U-shaped association of uric acid to overall-cause mortality and its impact on clinical management of hyperuricemia

William T Crawley, Cyprien G Jungels, Kurt R Stenmark, Mehdi A Fini, William T Crawley, Cyprien G Jungels, Kurt R Stenmark, Mehdi A Fini

Abstract

Serum uric acid (SUA) is significantly elevated in obesity, gout, type 2 diabetes mellitus, and the metabolic syndrome and appears to contribute to the renal, cardiovascular and pulmonary comorbidities that are associated with these disorders. Most previous studies have focused on the pathophysiologic effects of high levels of uric acid (hyperuricemia). More recently, research has also shifted to the impact of hypouricemia, with multiple studies showing the potentially damaging effects that can be caused by abnormally low levels of SUA. Along with these observations, recent inconclusive data from human studies evaluating the treatment of hyperuricemia with xanthine oxidoreductase (XOR) inhibitors have added to the debate about the causal role of UA in human disease processes. SUA, which is largely derived from hepatic degradation of purines, appears to exert both systemic pro-inflammatory effects that contribute to disease and protective antioxidant properties. XOR, which catalyzes the terminal two steps of purine degradation, is the major source of both reactive oxygen species (O2.-, H2O2) and UA. This review will summarize the evidence that both elevated and low SUA may be risk factors for renal, cardiovascular and pulmonary comorbidities. It will also discuss the mechanisms through which modulation of either XOR activity or SUA may contribute to vascular redox hemostasis. We will address future research studies to better account for the differential effects of high versus low SUA in the hope that this will identify new evidence-based approaches for the management of hyperuricemia.

Keywords: H(2)O(2); Hyperuricemia; Hypouricemia; U-shaped; Uric acid; XOR inhibitors.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1
Fig. 1
Causes of Abnormal Serum Uric Acid (SUA). Both causes of abnormal high level of serum uric acid (hyperuricemia) and low level of serum uric acid level (hypouricemia) have primary and secondary etiologies as listed. The main cause of secondary hypouricemia is following uric acid lowering treatment (ULT).
Fig. 2
Fig. 2
Consequences of hypouricemia. Complications of both hereditary (primary) and ULT induced (secondary) hypouricemia have been listed. The most important of these is the ULT induced major adverse cardiovascular events (MACE).
Fig. 3
Fig. 3
XOR is a major source of both uric acid and reactive oxygen species. Upregulation of circulating and vascular XOR result in increase in both systemic and locally derived ROS and UA which their imbalance has a role in perpetuating the inflammatory microenvironment seen in both systemic and pulmonary hypertension. ET-1, endothelin-1; eNOS, endothelial nitric oxide synthase; ROS, reactive oxygen species; SMC, smooth muscle cell; XDH, xanthine dehydrogenase; XO, xanthine oxidase.
Fig. 4
Fig. 4
Differential redox modulation in ULTs. Different uric acid lowering treatments (ULTs) will result in differential redox modulation of the systemic and pulmonary vasculature. Xanthine Oxidoreductase Inhibitors (XOIs) will have differential inhibitory effects on XOR activity mainly due to their differential affinity for the enzyme and mechanisms of inhibition (Add reference EE). Urocolytics and Uricosuric on the other hand exert their effects through changes in UA metabolism rather than directly inhibiting the enzyme. As a result, differential redox modulation in ULTs can have differential downstream physiologic effects on vascular response in different pathological condition (e.g. hypoxia, shear stress and inflammation).

References

    1. Hille R. Molybdenum-containing hydroxylases. Arch. Biochem. Biophys. 2005;433:107–116.
    1. Terkeltaub R. Update on gout: new therapeutic strategies and options. Nat. Rev. Rheumatol. 2010;6:30–38.
    1. Zhu Y., Pandya B.J., Choi H.K. Prevalence of gout and hyperuricemia in the US general population: the national health and nutrition examination survey 2007-2008. Arthritis Rheum. 2011;63:3136–3141.
    1. Deng Z., Gu Y., Hou X., Zhang L., Bao Y., Hu C., Jia W. Association between uric acid, cancer incidence and mortality in patients with type 2 diabetes: shanghai diabetes registry study. Diab. metab. res. rev. 2016;32:325–332.
    1. 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.
