Journal articles: 'Uremic toxin'

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Popkov, Vasily A., Anastasia A. Zharikova, Evgenia A. Demchenko, Nadezda V. Andrianova, Dmitry B. Zorov, and Egor Y. Plotnikov. "Gut Microbiota as a Source of Uremic Toxins." International Journal of Molecular Sciences 23, no. 1 (January 1, 2022): 483. http://dx.doi.org/10.3390/ijms23010483.

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Uremic retention solutes are the compounds that accumulate in the blood when kidney excretory function is impaired. Some of these compounds are toxic at high concentrations and are usually known as “uremic toxins”. The cumulative detrimental effect of uremic toxins results in numerous health problems and eventually mortality during acute or chronic uremia, especially in end-stage renal disease. More than 100 different solutes increase during uremia; however, the exact origin for most of them is still debatable. There are three main sources for such compounds: exogenous ones are consumed with food, whereas endogenous ones are produced by the host metabolism or by symbiotic microbiota metabolism. In this article, we identify uremic retention solutes presumably of gut microbiota origin. We used database analysis to obtain data on the enzymatic reactions in bacteria and human organisms that potentially yield uremic retention solutes and hence to determine what toxins could be synthesized in bacteria residing in the human gut. We selected biochemical pathways resulting in uremic retention solutes synthesis related to specific bacterial strains and revealed links between toxin concentration in uremia and the proportion of different bacteria species which can synthesize the toxin. The detected bacterial species essential for the synthesis of uremic retention solutes were then verified using the Human Microbiome Project database. Moreover, we defined the relative abundance of human toxin-generating enzymes as well as the possibility of the synthesis of a particular toxin by the human metabolism. Our study presents a novel bioinformatics approach for the elucidation of the origin of both uremic retention solutes and uremic toxins and for searching for the most likely human microbiome producers of toxins that can be targeted and used for the therapy of adverse consequences of uremia.

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Popkov, Vasily A., Denis N. Silachev, Arthur O. Zalevsky, Dmitry B. Zorov, and Egor Y. Plotnikov. "Mitochondria as a Source and a Target for Uremic Toxins." International Journal of Molecular Sciences 20, no. 12 (June 25, 2019): 3094. http://dx.doi.org/10.3390/ijms20123094.

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Elucidation of molecular and cellular mechanisms of the uremic syndrome is a very challenging task. More than 130 substances are now considered to be “uremic toxins” and represent a very diverse group of molecules. The toxicity of these molecules affects many cellular processes, and expectably, some of them are able to disrupt mitochondrial functioning. However, mitochondria can be the source of uremic toxins as well, as the mitochondrion can be the site of complete synthesis of the toxin, whereas in some scenarios only some enzymes of the pathway of toxin synthesis are localized here. In this review, we discuss the role of mitochondria as both the target and source of pathological processes and toxic compounds during uremia. Our analysis revealed about 30 toxins closely related to mitochondria. Moreover, since mitochondria are key regulators of cellular redox homeostasis, their functioning might directly affect the production of uremic toxins, especially those that are products of oxidation or peroxidation of cellular components, such as aldehydes, advanced glycation end-products, advanced lipoxidation end-products, and reactive carbonyl species. Additionally, as a number of metabolic products can be degraded in the mitochondria, mitochondrial dysfunction would therefore be expected to cause accumulation of such toxins in the organism. Alternatively, many uremic toxins (both made with the participation of mitochondria, and originated from other sources including exogenous) are damaging to mitochondrial components, especially respiratory complexes. As a result, a positive feedback loop emerges, leading to the amplification of the accumulation of uremic solutes. Therefore, uremia leads to the appearance of mitochondria-damaging compounds, and consecutive mitochondrial damage causes a further rise of uremic toxins, whose synthesis is associated with mitochondria. All this makes mitochondrion an important player in the pathogenesis of uremia and draws attention to the possibility of reducing the pathological consequences of uremia by protecting mitochondria and reducing their role in the production of uremic toxins.

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Castillo-Rodriguez, Esmeralda, Raul Fernandez-Prado, Raquel Esteras, Maria Perez-Gomez, Carolina Gracia-Iguacel, Beatriz Fernandez-Fernandez, Mehmet Kanbay, et al. "Impact of Altered Intestinal Microbiota on Chronic Kidney Disease Progression." Toxins 10, no. 7 (July 19, 2018): 300. http://dx.doi.org/10.3390/toxins10070300.

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In chronic kidney disease (CKD), accumulation of uremic toxins is associated with an increased risk of CKD progression. Some uremic toxins result from nutrient processing by gut microbiota, yielding precursors of uremic toxins or uremic toxins themselves, such as trimethylamine N-Oxide (TMAO), p-cresyl sulphate, indoxyl sulphate and indole-3 acetic acid. Increased intake of some nutrients may modify the gut microbiota, increasing the number of bacteria that process them to yield uremic toxins. Circulating levels of nutrient-derived uremic toxins are associated to increased risk of CKD progression. This offers the opportunity for therapeutic intervention by either modifying the diet, modifying the microbiota, decreasing uremic toxin production by microbiota, increasing toxin excretion or targeting specific uremic toxins. We now review the link between nutrients, microbiota and uremic toxin with CKD progression. Specific focus will be placed on the generation specific uremic toxins with nephrotoxic potential, the decreased availability of bacteria-derived metabolites with nephroprotective potential, such as vitamin K and butyrate and the cellular and molecular mechanisms linking these toxins and protective factors to kidney diseases. This information provides a conceptual framework that allows the development of novel therapeutic approaches.

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Kiss, István. "The uremic toxin indoxyl sulfate reflects cardio-renal risk and intestinal-renal relationship." Orvosi Hetilap 152, no. 43 (October 2011): 1724–30. http://dx.doi.org/10.1556/oh.2011.29223.

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Uremic syndrome and condition is primarily a result of kidney failure in which uremic toxins are accumulated. More and more attention is paid to possibilities for removal of uremic toxins, which not only means dialysis, but also takes into account special dietary considerations and treatments, which aim to absorb the toxins or reduce their production. These uremic toxins, which also increase the cardiovascular risks, play a major part in morbidity and mortality of patients suffering from chronic renal failure and those receiving renal replacement therapy. One of them is a member of the indol group, the indoxyl sulfate. This toxin is difficult to remove with dialysis and is an endogenous protein-bound uremic toxin. Today we know that indoxyl sulfate is a vascular-nephrotoxic agent, which is able to enhance progression of cardiovascular and renal diseases. It is of particular importance that because of its redox potency, this toxin causes oxidative stress and antioxidant effects at the same time and, on top of that, it is formed in the intestinal system. Its serum concentration depends on the nutrition and the tubular function and, therefore, it can also signal the progression of chronic renal failure independently of glomerular filtration rate. Successful removal of indoxyl sulfate reduces the morbidity and mortality and improves survival. Therefore, it could be a possible target or area to facilitate the reduction of uremia in chronic renal failure. The use of probiotics and prebiotics with oral adsorbents may prove to be a promising opportunity to reduce indoxyl sulfate accumulation. Orv. Hetil., 2011, 152, 1724–1730.

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Chen, Jia-Huang, and Chih-Kang Chiang. "Uremic Toxins and Protein-Bound Therapeutics in AKI and CKD: Up-to-Date Evidence." Toxins 14, no. 1 (December 23, 2021): 8. http://dx.doi.org/10.3390/toxins14010008.

