Urinary TIMP-2 Research Articles

Early Diagnostic and Prognostic Value of the Urinary TIMP-2 and IGFBP-7 in Acute Kidney Injury in Critically Ill Children.

Acute kidney injury (AKI) is a hidden complication among children within pediatric intensive care units (PICU). To evaluate the early predictive and diagnostic value of Urinary [TIMP-2][IGFBP7] to detect AKI in PICU patients. A case-control study was conducted on 112 children (72 admitted to PICU and 40 healthy controls) Urinary [TIMP-2][IGFBP7] was measured within 24 hours of PICU admission. Acute kidney injury developed in 52 (72.2%) out of 72 critically ill patients. The AKI group had significantly higher serum creatinine, CRP, and pediatric sequential organ failure assessment score (pSOFA) score (p = 0.001, 0.01, and 0.001, respectively) and significantly lower estimated creatinine clearance (eCCl) (p = 0.001). Urinary [TIMP-2][IGFBP7] was significantly higher in the AKI group as compared with the non-AKI group (p = 0.007). The duration of the PICU stay was 1.8-fold higher in the AKI group (p = 0.004). At the time of study enrollment, 7 (13.5%) patients had normal initial eCCl. 26 patients (50.0%) fulfilled the "Risk," 18 patients (34.6%) the "Injury," 1 patient (1.9%) the "Failure" and 0 patient (0%) the "Loss" criteria. Nine (17%) patients progressed to the next higher pediatrics risk, injury, failure, loss, end-stage renal disease (pRIFLE) stage. Urinary [TIMP-2][IGFBP7] was significantly higher in the "Failure" stage followed by "Injury," stage then the "Risk," stage (p = 0.001). Hypovolemia/dehydration had the highest [TIMP-2][IGFBP7] values followed by sepsis. Urinary [TIMP-2][IGFBP7] was significantly increased in mechanically ventilated and patients who received inotropic medications. [TIMP-2]·[IGFBP7] was higher in AKI patients compared with non-AKI ones especially cases with hypovolemia and sepsis. It may predict severe morbidity and mortality because its higher levels in mechanically ventilated children and those on positive inotropic support. Ismail M, Abdelhamid N, Hasanin HM, Hamed HM, Motawie A, Kamel S, et al. Early Diagnostic and Prognostic Value of the Urinary TIMP-2 and IGFBP-7 in Acute Kidney Injury in Critically Ill Children. Indian J Crit Care Med 2024;28(10):970-976.

Predictive enrichment for the need of renal replacement in sepsis-associated acute kidney injury: combination of furosemide stress test and urinary biomarkers TIMP-2 and IGFBP-7

BackgroundIn sepsis, initial resuscitation with fluids is followed by efforts to achieve a negative fluid balance. However, patients with sepsis-associated acute kidney injury (SA-AKI) often need diuretic or renal replacement therapy (RRT). The dilemma is to predict whether early RRT might be advantageous or diuretics will suffice. Both the Furosemide Stress Test (FST) and measurements of the urinary biomarkers TIMP-2*IGFBP-7, if applied solely, do not provide sufficient guidance. We tested the hypothesis that a combination of two tests, i.e., an upstream FST combined with downstream measurements of urinary TIMP-2*IGFBP-7 concentrations improves the accuracy in predicting RRT necessity.MethodsIn this prospective, multicenter study 100 patients with sepsis (diagnosed < 48h), AKI stage ≥ 2, and an indication for negative fluid balance were included between 02/2020 and 12/2022. All patients received a standardized FST and urinary biomarkers TIMP-2*IGFBP-7 were serially measured immediately before and up to 12 h after the FST. The primary outcome was the RRT requirement within 7 days after inclusion.Results32% (n = 32/99) of SA-AKI patients eventually required RRT within 7 days. With the FST, urine TIMP-2*IGFBP-7 decreased within 2 h from 3.26 ng2/mL2/1000 (IQR: 1.38–5.53) to 2.36 ng2/mL2/1000 (IQR: 1.61–4.87) in RRT and 1.68 ng2/mL2/1000 (IQR: 0.56–2.94) to 0.27 ng2/mL2/1000 (IQR: 0.12–0.89) and non-RRT patients, respectively. While TIMP-2*IGFBP-7 concentrations remained low for up to 12 h in non-RRT patients, we noted a rebound in RRT patients after 6 h. TIMP-2*IGFBP-7 before FST (accuracy 0.66; 95%-CI 0.55–0.78) and the FST itself (accuracy 0.74; 95%-CI: 0.64–0.82) yielded moderate test accuracies in predicting RRT requirement. In contrast, a two-step approach, utilizing FST as an upstream screening tool followed by TIMP-2*IGFBP-7 quantification after 2 h improved predictive accuracy (0.83; 95%-CI 0.74–0.90, p = 0.03) compared to the FST alone, resulting in a positive predictive value of 0.86 (95%-CI 0.64–0.97), and a specificity of 0.96 (95%-CI 0.88–0.99).ConclusionsThe combined application of an upstream FST followed by urinary TIMP-2*IGFBP-7 measurements supports highly specific identification of SA-AKI patients requiring RRT. Upcoming interventional trials should elucidate if this high-risk SA-AKI subgroup, identified by our predictive enrichment approach, benefits from an early RRT initiation.

