Sevelamer Use, Vitamin K Levels, Vascular Calcifications, and Vertebral Fractures in Hemodialysis Patients: Results from the VIKI Study.

Maria Fusaro, Mario Cozzolino, Mario Plebani, Giorgio Iervasi, Markus Ketteler, Maurizio Gallieni, Andrea Aghi, Francesco Locatelli, John Cunningham, Syazrah Salam, Martina Zaninotto, Maura Ravera, Domenico Russo, Maria Cristina Mereu, Sandro Giannini, Maria Luisa Brandi, Serge Ferrari, Stefania Sella, Colin Gerard Egan, Antonio Bellasi, Luca Di Lullo, Giovanni Tripepi, Thomas Nickolas

Journal: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2021;36(3):500-509

PMID: 33188702

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Abstract

Hyperphosphatemia is a risk factor for vascular calcifications (VCs), which are part of the chronic kidney disease-mineral and bone disorders (CKD-MBD). Vitamin K-dependent proteins such as matrix Gla protein (MGP) and bone Gla proteins (BGP, or osteocalcin) can inhibit VCs and regulate bone mineralization. In this analysis of the Vitamin K Italian (VIKI) study, the relationship between vitamin K status, vertebral fractures (VFs) and VCs in 387 hemodialysis (HD) patients with (N = 163; 42.1%) or without N = 224; 57.9%) sevelamer was evaluated. Levels of vitamin K vitamers K1 and K2 or menaquinones (MK; MK4-7), total and undercarboxylated (uc) forms for both BGP and MGP were determined. Although no differences in clinical characteristics were noted, lower levels of MK4 (0.45 versus 0.6 ng/mL, p = .01) and a greater MK4 deficiency was observed in sevelamer-treated patients (13.5% versus 5.4%, p = .005). Multivariate logistic regression revealed that MK4 deficiency was associated with sevelamer use (odds ratio [OR] = 2.64, 95% confidence interval [CI] 1.25-5.58, p = .011) and aortic calcification (OR = 8.04, 95% CI 1.07-60.26, p = .04). In the same logistic model, sevelamer amplified the effect of total BGP levels on the odds of VFs in patients with total BGP <150 μg/L compared with those with total BGP ≥150 μg/L (OR = 3.15, 95% CI 1.46-6.76, p = .003). In contrast, there was no such effect in those untreated (total BGP <150 μg/L versus total BGP ≥150 μg/L: OR = 1.21, 95% CI 0.66-2.23, p = .54]; p = .049 for effect modification by sevelamer). Sevelamer may interfere with MK4 levels in HD patients and interact with low BGP levels to increase bone fractures in CKD patients. © 2020 American Society for Bone and Mineral Research (ASBMR).

Address: National Research Council (CNR)-Institute of Clinical Physiology (IFC), Pisa, Italy.; Department of Medicine, University of Padua, Padua, Italy.; Renal Division, Department of Health Sciences, ASST Santi Paolo e Carlo, University of Milan, Milan, Italy.; Department of Laboratory Medicine, University Hospital of Padova, Padova, Italy.; National Research Council (CNR)-Institute of Clinical Physiology (IFC), Pisa, Italy.; Department of General Internal Medicine and Nephrology, Robert-Bosch-Krankenhaus, Stuttgart, Germany.; Nephrology and Dialysis Unit, Azienda Socio-Sanitaria Territoriale (ASST) Fatebenefratelli Sacco, Department of Clinical and Biomedical Sciences 'Luigi Sacco', Università di Milano, Milan, Italy.; Department of Medicine, Clinica Medica 1, University of Padova, Padova, Italy.; Alessandro Manzoni Hospital, ASST Lecco, Lecco, Italy.; The Royal Free Hospital and UCL Medical School, London, UK.; Sheffield Kidney Institute, Sheffield Teaching Hospitals National Health Service Foundation Trust, and Academic Unit of Bone Metabolism and Mellanby Centre for Bone Research, Medical School-University of Sheffield, Sheffield, UK.; Department of Medicine, University of Padua, Padua, Italy.; Clinica Nefrologica, Dialisi e Trapianto, Universita' di Genova e Policlinico San Martino, Genoa, Italy.; Department of Public Health, University of Naples Federico II, Naples, Italy.; Independent Researcher, Cagliari, Italy.; Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.; Service des Maladies Osseuses, Département de Médecine, HUG, Genève, Switzerland.; CE-Medical Writing, Pisa, Italy.; UOC Ricerca, Innovazione, Brand Reputation, ASST-Papa Giovanni XXIII, Bergamo, Italy.; Department of Nephrology and Dialysis, L. Parodi, Delfino Hospital, Rome, Italy.; CNR-IFC, Clinical Epidemiology and Pathophysiology of Renal Diseases and Hypertension, Reggio Calabria, Italy.; Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York City, NY, USA.

DOI: 10.1002/jbmr.4214

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MeSH Terms: Humans, Italy, Renal Dialysis, Sevelamer, Vascular Calcification, Vitamin K