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Uremic toxins are defined as harmful metabolites that accumulate in the human body of patients whose renal function declines, especially chronic kidney disease (CKD) patients. Growing evidence demonstrates the deteriorating effect of uremic toxins on CKD progression and CKD-related complications, and removing uremic toxins in CKD has become the conventional treatment in the clinic. However, studies rarely pay attention to uremic toxin clearance in the early stage of acute kidney injury (AKI) to prevent progression to CKD despite increasing reports demonstrating that uremic toxins are correlated with the severity of injury or mortality. This review highlights the current evidence of uremic toxin accumulation in AKI and the therapeutic value to prevent CKD progression specific to protein-bound uremic toxins (PBUTs).

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Jansen, Jitske, Joachim Jankowski, Prathibha R. Gajjala, Jack F. M. Wetzels, and Rosalinde Masereeuw. "Disposition and clinical implications of protein-bound uremic toxins." Clinical Science 131, no. 14 (June 30, 2017): 1631–47. http://dx.doi.org/10.1042/cs20160191.

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In patients with chronic kidney disease (CKD), adequate renal clearance is compromised, resulting in the accumulation of a plethora of uremic solutes. These uremic retention solutes, also named uremic toxins, are a heterogeneous group of organic compounds with intrinsic biological activities, many of which are too large to be filtered and/or are protein bound. The renal excretion of protein-bound toxins depends largely on active tubular secretion, which shifts the binding and allows for active secretion of the free fraction. To facilitate this process, renal proximal tubule cells are equipped with a range of transporters that co-operate in basolateral uptake and luminal excretion. Many of these transporters have been characterized as mediators of drug disposition, but have recently been recognized for their importance in the proximal renal tubular transport of uremic toxins as well. This also indicates that during uremia, drug disposition may be severely affected as a result of drug–uremic toxin interaction. In addition, CKD patients receive various drugs to treat their complications potentially resulting in drug–drug interactions (DDIs), also for drugs that are non-renally excreted. This review discusses the current knowledge on formation, disposition and removal of protein-bound uremic toxins. Furthermore, implications associated with drug treatment in kidney failure, as well as innovative renal replacement therapies targetting the protein-bound uremic toxins are being discussed. It will become clear that the complex problems associated with uremia warrant a transdisciplinary approach that unites research experts in the area of fundamental biomedical research with their colleagues in clinical nephrology.

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Chao, Chia-Ter, and Shih-Hua Lin. "Uremic Vascular Calcification: The Pathogenic Roles and Gastrointestinal Decontamination of Uremic Toxins." Toxins 12, no. 12 (December 21, 2020): 812. http://dx.doi.org/10.3390/toxins12120812.

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Uremic vascular calcification (VC) commonly occurs during advanced chronic kidney disease (CKD) and significantly increases cardiovascular morbidity and mortality. Uremic toxins are integral within VC pathogenesis, as they exhibit adverse vascular influences ranging from atherosclerosis, vascular inflammation, to VC. Experimental removal of these toxins, including small molecular (phosphate, trimethylamine-N-oxide), large molecular (fibroblast growth factor-23, cytokines), and protein-bound ones (indoxyl sulfate, p-cresyl sulfate), ameliorates VC. As most uremic toxins share a gut origin, interventions through gastrointestinal tract are expected to demonstrate particular efficacy. The “gastrointestinal decontamination” through the removal of toxin in situ or impediment of toxin absorption within the gastrointestinal tract is a practical and potential strategy to reduce uremic toxins. First and foremost, the modulation of gut microbiota through optimizing dietary composition, the use of prebiotics or probiotics, can be implemented. Other promising strategies such as reducing calcium load, minimizing intestinal phosphate absorption through the optimization of phosphate binders and the inhibition of gut luminal phosphate transporters, the administration of magnesium, and the use of oral toxin adsorbent for protein-bound uremic toxins may potentially counteract uremic VC. Novel agents such as tenapanor have been actively tested in clinical trials for their potential vascular benefits. Further advanced studies are still warranted to validate the beneficial effects of gastrointestinal decontamination in the retardation and treatment of uremic VC.

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Sato, Toshihiro, Hiroaki Yamaguchi, Takuma Kogawa, Takaaki Abe, and Nariyasu Mano. "Organic Anion Transporting Polypeptides 1B1 and 1B3 Play an Important Role in Uremic Toxin Handling and Drug-Uremic Toxin Interactions in the Liver." Journal of Pharmacy & Pharmaceutical Sciences 17, no. 4 (October 27, 2014): 475. http://dx.doi.org/10.18433/j3m89q.

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PURPOSE. Organic anion-transporting polypeptide (OATP) 1B1 and OATP1B3 contribute to hepatic uptake of numerous drugs. Thus, reduced OATP1B1 and OATP1B3 activity in chronic kidney disease (CKD) may have a major impact on the hepatic clearance of drugs. The effect of drug-uremic toxin interactions on OATP1B1 and OATP1B3 has not been well studied. In the present study, we examine the inhibitory effects of uremic toxins on OATP1B1 and OATP1B3 transport activity to evaluate the interactions between drugs and uremic toxins in patients with chronic kidney disease. METHODS. [3H]Estron-3-sulfate, [3H]taurocholate uptake and [3H]methotrexate by OATP1B1 and OATP1B3 expressing HEK293 cells were performed to evaluate the inhibitory effect of uremic toxins. To clarify whether the uremic toxins that interact with OATP1B1 and/or OATP1B3 were substrates for these transporters, we performed uptake studies. RESULTS. Four uremic toxins, kynurenic acid, indole-3-acetic acid, indoxyl sulfate, and p-cresol, inhibited OATP1B1- and OATP1B3-mediated transport in a concentration-dependent manner, with IC50 values of 180, 770, 2700, and 4600 µM, respectively, for OATP1B1 and 180, 1100, 1300, and 1700 µM, respectively, for OATP1B3. [3H]Methotrexate uptake by OATPs was also inhibited by the four uremic toxins in a dose-dependent manner. Uptake studies revealed that kynurenic acid is a substrate for both the OATP1B1 and OATP1B3. Moreover, OATP1B3 was involved in the transport of indoxyl sulfate. Indole-3-acetic acid and p-cresol were not significantly transported by OATP1B1 and OATP1B3. CONCLUSIONS. We showed that some uremic toxins inhibit OATP-mediated uptake in a concentration-dependent manner, and clarified OATPs contribution to uremic toxin handling in the liver. Thus, we provided basic information to estimate the inhibitory effects of uremic toxins on OATPs in CKD patients. These data suggest that the dose of drugs excreted via renal and non-renal pathways should be carefully adjusted in CKD patients.This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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Yamagami, Fumi, Kazuko Tajiri, Dai Yumino, and Masaki Ieda. "Uremic Toxins and Atrial Fibrillation: Mechanisms and Therapeutic Implications." Toxins 11, no. 10 (October 13, 2019): 597. http://dx.doi.org/10.3390/toxins11100597.

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Atrial fibrillation (AF) is the most prevalent arrhythmia in the general population. There is a close association between chronic kidney disease (CKD) and AF. In recent years, attention has been focused on the relationship between AF and uremic toxins, including indoxyl sulfate (IS). Several animal studies have shown that IS promotes the development and progression of AF. IS has been shown to cause fibrosis and inflammation in the myocardium and exacerbate AF by causing oxidative stress and reducing antioxidative defense. Administration of AST-120, an absorbent of uremic toxins, decreases uremic toxin-induced AF in rodents. We have recently reported that patients with a higher serum IS level exhibit a higher rate of AF recurrence after catheter ablation, with serum IS being a significant predictor of AF recurrence. In this review, we discuss the possible mechanisms behind the AF-promoting effects of uremic toxins and summarize the reported clinical studies of uremic toxin-induced AF.

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Masereeuw, Rosalinde. "The Dual Roles of Protein-Bound Solutes as Toxins and Signaling Molecules in Uremia." Toxins 14, no. 6 (June 11, 2022): 402. http://dx.doi.org/10.3390/toxins14060402.

