title: Proenkephalin, Renal Dysfunction, and Prognosis in Patients With Acute Heart Failure: A GREAT Network Study.
abstract: 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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom. Electronic address: lln1@le.ac.uk.
authors.forename: Leong L
authors.initials: LL
authors.lastname: Ng
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
authors.forename: Iain B
authors.initials: IB
authors.lastname: Squire
authors.affiliation: Department of Cancer Studies, University of Leicester, Leicester Royal Infirmary, Leicester, United Kingdom.
authors.forename: Donald J L
authors.initials: DJL
authors.lastname: Jones
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
authors.forename: Thong Huy
authors.initials: TH
authors.lastname: Cao
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
authors.forename: Daniel C S
authors.initials: DCS
authors.lastname: Chan
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
authors.forename: Jatinderpal K
authors.initials: JK
authors.lastname: Sandhu
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
authors.forename: Paulene A
authors.initials: PA
authors.lastname: Quinn
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
authors.forename: Joan E
authors.initials: JE
authors.lastname: Davies
authors.affiliation: Sphingotec GmbH, Hennigsdorf, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Struck
authors.affiliation: Sphingotec GmbH, Hennigsdorf, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Hartmann
authors.affiliation: Sphingotec GmbH, Hennigsdorf, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bergmann
authors.affiliation: U942 Inserm; APHP, Hôpitaux Universitaire Saint Louis Lariboisière; Université Paris Diderot, Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Mebazaa
authors.affiliation: U942 Inserm; APHP, Hôpitaux Universitaire Saint Louis Lariboisière; Université Paris Diderot, Paris, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Gayat
authors.affiliation: U942 Inserm; APHP, Hôpitaux Universitaire Saint Louis Lariboisière; Université Paris Diderot, Paris, France.
authors.forename: Mattia
authors.initials: M
authors.lastname: Arrigo
authors.affiliation: U942 Inserm; APHP, Hôpitaux Universitaire Saint Louis Lariboisière; Université Paris Diderot, Paris, France.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Akiyama
authors.affiliation: Cardiovascular Research Institute Basel and Department of Cardiology, University Hospital Basel, Basel, Switzerland.
authors.forename: Zaid
authors.initials: Z
authors.lastname: Sabti
authors.affiliation: Cardiovascular Research Institute Basel and Department of Cardiology, University Hospital Basel, Basel, Switzerland.
authors.forename: Jens
authors.initials: J
authors.lastname: Lohrmann
authors.affiliation: Cardiovascular Research Institute Basel and Department of Cardiology, University Hospital Basel, Basel, Switzerland.
authors.forename: Raphael
authors.initials: R
authors.lastname: Twerenbold
authors.affiliation: Cardiovascular Research Institute Basel and Department of Cardiology, University Hospital Basel, Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Herrmann
authors.affiliation: Cardiovascular Research Institute Basel and Department of Cardiology, University Hospital Basel, Basel, Switzerland.
authors.forename: Carmela
authors.initials: C
authors.lastname: Schumacher
authors.affiliation: Cardiovascular Research Institute Basel and Department of Cardiology, University Hospital Basel, Basel, Switzerland.
authors.forename: Nikola
authors.initials: N
authors.lastname: Kozhuharov
authors.affiliation: Cardiovascular Research Institute Basel and Department of Cardiology, University Hospital Basel, Basel, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Mueller
mesh_terms: D000208:Acute Disease; D000368:Aged; D015415:Biomarkers / Q000097:blood; D059347:Cardio-Renal Syndrome / Q000209:etiology* / Q000401:mortality / Q000503:physiopathology; D002423:Cause of Death / Q000639:trends; D004745:Enkephalins / Q000097:blood*; D005260:Female; D005500:Follow-Up Studies; D005602:France / Q000453:epidemiology; D005919:Glomerular Filtration Rate / Q000502:physiology*; D006333:Heart Failure / Q000097:blood* / Q000150:complications / Q000401:mortality; D006801:Humans; D007677:Kidney Function Tests; D008297:Male; D011379:Prognosis; D016016:Proportional Hazards Models; D011498:Protein Precursors / Q000097:blood*; D018570:Risk Assessment / Q000379:methods*; D015996:Survival Rate / Q000639:trends; D013557:Switzerland / Q000453:epidemiology; D013997:Time Factors; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D015415:Biomarkers; D004745:Enkephalins; D011498:Protein Precursors; C029992:proenkephalin
keywords: B-type natriuretic peptide; acute kidney injury; mortality; net reclassification improvement; opioids