New, reliable circulating oxidative stress markers have become available in chronic kidney disease (CKD) patients and have confirmed the long held belief that CKD is a pro-oxidant state. However, several questions related to this state of oxidative stress remain largely unresolved. First, the relative importance of each type of oxidant involved has been insufficiently evaluated. Only two recent studies have addressed this issue, and both suggested that chlorinated stress played a central role. Second, as only few population-based studies are available, the prevalence of oxidative stress among CKD patients remains undetermined. Third, although the link between oxidative stress and inflammation in CKD is emerging as a key process contributing to the genesis of oxidative stress in these patients, its pathogenesis remains poorly defined. Fourth, data favoring the involvement of oxidative stress in uremic toxicity are still limited. Finally, while two recent pilot studies have demonstrated that treatment of CKD patients with antioxidants is able to reduce cardiovascular events, information related to the pharmacokinetic characteristics of antioxidants, as well as their efficacy to prevent oxidative stress, is still limited in this patient group. Thus, although existing data suggest a prominent role of CKD-associated oxidative stress in uremic toxicity, further studies are required to definitively prove this concept.

The role of oxidative stress in chronic kidney disease.

Chronic kidney disease (CKD) is associated with an enhanced oxidative stress and deep modifications in lipid and lipoprotein metabolism. First, many oxidized lipids accumulate in CKD and were shown to exert toxic effects on cells and tissues. These lipids are known to interfere with many cell functions and to be pro-apoptotic and pro-inflammatory, especially in the cardiovascular system. Some, like F2-isoprostanes, are directly correlated with CKD progression. Their accumulation, added to their noxious effects, rendered their nomination as uremic toxins credible. Similarly, lipoproteins are deeply altered by CKD modifications, either in their metabolism or composition. These impairments lead to impaired effects of HDL on their normal effectors and may strongly participate in accelerated atherosclerosis and failure of statins in end-stage renal disease patients. This review describes the impact of oxidized lipids and other modifications in the natural history of CKD and its complications. Moreover, this review focuses on the modifications of lipoproteins and their impact on the emergence of cardiovascular diseases in CKD as well as the appropriateness of considering them as actual mediators of uremic toxicity.

https://www.mdpi.com/2072-6651/8/12/376/pdf

Modified Lipids and Lipoproteins in Chronic Kidney Disease: A New Class of Uremic Toxins.

RAGE is a multiligand receptor able to bind advanced glycation end-products (AGEs), amphoterin, calgranulins, and amyloid-beta peptides, identified in many tissues and cells, including neurons. RAGE stimulation induces the generation of reactive oxygen species (ROS) mainly through the activity of NADPH oxidases. In neuronal cells, RAGE-induced ROS generation is able to favor cell survival and differentiation or to induce death through the imbalance of redox state. The dual nature of RAGE signaling in neurons depends not only on the intensity of RAGE activation but also on the ability of RAGE-bearing cells to adapt to ROS generation. In this review we highlight these aspects of RAGE signaling regulation in neuronal cells.

/pdf/rage-expression-and-ros-generation-in-neurons-425w09jtch.pdf

RAGE Expression and ROS Generation in Neurons: Differentiation versus Damage

In chronic kidney disease patients, oxidative stress is generally associated with disease progression and pathogenesis of its comorbidities. Phenyl sulfate is a protein-bound uremic solute, which accumulates in chronic kidney disease patients, but little is known about its nature. Although many reports revealed that protein-bound uremic solutes induce reactive oxygen species production, the effects of these solutes on anti-oxidant level have not been well studied. Therefore, we examined the effects of protein-bound uremic solutes on glutathione levels. As a result, indoxyl sulfate, phenyl sulfate, and p-cresyl sulfate decreased glutathione levels in porcine renal tubular cells. Next we examined whether phenyl sulfate-treated cells becomes vulnerable to oxidative stress. In phenyl sulfate-treated cells, hydrogen peroxide induced higher rates of cell death than in control cells. Buthionine sulfoximine, which is known to decrease glutathione level, well mimicked the effect of phenyl sulfate. Finally, we evaluated a mixture of indoxyl sulfate, phenyl sulfate, and p-cresyl sulfate at concentrations comparable to the serum concentrations of hemodialysis patients, and we confirmed its decreasing effect on glutathione level. In conclusion, indoxyl sulfate, phenyl sulfate, and p-cresyl sulfate decrease glutathione levels, rendering the cells vulnerable to oxidative stress.

