Rossignol P, Duarte K, Bresso E, A Åsberg, Devignes M D, Eriksson N, Girerd N, Glerup R, Jardine A G, Holdaas H, Lamiral Z, Leroy C, Massy Z, März W, Krämer B, Wu P H, Schmieder R, Soveri I, Christensen J H, Svensson M, Zannad F, Fellström B
Université de Lorraine, Inserm, Centre d'Investigations Cliniques- 1433, and Inserm U1116, CHRU Nancy, F-CRIN INI-CRCT, 4, rue du Morvan, 54500 Nancy, France.
Department of Medical Specialties-Nephrology Hemodialysis, Princess Grace Hospital, and Monaco Private Hemodialysis Centre, Monaco, Monaco.
Eur Heart J Open. 2022 Nov 9;2(6):oeac069. doi: 10.1093/ehjopen/oeac069. eCollection 2022 Nov.
End-stage renal disease (ESRD) treated by chronic hemodialysis (HD) is associated with poor cardiovascular (CV) outcomes, with no available evidence-based therapeutics. A multiplexed proteomic approach may identify new pathophysiological pathways associated with CV outcomes, potentially actionable for precision medicine.
The AURORA trial was an international, multicentre, randomized, double-blind trial involving 2776 patients undergoing maintenance HD. Rosuvastatin vs. placebo had no significant effect on the composite primary endpoint of death from CV causes, nonfatal myocardial infarction or nonfatal stroke. We first compared CV risk-matched cases and controls ( = 410) to identify novel biomarkers using a multiplex proximity extension immunoassay (276 proteomic biomarkers assessed with Olink). We replicated our findings in 200 unmatched cases and 200 controls. External validation was conducted from a multicentre real-life Danish cohort [Aarhus-Aalborg (AA), = 331 patients] in which 92 Olink biomarkers were assessed. In AURORA, only -terminal pro-brain natriuretic peptide (NT-proBNP, positive association) and stem cell factor (SCF) (negative association) were found consistently associated with the trial's primary outcome across exploration and replication phases, independently from the baseline characteristics. Stem cell factor displayed a lower added predictive ability compared with NT-ProBNP. In the AA cohort, in multivariable analyses, BNP was found significantly associated with major CV events, while higher SCF was associated with less frequent CV deaths.
Our findings suggest that NT-proBNP and SCF may help identify ESRD patients with respectively high and low CV risk, beyond classical clinical predictors and also point at novel pathways for prevention and treatment.
慢性血液透析（HD）治疗的终末期肾病（ESRD）与不良心血管（CV）结局相关，且尚无循证治疗方法。多重蛋白质组学方法可能会识别出与CV结局相关的新病理生理途径，这可能对精准医学具有潜在的可操作性。
AURORA试验是一项国际多中心随机双盲试验，涉及2776例接受维持性HD的患者。瑞舒伐他汀与安慰剂相比，对CV原因导致的死亡、非致命性心肌梗死或非致命性中风的复合主要终点无显著影响。我们首先比较了CV风险匹配的病例和对照（n = 410），使用多重邻位延伸免疫分析（用Olink评估276种蛋白质组学生物标志物）来识别新的生物标志物。我们在200例未匹配的病例和200例对照中重复了我们的发现。从丹麦多中心真实队列[奥胡斯 - 奥尔堡（AA），n = 331例患者]进行外部验证，其中评估了92种Olink生物标志物。在AURORA试验中，在探索和重复阶段，仅发现N末端前脑钠肽（NT-proBNP，正相关）和干细胞因子（SCF）（负相关）与试验的主要结局始终相关，且独立于基线特征。与NT-ProBNP相比，干细胞因子的额外预测能力较低。在AA队列中，多变量分析发现BNP与主要CV事件显著相关，而较高的SCF与较少发生的CV死亡相关。
我们的研究结果表明NT-proBNP和SCF可能有助于识别CV风险分别高和低的ESRD患者，超越经典临床预测指标，也指出了预防和治疗的新途径。