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In patients with severe kidney disease, renal clearance is compromised, resulting in the accumulation of a plethora of endogenous waste molecules that cannot be removed by current dialysis techniques, the most often applied treatment. These uremic retention solutes, also named uremic toxins, are a heterogeneous group of organic compounds of which many are too large to be filtered and/or are protein-bound. Their renal excretion depends largely on renal tubular secretion, by which the binding is shifted towards the free fraction that can be eliminated. To facilitate this process, kidney proximal tubule cells are equipped with a range of transport proteins that cooperate in cellular uptake and urinary excretion. In recent years, innovations in dialysis techniques to advance uremic toxin removal, as well as treatments with drugs and/or dietary supplements that limit uremic toxin production, have provided some clinical improvements or are still in progress. This review gives an overview of these developments. Furthermore, the role protein-bound uremic toxins play in inter-organ communication, in particular between the gut (the side where toxins are produced) and the kidney (the side of their removal), is discussed.

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Sternkopf, Marieke, Sven Thoröe-Boveleth, Tobias Beck, Kirsten Oleschko, Ansgar Erlenkötter, Ulrich Tschulena, Sonja Steppan, et al. "A Bifunctional Adsorber Particle for the Removal of Hydrophobic Uremic Toxins from Whole Blood of Renal Failure Patients." Toxins 11, no. 7 (July 3, 2019): 389. http://dx.doi.org/10.3390/toxins11070389.

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Hydrophobic uremic toxins accumulate in patients with chronic kidney disease, contributing to a highly increased cardiovascular risk. The clearance of these uremic toxins using current hemodialysis techniques is limited due to their hydrophobicity and their high binding affinity to plasma proteins. Adsorber techniques may be an appropriate alternative to increase hydrophobic uremic toxin removal. We developed an extracorporeal, whole-blood bifunctional adsorber particle consisting of a porous, activated charcoal core with a hydrophilic polyvinylpyrrolidone surface coating. The adsorption capacity was quantified using analytical chromatography after perfusion of the particles with an albumin solution or blood, each containing mixtures of hydrophobic uremic toxins. A time-dependent increase in hydrophobic uremic toxin adsorption was depicted and all toxins showed a high binding affinity to the adsorber particles. Further, the particle showed a sufficient hemocompatibility without significant effects on complement component 5a, thrombin-antithrombin III complex, or thrombocyte concentration in blood in vitro, although leukocyte counts were slightly reduced. In conclusion, the bifunctional adsorber particle with cross-linked polyvinylpyrrolidone coating showed a high adsorption capacity without adverse effects on hemocompatibility in vitro. Thus, it may be an interesting candidate for further in vivo studies with the aim to increase the efficiency of conventional dialysis techniques.

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Burke, Steven K. "Phosphate Is a Uremic Toxin." Journal of Renal Nutrition 18, no. 1 (January 2008): 27–32. http://dx.doi.org/10.1053/j.jrn.2007.10.007.

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Rodriguez, Mariano, and Victor Lorenzo. "Parathyroid Hormone, A Uremic Toxin." Seminars in Dialysis 22, no. 4 (July 2009): 363–68. http://dx.doi.org/10.1111/j.1525-139x.2009.00581.x.

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Iwasaki, Yoshiko, Hideyuki Yamato, Tomoko Nii-Kono, Ayako Fujieda, Motoyuki Uchida, Atsuko Hosokawa, Masaru Motojima, and Masafumi Fukagawa. "Uremic toxin and bone metabolism." Journal of Bone and Mineral Metabolism 24, no. 2 (February 20, 2006): 172–75. http://dx.doi.org/10.1007/s00774-005-0667-7.

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Duque, Eduardo J., Rosilene M. Elias, and Rosa M. A. Moysés. "Parathyroid Hormone: A Uremic Toxin." Toxins 12, no. 3 (March 17, 2020): 189. http://dx.doi.org/10.3390/toxins12030189.

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Parathyroid hormone (PTH) has an important role in the maintenance of serum calcium levels. It activates renal 1α-hydroxylase and increases the synthesis of the active form of vitamin D (1,25[OH]2D3). PTH promotes calcium release from the bone and enhances tubular calcium resorption through direct action on these sites. Hallmarks of secondary hyperparathyroidism associated with chronic kidney disease (CKD) include increase in serum fibroblast growth factor 23 (FGF-23), reduction in renal 1,25[OH]2D3 production with a decline in its serum levels, decrease in intestinal calcium absorption, and, at later stages, hyperphosphatemia and high levels of PTH. In this paper, we aim to critically discuss severe CKD-related hyperparathyroidism, in which PTH, through calcium-dependent and -independent mechanisms, leads to harmful effects and manifestations of the uremic syndrome, such as bone loss, skin and soft tissue calcification, cardiomyopathy, immunodeficiency, impairment of erythropoiesis, increase of energy expenditure, and muscle weakness.

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Ritz, Eberhard, Ralf Dikow, Christian Morath, and Vedat Schwenger. "Salt – A Potential ‘Uremic Toxin’?" Blood Purification 24, no. 1 (December 23, 2005): 63–66. http://dx.doi.org/10.1159/000089439.

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Nakagawa, Takahiko, Marilda Mazzali, Duk-Hee Kang, L. Gabriela Sánchez-Lozada, Jaime Herrera-Acosta, and Richard J. Johnson. "Uric Acid – A Uremic Toxin?" Blood Purification 24, no. 1 (December 23, 2005): 67–70. http://dx.doi.org/10.1159/000089440.

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Wu, Chia-Lin, and Der-Cherng Tarng. "Targeting Uremic Toxins to Prevent Peripheral Vascular Complications in Chronic Kidney Disease." Toxins 12, no. 12 (December 20, 2020): 808. http://dx.doi.org/10.3390/toxins12120808.

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Chronic kidney disease (CKD) exhibits progressive kidney dysfunction and leads to disturbed homeostasis, including accumulation of uremic toxins, activated renin-angiotensin system, and increased oxidative stress and proinflammatory cytokines. Patients with CKD are prone to developing the peripheral vascular disease (PVD), leading to poorer outcomes than those without CKD. Cumulative evidence has showed that the synergy of uremic milieu and PVD could exaggerate vascular complications such as limb ischemia, amputation, stenosis, or thrombosis of a dialysis vascular access, and increase mortality risk. The role of uremic toxins in the pathogenesis of vascular dysfunction in CKD has been investigated. Moreover, growing evidence has shown the promising role of uremic toxins as a therapeutic target for PVD in CKD. This review focused on uremic toxins in the pathophysiology, in vitro and animal models, and current novel clinical approaches in reducing the uremic toxin to prevent peripheral vascular complications in CKD patients.

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Clark, William R., Nader Laal Dehghani, Vivek Narsimhan, and Claudio Ronco. "Uremic Toxins and their Relation to Dialysis Efficacy." Blood Purification 48, no. 4 (2019): 299–314. http://dx.doi.org/10.1159/000502331.

