Proenkephalin, Renal Dysfunction, and Prognosis in Patients With Acute Heart Failure: A GREAT Network Study

J Am Coll Cardiol. 2017 Jan 3;69(1):56-69. doi: 10.1016/j.jacc.2016.10.038.


Background: Proenkephalin A (PENK) and its receptors are widely distributed. Enkephalins are cardiodepressive and difficult to measure directly. PENK is a stable surrogate analyte of labile enkephalins that is correlated inversely with renal function. Cardiorenal syndrome is common in acute heart failure (HF) and portends poor prognosis.

Objectives: This study assessed the prognostic value of PENK in acute HF, by identifying levels that may be useful in clinical decisions, and evaluated its utility for predicting cardiorenal syndrome.

Methods: This multicenter study measured PENK in 1,908 patients with acute HF (1,186 male; mean age 75.66 ± 11.74 years). The primary endpoint was 1-year all-cause mortality; secondary endpoints were in-hospital mortality, all-cause mortality or HF rehospitalization within 1 year, and in-hospital worsening renal function, defined as a rise in plasma creatinine ≥26.5 μmol/l or 50% higher than the admission value within 5 days of presentation.

Results: During 1-year follow-up, 518 patients died. Measures of renal function were the major determinants of PENK levels. PENK independently predicted worsening renal function (odds ratio: 1.58; 95% confidence interval [CI]: 1.24 to 2.00; p < 0.0005) with a model receiver-operating characteristic area of 0.69. PENK was associated with the degree of worsening renal function. Multivariable Cox regression models showed that PENK level was an independent predictor of 1-year mortality (p < 0.0005) and 1-year death and/or HF (hazard ratio: 1.27; 95% CI: 1.10 to 1.45; p = 0.001). PENK levels independently predicted outcomes at 3 or 6 months and were independent predictors of in-hospital mortality, predominantly down-classifying risk in survivors when added to clinical scores; levels <133.3 pmol/l and >211.3 pmol/l detected low-risk and high-risk patients, respectively.

Conclusions: PENK levels reflect cardiorenal status in acute HF and are prognostic for worsening renal function and in-hospital mortality as well as mortality during follow-up.

Keywords: B-type natriuretic peptide; acute kidney injury; mortality; net reclassification improvement; opioids.

Publication types

  • Multicenter Study

MeSH terms

  • Acute Disease
  • Aged
  • Biomarkers / blood
  • Cardio-Renal Syndrome / etiology*
  • Cardio-Renal Syndrome / mortality
  • Cardio-Renal Syndrome / physiopathology
  • Cause of Death / trends
  • Enkephalins / blood*
  • Female
  • Follow-Up Studies
  • France / epidemiology
  • Glomerular Filtration Rate / physiology*
  • Heart Failure / blood*
  • Heart Failure / complications
  • Heart Failure / mortality
  • Humans
  • Kidney Function Tests
  • Male
  • Prognosis
  • Proportional Hazards Models
  • Protein Precursors / blood*
  • Risk Assessment / methods*
  • Survival Rate / trends
  • Switzerland / epidemiology
  • Time Factors
  • United Kingdom / epidemiology


  • Biomarkers
  • Enkephalins
  • Protein Precursors
  • proenkephalin