Inflammation and Cardiovascular Disease Associated With Hemodialysis for End-Stage Renal Disease

Abstract

Chronic kidney disease (CKD) and cardiac insufficiency often co-exist, particularly in uremic patients on hemodialysis (HD). The occurrence of abnormal renal function in patients with cardiac insufficiency is often indicative of a poor prognosis. It has long been established that in patients with cardiac insufficiency, poorer renal function tends to indicate poorer cardiac mechanics, including left atrial reserve strain, left ventricular longitudinal strain, and right ventricular free wall strain (Unger et al., Eur J Heart Fail, 2016, 18(1), 103-12). Similarly, patients with chronic kidney disease, particularly uremic patients on HD, often have cardiovascular complications in addition to abnormal endothelial function with volume overload, persistent inflammatory states, calcium overload, and imbalances in redox responses. Cardiac insufficiency due to uremia is therefore mainly due to multifaceted non-specific pathological changes rather than pure renal insufficiency. Several studies have shown that the risk of adverse cardiovascular events is greatly increased and persistent in all patients treated with HD, especially in those who have just started HD treatment. Inflammation, as an important intersection between CKD and cardiovascular disease, is involved in the development of cardiovascular complications in patients with CKD and is indicative of prognosis (Chan et al., Eur Heart J, 2021, 42(13), 1244-1253). Therefore, only by understanding the mechanisms underlying the sequential development of inflammation in CKD patients and breaking the vicious circle between inflammation-mediated renal and cardiac insufficiency is it possible to improve the prognosis of patients with end-stage renal disease (ESRD). This review highlights the mechanisms of inflammation and the oxidative stress that co-exists with inflammation in uremic patients on dialysis, as well as the mechanisms of cardiovascular complications in the inflammatory state, and provides clinical recommendations for the anti-inflammatory treatment of cardiovascular complications in such patients.

Keywords: cardiovascular disease; chronic kidney disease; complement activation pathway; hemodialysis; immune response; inflammation; oxidative stress.

FIGURE 1

Complement activation promotes coagulation. C3, the initiator of the complement activation pathway, can be cleaved into effector components, namely C3a and C3b. In CKD-induced complement activation, C3a directly promotes coagulation by enhancing platelet aggregation and adhesion. Meanwhile, C3b promotes the synthesis of C5 convertase to induce C5 cleavage to produce C5a and C5b. C5a directly stimulates neutrophils and monocytes to increase the expression of TF and thus induce thrombosis. In renal replacement therapy, C5b comes into contact with the dialysis membrane and, together with multiple complements (C6–C9), mediates the production of MAC and induces coagulation. In turn, coagulation secondary to complement activation can amplify complement and coagulation activation through positive feedback from thrombin on C3 cleavage. TF, tissue factor; MAC, membrane attack complex; AP, alternative pathway; LP, lectin pathway; CP, classical pathway.

FIGURE 2

The occurrence of renal oxidative stress affects mitochondrial structure and function. (A). In normal humans, oxidative phosphorylation, tricarboxylic acid cycle, and FA-β-oxidation provide energy to the kidney and induce the production of low doses of ROS. OXPHOS mainly provide ATP to the proximal tubule to maintain the normal physiological function of the kidney. A decrease in OXPHOS capacity during kidney damage leads to an increase in NOX levels. Abnormal NOX levels lead to excessive ROS production exacerbating oxidative stress and inflammation and inducing the development of renal fibrosis. Meanwhile, renal disease impairs mitochondrial function during OXPHOS due to reduced renal degradation of H₂O₂ a FA-βnd disrupts FA-β oxidation. overexpression of CD36 leads to reduced lipid metabolism resulting in involvement and causes impaired FA-β oxidation, leading to excessive ROS production (Ge et al., 2020; Martínez-Klimova et al., 2020). Excess ROS leads to growth mitochondrial damage, 1) decreased mitochondrial protein synthesis, and increased catabolism (Liesa and Shirihai, 2013). 2) Increased mitochondrial autophagy, which occurs mainly through degradation of proteasomes by the PINK1-Parkin pathway and phagocytic receptor interactions. (B). Excess ROS impair FA-β-oxidation by impairing TCA cycle function. reduced FA-β-oxidation leads to lipid accumulation and aggravates renal function. In turn, impaired FA β-oxidation leads to a decrease in acetyl coenzyme A, further diminishing TCA capacity (Bobulescu, 2010). ROS, reactive oxygen species; OS, oxidative stress; OXPHOS, oxidative phosphorylation; TCA, tricarboxylic acid cycle; NOX, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase; H₂O₂, hydrogen peroxide; CD36, long-chain FA fractionation cluster36.