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Dysuricemia: Recent Advances in Urate Research from Hypouricemia to Hyperuricemia/Gout

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 17137

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Special Issue Editors

Dr. Akiyoshi Nakayama

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Guest Editor

Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Saitama 359-8513, Japan
Interests: hypouricemia; hyperuricemia; gout; urate handling; transporter; genetics

Dr. Masafumi Kurajoh

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Guest Editor

Department of Metabolism, Endocrinology, and Molecular Medicine, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan‎
Interests: uric acid; xanthine oxidoreductase; endocrinology; sarcopenia

Special Issue Information

Dear Colleagues,

Gout caused by hyperuricemia is a globally widespread and increasingly burdensome disease. Recent studies have illuminated the pathophysiology of gout and hyperuricemia, as well as its genetic background, epidemiology, diagnosis, treatment, and complications.

It is of interest that the molecular targets for these diseases were initially provided by research on renal hypouricemia, which is often accompanied by complications such as exercise-induced acute kidney injury. The notion of “the lower, the better” when it comes to blood urate levels is in fact incorrect: a better understanding of urate handling and metabolism comes from an awareness that both excessively high and low levels cause problems.

Several studies have also revealed the physiological role of urate as an antioxidant and prooxidant, acting as both a scavenger and generator of reactive oxygen species (ROSs). These discoveries have prompted research interest in not only serum urate levels but also in xanthine oxidoreductase (XOR), an enzyme that synthesizes both urate and ROSs, as status or progression biomarkers of chronic kidney disease and cardiovascular disease.

The current body of evidence clearly indicates that urate is much more than just a metabolic waste product. The aim of this Special Issue, therefore, is to propose the novel disease concept of “Dysuricemia” to describe disorders of urate handling and/or metabolism via XOR, and to interpret the spectrum from hypouricemia to hyperuricemia/gout as a single disease category.

We believe that recent advances in dysuricemia research covered in the present Special Issue will illuminate many currently unknown roles of urate.

Dr. Akiyoshi Nakayama
Dr. Masafumi Kurajoh
Guest Editors

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Keywords

dysuricemia
gout
hyperuricemia
hypouricemia
urate metabolism
antioxidative effects

Published Papers (9 papers)

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Research

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16 pages, 3084 KiB

Open AccessArticle

Plasma and Urinary Metabolomic Analysis of Gout and Asymptomatic Hyperuricemia and Profiling of Potential Biomarkers: A Pilot Study

by Yuki Ohashi, Hiroshi Ooyama, Hideki Makinoshima, Tappei Takada, Hirotaka Matsuo and Kimiyoshi Ichida

Biomedicines 2024, 12(2), 300; https://doi.org/10.3390/biomedicines12020300 - 27 Jan 2024

Viewed by 1220

Abstract

Gout results from monosodium urate deposition caused by hyperuricemia, but most individuals with hyperuricemia remain asymptomatic. The pathogenesis of gout remains uncertain. To identify potential biomarkers distinguishing gout from asymptomatic hyperuricemia, we conducted a genetic analysis of urate transporters and metabolomic analysis as a proof-of-concept study, including 33 patients with gout and 9 individuals with asymptomatic hyperuricemia. The variant allele frequencies of rs72552713, rs2231142, and rs3733591, which are related to serum urate levels (SUA) and gout, did not differ between the gout and asymptomatic hyperuricemia groups. In metabolomic analysis, the levels of citrate cycle intermediates, especially 2-ketoglutarate, were higher in patients with gout than in those with asymptomatic hyperuricemia (fold difference = 1.415, p = 0.039). The impact on the TCA cycle was further emphasized in high-risk gout (SUA ≥ 9.0 mg/dL). Of note, urinary nicotinate was the most prominent biomarker differentiating high-risk gout from asymptomatic hyperuricemia (fold difference = 6.515, p = 0.020). Although urate transporters play critical roles in SUA elevation and promote hyperuricemia, this study suggests that the progression from asymptomatic hyperuricemia to gout might be closely related to other genetic and/or environmental factors affecting carbohydrate metabolism and urinary urate excretion. Full article

