Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea.
Gachon University College of Medicine, Incheon, Republic of Korea.
PLoS One. 2020 Jun 22;15(6):e0235077. doi: 10.1371/journal.pone.0235077. eCollection 2020.
Proteinuria and hyperphosphatemia are risk factors for cardiovascular disease in patients with chronic kidney disease (CKD). Although the interaction between proteinuria and the serum phosphate level is well established, the mechanistic link between the two, particularly the extent to which this interaction is mediated by phosphate-regulating factors, remains poorly understood. In this study, we examined the association between proteinuria and the serum phosphate level, as well as potential mediators, including circulating fibroblast growth factor (FGF23)/klotho, the 24-h urinary phosphate excretion rate to glomerular filtration rate ratio (EP/GFR), and the 24-h tubular phosphate reabsorption rate to GFR ratio (TRP/GFR). The analyses were performed with data from 1793 patients in whom 24-h urine protein and phosphate, serum phosphate, FGF23, and klotho levels were measured simultaneously, obtained from the KoreaN cohort study for Outcome in patients With Chronic Kidney Disease (KNOW-CKD). Multivariable linear regression and mediation analyses were performed. Total, direct, and indirect effects were also estimated. Patients with high serum phosphate levels were found to be more likely to exhibit greater proteinuria, higher FGF23 levels, and lower klotho levels. The 24-h EP/GFR increased and the 24-h TRP/GFR decreased with increasing proteinuria and CKD progression. Simple mediation analyses showed that 15.4% and 67.9% of the relationship between proteinuria and the serum phosphate level were mediated by the FGF23/klotho ratio and 24-h EP/GFR, respectively. Together, these two factors accounted for 73.1% of the relationship between serum markers. These findings suggest that proteinuria increases the 24-h EP/GFR via the FGF23/klotho axis as a compensatory mechanism for the increased phosphate burden well before the reduction in renal function is first seen.
蛋白尿和高磷血症是慢性肾脏病（CKD）患者心血管疾病的危险因素。尽管蛋白尿和血清磷酸盐水平之间的相互作用已得到充分证实，但两者之间的机制联系，尤其是这种相互作用在多大程度上受到磷酸盐调节因子的介导，仍知之甚少。在这项研究中，我们检查了蛋白尿与血清磷酸盐水平之间的关联，以及潜在的介质，包括循环成纤维细胞生长因子（FGF23）/klotho、24 小时尿磷酸盐排泄率与肾小球滤过率的比值（EP/GFR）和 24 小时肾小管磷酸盐重吸收率与 GFR 的比值（TRP/GFR）。这些分析是使用来自韩国慢性肾脏病患者结局研究（KNOW-CKD）的 1793 名患者的数据进行的，这些患者同时测量了 24 小时尿液蛋白和磷酸盐、血清磷酸盐、FGF23 和 klotho 水平。进行了多变量线性回归和中介分析。还估计了总效应、直接效应和间接效应。发现血清磷酸盐水平较高的患者更有可能出现蛋白尿增加、FGF23 水平升高和 klotho 水平降低。随着蛋白尿和 CKD 进展的增加，24 小时 EP/GFR 增加，24 小时 TRP/GFR 减少。简单的中介分析表明，蛋白尿与血清磷酸盐水平之间的关系分别有 15.4%和 67.9%是由 FGF23/klotho 比值和 24 小时 EP/GFR 介导的。这两个因素共同解释了血清标志物之间关系的 73.1%。这些发现表明，蛋白尿通过 FGF23/klotho 轴增加 24 小时 EP/GFR，作为在肾功能下降之前首先出现的增加磷酸盐负担的补偿机制。
