Oxidative stress and nucleic acid oxidation in patients with chronic kidney disease

Abstract

Patients with chronic kidney disease (CKD) have high cardiovascular mortality and morbidity and a high risk for developing malignancy. Excessive oxidative stress is thought to play a major role in elevating these risks by increasing oxidative nucleic acid damage. Oxidative stress results from an imbalance between reactive oxygen/nitrogen species (RONS) production and antioxidant defense mechanisms and can cause vascular and tissue injuries as well as nucleic acid damage in CKD patients. The increased production of RONS, impaired nonenzymatic or enzymatic antioxidant defense mechanisms, and other risk factors including gene polymorphisms, uremic toxins (indoxyl sulfate), deficiency of arylesterase/paraoxonase, hyperhomocysteinemia, dialysis-associated membrane bioincompatibility, and endotoxin in patients with CKD can inhibit normal cell function by damaging cell lipids, arachidonic acid derivatives, carbohydrates, proteins, amino acids, and nucleic acids. Several clinical biomarkers and techniques have been used to detect the antioxidant status and oxidative stress/oxidative nucleic acid damage associated with long-term complications such as inflammation, atherosclerosis, amyloidosis, and malignancy in CKD patients. Antioxidant therapies have been studied to reduce the oxidative stress and nucleic acid oxidation in patients with CKD, including alpha-tocopherol, N-acetylcysteine, ascorbic acid, glutathione, folic acid, bardoxolone methyl, angiotensin-converting enzyme inhibitor, and providing better dialysis strategies. This paper provides an overview of radical production, antioxidant defence, pathogenesis and biomarkers of oxidative stress in patients with CKD, and possible antioxidant therapies.

Figure 1

Synthesis of reactive oxygen species (ROS) in patients with chronic kidney disease (CKD). Excessive reactive ROS including ONOO⁻, OH⁻, and OCl⁻ are generated from oxygen through several main enzymes (NADPH oxidase, superoxide dismutase (SOD), and myeloperoxidase (MPO)). Several factors can also increase ROS generation, including cytokines (IL-8, IL-1β, and TNF-α) released from activated monocytes, uremic toxin (indoxyl sulfate), and endotoxin (LPS) from the HC procedure. The resulting excessive ROS can lead to nitrosative (ONOO⁻), chlorinative (OCl⁻), and oxidative (OH⁻) modifications to lipids, proteins, and DNA.

Figure 2

Impairment of antioxidant system in patients with CKD. Antioxidant systems, including nonenzymatic systems (thiol, alpha-tocopherol, and ascorbic acid) and enzymatic systems (superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx)), are impaired or deficient in patients with CKD. Hyperhomocysteinemia can lead to inhibition of the activity of the antioxidant enzymes SOD and GPx. GR: glutathione reductase; GSH: glutathione; GSSG: glutathione disulfide; Se: selenium.