(This article belongs to the Special Issue Dysuricemia: Recent Advances in Urate Research from Hypouricemia to Hyperuricemia/Gout)

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9 pages, 1555 KiB

Open AccessArticle

The Association of Smoking and Hyperuricemia with Renal Arteriolosclerosis in IgA Nephropathy

by Yuki Shinzato, Ryo Zamami, Nanako Oshiro, Takuto Nakamura, Akio Ishida, Yusuke Ohya and Kentaro Kohagura

Biomedicines 2023, 11(7), 2053; https://doi.org/10.3390/biomedicines11072053 - 21 Jul 2023

Viewed by 789

Abstract

The combination effects of smoking (SMK) and hyperuricemia (HU) on renal arteriolosclerosis in patients with IgA nephropathy remain unknown. We examined the cross-sectional association between smoking (current or former) and renal arteriolar hyalinosis and wall thickening with or without HU [uric acid (UA) level ≥ 7 and ≥5 mg/dL in men and women] in 87 patients with IgA nephropathy who underwent renal biopsy. Arteriolar hyalinosis and wall thickening were assessed by the semiquantitative grading of arterioles. The SMK/HU subgroup showed the highest indices for hyalinosis and wall thickening, followed by the non-SMK/HU, SMK/non-HU, and non-SMK/non-HU subgroups. Multiple logistic analysis showed that SMK/HU, but not SMK/non-HU, was significantly associated with an increased risk of higher-grade renal arteriolar wall thickening. However, this did not occur with hyalinosis compared to non-SMK/non-HU. The adjusted odds ratio (95% confidence interval, p value) for SMK/HU was 12.8 (1.36–119, p < 0.05) for wall thickening. An association between SMK and renal arteriolar wall thickening might be prevalent only among patients with HU and in patients with IgA nephropathy. Further prospective studies are needed to determine whether patients with HU and SMK history exhibit rapid eGFR deterioration. Full article

(This article belongs to the Special Issue Dysuricemia: Recent Advances in Urate Research from Hypouricemia to Hyperuricemia/Gout)

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16 pages, 1759 KiB

Open AccessArticle

A Newly Developed Method-Based Xanthine Oxidoreductase Activities in Various Human Liver Diseases

by Ken Sato, Atsushi Naganuma, Tamon Nagashima, Yosuke Arai, Yuka Mikami, Yuka Nakajima, Yuki Kanayama, Tatsuma Murakami, Sanae Uehara, Daisuke Uehara, Yuichi Yamazaki, Takayo Murase, Takashi Nakamura and Toshio Uraoka

Biomedicines 2023, 11(5), 1445; https://doi.org/10.3390/biomedicines11051445 - 14 May 2023

Viewed by 1502

Abstract

Studies evaluating xanthine oxidoreductase (XOR) activities in comprehensive liver diseases are scarce, and different etiologies have previously been combined in groups for comparison. To accurately evaluate XOR activities in liver diseases, the plasma XOR activities in etiology-based comprehensive liver diseases were measured using a novel, sensitive, and accurate assay that is a combination of liquid chromatography and triple quadrupole mass spectrometry to detect [¹³C₂, ¹⁵N₂]uric acid using [¹³C₂, ¹⁵N₂]xanthine as a substrate. We also mainly evaluated the association between the plasma XOR activities and parameters of liver tests, purine metabolism-associated markers, oxidative stress markers, and an inflammation marker. In total, 329 patients and 32 controls were enrolled in our study. Plasma XOR activities were generally increased in liver diseases, especially in the active phase, such as in patients with hepatitis C virus RNA positivity, those with abnormal alanine transaminase (ALT) levels in autoimmune liver diseases, and uncured hepatocellular carcinoma patients. Plasma XOR activities were numerically highest in patients with acute hepatitis B. Plasma XOR activities were closely correlated with parameters of liver tests, especially serum ALT levels, regardless of etiology and plasma xanthine levels. Our results indicated that plasma XOR activity might reflect the active phase in various liver diseases. Full article

