Identification and validation of biomarkers of persistent acute kidney injury: the RUBY study

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Abstract

Purpose

The aim of the RUBY study was to evaluate novel candidate biomarkers to enable prediction of persistence of renal dysfunction as well as further understand potential mechanisms of kidney tissue damage and repair in acute kidney injury (AKI).

Methods

The RUBY study was a multi-center international prospective observational study to identify biomarkers of the persistence of stage 3 AKI as defined by the KDIGO criteria. Patients in the intensive care unit (ICU) with moderate or severe AKI (KDIGO stage 2 or 3) were enrolled. Patients were to be enrolled within 36 h of meeting KDIGO stage 2 criteria. The primary study endpoint was the development of persistent severe AKI (KDIGO stage 3) lasting for 72 h or more (NCT01868724).

Results

364 patients were enrolled of whom 331 (91%) were available for the primary analysis. One hundred ten (33%) of the analysis cohort met the primary endpoint of persistent stage 3 AKI. Of the biomarkers tested in this study, urinary C–C motif chemokine ligand 14 (CCL14) was the most predictive of persistent stage 3 AKI with an area under the receiver operating characteristic curve (AUC) (95% CI) of 0.83 (0.78–0.87). This AUC was significantly greater than values for other biomarkers associated with AKI including urinary KIM-1, plasma cystatin C, and urinary NGAL, none of which achieved an AUC > 0.75.

Conclusion

Elevated urinary CCL14 predicts persistent AKI in a large heterogeneous cohort of critically ill patients with severe AKI. The discovery of CCL14 as a predictor of persistent AKI and thus, renal non-recovery, is novel and could help identify new therapeutic approaches to AKI.

Electronic supplementary material

The online version of this article (10.1007/s00134-019-05919-0) contains supplementary material, which is available to authorized users.

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Most cited references 18

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KDIGO Clinical Practice Guidelines for Acute Kidney Injury

Arif Khwaja, A. Khwaja (2012)

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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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Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD.

David A Ferenbach, Joseph V. Bonventre (2015)

Acute kidney injury is an increasingly common complication of hospital admission and is associated with high levels of morbidity and mortality. A hypotensive, septic, or toxic insult can initiate a cascade of events, resulting in impaired microcirculation, activation of inflammatory pathways and tubular cell injury or death. These processes ultimately result in acutely impaired kidney function and initiation of a repair response. This Review explores the various mechanisms responsible for the initiation and propagation of acute kidney injury, the prototypic mechanisms by which a substantially damaged kidney can regenerate its normal architecture, and how the adaptive processes of repair can become maladaptive. These mechanisms, which include G2/M cell-cycle arrest, cell senescence, profibrogenic cytokine production, and activation of pericytes and interstitial myofibroblasts, contribute to the development of progressive fibrotic kidney disease. The end result is a state that mimics accelerated kidney ageing. These mechanisms present important opportunities for the design of targeted therapeutic strategies to promote adaptive renal recovery and minimize progressive fibrosis and chronic kidney disease after acute insults.

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Author and article information

Contributors

Lakhmir S. Chawla:

ORCID: http://orcid.org/0000-0001-5987-8318

minkchawla@gmail.com

Journal

Journal ID (nlm-ta): Intensive Care Med

Journal ID (iso-abbrev): Intensive Care Med

Title: Intensive Care Medicine

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0342-4642

ISSN (Electronic): 1432-1238

Publication date (Electronic): 6 February 2020

Publication date PMC-release: 6 February 2020

Publication date (Print): 2020

Volume: 46

Issue: 5

Pages: 943-953

Affiliations

[1 ]GRID grid.5342.0, ISNI 0000 0001 2069 7798, Ghent University Hospital, , Ghent University, ; Ghent, Belgium

[2 ]GRID grid.15276.37, ISNI 0000 0004 1936 8091, Department of Medicine, , University of Florida, ; Gainesville, FL USA

[3 ]GRID grid.21925.3d, ISNI 0000 0004 1936 9000, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, ; Pittsburgh, PA USA