Tissue Inhibitor Metalloproteinase-2·IGF-Binding Protein 7 for the Prediction of Acute Kidney Injury following Cardiac Surgery

Introduction: Cardiac surgery-associated acute kidney injury (CSA-AKI) is a common complication associated with increased morbidity and mortality. Tissue inhibitor metalloproteinase-2·insulin-like growth factor-binding protein 7 (TIMP-2·IGFBP7) determines tubular stress markers, which may occur prior to tubular damage. Previous studies on the use of TIMP-2·IGFBP7 for the prediction of CSA-AKI showed divergent results. Therefore, this study aimed to explore the predictive value of TIMP-2·IGFBP7 measurements for the early detection of acute kidney injury (AKI) and short-term adverse outcomes after cardiac surgery. Methods: In the prospective cohort study, blood and urine samples were collected 6–12 h after cardiac surgery. Blood samples to monitor serum creatinine levels were additionally extracted from days 1 to 7. AKI was defined based on the KDIGO consensus guidelines. AKI within 7 days following surgery was the primary outcome. The initiation of renal replacement therapy, in intensive care unit mortality, and the combination of both were secondary outcomes. Results: A total of 557 patients were enrolled; 134 (24.06%) of them developed AKI and 33 (5.9%) had moderate or severe AKI. AKI developed more frequently in elderly patients with diabetes or with higher baseline serum creatinine levels. Patients with AKI had higher EuroSCORE II, Cleveland Clinic Score, and simplified renal index (SRI) than those without AKI. Urinary TIMP-2·IGFBP7 was significantly higher in patients with AKI. The area under the curve was 0.66 in predicting all AKI and 0.70 in predicting stages 2 and 3 AKI. The resulting sensitivity and specificity were 44.0% and 83.9%, respectively, for a calculated threshold TIMP-2·IGFBP7 value of 0.265 (ng/mL)2/1,000. The TIMP-2·IGFBP7 values, SRI score, and age were significantly associated with AKI within 7 days postoperatively. A total of 33 patients reached the composite endpoint; the percentage of patients who reached the composite endpoint in the TIMP-2·IGFBP7 of >0.265 (ng/ml)2/1,000 group was significantly higher than that of ≤0.265 (ng/mL)2/1,000 group. Conclusions: Postoperative implementation of TIMP-2·IGFBP7 improved the prediction of CSA-AKI and may aid in identifying patients at risk of short-term adverse outcomes. We identified an ideal calculated cutoff value of 0.265 (ng/mL)2/1,000 for the prediction of CSA-AKI among all AKI patients.

Acute Kidney Injury and Sepsis after Cardiac Surgery: The Roles of Tissue Inhibitor Metalloproteinase-2, Insulin-like Growth Factor Binding Protein-7, and Mid-Regional Pro-Adrenomedullin.

Identifying a panel of markers detecting kidney injury before the glomerular filtration rate reduction is a challenge to improving the diagnosis and management of acute kidney injury (AKI) in septic patients. This study evaluated the roles of tissue inhibitor metal proteinase-2, insulin growth factor binding protein-7 (TIMP2*IGFBP7), and mid-regional pro-adrenomedullin (MR-proADM) in patients with AKI. This study was prospectively conducted in an intensive care unit (ICU) enrolling 230 patients who underwent cardiac surgery. Biomarkers were evaluated before and after 4 h of the cardiac surgery. Whereas urine and creatinine alterations appeared at 23.2 (12.7-36.5) hours after cardiac surgery, urinary TIMP2*IGBP7 levels were higher at 4 h in AKI patients (1.1 ± 0.4 mg/L vs. 0.08 ± 0.02 mg/L; p < 0.001). Its concentration > 2 mg/L increases AKI risk within the following 24 h, clearly identifying the population at high risk of renal replacement therapy (RRT). In patients with sepsis, MR-proADM levels were 2.3 nmol/L (0.7-7.8 nmol/L), with the highest values observed in septic shock patients (5.6 nmol/L (3.2-18 nmol/L)) and a better diagnostic profile than procalcitonin and C-reactive protein to identify septic patients. MR-proADM values > 5.1 nmol/L and urine TIMP2*IGBP7 levels > 2 mg/L showed a significantly faster progression to RRT, with a mean follow-up time of 1.1 days. TIMP2*IGBP7 and MR-proADM precociously diagnose AKI in septic patients after cardiac surgery, giving prognostic information for RRT requirement.

MP52-07 MOLECULAR CHARACTERIZATION OF NEUROGENIC INTRINSIC SPHINCTER DEFICIENCY OF SPINA BIFIDA PATIENTS

You have accessJournal of UrologyCME1 Apr 2023MP52-07 MOLECULAR CHARACTERIZATION OF NEUROGENIC INTRINSIC SPHINCTER DEFICIENCY OF SPINA BIFIDA PATIENTS Benoit Peyronnet, Claire Richard, Claude Bendavid, Juliette Hascoet, Camille Haudebert, Caroline Voiry, Emmanuelle Samson, Jacques Kerdraon, Andrea Manunta, and Xavier Gamé Benoit PeyronnetBenoit Peyronnet More articles by this author , Claire RichardClaire Richard More articles by this author , Claude BendavidClaude Bendavid More articles by this author , Juliette HascoetJuliette Hascoet More articles by this author , Camille HaudebertCamille Haudebert More articles by this author , Caroline VoiryCaroline Voiry More articles by this author , Emmanuelle SamsonEmmanuelle Samson More articles by this author , Jacques KerdraonJacques Kerdraon More articles by this author , Andrea ManuntaAndrea Manunta More articles by this author , and Xavier GaméXavier Gamé More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003300.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Intrinsic sphincter deficiency is common in patients with spina bifida have a different pathophysiology and impact than in other neurogenic and non neurogenic populations. The objective of this study was to evaluate the association between five urinary biomarkers (NGF, BDNF, TIMP-2, TGF-B1 and PGE2) and intrinsic sphincter deficiency (ISD) in adults with spina bifida. METHODS: A single center prospective study was conducted between March 2015 and March 2017 including all consecutive adult spina bifida patients who were seen for urodynamic testing. Urinary tract imaging was also performed in all patients. At the end of the inclusion period, urines were defrosted and urinary NGF, BDNF, TIMP-2, TGF-B1 were assessed using validated ELISA kits. The urinary markers levels were adjusted on the urinary creatinine level. Urinary MMP-2 levels were assessed by zymography. Associations between urinary markers levels and clinical (stress urinary incontinence (SUI)) and/or urodynamic (lowered maximum urethral closure pressure (MUCP)) of intrinsic sphincter deficiency were sought. RESULTS: Forty patients were included. Of these, 17 had SUI (42.5%). The mean MUCP was 56.7 cm H2O. Urinary TIMP-2/Cr and urinary BDNF/Cr were the only two markers significantly associated with MUCP (r=-0.37; p=0.02 in both cases, Figure 1). TIMP-2/Cr was significantly higher in the SUI group (p=0.003), as was BDNF/Cr (p=0.02). Urinary NGF/Cr, TGF-B1/Cr and MMP2 did not differ significantly between SUI and non-SUI groups. CONCLUSIONS: Urinary TIMP-2 and BDNF may be associated with intrinsic sphincter deficiency in adults with spina bifida. These results suggest a possible pathophysiological role of extracellular matrix remodeling and both a fibrosis and a neurogenic component in the intrinsic sphincter deficiency of adults with spina bifida. Source of Funding: none © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e705 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Benoit Peyronnet More articles by this author Claire Richard More articles by this author Claude Bendavid More articles by this author Juliette Hascoet More articles by this author Camille Haudebert More articles by this author Caroline Voiry More articles by this author Emmanuelle Samson More articles by this author Jacques Kerdraon More articles by this author Andrea Manunta More articles by this author Xavier Gamé More articles by this author Expand All Advertisement PDF downloadLoading ...

