A Critical Role of Neutrophil-Driven Amplification of Chronic Microinflammation in the Biocompatibility of Hemodialysis

Abstract

This review highlights recent insights into the pathophysiology and therapeutic strategies for improving biocompatibility in hemodialysis. Hemodialysis activates the innate immune system, particularly the complement cascade and neutrophils, leading to acute microinflammation. Interleukin-8 (IL-8), which increases during dialysis, promotes neutrophil chemotaxis and neutrophil extracellular trap (NET) formation, triggering myeloperoxidase (MPO) release and oxidative stress. Neutrophil accumulation in atherosclerotic plaques exacerbates vascular inflammation through IL-6 upregulation. Elevated levels of IL-8, MPO, and NET-related biomarkers are associated with increased all-cause and cardiovascular mortality in dialysis patients. Strategies to mitigate these effects include the use of advanced membrane materials (e.g., AN69, vitamin E-coated, polymethyl methacrylate), novel dialysis modalities (e.g., high-volume online hemodiafiltration, cool dialysate, hydrogen-enriched dialysate), and citrate-based anticoagulation. These approaches aim to suppress complement activation, reduce oxidative stress, and limit neutrophil-induced damage. Enhancing biocompatibility is crucial for reducing cardiovascular complications and improving outcomes in dialysis patients. Suppressing the innate immune response during dialysis may become a future cornerstone in extracorporeal blood purification therapy.

Keywords: NETosis; biocompatibility; complement; hemodialysis; interleukin-6; interleukin-8; microinflammation.

Figure 1

The impact of biocompatibility on chronic microinflammation. When neutrophils are stimulated during hemodialysis, they undergo chemotaxis toward sites of systemic atherosclerosis, ischemia, and inflammation. In this process, neutrophils produce interleukin-8 (IL-8), forming a positive feedback loop that further enhances neutrophil chemotaxis. At the sites of infiltration, activated neutrophils stimulate interleukin-6 (IL-6) production from monocytes and macrophages. In other words, the biocompatibility of dialysis triggers acute microinflammation, which in turn amplifies and worsens local chronic microinflammation at distant lesion sites. Clinically, poor biocompatibility may increase the risk of exacerbating heart failure, sarcopenia, susceptibility to infections, cognitive impairment, and malnutrition.

Figure 2

Hemodialysis biocompatibility and microinflammation—molecular biological mechanisms. The dialysis membrane activates the complement system via the alternative pathway, leading to the production of C5a, which in turn activates neutrophils and monocytes. Activated neutrophils enhance local oxidative stress through the production of reactive oxygen species (ROS) via respiratory burst and degranulation (including the release of myeloperoxidase [MPO]). Neutrophils with enhanced chemotactic activity accumulate at sites such as atherosclerotic lesions where IL-8 is expressed, and amplify local inflammation and IL-6 production via NETosis. During dialysis, IL-8 production in neutrophils is stimulated, promoting the further clustering of neutrophils at lesion sites. In addition, dialysis materials can activate neutrophils independently of the complement system. Furthermore, damage-associated molecular patterns (DAMPs) released from neutrophils due to mechanical stress can also trigger NETosis.

Figure 3

Temporal changes in cytokines and chemokines during hemodialysis (Image). IL-6: interleukin-8, IL-8: inteleukin-8, MPO: myeloperoxidase, TNF-α: tumor necrosis factor-α [39,40,41,42,43].

Figure 4

Strategies for improving the biocompatibility of hemodialysis (including potential approaches). As fundamental strategies to enhance the biocompatibility of dialysis, two principal approaches can be identified: (1) inhibition of complement activation and (2) suppression of downstream proinflammatory mediators generated by neutrophil activation. For the former, complement adsorption or inhibition strategies are considered, such as the use of AN69 membranes or citrate-based anticoagulation, both of which have demonstrated efficacy in attenuating complement cascade activation. For the latter, targeted interventions include the attenuation of oxidative stress induced by neutrophil-derived myeloperoxidase (MPO) and reactive oxygen species (ROS) through agents such as citrate or molecular hydrogen (H₂), and the removal or adsorption of proinflammatory cytokines produced by neutrophil-monocyte lineage cells, as achieved with modalities like on-line hemodiafiltration (HDF) or polymethylmethacrylate (PMMA) membranes. Collectively, these measures are expected to mitigate neutrophil extracellular trap (NET) formation at distant inflammatory foci, thereby reducing chronic microinflammation and its systemic consequences.