Proenkephalin, Neutrophil Gelatinase-Associated Lipocalin, and Estimated Glomerular Filtration Rates in Patients With Sepsis

Abstract

Background: Proenkephalin (PENK) has been suggested as a novel biomarker for kidney function. We investigated the diagnostic and prognostic utility of plasma PENK in comparison with neutrophil gelatinase-associated lipocalin (NGAL) and estimated glomerular filtration rates (eGFR) in septic patients.

Methods: A total of 167 septic patients were enrolled: 99 with sepsis, 37 with septic shock, and 31 with suspected sepsis. PENK and NGAL concentrations were measured and GFR was estimated by using the isotope dilution mass spectrometry traceable-Modification of Diet in Renal Disease (MDRD) Study and three Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations: CKD-EPI(Cr), CDK-EPI(CysC), and CKD-EPI(Cr-CysC). The PENK, NGAL, and eGFR results were compared according to sepsis severity, presence or absence of acute kidney injury (AKI), and clinical outcomes.

Results: The PENK, NGAL, and eGFR results were significantly associated with sepsis severity and differed significantly between patients with and without AKI only in the sepsis group (all P<0.05). PENK was superior to NGAL in predicting AKI (P=0.022) and renal replacement therapy (RRT) (P=0.0085). Regardless of the variable GFR category by the different eGFR equations, PENK showed constant and significant associations with all eGFR equations. Unlike NGAL, PENK was not influenced by inflammation and predicted the 30-day mortality.

Conclusions: PENK is a highly sensitive and objective biomarker of AKI and RRT and is useful for prognosis prediction in septic patients. With its diagnostic robustness and predictive power for survival, PENK constitutes a promising biomarker in critical care settings including sepsis.

Keywords: Acute kidney injury; Glomerular filtration rate; Neutrophil gelatinase-associated lipocalin; Proenkephalin; Sepsis.

Fig. 1. Comparison of the receiver operating characteristics curves for the diagnosis of AKI in septic patients. PENK and the four eGFR equations showed fair discriminatory ability, but NGAL showed poor discriminatory ability. However, PENK, NGAL, and the four eGFR equations were all comparable and showed no statistical difference.

Abbreviations: see Table 1.

Fig. 2. Distribution and agreement of glomerular filtration rate (GFR) categories by each eGFR equation. The distribution of GFR categories varied across each eGFR equation. The proportion of reduced GFR (<60 mL/min/1.73 m²) was the highest based on the CKD-EPI_CysC equation and the lowest based on the CKD-EPI_Cr equation (58.7% vs 44.9%, P<0.0001, Chi-square test). All eGFR equations showed minimal to weak agreement with each other (Kappa value, 0.310–0.541). Abbreviations: see Table 1.

Fig. 3. Comparison of PENK and NGAL concentrations according to GFR category. The distribution of PENK and NGAL concentrations differed significantly according to eGFR by each eGFR equation (all P<0.000001, Kruskal-Wallis test). (A) The median PENK concentration was below the 154.5 pmol/L cut-off obtained by the ROC curve analysis and was also lower than or similar to the 99th percentile of the normal range (80 pmol/L) in the normal GFR categories (≥60 mL/min/1.73 m²). (B) The median concentration of NGAL was below the 493 ng/mL cut-off that was obtained by the ROC curve analysis; however, it was higher than the literature- and manufacturer-recommended 150 ng/mL cut-off in the normal GFR categories. Data are expressed as median (interquartile range). Abbreviations: see Table 1.