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

Johanna E. Emmens; Jozine M. Ter Maaten; Kevin Damman; Dirk J. Van Veldhuisen; Rudolf A. De Boer; Joachim Struck; Andreas Bergmann; Iziah E. Sama; Koen W. Streng; Stefan D. Anker; Kenneth Dickstein; Chim C. Lang; Marco Metra; Nilesh J. Samani; Leong L. Ng; Adriaan A. Voors

doi:10.1161/CIRCHEARTFAILURE.118.005544

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

Johanna E. Emmens, Jozine M. Ter Maaten, Kevin Damman, Dirk J. Van Veldhuisen, Rudolf A. De Boer, Joachim Struck, Andreas Bergmann, Iziah E. Sama, Koen W. Streng, Stefan D. Anker, Kenneth Dickstein, Chim C. Lang, Marco Metra, Nilesh J. Samani, Leong L. Ng, Adriaan A. Voors^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

23 Citations (Scopus)

Abstract

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.

Original language	English
Article number	e005544
Journal	Circulation: Heart Failure
Volume	12
Issue number	5
DOIs	https://doi.org/10.1161/CIRCHEARTFAILURE.118.005544
Publication status	Published - 1 May 2019
Externally published	Yes

Bibliographical note

Funding Information:
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).

Publisher Copyright:
© 2019 American Heart Association, Inc.

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10.1161/CIRCHEARTFAILURE.118.005544

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Emmens, J. E., Ter Maaten, J. M., Damman, K., Van Veldhuisen, D. J., De Boer, R. A., Struck, J., Bergmann, A., Sama, I. E., Streng, K. W., Anker, S. D., Dickstein, K., Lang, C. C., Metra, M., Samani, N. J., Ng, L. L., & Voors, A. A. (2019). Proenkephalin, an Opioid System Surrogate, as a Novel Comprehensive Renal Marker in Heart Failure. Circulation: Heart Failure, 12(5), Article e005544. https://doi.org/10.1161/CIRCHEARTFAILURE.118.005544

@article{19a9d6455b874d7b9b94eeefbcb7e533,

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

abstract = "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.",

author = "Emmens, {Johanna E.} and {Ter Maaten}, {Jozine M.} and Kevin Damman and {Van Veldhuisen}, {Dirk J.} and {De Boer}, {Rudolf A.} and Joachim Struck and Andreas Bergmann and Sama, {Iziah E.} and Streng, {Koen W.} and Anker, {Stefan D.} and Kenneth Dickstein and Lang, {Chim C.} and Marco Metra and Samani, {Nilesh J.} and Ng, {Leong L.} and Voors, {Adriaan A.}",

note = "Funding Information: 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). Publisher Copyright: {\textcopyright} 2019 American Heart Association, Inc.",

year = "2019",

month = may,

day = "1",

doi = "10.1161/CIRCHEARTFAILURE.118.005544",

language = "English",

volume = "12",

journal = "Circulation: Heart Failure",

issn = "1941-3289",

publisher = "Lippincott Williams & Wilkins",

number = "5",

}

Emmens, JE, Ter Maaten, JM, Damman, K, Van Veldhuisen, DJ, De Boer, RA, Struck, J, Bergmann, A, Sama, IE, Streng, KW, Anker, SD, Dickstein, K, Lang, CC, Metra, M, Samani, NJ, Ng, LL & Voors, AA 2019, 'Proenkephalin, an Opioid System Surrogate, as a Novel Comprehensive Renal Marker in Heart Failure', Circulation: Heart Failure, vol. 12, no. 5, e005544. https://doi.org/10.1161/CIRCHEARTFAILURE.118.005544

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 Information: 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). Publisher Copyright: © 2019 American Heart Association, Inc.

PY - 2019/5/1

Y1 - 2019/5/1

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.

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U2 - 10.1161/CIRCHEARTFAILURE.118.005544

DO - 10.1161/CIRCHEARTFAILURE.118.005544

M3 - Article

C2 - 31091993

AN - SCOPUS:85066819145

SN - 1941-3289

VL - 12

JO - Circulation: Heart Failure

JF - Circulation: Heart Failure

IS - 5

M1 - e005544

ER -

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

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