Supplementary Material for: Serum Obestatin: A Biomarker of Cardiovascular and All-Cause Mortality in Hemodialysis Patients

<b><i>Background:</i></b> Recent experimental studies have suggested that obestatin, a proposed anorexigenic gut hormone and a physiological opponent of acyl-ghrelin, has protective cardiovascular effects. We tested the hypothesis that obestatin is independent of inflammatory mediators and/or acyl-ghrelin in predicting outcomes of the maintenance hemodialysis (MHD) population. <b><i>Methods:</i></b> It was a 6-year cohort study on 261 MHD patients. Obestatin, acyl-ghrelin, adipokines (leptin and adiponectin), markers of inflammation and nutrition, prospective all-cause and cardiovascular mortality were studied. <b><i>Results:</i></b> During the follow-up, 160 patients died in total, with 74 deaths due to cardiovascular causes. For each ng/mL increase in baseline obestatin level in fully adjusted models (including malnutrition-inflammation score, Interleukin-6 [IL-6], adipokines and acyl-ghrelin), the hazard for death from all causes was 0.90 (95% CI 0.81–0.99) and for cardiovascular death 0.85 (95% CI 0.73–0.99). However, these associations were more robust in the subgroup of patients aged above 71 years: 0.85 (95% CI 0.73–0.98) for all-cause death and 0.66 (95% CI 0.52–0.85) for cardiovascular death. An interaction between high IL-6 (above median) and low obestatin (below median) levels for increased risk of all-cause mortality (synergy index [SI] 5.14, <i>p</i> = 0.001) and cardiovascular mortality (SI 4.81, <i>p</i> = 0.02) emerged in the development of multivariable adjusted models. Interactions were also observed between obestatin, Tumor necrosis factor-alpha, adipokines and acyl-ghrelin, which were associated with mortality risk. <b><i>Conclusion:</i></b> Serum obestatin behaves as a biomarker for cardiovascular and all-cause mortality in MHD patients. The prognostic ability of obestatin in this regard is independent of inflammation, nutritional status, acyl-ghrelin’s and adipokines’ activity and is modified by age being very prominent in patients older than 71 years.

背景：近期实验研究表明，肥胖抑制素（obestatin）是一种被提出的厌食性胃肠激素，同时也是酰基生长激素释放肽（acyl-ghrelin）的生理性拮抗物，具有心血管保护作用。本研究旨在验证如下假说：在预测维持性血液透析（maintenance hemodialysis, MHD）人群的预后时，肥胖抑制素的作用独立于炎症介质和/或酰基生长激素释放肽。
方法：本研究为一项纳入261例MHD患者的6年队列研究。研究检测了肥胖抑制素、酰基生长激素释放肽、脂肪细胞因子（瘦素（leptin）和脂联素（adiponectin））、炎症与营养标志物，并前瞻性记录了全因死亡及心血管死亡结局。
结果：随访期间，共计160例患者死亡，其中74例死于心血管疾病。在完全校正模型（包含营养不良-炎症评分、白细胞介素-6（Interleukin-6, IL-6）、脂肪细胞因子及酰基生长激素释放肽）中，基线肥胖抑制素水平每升高1 ng/mL，全因死亡风险比为0.90（95%置信区间：0.81~0.99），心血管死亡风险比为0.85（95%置信区间：0.73~0.99）。上述关联在年龄＞71岁的亚组患者中更为显著：该亚组的全因死亡风险比为0.85（95%置信区间：0.73~0.98），心血管死亡风险比为0.66（95%置信区间：0.52~0.85）。多变量校正模型分析显示，高IL-6水平（高于中位数）与低肥胖抑制素水平（低于中位数）存在交互作用，可升高全因死亡风险（协同指数（synergy index, SI）=5.14，p=0.001）及心血管死亡风险（SI=4.81，p=0.02）。此外，肥胖抑制素与肿瘤坏死因子-α（Tumor necrosis factor-alpha, TNF-α）、脂肪细胞因子及酰基生长激素释放肽之间也存在交互作用，上述交互作用均与死亡风险相关。
结论：血清肥胖抑制素可作为MHD患者心血管死亡及全因死亡的生物标志物。肥胖抑制素的上述预后预测能力独立于炎症状态、营养状况、酰基生长激素释放肽及脂肪细胞因子的活性，且受年龄因素调节，在71岁以上的患者中该预测作用尤为显著。