(This article belongs to the Special Issue Dysuricemia: Recent Advances in Urate Research from Hypouricemia to Hyperuricemia/Gout)

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Graphical abstract

12 pages, 629 KiB

Open AccessArticle

by Masafumi Kurajoh, Yoshikazu Hiura, Ryutaro Numaguchi, Yasutaka Ihara, Takumi Imai, Tomoaki Morioka, Masanori Emoto and Yukio Nishiguchi

Biomedicines 2023, 11(3), 854; https://doi.org/10.3390/biomedicines11030854 - 10 Mar 2023

Cited by 1 | Viewed by 1576

Abstract

Uric acid has antioxidant properties. To examine whether a low uric acid level is associated with severe coronavirus disease 2019 (COVID-19) progression via inflammation, alveolar damage, and/or coagulation abnormality, a retrospective observational study of 488 patients with non-severe COVID-19 and serum uric acid level ≤7 mg/dL at admission was conducted. Serum C-reactive protein (CRP), serum Krebs von den Lungen 6 (KL-6), and plasma D-dimer levels were also measured as markers of inflammation, alveolar damage, and coagulation abnormality, respectively. Median values for uric acid, CRP, KL-6, and D-dimer at admission were 4.4 mg/dL, 3.33 mg/dL, 252.0 U/mL, and 0.8 µg/mL, respectively. Among the total cohort, 95 (19.5%) progressed to severe COVID-19 with a median (interquartile range) time of 7 (4–14) days. Multivariable Cox proportional hazards regression analysis showed that low uric acid level was associated with a higher rate of severe COVID-19 progression. However, uric acid level was inversely associated with CRP level, and the association between the level of uric acid and severe COVID-19 progression was significantly different with and without CRP level inclusion. In contrast, no such association was found for KL-6 or D-dimer level. Low uric acid may contribute to severe COVID-19 progression via increased inflammation in subjects without hyperuricemia. Full article

(This article belongs to the Special Issue Dysuricemia: Recent Advances in Urate Research from Hypouricemia to Hyperuricemia/Gout)

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14 pages, 2921 KiB

Open AccessArticle

The Effects of Topiroxostat, a Selective Xanthine Oxidoreductase Inhibitor, on Arterial Stiffness in Hyperuricemic Patients with Liver Dysfunction: A Sub-Analysis of the BEYOND-UA Study

by Yuya Fujishima, Hitoshi Nishizawa, Yusuke Kawachi, Takashi Nakamura, Seigo Akari, Yoshiyuki Ono, Shiro Fukuda, Shunbun Kita, Norikazu Maeda, Satoshi Hoshide, Iichiro Shimomura and Kazuomi Kario

Biomedicines 2023, 11(3), 674; https://doi.org/10.3390/biomedicines11030674 - 23 Feb 2023

Cited by 2 | Viewed by 1785

Abstract

Background: The effects of uric acid (UA)-lowering therapy with xanthine oxidoreductase (XOR) inhibitors on the development of cardiovascular diseases remain controversial. Based on recent findings that plasma XOR activity increased in liver disease conditions, we conducted a sub-analysis of the BEYOND-UA study to examine the differential effects of topiroxostat on arterial stiffness based on liver function in hyperuricemic individuals with hypertension. Methods: Sixty-three subjects treated with topiroxostat were grouped according to baseline alanine aminotransferase (ALT) levels (above or below cut-off values of 22, 30, or 40 U/L). The primary endpoint was changes in the cardio-ankle vascular index (CAVI) from baseline to 24 weeks. Results: Significant reductions in CAVI during topiroxostat therapy occurred in subjects with baseline ALT ≥30 U/L or ≥40 U/L, and significant between-group differences were detected. Brachial-ankle pulse wave velocity significantly decreased in the ALT-high groups at all cut-off values. Reductions in morning home blood pressure and serum UA were similar regardless of the baseline ALT level. For eleven subjects with available data, ALT-high groups showed high plasma XOR activity, which was significantly suppressed by topiroxostat. Conclusions: Topiroxostat improved arterial stiffness parameters in hyperuricemic patients with liver dysfunction, which might be related to its inhibitory effect on plasma XOR. Full article

