Circulating Dephospho-Uncarboxylated Matrix G a-Protein Is Associated With Kidney Dysfunction and Arterial Stiffness

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 (beta = 0.21; P = 0.019). In formal mediation analyses, dp-ucMGP mediated a significant relationship between eGFR and higher CF-PWV (beta = -0.16; P = 0.005), whereas no significant dp-ucMGP-independent relationship was present (beta = - 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.