Supplementary Material for: QTc interval prolongation independently associates with FGF23 and predicts mortality in predialysis CKD.

Introduction: QTc interval prolongation is increasingly frequent as CKD advances and predicts death in dialysis. However, predictors and mortality-risk in predialysis CKD are understudied. FGF23 induces left ventricular hypertrophy (LVH) which is associated with QTc interval prolongation and death, suggesting a possible pathway from FGF23 to death that entails LVH and QTc prolongation. We looked for links between FGF23 and prolonged QTc intervals mediated by LVH, and for deaths associated with QTc prolongation in a prospective observational cohort of patients with predialysis CKD. Methods: Participants underwent protocolized baseline and semi-annual FGF23 testing, baseline and study end echocardiograms, and baseline and annual electrocardiograms over three years. Results: 2,254 participants (34.1% female; mean age 68.7 years; mean glomerular filtration rate 41.4 ml/min/m2) enrolled. Baseline LVH (left ventricular mass index >131 g/m2 (>100 g/m2 if female)) was present in 10.8% and prolonged QTc intervals (>=500 ms) in 1.5%. One hundred thirty-eight (6.1%) participants died during the study. In generalized mixed effects regression, each unit increase in the natural log of FGF23 - but not LVH - predicted an odds ratio of 1.76 (1.15, 2.70, p=0.009) for prolonged QTc intervals independently of 15 other covariates. Mediation analysis showed that only 13% of FGF23's total effect on prolonged QTc intervals was mediated by LVH. Patients with prolonged QTc intervals had higher unadjusted (log rank p<0.001) and adjusted (hazard ratio 3.15 (1.38, 7.16, p=0.006)) mortality rates than those with QTc intervals <500 ms. Conclusions: QTc interval prolongation ≥500 ms was prospectively associated with FGF23 independently of LVH, and with a tripling of mortality-risk in patients with predialysis CKD.

引言：随着慢性肾脏病（Chronic Kidney Disease, CKD）的进展，QTc间期延长的发生率逐渐升高，且可预测透析患者的死亡风险。然而，目前针对透析前CKD患者的QTc间期延长预测因素及死亡风险的研究仍较为匮乏。成纤维细胞生长因子23（Fibroblast Growth Factor 23, FGF23）可诱发左心室肥厚（Left Ventricular Hypertrophy, LVH），而LVH与QTc间期延长及死亡风险升高均存在关联，这提示FGF23可能通过LVH介导QTc间期延长，进而导致患者死亡。本研究旨在探究透析前CKD患者中，FGF23与QTc间期延长之间是否存在LVH介导的关联，并分析QTc间期延长与患者死亡的相关性，研究对象为前瞻性观察队列中的透析前CKD患者。方法：本研究纳入的受试者均接受了标准化的基线及每半年一次的FGF23检测，在基线及研究终点时接受超声心动图检查，并在为期3年的随访期间接受基线及年度心电图检查。结果：本研究共纳入2254名受试者，其中女性占34.1%，平均年龄68.7岁，平均肾小球滤过率为41.4 ml/min/m²。基线时，10.8%的受试者存在左心室肥厚（左心室质量指数＞131 g/m²，女性受试者该阈值为＞100 g/m²），1.5%的受试者存在QTc间期延长（≥500 ms）。研究期间共有138名（6.1%）受试者死亡。广义混合效应回归分析显示，FGF23自然对数每升高1个单位（而非LVH），可使QTc间期延长的比值比达到1.76（95%置信区间：1.15~2.70，p=0.009），该关联独立于其他15项协变量。中介分析显示，LVH仅介导了FGF23对QTc间期延长总效应的13%。与QTc间期＜500 ms的受试者相比，QTc间期延长的受试者未经校正的死亡率更高（log-rank检验p＜0.001），校正后的死亡风险比为3.15（95%置信区间：1.38~7.16，p=0.006）。结论：在透析前CKD患者中，QTc间期延长≥500 ms与FGF23水平升高存在前瞻性关联，且该关联独立于LVH；同时，此类患者的死亡风险可升高至原来的3倍。