|Year : 2019 | Volume
| Issue : 2 | Page : 48-50
Uremic toxins, oxidative stress, and inflammation in chronic kidney disease
Ratan Jha, Kiran Kumar Mukku
Department of Nephrology, Virinchi Hospital, Hyderabad, Telangana, India
|Date of Submission||21-Dec-2019|
|Date of Acceptance||24-Dec-2019|
|Date of Web Publication||08-Jan-2020|
Dr. Ratan Jha
Department of Nephrology, Virinchi Hospital, Hyderabad, Telangana
Source of Support: None, Conflict of Interest: None
Chronic kidney disease (CKD) is a state of exaggerated oxidative stress and chronic inflammation. The syndrome of CKD culminates in three spheres of dysfunction namely: accumulation of uremic toxins, oxidative stress and progressive systemic inflammation. It is postulated that uremic as well as non-uremic solutes may play an important role in worsening oxidative stress and activating many other inimical pathways which results in endothelial dysfunction and cytokine driven inflammatory process. This article briefly touches upon biomarkers and treatment strategies targeting uremia, oxidative stress and inflammation.
Keywords: Chronic kidney disease, inflammation, oxidative stress, uremic toxins
|How to cite this article:|
Jha R, Mukku KK. Uremic toxins, oxidative stress, and inflammation in chronic kidney disease. J Renal Nutr Metab 2019;5:48-50
|How to cite this URL:|
Jha R, Mukku KK. Uremic toxins, oxidative stress, and inflammation in chronic kidney disease. J Renal Nutr Metab [serial online] 2019 [cited 2020 Jan 28];5:48-50. Available from: http://www.jrnm.in/text.asp?2019/5/2/48/275409
| Introduction|| |
Chronic kidney disease (CKD) is a state of exaggerated oxidative stress and chronic inflammation. Understanding of these pathways may improve its management in an era of precision medicine. The inflammatory response is not only local but also systemic accompanied by increases in inflammatory markers, acute-phase proteins, cytokines, and adhesion molecules. Evaluation and monitoring of these biomarkers have been suggested as a new tool to support the decision-making in diagnosis, prognostication, and treatment.
The syndrome of CKD culminates in three spheres of dysfunction, namely (1) accumulation of uremic toxins, (2) oxidative stress, and (3) progressive systemic inflammation. It is postulated that uremic, as well as nonuremic solutes, may play an important role in worsening oxidative stress and activating many other inimical pathways which results in endothelial dysfunction and cytokine-driven inflammatory process. Therefore, oxidative stress, endothelial dysfunction, and inflammation represent a key triad which is the focus of targeted therapy to retard the process of atherosclerosis and CKD progression.,
| Uremia|| |
Azotemia refers to high levels of urea but not yet so severe as to produce symptoms. Uremia is the pathological manifestations of severe azotemia. Both uremia and uremic syndrome have been used interchangeably. Uremic toxins are classified into small, middle, and large molecules based on the size of the molecule: Small are <500 D, middle 500–5000 D, and large >5000 D. Small molecules may be water-soluble (e.g., urea, guanidines, creatinine, phosphorus, H + ions, and polyamines) or protein bound (e.g., phenols, indoles, homocysteine, furanpropanoic acid, myoinositol, and aliphatic amines). Middle molecules contain peptides or conjugated amino acids, but only some of them have been isolated. Examples for large molecules are β2-microglobulin, parathyroid hormone, leptin, complement factors, ribonuclease, and granulocyte inhibiting proteins, which also are grouped as larger middle molecules from the therapeutic strategy of dialysis technology.
| Oxidative Stress|| |
Oxidative stress is a condition in which the production of reactive species exceeds the capacity of the anti-oxidant system, resulting in disturbance in regular cellular and molecular function. Reactive oxygen species (ROS) and reactive nitrogen species often act together to create a state of oxidative stress. ROS are part of the organism's unspecified defense system. ROS levels are maintained at a normal range by scavenging through various enzyme activities such as superoxide dismutase, catalase, glutathione peroxidase, and other components such as reduced glutathione, transition metal ions, and ascorbic acid. Excessive ROS levels can produce cellular damage by interacting with biomolecules (proteins, lipids, and nucleic acids) and thus have negative effects on tissue function and structure.
Various factors contribute to an increase in ROS production and the dissemination of oxidative stress in CKD. They are activation of tissue angiotensin system, hypertension (HTN), uremic toxins (endogenous and exogenous), mitochondrial dysfunction, accumulation of oxidation-prone lipoprotein remnants, underlying comorbid conditions (e.g., diabetes and autoimmune diseases), increased tissue iron load (blood transfusion and excess intravenous iron), iatrogenic causes blood/dialyzer interaction, dialysate impurities, rejected transplant kidney, and reaction to failed arteriovenous grafts.