    1. Li Q., Yang Z., Lu B., Wen J., Ye Z., Chen L., He M., Tao X., Zhang W., Huang Y., Zhang Z., Qu S., Hu R. Serum uric acid level and its association with metabolic syndrome and carotid atherosclerosis in patients with type 2 diabetes. Cardiovasc. Diabetol. 2011;10:72.
    1. Lee Y.J., Cho S., Kim S.R. A possible role of serum uric acid as a marker of metabolic syndrome. Intern. Med. J. 2014;44:1210–1216.
    1. Lu W., Song K., Wang Y., Zhang Q., Li W., Jiao H., Wang G., Huang G. Relationship between serum uric acid and metabolic syndrome: an analysis by structural equation modeling. J. clinic. lipidol. 2012;6:159–167.
    1. Fini M.A., Elias A., Johnson R.J., Wright R.M. Contribution of uric acid to cancer risk, recurrence, and mortality. Clin. Transl. Med. 2012;1:16.
    1. Fini M.A., Lanaspa M.A., Gaucher E.A., Boutwell B., Nakagawa T., Wright R.M., Sanchez-Lozada L.G., Andrews P., Stenmark K.R., Johnson R.J. Brief report: the uricase mutation in humans increases our risk for cancer growth. Cancer Metabol. 2021;9:32.
    1. Borghi C., Rosei E.A., Bardin T., Dawson J., Dominiczak A., Kielstein J.T., Manolis A.J., Perez-Ruiz F., Mancia G. Serum uric acid and the risk of cardiovascular and renal disease. J. Hypertens. 2015;33:1729–1741. discussion 1741.
    1. C. G.P., Young K.S., Michael L., K. C.H. Hyperuricemia and incident hypertension: a systematic review and meta-analysis. Arthritis Care Res. 2011;63:102–110.
    1. Kanbay M., Segal M., Afsar B., Kang D.H., Rodriguez-Iturbe B., Johnson R.J. The role of uric acid in the pathogenesis of human cardiovascular disease. Heart. 2013;99:759–766.
    1. Wang J., Qin T., Chen J., Li Y., Wang L., Huang H., Li J. Hyperuricemia and risk of incident hypertension: a systematic review and meta-analysis of observational studies. PLoS One. 2014;9:e114259.
    1. Johnson R.J. Why focus on uric acid? Curr. Med. Res. Opin. 2015;31(Suppl 2):3–7.
    1. Hsu S.P., Pai M.F., Peng Y.S., Chiang C.K., Ho T.I., Hung K.Y. Serum uric acid levels show a 'J-shaped' association with all-cause mortality in haemodialysis patients. Nephrol. Dial. Transplant. 2004;19:457–462. official publication of the European Dialysis and Transplant Association - European Renal Association.
    1. Mazza A., Zamboni S., Rizzato E., Pessina A.C., Tikhonoff V., Schiavon L., Casiglia E. Serum uric acid shows a J-shaped trend with coronary mortality in non-insulin-dependent diabetic elderly people. The CArdiovascular STudy in the ELderly (CASTEL) Acta Diabetol. 2007;44:99–105.
    1. Latif W., Karaboyas A., Tong L., Winchester J.F., Arrington C.J., Pisoni R.L., Marshall M.R., Kleophas W., Levin N.W., Sen A., Robinson B.M., Saran R. Uric acid levels and all-cause and cardiovascular mortality in the hemodialysis population. Clin. J. Am. Soc. Nephrol. : CJASN. 2011;6:2470–2477.
    1. Lapsia V., Johnson R.J., Dass B., Shimada M., Kambhampati G., Ejaz N.I., Arif A.A., Ejaz A.A. Elevated uric acid increases the risk for acute kidney injury. Am. J. Med. 2012;125 302.e309-317.
    1. Feng S., Jiang L., Shi Y., Shen H., Shi X., Jin D., Zeng Y., Wang Z. Uric acid levels and all-cause mortality in peritoneal dialysis patients. Kidney Blood Pres. Res. 2013;37:181–189.
    1. Dahle D.O., Jenssen T., Holdaas H., Leivestad T., Vardal M., Mjoen G., Reisaeter A.V., Toft I., Hartmann A. Uric acid has a J-shaped association with cardiovascular and all-cause mortality in kidney transplant recipients. Clin. Transplant. 2014;28:134–140.
