使用聚甲基丙烯酸甲酯膜进行高通量血液透析可降低可溶性CD40L，其为尿毒症中心血管疾病的一种介质。

High-flux hemodialysis with polymethylmethacrylate membranes reduces soluble CD40L, a mediator of cardiovascular disease in uremia.

作者信息

Marengo Marita, Migliori Massimiliano, Merlotti Guido, Naso Erika, Dellepiane Sergio, Medica Davide, Cappellano Giuseppe, Cortazzi Simone, Colombatto Andrea, Quercia Alessandro D, Sacco Colombano, Leonardi Gianluca, Randone Olga, Maffei Stefano, Mancini Elvira, Borzumati Maurizio, Fabbrini Paolo, Vidali Matteo, Grossini Elena, Medana Claudio, Bello Federica Dal, Quaglia Marco, Panichi Vincenzo, Cantaluppi Vincenzo

机构信息

Nephrology and Dialysis Unit, ASL CN1, Cuneo, Italy.

Nephrology and Dialysis Unit, Versilia Hospital ASL Toscana Nord-Ovest, Camaiore (LU), Italy.

出版信息

Nephrol Dial Transplant. 2025 Jun 6. doi: 10.1093/ndt/gfaf101.

DOI:10.1093/ndt/gfaf101

PMID:40478750

Abstract

BACKGROUND AND HYPOTHESIS

Major Adverse Cardiovascular Events (MACE) are the main cause of mortality in hemodialysis (HD). Soluble CD40Ligand (sCD40L) binds to CD40 on endothelial cells (EC) and vascular smooth muscle cells (VSMC), playing a potential role in MACE. HD Registries showed a reduced mortality for MACE using the polymethylmethacrylate (PMMA) membrane. Study objectives: (1) to confirm the role of sCD40 L as independent predictor and mediator of MACE; (2) to evaluate the effect of PMMA on sCD40L-mediated vascular aging.

METHODS

In 201 patients treated by high-flux HD, sCD40 L levels were measured and correlated with MACE; 54/201 patients with sCD40L ≥ median value were randomized for 9 months in 2 cross-over groups alternatively treated with PMMA or polysulfone (PS): sCD40 L and dialytic parameters were recorded. In vitro, the role of sCD40 L was studied on EC dysfunction and VSMC calcification after incubation with patients' sera: cells engineered to knock down CD40 by siRNA were also used to confirm the role of CD40-CD40 L pathway activation.

RESULTS

At study admission, the sCD40 L median level of 8.4 ng/ml (IQR 2.9-12.7) showed the best statistical performance to identify MACE, that occurred in 51/201 (25.4%) patients. Indoxyl sulfate (IS) and p-Cresyl Sulfate (pCS) directly correlated with sCD40L levels and induced its release by platelets. In comparison to PS, PMMA treatment significantly reduced sCD40 L levels, in accordance with its enhanced mass removal by adsorption. In vitro, sera collected after PMMA treatment reduced EC dysfunction and VSMC osteoblastic differentiation through a mechanism involving the CD40-CD40 L pathway.

CONCLUSION

sCD40 L is an independent predictor and mediator of MACE in chronic HD patients. PMMA membrane stably reduced sCD40 L under the high-risk cut-off of 8.4 ng/ml. In vitro studies confirmed the role of PMMA in the reduction of EC dysfunction and VSMC calcification in association with sCD40 L modulation.

摘要

背景与假设

主要不良心血管事件（MACE）是血液透析（HD）患者死亡的主要原因。可溶性CD40配体（sCD40L）与内皮细胞（EC）和血管平滑肌细胞（VSMC）上的CD40结合，在MACE中发挥潜在作用。血液透析登记研究表明，使用聚甲基丙烯酸甲酯（PMMA）膜可降低MACE导致的死亡率。研究目的：（1）确认sCD40L作为MACE独立预测因子和介导因子的作用；（2）评估PMMA对sCD40L介导的血管老化的影响。

方法

对201例接受高通量血液透析治疗的患者测定sCD40L水平，并将其与MACE进行相关性分析；将201例sCD40L≥中位数的患者中的54例随机分为2个交叉组，分别交替接受PMMA或聚砜（PS）治疗9个月：记录sCD40L和透析参数。在体外，研究sCD40L与患者血清孵育后对EC功能障碍和VSMC钙化的作用：还使用经小干扰RNA（siRNA）设计敲低CD40的细胞来确认CD40 - CD40L途径激活的作用。

结果

研究入组时，sCD40L中位数水平为8.4 ng/ml（四分位间距2.9 - 12.7），在识别MACE方面具有最佳统计学表现，201例患者中有51例（25.4%）发生了MACE。硫酸吲哚酚（IS）和对甲酚硫酸盐（pCS）与sCD40L水平直接相关，并诱导血小板释放sCD40L。与PS相比，PMMA治疗显著降低了sCD40L水平，这与其通过吸附增强物质清除作用一致。在体外，PMMA治疗后收集的血清通过涉及CD40 - CD40L途径的机制降低了EC功能障碍和VSMC成骨细胞分化。