Diagnostic and short-term prognostic utility of plasma pro-enkephalin (pro-ENK) for acute kidney injury in patients admitted with sepsis in the emergency department

J Nephrol. 2015 Dec;28(6):717-24. doi: 10.1007/s40620-014-0163-z. Epub 2014 Dec 9.


Background: Acute kidney injury (AKI) aggravates the prognosis of patients with sepsis. Reliable biomarkers for early detection of AKI in this setting are lacking. Enkephalins influence kidney function, and may have a role in AKI from sepsis. We utilized a novel immunoassay for plasma proenkephalin (pro-ENK), a stable surrogate marker for endogenous enkephalins, in patients hospitalized with sepsis, in order to assess its clinical utility.

Methods: In an observational retrospective study we enrolled 101 consecutive patients admitted to the emergency department (ED) with suspected sepsis. Plasma levels of pro-ENK and neutrophil gelatinase-associated lipocalin (NGAL) were evaluated at ED arrival for their association with presence and severity of AKI and 7-day mortality.

Results: pro-ENK was inversely correlated to creatinine clearance (r = -0.72) and increased with severity of AKI as determined by RIFLE (risk, injury, failure, loss of function, end-stage renal disease) stages (p < 0.0001; pro-ENK median [interquartile range, IQR]) pmol/l: no AKI: 71 [41-97]; risk: 72 [51-120]; injury: 200 [104-259]; failure: 230 [104-670]; loss of function: 947 [273-811]. The majority of septic patients without AKI or at risk had pro-ENK concentrations within the normal range. While NGAL was similarly associated with AKI severity, it was strongly elevated already in septic patients without AKI. pro-ENK added predictive information to NGAL for detecting kidney dysfunction (added χ (2) 10.0, p = 0.0016). Admission pro-ENK outperformed creatinine clearance in predicting 7-day mortality (pro-ENK: χ (2) 13.4, p < 0.001, area under curve, AUC 0.69; creatinine clearance: χ (2) 4, p = 0.045, AUC: 0.61), and serial measurement improved prediction.

Conclusions: Use of pro-ENK in septic patients can detect the presence and severity of AKI. Moreover, pro-ENK is highly predictive of short-term mortality and could enable early identification of patients at risk of death.

Keywords: Acute kidney injury; Enkephalin; Mortality; NGAL; RIFLE; Sepsis.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / blood*
  • Acute Kidney Injury / diagnosis*
  • Acute Kidney Injury / mortality
  • Acute-Phase Proteins
  • Aged
  • Aged, 80 and over
  • Creatinine / blood
  • Creatinine / urine
  • Emergency Service, Hospital
  • Enkephalins / blood*
  • Female
  • Humans
  • Lipocalin-2
  • Lipocalins / blood
  • Male
  • Predictive Value of Tests
  • Prognosis
  • Protein Precursors / blood*
  • Proto-Oncogene Proteins / blood
  • Retrospective Studies
  • Sepsis / blood*
  • Sepsis / mortality
  • Time Factors


  • Acute-Phase Proteins
  • Enkephalins
  • LCN2 protein, human
  • Lipocalin-2
  • Lipocalins
  • Protein Precursors
  • Proto-Oncogene Proteins
  • proenkephalin
  • Creatinine