Davide Miozzo

Vitamin K, vertebral fractures, vascular calcifications, and mortality: VItamin K Italian (VIKI) dialysis study.

Vitamin K (vitamin K1 or phylloquinone and vitamin K2, a series of menaquinones [MKs]) is involved in the production of bone and matrix amino acid γ‐carboxy‐glutamic acid (Gla) proteins, regulating bone and vascular calcification. Low vitamin K concentrations are associated with increased risks of fractures and vascular calcification, and frequent complications in hemodialysis patients. We carried out an observational study to establish the prevalence of vitamin K deficiency and to assess the relationship between vitamin K status, vertebral fractures, vascular calcification, and survival in 387 patients on hemodialysis for ≥1 year. We determined plasma levels of vitamin K compound, bone‐Gla‐protein, matrix‐Gla‐protein, and routine biochemistry. Vertebral fractures (reduction in vertebral body height by ≥20%) and aortic and iliac calcifications were also investigated in a spine (D5–L4) radiograph. Three‐year patient survival was analyzed. Important proportions of patients had deficiency of MK7 (35.4%), vitamin K1 (23.5%), and MK4 (14.5%). A total of 55.3% of patients had vertebral fractures, 80.6% had abdominal aorta calcification, and 56.1% had iliac calcification. Vitamin K1 deficiency was the strongest predictor of vertebral fractures (odds ratio [OR], 2.94; 95% confidence interval [CI], 1.38–6.26). MK4 deficiency was a predictor of aortic calcification (OR, 2.82; 95% CI, 1.14–7.01), whereas MK5 deficiency actually protected against it (OR, 0.38; 95% CI, 0.15–0.95). MK7 deficiency was a predictor of iliac calcification (OR, 1.64; 95% CI, 1.03–2.60). The presence of vertebral fractures was also a predictor of vascular calcifications (OR, 1.76; 95% CI, 1.00–3.08). Increased alkaline phosphatase and C reactive protein (CRP), age, and cerebrovascular events were predictors of mortality. Our study suggests that the vitamin K system may be important for preserving bone mass and avoiding vascular calcification in hemodialysis patients, pointing out a possible role of vitamin K in bone and vascular health. Based on our results, we suggest that the general population should also be studied for vitamin K deficiency as a possible cause of both vertebral fractures and vascular calcification.

Vitamin K, bone fractures, and vascular calcifications in chronic kidney disease: An important but poorly studied relationship

Vitamin K denotes a group of lipophilic vitamins determining post- translational modification of proteins. There are 2 main forms of vitamin K: vitamin K1 (phylloquinone, found in vegetables); vitamin K2 (menaquinone, produced by bacteria in the intestine and in fermented foods). Vitamin K stores are limited in humans, but it can be recycled. Vitamin K1 is principally transported to the liver, regulating the production of coagulation factors. Vitamin K2, instead, is also transported to extra- hepatic tissues, such as bone and arteries, regulating the activity of matrix Gla- protein (MGP) and osteocalcin [bone Gla- protein (BGP)]. In patients with chronic kidney disease (CKD), cardiovascular mortality is the first cause of death. Some pathogenetic mechanisms of vascular calcification (such as hyperparathyroidism, hyperphosphatemia, hypercalcemia, role of vitamin D) have been widely investigated, but the potential role of vitamin K is still uncertain. Vitamin K could play a key role, as it transforms glutamic acid residues into γ- carboxyglutamic acid, through a carboxylation process, makings both MGP (cMGP) and BGP (cBGP) biologically active. cMGP inhibits vascular calcifications (VC), while cBGP has an important role for a proper mineralization process. Uncarboxylated MGP and BGP (ucMGP and ucBGP) concentrations are indirect markers of vitamin K2 deficiency. The purpose of this review is to analyze the current literature to understand the relationship between vitamin K2 status, fragility fractures and VC in CKD patients. This analysis could be of help in planning investigations of Vitamin K status and its possible supplementation in CKD patients to avert fragility fractures and VC.

Prevalence of vertebral fractures, vascular calcifications, and mortality in warfarin treated hemodialysis patients.

