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

Eric Hoste, Azra Bihorac, Ali Al-Khafaji, Luis M Ortega, Marlies Ostermann, Michael Haase, Kai Zacharowski, Richard Wunderink, Michael Heung, Matthew Lissauer, Wesley H Self, Jay L Koyner, Patrick M Honore, John R Prowle, Michael Joannidis, Lui G Forni, J Patrick Kampf, Paul McPherson, John A Kellum, Lakhmir S Chawla, RUBY Investigators, Eric Hoste, Azra Bihorac, Ali Al-Khafaji, Luis M Ortega, Marlies Ostermann, Michael Haase, Kai Zacharowski, Richard Wunderink, Michael Heung, Kyle Gunnerson, Matthew Lissauer, Daniel Herr, Wesley H Self, Jay L Koyner, Patrick M Honore, John R Prowle, Danielle Davison, Antonio Artigas, Michael Joannidis, Rebecca Schroeder, Sevag Demirjian, Lui G Forni, Luke Hodgson, Scott Wilber, Jennifer A Frey, Ian Reilly, Jing Shi, J Patrick Kampf, Thomas Kwan, Paul McPherson, John A Kellum, Lakhmir S Chawla, Eric Hoste, Azra Bihorac, Ali Al-Khafaji, Luis M Ortega, Marlies Ostermann, Michael Haase, Kai Zacharowski, Richard Wunderink, Michael Heung, Matthew Lissauer, Wesley H Self, Jay L Koyner, Patrick M Honore, John R Prowle, Michael Joannidis, Lui G Forni, J Patrick Kampf, Paul McPherson, John A Kellum, Lakhmir S Chawla, RUBY Investigators, Eric Hoste, Azra Bihorac, Ali Al-Khafaji, Luis M Ortega, Marlies Ostermann, Michael Haase, Kai Zacharowski, Richard Wunderink, Michael Heung, Kyle Gunnerson, Matthew Lissauer, Daniel Herr, Wesley H Self, Jay L Koyner, Patrick M Honore, John R Prowle, Danielle Davison, Antonio Artigas, Michael Joannidis, Rebecca Schroeder, Sevag Demirjian, Lui G Forni, Luke Hodgson, Scott Wilber, Jennifer A Frey, Ian Reilly, Jing Shi, J Patrick Kampf, Thomas Kwan, Paul McPherson, John A Kellum, Lakhmir S Chawla

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.

Keywords: Biomarkers; C-C motif chemokine ligand 14 (CCL14); KIM-1 (kidney injury molecule-1); NGAL (Neutrophil gelatinase-associated lipocalin); Persistent acute kidney injury; Plasma cystatin C.

Conflict of interest statement

Jing Shi, John Kellum, Jay Koyner, and Lakhmir Chawla report receiving consulting fees from Astute Medical. Paul McPherson, Patrick Kampf, and Thomas Kwan are employees of Astute Medical, a bioMérieux subsidiary. Marlies Ostermann reports receiving consulting fees from bioMérieux. Lui Forni reports receiving consulting fees from Ortho Clinical Diagnostics. John Prowle reports receiving research support from bioMérieux. Michael Haase reports receiving lecture fees and travel cost reimbursement from Abbott Diagnostics, Astute Medical, FastBiomedical, and Alere.

Figures

Fig. 1
Fig. 1
Patient flow diagram. After exclusions, 331 patients with urinary CCL14 results were available for analysis. 110 patients met the persistent severe AKI endpoint (at least 72 consecutive hours of stage 3 AKI, initiation of dialysis, or death following stage 3 AKI)
Fig. 2
Fig. 2
Area under the ROC curve (AUC) for prediction of persistent stage 3 AKI by urine CCL14 and other AKI biomarkers, including both injury and functional biomarkers. Biomarker concentrations were measured in urine and plasma samples collected at enrollment. The AUC for urine CCL14 was significantly (p < 0.05) greater than for all other biomarkers shown
Fig. 3
Fig. 3
Biomarker concentrations for different non-AKI acute and chronic conditions and by severity of persistent AKI for a urine CCL14, b urine CHI3L1, c plasma cystatin C, d plasma proenkephalin, e urine NGAL, and f urine L-FABP. Open boxes are for different acute and chronic conditions among patients who did not persist at any stage of AKI. Shaded boxes are for patients by persistent AKI stage. Box and whiskers show interquartile ranges and total observed ranges (censored by 1.5 times the box range), respectively
Fig. 4
Fig. 4
Composite of RRT initiation or death for patients stratified by urine CCL14 tertile. Development of the composite endpoint increased across tertiles, log-rank p < 0.001
Fig. 5
Fig. 5
Proposed CCL14 mechanism. a TNFα and other inflammatory mediators are released from injured epithelium and bind to TNF receptors, leading to release of CCL14 from tubular epithelial cells. b Binding of CCL14 to CCR1 and CCR5 receptors on monocytes and T cells induces chemotaxis towards site of injury. c Monocytes differentiate into macrophages and naïve T cells differentiate into proinflammatory Th1 cells

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