TY - JOUR
T1 - Proenkephalin, an Opioid System Surrogate, as a Novel Comprehensive Renal Marker in Heart Failure
AU - Emmens, Johanna E.
AU - Ter Maaten, Jozine M.
AU - Damman, Kevin
AU - van Veldhuisen, Dirk J.
AU - de Boer, Rudolf A.
AU - Struck, Joachim
AU - Bergmann, Andreas
AU - Sama, Iziah E.
AU - Streng, Koen W.
AU - Anker, Stefan D.
AU - Dickstein, Kenneth
AU - Lang, Chim C.
AU - Metra, Marco
AU - Samani, Nilesh J.
AU - Ng, Leong L.
AU - Voors, Adriaan A.
N1 - Funding: BIOSTAT-CHF (A Systems Biology Study to Tailored Treatment in Chronic Heart Failure) was funded by the European Commission (FP7-242209-BIOSTAT-CHF and EudraCT 2010-020808-29) and is encompassed in the multidisciplinary scientific consortium RECONNECT (Renal Connection to Microvascular Disease and Heart Failure With Preserved Ejection Fraction).
PY - 2019/5
Y1 - 2019/5
N2 - 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.
AB - 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.
KW - creatinine
KW - glomerular filtration rate
KW - heart failure
KW - incidence
KW - proenkephalin
UR - http://www.scopus.com/inward/record.url?scp=85066819145&partnerID=8YFLogxK
U2 - 10.1161/CIRCHEARTFAILURE.118.005544
DO - 10.1161/CIRCHEARTFAILURE.118.005544
M3 - Article
C2 - 31091993
SN - 1941-3289
VL - 12
JO - Circulation: Heart Failure
JF - Circulation: Heart Failure
IS - 5
M1 - e005544
ER -