The biomarkers of oxidative stress are elevated plasma and tissue malondialdehyde, elevated plasma, urine and tissue F2-isoprostane, elevated plasma and tissue nitrotyrosine (oxidation), increased protein carbonyls and oxidized thiols, increased plasma and urine oxidized nucleic acids, and elevated plasma and tissue advanced glycoxidation end products.
| Inflammation|| |
Inflammation in CKD has been the focus of current decade research after the era of dialysis adequacy of 1990s. Recognition came from various observations like elevated high sensitivity C-reactive protein (CRP) levels in more than 50% hemodialysis and peritoneal dialysis (PD) patients despite the absence of detectable foci of infection and association of malnutrition, inflammation, and atherosclerosis (MIA) syndrome. Inflammation may be symptomatic in the form of MIA syndrome or asymptomatic-covert inflammation even in the absence of overt clinical illness where acute phase response is evident.
The various contributing factors to CKD associated inflammation are oxidative stress, retained uremic metabolites and exogenous toxins, comorbid conditions (diabetes and autoimmune diseases), infections (blood access, PD catheters, and hepatitis ), iron overload, hypervolemia, HTN, increased pro-inflammatory low-density lipoprotein, impaired anti-inflammatory, high-density lipoprotein, influx of impurities from dialysate compartment, complement/leukocyte activation by dialyzer/pump, and influx of proinflammatory products from the gastrointestinal tract. Several inflammatory markers have been evaluated in CKD; although, there is no consensus approach to assess the severity of inflammation. Some of the positive acute phase reactants are CRP, ferritin, fibrinogen, and negative acute-phase reactants are albumin and transferrin which are used in the clinical assessment of CKD patients.
| Treatment Strategies Targeting Uremic Toxins|| |
Conventional hemodialysis is nonspecific and also removes essential compounds. Lipophilic compounds, which are responsible for functional alterations of uremia, are inadequately removed by current dialysis strategies. Treatment with high flux dialyzers was suggested to provide superior removal of middle molecules. It is also postulated that hemodiafiltration also helps in middle molecule elimination. Continuous or long-lasting low-efficiency dialysis also may clear the compounds more efficiently. Finally, removal is also influenced by intestinal uptake and residual renal function. Intestinal uptake can be reduced by influencing dietary uptake or by oral absorption of absorbents or probiotics. Preservation of residual renal function also aids in the removal of retention solutes.
| Treatment Strategies Targeting Oxidative Stress|| |
All conventional therapies with proven efficacy in retarding CKD progression (i.e., renin-angiotensin system blockade, glycemia, and HTN control) reduce oxidative stress and inflammation. Treatment with high doses of anti-oxidant vitamins is generally ineffective and may actually increase the risk of CVD and other complications. Some of the agents advocated in combating oxidative stress are Omega-3 polyunsaturated fatty acid, CoQ-mitochondrial-targeted anti-oxidants, allopurinol, N-acetyl cysteine (NAC), Vitamins A, C, E, beta carotene, and flavonoids (e.g., resveratrol). Experimental therapies currently in clinical trials worth noting are as follows: (1) AST-120, a specially formulated activated charcoal which limits the absorption of the pro-oxidant gut-derived uremic toxins and (2) The Nrf2 activator, bardoxolone, which can lower oxidative stress and inflammation by raising the expression of endogenous anti-oxidant enzymes and related molecules.
| Treatment Strategies Targeting Inflammation|| |
Control of the disease by proper control of glycemia, autoimmune disorders, or HTN may help in controlling or down-regulating inflammatory pathways. Various anti-inflammatory agents tried so far are statins, angiotensin-converting enzyme inhibitor and angiotensin receptor blocker, anti-oxidants (high dose Vitamins E, C, and NAC), Sevelamer, megestrol acetate (stimulates appetite and inhibits creatine kinase), thiazolidinediones, and allopurinol.
| Conclusion|| |
Several biomarkers of oxidative stress and inflammation are helpful to investigate and prognosticate, but their clinical utility needs further validation in CKD. With the changing paradigm of care in chronic diseases such as CKD molecules to target oxidative stress, inflammation, and control of toxins may become a reality. Innovative approaches such as supplementation of anti-oxidants (Vitamin E), anti-inflammatory agents (statins) and biologicals targeting chemokines, innovative technologies in dialysis (hemodiafiltration), and gut dialysis (proper species and dose of probiotics) are the evolving options in the care of CKD patients already in use. Current clinical evidence targeting oxidative stress and inflammation seems promising, but large-scale, randomized controlled trials with long-term follow-up are required to decide its clinical utility in management.
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Conflicts of interest
There are no conflicts of interest.
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