THE ACCEPTABILITY, FEASIBILITY & APPROPRIATENESS OF A NOVEL BIOMARKER-GUIDED QUALITY IMPROVEMENT TREATMENT BUNDLE FOR PATIENTS WITH SUBCLINICAL ACUTE KIDNEY INJURY AFTER CARDIAC SURGERY

<h3>Objective</h3> Urinary cell cycle arrest biomarkers TIMP-2 & IGFBP7 are predictive for subsequent KDIGO-defined AKI, & diagnostic for subclinical AKI, after cardiac surgery. Early identification of a subclinical disease state allows implementation of renal protective measures, which reduce subsequent KDIGO-defined moderate–severe AKI. Following an innovation project, using biomarkers to guide use of a renal care bundle, we sought to assess the acceptability, feasibility & appropriateness of the intervention amongst clinicians. <h3>Design & Method</h3> If [TIMP-2]x[IGFBP7]>0.30ng/ml)2/1000 in cardiac patients 2h after ICU admission, they received a renal care bundle of: nephrotoxin cessation, advanced haemodynamic monitoring & protocolised optimisation, 12hrly serum creatinine & fluid balance, avoidance of hyperglycaemia, avoidance of radiocontrast agents, discontinuation of ACE inhibitors, & avoidance of starch/gelatine/chloride-rich solutions. Following conclusion of the project, the medical, surgical & nursing staff were surveyed to gauge acceptability of this assessment-intervention bundle. Two frameworks of acceptability were assessed. Questions based around Weiner's framework of acceptability elicited responses on a scale of high (5) to low degree (1) of acceptability, feasibility and appropriateness. The individual domains of Sekhon's acceptability score were assessed using separate questions, with an average percentage of agreement assigned to each domain (affective attitude, ethical consequence, patient & user experience, burden of intervention, intention and opportunity cost), before assessing correlation with general acceptability. <h3>Results</h3> Cardiac ICU nurses (63.2%; n=12), cardiothoracic surgeons (10.5%; n=2) and cardiac anaesthesiologists/intensivists (26.3%; n=5) were surveyed, with 89.5% (n=17) completing all questions. Across the four measures of acceptability, an average 83.8% of respondents assigned positive acceptable responses (4-5) with an average of 82.4% indicating a high degree of feasibility (4-5) and 85.3% reported the highest degrees (4-5) of appropriateness. For the Sekhon acceptability scale, there was 83.5% general acceptability. For the highest-scoring domains, strong correlation was seen between general acceptability and affective attitude (82.4%; R=0.79, p<0.001), and moderate correlation for user (81.2%; R=0.69, p=0.002) & patient (83.5%; R=0.65, p=0.005) experience, with weaker correlation for ethical consequences (83.5%; R=0.33, p=0.2). For those domains with lower degrees of acceptability, the domain of intention was moderately correlated with overall acceptability (71.8%; R=0.41, p=0.1), and burden (68.2%; R=0.38, p=0.14) and opportunity costs (69.4%; R=0.3, p=0.24) were weakly correlated. <h3>Conclusions</h3> Using validated metrics of acceptability, feasibility and appropriateness, the suitability of this assessment-intervention bundle was confirmed amongst the multidisciplinary team. The high degree of general acceptability was contributed to by the affective attitude of adoption, and by user & patient experience. Staff awareness of the burden and opportunity costs involved did not appear to be prohibitively negative.

Comparative accuracy of biomarkers for the prediction of hospital-acquired acute kidney injury: a systematic review and meta-analysis

BackgroundSeveral biomarkers have been proposed to predict the occurrence of acute kidney injury (AKI); however, their efficacy varies between different trials. The aim of this study was to compare the predictive performance of different candidate biomarkers for AKI.MethodsIn this systematic review, we searched PubMed, Medline, Embase, and the Cochrane Library for papers published up to August 15, 2022. We selected all studies of adults (> 18 years) that reported the predictive performance of damage biomarkers (neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), liver-type fatty acid-binding protein (L-FABP)), inflammatory biomarker (interleukin-18 (IL-18)), and stress biomarker (tissue inhibitor of metalloproteinases-2 × insulin-like growth factor-binding protein-7 (TIMP-2 × IGFBP-7)) for the occurrence of AKI. We performed pairwise meta-analyses to calculate odds ratios (ORs) and 95% confidence intervals (CIs) individually. Hierarchical summary receiver operating characteristic curves (HSROCs) were used to summarize the pooled test performance, and the Grading of Recommendations, Assessment, Development and Evaluations criteria were used to appraise the quality of evidence.ResultsWe identified 242 published relevant studies from 1,803 screened abstracts, of which 110 studies with 38,725 patients were included in this meta-analysis. Urinary NGAL/creatinine (diagnostic odds ratio [DOR] 16.2, 95% CI 10.1–25.9), urinary NGAL (DOR 13.8, 95% CI 10.2–18.8), and serum NGAL (DOR 12.6, 95% CI 9.3–17.3) had the best diagnostic accuracy for the risk of AKI. In subgroup analyses, urinary NGAL, urinary NGAL/creatinine, and serum NGAL had better diagnostic accuracy for AKI than urinary IL-18 in non-critically ill patients. However, all of the biomarkers had similar diagnostic accuracy in critically ill patients. In the setting of medical and non-sepsis patients, urinary NGAL had better predictive performance than urinary IL-18, urinary L-FABP, and urinary TIMP-2 × IGFBP-7: 0.3. In the surgical patients, urinary NGAL/creatinine and urinary KIM-1 had the best diagnostic accuracy. The HSROC values of urinary NGAL/creatinine, urinary NGAL, and serum NGAL were 91.4%, 85.2%, and 84.7%, respectively.ConclusionsBiomarkers containing NGAL had the best predictive accuracy for the occurrence of AKI, regardless of whether or not the values were adjusted by urinary creatinine, and especially in medically treated patients. However, the predictive performance of urinary NGAL was limited in surgical patients, and urinary NGAL/creatinine seemed to be the most accurate biomarkers in these patients. All of the biomarkers had similar predictive performance in critically ill patients.Trial registrationCRD42020207883, October 06, 2020.

