Bouma-de Krijger Annet, van Ittersum Frans J, Hoekstra Tiny, Ter Wee Pieter M, Vervloet Marc G
Department of Nephrology, VU University Medical Center Amsterdam, Amsterdam, The Netherlands.
Amsterdam Cardiovascular Sciences Institute (ACS), O2 | Building for Human Life Sciences, Amsterdam, The Netherlands.
Clin Kidney J. 2019 Mar 25;12(5):678-685. doi: 10.1093/ckj/sfz027. eCollection 2019 Oct.
High concentrations of both phosphate and fibroblast growth factor 23 (FGF23) observed in chronic kidney disease (CKD) are associated with an increased risk of cardiovascular morbidity and mortality. Pulse wave velocity (PWV) is a surrogate marker for cardiovascular events and all-cause mortality. It is not known whether a reduction of FGF23 or phosphate alters cardiovascular risk. Sevelamer has shown to have the ability to reduce both phosphate and FGF23 concentrations. Furthermore, reduction of PWV is reported with sevelamer use as well, but it is unclear if this is mediated by decline of phosphate or FGF23. We investigated if sevelamer induced a decline in PWV and if this was associated with a reduction in FGF23.
In all, 24 normophosphataemic CKD Stage 3 patients started treatment with a fixed dose of sevelamer-carbonate (Renvela) 2.4 g twice daily, with their usual diet for 8 weeks in a single-arm study. PWV was measured and blood samples were obtained before, during and after washout of treatment with sevelamer. Vascular calcification was quantified using the Kauppila Index (KI). The primary outcome was the change of PWV from baseline to 8 weeks of treatment and the secondary endpoint was the difference of FGF23 following treatment with sevelamer. One of the linear mixed models was used to analyse the association between treatment and outcome. Mediation analysis was performed as a sensitivity analysis. The study was registered in the Dutch trial register (http://www.trialregister.nl: NTR2383).
A total of 18 patients completed 8 weeks of treatment with sevelamer and were analysed. Overall, treatment with sevelamer did not induce a significant reduction of PWV (β = -0.36, P = 0.12). However, in patients with less vascular calcification (lower KI score), there was a statistically significant reduction of PWV, adjusted for mean arterial pressure, after treatment (β = 0.63, P = 0.02). Addition of FGF23 to the model did not alter this association. Mediation analysis yielded similar results. FGF23 did not decrease during treatment with sevelamer.
In this short-term pilot study in normophosphataemic CKD patients, treatment with sevelamer did not improve PWV. In subgroup analysis, however, PWV improved in patients with no or limited abdominal aorta calcifications. This was not associated with a decline of FGF23.
在慢性肾脏病（CKD）中观察到的高磷酸盐浓度和成纤维细胞生长因子23（FGF23）均与心血管疾病发病率和死亡率增加相关。脉搏波速度（PWV）是心血管事件和全因死亡率的替代标志物。尚不清楚FGF23或磷酸盐的降低是否会改变心血管风险。司维拉姆已显示出降低磷酸盐和FGF23浓度的能力。此外，也有报道称使用司维拉姆可降低PWV，但尚不清楚这是否是由磷酸盐或FGF23的下降介导的。我们研究了司维拉姆是否会导致PWV下降，以及这是否与FGF23的降低相关。
在一项单臂研究中，总共24例血磷酸盐正常的CKD 3期患者开始接受固定剂量的碳酸司维拉姆（Renvela）治疗，每日两次，每次2.4 g，并维持其日常饮食8周。在使用司维拉姆治疗前、治疗期间和洗脱期后测量PWV并采集血样。使用考皮拉指数（KI）对血管钙化进行量化。主要结局是从基线到治疗8周时PWV的变化，次要终点是司维拉姆治疗后FGF23的差异。使用线性混合模型之一分析治疗与结局之间的关联。进行中介分析作为敏感性分析。该研究已在荷兰试验注册库（http://www.trialregister.nl: NTR2383）注册。
共有18例患者完成了8周的司维拉姆治疗并接受分析。总体而言，司维拉姆治疗未导致PWV显著降低（β = -0.36，P = 0.12）。然而，在血管钙化较少（KI评分较低）的患者中，校正平均动脉压后，治疗后PWV有统计学显著降低（β = 0.63，P = 0.02）。在模型中加入FGF23并未改变这种关联。中介分析得出了类似的结果。司维拉姆治疗期间FGF23未降低。
在这项针对血磷酸盐正常的CKD患者的短期初步研究中，司维拉姆治疗并未改善PWV。然而，在亚组分析中，腹主动脉无钙化或钙化有限的患者PWV有所改善。这与FGF23的下降无关。