(This article belongs to the Special Issue Dysuricemia: Recent Advances in Urate Research from Hypouricemia to Hyperuricemia/Gout)

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Review

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17 pages, 2148 KiB

Open AccessReview

Dysuricemia

by Akiyoshi Nakayama, Masafumi Kurajoh, Yu Toyoda, Tappei Takada, Kimiyoshi Ichida and Hirotaka Matsuo

Biomedicines 2023, 11(12), 3169; https://doi.org/10.3390/biomedicines11123169 - 28 Nov 2023

Viewed by 2843

Abstract

Gout results from elevated serum urate (SU) levels, or hyperuricemia, and is a globally widespread and increasingly burdensome disease. Recent studies have illuminated the pathophysiology of gout/hyperuricemia and its epidemiology, diagnosis, treatment, and complications. The genetic involvement of urate transporters and enzymes is also proven. URAT1, a molecular therapeutic target for gout/hyperuricemia, was initially derived from research into hereditary renal hypouricemia (RHUC). RHUC is often accompanied by complications such as exercise-induced acute kidney injury, which indicates the key physiological role of uric acid. Several studies have also revealed its physiological role as both an anti-oxidant and a pro-oxidant, acting as both a scavenger and a generator of reactive oxygen species (ROSs). These discoveries have prompted research interest in SU and xanthine oxidoreductase (XOR), an enzyme that produces both urate and ROSs, as status or progression biomarkers of chronic kidney disease and cardiovascular disease. The notion of “the lower, the better” is therefore incorrect; a better understanding of uric acid handling and metabolism/transport comes from an awareness that excessively high and low levels both cause problems. We summarize here the current body of evidence, demonstrate that uric acid is much more than a metabolic waste product, and finally propose the novel disease concept of “dysuricemia” on the path toward “normouricemia”, or optimal SU level, to take advantage of the dual roles of uric acid. Our proposal should help to interpret the spectrum from hypouricemia to hyperuricemia/gout as a single disease category. Full article

(This article belongs to the Special Issue Dysuricemia: Recent Advances in Urate Research from Hypouricemia to Hyperuricemia/Gout)

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15 pages, 1365 KiB

Open AccessReview

Impact of Hyper- and Hypo-Uricemia on Kidney Function

by Junichiro Miake, Ichiro Hisatome, Katsuyuki Tomita, Tadahiro Isoyama, Shinobu Sugihara, Masanari Kuwabara, Kazuhide Ogino and Haruaki Ninomiya

Biomedicines 2023, 11(5), 1258; https://doi.org/10.3390/biomedicines11051258 - 24 Apr 2023

