Hamano Takayuki
Department of Comprehensive Kidney Disease Research (CKDR), Osaka University Graduate School of Medicine, D11, 2-2 Yamadaoka, Suita, Osaka, Japan.
Clin Exp Nephrol. 2018 Apr;22(2):249-256. doi: 10.1007/s10157-017-1517-3. Epub 2017 Dec 21.
Bone fracture, cardiovascular events, and mortality are three outcomes of chronic kidney disease-mineral and bone disorder (CKD-MBD), and the umbrella concept originally described for dialysis patients. The reported association of serum phosphorus or fibroblast growth factor 23 (FGF23) levels with renal outcome suggests that the fourth relevant outcome of CKD-MBD in predialysis patients is renal outcome. We found that proteinuria of 2+ or greater with a dipstick test was associated with low vitamin D status due to urinary loss of 25-hydroxyvitamin D (25D). Moreover, active vitamin D or its analogues decrease proteinuria. Given our finding that maxacalcitol does not repress renin, the reduction of proteinuria by this agent is likely due to direct upregulation of the nephrin and podocin in podocytes. Moreover, this agent downregulates the mesenchymal marker desmin in podocytes and blocks transforming growth factor-beta autoinduction, leading to attenuation of renal fibrosis in a unilateral ureteral obstructive (UUO) model. These facts are reminiscent of the suppression of epithelial-mesenchymal transition (EMT) by vitamin D. EMT blockage may explain our finding that vitamin D prescription in renal transplant recipients is associated with a lower incidence of cancer. We also reported that low vitamin D status and high FGF23 levels predict a worse renal outcome. However, administration of massive doses of 25D exacerbates renal fibrosis in UUO kidneys in 1alpha-hydroxylase knockout mice. Moreover, FGF23 inhibits 1alpha-hydroxylase in proximal tubules and monocytes. Taken together, local 1,25(OH)D in the kidney tissue but not 25D seems to protect the kidney.
骨折、心血管事件和死亡率是慢性肾脏病 - 矿物质和骨异常（CKD - MBD）的三种结局，最初是针对透析患者描述的总体概念。血清磷或成纤维细胞生长因子23（FGF23）水平与肾脏结局之间的报道关联表明，透析前患者CKD - MBD的第四个相关结局是肾脏结局。我们发现，试纸条检测蛋白尿为2+或更高与维生素D水平低有关，原因是25 - 羟基维生素D（25D）经尿液流失。此外，活性维生素D或其类似物可降低蛋白尿。鉴于我们发现马沙骨化醇不会抑制肾素，该药物降低蛋白尿可能是由于直接上调足细胞中的nephrin和podocin。此外，该药物下调足细胞中的间充质标志物结蛋白，并阻断转化生长因子 - β的自诱导，导致单侧输尿管梗阻（UUO）模型中肾纤维化减轻。这些事实让人联想到维生素D对上皮 - 间充质转化（EMT）的抑制作用。EMT的阻断可能解释了我们的发现，即肾移植受者中维生素D的处方与较低的癌症发病率相关。我们还报道，低维生素D水平和高FGF23水平预示着更差的肾脏结局。然而，在1α - 羟化酶基因敲除小鼠中，给予大剂量的25D会加重UUO肾脏的肾纤维化。此外，FGF23抑制近端小管和单核细胞中的1α - 羟化酶。综上所述，似乎是肾脏组织中的局部1,25(OH)D而非25D对肾脏起到保护作用。
