Review Open Access
Copyright ©2014 Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Dec 15, 2014; 5(6): 787-795
Published online Dec 15, 2014. doi: 10.4239/wjd.v5.i6.787
Linking uric acid metabolism to diabetic complications
Akifumi Kushiyama, Kentaro Tanaka, Shigeko Hara, Shoji Kawazu, Division of Diabetes and Metabolism, The Institute for Adult Diseases, Asahi Life Foundation, 2-2-6, Tokyo 103-0002, Japan
Author contributions: All authors contributed to this work.
Correspondence to: Akifumi Kushiyama, MD, PhD, Assistant Division Chief, Division of Diabetes and Metabolism, The Institute for Adult Diseases, Asahi Life Foundation, 2-2-6, Nihonbashi Bakurocho, Chuo-ku, Tokyo 103-0002, Japan.
Telephone: +81-3-36395501 Fax: +81-3-36395520
Received: August 31, 2014
Revised: October 22, 2014
Accepted: November 7, 2014
Published online: December 15, 2014


Hyperuricemia have been thought to be caused by the ingestion of large amounts of purines, and prevention or treatment of hyperuricemia has intended to prevent gout. Xanthine dehydrogenase/xanthine oxidase (XDH/XO) is rate-limiting enzyme of uric acid generation, and allopurinol was developed as a uric acid (UA) generation inhibitor in the 1950s and has been routinely used for gout prevention since then. Serum UA levels are an important risk factor of disease progression for various diseases, including those related to lifestyle. Recently, other UA generation inhibitors such as febuxostat and topiroxostat were launched. The emergence of these novel medications has promoted new research in the field. Lifestyle-related diseases, such as metabolic syndrome or type 2 diabetes mellitus, often have a common pathological foundation. As such, hyperuricemia is often present among these patients. Many in vitro and animal studies have implicated inflammation and oxidative stress in UA metabolism and vascular injury because XDH/XO act as one of the major source of reactive oxygen species Many studies on UA levels and associated diseases implicate involvement of UA generation in disease onset and/or progression. Interventional studies for UA generation, not UA excretion revealed XDH/XO can be the therapeutic target for vascular injury and renal dysfunction. In this review, the relationship between UA metabolism and diabetic complications is highlighted.

Key Words: Uric acid, Xanthine dehydrogenase/xanthine oxidase, Diabetes mellitus, Diabetic complications, Xanthine oxidase inhibitor, Metabolism

Core tip: Uric acid (UA) is derived from essential metabolism, and UA metabolism is becoming a novel risk and interventional factor of lifestyle-related diseases in this obesity-prone era. The relationship between UA metabolism and diabetic complications is highlighted in this review and supposed molecular mechanisms are mentioned.


Gout, which is caused by increased serum uric acid (SUA) levels, is becoming one of the most prevalent lifestyle-related diseases. According to the National Livelihood Survey in Japan, 874000 people go to hospital for gout in 2004. This constitutes an increase of 3.4 times compared with 1986. Higher prevalence of metabolic syndrome (MetS) is one possible cause for this increase in gout cases, as both the reduced excretion and increased production of UA have been suggested to be associated with MetS. Increased visceral adiposity also causes MetS. In mice, evidence exists that UA is secreted from bloated adipocytes[1]. No studies in humans have confirmed this finding yet.

Uric acid (UA) (2,6,8-trihydroxypurine, C5H4N4O3) is a purine derivative. UA metabolism is a type of nucleic acid metabolism metabolizing purine and its derivatives (adenine, and guanine). Phosphorus oxidation of adenine and guanine (resulting in ATP and GTP) and UA production are essential for many physiological functions. For example, high fructose consumption cause hyperuricemia.


SUA levels are determined by a balance between UA production and excretion. At present, no method for detecting the UA production rate is available in humans. Instead, UA production are indirectly speculated through SUA level and urine excretion. The rate-limiting step of UA production is an enzymatic reaction of the xanthine dehydrogenase/xanthine oxidase (XDH/XO) enzyme that oxidizes hypoxanthine-xanthine into UA. Human XDH/XO was cloned in 1993 by Richard[2]. It is expressed in the liver and small intestine of XDH/XO-rich parenchyma cells[3] and is thought to be the major source for SUA. The enzyme is also expressed in adipose tissue, the vascular endothelium, and macrophages, all of which are implicated in lifestyle-related diseases[4]. The UA production rate is based on the amount of substrate and/or XO activity. Since the generation of reactive oxygen species (ROS) depends on XO activity, XO is one of the major sources of oxidative stress in cells along with nicotinamide adenine dinucleotide phosphate oxidase, myeloperoxidase, lipoxygenase, and nitric oxide synthase[5].

The kidney is an important regulator of circulating UA levels and is responsible for 60%-70% of total body UA excretion[6]. The remaining UA is secreted into the intestine, followed by bacterial uricolysis[6]. UA excretion in the kidney consists of urate secretion and reabsorption, and earlier research suggests the involvement of hyperfiltration[7]. UA apical transporters [uric acid transporter 1, organic anion transporter 4 (OAT4), OAT10, sodium-coupled monocarboxylate transporters 1/2, and Na+-dicarboxylate cotransporter (NaDC1)], which are expressed in the nephron lumen are implicated in the reabsorption process. The role of basolateral transporters in proximal tubular cell is not clarified except for glucose transporter type 9 (GLUT9). During the secretion process, UA is transported into proximal tubular cells via OAT1/3 and/or NaDC3 and then secreted by human uric acid transporter, Na+-phosphate cotransporter (NPT), ATP-binding cassette sub-family G member 2 (ABCG2), and/or ATP-binding cassette sub-family C member 4. Ninety percent of UA filtered by the kidney is reabsorbed[6]. In the intestine, ABCG2 is responsible for about 50% of UA efflux[8-10].

There are many studies about genetic variations exhibiting hyperuricemia. Among genes introduced above, variants of GLUT9 (SLC2A9)[11,12], NPT (SLC17A1)[13], ABCG2 (BCRP) variant[14], are well established and proved to be important in hyperuricemia as a result of decreased extra-renal urate excretion. Genome-wide association study is applied for detecting loci affecting serum UA level. Recent report identified 18 new loci (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4) associated UA concentrations[15]. Not only transporters, but also transcriptional factors, signaling receptors, enzymes are involved in serum UA level.


Table 1 shows association between life-style related diseases and UA metabolism[16-24]. Distinguishing cause and effect is difficult; some diseases raise SUA level, but UA affect disease onset or progression.

