Advanced

High Level of Fasting Plasma Proenkephalin-A Predicts Deterioration of Kidney Function and Incidence of CKD

Schulz, Christina-Alexandra LU ; Christensson, Anders LU ; Ericson, Ulrika LU ; Almgren, Peter LU ; Hindy, George LU ; Nilsson, Peter M LU ; Struck, Joachim; Bergmann, Andreas; Melander, Olle LU and Orho-Melander, Marju LU (2017) In Journal of the American Society of Nephrology : JASN 28(1). p.291-303
Abstract

High levels of proenkephalin-A (pro-ENK) have been associated with decreased eGFR in an acute setting. Here, we examined whether pro-ENK levels predict CKD and decline of renal function in a prospective cohort of 2568 participants without CKD (eGFR>60 ml/min per 1.73 m2) at baseline. During a mean follow-up of 16.6 years, 31.7% of participants developed CKD. Participants with baseline pro-ENK levels in the highest tertile had significantly greater yearly mean decline of eGFR (Ptrend<0.001) and rise of cystatin C (Ptrend=0.01) and creatinine (Ptrend<0.001) levels. Furthermore, compared with participants in the lowest tertile, participants in the highest tertile of baseline pro-ENK concentration had increased CKD incidence (odds... (More)

High levels of proenkephalin-A (pro-ENK) have been associated with decreased eGFR in an acute setting. Here, we examined whether pro-ENK levels predict CKD and decline of renal function in a prospective cohort of 2568 participants without CKD (eGFR>60 ml/min per 1.73 m2) at baseline. During a mean follow-up of 16.6 years, 31.7% of participants developed CKD. Participants with baseline pro-ENK levels in the highest tertile had significantly greater yearly mean decline of eGFR (Ptrend<0.001) and rise of cystatin C (Ptrend=0.01) and creatinine (Ptrend<0.001) levels. Furthermore, compared with participants in the lowest tertile, participants in the highest tertile of baseline pro-ENK concentration had increased CKD incidence (odds ratio, 1.51; 95% confidence interval, 1.18 to 1.94) when adjusted for multiple factors. Adding pro-ENK to a model of conventional risk factors in net reclassification improvement analysis resulted in reclassification of 14.14% of participants. Genome-wide association analysis in 4150 participants of the same cohort revealed the strongest association of pro-ENK levels with rs1012178 near the PENK gene, where the minor T-allele associated with a 0.057 pmol/L higher pro-ENK level per allele (P=4.67x10-21). Furthermore, the T-allele associated with a 19% increased risk of CKD per allele (P=0.03) and a significant decrease in the instrumental variable estimator for eGFR (P<0.01) in a Mendelian randomization analysis. In conclusion, circulating plasma pro-ENK level predicts incident CKD and may aid in identifying subjects in need of primary preventive regimens. Additionally, the Mendelian randomization analysis suggests a causal relationship between pro-ENK level and deterioration of kidney function over time.

(Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Cross-Sectional Studies, Enkephalins/blood, Fasting/blood, Female, Glomerular Filtration Rate, Humans, Incidence, Kidney/physiopathology, Male, Middle Aged, Predictive Value of Tests, Prospective Studies, Protein Precursors/blood, Renal Insufficiency, Chronic/blood
in
Journal of the American Society of Nephrology : JASN
volume
28
issue
1
pages
13 pages
publisher
American Society of Nephrology
external identifiers
  • scopus:85017254011
ISSN
1046-6673
DOI
10.1681/ASN.2015101177
language
English
LU publication?
yes
id
a91f5a47-d43d-4dfc-887b-3629ac310ab2
alternative location
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5198273/
date added to LUP
2019-05-16 13:40:46
date last changed
2019-07-16 04:08:55
@article{a91f5a47-d43d-4dfc-887b-3629ac310ab2,
  abstract     = {<p>High levels of proenkephalin-A (pro-ENK) have been associated with decreased eGFR in an acute setting. Here, we examined whether pro-ENK levels predict CKD and decline of renal function in a prospective cohort of 2568 participants without CKD (eGFR&gt;60 ml/min per 1.73 m2) at baseline. During a mean follow-up of 16.6 years, 31.7% of participants developed CKD. Participants with baseline pro-ENK levels in the highest tertile had significantly greater yearly mean decline of eGFR (Ptrend&lt;0.001) and rise of cystatin C (Ptrend=0.01) and creatinine (Ptrend&lt;0.001) levels. Furthermore, compared with participants in the lowest tertile, participants in the highest tertile of baseline pro-ENK concentration had increased CKD incidence (odds ratio, 1.51; 95% confidence interval, 1.18 to 1.94) when adjusted for multiple factors. Adding pro-ENK to a model of conventional risk factors in net reclassification improvement analysis resulted in reclassification of 14.14% of participants. Genome-wide association analysis in 4150 participants of the same cohort revealed the strongest association of pro-ENK levels with rs1012178 near the PENK gene, where the minor T-allele associated with a 0.057 pmol/L higher pro-ENK level per allele (P=4.67x10-21). Furthermore, the T-allele associated with a 19% increased risk of CKD per allele (P=0.03) and a significant decrease in the instrumental variable estimator for eGFR (P&lt;0.01) in a Mendelian randomization analysis. In conclusion, circulating plasma pro-ENK level predicts incident CKD and may aid in identifying subjects in need of primary preventive regimens. Additionally, the Mendelian randomization analysis suggests a causal relationship between pro-ENK level and deterioration of kidney function over time.</p>},
  author       = {Schulz, Christina-Alexandra and Christensson, Anders and Ericson, Ulrika and Almgren, Peter and Hindy, George and Nilsson, Peter M and Struck, Joachim and Bergmann, Andreas and Melander, Olle and Orho-Melander, Marju},
  issn         = {1046-6673},
  keyword      = {Cross-Sectional Studies,Enkephalins/blood,Fasting/blood,Female,Glomerular Filtration Rate,Humans,Incidence,Kidney/physiopathology,Male,Middle Aged,Predictive Value of Tests,Prospective Studies,Protein Precursors/blood,Renal Insufficiency, Chronic/blood},
  language     = {eng},
  number       = {1},
  pages        = {291--303},
  publisher    = {American Society of Nephrology},
  series       = {Journal of the American Society of Nephrology : JASN},
  title        = {High Level of Fasting Plasma Proenkephalin-A Predicts Deterioration of Kidney Function and Incidence of CKD},
  url          = {http://dx.doi.org/10.1681/ASN.2015101177},
  volume       = {28},
  year         = {2017},
}