Wishful Thinking: The Surprisingly Sparse Evidence for a Relationship between Oxidative Stress and Cardiovascular Disease in Hemodialysis Patients

Abstract

The increased frequency of cardiovascular disease observed in hemodialysis patients is secondary to the combination of many traditional (age, male sex, hypertension, smoking, diabetes mellitus, and dyslipidemia) and novel and uremia-related (inflammation, uremic toxins, adipokine imbalance, coagulation disorders, protein-energy wasting, volume overload, endothelial dysfunction, hyperparathyroidism, and subclinical hypothyroidism) risk factors. Usually, in the latter group, oxidative stress is included. However, after decades of research, it remains essentially unknown if oxidative stress has a causative role in the development of cardiovascular disease in long-term hemodialysis patients because adequate longitudinal studies are lacking. Data deriving from cross-sectional studies suggest that biomarkers of oxidative stress are associated with cardiovascular disease prevalence. Conversely, conflicting and inconclusive results have been obtained on the association between oxidative stress and coronary artery calcification, atherosclerosis, and all-cause and cardiovascular disease-related outcome. It is desirable that further studies are conducted on this topic in the near future.

Mechanisms and Modulation of Oxidative/Nitrative Stress in Type 4 Cardio-Renal Syndrome and Renal Sarcopenia

“…The impairment of antioxidant defense mechanisms (e.g., decreased levels of vitamin C and E, deficiency in the glutathione scavenging system, etc.) become more pronounced only in ESRD (Bossola and Tazza, 2015 ). Nuclear factor-erythroid-2-related factor 2 (Nrf2) is a transcription factor which coordinates the induction of several genes including antioxidant and detoxifying enzymes and associated proteins (Kim and Vaziri, 2010 ; Ruiz et al, 2013 ).…”

“…Elevated systemic oxidative/nitrative stress is believed to be mainly the consequence of higher ROS/RNS production in CKD (Bossola and Tazza, 2015 ; Duni et al, 2017 ). Reduced clearance of pro-oxidant substances due to renal dysfunction and impaired antioxidant defense mechanisms supposed to play a complementary role (Duni et al, 2017 ).…”

“…), and hemodialysis-related factors (e.g., membrane bio-incompatibility, endotoxins, etc.) especially in ESRD patients on long-term dialysis (Bossola and Tazza, 2015 ) (Figure 2 ). The impairment of antioxidant defense mechanisms (e.g., decreased levels of vitamin C and E, deficiency in the glutathione scavenging system, etc.)…”

New Pathogenic Concepts and Therapeutic Approaches to Oxidative Stress in Chronic Kidney Disease

“…Nevertheless, the causal connection of oxidative stress to the genesis of cardiovascular disease in chronic kidney disease has also been controversially discussed [ 35 , 36 ]. Those discussions were based on the one hand on the inconclusive results concerning the connection between supposed markers of oxidative stress and cardiovascular events and mortality in clinical studies [ 35 , 36 ].…”

“…Nevertheless, the causal connection of oxidative stress to the genesis of cardiovascular disease in chronic kidney disease has also been controversially discussed [ 35 , 36 ]. Those discussions were based on the one hand on the inconclusive results concerning the connection between supposed markers of oxidative stress and cardiovascular events and mortality in clinical studies [ 35 , 36 ]. On the other hand, the up to date limited success of antioxidant therapies on cardiovascular outcomes in CKD patients but also in other populations demands a more differentiated view on oxidative stress-related pathogenic concepts and asks for new therapeutic approaches [ 37 ].…”