Association between urinary biomarkers MMP-7/TIMP-2 and reduced renal function in children with ureteropelvic junction obstruction.

ImportanceExtracellular matrix proteins and enzymes involved in degradation have been found to be associated with tissue fibrosis and ureteropelvic junction obstruction (UPJO). In this study we developed a promising urinary biomarker model which can identify reduced renal function in UPJ obstruction patients. This can potentially serve as a non-invasive way to enhance surgical decision making for patients and urologists.ObjectiveWe sought to develop a predictive model to identify UPJO patients at risk for reduced renal function.DesignProspective cohort studySettingPre-operative urine samples were collected in a prospectively enrolled UPJO biomarker registry at our institution. Urinary MMP-2, MMP-7, TIMP-2, and NGAL were measured as well as clinical characteristics including hydronephrosis grade, differential renal function, t1/2, and UPJO etiology.ParticipantsChildren who underwent pyeloplasty for UPJOMain outcome measurementPrimary outcome was reduced renal function defined as MAG3 function <40%. Multivariable logistic regression was applied to identify the independent predictive biomarkers in the original Training cohort. Model validation and generalizability were evaluated in a new UPJO Testing cohort.ResultsWe included 71 patients with UPJO in the original training cohort and 39 in the validation cohort. Median age was 3.3 years (70% male). By univariate analysis, reduced renal function was associated with higher MMP-2 (p = 0.064), MMP-7 (p = 0.047), NGAL (p = 0.001), and lower TIMP-2 (p = 0.033). Combining MMP-7 with TIMP-2, the multivariable logistic regression model predicted reduced renal function with good performance (AUC = 0.830; 95% CI: 0.722–0.938). The independent testing dataset validated the results with good predictive performance (AUC = 0.738).Conclusions and relevanceCombination of urinary MMP-7 and TIMP-2 can identify reduced renal function in UPJO patients. With the high sensitivity cutoffs, patients can be categorized into high risk (aggressive management) versus lower risk (observation).

Empagliflozin reduces markers of acute kidney injury in patients with acute decompensated heart failure.

AimsIn this prospective, placebo‐controlled, double‐blind, exploratory study, we examined early and more delayed effects of empagliflozin treatment on haemodynamic parameters (primary endpoint: cardiac output) and kidney function including parameters of acute kidney injury (AKI) in patients with acute decompensated heart failure (HF).Methods and resultsPatients with acute decompensated HF with or without diabetes were randomized to empagliflozin 10 mg or placebo for 30 days. Haemodynamic, laboratory, and urinary parameters were assessed after 6 h, 1 day, 3 days, 7 days, and 30 days of treatment. Median time between hospital admission and randomization was 72 h. Baseline characteristics were not different in the empagliflozin (n = 10) and placebo (n = 9) groups. Empagliflozin led to a significant increase in urinary glucose excretion throughout the study (baseline: 37 ± 15 mg/24 h; Day 1: 14 565 ± 8663 mg/24 h; P = 0.001). Empagliflozin did not affect the primary endpoint of cardiac index or on systemic vascular resistance index at any time point. However, empagliflozin significantly reduced parameters of AKI (urinary TIMP‐2 and IGFBP7 by NephroCheck® as indicators of tubular kidney damage), which became significant after 3 days of treatment [placebo: 1.1 ± 1.1 (ng/mL)2/1000; empagliflozin: 0.3 ± 0.2 (ng/mL)2/1000; P = 0.02] and remained significant at the 7 day time point [placebo: 2.5 ± 3.8 (ng/mL)2/1000; empagliflozin: 0.3 ± 0.2 (ng/mL)2/1000; P = 0.003].ConclusionsIn this study, empagliflozin treatment did not affect haemodynamic parameters but significantly reduced markers of tubular injury in patients with acute decompensated HF.

Biomarker Rule-in or Rule-out in Patients With Acute Diseases for Validation of Acute Kidney Injury in the Emergency Department (BRAVA): A Multicenter Study Evaluating Urinary TIMP-2/IGFBP7.

BackgroundUrine tissue inhibitor of metalloproteinases-2/insulin-like growth factor-binding protein 7 (TIMP-2/IGFBP7) (NephroCheck, Ortho Clinical Diagnostics, Raritan, NJ, USA) is a US Food and Drug Administration-approved biomarker for risk assessment of acute kidney injury (AKI) in critically ill adult patients in intensive care units; however, its clinical impact in the emergency department (ED) remains unproven. We evaluated the utility of NephroCheck for predicting AKI development and short-term mortality in the ED.MethodsThis was a prospective, observational, five-center international study. We consecutively enrolled ED patients admitted with ≥30% risk of AKI development (assessed by ED physician ED score) or acute diseases. Serum creatinine was tested on ED arrival (T0), day 1, and day 2 (T48); urine for NephroCheck was collected at T0 and T48. We performed ROC curve and reclassification analyses.ResultsAmong the 529 patients enrolled (213 females; median age, 65 years), AKI developed in 59 (11.2%) patients. The T0 NephroCheck value was higher in the AKI group than in the non-AKI group (median 0.77 vs. 0.29 (ng/m)2/1,000, P=0.001), and better predicted AKI development than the ED score (area under the curve [AUC], 0.64 vs. 0.53; P=0.04). In reclassification analyses, adding NephroCheck to the ED score improved the prediction of AKI development (P<0.05). The T0 NephroCheck value predicted 30-day mortality (AUC, 0.68; P<0.001).ConclusionsNephroCheck can predict both AKI development and short-term mortality in at-risk ED patients. NephroCheck would be a useful biomarker for early ruling-in or ruling-out of AKI in the ED.