Warfarin inhibits vitamin-K dependent proteins involved in bone mineralization and the prevention of vascular calcification (bone Gla protein BGP, matrix Gla protein MGP). In this multicenter, cross-sectional study with 3-year follow-up, data from 387 patients on hemodialysis for ≥1 year at 18 dialysis units were analyzed. Patients on warfarin treatment for > 1 year (11.9% of the population) were compared with the remaining cohort for vertebral fractures, vascular calcifications and mortality. Vertebral fractures and vascular calcifications were sought in L-L vertebral X-rays (D5 to L4). Compared with controls, warfarin-treated male patients had more vertebral fractures (77.8 vs. 57.7%, p<0.04), but not females (42.1% vs. 48.4%, p=0.6); total BGP was significantly reduced (82.35 vs. 202 µg/L, p<0.0001), with lower levels in treated men (69.5 vs. women 117.0 µg/L, p=0.03). In multivariate logistic regression analyses, the use of warfarin was associated with increased odds of aortic (OR 2.58, p<0.001) and iliac calcifications (OR 2.86, p<0.001); identified confounders were age, atrial fibrillation, angina, PPI use and total BGP. Seventy-seven patients died during a 2.7±0.5 year follow-up. In univariate Cox regression analysis, patients on warfarin had a higher risk of all-cause mortality (HR 2.42, 95% CI 1.42-4.16, p=0.001) when compared with those untreated and data adjustment for confounders attenuated but confirmed the significant warfarin-mortality link (HR: 1.97, 95% CI: 1.02-3.84, P=0.046). In hemodialysis patients, additional studies are warranted to verify the risk/benefit ratio of warfarin, which appears to be associated with significant morbidity and increased mortality.

Bleeding, Vertebral Fractures and Vascular Calcifications in Patients Treated with Warfarin: Hope for Lower Risks with Alternative Therapies

Anticoagulant therapy in patients with atrial fibrillation requires careful evaluation because its benefits i.e. prevention of thromboembolism, must be greater than the risk of bleeding. Patients at higher risk of thrombosis are evaluated through specific scores, such as the CHA(2)DS(2)VASc, coupled with scoring systems for assessing bleeding risks, such as the HAS-BLED score. In addition to bleeding, other risks have been associated with the use of warfarin, including an increased susceptibility to vascular calcifications and fractures caused by a reduction in the levels of vitamin K dependent carboxylated enzymes, matrix Gla-protein (MGP) and bone Gla-protein or osteocalcin (BGP). In fact, while on one side warfarin is used to prevent embolism, on the other hand acting as a vitamin K antagonist it blocks the inhibitory effect of MGP on vascular calcification. Similarly, patients treated with warfarin carry a greater risk of developing osteoporosis and fractures, due to reduced BGP activity. Recently, a new generation of anticoagulant drugs has been developed, such as dabigatran, a direct thrombin inhibitor, and rivaroxaban, a direct factor-Xa inhibitor. They offer an interesting alternative to warfarin, because they do not require frequent blood tests for monitoring while offering similar results in terms of efficacy. Lacking the inhibitory effect on the vitamin K cycle, the consequent side effects can be avoided. If, compared to warfarin treated patients, a lower incidence of vascular calcifications and fractures will be demonstrated, the advantages over warfarin may be even greater, leading to further benefits in terms of morbidity and mortality.

Treatment with calcimimetic (cinacalcet) alters epoetin dosage requirements in dialysis patients: preliminary report.

Abstract Background: Secondary hyperparathyroidism (SHPT), known complication of chronic renal failure, in addition to effects on bone and cardiovascular systems, is associated with reduced response to erythropoietin (EPO). Calcimimetics such as cinacalcet are the latest generation of drugs used in the treatment of SHPT. Few studies have evaluated the effect of cinacalcet on anemia associated with SHPT in dialysis patients, while no study has compared this cinacalcet effect with that of vitamin D analogs such as paricalcitol. Patients and methods: Using a retrospective chart-based review of dialysis patients’ records to identify patients being treated with either cinacalcet or paricalcitol alone, matched for the same EPO treatment, which had been followed for 1 year, we have evaluated the effect of cinacalcet on anemia compared to that of paricalcitol. Results: Ten patient records were found that fit the criteria, five treated with cinacalcet (Group 1) and five treated with paricalcitol (Group 2), all treated with the same dose of darbepoetin. Darbepoetin dosage was the only parameter that significantly changed between groups, decreasing in Group 1 (−33%, p = 0.009) while remaining unchanged in Group 2. PTH-level reduction, which was significant versus baseline in both groups, although not statistically different between groups, was higher with cinacalcet. Conclusion: The combination of lower EPO dose in cinacalcet-treated patients compared with paricalcitol-treated patients, along with good SHPT control is a novel information and might have considerable benefits in dialysis patients not only preventing bone (fractures) and cardiovascular system (calcifications) damages but also in terms of cost savings via a reduction of EPO dosage.

