Proenkephalin, an Opioid System Surrogate, as a Novel Comprehensive Renal Marker in Heart Failure

Circ Heart Fail. 2019 May;12(5):e005544. doi: 10.1161/CIRCHEARTFAILURE.118.005544.


Background: PENK (proenkephalin) is a stable surrogate for enkephalins, endogenous opioid peptides, which exert cardiodepressive effects and improve renal function. PENK has been associated with heart failure (HF) severity and renal dysfunction. We therefore hypothesized that PENK could be associated with deterioration of kidney function and could have a role as a novel renal marker in HF.

Methods and results: In 2180 patients with HF of a large multicenter cohort (BIOSTAT-CHF [A Systems Biology Study to Tailored Treatment in Chronic Heart Failure]), the relationship between PENK and clinical variables, plasma and urinary biomarkers, and clinical end points was established. Data were validated in a separate cohort of 1703 patients with HF. PENK was elevated (>80 pmol/L, 99th percentile) in 1245 (57%) patients. Higher PENK was associated with more advanced HF and glomerular and tubular dysfunction. The strongest independent predictor of PENK was estimated glomerular filtration rate. Others were plasma NGAL (neutrophil gelatinase-associated lipocalin) and NT-proBNP (N-terminal pro-B-type natriuretic peptide; all P<0.001). Using correlation heatmaps and hierarchical cluster analyses, PENK clustered with estimated glomerular filtration rate, creatinine, NGAL, galectin-3, and urea. Higher PENK was independently associated with increased risk of deterioration of kidney function between baseline and 9 months (odds ratio, 1.29 [1.02-1.65] per PENK doubling; P=0.038; defined as >25% decrease in estimated glomerular filtration rate) and mortality (hazard ratio, 1.23 [1.07-1.43] per doubling; P=0.004). Analyses in the validation cohort yielded comparable findings.

Conclusions: Higher PENK levels are associated with more severe HF, with glomerular and tubular renal dysfunction, with incidence of a deterioration of kidney function, and with mortality. These findings suggest that the opioid system might be involved in deteriorating kidney function in HF.

Keywords: creatinine; glomerular filtration rate; heart failure; incidence; proenkephalin.

Publication types

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

MeSH terms

  • Aged
  • Aged, 80 and over
  • Biomarkers / blood*
  • Biomarkers / metabolism
  • Biomarkers / urine
  • Cohort Studies
  • Enkephalins / blood*
  • Enkephalins / metabolism
  • Female
  • Glomerular Filtration Rate
  • Heart Failure / blood*
  • Heart Failure / complications
  • Heart Failure / metabolism
  • Heart Failure / urine
  • Humans
  • Male
  • Middle Aged
  • Prognosis
  • Protein Precursors / blood*
  • Protein Precursors / metabolism
  • Renal Insufficiency / blood*
  • Renal Insufficiency / etiology
  • Renal Insufficiency / metabolism
  • Renal Insufficiency / urine


  • Biomarkers
  • Enkephalins
  • Protein Precursors
  • proenkephalin

Associated data

  • EudraCT/2010-020808-29