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Toxin retention is felt to be a major contributor to the development of uremia in patients with advanced chronic kidney disease and end-stage renal disease (ESRD). Uremic retention compounds are classically divided into 3 categories: small solutes, middle molecules, and protein-bound toxins. Compounds comprising the first category, for which the upper molecular weight limit is generally considered to be 500 Da, possess a high degree of water solubility and minimal or absent protein binding. The second category of middle molecules has largely evolved now to be synonymous with peptides and proteins that accumulate in uremia. Although not precisely defined, low-molecular weight proteins as a class have a molecular weight spectrum ranging from approximately 500 to 60,000 daltons. The final category of uremic retention compounds is protein-bound uremic toxins (PBUTs). As opposed to the above small, highly water-soluble toxins, which are largely by-products of protein metabolism, PBUTs have diverse origins and possess chemical characteristics that preclude the possibility of circulation in an unbound form despite being of low molecular weight. This review is the first in a series of papers designed to provide the current state of the art for extracorporeal treatment of ESRD. Subsequent papers in this series will address membranes, mass transfer mechanisms, and future directions. For small solutes and middle molecules, particular emphasis is placed on the important clinical trials that comprise the evidence base regarding the influence of dialytic solute removal on outcome. Because such trials do not exist for PBUTs, the discussion here is instead focused on solute characteristics and renal elimination mechanisms.

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Kim, Eun-Ji, Young Rok Ham, Jin Ah Shin, Jin Young Jeong, Ki Ryang Na, Kang Wook Lee, Jwa-Jin Kim, and Dae Eun Choi. "Omega-3 Polyunsaturated Fatty Acid Attenuates Uremia-Induced Brain Damage in Mice." International Journal of Molecular Sciences 22, no. 21 (October 30, 2021): 11802. http://dx.doi.org/10.3390/ijms222111802.

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Although the cause of neurological disease in patients with chronic kidney disease (CKD) has not been completely identified yet, recent papers have identified accumulated uremic toxin as its main cause. Additionally, omega-3 polyunsaturated fatty acid (ω-3 PUFA) plays an important role in maintaining normal nerve function, but its protective effects against uremic toxin is unclear. The objective of this study was to identify brain damage caused by uremic toxicity and determine the protective effects of ω-3 PUFA against uremic toxin. We divided mice into the following groups: wild-type (wt) sham (n = 8), ω-3 PUFA sham (n = 8), Fat-1 sham (n = 8), ischemia-reperfusion (IR) (n = 20), and ω-3 PUFA+IR (n = 20) Fat-1+IR (n = 20). Brain tissue, kidney tissue, and blood were collected three days after the operation of mice (sham and IR operation). This study showed that Ki67 and neuronal nuclei (NeuN) decreased in the brain of uremic mice as compared to wt mice brain, but increased in the ω-3 PUFA-treated uremic mice and the brain of uremic Fat-1 mice as compared to the brain of uremic mice. The pro-apoptotic protein expressions were increased, whereas anti-apoptotic protein expression decreased in the brain of uremic mice as compared to wt mice brain. However, apoptotic protein expression decreased in the ω-3 PUFA-treated uremic mice and the brain of uremic Fat-1 mice as compared to the brain of uremic mice. Furthermore, the brain of ω-3 PUFA-treated uremic mice and uremic Fat-1 mice showed increased expression of p-PI3K, p-PDK1, and p-Akt as compared to the brain of uremic mice. We confirm that uremic toxin damages the brain and causes cell death. In these injuries, ω-3 PUFA plays an important role in neuroprotection through PI(3)K-Akt signaling.

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Holmar, Jana, Sofia de la Puente-Secades, Jürgen Floege, Heidi Noels, Joachim Jankowski, and Setareh Orth-Alampour. "Uremic Toxins Affecting Cardiovascular Calcification: A Systematic Review." Cells 9, no. 11 (November 6, 2020): 2428. http://dx.doi.org/10.3390/cells9112428.

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Cardiovascular calcification is highly prevalent and associated with increased morbidity in chronic kidney disease (CKD). This review examines the impact of uremic toxins, which accumulate in CKD due to a failing kidney function, on cardiovascular calcification. A systematic literature search identified 41 uremic toxins that have been studied in relation to cardiovascular calcification. For 29 substances, a potentially causal role in cardiovascular calcification was addressed in in vitro or animal studies. A calcification-inducing effect was revealed for 16 substances, whereas for three uremic toxins, namely the guanidino compounds asymmetric and symmetric dimethylarginine, as well as guanidinosuccinic acid, a calcification inhibitory effect was identified in vitro. At a mechanistic level, effects of uremic toxins on calcification could be linked to the induction of inflammation or oxidative stress, smooth muscle cell osteogenic transdifferentiation and/or apoptosis, or alkaline phosphatase activity. For all middle molecular weight and protein-bound uremic toxins that were found to affect cardiovascular calcification, an increasing effect on calcification was revealed, supporting the need to focus on an increased removal efficiency of these uremic toxin classes in dialysis. In conclusion, of all uremic toxins studied with respect to calcification regulatory effects to date, more uremic toxins promote rather than reduce cardiovascular calcification processes. Additionally, it highlights that only a relatively small part of uremic toxins has been screened for effects on calcification, supporting further investigation of uremic toxins, as well as of associated post-translational modifications, on cardiovascular calcification processes.

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Hobson, Sam, Henriette de Loor, Karolina Kublickiene, Joachim Beige, Pieter Evenepoel, Peter Stenvinkel, and Thomas Ebert. "Lipid Profile Is Negatively Associated with Uremic Toxins in Patients with Kidney Failure—A Tri-National Cohort." Toxins 14, no. 6 (June 16, 2022): 412. http://dx.doi.org/10.3390/toxins14060412.

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Patients with kidney failure (KF) have a high incidence of cardiovascular (CV) disease, partly driven by insufficient clearance of uremic toxins. Recent investigations have questioned the accepted effects of adverse lipid profile and CV risk in uremic patients. Therefore, we related a panel of uremic toxins previously associated with CV morbidity/mortality to a full lipid profile in a large, tri-national, cross-sectional cohort. Total, high-density lipoprotein (HDL), non-HDL, low-density lipoprotein (LDL), and remnant cholesterol, as well as triglyceride, levels were associated with five uremic toxins in a cohort of 611 adult KF patients with adjustment for clinically relevant covariates and other patient-level variables. Univariate analyses revealed negative correlations of total, non-HDL, and LDL cholesterol with all investigated uremic toxins. Multivariate linear regression analyses confirmed independent, negative associations of phenylacetylglutamine with total, non-HDL, and LDL cholesterol, while indole-3 acetic acid associated with non-HDL and LDL cholesterol. Furthermore, trimethylamine-N-Oxide was independently and negatively associated with non-HDL cholesterol. Sensitivity analyses largely confirmed findings in the entire cohort. In conclusion, significant inverse associations between lipid profile and distinct uremic toxins in KF highlight the complexity of the uremic milieu, suggesting that not all uremic toxin interactions with conventional CV risk markers may be pathogenic.

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Chao, Chia-Ter, and Shih-Hua Lin. "Uremic Toxins and Frailty in Patients with Chronic Kidney Disease: A Molecular Insight." International Journal of Molecular Sciences 22, no. 12 (June 10, 2021): 6270. http://dx.doi.org/10.3390/ijms22126270.

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The accumulation of uremic toxins (UTs) is a prototypical manifestation of uremic milieu that follows renal function decline (chronic kidney disease, CKD). Frailty as a potential outcome-relevant indicator is also prevalent in CKD. The intertwined relationship between uremic toxins, including small/large solutes (phosphate, asymmetric dimethylarginine) and protein-bound ones like indoxyl sulfate (IS) and p-cresyl sulfate (pCS), and frailty pathogenesis has been documented recently. Uremic toxins were shown in vitro and in vivo to induce noxious effects on many organ systems and likely influenced frailty development through their effects on multiple preceding events and companions of frailty, such as sarcopenia/muscle wasting, cognitive impairment/cognitive frailty, osteoporosis/osteodystrophy, vascular calcification, and cardiopulmonary deconditioning. These organ-specific effects may be mediated through different molecular mechanisms or signal pathways such as peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α), mitogen-activated protein kinase (MAPK) signaling, aryl hydrocarbon receptor (AhR)/nuclear factor-κB (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), Runt-related transcription factor 2 (RUNX2), bone morphogenic protein 2 (BMP2), osterix, Notch signaling, autophagy effectors, microRNAs, and reactive oxygen species induction. Anecdotal clinical studies also suggest that frailty may further accelerate renal function decline, thereby augmenting the accumulation of UTs in affected individuals. Judging from these threads of evidence, management strategies aiming for uremic toxin reduction may be a promising approach for frailty amelioration in patients with CKD. Uremic toxin lowering strategies may bear the potential of improving patients’ outcomes and restoring their quality of life, through frailty attenuation. Pathogenic molecule-targeted therapeutics potentially disconnect the association between uremic toxins and frailty, additionally serving as an outcome-modifying approach in the future.

