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

• Published in: Journal of the American Society of Nephrology Vol. 28; no. 1; pp. 291 - 303
• Main Authors: Schulz, Christina-Alexandra, Christensson, Anders, Ericson, Ulrika, Almgren, Peter, Hindy, George, Nilsson, Peter M., Struck, Joachim, Bergmann, Andreas, Melander, Olle, Orho-Melander, Marju
• Format: Journal Article
• Language: English
• Published: United States American Society of Nephrology 01.01.2017
• Subjects: Basic Medicine; Clinical Epidemiology; Clinical Medicine; Cross-Sectional Studies; Enkephalins - blood; Fasting - blood; Female; Glomerular Filtration Rate; Humans; Incidence; Kidney - physiopathology; Klinisk medicin; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Middle Aged; Predictive Value of Tests; Prospective Studies; Protein Precursors - blood; Renal Insufficiency, Chronic - blood; Renal Insufficiency, Chronic - epidemiology; cystatin C; chronic kidney disease; creatinine; proenkephalin; glomerular filtration rate; PENK
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/ASN.2015101177

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 m 2 ) 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 ( P trend <0.001) and rise of cystatin C ( P trend =0.01) and creatinine ( P trend <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.