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Calcimimetic and vitamin D analog use in hemodialyzed patients is associated with increased levels of vitamin K dependent proteins

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Abstract

Matrix Gla protein (MGP) and bone Gla protein (BGP) are two vitamin K-dependent proteins (VKDPs) involved in the regulation of vascular calcification (VC). We carried out a secondary analysis of the VIKI study to evaluate associations between drug consumption and VKDP levels in 387 hemodialyzed patients. The VIKI study assessed the prevalence of vitamin K deficiency in hemodialysis patients. We evaluated drug consumption, determined BGP and MGP levels, and verified the presence of any vertebral fractures (VF) and VC by spine radiographs. Total BGP levels were twice as high with calcimimetics versus no calcimimetics (290 vs. 158.5 mcg/L, p < 0.0001) and 69 % higher with vitamin D analogs (268 vs. 159 mcg/L, p < 0.0001). Total MGP was 19 % higher with calcimimetics (21.5 vs. 18.1 mcg/L, p = 0.04) and 54 % higher with calcium acetate (27.9 vs. 18.1 mcg/L, p = 0.003); no difference was found with vitamin D analogs (21.1 vs. 18.3 mcg/L, p = 0.43). Median Total BGP level was 29 % lower in patients with ≥1 VF (151 vs. 213 mcg/L, p = 0.0091) and 36 % lower in patients with VC (164 vs. 262.1 mcg/L, p = 0.0003). In non-survivors, median BGP and MGP were lower, but only for MGP this difference reached the statistical significance (152 vs. 191 mcg/L, p = 0.20 and 15.0 vs. 19.7 mcg/L, p = 0.02, respectively). Pending studies on vitamin K supplementation, calcimimetics, and vitamin D analogs may play a role in preserving vitamin K-dependent protein activity, thus contributing to bone and vascular health in CKD patients.

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Acknowledgments

We thank the VIKI Dialysis Study Investigators, who provided patient clinical care and collected clinical data. They were the following: MT Vilei, MC Tineo, M. Rebeschini, A. Naso (Padua), C. Grimaldi, A. Mannarino (Florence), D. Ciurlino, S. Bertoli (Sesto San Giovanni, Milan), R. Puggia, A. Caberlotto, S. Mastrosimone, C. Cascone (Treviso), R. Corradini, M. Avolio, B. Giacon (Bolzano), A. Foschi, C. Barbieri, F. Milanesi (Voghera), A. Pica, C. Venturelli, G. Brunori (Trento), T. Pati, A. Gemelli, A.M. Bernardi (Rovigo), F. Barbisoni, A. Elli (Lodi), P. Morachiello, M. Feriani (Mestre), F. Stoppa (Adria), G. Tarroni, E. De Paoli Vitali (Belluno), S. Lucatello, G. Meneghel (Dolo), A. Vianello, F. Antonucci (Feltre, Belluno), V. Pellanda, R. Dell’Aquila (Bassano del Grappa), A. Ferraro, M. De Luca (Castelfranco Veneto, Padua), F.M. Magonara, M. Axia (Schio), M. Spinello, M. Urso (Chioggia, Venice). We also thank Jennifer S Hartwig, MD, medical writer, for editing the manuscript. Availability/disclosure of materials and methods and author access to data: the CNR was the coordinating center; the complete clinical trial archive is there and the statistical analysis was performed there. MF and MN had full access to all the raw data and made them available to the other authors, as appropriate. Any requests regarding clinical or radiographic data should be addressed to MF. Requests regarding laboratory data and laboratory methods should be addressed to MP in Padua (vitamin D and Gla proteins).

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Authors and Affiliations

  1. National Research Council (CNR), Neuroscience Institute, Via Giustiniani, 2, 35128, Padua, Italy

    Maria Fusaro & Marianna Noale

  2. Department of Medicine, Clinica Medica 1, University of Padua, Padua, Italy

    Sandro Giannini, Fabrizio Fabris, Sabina Zambon & Stefania Sella

  3. Nephrology and Dialysis Unit, San Carlo Borromeo Hospital, Department of Biomedical and Clinical Sciences “L. Sacco”, University of Milan, Milan, Italy

    Maurizio Gallieni

  4. CNR-IFC Pathophysiology of Renal Diseases and Hypertension Unit, Reggio Calabria, Italy

    Giovanni Tripepi

  5. Rheumatology Unit, Department of Medicine, University of Verona, Verona, Italy

    Maurizio Rossini

  6. Fondazione Ca’ Granda-IRCCS Ospedale Maggiore Policlinico, Milan, Italy

    Piergiorgio Messa

  7. Kidney – Pancreas Transplant Unit, Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, Padua, Italy

    Paolo Rigotti

  8. Nephrology and Dialysis Unit, Hospital of Rovigo, Rovigo, Italy

    Tecla Pati

  9. Nephrology and Dialysis Unit, Hospital of Lodi, Lodi, Italy

    Francesco Barbisoni

  10. Nephrology Unit, University of Padua, Padua, Italy

    Antonio Piccoli, Andrea Aghi, Marianna Alessi & Luciana Bonfante

  11. CNR Institute of Clinical Physiology, Pisa, Italy

    Giorgio Iervasi

  12. Laboratory Medicine Unit, Department of Medicine, University of Padua, Padua, Italy

    Mario Plebani

Authors
  1. Maria Fusaro
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  2. Sandro Giannini
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  3. Maurizio Gallieni
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  4. Marianna Noale
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  6. Maurizio Rossini
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  15. Fabrizio Fabris
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  17. Stefania Sella
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  18. Giorgio Iervasi
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  19. Mario Plebani
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Corresponding author

Correspondence to Maria Fusaro.

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Conflict of interest

M.F. has received grants from Boehringer Ingelheim, AbbVie, Amgen and Fresenius. SG has received grants from MSD, Abiogen and Amgen. Maurizio Gallieni: In the past 5 years, travel support for participation to meetings and speaking honoraria from Abbvie, Amgen, Genzyme. PM has received grants from AbbVie, Amgen, Fresenius, and Roche. PR has received research grants from Novartis and has participated to advisory boards with Novartis, Astellas, and Chiesi. F.F. has received lectures fees from Bayer, GSK, and Amgen. M.N., G.T., M.R., T.P., F.B., A.P., A.A., M.A., L.B., S.Z., S.S., G.I., and M.P. have no interests to disclose.

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Fusaro, M., Giannini, S., Gallieni, M. et al. Calcimimetic and vitamin D analog use in hemodialyzed patients is associated with increased levels of vitamin K dependent proteins. Endocrine 51, 333–341 (2016). https://doi.org/10.1007/s12020-015-0673-z

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  • DOI: https://doi.org/10.1007/s12020-015-0673-z

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