    1. Kanda E., Muneyuki T., Kanno Y., Suwa K., Nakajima K. Uric acid level has a U-shaped association with loss of kidney function in healthy people: a prospective cohort study. PLoS One. 2015;10
    1. Bae E., Cho H.J., Shin N., Kim S.M., Yang S.H., Kim D.K., Kim Y.L., Kang S.W., Yang C.W., Kim N.H., Kim Y.S., Lee H. Lower serum uric acid level predicts mortality in dialysis patients. Medicine. 2016;95
    1. Oh I.H., Kim J.E., Lee C.H., Kim G.H., Park J.S. A J-shaped association between serum uric acid level and allograft outcomes after living donor kidney transplantation. Artif. Organs. 2016;40:136–143.
    1. Gwag H.B., Yang J.H., Park T.K., Song Y.B., Hahn J.Y., Choi J.H., Lee S.H., Gwon H.C., Choi S.H. Uric acid level has a U-shaped association with clinical outcomes in patients with vasospastic angina. J. Kor. Med. Sci. 2017;32:1275–1280.
    1. Hsieh Y.-P., Chang C.-C., Kor C.-T., Yang Y., Wen Y.-K., Chiu P.-F., Lin C.-C. Relationship between uric acid and technique failure in patients on continuous ambulatory peritoneal dialysis: a long-term observational cohort study. BMJ Open. 2017;7
    1. Hsieh Y.P., Yang Y., Chang C.C., Kor C.T., Wen Y.K., Chiu P.F., Lin C.C. U-shaped relationship between uric acid and residual renal function decline in continuous ambulatory peritoneal dialysis patients. Nephrology. 2017;22:427–435.
    1. Kang E., Hwang S.-s., Kim D.K., Oh K.-H., Joo K.W., Kim Y.S., Lee H. Sex-specific relationship of serum uric acid with all-cause mortality in adults with normal kidney function: an observational study. J. Rheumatol. 2017;44:380–387.
    1. Lee H., Jung Y.H., Kwon Y.J., Park B. Uric acid level has a J-shaped association with arterial stiffness in Korean postmenopausal women. Kor. j. family med. 2017;38:333–337.
    1. Matsukuma Y., Masutani K., Tanaka S., Tsuchimoto A., Fujisaki K., Torisu K., Katafuchi R., Hirakata H., Tsuruya K., Kitazono T. A J-shaped association between serum uric acid levels and poor renal survival in female patients with IgA nephropathy. Hypertens. Res. : off. j. Jpn. Soci. Hyper. 2017;40:291–297.
    1. Uedono H., Tsuda A., Ishimura E., Nakatani S., Kurajoh M., Mori K., Uchida J., Emoto M., Nakatani T., Inaba M. U-shaped relationship between serum uric acid levels and intrarenal hemodynamic parameters in healthy subjects. Am. J. Physiol. Ren. Physiol. 2017;312:F992–f997.
    1. Cho S.K., Chang Y., Kim I., Ryu S., Hoboken N.J. Arthritis & rheumatology; 2018. U-Shaped Association between Serum Uric Acid Level and Risk of Mortality: A Cohort Study.
    1. Srivastava A., Kaze A.D., McMullan C.J., Isakova T., Waikar S.S. Uric acid and the risks of kidney failure and death in individuals with CKD. Am. J. Kidney Dis. 2018;71:362–370.
    1. Tseng W.C., Chen Y.T., Ou S.M., Shih C.J., Tarng D.C., Taiwan geriatric kidney disease research, G. U-shaped association between serum uric acid levels with cardiovascular and all-cause mortality in the elderly: the role of malnourishment. J. Am. Heart Assoc. 2018;7
    1. Son C.N., Kim J.M., Kim S.H., Cho S.K., Choi C.B., Sung Y.K., Kim T.H., Bae S.C., Yoo D.H., Jun J.B. Prevalence and possible causes of hypouricemia at a tertiary care hospital. Korean J. Intern. Med. (Engl. Ed.) 2016;31:971–976.
    1. Ichida K., Amaya Y., Okamoto K., Nishino T. Mutations associated with functional disorder of xanthine oxidoreductase and hereditary xanthinuria in humans. Int. J. Mol. Sci. 2012;13:15475–15495.
    1. Bugdayci G., Balaban Y., Sahin O. Causes of hypouricemia among outpatients. Lab. Med. 2008;39:550–552.
    1. Phay J.E., Hussain H.B., Moley J.F. Cloning and expression analysis of a novel member of the facilitative glucose transporter family, SLC2A9 (GLUT9) Genomics. 2000;66:217–220.