[4 ]GRID grid.413621.3, ISNI 0000 0004 0455 1168, Allegheny General Hospital, ; Pittsburgh, PA USA

[5 ]GRID grid.13097.3c, ISNI 0000 0001 2322 6764, King’s College London, Guy’s & St Thomas’ Hospital, ; London, UK

[6 ]MVZ Diaverum Am Neuen Garten, Potsdam, Germany

[7 ]GRID grid.5807.a, ISNI 0000 0001 1018 4307, Medizinische Fakultät, Otto-Von-Guericke Universität Magdeburg, ; Magdeburg, Germany

[8 ]GRID grid.411088.4, ISNI 0000 0004 0578 8220, University Hospital Frankfurt, Goethe University, ; Frankfurt, Germany

[9 ]GRID grid.16753.36, ISNI 0000 0001 2299 3507, Department of Medicine, Pulmonary and Critical Care Division, , Northwestern University Feinberg School of Medicine, ; Chicago, IL USA

[10 ]GRID grid.214458.e, ISNI 0000000086837370, Division of Nephrology, Department of Medicine, , University of Michigan, ; Ann Arbor, MI USA

[11 ]GRID grid.430387.b, ISNI 0000 0004 1936 8796, Rutgers-Robert Wood Johnson Medical School, ; New Brunswick, NJ 08901 USA

[12 ]GRID grid.412807.8, ISNI 0000 0004 1936 9916, Department of Emergency Medicine, , Vanderbilt University Medical Center, ; Nashville, TN USA

[13 ]GRID grid.170205.1, ISNI 0000 0004 1936 7822, Section of Nephrology, Department of Medicine, , University of Chicago, ; Chicago, IL USA

[14 ]GRID grid.411326.3, ISNI 0000 0004 0626 3362, University Hospital Brussels, ; Brussels, Belgium

[15 ]GRID grid.416041.6, ISNI 0000 0001 0738 5466, Royal London Hospital, Barts Health NHS Trust, ; London, UK

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

[17 ]GRID grid.5475.3, ISNI 0000 0004 0407 4824, Department of Clinical & Experimental Medicine, Faculty of Health Sciences, University of Surrey, ; Guildford, UK

[18 ]GRID grid.478287.6, Astute Medical, Inc, ; San Diego, CA USA

[19 ]GRID grid.21925.3d, ISNI 0000 0004 1936 9000, Department of Critical Care Medicine, Center for Critical Care Nephrology, , University of Pittsburgh, ; Pittsburgh, PA USA

[20 ]GRID grid.416792.f, Department of Medicine, , Veterans Affairs Medical Center, ; 3350 La Jolla Village Dr, San Diego, CA 92161 USA

Author information

Lakhmir S. Chawla http://orcid.org/0000-0001-5987-8318

Article

Publisher ID: 5919

DOI: 10.1007/s00134-019-05919-0

PMC ID: 7210248

PubMed ID: 32025755

SO-VID: 1144f090-01f1-442e-8d76-9fed586afba3

License:

Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

History

Date received : 29 August 2019

Date accepted : 26 December 2019

Custom metadata

ScienceOpen disciplines: Emergency medicine & Trauma

Keywords: persistent acute kidney injury,biomarkers,c-c motif chemokine ligand 14 (ccl14),ngal (neutrophil gelatinase-associated lipocalin),plasma cystatin c,kim-1 (kidney injury molecule-1)

Data availability:

ScienceOpen disciplines: Emergency medicine & Trauma

Keywords: persistent acute kidney injury, biomarkers, c-c motif chemokine ligand 14 (ccl14), ngal (neutrophil gelatinase-associated lipocalin), plasma cystatin c, kim-1 (kidney injury molecule-1)

Identification and validation of biomarkers of persistent acute kidney injury: the RUBY study

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Abstract

Purpose

Methods

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Conclusion

Electronic supplementary material

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Journal of Circulating Biomarkers

Most cited references 18

KDIGO Clinical Practice Guidelines for Acute Kidney Injury

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

Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD.

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