The intact nephron hypothesis: the concept and its implications for phosphate management in CKD-related mineral and bone disorder.
The intact nephron hypothesis: the concept and its implications for phosphate management in CKD-related mineral and bone disorder.
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DOI：
10.1038/ki.2011.23
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发表时间：
2011-04
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在过去的五十年里，对慢性肾病（CKD）中继发性甲状旁腺功能亢进、血管钙化和磷酸盐代谢调节的机制了解取得了显着进展。1960年，Bricker提出了“完整肾单位假说”，为数百项研究打开了大门。他强调，“随着功能肾单位数量的减少，每个剩余的肾单位必须执行总肾脏排泄的更大部分”。磷酸盐本身，独立于Ca 2+和骨化三醇，直接影响甲状旁腺增生和继发性甲状旁腺功能亢进的发展。维生素D受体、Ca 2+敏感受体和Klotho-成纤维细胞生长因子（FGF）受体-1复合物在CKD患者的甲状旁腺中均显著降低。十二指肠灌注磷酸盐可迅速减少甲状旁腺激素的释放，而不改变钙或骨化三醇。同样的过程也迅速增加肾磷酸盐排泄独立于FGF-23，这表明了“肠磷酸化”的可能性。这些观察结果表明，甲状旁腺和胃肠道中可能存在一种“磷酸盐传感器”，尽管目前还没有证据证明这种传感器的存在。有证据表明，磷酸盐通过激活转化生长因子-α-表皮生长因子受体复合物在甲状旁腺增生中起关键作用。因此，在CKD病程早期控制血清磷将显著改善肾功能进行性恶化期间观察到的病理表现。
Mechanistic understanding of secondary hyperparathyroidism, vascular calcification, and regulation of phosphate metabolism in chronic kidney disease (CKD) has advanced significantly in the past five decades. In 1960, Bricker developed the ‘intact nephron hypothesis', opening the door for hundreds of investigations. He emphasized that ‘as the number of functioning nephrons decreases, each remaining nephron must perform a greater fraction of total renal excretion'. Phosphate per se, independent of Ca2+ and calcitriol, directly affects the development of parathyroid gland hyperplasia and secondary hyperparathyroidism. Vitamin D receptor, Ca2+ sensing receptor, and Klotho–fibroblast growth factor (FGF) receptor-1 complex are all significantly decreased in the parathyroid glands of patients with CKD. Duodenal instillation of phosphate rapidly decreases parathyroid hormone release without changes in calcium or calcitriol. The same procedure also rapidly increases renal phosphate excretion independently of FGF-23, suggesting the possibility of an ‘intestinal phosphatonin'. These observations suggest a possible ‘phosphate sensor' in the parathyroid glands and gastrointestinal tract, although as yet there is no proof for the existence of such a sensor. Evidence shows that phosphate has a key role in parathyroid hyperplasia by activating the transforming growth factor-α–epidermal growth factor receptor complex. Thus, control of serum phosphorus early in the course of CKD will significantly ameliorate the pathological manifestations observed during progressive deterioration of renal function.