A biomarker for vascular calcification: shedding light on an unfinished story?
A biomarker for vascular calcification: shedding light on an unfinished story?
复制标题
血管钙化的生物标志物：揭示一个未完成的故事？
DOI：
10.1093/cvr/cvab071
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发表时间：
2021
影响因子：
10.8
通讯作者：
Demer,LindaL
中科院分区：
文献类型：
--
作者：
Hsu,JeffreyJ;Tintut,Yin;Demer,LindaL
血管钙化（VC）在慢性肾脏病（CKD）患者中非常普遍，尤其是接受透析的终末期肾病（ESRD）患者。 1 在该患者群体中，VC，尤其是冠状动脉钙化，是死亡率的有力预测因子。 2 即使在年轻人中，VC 也会进展，尤其是肾功能下降（eGFR< 60–75 mL/min/1.73 m2）、3 蛋白尿恶化、4 和透析时间延长时。 3 与较高水平 VC 相关的不良临床结果包括急性心肌梗死、缺血性心脏事件、左心室肥厚和猝死。 4 除了 VC 的传统危险因素外，CKD 患者还存在矿物质代谢紊乱，特别是由于肾脏清除功能受损、继发性甲状旁腺功能亢进、维生素 D 状态改变和骨代谢异常而导致的高磷酸血症。 5 血清磷酸盐（一种已知的异位钙化促成因素）水平升高，以及钙化抑制剂（包括胎球蛋白-A、骨钙素、骨保护素、基质 GLA 蛋白和焦磷酸盐）水平降低，所有这些都为血管平滑肌细胞 (VSMC) 的转分化和细胞外基质的不受阻碍的矿化创造了环境。 6 托勒恰当地将这称为矿化的“完美风暴”。目前，VC 使用非侵入性成像方式（例如胸部 X 线摄影和计算机断层扫描 (CT)）或侵入性技术（例如冠状动脉血管内超声）来识别。虽然 VC 经常在此类研究中偶然发现，但由于较高的 CAC 评分与较差的预后密切相关，使用心脏 CT 作为计算冠状动脉钙 (CAC) 评分的筛查测试的情况显着增加。这些成像方式被广泛使用，但成本、可用性和辐射暴露等因素可能会限制某些患者的使用。因此，识别血液中可以识别 VC 存在的循环生物标志物可以提供更有吸引力的替代方案。在本期中，Chao 等人使用细致、逐步的 miRNA 和转录组分析。 7 确定了一组新的循环血清生物标志物，用于诊断 ESRD 患者尿毒症 VC 的存在和严重程度。研究人员使用来自尿毒症细胞培养物和啮齿动物模型的样本的 miRNA 和 mRNA 微阵列来寻找差异调节的 miRNA。他们的初步分析发现，随着 VC 水平的增加，122 个下调的 miRNA 和 119 个上调的 miRNA。他们使用生物信息学辅助方法对与目标基因的匹配趋势进行排序，将候选 miRNA 生物标志物缩小到 9 个 VC 下调的 miRNA。使用原始体外和体内模型以及额外的离体 VC 模型对这 9 个候选基因进行了进一步的实验验证，进一步将候选基因范围缩小到 4 个 miRNA（miR-10b-5p、miR-195、miR125b-2-3p 和 miR-378a-3p）和 1 个 mRNA (SULF1)。最后，他们测量了两组患者中这些候选药物的循环水平：依赖透析的 ESRD 患者和非透析依赖的 CKD 患者。在这两个队列中，他们发现 VC 严重程度与 miR-125b-2-3p 和 mir-378a-3p 血清水平降低相关，而与 miR-378a-3p 潜在靶标 SULF1 水平升高相关。在回归分析中，他们得出结论，miRNA/mRNA 对——miR-378a-30/SULF1——与传统临床特征相结合似乎有助于改善 CKD/ESRD 患者尿毒症 VC 的严重程度的诊断和分类。作者……
Vascular calcification (VC) is highly prevalent in patients with chronic kidney disease (CKD), and particularly those with end-stage renal disease (ESRD) on dialysis. 1 In this patient population, VC, especially coronary artery calcification, is a strong predictor of mortality. 2 Even in young adults, VC progresses, particularly with declining kidney function (eGFR< 60–75 mL/min/1.73 m2), 3 worsening albuminuria, 4 and longer duration of dialysis. 3 The adverse clinical outcomes associated with higher levels of VC include acute myocardial infarction, ischaemic cardiac events, left ventricular hypertrophy, and sudden death. 4 In addition to traditional risk factors for VC, patients with CKD have disordered mineral metabolism, particularly hyperphosphataemia, resulting from impaired renal clearance, secondary hyperparathyroidism, alterations in vitamin D status, and abnormal bone metabolism. 5 Increased levels of serum phosphate, a known contributor to ectopic calcification, and reduced levels of calcification inhibitors, including fetuin-A, osteocalcin, osteoprotegerin, matrix GLA protein, and pyrophosphate, all create a milieu for trans-differentiation of vascular smooth muscle cells (VSMCs) and unopposed mineralization of the extracellular matrix. 6 Towler has aptly termed this a ‘perfect storm’for mineralization. VC is currently identified using non-invasive imaging modalities, such as chest radiography and computed tomography (CT), or invasive techniques, such as intravascular ultrasound of the coronary arteries. While VC is often incidentally found on such studies, there has been a marked rise in the use of cardiac CT as a screening test to calculate a coronary artery calcium (CAC) score, owing to the strong association of higher CAC scores with worse prognoses. These imaging modalities are widely used, yet factors such as cost, availability, and radiation exposure may limit their accessibility to some patients. Accordingly, the identification of circulating biomarkers in the blood that can identify the presence of VC could offer a more appealing alternative. In this issue, using meticulous, step-wise miRNA and transcriptomic profiling, Chao et al. 7 identified a novel panel of circulating serum biomarkers for diagnosing the presence and severity of uraemic VC in patients with ESRD. The researchers used miRNA and mRNA microarrays of samples from uraemic cell culture and rodent models to search for differentially regulated miRNAs. Their initial analysis identified 122 down-regulated and 119 up-regulated miRNAs with increasing levels of VC. Using a bioinformatics-assisted approach that sorted for matching trends with target genes, they narrowed the miRNA biomarker candidates to nine miRNAs that were down-regulated with VC. These nine candidates were further validated experimentally using the original in vitro and in vivo models, as well as an additional ex vivo VC model, which further narrowed their candidates to four miRNAs (miR-10b-5p, miR-195, miR125b-2-3p, and miR-378a-3p) and one mRNA (SULF1). Finally, they measured circulating levels of these candidates in two cohorts of patients: dialysis-dependent patients with ESRD and non-dialysisdependent patients with CKD. In both cohorts, they found that VC severity correlated with decreased serum levels of miR-125b-2-3p and mir-378a-3p, whereas it correlated with increased levels of SULF1, a potential target of miR-378a-3p. In their regression analyses, they conclude that the miRNA/mRNA pair—miR-378a-30/SULF1—in combination with traditional clinical features appears to be useful for improved diagnosis and classification of severity of uraemic VC in patients with CKD/ESRD. The authors …