/pdf/phenyl-sulfate-indoxyl-sulfate-and-p-cresyl-sulfate-decrease-49etx72vh0.pdf

Phenyl sulfate, indoxyl sulfate and p-cresyl sulfate decrease glutathione level to render cells vulnerable to oxidative stress in renal tubular cells.

Glucosamine browning at 50 °C with (GlcN/Fe2+) or without iron (GlcN) was studied over time from 0 to 48 h. Generation of reactive oxygen species (ROS), H2O2, and 1O2, along with α-dicarbonyls, fructosazine, and deoxyfructosazine, was evaluated. Singlet oxygen generation increased over time and was greater in GlcN/Fe2+ caramel solution. The presence of iron significantly increased the concentration of α-dicarbonyls at an early incubation time (3 h). Fructosazine and deoxyfructosazine were the major degradation products at 48 h comprising together up to 37 and 49% in GlcN and GlcN/Fe2+, respectively. GlcN/Fe2+ (48 h) exhibited a MIC50 against highly heat-resistant Escherichia coli AW 1.7 at pH 5, but not at pH 7. Despite several antimicrobial compounds being produced during browning, GlcN/Fe2+ created a synergistic environment for the fructosazine-organic acids to confer their antimicrobial activity. GlcN caramel solutions have the potential to serve as both flavoring compounds and antimicrobial agents in ...

Iron (Fe2+)-Catalyzed Glucosamine Browning at 50 °C: Identification and Quantification of Major Flavor Compounds for Antibacterial Activity

. Urea hydrogen peroxide (UHP) is a stable form of H 2 O 2 and cytotoxic agent. This study describes examination of UHP formation from collagen glycation and relevant glycoxidative damage in chronic renal failure (CRF). Renal fibers were incubated with 50 mM ribose in either serum ultrafiltrate or phosphate-buffered saline in the presence of various concentrations of urea. UHP was determined by a modified ferrous oxidation in xylenol orange (FOX) assay. The presence of urea resulted in an increase in the generation of UHP in a dose-dependent manner of urea in these incubation systems. Pentosidine levels analyzed by HPLC also increased in a dose-dependent manner of urea. Blocking experiments showed that pentosidine and carboxymethyllysine formation was significantly enhanced by hydroxyl radical generated from UHP via Fenton reaction. The renal and cardiac levels of UHP, pentosidine, and carboxymethyllysine in patients with CRF, including seven predialysis and eight hemodialysis subjects, were significantly higher than that in controls ( n = 16). The renal and cardiac levels of UHP closely correlated with the levels of renal and cardiac pentosidine and carboxymethyllysine and inversely correlated with left ventricle ejection fraction in CRF patients. This study provides evidence, for the first time, that UHP can be produced from Maillard reaction. Increased UHP in chronic renal failure enhances the formation of pentosidine and carboxymethyllysine via Fenton reaction (UHP-Fenton pathway).

/pdf/increased-production-of-urea-hydrogen-peroxide-from-maillard-2l40r8ma19.pdf

Increased Production of Urea Hydrogen Peroxide from Maillard Reaction and a UHP-Fenton Pathway Related to Glycoxidation Damage in Chronic Renal Failure

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Increased Production of Urea Hydrogen Peroxide from Maillard Reaction and a UHP-Fenton Pathway Related to Glycoxidation Damage in Chronic Renal Failure