title: High Level of Fasting Plasma Proenkephalin-A Predicts Deterioration of Kidney Function and Incidence of CKD.
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 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.
authors.affiliation: Department of Clinical Sciences, University Hospital Malmo Clinical Research Center, Lund University, Malmo, Sweden.
authors.forename: Christina-Alexandra
authors.initials: CA
authors.lastname: Schulz
authors.affiliation: Department of Clinical Sciences, University Hospital Malmo Clinical Research Center, Lund University, Malmo, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Christensson
authors.affiliation: Department of Clinical Sciences, University Hospital Malmo Clinical Research Center, Lund University, Malmo, Sweden.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Ericson
authors.affiliation: Department of Clinical Sciences, University Hospital Malmo Clinical Research Center, Lund University, Malmo, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Almgren
authors.affiliation: Department of Clinical Sciences, University Hospital Malmo Clinical Research Center, Lund University, Malmo, Sweden.
authors.forename: George
authors.initials: G
authors.lastname: Hindy
authors.affiliation: Department of Clinical Sciences, University Hospital Malmo Clinical Research Center, Lund University, Malmo, Sweden.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Nilsson
authors.affiliation: Sphingotec GmbH, Hennigsdorf, Germany; and.
authors.forename: Joachim
authors.initials: J
authors.lastname: Struck
authors.affiliation: Sphingotec GmbH, Hennigsdorf, Germany; and.|Waltraut Bergmann Foundation, Hohen Neuendorf, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bergmann
authors.affiliation: Department of Clinical Sciences, University Hospital Malmo Clinical Research Center, Lund University, Malmo, Sweden.
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
authors.affiliation: Department of Clinical Sciences, University Hospital Malmo Clinical Research Center, Lund University, Malmo, Sweden; marju.orho-melander@med.lu.se.
authors.forename: Marju
authors.initials: M
authors.lastname: Orho-Melander
mesh_terms: D003430:Cross-Sectional Studies; D004745:Enkephalins / Q000097:blood*; D005215:Fasting / Q000097:blood*; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D015994:Incidence; D007668:Kidney / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011446:Prospective Studies; D011498:Protein Precursors / Q000097:blood*; D051436:Renal Insufficiency, Chronic / Q000097:blood* / Q000453:epidemiology
chemical_list: D004745:Enkephalins; D011498:Protein Precursors; C029992:proenkephalin
keywords: PENK; chronic kidney disease; creatinine; cystatin C; glomerular filtration rate; proenkephalin