Leierer Johannes, Salib Madonna, Evgeniou Michail, Rossignol Patrick, Massy Ziad A, Kratochwill Klaus, Mayer Gert, Fellström Bengt, Girerd Nicolas, Zannad Faiez, Perco Paul
Medical University of Innsbruck, Department of Internal Medicine IV, Innsbruck, Austria.
Université de Lorraine, Inserm, Centre d'Investigations Cliniques- 1433, and Inserm U1116, CHRU Nancy, F-CRIN INI-CRCT, Nancy, France.
Heliyon. 2024 May 6;10(9):e30709. doi: 10.1016/j.heliyon.2024.e30709. eCollection 2024 May 15.
Statins are widely used to reduce the risk of cardiovascular disease (CVD). Patients with end-stage renal disease (ESRD) on hemodialysis have significantly increased risk of developing CVD. Statin treatment in these patients however did not show a statistically significant benefit in large trials on a patient cohort level.
We generated gene expression profiles for statins to investigate the impact on cellular programs in human renal proximal tubular cells and mesangial cells in-vitro. We subsequently selected biomarkers from key statin-affected molecular pathways and assessed these biomarkers in plasma samples from the AURORA cohort, a double-blind, randomized, multi-center study of patients on hemodialysis or hemofiltration that have been treated with rosuvastatin. Patient clusters (phenotypes) were created based on the identified biomarkers using Latent Class Model clustering and the associations with outcome for the generated phenotypes were assessed using Cox proportional hazards regression models. The multivariable models were adjusted for clinical and biological covariates based on previously published data in AURORA.
The impact of statin treatment on mesangial cells was larger as compared with tubular cells with a large overlap of differentially expressed genes identified for atorvastatin and rosuvastatin indicating a predominant drug class effect. Affected molecular pathways included TGFB-, TNF-, and MAPK-signaling and focal adhesion among others. Four patient clusters were identified based on the baseline plasma concentrations of the eight biomarkers. Phenotype 1 was characterized by low to medium levels of the hepatocyte growth factor (HGF) and high levels of interleukin 6 (IL6) or matrix metalloproteinase 2 (MMP2) and it was significantly associated with outcome showing increased risk of developing major adverse cardiovascular events (MACE) or cardiovascular death. Phenotype 2 had high HGF but low Fas cell surface death receptor (FAS) levels and it was associated with significantly better outcome at 1 year.
In this translational study, we identified patient subgroups based on mechanistic markers of statin therapy that are associated with disease outcome in patients on hemodialysis.
他汀类药物被广泛用于降低心血管疾病（CVD）风险。接受血液透析的终末期肾病（ESRD）患者发生CVD的风险显著增加。然而，在大型试验中，针对这些患者的他汀类药物治疗在患者队列水平上并未显示出统计学上的显著益处。
我们生成了他汀类药物的基因表达谱，以研究其对人肾近端小管细胞和系膜细胞体外细胞程序的影响。随后，我们从他汀类药物影响的关键分子途径中选择生物标志物，并在AURORA队列的血浆样本中评估这些生物标志物。AURORA队列是一项针对接受血液透析或血液滤过且已接受瑞舒伐他汀治疗的患者的双盲、随机、多中心研究。使用潜在类别模型聚类基于已识别的生物标志物创建患者聚类（表型），并使用Cox比例风险回归模型评估所生成表型与结局的关联。多变量模型根据AURORA先前发表的数据对临床和生物学协变量进行了调整。
与肾小管细胞相比，他汀类药物治疗对系膜细胞的影响更大，阿托伐他汀和瑞舒伐他汀鉴定出的差异表达基因有很大重叠，表明存在主要的药物类别效应。受影响的分子途径包括TGFB、TNF和MAPK信号通路以及粘着斑等。根据八种生物标志物的基线血浆浓度鉴定出四个患者聚类。表型1的特征是肝细胞生长因子（HGF）水平低至中等，白细胞介素6（IL6）或基质金属蛋白酶2（MMP2）水平高，并且它与结局显著相关，显示发生主要不良心血管事件（MACE）或心血管死亡的风险增加。表型2的HGF水平高但Fas细胞表面死亡受体（FAS）水平低，并且在1年时与显著更好的结局相关。
在这项转化研究中，我们基于他汀类药物治疗的机制标志物确定了患者亚组，这些亚组与血液透析患者的疾病结局相关。
