High Level of Fasting Plasma Proenkephalin-A Predicts Deterioration of Kidney Function and Incidence of CKD
(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)
- author
- 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
- organization
- publishing date
- 2017-01
- 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
- pmid:27401687
- ISSN
- 1046-6673
- DOI
- 10.1681/ASN.2015101177
- language
- English
- LU publication?
- yes
- additional info
- Copyright © 2016 by the American Society of Nephrology.
- 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
- 2024-09-03 19:40:55
@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>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.</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}}, 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}}, 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}}, doi = {{10.1681/ASN.2015101177}}, volume = {{28}}, year = {{2017}}, }