days in septic patients (HR 4.1, 95% CI 1.4-11.8, p?=?0.001).ConclusionsAlthough combining the results of [TIMP-2]?×?[IGFBP7] and PCT may be a useful tool to identify and stratify ICU patients at high risk for septic AKI and short-term adverse outcomes, data should be confirmed in a large prospective study.

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.

Dataset Information

Clinical use of [TIMP-2]•[IGFBP7] biomarker testing to assess risk of acute kidney injury in critical care: guidance from an expert panel.

Publications

Clinical use of [TIMP-2]•[IGFBP7] biomarker testing to assess risk of acute kidney injury in critical care: guidance from an expert panel.

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