The relationship between the Spine Deformity Index, biochemical parameters of bone metabolism and vascular calcifications: results from the Epidemiological VERtebral FRACtures iTalian Study (EVERFRACT) in dialysis patients.

Abstract Background: The Spine Deformity Index (SDI) is a measure of vertebral fractures (VFs), providing information on both their number and severity. Methods: We evaluated the relationships between SDI and clinical, biochemical and arterial calcification parameters in 387 hemodialysis (HD) patients. VFs, assessed by quantitative vertebral morphometry, and vascular calcifications were identified in the same lateral spinal X-ray. To improve the detection of fracture severity, we created a corrected SDI (c-SDI), by dividing SDI for the number of VFs. We assessed routine biochemistry, bone-Gla-protein (BGP), undercaboxylated BGP (ucBGP), and matrix-Gla-protein (MGP). Results: VFs prevalence was 55.3%. HD patients with a SDI >1 were more frequently males (p<0.05), and had lower BGP (p<0.01). Patients with a c-SDI >1 had higher LDL-cholesterol (p<0.05) and lower ucBGP (p<0.05) and MGP (p<0.05). Calcifications of the abdominal aorta (AAoC) were more frequent in patients with SDI >1 (p<0.05) and with c-SDI >1 (p<0.05). Multivariate logistic regression showed that male sex (OR 1.86, CI 1.20–2.91), age (OR 1.03, CI 1.01–1.05) and albumin ≥3.5 g/dL (OR 0.54, CI 0.31–0.93) were predictors of a SDI >1. Age (OR 1.05, CI 1.03–1.07), LDL-cholesterol (OR 1.74, CI 1.04–2.92) and ucBGP (OR 0.35, CI 0.18–0.70) were associated with c-SDI >1. Conclusions: We conclude that the severity of VFs was associated with age, atherogenic factors and bone metabolism markers.

Effects of vitamin K intake on gamma-carboxylated proteins, bone fractures, and vascular calcifications.

Dear Editor, We read with great interest the article by Fujita and collaborators [1], recently published on the website of Osteoporosis International. This relevant work confirms that vitamin K status is important for bone health. In addition, it demonstrates that dietary vitamin K intake can be protective against loss of bone mineral density, opening the possibility of vitamin K supplementation for the prevention or treatment of osteoporosis. Therefore, vitamin K can be important for bone health at both the quantitative and qualitative levels [2]. We would like to further expand the relevance of this report by pointing out that not only can vitamin K intake affect osteocalcin activity and bone mineral density, but it can potentially reduce the burden of cardiovascular calcifications by maintaining an adequate activity of matrix Gla protein, a vitamin K2-dependent, gamma-carboxylated protein which inhibits vascular calcification [3]. Calcium intake, vitamin D and vitamin K supplementation are probably strictly interacting in the maintenance of both bone and vascular health. Although for a long time, calcium intake and vitamin D supplementation have been the mainstay of treatment for osteoporosis, recent evidence suggests that calcium supplements increase the risk of cardiovascular disease [4]. Thus, the benefit of a reduction in fracture risk exerted by calcium supplements may be canceled by the increase in cardiovascular risk. In this perspective, the protective role of vitamin K2 on both vascular calcification and vertebral fractures should be better studied, in combination with vitamin D treatment and dietary calcium. It is possible that without adequate vitamin K2 intake, calcium will have less chances to be deposited in the bone matrix but, instead, will favor the onset or worsening of vascular calcification and cardiovascular disease. Adequate levels of vitamin K2 in the circulation could favor a better handling of serum calcium to maintain bone and vessel health [5]. Japanese patients consuming natto and, therefore, with high dietary vitamin K intake (specifically menaquinone-7, the K2 vitamin with better bioavailability due its longer half-life), could not only be protected by osteoporosis and fractures, but also from cardiovascular calcification, which may affect survival. Further studies on this population could be of great help in confirming this hypothesis. A reply to this letter can be found at doi 10.1007/s00198-011-1690-2.