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Kim, Ji Eun, Hyo-Eun Kim, Ji In Park, Hyunjeong Cho, Min-Jung Kwak, Byung-Yong Kim, Seung Hee Yang, et al. "The Association between Gut Microbiota and Uremia of Chronic Kidney Disease." Microorganisms 8, no. 6 (June 16, 2020): 907. http://dx.doi.org/10.3390/microorganisms8060907.

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Chronic kidney disease (CKD)-associated uremia aggravates—and is aggravated by—gut dysbiosis. However, the correlation between CKD severity and gut microbiota and/or their uremic metabolites is unclear. We enrolled 103 CKD patients with stage 1 to 5 and 46 healthy controls. We analyzed patients’ gut microbiota by MiSeq system and measured the serum concentrations of four uremic metabolites (p-cresyl sulfate, indoxyl sulfate, p-cresyl glucuronide, and trimethylamine N-oxide) by liquid chromatography–tandem mass spectrometry. Serum concentrations of the uremic metabolites increased with kidney function deterioration. Gut microbial diversity did not differ among the examined patient and control groups. In moderate or higher stage CKD groups, Oscillibacter showed positive interactions with other microbiota, and the proportions of Oscillibacter were positively correlated with those of the uremic metabolites. The gut microbiota, particularly Oscillibacter, was predicted to contribute to pyruvate metabolism which increased with CKD progression. Relative abundance of Oscillibacter was significantly associated with both serum uremic metabolite levels and kidney function. Predicted functional analysis suggested that kidney-function-associated changes in the contribution of Oscillibacter to pyruvate metabolism in CKD may greatly affect the gut environment according to kidney function, resulting in dysbiosis concomitant with uremic toxin production. The gut microbiota could be associated with uremia progression in CKD. These results may provide basis for further metagenomics analysis of kidney diseases.

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Harlacher, Eva, Julia Wollenhaupt, Constance C. F. M. J. Baaten, and Heidi Noels. "Impact of Uremic Toxins on Endothelial Dysfunction in Chronic Kidney Disease: A Systematic Review." International Journal of Molecular Sciences 23, no. 1 (January 4, 2022): 531. http://dx.doi.org/10.3390/ijms23010531.

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Patients with chronic kidney disease (CKD) are at a highly increased risk of cardiovascular complications, with increased vascular inflammation, accelerated atherogenesis and enhanced thrombotic risk. Considering the central role of the endothelium in protecting from atherogenesis and thrombosis, as well as its cardioprotective role in regulating vasorelaxation, this study aimed to systematically integrate literature on CKD-associated endothelial dysfunction, including the underlying molecular mechanisms, into a comprehensive overview. Therefore, we conducted a systematic review of literature describing uremic serum or uremic toxin-induced vascular dysfunction with a special focus on the endothelium. This revealed 39 studies analyzing the effects of uremic serum or the uremic toxins indoxyl sulfate, cyanate, modified LDL, the advanced glycation end products N-carboxymethyl-lysine and N-carboxyethyl-lysine, p-cresol and p-cresyl sulfate, phosphate, uric acid and asymmetric dimethylarginine. Most studies described an increase in inflammation, oxidative stress, leukocyte migration and adhesion, cell death and a thrombotic phenotype upon uremic conditions or uremic toxin treatment of endothelial cells. Cellular signaling pathways that were frequently activated included the ROS, MAPK/NF-κB, the Aryl-Hydrocarbon-Receptor and RAGE pathways. Overall, this review provides detailed insights into pathophysiological and molecular mechanisms underlying endothelial dysfunction in CKD. Targeting these pathways may provide new therapeutic strategies reducing increased the cardiovascular risk in CKD.

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Korytowska, Natalia, Bartłomiej Sankowski, Aleksandra Wyczałkowska-Tomasik, Leszek Pączek, Piotr Wroczyński, and Joanna Giebułtowicz. "The utility of saliva testing in the estimation of uremic toxin levels in serum." Clinical Chemistry and Laboratory Medicine (CCLM) 57, no. 2 (December 19, 2018): 230–37. http://dx.doi.org/10.1515/cclm-2018-0087.

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Abstract Background p-Cresol sulfate (pCS) and indoxyl sulfate (IS) are uremic toxins, high concentrations of which are related to renal failure progression. Saliva could become the first-line diagnostic sample of choice, especially for monitoring purposes. Recently, a method for determination of pCS and IS in saliva was developed. Since no data exist on correlations between the levels of toxins in saliva and serum, the applicability of saliva as a diagnostic material is yet to be established. Here, we present a study on the assessment of the utility of saliva testing in the estimation of uremic toxin levels in serum. Methods The study material included serum and unstimulated, fasting saliva obtained from healthy volunteers (n=26) and patients at all stages of chronic kidney diseases (CKD, n=93). The concentration of pCS and IS in saliva and serum (total and unbound fractions) was determined. The daytime variation of the toxins was studied. Results A correlation was found between pCS and IS in saliva and biological active fractions in serum (0.74; 0.81). The variation of the serum/saliva ratio during the day was negligible, with a median of 10% for pCS and 6% for IS, making saliva a reliable material for the estimation of the uremic toxins in circulation at any time of the day. Significant correlations were observed between salivary toxin levels and estimated glomerular filtration rate (pCS: −0.61; IS: −0.70) as well as significant differences in toxin levels between the stages of CKD. Conclusions Saliva could be a valuable diagnostic material for the estimation of toxin levels in circulation.

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Vanholder, Raymond, Sanjay K. Nigam, Stéphane Burtey, and Griet Glorieux. "What If Not All Metabolites from the Uremic Toxin Generating Pathways Are Toxic? A Hypothesis." Toxins 14, no. 3 (March 17, 2022): 221. http://dx.doi.org/10.3390/toxins14030221.

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The topic of uremic toxicity has received broad attention from the nephrological community over the past few decades. An aspect that is much less often considered is the possibility that the metabolic pathways that generate uremic toxins also may produce molecules that benefit body functions. Here, we discuss this dualism based on the example of tryptophan-derived metabolites, which comprise elements that are mainly toxic, such as indoxyl sulfate, kynurenine and kynurenic acid, but also beneficial compounds, such as indole, melatonin and indole-3-propionic acid, and ambivalent (beneficial for some aspects and harmful for others) compounds such as serotonin. This dualism can also be perceived at the level of the main receptor of the tryptophan-derived metabolites, the aryl hydrocarbon receptor (AHR), which has also been linked to both harm and benefit. We hypothesize that these beneficial effects are the reason why uremic toxin generation remained preserved throughout evolution. This duality is also not unique for the tryptophan-derived metabolites, and in this broader context we discuss the remote sensing and signaling theory (RSST). The RSST proposes that transporters (e.g., organic anion transporter 1—OAT1; ATP-binding cassette transporter G—ABCG2) and drug metabolizing enzymes form a large network of proteins interacting to promote small molecule remote communication at the inter-organ (e.g., gut–liver–heart–brain–kidney) and inter-organismal (e.g., gut microbe–host) levels. These small molecules include gut microbe-derived uremic toxins as well as beneficial molecules such as those discussed here. We emphasize that this positive side of uremic metabolite production needs more attention, and that this dualism especially needs to be considered when assessing and conceiving of therapeutic interventions. These homeostatic considerations are central to the RSST and suggest that interventions be aimed at preserving or restoring the balance between positive and negative components rather than eliminating them all without distinction.

