Circulating Dephospho-Uncarboxylated Matrix Gla-Protein Is Associated with Kidney Dysfunction and Arterial Stiffness

Abstract

Background: Large artery stiffening is increased in advanced chronic kidney disease (CKD) but likely develops progressively in earlier stages of CKD. Active matrix Gla-protein (MGP) is a potent Vitamin K-dependent inhibitor of vascular calcification. A recent animal model demonstrated intrinsic abnormalities in Vitamin K metabolism even in early CKD, but whether early human CKD is associated with vascular Vitamin K deficiency is unknown. Methods: We enrolled 137 adults without HF with varying degrees of renal function: normal estimated glomerular filtration rate (eGFR; >90 ml/min; n = 59), mildly reduced eGFR (stage 2 CKD: eGFR = 60-89 ml/min; n = 53) or at least moderately reduced eGFR (stage 3-5 CKD; eGFR < 60 ml/min; n = 25). Carotid-femoral pulse wave velocity (CF-PWV) was measured with carotid and femoral tonometry. Dephospho-uncarboxylated matrix gla-protein (dp-ucMGP) was measured with enzyme-linked immunosorbent assay (ELISA) (VitaK; Maastricht University; The Netherlands). Result: Dp-ucMGP levels were progressively increased with decreasing renal function (eGFR ≥ 90: 247 pmol/l; eGFR 60-89: 488 pmol/l; eGFR < 60: 953 pmol/l; P < 0.0001). These differences persisted after adjustment for multiple potential confounders (eGFR ≥ 90: 314 pmol/l; eGFR 60-89: 414 pmol/l; eGFR < 60: 770 pmol/l; P < 0.0001). In a multivariable model adjusted for various confounders, dp-ucMGP was a significant independent predictor of CF-PWV (β = 0.21; P = 0.019). In formal mediation analyses, dp-ucMGP mediated a significant relationship between eGFR and higher CF-PWV (β = -0.16; P = 0.005), whereas no significant dp-ucMGP-independent relationship was present (β = -0.02; P = 0.80). Conclusions: CKD is associated with increased (inactive) dp-ucMGP, a Vitamin K- dependent inhibitor of vascular calcification, which correlates with large artery stiffness. Further studies are needed to assess whether Vitamin K2 supplementation represents a suitable therapeutic strategy to prevent or reduce arterial stiffening in CKD. c American Journal of Hypertension, Ltd 2018. All rights reserved.