Table 1 Association between life-style related diseases and uric acid metabolism.
Diseases/statusSUA levelUA productionFocus 1UA excresionFocus 2
Insulin resistanceHighDownProximal tubule cell
Use of SGLT2 inhibitorLowUp
MetSHighUpAdipocyte/liver?DownProximal tubule cell
CKDHighUpVascular endothelial cell/inflammatory cellDown/upKidney/intestine
AtherosclerosisUpVascular endothelial cell/inflammatory cell
Reperfusion injuryUpVascular endothelial cell
Heart failureUpInflammatory cell
Fructose intakeHighUpLiverDown
Sodium intakeHighDown
Thiazide administrationHighDownProximal tubule cell

In patients with diabetes, the SUA level is low due to increased urate clearance[20,25]. In these patients, hypouricemia is associated with glycosuria[26], decreased metabolic control, hyperfiltration, and a late onset of disease, while elevated SUA is a feature of hyperinsulinemia or insulin resistance[7]. Type 2 diabetes mellitus (T2DM) is a risk factor for nephrolithiasis and has been associated with UA stones[27]. It has been suggested that patients with UA stones, especially if overweight, should be screened for T2DM or MetS[28]. The rate of obesity is increasing in Asia as well as in Western countries[29], and hyperuricemia will increase in patients with T2DM. Novel class of anti-diabetic agent, sodium glucose cotransporter 2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria[21,30].


Besides age, race, family history of diabetes, body mass index (BMI), glucose intolerance, and MetS, SUA levels have been suggested to be associated with T2DM risk[31]. If elevated SUA levels play a causal role in T2DM, SUA might also indirectly affect the prevalence of diabetic complications. The diabetogenic action of UA was reported in 1950[32]; however, its physiological mechanism is not yet known. SUA levels affect insulin resistance[19] and show a significant correlation with risk factors for MetS (high BMI, blood pressure, fasting plasma glucose, and triglyceride levels) and low HDL cholesterol values[19,31,33,34]. Moreover, high SUA levels were shown to predict MetS in a Japanese cohort[35]. We previously reported an association between inflammation, macrophage activation, and SUA production via XDH/XO activation in an animal model[36]. In summary, a link between SUA and insulin resistance has repeatedly been shown, and UA itself reportedly plays an important role in the exacerbation of insulin resistance[37].


SUA independently predicted the development of vascular complications, both retinopathy and nephropahy and coronary artery calcification in type 1 diabetes study by Bjornstad et al[38]. The following section discusses the relationship between SUA levels and each diabetic complication.


Diabetic neuropathy is occasionally the initial manifestation of disease in T2DM patients[39]. It leads to chronic pain, numbness, and substantial loss of quality of life. The prevalence of diabetic peripheral neuropathy shows a significant correlation with increased UA levels[40]. Several studies demonstrated that, when controlled for confounding factors such as age, gender, BMI, renal function, and/or diabetic duration, SUA levels were high in patients with diabetic polyneuropathy and sudomotor dysfunction[41-43].

The pathophysiology of diabetic neuropathy is not completely understood, and multiple metabolic imbalances underlie the development of diabetic neuropathy[44]. Hyperglycemia, dyslipidemia, and cardiovascular dysfunction are all independent risk factors for neuropathy. Probable etiologic factors include the polyol pathway, non-enzymatic glycation, free radicals, oxidative stress, and inflammation. Oxidative stress and inflammation are involved in XDH/XO activity. It is therefore speculated that UA generation by XDH/XO plays a role in diabetic neuropathy.

Diabetic retinopathy

The presence of diabetic retinopathy (DR) is associated with visceral fat accumulation and insulin resistance in T2DM patients[45]. An earlier report found no significant difference in UA levels between patients with or without retinopathy[46], but several recent studies showed a significant increase of UA-related metabolites levels in DR compared to T2DM[47]. SUA concentration was shown to be associated with an increased severity of DR over a three-year period in patients with T2DM. Cox regression analysis showed that patients with SUA levels in the third (5.9-6.9 mg/dL) and fourth (≥ 7.0 mg/dL) quartiles had increased hazard ratios for DR when compared with patients with SUA in the first quartile (< 4.9 mg/dL)[48]. Furthermore, vitreous UA and glucose concentrations were higher in proliferative than in non-proliferative DR. Focal UA production in the vitreous is thought to be involved in the pathogenesis and progression of DR[49].


Shichiri et al[50] showed that glomerular hyperfiltration also occurs in non-insulin-dependent diabetes mellitus (NIDDM) and that it lowers SUA levels by increasing the renal clearance of urate during the hyperfiltration phase[50]. They suggested that hypouricemia can predict the future progression of incipient nephropathy in NIDDM[50]. However, other reports have implied that high (and not low) SUA levels define the prognosis of chronic kidney disease (CKD)[51]. SUA is also associated with known risk factors for kidney disease progression[52], including hypertension[53], cardiovascular disease[54-56], and atherosclerosis[55]. SUA is an independent risk factor for CKD, even without diabetes[57].

SUA is known to be associated with disease progression in the early stage of diabetic nephropathy[17,58]. We found that the progression of renal dysfunction in patients with type 2 diabetic overt nephropathy with an SUA concentration of ≥ 6.3 mg/dL carries a poor prognosis, even though their SUA range is considered high-normal[59]. Our data shows the association between UA and disease progression is independent of diabetic control in multivariate analysis. Another report provided evidence for a clear dose-response relationship between SUA levels and early glomerular filtration rate (GFR) loss in patients with T1DM. The progression and regression of urinary albumin excretion were not associated with UA levels[60]. These studies show that UA is an independent risk factor for renal dysfunction, even after adjustments for confounding factors. Furthermore, even high-normal SUA levels accelerated renal dysfunction in T2DM patients[17,59-62].

UA is lowered in diabetes mellitus (DM) due to hyperfiltration[50], but decreased UA excretion during renal dysfunction raises SUA levels. Our previous study showed that UA levels in the patients who doubled Cr in the observation period (Cr doubling group) were higher than in the non-doubling group at the same estimated GFR (eGFR) level, suggesting that UA production was increased in the Cr doubling group[59]. These data suggest that higher levels of UA production are involved in the pathophysiology of nephropathy progression.

Several recent studies have been investigating therapeutic interventions to delay nephropathy progression[63-65]. Allopurinol therapy significantly decreases SUA levels in hyperuricemic patients with mild to moderate CKD. Its use is safe and has been shown to help preserve kidney function when used for a duration of 12 mo[63]. Febuxostat has a higher renoprotective effect than allopurinol, inhibits oxidative stress, has anti-atherogenic activity, reduces blood pressure, and decreases pulse wave velocity and left ventricular mass index, most likely due to a strong SUA lowering effect[65]. In an animal diabetic nephropathy model, allopurinol attenuated transforming growth factor-beta1-induced Smad pathway activation in tubular cells[66].

Diabetic foot

There are a few reports regarding the relationship between diabetic foot and UA levels. One study states that elevated UA levels are a significant and independent risk factor for diabetic foot ulcer in female Chinese patients with T2DM[67].

Macrovascular complication

A relationship between SUA levels and the development of atherosclerotic disease has been suggested[68-70]. Moreover, there is epidemiological evidence of an association between hyperuricemia and mortality in patients undergoing percutaneous coronary intervention or presenting with acute myocardial infarction[71-73]. Our study showed that SUA is an independent risk factor for vascular complications, even when adjusted for several confounders, including eGFR[56].