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Mydlík, Miroslav, and Katarína Derzsiová. "Oxalic Acid as a Uremic Toxin." Journal of Renal Nutrition 18, no. 1 (January 2008): 33–39. http://dx.doi.org/10.1053/j.jrn.2007.10.008.

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Kishore, B. K. "Is Malondialdehyde a Putative Uremic Toxin?" Nephron 52, no. 3 (1989): 286. http://dx.doi.org/10.1159/000185661.

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Petruzziello-Pellegrini, Tania N., and Philip A. Marsden. "Shiga toxin-associated hemolytic uremic syndrome." Current Opinion in Nephrology and Hypertension 21, no. 4 (July 2012): 433–40. http://dx.doi.org/10.1097/mnh.0b013e328354a62e.

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Meert, Natalie, Eva Schepers, Rita De Smet, Angel Argiles, Gerald Cohen, Reinhold Deppisch, Tilman Drüeke, et al. "Inconsistency of Reported Uremic Toxin Concentrations." Artificial Organs 31, no. 8 (August 2007): 600–611. http://dx.doi.org/10.1111/j.1525-1594.2007.00434.x.

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Mair, Robert, Tammy Sirich, and Timothy Meyer. "Uremic Toxin Clearance and Cardiovascular Toxicities." Toxins 10, no. 6 (June 2, 2018): 226. http://dx.doi.org/10.3390/toxins10060226.

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Skye, Sarah M., and Stanley L. Hazen. "Microbial Modulation of a Uremic Toxin." Cell Host & Microbe 20, no. 6 (December 2016): 691–92. http://dx.doi.org/10.1016/j.chom.2016.11.005.

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Keir, Lindsay Susan. "Shiga Toxin Associated Hemolytic Uremic Syndrome." Hematology/Oncology Clinics of North America 29, no. 3 (June 2015): 525–39. http://dx.doi.org/10.1016/j.hoc.2015.01.007.

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Cooling, Laura L. W., Katherine E. Walker, Theresa Gille, and Theodore A. W. Koerner. "Shiga Toxin Binds Human Platelets via Globotriaosylceramide (Pk Antigen) and a Novel Platelet Glycosphingolipid." Infection and Immunity 66, no. 9 (September 1, 1998): 4355–66. http://dx.doi.org/10.1128/iai.66.9.4355-4366.1998.

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ABSTRACT Hemolytic-uremic syndrome is a clinical syndrome characterized by acute renal failure, microangiopathic hemolytic anemia, and thrombocytopenia that often follows infection by Shiga toxin- or verotoxin-producing strains of Escherichia coli. Because thrombocytopenia and platelet activation are hallmark features of hemolytic-uremic syndrome, we examined the ability of Shiga toxin to bind platelets by flow cytometry and high-performance thin-layer chromatography (HPTLC) of isolated platelet glycosphingolipids. By HPTLC, Shiga toxin was shown to bind globotriaosylceramide (Gb3) and a minor platelet glycolipid with anRf of 0.03, band 0.03. In a survey of 20 human tissues, band 0.03 was identified only in platelets. In individuals, band 0.03 was expressed by 20% of donors and was specifically associated with increased platelet Gb3 expression. Based on glycosidase digestion and epitope mapping, band 0.03 was hypothesized to represent a novel glycosphingolipid, IV3-β-Galα1-4galactosylglobotetraosylceramide. Based on incidence, structure, and association with increased Gb3 expression, band 0.03 may represent the antithetical Luke blood group antigen. By flow cytometry, Shiga toxin bound human platelets, although the amount of Shiga toxin bound varied in donors. Differences in Shiga toxin binding to platelet membranes did not reflect differences in platelet Gb3 expression. In contrast, there was a loose association between Shiga toxin binding and decreasing forward scatter, suggesting that Shiga toxin and verotoxins bind more efficiently to smaller, older platelets. In summary, Shiga and Shiga-like toxins may bind platelets via specific glycosphingolipid receptors. Such binding may contribute to the thrombocytopenia, platelet activation, and microthrombus formation observed in hemolytic-uremic syndrome.

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Laville, Solène M., Ziad A. Massy, Said Kamel, Jean Marc Chillon, Gabriel Choukroun, and Sophie Liabeuf. "Intestinal Chelators, Sorbants, and Gut-Derived Uremic Toxins." Toxins 13, no. 2 (January 26, 2021): 91. http://dx.doi.org/10.3390/toxins13020091.

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Chronic kidney disease (CKD) is a highly prevalent condition and is associated with a high comorbidity burden, polymedication, and a high mortality rate. A number of conventional and nonconventional risk factors for comorbidities and mortality in CKD have been identified. Among the nonconventional risk factors, uremic toxins are valuable therapeutic targets. The fact that some uremic toxins are gut-derived suggests that intestinal chelators might have a therapeutic effect. The phosphate binders used to prevent hyperphosphatemia in hemodialysis patients act by complexing inorganic phosphate in the gastrointestinal tract but might conceivably have a nonspecific action on gut-derived uremic toxins. Since phosphorous is a major nutrient for the survival and reproduction of bacteria, changes in its intestinal concentration may impact the gut microbiota’s activity and composition. Furthermore, AST-120 is an orally administered activated charcoal adsorbent that is widely used in Asian countries to specifically decrease uremic toxin levels. In this narrative review, we examine the latest data on the use of oral nonspecific and specific intestinal chelators to reduce levels of gut-derived uremic toxins.

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Glorieux, Griet, Tessa Gryp, and Alessandra Perna. "Gut-Derived Metabolites and Their Role in Immune Dysfunction in Chronic Kidney Disease." Toxins 12, no. 4 (April 11, 2020): 245. http://dx.doi.org/10.3390/toxins12040245.

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Several of the uremic toxins, which are difficult to remove by dialysis, originate from the gut bacterial metabolism. This opens opportunities for novel targets trying to decrease circulating levels of these toxins and their pathophysiological effects. The current review focuses on immunomodulatory effects of these toxins both at their side of origin and in the circulation. In the gut end products of the bacterial metabolism such as p-cresol, trimethylamine and H2S affect the intestinal barrier structure and function while in the circulation the related uremic toxins stimulate cells of the immune system. Both conditions contribute to the pro-inflammatory status of patients with chronic kidney disease (CKD). Generation and/or absorption of these toxin precursors could be targeted to decrease plasma levels of their respective uremic toxins and to reduce micro-inflammation in CKD.

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Graboski, Amanda L., and Matthew R. Redinbo. "Gut-Derived Protein-Bound Uremic Toxins." Toxins 12, no. 9 (September 11, 2020): 590. http://dx.doi.org/10.3390/toxins12090590.

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Chronic kidney disease (CKD) afflicts more than 500 million people worldwide and is one of the fastest growing global causes of mortality. When glomerular filtration rate begins to fall, uremic toxins accumulate in the serum and significantly increase the risk of death from cardiovascular disease and other causes. Several of the most harmful uremic toxins are produced by the gut microbiota. Furthermore, many such toxins are protein-bound and are therefore recalcitrant to removal by dialysis. We review the derivation and pathological mechanisms of gut-derived, protein-bound uremic toxins (PBUTs). We further outline the emerging relationship between kidney disease and gut dysbiosis, including the bacterial taxa altered, the regulation of microbial uremic toxin-producing genes, and their downstream physiological and neurological consequences. Finally, we discuss gut-targeted therapeutic strategies employed to reduce PBUTs. We conclude that targeting the gut microbiota is a promising approach for the treatment of CKD by blocking the serum accumulation of PBUTs that cannot be eliminated by dialysis.

