Risk Factors Associated With Altered Circulating Micro RNA -125b and Their Influences on Uremic Vascular Calcification Among Patients With End-Stage Renal Disease

Abstract

Background Micro RNA -125b (miR-125b) has been shown to regulate vascular calcification ( VC ), and serum miR-125b levels are a potential biomarker for estimating the risk of uremic VC status. However, it is unknown whether clinical features, including chronic kidney disease-mineral bone disorder molecules, affect serum miR-125b levels. Methods and Results Patients receiving chronic dialysis for ≥3 months were recruited from different institutes. Serum miR-125b and chronic kidney disease-mineral bone disorder effectors, including intact parathyroid hormone, 25- OH -D, fibroblast growth factor-23, osteoprotegerin, and fetuin-A, were quantified. We used multivariate regression analyses to identify factors associated with low serum miR-125b levels and an area under receiver operating characteristic curve curve to derive optimal cutoffs for factors exhibiting close associations. Further regression analyses evaluated the influence of miR-125b on VC risk. Among 223 patients receiving chronic dialysis (mean age, 67.3 years; mean years of dialysis, 5.2), 54 (24.2%) had high serum miR-125b levels. Osteoprotegerin ( P=0.013), fibroblast growth factor-23 ( P=0.006), and fetuin-A ( P=0.036) were linearly associated with serum miR-125b levels. High osteoprotegerin levels independently correlated with high serum miR-125 levels. Adding serum miR-125b levels and serum osteoprotegerin levels (≥400 pg/mL) into models estimating the risk of uremic VC increased the area under receiver operating characteristic curve values (for models without miR-125b/osteoprotegerin, with miR-125b, and both: 0.74, 0.79, and 0.81, respectively). Conclusions Serum osteoprotegerin levels ≥400 pg/mL and serum miR-125b levels synergistically increased the accuracy of estimating VC risk among patients receiving chronic dialysis. Taking miR-125b and osteoprotegerin levels into consideration when estimating VC risk may be recommended.

Keywords: biomarker; chronic kidney disease; end‐stage renal disease; fibroblast growth factor‐23; microRNA‐125b; osteoprotegerin; vascular calcification.

Figure 1

An illustrative figure showing the VC staging system used in this study. (Left upper, right upper, left lower, and right lower represented stage 0, 1, 2, and 3, respectively). VC indicates vascular calcification. Red areas mark the part with calcification opacity.

Figure 2

Scatter plot illustrating the correlations between serum miR‐125b levels (natural log transformed) and osteoprotegerin (A), FGF‐23 (natural log transformed) (B), and fetuin‐A (C). FGF‐23 indicates fibroblast growth factor‐23.

Figure 3

Receiver‐operating characteristics curves for multivariate logistic regression models with serum miR‐125b levels (A) or vascular calcification status (B) as the dependent variable. Cutoff values of osteoprotegerin with their sensitivity and specificity for each model was shown (A). OPG indicates osteoprotegerin; Sen, sensitivity; Spe, specificity.

Figure 4

MiR‐125b‐protein and protein‐protein interaction network of differentially expressed genes, with particular focus on AHSG (fetuin‐A), FGF‐23, and TNFRSF11B (osteoprotegerin). hsa04064, NF‐κB signaling pathway; hsa04218, cellular senescence pathway; hsa04270, vascular smooth muscle contraction pathway; hsa04668, TNF signaling pathway. 3 path, hsa04064, hsa04218, and hsa04668. Lines of different colors represent the specific pathway(s) being enriched. TNF indicates tumor necrosis factor.