Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Internal Medicine, Fukuoka Dental College Medical and Dental Hospital, Fukuoka, Japan.
Department of Internal Medicine, Fukuoka Dental College Medical and Dental Hospital, Fukuoka, Japan.
Am J Physiol Renal Physiol. 2014 Jun 15;306(12):F1418-28. doi: 10.1152/ajprenal.00633.2013. Epub 2014 May 7.
Hyperphosphatemia contributes to increased cardiovascular mortality through vascular calcification (VC) in patients with chronic kidney disease (CKD). Malnutrition and inflammation are also closely linked to an increased risk of cardiovascular death in CKD. However, the effects of Pi overload on inflammation and malnutrition remain to be elucidated. The aim of the present study was to investigate the effects of dietary Pi loading on the interactions among inflammation, malnutrition, and VC in CKD. We used control rats fed normal diets and adenine-induced CKD rats fed diets with different Pi concentrations ranging from 0.3% to 1.2% for 8 wk. CKD rats showed dietary Pi concentration-dependent increases in serum and tissue levels of TNF-α and urinary and tissue levels of oxidative stress markers and developed malnutrition (decrease in body weight, serum albumin, and urinary creatinine excretion), VC, and premature death without affecting kidney function. Treatment with 6% lanthanum carbonate blunted almost all changes induced by Pi overload. Regression analysis showed that serum Pi levels closely correlated with the extent of inflammation, malnutrition, and VC. Also, in cultured human vascular smooth muscle cells, high-Pi medium directly increased the expression of TNF-α in advance of the increase in osteochondrogenic markers. Our data suggest that dietary Pi overload induces systemic inflammation and malnutrition, accompanied by VC and premature death in CKD, and that inhibition of Pi loading through dietary or pharmacological interventions or anti-inflammatory therapy may be a promising treatment for the prevention of malnutrition-inflammation-atherosclerosis syndrome.
高磷血症通过血管钙化（VC）增加慢性肾脏病（CKD）患者的心血管死亡率。营养不良和炎症也与 CKD 患者心血管死亡风险增加密切相关。然而，Pi 过载对炎症和营养不良的影响仍有待阐明。本研究旨在探讨饮食 Pi 负荷对 CKD 中炎症、营养不良和 VC 之间相互作用的影响。我们使用正常饮食喂养的对照大鼠和不同 Pi 浓度（0.3%至 1.2%）饮食喂养的腺嘌呤诱导的 CKD 大鼠，为期 8 周。CKD 大鼠表现出血清和组织中 TNF-α水平以及尿和组织中氧化应激标志物水平随饮食 Pi 浓度的依赖性增加，并出现营养不良（体重、血清白蛋白和尿肌酐排泄减少）、VC 和过早死亡，而肾功能不受影响。用 6%碳酸镧治疗可明显减轻 Pi 过载引起的几乎所有变化。回归分析表明，血清 Pi 水平与炎症、营养不良和 VC 的严重程度密切相关。此外，在培养的人血管平滑肌细胞中，高 Pi 培养基直接增加 TNF-α的表达，随后才增加成骨软骨生成标志物的表达。我们的数据表明，饮食 Pi 过载会在 CKD 中引起全身炎症和营养不良，并伴有 VC 和过早死亡，通过饮食或药物干预或抗炎治疗抑制 Pi 负荷可能是预防营养不良-炎症-动脉粥样硬化综合征的一种有前途的治疗方法。
