Mechanisms Underlying Increased TIMP2 and IGFBP7 Urinary Excretion in Experimental AKI

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<div class="section"> <a class="named-anchor" id="d6589129e140">  </a> <h5 class="section-title" id="d6589129e141">Background</h5> <p id="d6589129e143">Recent clinical data support the utility/superiority of a new AKI biomarker (“NephroCheck”), the arithmetic product of urinary TIMP × IGFBP7 concentrations. However, the pathophysiologic basis for its utility remains ill defined. </p> </div><div class="section"> <a class="named-anchor" id="d6589129e145">  </a> <h5 class="section-title" id="d6589129e146">Methods</h5> <p id="d6589129e148">To clarify this issue, CD-1 mice were subjected to either nephrotoxic (glycerol, maleate) or ischemic AKI. Urinary TIMP2/IGFBP7 concentrations were determined at 4 and 18 hours postinjury and compared with urinary albumin levels. Gene transcription was assessed by measuring renal cortical and/or medullary TIMP2/IGFBP7 mRNAs (4 and 18 hours after AKI induction). For comparison, the mRNAs of three renal “stress” biomarkers (NGAL, heme oxygenase 1, and p21) were assessed. Renal cortical TIMP2/IGFBP7 protein was gauged by ELISA. Proximal tubule–specific TIMP2/IGFBP7 was assessed by immunohistochemistry. </p> </div><div class="section"> <a class="named-anchor" id="d6589129e150">  </a> <h5 class="section-title" id="d6589129e151">Results</h5> <p id="d6589129e153">Each AKI model induced prompt (4 hours) and marked urinary TIMP2/IGFBP7 increases without an increase in renal cortical concentrations. Furthermore, TIMP2/IGFBP7 mRNAs remained at normal levels. Endotoxemia also failed to increase TIMP2/IGFBP7 mRNAs. In contrast, each AKI model provoked massive NGAL, HO-1, and p21 mRNA increases, confirming that a renal “stress response” had occurred. Urinary albumin rose up to 100-fold and strongly correlated ( <i>r</i>=0.87–0.91) with urinary TIMP2/IGFBP7 concentrations. Immunohistochemistry showed progressive TIMP2/IGFBP7 losses from injured proximal tubule cells. Competitive inhibition of endocytic protein reabsorption in normal mice tripled urinary TIMP2/IGFBP7 levels, confirming this pathway’s role in determining urinary excretion. </p> </div><div class="section"> <a class="named-anchor" id="d6589129e158">  </a> <h5 class="section-title" id="d6589129e159">Conclusions</h5> <p id="d6589129e161">AKI-induced urinary TIMP2/IGFBP7 elevations are not due to stress-induced gene transcription. Rather, increased filtration, decreased tubule reabsorption, and proximal tubule cell TIMP2/IGFBP7 urinary leakage seem to be the most likely mechanisms. </p> </div><p class="first" id="d6589129e164"> <div class="fig panel" id="absf1"> <a class="named-anchor" id="absf1">  </a> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/45bdc48f-2a65-41f7-a5f2-3eac965a1a4a/PubMedCentral/image/ASN.2018030265absf1"/> </div> <div class="panel-content"/> </div> </p>

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Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury

Kianoush B Kashani, Ali Al-Khafaji, Thomas Ardiles … (2013)

Introduction Acute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI. Methods We performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection. Results Moderate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2]·[IGFBP7] was significantly superior to all previously described markers of AKI (P 0.72. Furthermore, [TIMP-2]·[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2]·[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method. Conclusions Two novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI. Trial registration ClinicalTrials.gov number NCT01209169.

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Validation of cell-cycle arrest biomarkers for acute kidney injury using clinical adjudication.

