Combining phosphate binder therapy with vitamin K2 inhibits vascular calcification in an experimental animal model of kidney failure

Abstract

Background Hyperphosphatemia is strongly associated with cardiovascular disease and mortality. Recently, phosphate binders (PBs), which are used to bind intestinal phosphate have been shown also to bind vitamin K, thereby potentially aggravating vitamin K deficiency. This vitamin K-binding by PBs may offset beneficial effects of phosphate level reduction on reducing vascular calcification (VC). Here we assessed whether combining PBs with vitamin K2 supplementation inhibits VC. Methods We performed 3/4Nx in rats, after which warfarin was given for three weeks to induce vitamin K-deficiency. Next, animals were fed a high phosphate diet in the presence of low or high vitamin K2 and were randomized to either control or one of four different PBs for eight weeks. Primary outcome was the amount of thoracic and abdominal aorta VC measured by high-resolution micro-Computed Tomography (μ-CT). Vitamin K status was measured by plasma MK7 levels and immunohistochemically analyzed in vasculature using ucMGP specific antibodies. Results Combination of high vitamin K2 diet and PB treatment significantly reduced VC as measured by μ-CT, for both thoracic (p = 0.026) and abdominal aorta (p = 0.023), compared to MK7 or PB treatment alone. UcMGP stain was significantly more present in the low vitamin K2 treated groups in both thoracic (p<0.01) and abdominal aorta (p<0.01) as compared to high vitamin K2 treated groups. Moreover, high vitamin K diet and PBs led to reduced vascular oxidative stress. Conclusion In an animal model of kidney failure with vitamin K-deficiency, neither PB therapy nor vitamin K2 supplementation alone prevented VC. However, the combination of high vitamin K2 with PB treatment significantly attenuated VC.

Vitamin K1 and progression of cardiovascular calcifications in hemodialysis patients: The VitaVasK randomized controlled trial

“…While experimentally the combination of any phosphate binder with vitamin K2 was more potent than either measure alone to retard progression of calcification [31], there are also data indicating that sevelamer in particular may interfere with vitamin K absorption in dialysis patients [26,32]. However, within the limitations of our trial, we found no evidence for any significant effect of sevelamer on the efficacy of our vitamin K1 therapy.…”

Vitamin K-Dependent Carboxylation of Osteocalcin in Bone—Ally or Adversary of Bone Mineral Status in Rats with Experimental Chronic Kidney Disease?

“…Thus, the increased serum Glu-OC in the condition of uremia and hyperparathyroidism, observed in this study, does not necessarily reflect VK deficiency. A good alternative to determine VK status is measurement serum ucMGP, which is a recognized marker of VK status in nephrectomized rats [ 63 ]. In contrast to Glu-OC, ucMGP concentration did not differ between the studied groups in this study.…”

Effect of phosphate binder therapy on FGF-23 levels in dialysis patients

“…Известно, что фосфат-связываю щий препарат, севеламера карбонат, обладает плейотропными эффектами на параметры, связанные с сердечно-сосудистым риском: улучшение эндотелиальной и/или сосудистой функции, замедление сосудистой кальцификации, снижение уровня FGF-23, уменьшение количества провоспалительных и окислительных молекул [20,21].…”