Macroangiopathy includes stroke, peripheral artery disease, and ischemic heart disease. In stroke, SUA levels are higher in patients with cardiac syndrome X, and elevated SUA levels are associated with carotid atherosclerosis[74]. A U-shaped relationship was shown for this correlation, as both the upper and bottom quintiles of SUA were associated with a higher risk of fatal stroke[75]. Besides, our study, a link between peripheral artery disease and UA has been rarely reported[56].

Several interventional studies have proven the efficacy of hyperuricemia treatments. A randomized controlled study showed that allopurinol prolongs exercise capacity (especially exercise time until ST depression) when a high dose of 600 mg/d of allopurinol was administered to patients with chronic stable angina[76]. Allopurinol treatment also protects the heart from ischemic reperfusion[77], and oxypurinol, an allopurinol derivative, improves the left ventricular ejection fraction (LVEF) in congestive heart failure patients with low LVEF[22]. Despite the numerous aforementioned studies, several studies have indicated that no association between UA and ischemic stroke[78] or heart disease[79] exists.


UA itself reportedly functions as an anti-oxidant[80]. For example, XDH-null mutant Drosophila melanogaster have increased vulnerability to oxidative stress[81]. Uric acid administration improved endothelial function in the forearm vascular bed of patients with type 1 diabetes and smokers[82]. However, UA synthesis is accompanied by the generation of ROS.

XDH/XO in the vascular endothelium is associated with ischemia reperfusion injury. It has also been suggested that XO inhibitors improve endothelium-dependent vascular relaxation in blood vessels of hyperlipidemic rabbits[83]. XO as the source of ROS in ischemia/reperfusion injury has been discovered 30 years ago[84,85], and this injury is preventable with XO inhibitors[86]. XOR inhibition reverses endothelial dysfunction in heavy smokers[87,88]. XO inhibitors have the potential to act as free radical scavengers. Febuxostat, however, does not have this activity but can improve organ changes induced by ischemia/reperfusion[23].


Adipose tissue has a high xanthine oxidoreductase activity in mice[1], and UA is secreted from adipocytes. XDH/XO is a novel regulator of adipogenesis and peroxisome proliferator-activated receptor gamma (PPARγ) activity and is essential for the regulation of fat accretion[89]. In addition, UA and adipose tissue XOR mRNAs are increased in ob/ob mice, and fat mass is reduced by 50% in XOR-/- mice.


XDH/XO is localized to CD68 positive macrophages in the pathological state[36,90]. Inhibition of XDH/XO in inflammatory mononuclear phagocytes inhibits the migration of neutrophils during acute lung injury[91]. Through inhibition of XDH/XO activity, cytokine-induced neutrophil chemoattractant secretion from mononuclear phagocytes is reduced, and small ubiquitin-like modifier of PPARγ and hypoxia-inducible factor 1α levels are increased[92]. Febuxostat activates mitogen-activated protein kinase phosphatase-1 and inhibits inflammation by lipopolysaccharide stimulation through the inhibition of ROS generation[93]. Tungsten, acting as a xanthine oxidase inhibitor, prevents the development of atherosclerosis in ApoE knockout mice fed a Western-type diet[94].

XDH/XO activity is also important for lipid accumulation[36]. XDH/XO knockdown or allopurinol administration inhibited foam cell formation in macrophage J774.1 cells. The production of inflammatory cytokines associated with foam cell formation was reduced by allopurinol and febuxostat, and these medications also significantly improved calcification and lipid accumulation in the aortic plaque of ApoE-KO mice[36,95]. It should be noted that the expression of XDH/XO and the deposition of UA are seen in macrophages in arteriosclerotic lesions[96]. In vitro, febuxostat inhibited cholesterol crystal-induced ROS formation[95].

Some reports describe XDH/XO as an endogenous regulator of cyclooxygenase (Cox)-2[97] in the inflammatory system, and XDH/XO is central to innate immune function[98]. XDH/XO is thought to be upstream of PPARγ in lipid retention[89] and also induces Cox-2 to induce inflammation, forming a potential feedback loop. In our study, administration of allopurinol to J774.1 cells inhibited secretion of inflammatory cytokines such as tumor necrosis factor α, interleukin (IL)-1β, and IL-6[36]. Gout-associated uric acid crystals activate the NALP3 inflammasome[99]. UA crystals can injure organelle such as lysosomes, and damaged organelle selectively sequestered by autophagy[100]. If mitochondria is damaged, autophagosome is driven via microtubule to NLRP3 inflammasome[101]. Colchine treatment expresses the anti-inflammatory effect for gout by inhibiting microtubule-driven spatial arrangement, not by inhibiting UA crystallization. Therefore uric acid crystal in inflammatory cells of atherosclerosis lesion might activate inflammation, while solvent uric acid acts as antioxidant. Microtubule-driven spatial arrangement might be a possible target for diabetic complication derived from UA crystals.


XDH/XO has been studied for more than a century, and allopurinol has been used before enzyme inhibition therapy was established. In recent years, the various roles of XDH/XO in diverse pathological conditions have been revealed using a wide variety of research techniques, particularly in the field of molecular biology. This progress in research is related to the global demand to target lifestyle-related diseases such as T2DM, coronary artery disease, CKD, and MetS. Novel research has also led to the development of new powerful and safe UA lowering agent.

Obesity rates are increasing rapidly, and consequently, the pathophysiology of T2DM will be increasingly correlated with fat accumulation, chronic inflammation, and oxidative stress. UA metabolism (involving XDH/XO) is thought to play a central role in the pathogenesis of these conditions. Hence, the need for novel research will increase in the future.


The incidence of hyperuricemia has been on the increase since decades. The condition seems to be associated with increased insulin resistance and onset and progression of diabetic complications. UA might thus be suitable marker for both risk evaluation and intervention.


