TIMP-2/IGFBP7 predicts acute kidney injury in out-of-hospital cardiac arrest survivors

Adler, Christoph; Heller, Tobias; Schregel, Felix; Hagmann, Henning; Hellmich, Martin; Adler, Jeffrey M.; Reuter, Hannes

doi:10.1186/s13054-018-2042-9

Cited by 29 publications

(25 citation statements)

References 26 publications

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“…Adler et al . [ 23 ] found that TIMP-2*IGFBP-7 can be used to predict AKI in out-of-hospital CA survivors. In our experiment, urine TIMP-2*IGFBP-7 in the ECPR group at every time point from baseline to ROSC6 were smaller than that in the CCPR group and serum and urinary NGAL were also found to be lower in ECPR group.…”

Section: Discussionmentioning

confidence: 99%

Extracorporeal Membrane Oxygenation Improving Survival and Alleviating Kidney Injury in a Swine Model of Cardiac Arrest Compared to Conventional Cardiopulmonary Resuscitation

Yuan

Liu

Zhang

et al. 2018

Chinese Medical Journal

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Background:Acute kidney injury (AKI) frequently occurs in cardiopulmonary resuscitation patients. Studies comparing the effects of extracorporeal membrane oxygenation (ECMO) with conventional cardiopulmonary resuscitation (CCPR) on AKI were rare. This study aimed to compare the effects of ECMO with those of CCPR on survival rate and AKI and explore the underlying mechanisms in a swine model of cardiac arrest (CA).Methods:Sixteen male pigs were treated with ventricular fibrillation to establish CA model and then underwent CCPR (CCPR group, n = 8) or ECMO during cardiopulmonary resuscitation (ECPR group, n = 8). The study endpoints were 6 h after return of spontaneous circulation (ROSC) or death. Serum and urine samples were collected at baseline and during the 6 h after ROSC. The biomarkers of AKI were detected by enzyme-linked immunosorbent assay. The apoptosis of renal tubular epithelial cells was discovered by transmission electron microscope (TEM) and terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Apoptosis-related genes were detected by immune-staining and Western blotting. Data were compared by Student's t-test.Results:All pigs in ECPR group were successfully resuscitated with a higher 6-h survival rate (8/8) compared to CCPR group (6/8). The expressions of AKI biomarkers including neutrophil gelatinase-associated lipocalin (NGAL), tissue inhibitor of metalloproteinase2 (TIMP2), insulin-like growth factor-binding protein 7 (IGFBP7), liver fatty acid-binding protein (LFABP), and kidney injury molecule1 (Kim-1) were all increased along with the time after ROSC in both groups and lower in ECPR group compared with CCPR group. Especially, products of urinary TIMP and IGFBP levels (TIMP*IGFBP) were significantly lower at ROSC4 (0.58 ± 0.10 ng2/ml2 vs. 1.18 ± 0.38 ng2/ml2, t = 4.33, P = 0.003) and ROSC6 (1.79 ± 0.45 ng2/ml2 vs. 3.00 ± 0.44 ng2/ml2, t = 5.49, P < 0.001); urinary LFABP was significantly lower at ROSC6 (0.74 ± 0.06 pg/ml vs. 0.85 ± 0.11 pg/ml, t = 2.41, P = 0.033); and urinary Kim-1 was significantly lower at ROSC4 (0.66 ± 0.09 pg/ml vs. 0.83 ± 0.06 pg/ml, t = 3.99, P = 0.002) and ROSC6 (0.73 ± 0.12 pg/ml vs. 0.89 ± 0.08 pg/ml, t = 2.82, P = 0.016). Under light microscope and TEM, the morphological injures in renal tissues were found to be improved in ECPR group. Moreover, apoptosis was also alleviated in ECPR group.Conclusions:Compared with CCPR, ECMO improves survival rate and alleviates AKI in a swine model of CA. The mechanism of which might be via downregulating AKI biomarkers and apoptosis in kidney.

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Section: Discussionmentioning

confidence: 99%

Extracorporeal Membrane Oxygenation Improving Survival and Alleviating Kidney Injury in a Swine Model of Cardiac Arrest Compared to Conventional Cardiopulmonary Resuscitation

Yuan

Liu

Zhang

et al. 2018

Chinese Medical Journal

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“…Several biomarkers such as kidney injury molecule-1 (Kim-1), neutrophil gelatinase-associated lipocalin (NGAL), and tissue inhibitor of metalloproteinase-2/IGF-binding protein-7 (TIMP-2/IGFBP7) have been identified, and some of them are successfully applied in the clinic. [6][7][8][9][10][11] Recently, we reported that urinary matrix metalloproteinase-7 (uMMP-7) is an early and noninvasive biomarker that predicts severe AKI in patients after cardiac surgery. 12 In 2 cohorts of 721 patients, uMMP-7 outperformed all other biomarkers tested, suggesting that it is a potentially better predictor for AKI.…”

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confidence: 99%

Matrix metalloproteinase-7 protects against acute kidney injury by priming renal tubules for survival and regeneration

