The Role of Oxidative Stress and Systemic Inflammation in Kidney Disease and Its Associated Cardiovascular Risk

Abstract

Chronic kidney disease (CKD) is a major global health burden, with a prevalence of 10-15% and high mortality rates. In particular, CKD portends a disproportionately high risk of cardiovascular disease beyond the traditional cardiovascular risk factors, with pathophysiological factors such as oxidative stress, inflammation and hyperuricaemia considered to exert an additional role in accelerated atherosclerosis. The presence of heightened oxidative stress and systemic inflammation in CKD is associated with increased mortality. The possible underlying mechanisms include gut dysbiosis, dialysis factors, infections, metabolic acidosis and hyperuricaemia. The state of oxidative stress and systemic inflammation are closely linked and perpetuate each other resulting in progression of CKD and cardiovascular disease. Potential interventions to alleviate the oxidative stress and inflammation in CKD include lifestyle modifications including dietary changes and exercise, optimization of dialysis procedure and pharmacotherapeutic agents including antioxidants. They present a potentially highly effective approach to add to the currently available traditional risk-modification strategies. To date, the majority of the published trials have had a small number of participants with a short duration of follow up. Therefore, no robust evidence has been established. Larger trials with meaningful clinical outcomes and longer follow up are required to evaluate such potential therapies.

Mechanisms of Metabolic Acidosis–Induced Kidney Injury in Chronic Kidney Disease

“…108,156 Metabolic acidosis induces oxidative stress in the kidney that can stimulate further inflammation and fibrosis, extending the damage in the failing kidney. [157][158][159] CKD produces elevated oxidative stress, as evidenced by an increased concentration of reactive oxygen and nitrogen species, oxidized end products, and reduced levels of antioxidants in patients. 160,161 In cultured LLC-PK1 cells exposed to a chronic acid environment, total cellular glutathione and protein thiol content was reduced, along with an increase in glutathione peroxidase activity, ammonia generation, and the expression of heat shock proteins HSP70 and HSP60, all markers of oxidative stress.…”

“…163 Finally, oxidative stress and a chronically elevated inflammatory state in CKD may contribute to accelerated atherosclerosis via direct endothelial injury and alteration in nitrogen handling. 158 In animal models, prolonged acid exposure directly damages kidney substructures, such as podocytes and the glomerular filtration apparatus, and disrupts the signaling within proximal and distal tubules that is needed to maintain acid-base balance. 36,37 Sustained acid exposure causes cortical and tubular necrosis, and treating metabolic acidosis with calcium citrate in 5/6 nephrectomized rats ameliorated glomerular and tubule-interstitial damage as measured by reduction of glomerular and tubular proliferating cell nuclear antigen, a sensitive marker of direct cellular damage in the kidney.…”

Chronic Kidney Disease Interplay with Comorbidities and Carbohydrate Metabolism: A Review

“…Several factors contribute to heightened oxidative stress in individuals with CKD, including gut dysbiosis, hyperglycemia, dialysis, and inflammation [89][90][91][92].…”

Biomarkers of Uremic Cardiotoxicity

“…Inflammation and oxidative stress are well-known contributors for atherosclerosis, which is among the underlying mechanisms not only for progressive kidney damage, but also for CV comorbidity [ 8 , 9 , 10 , 11 ]. As biomarker of inflammation, interleukin 18 (IL-18), has been tested for being a predictor of CV mortality and seems to be a very important indicator of CV-related death in CKD patients [ 12 ].…”