P- Reviewer: Isaka Y S- Editor: Ji FF L- Editor: A E- Editor: Liu SQ

1.  Tsushima Y, Nishizawa H, Tochino Y, Nakatsuji H, Sekimoto R, Nagao H, Shirakura T, Kato K, Imaizumi K, Takahashi H. Uric acid secretion from adipose tissue and its increase in obesity. J Biol Chem. 2013;288:27138-27149.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 188]  [Cited by in F6Publishing: 204]  [Article Influence: 20.4]  [Reference Citation Analysis (0)]
2.  Wright RM, Vaitaitis GM, Wilson CM, Repine TB, Terada LS, Repine JE. cDNA cloning, characterization, and tissue-specific expression of human xanthine dehydrogenase/xanthine oxidase. Proc Natl Acad Sci USA. 1993;90:10690-10694.  [PubMed]  [DOI]  [Cited in This Article: ]
3.  Pritsos CA. Cellular distribution, metabolism and regulation of the xanthine oxidoreductase enzyme system. Chem Biol Interact. 2000;129:195-208.  [PubMed]  [DOI]  [Cited in This Article: ]
4.  Moriwaki Y, Yamamoto T, Suda M, Nasako Y, Takahashi S, Agbedana OE, Hada T, Higashino K. Purification and immunohistochemical tissue localization of human xanthine oxidase. Biochim Biophys Acta. 1993;1164:327-330.  [PubMed]  [DOI]  [Cited in This Article: ]
5.  Bonomini F, Tengattini S, Fabiano A, Bianchi R, Rezzani R. Atherosclerosis and oxidative stress. Histol Histopathol. 2008;23:381-390.  [PubMed]  [DOI]  [Cited in This Article: ]
6.  Bobulescu IA, Moe OW. Renal transport of uric acid: evolving concepts and uncertainties. Adv Chronic Kidney Dis. 2012;19:358-371.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 214]  [Cited by in F6Publishing: 227]  [Article Influence: 20.6]  [Reference Citation Analysis (0)]
7.  Bo S, Cavallo-Perin P, Gentile L, Repetti E, Pagano G. Hypouricemia and hyperuricemia in type 2 diabetes: two different phenotypes. Eur J Clin Invest. 2001;31:318-321.  [PubMed]  [DOI]  [Cited in This Article: ]
8.  Hosomi A, Nakanishi T, Fujita T, Tamai I. Extra-renal elimination of uric acid via intestinal efflux transporter BCRP/ABCG2. PLoS One. 2012;7:e30456.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 144]  [Cited by in F6Publishing: 156]  [Article Influence: 14.2]  [Reference Citation Analysis (0)]
9.  Yano H, Tamura Y, Kobayashi K, Tanemoto M, Uchida S. Uric acid transporter ABCG2 is increased in the intestine of the 5/6 nephrectomy rat model of chronic kidney disease. Clin Exp Nephrol. 2014;18:50-55.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 64]  [Cited by in F6Publishing: 69]  [Article Influence: 6.9]  [Reference Citation Analysis (0)]
10.  Matsuo H, Takada T, Nakayama A, Shimizu T, Sakiyama M, Shimizu S, Chiba T, Nakashima H, Nakamura T, Takada Y. ABCG2 dysfunction increases the risk of renal overload hyperuricemia. Nucleosides Nucleotides Nucleic Acids. 2014;33:266-274.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 27]  [Cited by in F6Publishing: 24]  [Article Influence: 3.0]  [Reference Citation Analysis (1)]
11.  Vitart V, Rudan I, Hayward C, Gray NK, Floyd J, Palmer CN, Knott SA, Kolcic I, Polasek O, Graessler J. SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat Genet. 2008;40:437-442.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 530]  [Cited by in F6Publishing: 573]  [Article Influence: 38.2]  [Reference Citation Analysis (0)]
12.  Hamajima N, Okada R, Kawai S, Hishida A, Morita E, Yin G, Wakai K, Matsuo H, Inoue H, Takada Y. Significant association of serum uric acid levels with SLC2A9 rs11722228 among a Japanese population. Mol Genet Metab. 2011;103:378-382.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 20]  [Article Influence: 1.7]  [Reference Citation Analysis (0)]
13.  Chiba T, Matsuo H, Kawamura Y, Nagamori S, Nishiyama T, Wei L, Nakayama A, Nakamura T, Sakiyama M, Takada T. NPT1/SLC17A1 is a renal urate exporter in humans and its common gain-of-function variant decreases the risk of renal underexcretion gout. Arthritis Rheumatol. 2014;Epub ahead of print.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 50]  [Cited by in F6Publishing: 53]  [Article Influence: 6.6]  [Reference Citation Analysis (0)]
14.  Matsuo H, Takada T, Ichida K, Nakamura T, Nakayama A, Takada Y, Okada C, Sakurai Y, Hosoya T, Kanai Y. Identification of ABCG2 dysfunction as a major factor contributing to gout. Nucleosides Nucleotides Nucleic Acids. 2011;30:1098-1104.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 22]  [Cited by in F6Publishing: 20]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
15.  Köttgen A, Albrecht E, Teumer A, Vitart V, Krumsiek J, Hundertmark C, Pistis G, Ruggiero D, O’Seaghdha CM, Haller T. Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet. 2013;45:145-154.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 531]  [Cited by in F6Publishing: 560]  [Article Influence: 50.9]  [Reference Citation Analysis (0)]
16.  Reungjui S, Roncal CA, Mu W, Srinivas TR, Sirivongs D, Johnson RJ, Nakagawa T. Thiazide diuretics exacerbate fructose-induced metabolic syndrome. J Am Soc Nephrol. 2007;18:2724-2731.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 78]  [Cited by in F6Publishing: 85]  [Article Influence: 5.3]  [Reference Citation Analysis (0)]
17.  Kim WJ, Kim SS, Bae MJ, Yi YS, Jeon YK, Kim BH, Song SH, Kim IJ, Kim YK. High-normal serum uric acid predicts the development of chronic kidney disease in patients with type 2 diabetes mellitus and preserved kidney function. J Diabetes Complications. 2014;28:130-134.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 44]  [Cited by in F6Publishing: 44]  [Article Influence: 4.9]  [Reference Citation Analysis (0)]
18.  Mount DB. The kidney in hyperuricemia and gout. Curr Opin Nephrol Hypertens. 2013;22:216-223.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 40]  [Cited by in F6Publishing: 42]  [Article Influence: 4.2]  [Reference Citation Analysis (0)]
19.  Yoo TW, Sung KC, Shin HS, Kim BJ, Kim BS, Kang JH, Lee MH, Park JR, Kim H, Rhee EJ. Relationship between serum uric acid concentration and insulin resistance and metabolic syndrome. Circ J. 2005;69:928-933.  [PubMed]  [DOI]  [Cited in This Article: ]
20.  Shichiri M, Iwamoto H, Shiigai T. Diabetic renal hypouricemia. Arch Intern Med. 1987;147:225-228.  [PubMed]  [DOI]  [Cited in This Article: ]
21.  Chino Y, Samukawa Y, Sakai S, Nakai Y, Yamaguchi J, Nakanishi T, Tamai I. SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria. Biopharm Drug Dispos. 2014;35:391-404.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 200]  [Cited by in F6Publishing: 218]  [Article Influence: 24.2]  [Reference Citation Analysis (0)]
