Heparin-binding protein (HBP) improves prediction of sepsis-related acute kidney injury

Abstract

Background: Sepsis-related acute kidney injury (AKI) accounts for major morbidity and mortality among the critically ill. Heparin-binding protein (HBP) is a promising biomarker in predicting development and prognosis of severe sepsis and septic shock that has recently been proposed to be involved in the pathophysiology of AKI. The objective of this study was to investigate the added predictive value of measuring plasma HBP on admission to the intensive care unit (ICU) regarding the development of septic AKI.

Methods: We included 601 patients with severe sepsis or septic shock from the prospective, observational FINNAKI study conducted in seventeen Finnish ICUs during a 5-month period (1 September 2011-1 February 2012). The main outcome measure was the development of KDIGO AKI stages 2-3 from 12 h after admission up to 5 days. Statistical analysis for the primary endpoint included construction of a clinical risk model, area under the receiver operating curve (ROC area), category-free net reclassification index (cfNRI) and integrated discrimination improvement (IDI) with 95% confidence intervals (95% CI).

Results: Out of 511 eligible patients, 101 (20%) reached the primary endpoint. The addition of plasma HBP to a clinical risk model significantly increased ROC area (0.82 vs. 0.78, p = 0.03) and risk classification scores: cfNRI 62.0% (95% CI 40.5-82.4%) and IDI 0.053 (95% CI 0.029-0.075).

Conclusions: Plasma HBP adds predictive value to known clinical risk factors in septic AKI. Further studies are warranted to compare the predictive performance of plasma HBP to other novel AKI biomarkers.

Keywords: Acute kidney injury; Biomarker; Heparin-binding protein; Risk model; Sepsis.

Fig. 1

Flow chart of participants. HBP was tested on 601 patients, who were all included in the secondary endpoint analyses. Ninety patients were excluded from the primary endpoint analysis because they developed AKI stages 2–3 within 12 h, resulting in 511 patients eligible for the primary endpoint analysis

Fig. 2

Fluid balance and 28-day survival. The left boxplot describes patients’ fluid balance within 24 h from ICU admission separated by plasma HBP quartiles and includes testing for significant difference between plasma HBP levels of each individual group (n = 601, ns: not significant). The right Kaplan–Meier survival curve pictures survival within 28 days from ICU admission among patients with a high versus low plasma HBP on ICU admission (n = 601)

Fig. 3

Proposed mechanism for HBP’s involvement in sepsis-related AKI pathophysiology. 1 Neutrophils activated by bacterial antigen release pre-produced HBP from secretory vesicles into peripheral tissue and blood vessels. HBP is filtered through the glomeruli, and the Bowman’s capsule into the tubular lumen 2 HBP induces inflammation in tubular epithelial cells, supported by evidence of IL-6 production [7]. 3 HBP act on peritubular vascular cells inducing capillary leakage through loosened tight junctions, supported by evidence of interstitial haemorrhage and protein aggregates in extracellular matrix [7]