Zhou

Zhu

et al. 2019

Kidney International

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Matrix metalloproteinase-7 (MMP-7) is a secreted endopeptidase that degrades a broad range of substrates. Recent studies have identified MMP-7 as an early biomarker to predict severe acute kidney injury (AKI) and poor outcomes after cardiac surgery; however, the role of MMP-7 in the pathogenesis of AKI is unknown. In this study, we investigated the expression of MMP-7 and the impact of MMP-7 deficiency in several models of AKI. MMP-7 was induced in renal tubules following ischemia/ reperfusion injury or cisplatin administration, and in folic acid-induced AKI. MMP-7 knockout mice experienced higher mortality, elevated serum creatinine, and more severe histologic lesions after ischemic or toxic insults. Tubular apoptosis and interstitial inflammation were more prominent in MMP-7 knockout kidneys. These histologic changes were accompanied by increased expression of FasL and other components of the extrinsic apoptotic pathway, as well as increased expression of pro-inflammatory chemokines. In a rescue experiment, exogenous MMP-7 ameliorated kidney injury in MMP-7 knockout mice after ischemia/ reperfusion. In vitro, MMP-7 protected tubular epithelial cells against apoptosis by directly degrading FasL. In isolated tubules ex vivo, MMP-7 promoted cell proliferation by degrading E-cadherin and thereby liberating b-catenin, priming renal tubules for regeneration. Taken together, these results suggest that induction of MMP-7 is protective in AKI by degrading FasL and mobilizing b-catenin, thereby priming kidney tubules for survival and regeneration.Matrix metalloproteinase-7 (MMP-7) is an early and valuable biomarker for predicting severe AKI and poor outcomes in patients after cardiac surgery. The present study indicates that induction of endogenous MMP-7 is protective in AKI by priming kidney tubules to survival and regeneration. These results suggest that other urinary biomarkers of the early phase of AKI manifest an initial attempt of the kidney to protect against injury and to promote repair after AKI. Whether infusion of exogenous MMP-7 can protect kidneys against AKI in patients warrants further investigation. www.kidney-international.org b a s i c r e s e a r c h Kidney International (2019) 95, 1167-1180

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“…Serum creatinine measurement is inadequate for the early detection of AKI because it requires 48-72 h for its elevation. Increased urinary x [IGFBP-7] levels at admission in ICU is associated with the development of AKI only in the first hours probably due to the short half-lives of these markers, 30 with a time window of about 3 hours after CA. 31,32 These findings show that x [IGFBP-7] could be an early predictive urinary biomarker of AKI in patients resuscitated after CA with limitations related to the markers short half-lives.…”

Section: Discussionmentioning

confidence: 99%

“…29 Increased urine x [IGFBP-7] levels at admission were significantly associated with the development of AKI (0.65 vs 0.25, p<0.01) but no at day 3 (0.15 vs 0.24, p=0.079) probably due to the short half-lives of these markers. According to Beitland's study, Adler et al 30 observed, in a group of 48 patients, that increased urine x [IGFBP-7] levels, checked 3 hours after CA, can predict AKI. Titeca-Beauport et al, 31 analyzing 115 patients after CA, found that urinary x [IGFBP-7] levels after 240 minutes of CA predict the development of AKI.…”

Section: Cardiac Arrestmentioning

confidence: 99%

<p>Evaluating Nephrocheck<sup>®</sup> as a Predictive Tool for Acute Kidney Injury</p>

Nalesso¹,

Cattarin²,

Gobbi³

et al. 2020

IJNRD

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Acute kidney injury (AKI) is a common complication in critically ill patients in the intensive settings with increased risks of short-and long-term complications and mortality. AKI is also associated with an increased length of stay in intensive care units (ICU) and worse kidney function recovery at hospital discharge. The management of AKI is one of the major challenges for nephrologists and intensivists overall for its early diagnosis. The current KDIGO criteria used to define AKI include the serum creatinine and urinary output that are neither sensitive nor specific markers of kidney function, since they can be altered only after hours from the kidney injury. In order to allow an early AKI detection, in the last years, several studies focused on the identification of new biomarkers. Among all these markers, urinary insulin-like growth factor-binding protein (IGFBP-7) and tissue inhibitor of metalloproteinase (TIMP-2) have been proven as the best-performing and have been proposed as a predictive tool for the AKI detection in the critical settings in order to perform an early diagnosis. Patients undergoing major surgery, cardiac surgery, those with hemodynamic instability or those with sepsis are believed to be the top priority patient populations for the biomarker test. In this view, the urinary [TIMP-2] x [IGFBP-7] becomes an important tool for the early detection of patients at high risk for AKI and its integration with the local ICU experience has to provide a multidisciplinary management of AKI with the institution of a rapid response team in order to assess patients and customize AKI management.

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TIMP-2/IGFBP7 predicts acute kidney injury in out-of-hospital cardiac arrest survivors

Cited by 29 publications

References 26 publications

Extracorporeal Membrane Oxygenation Improving Survival and Alleviating Kidney Injury in a Swine Model of Cardiac Arrest Compared to Conventional Cardiopulmonary Resuscitation

Extracorporeal Membrane Oxygenation Improving Survival and Alleviating Kidney Injury in a Swine Model of Cardiac Arrest Compared to Conventional Cardiopulmonary Resuscitation

Matrix metalloproteinase-7 protects against acute kidney injury by priming renal tubules for survival and regeneration

<p>Evaluating Nephrocheck<sup>®</sup> as a Predictive Tool for Acute Kidney Injury</p>

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