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1.
The biology of urate.
Keenan, RT
Seminars in arthritis and rheumatism. 2020;(3S):S2-S10
Abstract
Urate is the end-product of the purine metabolism in humans. The dominant source of urate is endogenous purines and the remainder comes through diet. Approximately two thirds of urate is eliminated via the kidney with the rest excreted in the feces. While the transporter BCRP, encoded by ABCG2, has been found to play a role in both the gut and kidney, SLC22A12 and SLC2A9 encoding URAT1 and GLUT9, respectively, are the two transporters best characterized. Only 8-12% of the filtered urate is excreted by the kidney. Renal elimination of urate depends substantially on specific transporters, including URAT1, GLUT9 and BCRP. Studies that have assessed the biologic effects of urate have produced highly variable results. Although there is a suggestion that urate may have anti-oxidant properties in some circumstances, the majority of evidence indicates that urate is pro-inflammatory. Hyperuricemia can result in the formation of monosodium urate (MSU) crystals that may be recognized as danger signals by the immune system. This immune response results in the activation of the NLRP3 inflammasome and ultimately in the production and release of interleukin-1β, and IL-18, that mediate both inflammation, pyroptotic cell death, and necroinflammation. It has also been demonstrated that soluble urate mediates effects on the kidney to induce hypertension and can induce long term epigenetic reprogramming in myeloid cells to induce "trained immunity." Together, these sequelae of urate are thought to mediate most of the physiological effects of hyperuricemia and gout, illustrating this biologically active molecule is more than just an "end-product" of purine metabolism.
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2.
Uric Acid Elevation by Favipiravir, an Antiviral Drug.
Mishima, E, Anzai, N, Miyazaki, M, Abe, T
The Tohoku journal of experimental medicine. 2020;(2):87-90
Abstract
In light of the recent pandemic, favipiravir (Avigan®), a purine nucleic acid analog and antiviral agent approved for use in influenza in Japan, is being studied for the treatment of coronavirus disease 2019 (COVID-19). Increase in blood uric acid level is a frequent side effect of favipiravir. Here, we discussed the mechanism of blood uric acid elevation during favipiravir treatment. Favipiravir is metabolized to an inactive metabolite M1 by aldehyde oxidase and xanthine oxidase, and excreted into urine. In the kidney, uric acid handling is regulated by the balance of reabsorption and tubular secretion in the proximal tubules. Favipiravir and M1 act as moderate inhibitors of organic anion transporter 1 and 3 (OAT1 and OAT3), which are involved in uric acid excretion in the kidney. In addition, M1 enhances uric acid reuptake via urate transporter 1 (URAT1) in the renal proximal tubules. Thus, favipiravir is thought to decrease uric acid excretion into urine, resulting in elevation of uric acid levels in blood. Elevated uric acid levels were returned to normal after discontinuation of favipiravir, and favipiravir is not used for long periods of time for the treatment of viral infection. Thus, the effect on blood uric acid levels was subclinical in most studies. Nevertheless, the adverse effect of favipiravir might be clinically important in patients with a history of gout, hyperuricemia, kidney function impairment (in which blood concentration of M1 increases), and where there is concomitant use of other drugs affecting blood uric acid elevation.
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3.
Dietary Antioxidant Supplements and Uric Acid in Chronic Kidney Disease: A Review.
Roumeliotis, S, Roumeliotis, A, Dounousi, E, Eleftheriadis, T, Liakopoulos, V
Nutrients. 2019;(8)
Abstract
Increased serum levels of uric acid have been associated with the onset and development of chronic kidney disease (CKD), cardiovascular disease, and mortality, through several molecular pathogenetic mechanisms, such as inflammation and oxidative stress. Oxidative stress is present even in the early stages of CKD, progresses parallelly with the deterioration of kidney function, and is even more exacerbated in end-stage renal disease patients undergoing maintenance hemodialysis. Although acting in the plasma as an antioxidant, once uric acid enters the intracellular environment; it behaves as a powerful pro-oxidant. Exogenous intake of antioxidants has been repeatedly shown to prevent inflammation, atherosclerosis and oxidative stress in CKD patients. Moreover, certain antioxidants have been proposed to exert uric acid-lowering properties. This review aims to present the available data regarding the effects of antioxidant supplements on both oxidative stress and uric acid serum levels, in a population particularly susceptible to oxidative damage such as CKD patients.
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4.
Diagnostic advances in synovial fluid analysis and radiographic identification for crystalline arthritis.