    1. Komoda F., Sekine T., Inatomi J., Enomoto A., Endou H., Ota T., Matsuyama T., Ogata T., Ikeda M., Awazu M., Muroya K., Kamimaki I., Igarashi T. The W258X mutation in SLC22A12 is the predominant cause of Japanese renal hypouricemia. Pediatr. Nephrol. 2004;19:728–733.
    1. Kuwabara M., Niwa K., Ohtahara A., Hamada T., Miyazaki S., Mizuta E., Ogino K., Hisatome I. Prevalence and complications of hypouricemia in a general population: a large-scale cross-sectional study in Japan. PLoS One. 2017;12
    1. Furuhashi M., Mori K., Tanaka M., Maeda T., Matsumoto M., Murase T., Nakamura T., Koyama M., Moniwa N., Ohnishi H., Saitoh S., Shimamoto K., Miura T. Unexpected high plasma xanthine oxidoreductase activity in female subjects with low levels of uric acid. Endocr. J. 2018;65:1083–1092.
    1. Hershfield M.S. Reassessing serum urate targets in the management of refractory gout: can you go too low? Curr. Opin. Rheumatol. 2009;21:138–142.
    1. Srivastava A., Kaze A.D., McMullan C.J., Isakova T., Waikar S.S. Uric acid and the risks of kidney failure and death in individuals with CKD. Am. J. Kidney Dis. 2018;71:362–370.
    1. Suliman M.E., Johnson R.J., Garcia-Lopez E., Qureshi A.R., Molinaei H., Carrero J.J., Heimburger O., Barany P., Axelsson J., Lindholm B., Stenvinkel P. J-shaped mortality relationship for uric acid in CKD. Am. J. Kidney Dis. : the off. j. Nat. Kid. Found. 2006;48:761–771.
    1. Verdecchia P., Schillaci G., Reboldi G., Santeusanio F., Porcellati C., Brunetti P. Relation between serum uric acid and risk of cardiovascular disease in essential hypertension The PIUMA study. Hypertension. 2000;36:1072–1078.
    1. Seet R.C., Kasiman K., Gruber J., Tang S.Y., Wong M.C., Chang H.M., Chan Y.H., Halliwell B., Chen C.P. Is uric acid protective or deleterious in acute ischemic stroke? A prospective cohort study. Atherosclerosis. 2010;209:215–219.
    1. Lapsia V., Johnson R.J., Dass B., Shimada M., Kambhampati G., Ejaz N.I., Arif A.A., Ejaz A.A. Elevated uric acid increases the risk for acute kidney injury. Am. J. Med. 2012;125:302. e309-302.e317.
    1. Huang C., Niu K., Kobayashi Y., Guan L., Momma H., Cui Y., Chujo M., Otomo A., Guo H., Tadaura H., Nagatomi R. An inverted J-shaped association of serum uric acid with muscle strength among Japanese adult men: a cross-sectional study. BMC Muscoskel. Disord. 2013;14:258.
    1. Li H., Zha X., Zhu Y., Liu M., Guo R., Wen Y. An invert U-shaped curve: relationship between fasting plasma glucose and serum uric acid concentration in a large health check-up population in China. Medicine. 2016;95
    1. Zhang W., Iso H., Murakami Y., Miura K., Nagai M., Sugiyama D., Ueshima H., Okamura T. Serum uric acid and mortality form cardiovascular disease: EPOCH-Japan study. J. Atherosclerosis Thromb. 2016;23:692–703.
    1. Kamei K., Konta T., Hirayama A., Ichikawa K., Kubota I., Fujimoto S., Iseki K., Moriyama T., Yamagata K., Tsuruya K., Narita I., Kondo M., Shibagaki Y., Kasahara M., Asahi K., Watanabe T. Associations between serum uric acid levels and the incidence of nonfatal stroke: a nationwide community-based cohort study. Clin. Exp. Nephrol. 2017;21:497–503.
    1. Wang Y., Chi J., Che K., Chen Y., Sun X., Wang Y., Wang Z. Fasting plasma glucose and serum uric acid levels in a general Chinese population with normal glucose tolerance: a U-shaped curve. PLoS One. 2017;12
    1. Yang Y., Zhang Y., Li Y., Ding L., Sheng L., Xie Z., Wen C. U-shaped relationship between functional outcome and serum uric acid in ischemic stroke. Cell. Physiol. Biochem. 2018;47:2369–2379.
    1. Latourte A., Bardin T., Richette P. Uric acid and cognitive decline: a double-edge sword? Curr. Opin. Rheumatol. 2018;30:183–187.
