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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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.

Electronic supplementary material

The online version of this article (10.1186/s13054-019-2504-8) contains supplementary material, which is available to authorized users.

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Most cited references 21

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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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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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Biomarker-guided Intervention to Prevent Acute Kidney Injury After Major Surgery

Ivan Gocze, Dominik Jauch, Markus Götz … (2018)

To determine the impact of renal biomarker-guided implementation of the Kidney Disease Improving Global Outcomes (KDIGO) care bundle on the incidence of acute kidney injury (AKI) after major noncardiac surgery in a single-center unblinded randomized clinical trial.

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Author and article information

Contributors

Louis M. Guzzi: bigtuna4@aol.com

Tobias Bergler: tobias.bergler@ukr.de

Brian Binnall: brian.binnall@baystatehealth.org

Daniel T. Engelman: daniel.engelman@baystatehealth.org

Lui Forni: luiforni@nhs.net

Michael J. Germain: michael.germain@baystatehealth.org

Eric Gluck: egluck@aol.com

Ivan Göcze: ivan.goecze@ukr.de

Michael Joannidis: michael.joannidis@i-med.ac.at

Jay L. Koyner: jkoyner@medicine.bsd.uchicago.edu

V. Seenu Reddy: vsreddymd@gmail.com

Thomas Rimmelé: thomas.rimmele@chu-lyon.fr

Claudio Ronco: cronco@goldnet.it

Julien Textoris: julien.textoris@chu-lyon.fr

Alexander Zarbock: zarbock@uni-muenster.de

John A. Kellum:

ORCID: http://orcid.org/0000-0003-1995-2653

412-383-4293 , kellumja@upmc.edu

Journal

Journal ID (nlm-ta): Crit Care

Title: Critical Care

Publisher: BioMed Central (London )

ISSN (Print): 1364-8535

ISSN (Electronic): 1466-609X

Publication date (Electronic): 20 June 2019

Publication date PMC-release: 20 June 2019

Publication date Collection: 2019

Volume: 23

Electronic Location Identifier: 225

Affiliations

[1 ]ISNI 0000 0004 0447 7121, GRID grid.414935.e, Florida Hospital, ; 601 E. Rollins Street, Orlando, FL 32803 USA

[2 ]ISNI 0000 0000 9194 7179, GRID grid.411941.8, University Hospital Regensburg, ; Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany

[3 ]ISNI 0000 0004 0433 813X, GRID grid.281162.e, Baystate Medical Center, ; 759 Chestnut Street, Springfield, MA 01107 USA

[4 ]ISNI 0000 0001 0372 6120, GRID grid.412946.c, The Royal Surrey County Hospital NHS Foundation Trust, ; Egerton Rd, Guildford, Surrey GU2 7XX UK

[5 ]ISNI 0000 0004 0407 4824, GRID grid.5475.3, University of Surrey, ; 388 Stag Hill, Guildford, Surrey GU2 7XH UK

[6 ]ISNI 0000 0004 0383 0448, GRID grid.416777.4, Swedish Covenant Hospital, ; 5145 N California Ave, Chicago, IL 60625 USA

[7 ]ISNI 0000 0000 8853 2677, GRID grid.5361.1, Division of Intensive Care and Emergency Medicine, Department of Internal Medicine, , Medical University of Innsbruck, ; Anichstraße 35, 6020 Innsbruck, Austria

[8 ]ISNI 0000 0004 1936 7822, GRID grid.170205.1, Section of Nephrology, Department of Medicine, , University of Chicago, ; 5841 South Maryland Ave, Suite S-507, MC5100, Chicago, IL 60637 USA

[9 ]ISNI 0000 0004 0446 7206, GRID grid.413696.f, Tristar Centennial Medical Center, ; 2400 Patterson St #307, Nashville, TN 37203 USA

[10 ]ISNI 0000 0001 2198 4166, GRID grid.412180.e, Hospices Civils de Lyon, Edouard Herriot Hospital, ; 5 Place d’Arsonval, 69003 Lyon, France

[11 ]ISNI 0000 0004 1758 2035, GRID grid.416303.3, Department of Nephrology University of Padua, Padua Italy; San Bortolo Hospital, Vicenza, Italy; International Renal Research Institute Vicenza, ; Vicenza, Italy

[12 ]ISNI 0000 0004 0387 6489, GRID grid.424167.2, bioMérieux, ; 5 Place d’Arsonval, 69003 Lyon, France

[13 ]ISNI 0000 0004 0551 4246, GRID grid.16149.3b, University Hospital Münster, ; Albert-Schweitzer Campus 1, Building A1, 48149 Münster, Germany

[14 ]ISNI 0000 0004 1936 9000, GRID grid.21925.3d, The Center for Critical Care Nephrology, Department of Critical Care Medicine, , University of Pittsburgh, ; 3347 Forbes Avenue, Suite 220, Pittsburgh, PA 15213 USA

[15 ]Critical Care Medicine, Clinical & Translational Science, and Bioengineering, Center for Critical Care Nephrology, 3347 Forbes Avenue, Suite 220, Pittsburgh, PA 15213 USA

Author information

John A. Kellum http://orcid.org/0000-0003-1995-2653

Article

Publisher ID: 2504

DOI: 10.1186/s13054-019-2504-8

PMC ID: 6585126

PubMed ID: 31221200

SO-VID: 6feb10ac-88af-4178-843a-2d411f47a53a

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 8 January 2019

Date accepted : 4 June 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100009777, Astute Medical;

Award ID: na

Award Recipient : Tobias Bergler Michael Joannidis Jay L. Koyner Alexander Zarbock

Funded by: bioMérieux

Award ID: na

Custom metadata

ScienceOpen disciplines: Emergency medicine & Trauma

Keywords: biomarker testing,acute kidney injury,critical care,expert panel,protocols,clinical guidelines,tissue inhibitor of metalloproteinases-2,insulin-like growth factor binding protein 7,biomarker technology,diagnosis

Data availability:

ScienceOpen disciplines: Emergency medicine & Trauma

Keywords: biomarker testing, acute kidney injury, critical care, expert panel, protocols, clinical guidelines, tissue inhibitor of metalloproteinases-2, insulin-like growth factor binding protein 7, biomarker technology, diagnosis

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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Most cited references 21

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

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

Biomarker-guided Intervention to Prevent Acute Kidney Injury After Major Surgery

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