What else matters for endothelial dysfunction biomarkers in hemodialysis patients?

What else matters for endothelial dysfunction biomarkers in hemodialysis patients?Dear editors, We read with great interest the recent study by lo et al. [1], which elegantly demonstrates that serum lipoprotein(a) (lp(a)) levels are negatively correlated with the vascular reactivity index (Vri) and may serve as a potential biomarker for the early detection of endothelial dysfunction (eD) in maintenance hemodialysis (mHD) patients.thisfinding enriches the understanding of eD biomarkers in mHD patients.eD is highly prevalent in mHD patients, owing to the combined impact of uremic toxins, chronic inflammation, oxidative stress, and dialysis-related factors such as bioincompatibility.As lp(a) exerts pro-inflammatory, pro-atherogenic, and pro-thrombotic effects by competing with plasminogen and activating monocytes [2], its role as a candidate biomarker for eD is biologically plausible and clinically relevant.However, eD is a complex multifactorial disorder triggered by a diverse array of pathways (Figure 1) [3], and single-biomarker assessment is insufficient to capture the full spectrum of endothelial injury in mHD patients.We aim to complement the findings of lo et al. [1] by discussing additional eD-related biomarkers, therapeutic targets and key clinical confounders.First, monocyte chemoattractant protein 1 (mcP1), a key pro-inflammatory cytokine that mediates endothelial injury and is closely associated with eD in cKD patients, has been demonstrated to contribute to arteriovenous (AV) fistula failure in dialysis patients [4].myostatin, a member of the transforming growth factor- superfamily secreted by mature muscle cells, exerts endotheliotoxic effects in the presence of uremic concentrations of indoxyl sulfate, amplifies the upregulation of mcP-1, and contributes to AV access complications [5].moreover, early AV fistula failure is closely related to eD, and different vascular access types (central venous catheter vs. AV fistula vs. AV graft) may have distinct impacts on baseline endothelial function due to differences in vascular injury and hemodynamic changes.Second, endocan, a glycoprotein specifically secreted by activated endothelial cells, has emerged as a key mediator of inflammation, vascular smooth muscle cells proliferation, and angiogenesis, and serves as a novel biomarker for eD in chronic kidney disease(cKD) and mHD patients.Plasma endocan levels are significantly elevated in cKD patients (4.7 ng/ml, interquartile range(ir) 1.9-9.4ng/ml) compared with controls (1.2 ng/ml, ir 1.1-1.5 ng/ml, p < 0.001), with values progressively higher across stages of cKD [6].A recent study of 122 mHD patients further confirmed that the development of aortic stiffness was independently associated with endocan (or 1.566, 95% ci 1.224 ~ 2.002, p < 0.001), and logarithmically transformed endocan was an independent predictor of carotid-femoral pulse wave velocity ( = 0.405, adjusted r 2 change = 0.152, p < 0.001) upon multivariate liner regression analysis [7].However, endocan levels are not specific to eD, as they can also be influenced by systemic inflammation, oxidative stress and comorbid cardiovascular diseases.third, serum asymmetric dimethylarginine (ADmA), a well-recognized marker of eD and nitric oxide synthase inhibition, has been shown to respond to targeted pharmacological interventions in mHD patients.in a randomized, double-blind, placebo-controlled trial of 135 hypertensive mHD patients, 16-week treatment with ramipril (2.5 mg daily) resulted in a marked reduction in serum ADmA levels, indicating its potential to improve biomarkers of eD [8].Similarly, a prospective, placebo-controlled, block-randomized, double-blinded study demonstrated that oral febuxostat significantly lowered serum ADmA levels and high-sensitivity c-reactive protein levels in mHD patients, with a direct ameliorating