Levels of protein C and soluble thrombomodulin in critically ill patients with acute kidney injury: a multicenter prospective observational study.

Josée Bouchard,Ashita J Tolwani,Shamik Shah,Rakesh Malhotra,David T Berg,Akanksha Gupta,Brenda Stofan,Ravindra L Mehta,Yu-Ting Kao,Florin Vaida,Brian W Grinnell

doi:10.1371/journal.pone.0120770

Josée Bouchard, Ashita J Tolwani + Show 9 more

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https://doi.org/10.1371/journal.pone.0120770

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Abstract

Endothelial dysfunction contributes to the development of acute kidney injury (AKI) in animal models of ischemia reperfusion injury and sepsis. There are limited data on markers of endothelial dysfunction in human AKI. We hypothesized that Protein C (PC) and soluble thrombomodulin (sTM) levels could predict AKI. We conducted a multicenter prospective study in 80 patients to assess the relationship of PC and sTM levels to AKI, defined by the AKIN creatinine (AKI Scr) and urine output criteria (AKI UO). We measured marker levels for up to 10 days from intensive care unit admission. We used area under the curve (AUC) and time-dependent multivariable Cox proportional hazard model to predict AKI and logistic regression to predict mortality/non-renal recovery. Protein C and sTM were not different in patients with AKI UO only versus no AKI. On intensive care unit admission, as PC levels are usually lower with AKI Scr, the AUC to predict the absence of AKI was 0.63 (95%CI 0.44-0.78). The AUC using log10 sTM levels to predict AKI was 0.77 (95%CI 0.62-0.89), which predicted AKI Scr better than serum and urine neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C, urine kidney injury molecule-1 and liver-fatty acid-binding protein. In multivariable models, PC and urine NGAL levels independently predicted AKI (p=0.04 and 0.02) and PC levels independently predicted mortality/non-renal recovery (p=0.04). In our study, PC and sTM levels can predict AKI Scr but are not modified during AKI UO alone. PC levels could independently predict mortality/non-renal recovery. Additional larger studies are needed to define the relationship between markers of endothelial dysfunction and AKI.

Highlights

In critically ill patients, acute kidney injury (AKI) portends a high mortality rate [1] and is usually detected based on serum creatinine (Scr) levels several hours after injury has occurred
We found that soluble thrombomodulin (sTM) levels were significantly higher before AKI and declined thereafter to levels comparable to those without AKI
Protein C (PC) levels remained below normal range until 24 hours before AKI and increased substantially after AKI diagnosis

Summary

Introduction

Acute kidney injury (AKI) portends a high mortality rate [1] and is usually detected based on serum creatinine (Scr) levels several hours after injury has occurred. More recently changes in urine output (UO) have been recognized as early markers of renal functional changes [2]. Both Scr and UO are not specific with respect to the etiology and underlying pathophysiology of AKI. Most observational studies have focused on well-established markers of AKI few have evaluated the contribution of more systemic markers of organ dysfunction [9,10]. Endothelial dysfunction is an early event which has been implicated in the pathophysiology of several conditions including sepsis, ischemia-reperfusion injury and acute lung injury [11]. Experimental studies have shown that AKI represents a systemic disorder where endothelial dysfunction is an early event [14]

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