The Pathophysiology of Early-Stage Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD) and Response to Phosphate Binders in the Rat
The Pathophysiology of Early-Stage Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD) and Response to Phosphate Binders in the Rat
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DOI：
10.1002/jbmr.485
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发表时间：
2011-11-01
影响因子：
6.2
通讯作者：
Chen, Neal X.
中科院分区：
文献类型：
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作者：
Moe, Sharon M.;Radcliffe, J. Scott;Chen, Neal X.
慢性肾脏病-矿物质骨病（CKD-MBD）是一种全身性疾病，描述了CKD中发生的复杂骨和矿物质异常。为了了解CKD-MBD的病理生理学，并确定早期使用磷结合剂是否会改变这种生理学，我们使用了一种自然发生的慢性进展性CKD-MBD模型，Cy/+大鼠。在无磷结合剂、碳酸钙或碳酸司维拉姆给药1周后，将雄性Cy/+大鼠与20周龄时的正常同窝大鼠进行比较。Cy/+大鼠的肾功能为正常同窝仔的50%，甲状旁腺激素（PTH）和成纤维细胞生长因子23（FGF 23）升高，1，25-二羟维生素D-3 [1，25（OH）（2）D-3]水平降低，但钙和磷水平正常。血FGF 23与血磷、血FGF 23与尿磷呈显著正相关。FGF 23与钙水平呈负相关。来自肾脏的mRNA显示klotho和Npt 2a表达降低50%，但CYP 27 B1无差异。在肠道中，与正常同窝仔相比，使用改良的Ussing室，CKD动物空肠中的活性磷酸盐吸收减少，整个小肠中的Npt 2b表达减少。在骨骼中，FGF 23的mRNA表达降低（由磷酸盐结合剂降低驱动），而TRAP表达在CKD中增加。通过组织学检查，破骨细胞活性和数量增加，股骨颈机械强度的某些指标降低。一周的磷结合剂减少肠磷通量，血清磷水平，尿磷排泄。这些结果表明在早期CKD-MBD中肾脏、肠和骨的显著异常。虽然磷结合剂可有效降低尿磷，但给药1周后对终末器官的影响很小。(C)2011年美国骨与矿物质研究学会。
Chronic kidney disease-mineral bone disorder (CKD-MBD) is a systemic disorder that describes the complex bone and mineral abnormalities that occur in CKD. To understand the pathophysiology of CKD-MBD and determine whether the early use of phosphate binders would alter this physiology, we used a naturally occurring, slowly progressive model of CKD-MBD, the Cy/+ rat. Male Cy/+ rats were compared with their normal littermates at 20 weeks of age after 1 week of no phosphate binder, calcium carbonate, or sevelamer carbonate. The Cy/+ rat had renal function that was 50% of that of normal littermates, elevated parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23), decreased 1,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3] levels, but normal calcium and phosphorus levels. There was a significant positive correlation of blood FGF23 and phosphorus levels and blood FGF23 and urine phosphorus levels. There was an inverse correlation between FGF23 and calcium levels. mRNA from the kidney demonstrated 50% reduction in klotho and Npt2a expression but no difference in CYP27B1. In the intestine, CKD animals had reduced active phosphate absorption in the jejunum using modified Ussing chambers and a reduction in Npt2b expression throughout the small intestine compared with normal littermates. In bone, mRNA expression of FGF23 was reduced (driven by lowering with phosphate binders), and TRAP expression was increased in CKD. By histology, there was increased osteoclast activity and number, and there were reductions in some measures of femoral neck mechanical strength. One week of phosphate binders reduced intestinal phosphate flux, serum phosphorus levels, and urinary phosphate excretion. These results demonstrate marked abnormalities in kidney, intestine, and bone in early CKD-MBD. While phosphate binders were effective in lowering urine phosphorus, they had little effect on end organs after 1 week of administration. (C) 2011 American Society for Bone and Mineral Research.