Supplementary Material for: Serum Calcification Propensity and Fetuin-A: Biomarkers of Cardiovascular Disease in Kidney Transplant Recipients

<b><i>Background:</i></b> “T50,” shortened transformation time from primary to secondary calciprotein particles may reflect deranged mineral metabolism predisposing to vascular calcification and cardiovascular disease (CVD). The glycoprotein fetuin-A is a major T50 determinant. <b><i>Methods:</i></b> The Folic Acid For Vascular Outcome Prevention In Transplantation (FAVORIT) cohort is a completed, large, multiethnic controlled clinical trial cohort of chronic, stable kidney transplant recipients (KTRs). We conducted a longitudinal case-cohort analysis using a randomly selected subcohort of patients, and all individual cases who developed CVD. Serum T50 and fetuin-A were determined in this total of <i>n</i> = 685 FAVORIT trial participants at randomization. <b><i>Results:</i></b> During a median surveillance of 2.18-years, 311 incident or recurrent CVD events occurred. Shorter T50 (minutes) or reduced fetuin-A concentrations (g/L) were associated with CVD after adjustment for treatment assignment, systolic blood pressure, age, sex, race, preexisting CVD and diabetes, smoking, body mass index, total cholesterol/HDL cholesterol, kidney allograft vintage and type, calcineurin inhibitor, or lipid-lowering drug use, estimated glomerular filtration rate, and urinary albumin/creatinine: tertile 1 (lowest) to tertile 3 (highest) comparisons, T50, (hazard ratio [HR] 1.86; 95% CI 1.20–2.89); fetuin-A, (HR 2.25; 95% CI 1.38–3.69). Elevated high sensitivity c-reactive protein (hsCRP) was an effect modifier of both these associations. <b><i>Conclusions:</i></b> Shortened T50, as well as reduced fetuin-A levels, ostensible promoters of vascular calcification, remained associated with greater risk for CVD outcomes, after adjustment for major CVD risk factors, measures of kidney function and damage, and KTR clinical characteristics and demographics, in a large, multiethnic cohort of long-term KTRs. Increased hsCRP was an effect modifier of these CVD risk associations.

<b><i>研究背景：</i></b> “T50”即初级钙蛋白颗粒向次级钙蛋白颗粒转化的缩短时长，可反映矿质代谢紊乱，后者易诱发血管钙化与心血管疾病（cardiovascular disease, CVD）。糖蛋白胎球蛋白-A（fetuin-A）是调控T50水平的关键决定因子。<b><i>研究方法：</i></b> 叶酸用于移植术后血管结局预防（Folic Acid For Vascular Outcome Prevention In Transplantation, FAVORIT）队列是一项已完成的大型多种族对照临床试验队列，纳入对象为慢性稳定期肾移植受者（kidney transplant recipients, KTRs）。本研究采用纵向病例队列分析方案，纳入随机选取的患者亚队列，以及所有发生心血管疾病的病例。本研究共纳入n=685名FAVORIT试验的随机入组参与者，并于随机入组时检测其血清T50与胎球蛋白-A水平。<b><i>研究结果：</i></b> 在中位随访2.18年期间，共发生311例新发或复发性心血管疾病事件。在校正治疗分组、收缩压、年龄、性别、种族、既往心血管疾病与糖尿病、吸烟史、体质量指数、总胆固醇/高密度脂蛋白胆固醇比值、肾移植术后时长与移植类型、钙调磷酸酶抑制剂或调脂药物使用情况、估算肾小球滤过率，以及尿白蛋白/肌酐比值后，较短的T50（单位：分钟）或较低的胎球蛋白-A浓度（单位：g/L）均与心血管疾病风险升高相关：按第1分位（最低）与第3分位（最高）比较，T50的风险比（hazard ratio, HR）为1.86，95%置信区间（confidence interval, CI）为1.20~2.89；胎球蛋白-A的HR为2.25，95%CI为1.38~3.69。高敏C反应蛋白（high sensitivity c-reactive protein, hsCRP）水平升高是这两种关联的效应修饰因子。<b><i>研究结论：</i></b> 在针对大型多种族长期肾移植受者队列的分析中，在校正主要心血管疾病危险因素、肾功能与肾损伤指标，以及肾移植受者的临床特征与人口学特征后，缩短的T50与降低的胎球蛋白-A水平——二者均为血管钙化的潜在促发因素——仍与更高的心血管疾病结局风险相关。高敏C反应蛋白水平升高仍是上述心血管疾病风险关联的效应修饰因子。