Zell, M, Zhang, D, FitzGerald, J
Current opinion in rheumatology. 2019;(2):134-143
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Abstract
PURPOSE OF REVIEW The present review addresses diagnostic methods for crystalline arthritis including synovial fluid analysis, ultrasound, and dual energy CT scan (DECT). RECENT FINDINGS There are new technologies on the horizon to improve the ease, sensitivity, and specificity of synovial fluid analysis. Raman spectroscopy uses the spectral signature that results from a material's unique energy absorption and scatter for crystal identification. Lens-free microscopy directly images synovial fluid aspirate on to a complementary metal-oxide semiconductor chip, providing a high-resolution, wide field of view (∼20 mm) image. Raman spectroscopy and lens-free microscopy may provide additional benefit over compensated polarized light microscopy synovial fluid analysis by quantifying crystal density in synovial fluid samples. Ultrasound and DECT have good sensitivity and specificity for the identification of monosodium urate (MSU) and calcium pyrophosphate (CPP) crystals. However, both have limitations in patients with recent onset gout and low urate burdens. SUMMARY New technologies promise improved methods for detection of MSU and CPP crystals. At this time, limitations of these technologies do not replace the need for synovial fluid aspiration for confirmation of crystal detection. None of these technologies address the often concomitant indication to rule out infectious arthritis.
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5.
Uric Acid and Cognitive Function in Older Individuals.
Tana, C, Ticinesi, A, Prati, B, Nouvenne, A, Meschi, T
Nutrients. 2018;(8)
Abstract
Hyperuricemia has been recognized as an independent cardiovascular risk factor in epidemiological studies. However, uric acid can also exert beneficial functions due to its antioxidant properties, which may be particularly relevant in the context of neurodegenerative diseases. In this paper, we critically revise the evidence on the relationship between serum uric acid levels and cognitive function in older individuals, focusing on the etiology of cognitive impairment (Alzheimer's disease, Parkinson's dementia, and vascular dementia) and on the interactive connections between uric acid, dementia, and diet. Despite high heterogeneity in the existing studies, due to different characteristics of studied populations and methods of cognitive dysfunction assessment, we conclude that serum uric acid may modulate cognitive function in a different way according to the etiology of dementia. Current studies indeed demonstrate that uric acid may exert neuroprotective actions in Alzheimer's disease and Parkinson's dementia, with hypouricemia representing a risk factor for a quicker disease progression and a possible marker of malnutrition. Conversely, high serum uric acid may negatively influence the disease course in vascular dementia. Further studies are needed to clarify the physio-pathological role of uric acid in different dementia types, and its clinical-prognostic significance.
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Hyperuricemia and endothelial function: From molecular background to clinical perspectives.
Maruhashi, T, Hisatome, I, Kihara, Y, Higashi, Y
Atherosclerosis. 2018;:226-231
Abstract
Uric acid is the end product of purine metabolism catalyzed by xanthine oxidase in humans. In the process of purine metabolism, reactive oxygen species, including superoxide, are generated concomitantly with uric acid production, which may deteriorate endothelial function through the reaction of superoxide with nitric oxide (NO), leading to decreased NO bioavailability and increased production of peroxynitrite, a reactive oxidant. Therefore, xanthine oxidase may be a therapeutic target in the treatment of endothelial dysfunction. Indeed, clinical studies have shown that endothelial dysfunction is restored by treatment with a xanthine oxidase inhibitor in patients with cardiovascular risk factors. However, it has not been fully determined whether uric acid per se is an independent causal risk factor of endothelial dysfunction in humans. Although experimental studies have indicated that uric acid absorbed into endothelial cells via the activation of uric acid transporters expressed in endothelial cells causes endothelial dysfunction through increased oxidative stress and inflammation, an actual biological effect of uric acid on endothelial function in vivo has not been fully elucidated, in part, because of the difficulty in investigating the effect of uric acid alone on endothelial function due to the close associations of uric acid with other conventional cardiovascular risk factors and the complicated relationship between uric acid and endothelial function attributed to the potent antioxidant properties of uric acid. In this review, we focus on the relationship between uric acid and endothelial function from molecular to clinical perspectives.
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An evidence-based review on urate-lowering treatments: implications for optimal treatment of chronic hyperuricemia.
