Supplementary Material for: Severe coronary artery calcifications in chronic kidney disease patients, coupled with inflammation and bone mineral disease derangement, promote major adverse cardiovascular events (MACE) through vascular remodeling

Introduction: Cardiovascular (CV) diseases persist as the foremost cause of morbidity/mortality among chronic kidney disease (CKD) patients. This paper examines the values of coronary artery calcifications (CAC) and biomarkers of CV on major adverse CV events (MACE)/CV death in a sample of 425 non-dialysis CKD patients.
Methods: At inclusion, patients underwent chest multidetector computed tomography for CAC scoring and biomarkers of CV risk including CRP, mineral metabolism markers, FGF-23, α-Klotho, osteoprotegerin, TRAP5b, sclerostin, Matrix-Gla-Protein (both dephosphorylated-uncarboxylated and total-uncarboxylated) and GDF-15 were measured. Patients were followed for a median of 3.61 years [25th-75th percentiles=1.92-6.70].
Results: Our results reported that CAC was a major independent factor of MACE/CV mortality showing a hazard ratio of 1.71 95% confidence interval=[1.00-2.93] after adjustment for age, gender, diabetes and history of CV events for patients with CAC>300. Interestingly, CAC effect was further enhanced in the presence of low levels of 25(OH) vitamin D3 or α-Klotho and high levels of iPTH, hsCRP, FGF-23, osteoprotegerin, sclerostin, dp-ucMGP or GDF-15.
Conclusion: CAC constitutes a significant CV risk, further exacerbated by inflammation, hyperparathyroidism and regulation of bone molecules implicated in calcification progression. This finding aligns with the original concept of multiple hits. Consequently, addressing the detrimental environment that fosters plaque vulnerability, reducing chronic low-grade inflammation, and normalizing mineral metabolism markers (such as vitamin D and PTH) and bone-regulating molecules may emerge as a viable therapeutic strategy.

引言：心血管疾病（CV）持续成为慢性肾脏病（CKD）患者发病率和死亡率的首要原因。本文旨在探讨冠状动脉钙化（CAC）及心血管生物标志物在425例非透析CKD患者样本中，对主要不良心血管事件（MACE）/心血管死亡的影响。方法：在纳入研究时，对患者进行胸部多排螺旋计算机断层扫描以评估CAC评分及心血管风险标志物，包括C反应蛋白、矿物质代谢标志物、FGF-23、α-Klotho、骨保护素、TRAP5b、硬化素、基质Gla蛋白（去磷酸化未羧化型及总未羧化型）和GDF-15。患者平均随访时间为3.61年[第25-75百分位数=1.92-6.70年]。结果：我们的研究结果显示，CAC是MACE/CV死亡率的主要独立预测因素，调整年龄、性别、糖尿病和心血管事件史后，CAC>300的患者风险比（HR）为1.71，95%置信区间为[1.00-2.93]。有趣的是，在25(OH)维生素D3或α-Klotho水平较低、iPTH、hsCRP、FGF-23、骨保护素、硬化素、dp-ucMGP或GDF-15水平较高的情况下，CAC的影响进一步加剧。结论：CAC构成了显著的 cardiovascular risk，进一步受到炎症、高血钙素症以及参与钙化进展的骨骼分子调节的影响。此发现与多因素打击的原始概念相吻合。因此，针对促进斑块脆弱性的有害环境进行干预，降低慢性低度炎症，以及正常化矿物质代谢标志物（如维生素D和PTH）及骨调节分子，可能成为一种可行的治疗策略。