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

Abstract

BACKGROUND: Hyperphosphatemia is a risk factor for vascular calcifications (VCs) and VCs belong to mineral bone disorders (MBD) in chronic kidney disease (CKD) patients. Vitamin Kdependent proteins such as Matrix Gla Protein (MGP) and Bone Gla Proteins (BGP or osteocalcin) can inhibit VCs and regulate bone mineralization. OBJECTIVE: To evaluate whether the phosphate binder, sevelamer, could influence vitamin K levels in hemodialysis (HD) patients. METHODS: In a secondary analysis of the VItamin K Italian (VIKI) study, we evaluated the relationship between vitamin K status, VFs and VCs in 387 HD patients with/without sevelamer. Levels of serum vitamin 25(OH)D, alkaline phosphatase (ALP), vitamin k vitamers: K1 and K2 or menaquinone (MK, including: MK4, MK5, MK6 and MK7), total and undercarboxylated (uc) forms for both BGP and MGP were determined. RESULTS: No significant differences were observed between sevelamer-treated and untreated patients for main clinical characteristics. Lower MK4 levels (0.45 vs. 0.6 ng/mL, p=0.01) and a higher MK4 deficiency was observed in sevelamer-treated patients (13.5% vs. 5.4%, p=0.005). Multivariate logistic regression revealed that MK4 deficiency was associated with sevelamer use (Odds Ratio; OR: 2.64, 95% CI: 1.25-5.58, p=0.011) and aortic calcification (OR: 8.04, 95% CI: 1.07-60.26, p=0.04). In the same multivariate logistic regression model, sevelamer significantly amplified the effect of total BGP levels on the odds of fractures so that in sevelamer-treated patients, the OR of VFs was about 3 times higher in patients with total BGP <150 µg/L compared to those with total BGP ≥150 µg/L (OR: 3.15, 95% CI: 1.46-6.76, p=0.003), whereas no such effect was found in those untreated (total BGP <150 µg/L vs. total BGP ≥150 µg/L: OR: 1.21, 95% CI: 0.66-2.23, p=0.54] (p=0.049 for effect modification by sevelamer). CONCLUSION: These data suggest that sevelamer could interfere with MK4 levels in HD patients and its use in patients with low BGP levels (<150 µg/L) could increase bone fragility in CKD patients.

Vitamin K in CKD Bone Disorders

“…In a cross-sectional study of 387 hemodialysis patients (VItaminKItalian: VIKI study), Fusaro et al showed that MK-4 deficiency was the strongest predictor of aortic calcification (OR, 2.82; 95% CI, 1.14-7.01) [31]. In a secondary analysis, they found in patients treated with Sevelamer an odds ratio of MK-4 deficiency of 2.64 (95% CI 1.25-5.58, p = 0.01) [44]. Furthermore, sevelamer use significantly amplified the effect of total OC levels on the risk of VFs: BGP < 150 μg/L compared to those with total BGP ≥ 150 μg/L (OR 3.15, 95% CI 1.46-6.76, p = 0.003) [44].…”

Phosphate, Microbiota and CKD

“…There are multiple studies addressing the potential consequences of sevelamer binding molecules beyond phosphate. Sevelamer may interfere with absorption of fat-soluble vitamins (D, K) [ 31 , 36 ] and has been associated with evidence of vitamin K deficiency, such as menaquinone MK4 deficiency and increased non-phosphorylated uncarboxylated matrix-Gla protein (dp-ucMGP) [ 39 , 40 ]. These defects were recently described in a cross-sectional study in association with a wider disturbance in uremic toxins of microbiota origin, including increased serum indoxyl sulfate (IS) and phenylacetylglutamine (PAG) in end stage kidney disease (ESKD), mostly dialysis, patients.…”

Predictive Value of Measures of Vascular Calcification Burden and Progression for Risk of Death in Incident to Dialysis Patients

“…Vascular calcification (VC) is a useful marker of cardiovascular disease and several methods are available for the assessment of their presence and extension [1][2][3][4][5]. Although the pathogenesis of VC is not well established, several studies suggest that the prevalence of VC increases as renal function declines, likely due to the many metabolic abnormalities that characterize chronic kidney disease (CKD) [3,5,6].…”

“…In these regards, the Kauppila score (KS) using lateral-lateral plain X-ray of the lumbar spine has been proposed to evaluate VC in the abdominal aorta. A few reports suggest a close correlation of KS and CAC as well as KS and risk of death in dialysis patients [1][2][3][4][5]. However, which VC measures best predicts long-term survival and whether a measure of vascular calcification adds to the predictive value of traditional Framingham risk stratification in incident to hemodialysis (HD) patients, has not been determined through a concurrent comparison of these measures in a single prospective cohort [5].…”