Combining renal cell arrest and damage biomarkers to predict progressive AKI in patient with sepsis

BackgroundSepsis is the most common trigger for AKI and up to 40% of mild or moderate septic AKI would progress to more severe AKI, which is associated with significantly increased risk for death and later CKD/ESRD. Early identifying high risk patients for AKI progression is a major challenge in patients with septic AKI.MethodsThis is a prospective, multicenter cohort study which enrolled adult patients with sepsis and initially developed stage 1 or 2 AKI in the intensive care unit from January 2014 to March 2018. AKI was diagnosed and staged according to 2012 KDIGO-AKI guidelines. Renal cell arrest biomarkers (urinary TIMP2*IGFBP7, u[TIMP-2]*[IGFBP7]) and renal damage biomarkers (urinary KIM-1[uKIM-1] and urinary IL-18 [uIL-18]) were measured at time of AKI clinical diagnosis, and the performance of biomarkers for predicting septic AKI progression alone or in combination were evaluated. The primary outcome was AKI progression defined as worsening of AKI stage. The secondary outcome was AKI progression with subsequent death during hospitalization.ResultsAmong 433 screened patients, 149 patients with sepsis and stage 1 or 2 AKI were included, in which 63 patients developed progressive AKI and 49 patients subsequently died during hospitalization. u[TIMP-2]*[IGFBP7], uKIM-1 and uIL-18 independently predicted the progression of septic AKI in which u[TIMP-2]*[IGFBP7] showed the greatest AUC (0.745; 95%CI, 0.667-0.823) as compared to uKIM-1 (AUC 0.719; 95%CI 0.638-0.800) and uIL-18 (AUC 0.619; 95%CI 0.525-0.731). Combination of u[TIMP-2]*[IGFBP7] with uKIM-1 improved the performance of predicting septic AKI progression with AUC of 0.752. u[TIMP-2]*[IGFBP7], alone or combined with uKIM-1/uIL-18, improved the risk reclassification over the clinical risk factor model alone both for the primary and secondary outcomes, as evidenced by significant category-free net reclassification index.ConclusionsCombination of renal cell arrest and damage biomarkers enhanced the prediction of AKI progression in patients with sepsis and improved risk reclassification over the clinical risk factors.

Quantitative and qualitative analyses of urinary L-FABP for predicting acute kidney injury after emergency laparotomy.

The aim of this study was to explore the clinical utility of urinary L-FABP for earlier prediction of acute kidney injury (AKI) after emergency laparotomy, and to assess the clinical utility of a point-of-care (POC) kit for urinary L-FABP. Forty-eight patients undergoing emergency laparotomy were divided into AKI and non-AKI groups by the kidney diseases: improving global outcome (KDIGO) criteria. Ten patients were included in the AKI group. Urinary L-FABP, albumin, N-acetyl-β-D-glucosaminidase (NAG), TIMP-2, IGFBP7, serum creatinine(SCr), and blood presepsin were measured perioperatively and compared between groups. Perioperative urinary L-FABP was also evaluated qualitatively using a POC kit. L-FABP and albumin levels were significantly higher in the AKI group at all measurement points. NAG was significantly higher only postoperatively in the AKI group. There were no inter-group differences in [TIMP-2] × [IGFBP7] at any measuring point. The area under the receiver operating characteristic curve of urinary L-FABP was greater than 0.8 perioperatively, which was larger than that of other biomarkers throughout the study period. The correlation coefficient at 2h after entering the operating room between quantitative and qualitative tests for urinary L-FABP was 0.714, which was the maximum. The sensitivity, specificity, and negative predictive value of the urinary L-FABP POC kit at 2h after entry were 55.6%, 91.9%, and 89.5%, respectively. Quantitative L-FABP analyses is suitable for predicting postoperative AKI earlier in the perioperative period of emergency laparotomy. Conversely, the higher specificity of qualitative L-FABP analysis suggests that it may be useful for excluding the risk of AKI but its overall clinical validity should be further investigated.

The Role of Urinary Biomarkers as Diagnostic and Prognostic Predictors of Acute Kidney Injury Associated With Vancomycin.

Introduction: The incidence of acute kidney injury (AKI) related to vancomycin is variable, and several risk factors related to the treatment and patients may explain the nephrotoxicity. The role of urinary biomarkers in AKI related to vancomycin is unknown. Objective: The aim of this study was to evaluate the role of urinary IL-18, KIM-1, NGAL, TIMP-2, and IGFBP7 as diagnostic and prognostic predictors of AKI related to vancomycin. Methods: A prospective cohort study of patients receiving vancomycin and admitted to wards of a public university hospital from July 2019 to May 2020 was performed. We excluded patients that had AKI before starting vancomycin, hemodynamic instability, inability to collect urine, and chronic kidney disease stage 5. Results: Ninety-four patients were included, and the prevalence of AKI was 24.5%, while the general mortality was 8.7%. AKI occurred 11 ± 2 days after the first vancomycin dose. The most frequent KDIGO stage was 1 (61%). There was no difference between patients who developed and did not develop AKI due to gender, length of hospital stay, dose, and time of vancomycin use. Logistic regression identified age (OR 6.6, CI 1.16–38.22, p = 0.03), plasmatic vancomycin concentrations between 96 and 144 h (OR 1.18, CI 1.04-1.40, p = 0.04), and urinary NGAL levels between 96 and 144 h (OR 1.123, CI 1.096–1.290, p = 0.03) as predictors of AKI. The time of vancomycin use (OR 4.61, CI 1.11–22.02, p = 0.03), higher plasmatic vancomycin concentrations between 192 and 240 h (OR 1.02, CI 0.98–1.06, p = 0.26), and higher cell cycle arrest urinary biomarkers TIMP-2 multiplied by IGFBP-7 between 144 and 192 h (OR 1.33, CI 1.10–1.62, p = 0.02; OR 1.19, CI 1.09–1.39, p = 0.04, respectively) were identified as prognostic factors for non-recovery of kidney function at discharge. Conclusion: AKI related to vancomycin was frequent in patients hospitalized in wards. Age, plasmatic vancomycin concentrations, and NGAL between 96 and 144 h were identified as predictors of AKI related to vancomycin use. Plasmatic vancomycin concentrations and urinary NGAL were predictors of AKI diagnosis within the next 5 days. The urinary biomarkers of cell cycle arrest TIMP-2 and IGFBP-7 and the duration of vancomycin use were associated with non-recovery of kidney function at hospital discharge moment.