Bove, M, Cicero, AF, Veronesi, M, Borghi, C
Vascular health and risk management. 2017;:23-28
Abstract
Several studies suggest that chronic hyperuricemia, the main precursor of gout, is involved in the pathogenesis of different systemic disorders that affect cardiovascular and renal systems, such as hypertension, obesity, hypercholesterolemia, atherosclerosis, metabolic syndrome, chronic heart failure, and chronic kidney disease. Recent epidemiological evidence has shown an increasing trend in the prevalence of hyperuricemia and gout in the Western world: a number of population-based studies estimate a prevalence of up to 21% for hyperuricemia and 1%-4% for gout. As such, early detection and careful management of this pathological condition is required, starting from lifestyle changes (mainly based on a diet low in red meat, sugars, and alcoholic beverages, with increased intake of vegetables, water, and vitamin C sources), adding specific drugs to lead serum uric acid (SUA) levels under the target value of 7 mg/dL. In particular, nonselective and selective XO inhibitors (allopurinol, oxypurinol, febuxostat) reduce SUA levels and the overproduction of reactive oxygen species, mainly related to XO overactivity that often causes inflammatory damage to the vascular endothelium. The effect of lowering SUA levels via XO inhibition includes an attenuation of oxidative stress and related endothelial dysfunction that largely contribute to the pathophysiology of metabolic syndrome and cardiovascular diseases. Therefore, the inhibition of XO overactivation seems to be an excellent therapeutic option to limit the harmful effects of excess UA and reactive oxygen species. In conclusion, rapid diagnosis and correct therapy for hyperuricemia may also improve the prevention and/or treatment of serious and multifactorial diseases. The available evidence supports the importance of promoting new experimental clinical trials to confirm the emerging antioxidant role of XO inhibitors, which could effectively contribute to cardiovascular and chronic kidney disease prevention.
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8.
Fructose Intake, Serum Uric Acid, and Cardiometabolic Disorders: A Critical Review.
Caliceti, C, Calabria, D, Roda, A, Cicero, AFG
Nutrients. 2017;(4)
Abstract
There is a direct relationship between fructose intake and serum levels of uric acid (UA), which is the final product of purine metabolism. Recent preclinical and clinical evidence suggests that chronic hyperuricemia is an independent risk factor for hypertension, metabolic syndrome, and cardiovascular disease. It is probably also an independent risk factor for chronic kidney disease, Type 2 diabetes, and cognitive decline. These relationships have been observed for high serum UA levels (>5.5 mg/dL in women and >6 mg/dL in men), but also for normal to high serum UA levels (5-6 mg/dL). In this regard, blood UA levels are much higher in industrialized countries than in the rest of the world. Xanthine-oxidase inhibitors can reduce UA and seem to minimize its negative effects on vascular health. Other dietary and pathophysiological factors are also related to UA production. However, the role of fructose-derived UA in the pathogenesis of cardiometabolic disorders has not yet been fully clarified. Here, we critically review recent research on the biochemistry of UA production, the relationship between fructose intake and UA production, and how this relationship is linked to cardiometabolic disorders.
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9.
Uric acid and transforming growth factor in fructose-induced production of reactive oxygen species in skeletal muscle.
Madlala, HP, Maarman, GJ, Ojuka, E
Nutrition reviews. 2016;(4):259-66
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Abstract
The consumption of fructose, a major constituent of the modern diet, has raised increasing concern about the effects of fructose on health. Research suggests that excessive intake of fructose (>50 g/d) causes hyperuricemia, insulin resistance, mitochondrial dysfunction, de novo lipogenesis by the liver, and increased production of reactive oxygen species (ROS) in muscle. In a number of tissues, uric acid has been shown to stimulate the production of ROS via activation of transforming growth factor β1 and NADPH (nicotinamide adenine dinucleotide phosphate) oxidase 4. The role of uric acid in fructose-induced production of ROS in skeletal muscle, however, has not been investigated. This review examines the evidence for fructose-induced production of ROS in skeletal muscle, highlights proposed mechanisms, and identifies gaps in current knowledge.
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10.
Management of Chronic Kidney Disease: The Relationship Between Serum Uric Acid and Development of Nephropathy.
Mende, C
Advances in therapy. 2015;(12):1177-91
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Abstract
UNLABELLED Chronic kidney disease (CKD) is increasingly recognized as a global health problem, and new and effective strategies are needed for the management of this condition. Recently, there has been renewed interest in the relationship between serum uric acid (SUA) levels and CKD, and several recent trials have demonstrated a possible link between SUA and the development and/or progression of CKD in patients with and without diabetes. The identification of key urate transporters such as urate transporter 1 and glucose transporter 9 has provided not only insights into the pathophysiology of hyperuricemia, but also possible links to other processes, such as glucose homeostasis. The renewed interest in the role of SUA in CKD has coincided with the development of sodium glucose co-transporter 2 inhibitors for the treatment of diabetes. In addition to improving glycemic control, these agents, acting via the kidneys in an insulin-independent manner, have also been shown to reduce SUA levels and potentially improve some measures of renal function. This review will discuss the role of uric acid in CKD treatment, and how SUA-lowering therapies may prevent or delay the progression of CKD. FUNDING Janssen Scientific Affairs.