    1. Zhou G., Holzman C., Luo Z., Margerison C. Maternal serum uric acid levels and blood pressure during pregnancy: a community-based cohort study. Eur. J. Obstet. Gynecol. Reprod. Biol. 2018;222:64–69.
    1. Zhou G., Holzman C., Luo Z., Margerison C. Maternal serum uric acid levels in pregnancy and fetal growth. J. Matern. Fetal Neonatal Med. 2018:1–9.
    1. Feig D.I., Kang D.H., Johnson R.J. Uric acid and cardiovascular risk. N. Engl. J. Med. 2008;359:1811–1821.
    1. Saravanan P., Davidson N.C. Risk assessment for sudden cardiac death in dialysis patients. Circ. Arrhythm. Electrophysiol. 2010;3:553–559.
    1. Wingrove C.S., Walton C., Stevenson J.C. The effect of menopause on serum uric acid levels in non-obese healthy women. Metabolism. 1998;47:435–438.
    1. Wei X., Fu B., Chen X., Chen W., Wang Z., Yu D., Jiang G., Chen J. U-shaped association between serum uric acid and short-term mortality in patients with infective endocarditis. Front. Endocrinol. 2021;12:750818.
    1. Li Q., Wu C., Kuang W., Zhan X., Zhou J. Correlation analysis of low-level serum uric acid and cardiovascular events in patients on peritoneal dialysis. Int. Urol. Nephrol. 2021;53:2399–2408.
    1. Fujimura Y., Yamauchi Y., Murase T., Nakamura T., Fujita S.-i., Fujisaka T., Ito T., Sohmiya K., Hoshiga M., Ishizaka N. Relationship between plasma xanthine oxidoreductase activity and left ventricular ejection fraction and hypertrophy among cardiac patients. PLoS One. 2017;12
    1. Otaki Y., Watanabe T., Kinoshita D., Yokoyama M., Takahashi T., Toshima T., Sugai T., Murase T., Nakamura T., Nishiyama S., Takahashi H., Arimoto T., Shishido T., Miyamoto T., Kubota I. Association of plasma xanthine oxidoreductase activity with severity and clinical outcome in patients with chronic heart failure. Int. J. Cardiol. 2017;228:151–157.
    1. Bobulescu I.A., Moe O.W. Renal transport of uric acid: evolving concepts and uncertainties. Adv. Chron. Kidney Dis. 2012;19:358–371.
    1. Cross C.E., van der Vliet A., O'Neill C.A., Louie S., Halliwell B. Oxidants, antioxidants, and respiratory tract lining fluids. Environ. Health Perspect. 1994;102(Suppl 10):185–191.
    1. The Global Initiative for Chronic Obstructive Lung Disease (GOLD).
    1. Adeloye D., Chua S., Lee C., Basquill C., Papana A., Theodoratou E., Nair H., Gasevic D., Sridhar D., Campbell H., Chan K.Y., Sheikh A., Rudan I., Global Health Epidemiology Reference G. Global and regional estimates of COPD prevalence: systematic review and meta-analysis. J. Glob. Health. 2015;5
    1. Okutan O., Tas D., Demirer E., Kartaloglu Z. Evaluation of quality of life with the chronic obstructive pulmonary disease assessment test in chronic obstructive pulmonary disease and the effect of dyspnea on disease-specific quality of life in these patients. Yonsei Med. J. 2013;54:1214–1219.
    1. Flattet Y., Garin N., Serratrice J., Perrier A., Stirnemann J., Carballo S. Determining prognosis in acute exacerbation of COPD. Int. J. Chronic Obstr. Pulm. Dis. 2017;12:467–475.
    1. Bendayan D., Shitrit D., Ygla M., Huerta M., Fink G., Kramer M.R. Hyperuricemia as a prognostic factor in pulmonary arterial hypertension. Respir. Med. 2003;97:130–133.
    1. Hoeper M.M., Hohlfeld J.M., Fabel H. Hyperuricaemia in patients with right or left heart failure. Eur. Respir. J. 1999;13:682–685.
    1. Van Albada M.E., Loot F.G., Fokkema R., Roofthooft M.T., Berger R.M. Biological serum markers in the management of pediatric pulmonary arterial hypertension. Pediatr. Res. 2008;63:321–327.
