Cross-species validation of cell cycle arrest markers for acute kidney injury in the rat during sepsis

Zhi-Yong Peng; Feihu Zhou; John A Kellum

doi:10.1186/s40635-016-0086-1

Cross-species validation of cell cycle arrest markers for acute kidney injury in the rat during sepsis

Intensive Care Med Exp. 2016 Dec;4(1):12. doi: 10.1186/s40635-016-0086-1. Epub 2016 May 31.

Authors

Zhi-Yong Peng^{1

2}, Feihu Zhou³, John A Kellum⁴

Affiliations

¹ Department of Critical Care Medicine, The Center for Critical Care Nephrology, CRISMA (Clinical Research, Investigation, and Systems Modeling of Acute Illness) Center, University of Pittsburgh School of Medicine, 604 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA, 15261, USA.
² Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University School of medicine, Wuhan, 630071, China.
³ Department of Critical Care Medicine, Chinese People's Liberation Army General Hospital, Beijing, China.
⁴ Department of Critical Care Medicine, The Center for Critical Care Nephrology, CRISMA (Clinical Research, Investigation, and Systems Modeling of Acute Illness) Center, University of Pittsburgh School of Medicine, 604 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA, 15261, USA. kellumja@ccm.upmc.edu.

Abstract

Background: The recent discovery of cell cycle arrest biomarkers, tissue inhibitor of metalloproteinases (TIMP)-2 and insulin-like growth factor binding protein 7 (IGFBP7), has led to a newly available clinical test for acute kidney injury. The performance of these markers in preclinical studies has not been established. Therefore, we sought to evaluate the performance of TIMP-2 and IGFBP7 in rats undergoing cecal ligation and puncture.

Methods: In this secondary analysis, we analyzed banked urine samples from 60 Sprague-Dawley rats undergoing cecal ligation and puncture (CLP). Samples were obtained from baseline, 18 h after CLP, at the end of fluid resuscitation (22 h after CLP), and again 24 h later. We measured TIMP-2 and IGFBP7 and compared the results to acute kidney injury by RIFLE criteria for creatinine using area under the receiver operating characteristic curve (AUC). The primary endpoint was moderate-to-severe acute kidney injury (AKI) (I or F criteria), and the primary time point was immediately after fluid resuscitation. Secondary outcomes included mortality and comparisons with other biomarkers: cystatin C and neutrophil gelatinase-associated lipocalin (NGAL) in both urine and plasma.

Results: After fluid resuscitation, urine [TIMP-2] and [IGFBP7] were significantly higher in animals developing moderate-to-severe AKI (p = 0.002 and p = 0.01). AUC of [TIMP-2]·[IGFBP7] for AKI was 0.89 (95 % CI 0.80-0.98). By contrast, the next best AUC was seen with plasma cystatin C (0.78; 95 % CI 0.65-0.90). [TIMP-2]·[IGFBP7] also predicted mortality (AUC 0.69; 95 % CI 0.53-0.85).

Conclusions: In this experimental model of sepsis in the rat, cell cycle arrest biomarkers TIMP-2 and IGFBP7 are valid predictors of acute kidney injury.

Keywords: Acute kidney injury; Biomarkers; Cell cycle arrest; Insulin-like growth factor binding protein 7 (IGFBP7); Sepsis; Tissue inhibitor of metalloproteinases (TIMP)-2.