Cited by 5 | Viewed by 2469

Abstract

Uric acid (UA) forms monosodium urate (MSU) crystals to exert proinflammatory actions, thus causing gout arthritis, urolithiasis, kidney disease, and cardiovascular disease. UA is also one of the most potent antioxidants that suppresses oxidative stress. Hyper andhypouricemia are caused by genetic mutations or polymorphism. Hyperuricemia increases urinary UA concentration and is frequently associated with urolithiasis, which is augmented by low urinary pH. Renal hypouricemia (RHU) is associated with renal stones by increased level of urinary UA, which correlates with the impaired tubular reabsorption of UA. Hyperuricemia causes gout nephropathy, characterized by renal interstitium and tubular damage because MSU precipitates in the tubules. RHU is also frequently associated with tubular damage with elevated urinary beta2-microglobulin due to increased urinary UA concentration, which is related to impaired tubular UA reabsorption through URAT1. Hyperuricemia could induce renal arteriopathy and reduce renal blood flow, while increasing urinary albumin excretion, which is correlated with plasma xanthine oxidoreductase (XOR) activity. RHU is associated with exercise-induced kidney injury, since low levels of SUA could induce the vasoconstriction of the kidney and the enhanced urinary UA excretion could form intratubular precipitation. A U-shaped association of SUA with organ damage is observed in patients with kidney diseases related to impaired endothelial function. Under hyperuricemia, intracellular UA, MSU crystals, and XOR could reduce NO and activate several proinflammatory signals, impairing endothelial functions. Under hypouricemia, the genetic and pharmacological depletion of UA could impair the NO-dependent and independent endothelial functions, suggesting that RHU and secondary hypouricemia might be a risk factor for the loss of kidney functions. In order to protect kidney functions in hyperuricemic patients, the use of urate lowering agents could be recommended to target SUA below 6 mg/dL. In order to protect the kidney functions in RHU patients, hydration and urinary alkalization may be recommended, and in some cases an XOR inhibitor might be recommended in order to reduce oxidative stress. Full article

(This article belongs to the Special Issue Dysuricemia: Recent Advances in Urate Research from Hypouricemia to Hyperuricemia/Gout)

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17 pages, 948 KiB

Open AccessReview

Dysuricemia—A New Concept Encompassing Hyperuricemia and Hypouricemia

by Naoyuki Otani, Motoshi Ouchi, Einosuke Mizuta, Asuka Morita, Tomoe Fujita, Naohiko Anzai and Ichiro Hisatome

Biomedicines 2023, 11(5), 1255; https://doi.org/10.3390/biomedicines11051255 - 23 Apr 2023

Cited by 2 | Viewed by 1726

Abstract

The importance of uric acid, the final metabolite of purines excreted by the kidneys and intestines, was not previously recognized, except for its role in forming crystals in the joints and causing gout. However, recent evidence implies that uric acid is not a biologically inactive substance and may exert a wide range of effects, including antioxidant, neurostimulatory, proinflammatory, and innate immune activities. Notably, uric acid has two contradictory properties: antioxidant and oxidative ones. In this review, we present the concept of “dysuricemia”, a condition in which deviation from the appropriate range of uric acid in the living body results in disease. This concept encompasses both hyperuricemia and hypouricemia. This review draws comparisons between the biologically biphasic positive and negative effects of uric acid and discusses the impact of such effects on various diseases. Full article

(This article belongs to the Special Issue Dysuricemia: Recent Advances in Urate Research from Hypouricemia to Hyperuricemia/Gout)

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15 pages, 1497 KiB

Open AccessReview

Human Plasma Xanthine Oxidoreductase Activity in Cardiovascular Disease: Evidence from a Population-Based Study

by Yuka Kotozaki, Mamoru Satoh, Takahito Nasu, Kozo Tanno, Fumitaka Tanaka and Makoto Sasaki

Biomedicines 2023, 11(3), 754; https://doi.org/10.3390/biomedicines11030754 - 1 Mar 2023

Cited by 3 | Viewed by 2065

Abstract

Xanthine oxidoreductase (XOR) and its products contribute to the development of chronic inflammation and oxidative stress. Excessive XOR activity is believed to promote inflammatory responses and atherosclerotic plaque formation, which are major cardiovascular risk factors. The mechanisms of XOR activity in the development and progression of cardiovascular disease (CVD), coupled with the complexity of the relationship between XOR activity and the biological effects of uric acid; reactive oxygen species; and nitric oxide, which are the major products of XOR activity, have long been debated, but have not yet been clearly elucidated. Recently, a system for measuring highly sensitive XOR activity in human plasma was established, and there has been progress in the research on the mechanisms of XOR activity. In addition, there are accumulating findings about the relationship between XOR activity and CVD. In this narrative review, we summarize existing knowledge regarding plasma XOR activity and its relationship with CVD and discuss future perspectives. Full article

(This article belongs to the Special Issue Dysuricemia: Recent Advances in Urate Research from Hypouricemia to Hyperuricemia/Gout)

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