22.  Cingolani HE, Plastino JA, Escudero EM, Mangal B, Brown J, Pérez NG. The effect of xanthine oxidase inhibition upon ejection fraction in heart failure patients: La Plata Study. J Card Fail. 2006;12:491-498.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 81]  [Cited by in F6Publishing: 77]  [Article Influence: 4.5]  [Reference Citation Analysis (0)]
23.  Shafik AN. Febuxostat improves the local and remote organ changes induced by intestinal ischemia/reperfusion in rats. Dig Dis Sci. 2013;58:650-659.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 26]  [Cited by in F6Publishing: 27]  [Article Influence: 2.7]  [Reference Citation Analysis (0)]
24.  Cantu-Medellin N, Kelley EE. Xanthine oxidoreductase-catalyzed reactive species generation: A process in critical need of reevaluation. Redox Biol. 2013;1:353-358.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 140]  [Cited by in F6Publishing: 144]  [Article Influence: 14.4]  [Reference Citation Analysis (0)]
25.  Tuomilehto J, Zimmet P, Wolf E, Taylor R, Ram P, King H. Plasma uric acid level and its association with diabetes mellitus and some biologic parameters in a biracial population of Fiji. Am J Epidemiol. 1988;127:321-336.  [PubMed]  [DOI]  [Cited in This Article: ]
26.  Andrade JA, Kang HC, Greffin S, Garcia Rosa ML, Lugon JR. Serum uric acid and disorders of glucose metabolism: the role of glycosuria. Braz J Med Biol Res. 2014;0:0.  [PubMed]  [DOI]  [Cited in This Article: ]
27.  Cameron MA, Maalouf NM, Adams-Huet B, Moe OW, Sakhaee K. Urine composition in type 2 diabetes: predisposition to uric acid nephrolithiasis. J Am Soc Nephrol. 2006;17:1422-1428.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 156]  [Cited by in F6Publishing: 164]  [Article Influence: 9.6]  [Reference Citation Analysis (0)]
28.  Daudon M, Traxer O, Conort P, Lacour B, Jungers P. Type 2 diabetes increases the risk for uric acid stones. J Am Soc Nephrol. 2006;17:2026-2033.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 192]  [Cited by in F6Publishing: 207]  [Article Influence: 12.2]  [Reference Citation Analysis (0)]
29.  Kushiyama A, Yoshida Y, Kikuchi T, Suzawa N, Yamamoto M, Tanaka K, Okayasu M, Tahara T, Takao T, Onishi Y. Twenty-year trend of increasing obesity in young patients with poorly controlled type 2 diabetes at first diagnosis in urban Japan. J Diabetes Investig. 2013;4:540-545.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 17]  [Cited by in F6Publishing: 20]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]
30.  Musso G, Gambino R, Cassader M, Pagano G. A novel approach to control hyperglycemia in type 2 diabetes: sodium glucose co-transport (SGLT) inhibitors: systematic review and meta-analysis of randomized trials. Ann Med. 2012;44:375-393.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 200]  [Cited by in F6Publishing: 210]  [Article Influence: 19.1]  [Reference Citation Analysis (0)]
31.  Kodama S, Saito K, Yachi Y, Asumi M, Sugawara A, Totsuka K, Saito A, Sone H. Association between serum uric acid and development of type 2 diabetes. Diabetes Care. 2009;32:1737-1742.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 319]  [Cited by in F6Publishing: 332]  [Article Influence: 23.7]  [Reference Citation Analysis (0)]
32.  Griffiths M. The mechanism of the diabetogenic action of uric acid. J Biol Chem. 1950;184:289-298.  [PubMed]  [DOI]  [Cited in This Article: ]
33.  Klein BE, Klein R, Lee KE. Components of the metabolic syndrome and risk of cardiovascular disease and diabetes in Beaver Dam. Diabetes Care. 2002;25:1790-1794.  [PubMed]  [DOI]  [Cited in This Article: ]
34.  Tsouli SG, Liberopoulos EN, Mikhailidis DP, Athyros VG, Elisaf MS. Elevated serum uric acid levels in metabolic syndrome: an active component or an innocent bystander? Metabolism. 2006;55:1293-1301.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 169]  [Cited by in F6Publishing: 167]  [Article Influence: 9.8]  [Reference Citation Analysis (1)]
35.  Hara S, Tsuji H, Ohmoto Y, Amakawa K, Hsieh SD, Arase Y, Nakajima H. High serum uric acid level and low urine pH as predictors of metabolic syndrome: a retrospective cohort study in a Japanese urban population. Metabolism. 2012;61:281-288.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 42]  [Cited by in F6Publishing: 36]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
36.  Kushiyama A, Okubo H, Sakoda H, Kikuchi T, Fujishiro M, Sato H, Kushiyama S, Iwashita M, Nishimura F, Fukushima T. Xanthine oxidoreductase is involved in macrophage foam cell formation and atherosclerosis development. Arterioscler Thromb Vasc Biol. 2012;32:291-298.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 79]  [Cited by in F6Publishing: 81]  [Article Influence: 6.8]  [Reference Citation Analysis (0)]
37.  Facchini F, Chen YD, Hollenbeck CB, Reaven GM. Relationship between resistance to insulin-mediated glucose uptake, urinary uric acid clearance, and plasma uric acid concentration. JAMA. 1991;266:3008-3011.  [PubMed]  [DOI]  [Cited in This Article: ]
38.  Bjornstad P, Maahs DM, Rivard CJ, Pyle L, Rewers M, Johnson RJ, Snell-Bergeon JK. Serum uric acid predicts vascular complications in adults with type 1 diabetes: the coronary artery calcification in type 1 diabetes study. Acta Diabetol. 2014;51:783-791.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 45]  [Cited by in F6Publishing: 46]  [Article Influence: 5.1]  [Reference Citation Analysis (0)]
39.  Boulton AJ, Gries FA, Jervell JA. Guidelines for the diagnosis and outpatient management of diabetic peripheral neuropathy. Diabet Med. 1998;15:508-514.  [PubMed]  [DOI]  [Cited in This Article: ]
40.  Chuengsamarn S, Rattanamongkolgul S, Jirawatnotai S. Association between serum uric acid level and microalbuminuria to chronic vascular complications in Thai patients with type 2 diabetes. J Diabetes Complications. 2014;28:124-129.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 27]  [Cited by in F6Publishing: 31]  [Article Influence: 3.4]  [Reference Citation Analysis (0)]
41.  Kiani J, Habibi Z, Tajziehchi A, Moghimbeigi A, Dehghan A, Azizkhani H. Association between serum uric acid level and diabetic peripheral neuropathy (A case control study). Caspian J Intern Med. 2014;5:17-21.  [PubMed]  [DOI]  [Cited in This Article: ]
42.  Papanas N, Katsiki N, Papatheodorou K, Demetriou M, Papazoglou D, Gioka T, Maltezos E. Peripheral neuropathy is associated with increased serum levels of uric acid in type 2 diabetes mellitus. Angiology. 2011;62:291-295.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 45]  [Cited by in F6Publishing: 50]  [Article Influence: 4.2]  [Reference Citation Analysis (0)]