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Vigorito, Carmela, Evgeniya Anishchenko, Luigi Mele, Giovanna Capolongo, Francesco Trepiccione, Miriam Zacchia, Patrizia Lombari, Rosanna Capasso, Diego Ingrosso, and Alessandra F. Perna. "Uremic Toxin Lanthionine Interferes with the Transsulfuration Pathway, Angiogenetic Signaling and Increases Intracellular Calcium." International Journal of Molecular Sciences 20, no. 9 (May 8, 2019): 2269. http://dx.doi.org/10.3390/ijms20092269.

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(1) The beneficial effects of hydrogen sulfide (H2S) on the cardiovascular and nervous system have recently been re-evaluated. It has been shown that lanthionine, a side product of H2S biosynthesis, previously used as a marker for H2S production, is dramatically increased in circulation in uremia, while H2S release is impaired. Thus, lanthionine could be classified as a novel uremic toxin. Our research was aimed at defining the mechanism(s) for lanthionine toxicity. (2) The effect of lanthionine on H2S release was tested by a novel lead acetate strip test (LAST) in EA.hy926 cell cultures. Effects of glutathione, as a redox agent, were assayed. Levels of sulfane sulfur were evaluated using the SSP4 probe and flow cytometry. Protein content and glutathionylation were analyzed by Western Blotting and immunoprecipitation, respectively. Gene expression and miRNA levels were assessed by qPCR. (3) We demonstrated that, in endothelial cells, lanthionine hampers H2S release; reduces protein content and glutathionylation of transsulfuration enzyme cystathionine-β-synthase; modifies the expression of miR-200c and miR-423; lowers expression of vascular endothelial growth factor VEGF; increases Ca2+ levels. (4) Lanthionine-induced alterations in cell cultures, which involve both sulfur amino acid metabolism and calcium homeostasis, are consistent with uremic dysfunctional characteristics and further support the uremic toxin role of this amino acid.

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Lekawanvijit, Suree. "Cardiotoxicity of Uremic Toxins: A Driver of Cardiorenal Syndrome." Toxins 10, no. 9 (September 1, 2018): 352. http://dx.doi.org/10.3390/toxins10090352.

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Cardiovascular disease (CVD) is highly prevalent in the setting of chronic kidney disease (CKD). Such coexistence of CVD and CKD—the so-called “cardiorenal or renocardiac syndrome”—contributes to exponentially increased risk of cardiovascular (CV) mortality. Uremic cardiomyopathy is a characteristic cardiac pathology commonly found in CKD. CKD patients are also predisposed to heart rhythm disorders especially atrial fibrillation. Traditional CV risk factors as well as known CKD-associated CV risk factors such as anemia are insufficient to explain CV complications in the CKD population. Accumulation of uremic retention solutes is a hallmark of impaired renal excretory function. Many of them have been considered inert solutes until their biological toxicity is unraveled and they become accepted as “uremic toxins”. Direct cardiotoxicity of uremic toxins has been increasingly demonstrated in recent years. This review offers a mechanistic insight into the pathological cardiac remodeling and dysfunction contributed by uremic toxins with a main focus on fibroblastic growth factor-23, an emerging toxin playing a central role in the chronic kidney disease–mineral bone disorder, and the two most investigated non-dialyzable protein-bound uremic toxins, indoxyl sulfate and p-cresyl sulfate. Potential therapeutic strategies that could address these toxins and their relevant mediated pathways since pre-dialysis stages are also discussed.

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Mikhailova, Nataliia A. "The value of a low-protein diet and ketoanalogues of essential amino acids in the сontrol of protein carbamylation and toxic effects of urea in chronic kidney disease." Terapevticheskii arkhiv 93, no. 6 (June 15, 2021): 729–35. http://dx.doi.org/10.26442/00403660.2021.06.200915.

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Chronic kidney disease (CKD) is characterized by high mortality from cardiovascular diseases, the development of which is facilitated by traditional risk factors (typical for the general population) and by nontraditional ones (specific to patients with CKD) as well. These factors include also uremic toxins, for which a causal relationship has been established with specific pathological processes in patients with CKD, comprising the development of vascular dysfunction and accelerated progression of atherosclerosis. Urea has long been considered not as a uremic toxin, but as a marker of metabolic imbalance or dialysis efficiency (Kt/V) in CKD patients. In recent years, more and more publications have appeared on the study of the toxic effects of urea with the development of toxic-uremic complications and the phenotype of premature aging, common in CKD. It was found that an increase in urea levels in uremic syndrome causes damage to the intestinal epithelial barrier with translocation of bacterial toxins into the bloodstream and the development of systemic inflammation, provokes apoptosis of vascular smooth muscle cells, as well as endothelial dysfunction, which directly contributes to the development of cardiovascular complications. The indirect effects of increased urea levels are associated with carbamylation reactions, when isocyanic acid (a product of urea catabolism) changes the structure and function of proteins in the body. Carbamylation of proteins in CKD patients is associated with the development of renal fibrosis, atherosclerosis and anemia. Thus, urea is now regarded as an important negative agent in the pathogenesis of complications in CKD. Studies on a low-protein diet with using ketoanalogues of essential amino acids to minimize the accumulation of urea and other uremic toxins demonstrate the clinical benefit of such an intervention in slowing the progression of CKD and the development of cardiovascular complications.

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Hwang, Yuri, Ji yeon Jang, Yeon-Ho Chung, Bonah Kim, Dong Hyun Kim, Sungha Park, Doo Hyun Chung, and Won-Woo Lee. "The role of indoxyl sulfate, a circulating uremic toxin, for inflammatory responses in the patients with end-stage renal disease (HUM1P.304)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 52.29. http://dx.doi.org/10.4049/jimmunol.194.supp.52.29.

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Abstract In the ESRD patients, a major cause of death is cardiovascular disease (CVD) and its pathologic processes have been suggested to link to uremia-related chronic inflammation. Although concept of ESRD-related immune dysfunction is well-accepted, little is known about how uremic toxins affect cellular immunity involved with pathogenesis of CVD in the patients. Thus, we investigated phenotypic and functional features of CD4 T cells and monocytes in the ESRD patients and their immune responses mediated by indoxyl sulfate (IS), a key uremic toxin in order to explore the pathogenic roles of these cells for vascular endothelial cells (VEC). In ESRD patients, CD4+CD28null T cells and CD16+ monocytes were expanded as compared with HC. To explore how uremic milieu affects immune responses, monocytes were stimulated with IS. These monocytes produced a large amount of TNF-α through aryl hydrocarbon receptor. TNF-α stimulated VEC greatly produced CX3CL1, a ligand of CX3CR1 which is overexpressed by CD4+CD28null T cells and CD16+ monocytes. CD4+CD28null T cells are preferentially recruited by CX3CL1 and moreover, CD4+CD28null T cells have cytotoxic capability allowing for induced apoptosis of VEC in response to TCR stimulation. Our findings suggest that IS-mediated immune dysfunction may play a critical role for development and accelerated progression of CVD through VEC damage in the ESRD patients.

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Ebrahim, Zarina, Sebastian Proost, Raul Yhossef Tito, Jeroen Raes, Griet Glorieux, Mohammed Rafique Moosa, and Renée Blaauw. "The Effect of ß-Glucan Prebiotic on Kidney Function, Uremic Toxins and Gut Microbiome in Stage 3 to 5 Chronic Kidney Disease (CKD) Predialysis Participants: A Randomized Controlled Trial." Nutrients 14, no. 4 (February 14, 2022): 805. http://dx.doi.org/10.3390/nu14040805.

