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The elephant in uremia: Oxidant stress as a unifying concept of cardiovascular disease in uremia
Open accessAbstract
Cardiovascular disease is the leading cause of mortality in uremic patients. In large cross-sectional studies of dialysis patients, traditional cardiovascular risk factors such as hypertension and hypercholesterolemia have been found to have low predictive power, while markers of inflammation and malnutrition are highly correlated with cardiovascular mortality. However, the pathophysiology of the disease process that links uremia, inflammation, and malnutrition with increased cardiovascular complications is not well understood. We hereby propose the hypothesis that increased oxidative stress and its sequalae is a major contributor to increased atherosclerosis and cardiovascular morbidity and mortality found in uremia. This hypothesis is based on studies that conclusively demonstrate an increased oxidative burden in uremic patients, before and particularly after renal replacement therapies, as evidenced by higher concentrations of multiple biomarkers of oxidative stress. This hypothesis also provides a framework to explain the link that activated phagocytes provide between oxidative stress and inflammation (from infectious and non-infections causes) and the synergistic role that malnutrition (as reflected by low concentrations of albumin and/or antioxidants) contributes to the increased burden of cardiovascular disease in uremia. We further propose that retained uremic solutes such as beta-2 microglobulin, advanced glycosylated end products (AGE), cysteine, and homocysteine, which are substrates for oxidative injury, further contribute to the pro-atherogenic milieu of uremia. Dialytic therapy, which acts to reduce the concentration of oxidized substrates, improves the redox balance. However, processes related to dialytic therapy, such as the prolonged use of catheters for vascular access and the use of bioincompatible dialysis membranes, can contribute to a pro-inflammatory and pro-oxidative state and thus to a pro-atherogenic state. Anti-oxidative therapeutic strategies for patients with uremia are in their very early stages; nonetheless, early studies demonstrate the potential for significant efficacy in reducing cardiovascular complications.
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“The uncoupling of endothelial nitric oxide synthase (eNOS), oxidative stress mechanism is involved in uremia, a condition when the kidney does not work properly and waste products instead of urine are excreted into the bloodstream (Himmelfarb et al. 2002).”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Himmelfarb et al. 2002
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Mihai, S., Codrici, E., Popescu, I. D., Enciu, A., Necula, L. G., Anton, G., & Tănase, C. (2018) · InTech eBooks · doi:10.5772/intechopen.72716 · Cited by 6
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Origins of Cardiorenal Syndrome and the Cardiorenal Connection
G., L., Mathias Christopher, J., & A., J. (2012) · InTech eBooks · doi:10.5772/25350 · Cited by 6
Handelman, G. J. (2003) · Seminars in Dialysis · doi:10.1046/j.1525-139x.2003.16105.x · Cited by 6
Vascular Sources of Oxidative Stress: Implications for Uremia-Related Cardiovascular Disease
Zanetti, M., Barazzoni, R., Bosutti, A., Stocca, A., Grassi, G., & Guarnieri, G. (2007) · Journal of Renal Nutrition · doi:10.1053/j.jrn.2006.10.008 · Cited by 6
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Stenvinkel, P., & Herzog, C. A. (2010) · Elsevier eBooks · doi:10.1016/b978-0-323-05876-6.00078-2 · Cited by 6
Self-citationBerns, J. S. (2017) · Clinical Kidney Journal · doi:10.1093/ckj/sfx042 · Cited by 6
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Metadata
- Authors
- Himmelfarb, J., Stenvinkel, P., Ikizler, T. A., & Hakim, R. M.
- Affiliations
- Maine Medical Center (US)
- Corresponding author
- Himmelfarb, Jonathan
- Venue
- Kidney International
- Publisher
- Elsevier BV
- Published
- 2002-11
- Volume
- 62
- Issue
- 5
- Pages
- 1524-1538
- ISSN
- 0085-2538 (ISSN-L)
- OpenAlex
- W1996978408
- Cited by
- 1,179
- References
- 294
- Citations by year
- 2026: 15 · 2025: 16 · 2024: 29 · 2023: 31 · 2022: 36 · 2021: 51 · 2020: 40 · 2019: 30 · 2018: 43 · 2017: 57 · 2016: 49 · 2015: 57 · 2014: 58 · 2013: 71 · 2012: 68
- FWCI
- 10.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Kidney International (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Nephrology › Dialysis and Renal Disease Management
- Health Sciences › Medicine › Biochemistry (medical) › Antioxidant Activity and Oxidative Stress
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Keywords
- uremia, oxidative stress, cardiovascular disease, atherosclerosis, inflammation, malnutrition, dialysis, uremic solutes, beta2-microglobulin, homocysteine, cysteine, antioxidant therapy, vascular access catheters, cardiovascular mortality
- MeSH terms
- Cardiovascular Diseases, Humans, Uremia, Oxidative Stress
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