**2. Bio-incompatibility of dialysis membranes, activation of oxidative stress, and inflammation**

CKD in RRT is characterized by higher level of uremia and the impact of dialysis procedure itself. Despite the successes of modern hemodialysis therapy, the problem of hemodialysis membranes' bio-incompatibility is still unresolved. A key inducer of blood cell activation is dialyzer membrane material, along with the endotoxin contamination of dialysis solutions. Membrane contact with blood causes proinflammatory and pro-oxidant stress, thrombosis, and release of oxidative stress biomarkers, inflammatory and anti-inflammatory cytokines (IFN-γ, TNF-α, IL -1β, IL-4, IL-6, IL-10, IL-12, and IL-18), and acute phase proteins (C-reactive protein, fibrinogen) [5]. Other consequences of bio-incompatibility are complement [6] and platelet activation [7].

The oxidative events induced by extracorporeal treatment are thought to affect the concomitant pathology. Chronic inflammation, besides cardiovascular dysfunction, contributes to worsening renal anemia by reducing sensitivity to the erythropoietin-stimulating agent and shortening the life span of red blood cells [8, 9]. Also, blood leukocyte activation, oxidative stress, and mechanical factors damage the red blood cells. Leukocytes in contact with bio-incompatible dialysis membranes re-activate. The resultant leukopeniais considered a major cause of defective cellular immune response in patients on hemodialysis (HD) [10, 11]. Changes in lymphocyte phenotype (from Th1 to Th2) cause this response and excessive synthesis of pro-inflammatory cytokines [5]. Bio-incompatible membranes release pyrogens and active inflammatory mediators (histamine and bradykinin). These contribute to fever and hemodialysis-induced hypotension [12]. The latter is a key factor in residual renal function reducing in patients on regular HD [13].

Dialysate composition for peritoneal dialysis (PD) can also cause oxidative stress and inflammation [14, 15]. High concentrations of glucose and lactate, and low pH or hyperosmolality of dialysate for PD contribute to excessive production of reactive oxygen species and accumulation of oxidative damage products in the peritoneum, increasing calcification and fibrosis. The relationship between the preserved residual renal function and oxidative stress has been shown to correlate with cardiovascular risk and survival in patients on PD [14]. Given the longer preservation of residual renal function in patients on PD treatment, this method can be considered more favorable for patients with cardiovascular diseases (CVD). Also, several studies have shown a higher accumulation of oxidants and depletion of antioxidant reserves in patients on HD compared with those on PD [15, 16].

The accumulation of oxidative stress products is the highest in patients with ESRD. Peroxidizing agents oxidize unsaturated lipids [17–19] and endogenous pro-oxidants damage plasma proteins with the formation of glycation products [20–22]. Small reactive carbonyls and larger posttranslational uremic-modified proteins form many inflammatory mediators, reflecting uremic toxicity that is little dependent on the method of dialysis therapy [23]. However, all modern diffusion, convective, or mixed methods do not remove medium- and high-molecular-weight dissolved substances modified by reactive oxygen species (ROS) and reactive carbonyls effectively from blood [24–26].

Oxidative stress plays a key role in the development of cardiac dysfunction in patients on RRT. In patients with ESRD, the balance between nitric oxide (NO) and ROS is shifted toward the latter by increasing ROS production and decreasing NO availability [27]. Pro-inflammatory cytokines such as IL-1β, IL-6, TNF-α can stimulate renin synthesis and norepinephrine secretion [28, 29]. IL-6 induces AT-1 receptors and angiotensin II-mediated ROS production in cultured rat smooth muscle cells, supporting the link between inflammation, renin-angiotensin-aldosterone system (RAAS) activation, and oxidative stress [30]. Volume overload on RRT and venous stasis are additional sources of inflammatory mediators [31, 32]. Because of intravascular overload, the vascular endothelium may be a major source of cytokine production in response to biomechanical stress [33]. Thus, the above data confirms the potential role of circulating cellular precursors of ROS and/or local agonists of ROS synthesis in the development of CRS in dialysis patients.

C. Vida et al. have shown in dialysis patients the activation of peripheral blood polymorphonuclear and mononuclear leukocytes, which leads to excess production of oxidative compounds such as reactive oxygen species, and it is this process that plays the leading role [34].

The imbalance between the RAAS, sympathetic nervous system, and inflammation speeds up the CRS formation in dialysis patients. To prevent and slow the cardiac pathology in HD treatment, highly purified dialysis solutions and synthetic dialysis membranes are being developed to reduce the risk of oxidative stress and other manifestations caused by low biocompatibility of membranes. For example, dialysis membranes made of regenerated cellulose that interact with the β-Dglucose hydroxyl groups of blood components cause activation of the complement system and leukopenia. To improve the biocompatibility of these membranes, hydroxyl groups are modified chemically by acetylation to produce triacetate cellulose or addition of D-α-tocopherol polyethylene glycol-1000 succinate chains, an esterified form of α-tocopherol. HD and PD in CKD permanently excrete antioxidants through the membranes. To normalize their blood levels and suppress ROS generation in patients on HD, vitamins C, E, and glutathione are supplemented orally [27].
