de Seigneux Sophie, Wilhelm-Bals Alexandra, Courbebaisse Marie
Service and laboratory of Nephrology, Department of Internal Medicine Specialties and Department of Physiology and Metabolism, University Hospital and University of Geneva, Switzerland.
Unité Pédiatrique Néphrologique Romande, Department of Paediatrics, University Hospital of Geneva and University Hospital Centre of Lausanne, Switzerland.
Swiss Med Wkly. 2017 Oct 18;147:w14509. doi: 10.4414/smw.2017.14509. eCollection 2017.
Albuminuria is strongly associated with renal and cardiovascular outcomes independently of renal function level. However, the pathophysiology of these associations is debated. In chronic kidney disease (CKD), phosphate retention participates in cardiovascular events and increased cardiovascular mortality. We hypothesised that albuminuria may modulate tubular phosphate handling by the kidney. To verify this hypothesis, we first studied the association between phosphataemia and albuminuria in children with nephrotic syndrome and in adults with CKD. In both cases, higher albuminuria was associated with higher phosphate level, independently of glomerular filtration rate. We further tried to decipher the molecular mechanisms of these observations. Using animal models of nephrotic proteinuria, we could show that albuminuric rats and mice had abnormally elevated sodium-phosphate apical co-transporter expression, despite elevated fibroblast growth factor 23 (FGF23). The FGF23 downstream pathway was inhibited despite elevated FGF23 levels. Klotho protein expression was also lower in proteinuric animals compared to controls. Finally, albumin had no direct effects on phosphate transport in cells. Altogether, we show that albuminuria induces alteration of phosphate tubular handling, independently of glomerular filtration rate. The mechanisms involved appear to include Klotho down-regulation and resistance to FGF23. This observation may link albuminuria to increased cardiovascular disease via altered phosphate handling. Finally, this observation opens up further opportunities to better understand the link between albuminuria, Klotho, FGF23 and phosphate handling.
蛋白尿与肾脏和心血管结局密切相关，且独立于肾功能水平。然而，这些关联的病理生理学仍存在争议。在慢性肾脏病（CKD）中，磷潴留参与心血管事件并增加心血管死亡率。我们推测蛋白尿可能会调节肾脏对磷酸盐的肾小管处理。为了验证这一假设，我们首先研究了肾病综合征儿童和CKD成人的血磷水平与蛋白尿之间的关联。在这两种情况下，较高的蛋白尿均与较高的血磷水平相关，且独立于肾小球滤过率。我们进一步试图解读这些观察结果的分子机制。使用肾病性蛋白尿的动物模型，我们发现，尽管成纤维细胞生长因子23（FGF23）水平升高，但蛋白尿大鼠和小鼠的钠-磷酸盐顶端共转运体表达异常升高。尽管FGF23水平升高，但FGF23下游通路受到抑制。与对照组相比，蛋白尿动物的klotho蛋白表达也较低。最后，白蛋白对细胞中的磷酸盐转运没有直接影响。总之，我们表明蛋白尿会导致磷酸盐肾小管处理的改变，且独立于肾小球滤过率。其中涉及的机制似乎包括klotho下调和对FGF23的抵抗。这一观察结果可能通过改变磷酸盐处理将蛋白尿与心血管疾病增加联系起来。最后，这一观察结果为更好地理解蛋白尿、klotho、FGF23和磷酸盐处理之间的联系提供了更多机会。