The Association between Urinary Tissue Inhibitor Metalloproteinase 2 (TIMP-2) and Insulin-like Growth Factor Binding Protein 7 (IGFBP-7) and Renal Recovery in Acute Kidney Injury

Background. Acute kidney injury (AKI) is a common and serious medical condition associated with significant increases in morbidity, mortality, cost of care and non recovery of kidney function that leads to progression to chronic kidney disease. Cell cycle arrest is implicated in the pathogenesis and repair process following AKI. The urinary cell-cycle arrest markers tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP-7) have been utilized to predict the risk of AKI in many studies from specific population with good performance. However, their use in predicting recovery is still lacking. The aim of this study was to determine the association between two novel AKI biomarkers, urinary TIMP2 and IGFBP7 and renal recovery after 7 days of treatment in AKI patients at Dr. Mohammad Hoesin Hospital Palembang.&#x0D; Method. This was a prospective cohort study conducted in dr. Mohammad Hoesin Hospital Palembang from January 2021 until March 2021. Subjects enrolled in this study were patients whom diagnosed AKI based on KDIGO 2012 criteria. Urine samples were collected upon patients’ enrollment within 24 hours of AKI diagnosis. We utilized Sandwich Enzyme Linked Immunosorbant Assay (ELISA) method to detect urinary TIMP-2 and IGFBP-7 levels. The primary outcome is recovery from AKI after 7 days of treatment. Chi square test is used to analyze the association between urinary TIMP-2 and IGFBP-7 levels and renal recovery.&#x0D; Results. There were 70 subjects, only 22 of them were recovered after 7 days (31%). Median of urinary TIMP-2 and IGFBP-7 was 0,0047(0,0001-0,1439) [(ng/ml)2/1000]. There was significant association between urinary TIMP2 and IGFBP7 and renal recovery (p=0,027; OR 3,19; 95% CI 1,116-9,128).&#x0D; Conclusion. There was significant association between urinary TIMP2 and IGFBP7 and renal recovery in AKI patients.

Xuebijing injection in septic rats mitigates kidney injury, reduces cortical microcirculatory disorders, and suppresses activation of local inflammation

Ethnopharmacological relevanceXuebijing injections originate from the traditional Chinese medicine (TCM) prescription XuefuZhuyu Decoction. It is composed of five Chinese herbal extracts; Carthami flos, Paeoniae radix rubra, Chuanxiong rhizoma, Salviae miltiorrhizae, and Angelicae Sinensis radix. The China Food and Drug Administration approved Xuebijing injections as a TCM preparation for the adjuvant treatment of sepsis. Aim of the studyThis study aims to determine the effects of Xuebijing injections as an adjuvant to antibiotics for the treatment of renal microcirculatory dysfunction and renal inflammation in rats with sepsis. Materials and methodsThe rats received a sham operation (Sham), sham operation followed by Xuebijign injection (Sxbj), cecal ligation and puncture (CLP), or CLP followed by Xuebijing injection (Cxbj). Renal microvascular perfusion in the cortex and oxygenation were assessed at different times after sepsis induction. Renal levels of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and high mobility group box (HMGB)-1 were measured. Urinary TIMP-2 × IGFBP-7 and neutrophil gelatinase-associated lipocalin (NGAL) were measured as kidney biomarkers, and serum creatinine (SCr) was used to assess kidney injury. Tissue samples were stained for histologic evaluation. ResultsThe induction of sepsis increased local inflammation and decreased renal microvascular perfusion and oxygenation. Compared with the CLP group, the Cxbj group displayed improvements in microvascular perfusion and oxygenation (p < 0.05). The CLP group had significant increases in renal inflammatory biomarkers (IL-1β, IL-6, TNF-α, and HMGB-1; p < 0.05) and Xuebijing injection reduced the levels of these markers. The levels of urinary TIMP-2 × IGFBP-7, NAGL, and SCr were lower in the Cxbj group than in the CLP group (p < 0.05), and the CLP group had a higher Paller score than the Cxbj group (p < 0.05). However, the CLP and Cxbj groups had no significant difference in mortality. ConclusionsThis study into the early stages of sepsis in a rat model indicated that as an adjuvant therapy to antibiotics, Xuebijing injection improved renal perfusion and oxygenation, suppressed renal inflammation, and ameliorated kidney dysfunction. However, Xuebijing injection had no impact on mortality.