Frederick J Zimmerman, James Miner, Ian Graham … (2014)

We recently reported two novel biomarkers for acute kidney injury (AKI), tissue inhibitor of metalloproteinases (TIMP)-2 and insulin-like growth factor binding protein 7 (IGFBP7), both related to G1 cell cycle arrest. We now validate a clinical test for urinary [TIMP-2]·[IGFBP7] at a high-sensitivity cutoff greater than 0.3 for AKI risk stratification in a diverse population of critically ill patients. We conducted a prospective multicenter study of 420 critically ill patients. The primary analysis was the ability of urinary [TIMP-2]·[IGFBP7] to predict moderate to severe AKI within 12 hours. AKI was adjudicated by a committee of three independent expert nephrologists who were masked to the results of the test. Urinary TIMP-2 and IGFBP7 were measured using a clinical immunoassay platform. The primary endpoint was reached in 17% of patients. For a single urinary [TIMP-2]·[IGFBP7] test, sensitivity at the prespecified high-sensitivity cutoff of 0.3 (ng/ml)(2)/1,000 was 92% (95% confidence interval [CI], 85-98%) with a negative likelihood ratio of 0.18 (95% CI, 0.06-0.33). Critically ill patients with urinary [TIMP-2]·[IGFBP7] greater than 0.3 had seven times the risk for AKI (95% CI, 4-22) compared with critically ill patients with a test result below 0.3. In a multivariate model including clinical information, urinary [TIMP-2]·[IGFBP7] remained statistically significant and a strong predictor of AKI (area under the curve, 0.70, 95% CI, 0.63-0.76 for clinical variables alone, vs. area under the curve, 0.86, 95% CI, 0.80-0.90 for clinical variables plus [TIMP-2]·[IGFBP7]). Urinary [TIMP-2]·[IGFBP7] greater than 0.3 (ng/ml)(2)/1,000 identifies patients at risk for imminent AKI. Clinical trial registered with www.clinicaltrials.gov (NCT 01573962).

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Urinary TIMP-2 and IGFBP7 as Early Biomarkers of Acute Kidney Injury and Renal Recovery following Cardiac Surgery

Melanie Meersch, Christoph Schmidt, Hugo Van Aken … (2014)

Background Difficulties in prediction and early identification of (acute kidney injury) AKI have hindered the ability to develop preventive and therapeutic measures for this syndrome. We tested the hypothesis that a urine test measuring insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in acute kidney injury (AKI), could predict AKI in cardiac surgery patients. Methods We studied 50 patients at high risk for AKI undergoing cardiac surgery with cardiopulmonary bypass (CPB). Serial urine samples were analyzed for [TIMP-2]*[IGFBP7] concentrations. The primary outcome measure was AKI as defined by international consensus criteria following surgery. Furthermore, we investigated whether urine [TIMP-2]*[IGFBP7] could predict renal recovery from AKI prior to hospital discharge. Results 26 patients (52%) developed AKI. Diagnosis based on serum creatinine and/or oliguria did not occur until 1–3 days after CPB. In contrast, urine concentration of [TIMP-2]*[IGFBP7] rose from a mean of 0.49 (SE 0.24) at baseline to 1.51 (SE 0.57) 4 h after CPB in patients who developed AKI. The maximum urinary [TIMP-2]*[IGFBP7] concentration achieved in the first 24 hours following surgery (composite time point) demonstrated an area under the receiver-operating characteristic curve of 0.84. Sensitivity was 0.92, and specificity was 0.81 for a cutoff value of 0.50. The decline in urinary [TIMP-2]*[IGFBP7] values was the strongest predictor for renal recovery. Conclusions Urinary [TIMP-2]*[IGFBP7] serves as a sensitive and specific biomarker to predict AKI early after cardiac surgery and to predict renal recovery. Clinical Trial Registration Information: www.germanctr.de/, DRKS-ID: DRKS00005062

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Journal

Title: Journal of the American Society of Nephrology

Abbreviated Title: JASN

Publisher: American Society of Nephrology (ASN)

ISSN (Print): 1046-6673

ISSN (Electronic): 1533-3450

Publication date Created: July 31 2018

Publication date Created: August 2018

Publication date (Print): August 2018

Publication date (Electronic): July 06 2018

Volume: 29

Issue: 8

Pages: 2157-2167

Article

DOI: 10.1681/ASN.2018030265

PMC ID: 6065093

PubMed ID: 29980651

SO-VID: 854a2347-9cf2-48c8-9516-43af6446f47d

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Mechanisms Underlying Increased TIMP2 and IGFBP7 Urinary Excretion in Experimental AKI

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Most cited references 49

Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury

Validation of cell-cycle arrest biomarkers for acute kidney injury using clinical adjudication.

Urinary TIMP-2 and IGFBP7 as Early Biomarkers of Acute Kidney Injury and Renal Recovery following Cardiac Surgery

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