Dianet Amsterdam/Department of Nephrology Amsterdam UMC, Amsterdam, The Netherlands.
Department of Biochemistry, CARIM, Maastricht University, Maastricht, The Netherlands.
Nephrol Dial Transplant. 2022 Mar 25;37(4):652-662. doi: 10.1093/ndt/gfab314.
Hyperphosphataemia is strongly associated with cardiovascular disease and mortality. Recently, phosphate binders (PBs), which are used to bind intestinal phosphate, have been shown to bind vitamin K, thereby potentially aggravating vitamin K deficiency. This vitamin K binding by PBs may offset the beneficial effects of phosphate reduction in reducing vascular calcification (VC). Here we assessed whether combining PBs with vitamin K2 supplementation inhibits VC.
We performed 3/4 nephrectomy in rats, after which warfarin was given for 3 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 8 weeks. The primary outcome was the amount of thoracic and abdominal aorta VC measured by high-resolution micro-computed tomography (µCT). Vitamin K status was measured by plasma MK7 levels and immunohistochemically analysed in vasculature using uncarboxylated matrix Gla protein (ucMGP) specific antibodies.
The combination of a high vitamin K2 diet and PB treatment significantly reduced VC as measured by µCT for both the thoracic (P = 0.026) and abdominal aorta (P = 0.023), compared with MK7 or PB treatment alone. UcMGP stain was significantly more present in the low vitamin K2-treated groups in both the thoracic (P < 0.01) and abdominal aorta (P < 0.01) as compared with high vitamin K2-treated groups. Moreover, a high vitamin K diet and PBs led to reduced vascular oxidative stress.
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.
高磷血症与心血管疾病和死亡率密切相关。最近，用于结合肠道磷的磷结合剂（PBs）已被证明会结合维生素 K，从而可能加剧维生素 K 缺乏。这种 PB 对维生素 K 的结合可能会抵消通过降低磷酸盐来减少血管钙化（VC）的有益作用。在这里，我们评估了 PB 与维生素 K2 补充剂联合使用是否可以抑制 VC。
我们在大鼠中进行了 3/4 肾切除术，之后给予华法林 3 周以诱导维生素 K 缺乏。接下来，在存在低或高维生素 K2 的情况下，动物喂食高磷饮食，并随机分为对照组或 4 种不同 PB 中的一种，治疗 8 周。主要结果是通过高分辨率微计算机断层扫描（µCT）测量的胸主动脉和腹主动脉 VC 的量。通过 MK7 水平的血浆和未羧化基质 Gla 蛋白（ucMGP）特异性抗体在血管中的免疫组织化学分析来测量维生素 K 状态。
与单独使用 MK7 或 PB 相比，高维生素 K2 饮食和 PB 联合治疗显著降低了 µCT 测量的胸主动脉（P = 0.026）和腹主动脉（P = 0.023）的 VC。与高维生素 K2 治疗组相比，低维生素 K2 治疗组的胸主动脉（P < 0.01）和腹主动脉（P < 0.01）ucMGP 染色明显更多。此外，高维生素 K 饮食和 PBs 导致血管氧化应激减少。
在维生素 K 缺乏的肾衰竭动物模型中，单独使用 PB 治疗或维生素 K2 补充都不能预防 VC。然而，高维生素 K2 与 PB 治疗联合使用显著减轻了 VC。