Acute Kidney Injury Risk is Exacerbated During Prolonged Exposure to Uncompensable Heat

Recent predictions indicate that extreme heat events will soon approach or exceed a wet bulb temperature of 35°C, which is considered the limit of thermal compensability in humans during resting conditions. Exposure to extreme heat events increases the risk of acute kidney injury (AKI), which is largely of renal tubular etiology and contributed to by elevations in core temperature and the development of dehydration. The effects of prolonged resting exposure to extreme heat that approaches of exceeds the limits of thermal compensability on AKI risk in humans is unknown. Therefore, we tested the hypothesis that AKI risk is elevated to a greater extent during an eight hour resting exposure to uncompensable heat stress, compared to compensable heat stress. Methods Fifteen healthy males (age: 23 ± 3 y; height: 179 ± 9 cm; weight 84.5 ± 18.4 kg) participated in resting exposures for 8 h in three warm (32°C, 33°C, 35°C dry bulb temperature) and extremely humid (>95% relative humidity) environments. Wet bulb temperatures differed between the three trials (31.6 ± 0.5°C, 32.1 ± 0.4°C, and 34.4 ± 0.5°C) resulting in two compensable (32°C, 33°C) and one uncompensable (35°C) environment, respectively. Core body temperature and body mass were measured every hour. Insulin-like growth factor-binding protein 7 [IGFBP7] and tissue inhibitor of metalloproteinase 2 [TIMP-2] were measured from urine samples collected at 0, 4 and 8 h of exposure. The product of IGFBP7 and TIMP-2 [IGFBP7xTIMP-2] provided an index of AKI risk, which is consistent with the FDA approved interpretation. IGFBP7 and TIMP-2 on their own provide an indication of proximal and distal tubular injury, respectively. Data are presented as an absolute change from 0 h as mean ± SD. Results Core temperature, body mass, IGFBP7, and TIMP-2 were not different at 0 h (all p>0.05). Core temperature increased over time in all trials (p<0.01). Changes in core temperature did not differ between the 32°C (0.6 ± 0.3°C) and 33°C (0.7 ± 0.3°C) trials (p=0.68), but was higher in the 35°C trial at 8 h (1.4 ± 0.4°C) compared to the 32°C and 33°C trials (p<0.01). Body mass decreased over time in all three trials (p<0.01). At 8 h, the change in body mass was not different between the 32°C (-1.4 ± 0.4%) and 33°C (-1.6 ± 0.7%) trials (p=0.68), but the reduction in body mass was greater in the 35°C trial (-1.9 ± 0.5%) compared to the 32°C trial (p=0.01). Urinary IGFBP7 increased over time in all trials (p<0.01). The increase in urinary IGFBP7 at 8 h differed between the 35°C (930 ± 749 ng/dL) and 32°C (337 ± 207 ng/dL) trials (p=0.04), but not the 33°C trial (373 ± 197 ng/dL; p=0.06). Similarly, urinary TIMP-2 increased over time in all three trials (p<0.01) and was greater at 8 h in the 35°C (21 ± 11 ng/dL) trial compared to the 32°C trial (9 ± 6 ng/dL; p=0.01). Finally, the increase in [IGFBP7xTIMP-2]was markedly greater at 8 h in the 35°C trial (868 ± 756 ng/dL2) compared to the 32°C (8 ± 9 ng/dL2; p<0.01) and 33°C (22 ± 26 ng/dL2; p<0.01) trials. Conclusion AKI risk is exacerbated during prolonged resting exposures to uncompensable heat stress, compared to compensable conditions, which is contributed to by injury in both the proximal and distal tubules.

Usefulness of the Biomarker TIMP-2•IGFBP7 for Acute Kidney Injury Assessment in Critically Ill Patients: A Narrative Review.

To review the clinical usefulness of the biomarker TIMP-2•IGFBP7 in adult, general medical-surgical intensive care unit (ICU) settings. PubMed (1946 to mid-February 2021) and EMBASE (1947 to mid-February 2021) with bibliographies of retrieved articles reviewed for additional articles. Studies evaluating use of the urinary TIMP-2•IGFBP7 assay in adult patients in ICU settings. Studies published after investigations leading to TIMP-2•IGFBP7 assay approval confirm the appropriateness of considerations discussed in product labeling, such as use of the test within 12 hours of assessment, use of a dichotomous 0.3 (ng/mL)2/1000 cutoff, and use only in combination with other assessments of acute kidney injury (AKI). However, as a biomarker routinely used for early identification of patients at risk for AKI in mixed ICU populations, the additional resources required for TIMP-2•IGFBP monitoring are difficult to justify because of limited data demonstrating usefulness in preventing or ameliorating AKI and its attendant complications. Biomarkers are potentially useful not only for assessment and diagnosis of AKI, but also for practitioners involved in the management of nephrotoxic medications and medications needing adjustment for decreased kidney function. Although there is evidence to suggest that the urinary TIMP-2•IGFBP7 biomarker is helpful in predicting AKI progression in general medical-surgical ICU patients when used within 12 hours of patient assessment in combination with routine testing, including serum creatinine and urine output, there is little evidence that its use leads to improvements in clinically important patient outcomes.

Tubular injury and cell-cycle arrest biomarkersto predict acute kidney injury in noncritically ill children receiving aminoglycosides.

Aim: NGAL, IL-18, KIM-1as well as urinary TIMP2and IGFBP7and their mathematical product (TIMP2*IGFBP7) were evaluated for detecting pediatric aminoglycoside acute kidney injury (AG-AKI). Methods: In a prospective study, noncritically ill children received aminoglycosides (AG) ≥3days. The area under the curve (AUC) for biomarkers to detect AKI was calculated by a) days before AKI onset; b) treatment days. Results: There were 113 AG episodes (68% febrile neutropenia). The AKI group had a higher proportion with febrile neutropenia. The AKI group had significantly lower NGAL 3days before AKI, as patients with febrile neutropenia had a lower NGAL during AG treatment (p<0.05). NGAL, IL-18 and TIMP2*IGFBP7 had AUC ≥0.73 at 3, 2 and 2days before AKI onset. Conclusion: NGAL, IL-18 and TIMP2*IGFBP7 were modest early biomarkers of AG-AKI. Febrile neutropenia was associated with lower NGAL.

Selected Metal Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases as Potential Biomarkers for Tubulointerstitial Fibrosis in Children with Unilateral Hydronephrosis.