43.  Papanas N, Demetriou M, Katsiki N, Papatheodorou K, Papazoglou D, Gioka T, Kotsiou S, Maltezos E, Mikhailidis DP. Increased serum levels of uric acid are associated with sudomotor dysfunction in subjects with type 2 diabetes mellitus. Exp Diabetes Res. 2011;2011:346051.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 12]  [Cited by in F6Publishing: 15]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
44.  Vincent AM, Callaghan BC, Smith AL, Feldman EL. Diabetic neuropathy: cellular mechanisms as therapeutic targets. Nat Rev Neurol. 2011;7:573-583.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 325]  [Cited by in F6Publishing: 352]  [Article Influence: 29.3]  [Reference Citation Analysis (0)]
45.  Anan F, Masaki T, Ito Y, Eto T, Umeno Y, Eshima N, Saikawa T, Yoshimatsu H. Diabetic retinopathy is associated with visceral fat accumulation in Japanese type 2 diabetes mellitus patients. Metabolism. 2010;59:314-319.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 10]  [Cited by in F6Publishing: 12]  [Article Influence: 0.9]  [Reference Citation Analysis (0)]
46.  Feldman T, Weitzman S, Biedner B. [Retinopathy and serum uric acid in diabetics]. Harefuah. 1995;128:681-63, 744.  [PubMed]  [DOI]  [Cited in This Article: ]
47.  Xia J, Wang Z, Zhang F. Association between Related Purine Metabolites and Diabetic Retinopathy in Type 2 Diabetic Patients. Int J Endocrinol. 2014;2014:651050.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 32]  [Cited by in F6Publishing: 35]  [Article Influence: 3.9]  [Reference Citation Analysis (0)]
48.  Lee JJ, Yang IH, Kuo HK, Chung MS, Chen YJ, Chen CH, Liu RT. Serum uric acid concentration is associated with worsening in severity of diabetic retinopathy among type 2 diabetic patients in Taiwan-A 3-year prospective study. Diabetes Res Clin Pract. 2014;Epub ahead of print.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 28]  [Cited by in F6Publishing: 30]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
49.  Krizova L, Kalousova M, Kubena A, Benakova H, Zima T, Kovarik Z, Kalvoda J, Kalvodova B. Increased uric acid and glucose concentrations in vitreous and serum of patients with diabetic macular oedema. Ophthalmic Res. 2011;46:73-79.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 24]  [Cited by in F6Publishing: 25]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
50.  Shichiri M, Iwamoto H, Marumo F. Diabetic hypouricemia as an indicator of clinical nephropathy. Am J Nephrol. 1990;10:115-122.  [PubMed]  [DOI]  [Cited in This Article: ]
51.  Obermayr RP, Temml C, Gutjahr G, Knechtelsdorfer M, Oberbauer R, Klauser-Braun R. Elevated uric acid increases the risk for kidney disease. J Am Soc Nephrol. 2008;19:2407-2413.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 410]  [Cited by in F6Publishing: 427]  [Article Influence: 28.5]  [Reference Citation Analysis (0)]
52.  Merjanian R, Budoff M, Adler S, Berman N, Mehrotra R. Coronary artery, aortic wall, and valvular calcification in nondialyzed individuals with type 2 diabetes and renal disease. Kidney Int. 2003;64:263-271.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 85]  [Cited by in F6Publishing: 90]  [Article Influence: 4.5]  [Reference Citation Analysis (0)]
53.  Krishnan E, Kwoh CK, Schumacher HR, Kuller L. Hyperuricemia and incidence of hypertension among men without metabolic syndrome. Hypertension. 2007;49:298-303.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 188]  [Cited by in F6Publishing: 203]  [Article Influence: 11.9]  [Reference Citation Analysis (0)]
54.  Zoppini G, Targher G, Negri C, Stoico V, Perrone F, Muggeo M, Bonora E. Elevated serum uric acid concentrations independently predict cardiovascular mortality in type 2 diabetic patients. Diabetes Care. 2009;32:1716-1720.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 93]  [Cited by in F6Publishing: 100]  [Article Influence: 7.1]  [Reference Citation Analysis (0)]
55.  Tavil Y, Kaya MG, Oktar SO, Sen N, Okyay K, Yazici HU, Cengel A. Uric acid level and its association with carotid intima-media thickness in patients with hypertension. Atherosclerosis. 2008;197:159-163.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 62]  [Cited by in F6Publishing: 60]  [Article Influence: 3.8]  [Reference Citation Analysis (0)]
56.  Tanaka K, Hara S, Kushiyama A, Ubara Y, Yoshida Y, Mizuiri S, Aikawa A, Kawatzu S. Risk of macrovascular disease stratified by stage of chronic kidney disease in type 2 diabetic patients: critical level of the estimated glomerular filtration rate and the significance of hyperuricemia. Clin Exp Nephrol. 2011;15:391-397.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 20]  [Cited by in F6Publishing: 17]  [Article Influence: 1.4]  [Reference Citation Analysis (0)]
57.  Li L, Yang C, Zhao Y, Zeng X, Liu F, Fu P. Is hyperuricemia an independent risk factor for new-onset chronic kidney disease?: A systematic review and meta-analysis based on observational cohort studies. BMC Nephrol. 2014;15:122.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 236]  [Cited by in F6Publishing: 202]  [Article Influence: 22.4]  [Reference Citation Analysis (0)]
58.  Miao Y, Ottenbros SA, Laverman GD, Brenner BM, Cooper ME, Parving HH, Grobbee DE, Shahinfar S, de Zeeuw D, Lambers Heerspink HJ. Effect of a reduction in uric acid on renal outcomes during losartan treatment: a post hoc analysis of the reduction of endpoints in non-insulin-dependent diabetes mellitus with the Angiotensin II Antagonist Losartan Trial. Hypertension. 2011;58:2-7.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 124]  [Cited by in F6Publishing: 136]  [Article Influence: 11.3]  [Reference Citation Analysis (0)]
59.  Tanaka K, Hara S, Hattori M, Sakai K, Onishi Y, Yoshida Y, Kawazu S, Kushiyama A. Role of elevated serum uric acid levels at the onset of overt nephropathy in the risk for renal function decline in patients with type 2 diabetes. JDI. 2014;.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 24]  [Article Influence: 2.7]  [Reference Citation Analysis (0)]
60.  Ficociello LH, Rosolowsky ET, Niewczas MA, Maselli NJ, Weinberg JM, Aschengrau A, Eckfeldt JH, Stanton RC, Galecki AT, Doria A. High-normal serum uric acid increases risk of early progressive renal function loss in type 1 diabetes: results of a 6-year follow-up. Diabetes Care. 2010;33:1337-1343.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 168]  [Cited by in F6Publishing: 174]  [Article Influence: 13.4]  [Reference Citation Analysis (0)]
61.  Cai XL, Han XY, Ji LN. High-normal serum uric acid is associated with albuminuria and impaired glomerular filtration rate in Chinese type 2 diabetic patients. Chin Med J (Engl). 2011;124:3629-3634.  [PubMed]  [DOI]  [Cited in This Article: ]