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There is growing evidence that gut dysbiosis contributes to the progression of chronic kidney disease (CKD) owing to several mechanisms, including microbiota-derived uremic toxins, diet and immune-mediated factors. The aim of this study was to investigate the effect of a ß-glucan prebiotic on kidney function, uremic toxins and the gut microbiome in stage 3 to 5 CKD participants. Fifty-nine participants were randomized to either the ß-glucan prebiotic intervention group (n = 30) or the control group (n = 29). The primary outcomes were to assess kidney function (urea, creatinine and glomerular filtration rate), plasma levels of total and free levels of uremic toxins (p-cresyl sulfate (pCS), indoxyl-sulfate (IxS), p-cresyl glucuronide (pCG) and indoxyl 3-acetic acid (IAA) and gut microbiota using 16S rRNA sequencing at baseline, week 8 and week 14. The intervention group (age 40.6 ± 11.4 y) and the control group (age 41.3 ± 12.0 y) did not differ in age or any other socio-demographic variables at baseline. There were no significant changes in kidney function over 14 weeks. There was a significant reduction in uremic toxin levels at different time points, in free IxS at 8 weeks (p = 0.003) and 14 weeks (p < 0.001), free pCS (p = 0.006) at 14 weeks and total and free pCG (p < 0.001, p < 0.001, respectively) and at 14 weeks. There were no differences in relative abundances of genera between groups. Enterotyping revealed that the population consisted of only two of the four enterotypes: Bacteroides 2 and Prevotella. The redundancy analysis showed a few factors significantly affected the gut microbiome: these included triglyceride levels (p < 0.001), body mass index (p = 0.002), high- density lipoprotein (p < 0.001) and the prebiotic intervention (p = 0.002). The ß-glucan prebiotic significantly altered uremic toxin levels of intestinal origin and favorably affected the gut microbiome.

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Vanholder, Raymond C., Sunny Eloot, and Griet L. R. L. Glorieux. "Future Avenues to Decrease Uremic Toxin Concentration." American Journal of Kidney Diseases 67, no. 4 (April 2016): 664–76. http://dx.doi.org/10.1053/j.ajkd.2015.08.029.

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Rossi, Megan, Katrina L. Campbell, David W. Johnson, Tony Stanton, Brian A. Haluska, Carmel M. Hawley, Goce Dimeski, et al. "Uremic Toxin Development in Living Kidney Donors." Transplantation 97, no. 5 (March 2014): 548–54. http://dx.doi.org/10.1097/01.tp.0000436906.48802.c4.

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Vanholder, Raymond, and Ziad A. Massy. "Progress in Uremic Toxin Research: An Introduction." Seminars in Dialysis 22, no. 4 (July 2009): 321–22. http://dx.doi.org/10.1111/j.1525-139x.2009.00573.x.

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Siegler, Richard L. "Postdiarrheal Shiga Toxin–Mediated Hemolytic Uremic Syndrome." JAMA 290, no. 10 (September 10, 2003): 1379. http://dx.doi.org/10.1001/jama.290.10.1379.

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Palm, Fredrik, Masaomi Nangaku, Angelica Fasching, Tetsuhiro Tanaka, Lina Nordquist, Peter Hansell, Takahisa Kawakami, Fuyuhiko Nishijima, and Toshiro Fujita. "Uremia induces abnormal oxygen consumption in tubules and aggravates chronic hypoxia of the kidney via oxidative stress." American Journal of Physiology-Renal Physiology 299, no. 2 (August 2010): F380—F386. http://dx.doi.org/10.1152/ajprenal.00175.2010.

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In addition to causing uremic symptoms, uremic toxins accelerate the progression of renal failure. To elucidate the pathophysiology of uremic states, we investigated the effect of indoxyl sulfate (IS), a representative uremic toxin, on oxygen metabolism in tubular cells. We demonstrated an increase in oxygen consumption by IS in freshly isolated rat and human proximal tubules. Studies utilizing ouabain, the Na-K-ATPase inhibitor, and apocynin, the NADPH oxidase inhibitor, as well as the in vivo gene-silencing approach to knock down p22phox showed that the increase in tubular oxygen consumption by IS is dependent on Na-K-ATPase and oxidative stress. We investigated whether the enhanced oxygen consumption led to subsequent hypoxia of the kidney. An increase in serum IS concentrations in rats administered indole was associated with a decrease in renal oxygenation (8 h). The remnant kidney in rats developed hypoxia at 16 wk. Treatment of the rats with AST-120, an oral adsorbent that removes uremic toxins, reduced serum IS levels and improved oxygenation of the kidney. Amelioration of hypoxia in the remnant kidney was associated with better renal functions and less histological injury. Reduction of serum IS levels also led to a decrease in oxidative stress in the kidney. Our ex vivo and in vivo studies implicated that uremic states may deteriorate renal dysfunction via dysregulating oxygen metabolism in tubular cells. The abnormal oxygen metabolism in tubular cells by uremic toxins was, at least in part, mediated by oxidative stress.

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Vanholder, Raymond. "“Uremic Toxin” Section in the Journal Toxins: A Powerful Tool to Bundle and Advance Knowledge on Uremia." Toxins 9, no. 5 (May 18, 2017): 170. http://dx.doi.org/10.3390/toxins9050170.

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King, Jasia, Silvia M. Mihaila, Sabbir Ahmed, Roman Truckenmüller, Stefan Giselbrecht, Rosalinde Masereeuw, and Aurélie Carlier. "The Influence of OAT1 Density and Functionality on Indoxyl Sulfate Transport in the Human Proximal Tubule: An Integrated Computational and In Vitro Study." Toxins 13, no. 10 (September 22, 2021): 674. http://dx.doi.org/10.3390/toxins13100674.

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Research has shown that traditional dialysis is an insufficient long-term therapy for patients suffering from end-stage kidney disease due to the high retention of uremic toxins in the blood as a result of the absence of the active transport functionality of the proximal tubule (PT). The PT’s function is defined by the epithelial membrane transporters, which have an integral role in toxin clearance. However, the intricate PT transporter–toxin interactions are not fully explored, and it is challenging to decouple their effects in toxin removal in vitro. Computational models are necessary to unravel and quantify the toxin–transporter interactions and develop an alternative therapy to dialysis. This includes the bioartificial kidney, where the hollow dialysis fibers are covered with kidney epithelial cells. In this integrated experimental–computational study, we developed a PT computational model that focuses on indoxyl sulfate (IS) transport by organic anionic transporter 1 (OAT1), capturing the transporter density in detail along the basolateral cell membrane as well as the activity of the transporter and the inward boundary flux. The unknown parameter values of the OAT1 density (1.15×107 transporters µm−2), IS uptake (1.75×10−5 µM−1 s−1), and dissociation (4.18×10−4 s−1) were fitted and validated with experimental LC-MS/MS time-series data of the IS concentration. The computational model was expanded to incorporate albumin conformational changes present in uremic patients. The results suggest that IS removal in the physiological model was influenced mainly by transporter density and IS dissociation rate from OAT1 and not by the initial albumin concentration. While in uremic conditions considering albumin conformational changes, the rate-limiting factors were the transporter density and IS uptake rate, which were followed closely by the albumin-binding rate and IS dissociation rate. In summary, the results of this study provide an exciting avenue to help understand the toxin–transporter complexities in the PT and make better-informed decisions on bioartificial kidney designs and the underlining transporter-related issues in uremic patients.

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Journal articles on the topic 'Uremic toxin'

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