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

Circulating Dephospho-Uncarboxylated Matrix Gla-Protein Is Associated With Kidney Dysfunction and... BACKGROUNDLarge 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.METHODSWe 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).RESULTDp-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).CONCLUSIONSCKD 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png American Journal of Hypertension Oxford University Press

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

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Publisher
Oxford University Press
Copyright
© The Author(s) 2018. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
ISSN
0895-7061
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1941-7225
DOI
10.1093/ajh/hpy079
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Abstract

BACKGROUNDLarge 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.METHODSWe 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).RESULTDp-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).CONCLUSIONSCKD 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.

Journal

American Journal of Hypertension – Oxford University Press

Published: Aug 3, 2018

Keywords: arterial stiffness; blood pressure; chronic kidney disease; hypertension; MGP; pulse wave velocity; vitamin K

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