62.  Rosolowsky ET, Ficociello LH, Maselli NJ, Niewczas MA, Binns AL, Roshan B, Warram JH, Krolewski AS. High-normal serum uric acid is associated with impaired glomerular filtration rate in nonproteinuric patients with type 1 diabetes. Clin J Am Soc Nephrol. 2008;3:706-713.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 114]  [Cited by in F6Publishing: 122]  [Article Influence: 8.1]  [Reference Citation Analysis (0)]
63.  Siu YP, Leung KT, Tong MK, Kwan TH. Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level. Am J Kidney Dis. 2006;47:51-59.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 580]  [Cited by in F6Publishing: 613]  [Article Influence: 36.1]  [Reference Citation Analysis (0)]
64.  Maahs DM, Caramori L, Cherney DZ, Galecki AT, Gao C, Jalal D, Perkins BA, Pop-Busui R, Rossing P, Mauer M. Uric acid lowering to prevent kidney function loss in diabetes: the preventing early renal function loss (PERL) allopurinol study. Curr Diab Rep. 2013;13:550-559.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 117]  [Cited by in F6Publishing: 105]  [Article Influence: 10.5]  [Reference Citation Analysis (0)]
65.  Sezai A, Soma M, Nakata K, Hata M, Yoshitake I, Wakui S, Hata H, Shiono M. Comparison of febuxostat and allopurinol for hyperuricemia in cardiac surgery patients (NU-FLASH Trial). Circ J. 2013;77:2043-2049.  [PubMed]  [DOI]  [Cited in This Article: ]
66.  Kim SM, Choi YW, Seok HY, Jeong KH, Lee SH, Lee TW, Ihm CG, Lim SJ, Moon JY. Reducing serum uric acid attenuates TGF-β1-induced profibrogenic progression in type 2 diabetic nephropathy. Nephron Exp Nephrol. 2012;121:e109-e121.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 28]  [Cited by in F6Publishing: 33]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
67.  Ye X, Cao Y, Gao F, Yang Q, Zhang Q, Fu X, Li J, Xue Y. Elevated serum uric acid levels are independent risk factors for diabetic foot ulcer in female Chinese patients with type 2 diabetes. J Diabetes. 2014;6:42-47.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 13]  [Cited by in F6Publishing: 13]  [Article Influence: 1.4]  [Reference Citation Analysis (0)]
68.  Ishizaka N, Ishizaka Y, Toda E, Nagai R, Yamakado M. Association between serum uric acid, metabolic syndrome, and carotid atherosclerosis in Japanese individuals. Arterioscler Thromb Vasc Biol. 2005;25:1038-1044.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 204]  [Cited by in F6Publishing: 223]  [Article Influence: 12.4]  [Reference Citation Analysis (0)]
69.  Silbernagel G, Hoffmann MM, Grammer TB, Boehm BO, März W. Uric acid is predictive of cardiovascular mortality and sudden cardiac death in subjects referred for coronary angiography. Nutr Metab Cardiovasc Dis. 2013;23:46-52.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 31]  [Cited by in F6Publishing: 33]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
70.  Rodrigues TC, Maahs DM, Johnson RJ, Jalal DI, Kinney GL, Rivard C, Rewers M, Snell-Bergeon JK. Serum uric acid predicts progression of subclinical coronary atherosclerosis in individuals without renal disease. Diabetes Care. 2010;33:2471-2473.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 48]  [Cited by in F6Publishing: 52]  [Article Influence: 4.0]  [Reference Citation Analysis (0)]
71.  Spoon DB, Lerman A, Rule AD, Prasad A, Lennon RJ, Holmes DR, Rihal CS. The association of serum uric acid levels with outcomes following percutaneous coronary intervention. J Interv Cardiol. 2010;23:277-283.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 23]  [Cited by in F6Publishing: 25]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
72.  Kowalczyk J, Francuz P, Swoboda R, Lenarczyk R, Sredniawa B, Golda A, Kurek T, Mazurek M, Podolecki T, Polonski L. Prognostic significance of hyperuricemia in patients with different types of renal dysfunction and acute myocardial infarction treated with percutaneous coronary intervention. Nephron Clin Pract. 2010;116:c114-c122.  [PubMed]  [DOI]  [Cited in This Article: ]
73.  Lazzeri C, Valente S, Chiostri M, Sori A, Bernardo P, Gensini GF. Uric acid in the acute phase of ST elevation myocardial infarction submitted to primary PCI: its prognostic role and relation with inflammatory markers: a single center experience. Int J Cardiol. 2010;138:206-209.  [PubMed]  [DOI]  [Cited in This Article: ]
74.  Acikgoz N, Ermis N, Yagmur J, Muezzinoglu K, Karakus Y, Cansel M, Pekdemir H, Ozdemir R. Uric acid level and its association with carotid intima-media thickness in patients with cardiac syndrome X. Med Princ Pract. 2012;21:115-119.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 9]  [Cited by in F6Publishing: 10]  [Article Influence: 0.9]  [Reference Citation Analysis (0)]
75.  Gerber Y, Tanne D, Medalie JH, Goldbourt U. Serum uric acid and long-term mortality from stroke, coronary heart disease and all causes. Eur J Cardiovasc Prev Rehabil. 2006;13:193-198.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 41]  [Cited by in F6Publishing: 45]  [Article Influence: 2.6]  [Reference Citation Analysis (0)]
76.  Noman A, Ang DS, Ogston S, Lang CC, Struthers AD. Effect of high-dose allopurinol on exercise in patients with chronic stable angina: a randomised, placebo controlled crossover trial. Lancet. 2010;375:2161-2167.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 261]  [Cited by in F6Publishing: 219]  [Article Influence: 16.8]  [Reference Citation Analysis (0)]
77.  Johnson WD, Kayser KL, Brenowitz JB, Saedi SF. A randomized controlled trial of allopurinol in coronary bypass surgery. Am Heart J. 1991;121:20-24.  [PubMed]  [DOI]  [Cited in This Article: ]
78.  Seet RC, Kasiman K, Gruber J, Tang SY, Wong MC, Chang HM, Chan YH, Halliwell B, Chen CP. Is uric acid protective or deleterious in acute ischemic stroke? A prospective cohort study. Atherosclerosis. 2010;209:215-219.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 53]  [Cited by in F6Publishing: 50]  [Article Influence: 3.6]  [Reference Citation Analysis (0)]
79.  Stark K, Reinhard W, Grassl M, Erdmann J, Schunkert H, Illig T, Hengstenberg C. Common polymorphisms influencing serum uric acid levels contribute to susceptibility to gout, but not to coronary artery disease. PLoS One. 2009;4:e7729.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 75]  [Cited by in F6Publishing: 87]  [Article Influence: 6.2]  [Reference Citation Analysis (0)]
80.  Álvarez-Lario B, Macarrón-Vicente J. Uric acid and evolution. Rheumatology (Oxford). 2010;49:2010-2015.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 188]  [Cited by in F6Publishing: 204]  [Article Influence: 15.7]  [Reference Citation Analysis (0)]
