26 Citations (SciVal)

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.

Original languageEnglish
Pages (from-to)291-303
Number of pages13
JournalJournal of the American Society of Nephrology: JASN
Volume28
Issue number1
DOIs
Publication statusPublished - 2017 Jan

Subject classification (UKÄ)

  • Urology and Nephrology
  • Basic Medicine

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

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