Supplementary Material for: Association of Serum Polyamines with Cardiovascular Events and All-Cause Mortality in Chronic Kidney Disease

Background: Emerging evidence indicates that serum polyamines, including putrescine, spermidine, and spermine, may serve as potential biomarkers for chronic kidney disease (CKD) and its progression. However, the association between serum polyamine levels, cardiovascular events, and mortality in CKD patients remains poorly understood.
Methods: A retrospective cohort study was conducted, involving 297 adult patients with CKD at stages 1-5 from March 2015 to September 2018, with follow-up until May 2023. Serum polyamine levels were quantified using high-performance liquid chromatography and subsequently categorized into quartiles. The Kaplan-Meier curve was employed to assess the survival probabilities of CV events and overall mortality in relation to serum polyamine levels. The relationship between serum polyamines and the risk of CVD and overall mortality was explored using univariate and multivariate Cox regression analyses. Furthermore, we conducted a competing-risk analysis to investigate the link between serum polyamines and CV events, with mortality as the competing event.
Results: Over a median follow-up of 6.11 years, our findings revealed a negative correlation between putrescine levels and estimated glomerular filtration rate (eGFR), while spermidine and spermine levels were positively correlated with eGFR. The Kaplan-Meier curve demonstrated that serum polyamines were significantly associated with risk of CV events and all-cause mortality. Moreover, Cox regression analyses showed that, in multivariate Cox model, patients in the highest quartile of putrescine displayed a significantly higher risk of CV events (hazard ratio [HR] 6.972, 95% confidence interval [CI] 2.520-19.242, p＜0.001) compared to those in the lowest quartile. Conversely, higher levels of spermidine were associated with a lower risk of CV events (HR= 0.077, 95% CI 0.022-0.274, p＜0.001), and higher levels of spermine also appeared to reduce the risk of CV events (HR= 0.180, 95% CI 0.061-0.530, p=0.002). The relationship between serum polyamines and CVD remained robust in the competing risk models. Additionally, in the multivariate model, spermidine and spermine showed a significant protective effect on the risk of overall mortality; however, the protective effect was diminished upon the inclusion of eGFR as a covariate.
Conclusions: Our study demonstrates significant disruption in serum polyamine levels among CKD patients, which correlates with eGFR. Altered polyamine levels are linked to an increased risk of CV events and overall mortality. Thus, serum polyamines may be considered valuable prognostic indicators for CKD patients.

背景：越来越多的证据表明，血清多胺（polyamines）——包括腐胺（putrescine）、亚精胺（spermidine）和精胺（spermine）——或可作为慢性肾脏病（chronic kidney disease, CKD）及其进展的潜在生物标志物。然而，目前对于慢性肾脏病患者血清多胺水平与心血管事件（cardiovascular events, CV）、死亡率之间的关联仍知之甚少。
方法：本研究为一项回顾性队列研究，纳入2015年3月至2018年9月期间的297例1~5期慢性肾脏病成年患者，随访至2023年5月。采用高效液相色谱法（high-performance liquid chromatography）对血清多胺水平进行定量检测，随后将其按四分位数进行分组。采用Kaplan-Meier曲线评估血清多胺水平与心血管事件、全因死亡率的生存概率关联。采用单因素及多因素Cox回归分析探讨血清多胺与心血管疾病（cardiovascular disease, CVD）发病风险及全因死亡率的关联。此外，本研究以死亡为竞争事件，开展竞争风险分析以探究血清多胺与心血管事件的关联。
结果：在中位随访6.11年期间，本研究结果显示，腐胺水平与估算肾小球滤过率（estimated glomerular filtration rate, eGFR）呈负相关，而亚精胺与精胺水平则与eGFR呈正相关。Kaplan-Meier曲线分析结果显示，血清多胺水平与心血管事件及全因死亡率风险存在显著关联。进一步的Cox回归分析结果显示，在多因素Cox模型中，腐胺最高四分位组患者的心血管事件风险显著高于最低四分位组患者（风险比[hazard ratio, HR] 6.972，95%置信区间[confidence interval, CI] 2.520~19.242，P＜0.001）。与之相反，亚精胺水平升高与心血管事件风险降低相关（HR=0.077，95%CI 0.022~0.274，P＜0.001），精胺水平升高同样可降低心血管事件风险（HR=0.180，95%CI 0.061~0.530，P=0.002）。竞争风险模型分析显示，血清多胺与心血管疾病的关联依然稳定。此外，在多因素模型中，亚精胺与精胺对全因死亡率风险具有显著的保护作用；但当将eGFR作为协变量纳入模型后，该保护作用有所减弱。
结论：本研究证实，慢性肾脏病患者的血清多胺水平存在显著紊乱，且该紊乱与eGFR相关。多胺水平异常与心血管事件及全因死亡率风险升高相关。因此，血清多胺或可作为慢性肾脏病患者具有价值的预后指标。