81.  Hilliker AJ, Duyf B, Evans D, Phillips JP. Urate-null rosy mutants of Drosophila melanogaster are hypersensitive to oxygen stress. Proc Natl Acad Sci USA. 1992;89:4343-4347.  [PubMed]  [DOI]  [Cited in This Article: ]
82.  Waring WS, McKnight JA, Webb DJ, Maxwell SR. Uric acid restores endothelial function in patients with type 1 diabetes and regular smokers. Diabetes. 2006;55:3127-3132.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 146]  [Cited by in F6Publishing: 156]  [Article Influence: 9.2]  [Reference Citation Analysis (0)]
83.  Ohara Y, Peterson TE, Harrison DG. Hypercholesterolemia increases endothelial superoxide anion production. J Clin Invest. 1993;91:2546-2551.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1336]  [Cited by in F6Publishing: 1398]  [Article Influence: 46.6]  [Reference Citation Analysis (0)]
84.  McCord JM. Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med. 1985;312:159-163.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3970]  [Cited by in F6Publishing: 4140]  [Article Influence: 108.9]  [Reference Citation Analysis (0)]
85.  Ono T, Tsuruta R, Fujita M, Aki HS, Kutsuna S, Kawamura Y, Wakatsuki J, Aoki T, Kobayashi C, Kasaoka S. Xanthine oxidase is one of the major sources of superoxide anion radicals in blood after reperfusion in rats with forebrain ischemia/reperfusion. Brain Res. 2009;1305:158-167.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 57]  [Cited by in F6Publishing: 52]  [Article Influence: 3.7]  [Reference Citation Analysis (0)]
86.  Stewart JR, Crute SL, Loughlin V, Hess ML, Greenfield LJ. Prevention of free radical-induced myocardial reperfusion injury with allopurinol. J Thorac Cardiovasc Surg. 1985;90:68-72.  [PubMed]  [DOI]  [Cited in This Article: ]
87.  McCord JM, Roy RS, Schaffer SW. Free radicals and myocardial ischemia. The role of xanthine oxidase. Adv Myocardiol. 1985;5:183-189.  [PubMed]  [DOI]  [Cited in This Article: ]
88.  Guthikonda S, Sinkey C, Barenz T, Haynes WG. Xanthine oxidase inhibition reverses endothelial dysfunction in heavy smokers. Circulation. 2003;107:416-421.  [PubMed]  [DOI]  [Cited in This Article: ]
89.  Cheung KJ, Tzameli I, Pissios P, Rovira I, Gavrilova O, Ohtsubo T, Chen Z, Finkel T, Flier JS, Friedman JM. Xanthine oxidoreductase is a regulator of adipogenesis and PPARgamma activity. Cell Metab. 2007;5:115-128.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 145]  [Cited by in F6Publishing: 126]  [Article Influence: 7.9]  [Reference Citation Analysis (1)]
90.  de Jong JW, Schoemaker RG, de Jonge R, Bernocchi P, Keijzer E, Harrison R, Sharma HS, Ceconi C. Enhanced expression and activity of xanthine oxidoreductase in the failing heart. J Mol Cell Cardiol. 2000;32:2083-2089.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 91]  [Cited by in F6Publishing: 90]  [Article Influence: 3.9]  [Reference Citation Analysis (0)]
91.  Wright RM, Ginger LA, Kosila N, Elkins ND, Essary B, McManaman JL, Repine JE. Mononuclear phagocyte xanthine oxidoreductase contributes to cytokine-induced acute lung injury. Am J Respir Cell Mol Biol. 2004;30:479-490.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 52]  [Cited by in F6Publishing: 55]  [Article Influence: 2.8]  [Reference Citation Analysis (0)]
92.  Gibbings S, Elkins ND, Fitzgerald H, Tiao J, Weyman ME, Shibao G, Fini MA, Wright RM. Xanthine oxidoreductase promotes the inflammatory state of mononuclear phagocytes through effects on chemokine expression, peroxisome proliferator-activated receptor-{gamma} sumoylation, and HIF-1{alpha}. J Biol Chem. 2011;286:961-975.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 36]  [Cited by in F6Publishing: 37]  [Article Influence: 2.8]  [Reference Citation Analysis (0)]
93.  Nomura J, Busso N, Ives A, Tsujimoto S, Tamura M, So A, Yamanaka Y. Febuxostat, an inhibitor of xanthine oxidase, suppresses lipopolysaccharide-induced MCP-1 production via MAPK phosphatase-1-mediated inactivation of JNK. PLoS One. 2013;8:e75527.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 52]  [Cited by in F6Publishing: 57]  [Article Influence: 5.7]  [Reference Citation Analysis (0)]
94.  Schröder K, Vecchione C, Jung O, Schreiber JG, Shiri-Sverdlov R, van Gorp PJ, Busse R, Brandes RP. Xanthine oxidase inhibitor tungsten prevents the development of atherosclerosis in ApoE knockout mice fed a Western-type diet. Free Radic Biol Med. 2006;41:1353-1360.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 66]  [Cited by in F6Publishing: 66]  [Article Influence: 3.9]  [Reference Citation Analysis (0)]
95.  Nomura J, Busso N, Ives A, Matsui C, Tsujimoto S, Shirakura T, Tamura M, Kobayashi T, So A, Yamanaka Y. Xanthine oxidase inhibition by febuxostat attenuates experimental atherosclerosis in mice. Sci Rep. 2014;4:4554.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 108]  [Cited by in F6Publishing: 116]  [Article Influence: 12.9]  [Reference Citation Analysis (0)]
96.  Patetsios P, Rodino W, Wisselink W, Bryan D, Kirwin JD, Panetta TF. Identification of uric acid in aortic aneurysms and atherosclerotic artery. Ann N Y Acad Sci. 1996;800:243-245.  [PubMed]  [DOI]  [Cited in This Article: ]
97.  Ohtsubo T, Rovira II, Starost MF, Liu C, Finkel T. Xanthine oxidoreductase is an endogenous regulator of cyclooxygenase-2. Circ Res. 2004;95:1118-1124.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 76]  [Cited by in F6Publishing: 79]  [Article Influence: 4.2]  [Reference Citation Analysis (0)]
98.  Vorbach C, Harrison R, Capecchi MR. Xanthine oxidoreductase is central to the evolution and function of the innate immune system. Trends Immunol. 2003;24:512-517.  [PubMed]  [DOI]  [Cited in This Article: ]
99.  Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440:237-241.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3520]  [Cited by in F6Publishing: 3705]  [Article Influence: 217.9]  [Reference Citation Analysis (0)]
100.  Maejima I, Takahashi A, Omori H, Kimura T, Takabatake Y, Saitoh T, Yamamoto A, Hamasaki M, Noda T, Isaka Y. Autophagy sequesters damaged lysosomes to control lysosomal biogenesis and kidney injury. EMBO J. 2013;32:2336-2347.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 335]  [Cited by in F6Publishing: 349]  [Article Influence: 34.9]  [Reference Citation Analysis (0)]
101.  Misawa T, Takahama M, Kozaki T, Lee H, Zou J, Saitoh T, Akira S. Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome. Nat Immunol. 2013;14:454-460.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 546]  [Cited by in F6Publishing: 569]  [Article Influence: 56.9]  [Reference Citation Analysis (0)]