Renal tubulointerstitial fibrosis caused by congenital ureteropelvic junction obstruction (UPJO) may lead to the development of obstructive nephropathy (ON) and the impairment of kidney function. Hence, the identification of early biomarkers of this condition might be of assistance in therapeutic decisions. This study evaluates serum and urinary metalloproteinases MMP-1, MMP-2, and MMP-9 and tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2 as potential biomarkers of ON in children with congenital unilateral hydronephrosis (HN) caused by UPJO. Forty-five (45) children with congenital HN of different grades of severity and twenty-one (21) healthy controls were enrolled in the study. Urinary and serum concentrations of MMP-1, MMP-2, MMP-9, TIMP-1 and TIMP-2 were measured using specific ELISA kits. The urinary excretions were expressed as biomarker/creatinine (Cr) ratios. To evaluate the extracellular matrix remodelling process activity, the serum and urinary MMP-1, -2, -9/TIMP-1, -2 ratios were also calculated. In comparison with the controls, patients with HN, independent of the grade, showed significantly increased median serum MMP-9, TIMP-1, and TIMP-2, median urinary MMP-9/Cr, and TIMP-2/Cr ratios. Lower median values of serum MMP-2/TIMP-1, MMP-9/TIMP-1 in patients with HN were also revealed. Additionally, higher urinary MMP-2/Cr, lower urinary MMP-2/TIMP-2, and lower serum MMP-9/TIMP-2 ratios were observed in patients with HN grades 3 and 4. Patients with ON diagnosed by renal scintigraphy had a significantly higher median serum MMP-9 concentration and lower median serum MMP-9/TIMP-1, -2 ratios in comparison with those without this condition. Patients with nonglomerular proteinuria had a significantly higher median serum TIMP-1 concentration, a higher median urinary TIMP-2/Cr ratio, and a lower serum MMP-9/TIMP-1 ratio compared to those without this symptom. The relationship between the measured biomarkers and the relative function of the obstructed kidney showed no correlations. The ROC curve analysis showed a promising diagnostic profile for the detection of ON for serum MMP-9 and the serum MMP-9/TIMP-1 and MMP-9/TIMP-2 ratios. In conclusion, the results of this study suggest that patients with HN, particularly with grades 3 and 4, are at higher risk of renal tubulointerstitial fibrosis. The noninvasive markers of this condition considered are urinary MMP-2/Cr and MMP-9/Cr, serum MMP-9, serum and urinary MMP-2, MMP-9/TIMP-1, -2. Additionally, serum MMP-9 and MMP-9/TIMP-1, -2 may become promising markers of ON.

MP48-14 URINARY TIMP-2 AND MMP-2 ARE SIGNIFICANTLY ASSOCIATED WITH POOR BLADDER COMPLIANCE IN ADULT PATIENTS WITH SPINA BIFIDA

You have accessJournal of UrologyUrodynamics/Lower Urinary Tract Dysfunction/Female Pelvic Medicine: Neurogenic Voiding Dysfunction (MP48)1 Apr 2020MP48-14 URINARY TIMP-2 AND MMP-2 ARE SIGNIFICANTLY ASSOCIATED WITH POOR BLADDER COMPLIANCE IN ADULT PATIENTS WITH SPINA BIFIDA Benoit Peyronnet*, Claire Richard, Claude Bendavid, Juliette Hascoet, Magali Jezequel, Charlene Brochard, Quentin Alimi, Zineddine Khene, Guillaume Bouguen, Jacques Kerdraon, Andrea Manunta, and Xavier Game Benoit Peyronnet* Benoit Peyronnet* More articles by this author , Claire RichardClaire Richard More articles by this author , Claude BendavidClaude Bendavid More articles by this author , Juliette HascoetJuliette Hascoet More articles by this author , Magali JezequelMagali Jezequel More articles by this author , Charlene BrochardCharlene Brochard More articles by this author , Quentin AlimiQuentin Alimi More articles by this author , Zineddine KheneZineddine Khene More articles by this author , Guillaume BouguenGuillaume Bouguen More articles by this author , Jacques KerdraonJacques Kerdraon More articles by this author , Andrea ManuntaAndrea Manunta More articles by this author , and Xavier GameXavier Game More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000903.014AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The aim of this study was to assess the predictive values of six urinary markers (NGF, BDNF, MMP-2, TIMP-2, TGF-B1 et PGE2) for adverse urodynamic features and for upper urinary tract damage in adult patients with spina bifida. METHODS: A single-center prospective trial was conducted from March 2015 to March 2017 including all consecutive adult spina bifida patients seen for urodynamic testing. The urine was collected and stored at -80°C. A urodynamic and an upper urinary tract were systematically performed. At the end of the inclusion period, urines were defrosted and urinary NGF, BDNF, TIMP-2, TGF-B1 were assessed using validated ELISA kits. The urinary markers levels were adjusted on the urinary creatinine level. Urinary MMP-2 levels were assessed by zymography. RESULTS: Fourty patients were included. Only TIMP-2 and MMP-2 were significantly associated with poor bladder compliance (p=0.043 and p=0.039 respectively). TIMP-2 was also the only urinary marker significantly associated with upper urinary tract damage on imaging (OR=19.81; p=0.02). Of all urodynamic parameters, bladder compliance and maximum detrusor pressure were the only ones associated with upper urinary tract damage on imaging (p=0.01 and p=0.02), The diagnostic performances of urinary TIMP-2 for upper urinary tract damage were slightly superior to PdetMax and bladder compliance with an area under the curve (AUC) of 0.72. CONCLUSIONS: Urinary TIMP-2 and MMP-2 were significantly associated withpoor bladder compliance and urinary TIMP-2 was significantly associated with upper urinary tract damage.These findings support a pathophysiological role of extracellular matrix remodeling in poor bladder compliance of adult spina bifida patients. Source of Funding: university of rennesfondation de l'avenir © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e699-e700 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Benoit Peyronnet* More articles by this author Claire Richard More articles by this author Claude Bendavid More articles by this author Juliette Hascoet More articles by this author Magali Jezequel More articles by this author Charlene Brochard More articles by this author Quentin Alimi More articles by this author Zineddine Khene More articles by this author Guillaume Bouguen More articles by this author Jacques Kerdraon More articles by this author Andrea Manunta More articles by this author Xavier Game More articles by this author Expand All Advertisement PDF downloadLoading ...