Department of Nephrology, University Hospital of the RWTH Aachen, Aachen, Germany.
Department of Cardiology, University Hospital of the RWTH Aachen, Aachen, Germany.
Nephrol Dial Transplant. 2020 Jan 1;35(1):65-73. doi: 10.1093/ndt/gfy410.
Optimal phosphate control is an unmet need in chronic kidney disease (CKD). High serum phosphate increases calcification burden and is associated with mortality and cardiovascular disease in CKD. Nicotinamide (NA) alone or in combination with calcium-free phosphate binders might be a strategy to reduce phosphate levels and calcification and thus impact cardiovascular disease in CKD.
We studied the effect of NA alone and in combination with magnesium carbonate (MgCO3) as a potential novel treatment strategy. CKD was induced in dilute brown non-agouti/2 mice by subtotal nephrectomy followed by a high-phosphate diet (HP) and 7 weeks of treatment with NA, MgCO3 or their combination. Control mice underwent subtotal nephrectomy and received an HP or underwent sham surgery and received standard chow plus NA.
CKD mice showed increased serum fibroblast growth factor 23 and calcium-phosphate product that was normalized by all treatment regimes. NA alone increased soft tissue and vascular calcification, whereas any treatment with MgCO3 significantly reduced calcification severity in CKD. While MgCO3 supplementation alone resulted in decreased calcification severity, it resulted in increased intestinal expression of the phosphate transporters type II sodium-dependent phosphate transporter 1 (Pit-1). Combined therapy of MgCO3 and NA reduced tissue calcification and normalized expression levels of intestinal phosphate transporter proteins.
In conclusion, the data indicate that NA increases while MgCO3 reduces ectopic calcification severity. Augmented expression of intestinal phosphate transporters by MgCO3 treatment was abolished by the addition of NA. However, the clinical relevance of the latter remains to be explored. Importantly, the data suggest no benefit of NA regarding treatment of calcification in addition to MgCO3.
慢性肾脏病（CKD）存在磷酸盐控制不理想的问题。高血清磷酸盐会增加钙化负担，并与 CKD 患者的死亡率和心血管疾病相关。烟酰胺（NA）单独或与无钙磷酸盐结合剂联合使用可能是降低磷酸盐水平和钙化的一种策略，从而影响 CKD 的心血管疾病。
我们研究了 NA 单独使用以及与碳酸镁（MgCO3）联合使用作为一种潜在的新型治疗策略的效果。通过部分肾切除术，随后给予高磷饮食（HP）和 7 周的 NA、MgCO3 或两者联合治疗，诱导稀有的棕色非阿加蒂/2 小鼠发生 CKD。对照组小鼠接受部分肾切除术并给予 HP，或接受假手术并给予标准饲料加 NA。
CKD 小鼠的血清成纤维细胞生长因子 23 和钙磷乘积增加，所有治疗方案均可使其恢复正常。NA 单独使用会增加软组织和血管钙化，而任何形式的 MgCO3 治疗都能显著减轻 CKD 中的钙化严重程度。尽管单独补充 MgCO3 会降低钙化严重程度，但会导致肠道磷酸盐转运体 II 型钠依赖性磷酸盐转运体 1（Pit-1）的表达增加。MgCO3 和 NA 的联合治疗可减少组织钙化并使肠道磷酸盐转运蛋白的表达水平正常化。
总之，数据表明 NA 增加而 MgCO3 减少异位钙化的严重程度。MgCO3 治疗导致的肠道磷酸盐转运体表达增加被 NA 的加入所消除。然而，后者的临床相关性仍有待探索。重要的是，数据表明 NA 对 MgCO3 治疗之外的钙化没有益处。