    1. Cerik I.B., Dindas F., Koyun E., Dereli S., Sahin A., Turgut O.O., Gul I. New prognostic markers in pulmonary arterial hypertension: CRP to albumin ratio and uric acid. Clin. Biochem. 2021
    1. Uk Kang T., Park K.Y., Kim H.J., Ahn H.S., Yim S.Y., Jun J.B. Association of hyperuricemia and pulmonary hypertension: a systematic review and meta-analysis. Mod. Rheumatol. 2019;29:1031–1041.
    1. Zare E., Kafshbani P., Chenaghlou M., Noori M., Ghaemmaghami Z., Amin A., Taghavi S., Naderi N. ESC Heart Fail; 2021. Prognostic Significance of Insulin Resistance in Pulmonary Hypertension.
    1. Peled N., Kassirer M., Shitrit D., Kogan Y., Shlomi D., Berliner A.S., Kramer M.R. The association of OSA with insulin resistance, inflammation and metabolic syndrome. Respir. Med. 2007;101:1696–1701.
    1. Friedl H.P., Till G.O., Trentz O., Ward P.A. Role of oxygen radicals in tourniquet-related ischemia-reperfusion injury of human patients. Klin. Wochenschr. 1991;69:1109–1112.
    1. Bartziokas K., Papaioannou A.I., Loukides S., Papadopoulos A., Haniotou A., Papiris S., Kostikas K. Serum uric acid as a predictor of mortality and future exacerbations of COPD. Eur. Respir. J. 2014;43:43–53.
    1. Embarak S.S., A., Abdrabboh M., Mokhtar A. Serum uric acid as a biomarker for prediction of outcomes of patients hospitalized for acute exacerbation of chronic obstructive pulmonary disease. Egyp. J. Bronchol. 2014;8:115–120.
    1. Ergün R., Ergün D. Prognostic value of serum uric acid level for short term survival in patients needing mechanical ventilation due to chronic obstructive pulmonary disease exacerbations. Int. J. Sci. Res. 2018;74
    1. Zhang X., Liu L., Liang R., Jin S. Hyperuricemia is a biomarker of early mortality in patients with chronic obstructive pulmonary disease. Int. J. Chronic Obstr. Pulm. Dis. 2015;10:2519–2523.
    1. Arslan Z.O.z., Ö., Karakoc F., Kara D., Naldan M., Uzlas E., Oral E., Aydın P. What are the factors affecting on the mortality of COPD patients in the ICU? W. Indian Med. J. 2017
    1. Vafaei A S.Z., Moghaddam SGh Mortazavi, Javid Arabshahi Z. The relationship between serum uric acid and severity of chronic obstructive pulmonary disease (COPD) J. Cardiothorac. Med. 2017;5:181–186.
    1. Fukuhara A., Saito J., Sato S., Saito K., Fukuhara N., Tanino Y., Wang X., Rinno K., Suzuki H., Munakata M. The association between risk of airflow limitation and serum uric acid measured at medical health check-ups. Int. J. Chronic Obstr. Pulm. Dis. 2017;12:1213–1219.
    1. Kahnert K., Alter P., Welte T., Huber R.M., Behr J., Biertz F., Watz H., Bals R., Vogelmeier C.F., Jorres R.A. Uric acid, lung function, physical capacity and exacerbation frequency in patients with COPD: a multi-dimensional approach. Respir. Res. 2018;19:110.
    1. Aida Y., Shibata Y., Osaka D., Abe S., Inoue S., Fukuzaki K., Tokairin Y., Igarashi A., Yamauchi K., Nemoto T., Nunomiya K., Kishi H., Sato M., Watanabe T., Konta T., Kawata S., Kato T., Kubota I. The relationship between serum uric acid and spirometric values in participants in a health check: the Takahata study. Int. J. Med. Sci. 2011;8:470–478.
    1. Horsfall L.J., Nazareth I., Petersen I. Serum uric acid and the risk of respiratory disease: a population-based cohort study. Thorax. 2014;69:1021–1026.
    1. Nicks M.E., O'Brien M.M., Bowler R.P. Plasma antioxidants are associated with impaired lung function and COPD exacerbations in smokers. COPD. 2011;8:264–269.
    1. Holzman C., Bullen B., Fisher R., Paneth N., Reuss L., Prematurity Study G. Pregnancy outcomes and community health: the POUCH study of preterm delivery. Paediatr. Perinat. Epidemiol. 2001;15(Suppl 2):136–158.
    1. Robinson P.C., Dalbeth N. Febuxostat for the treatment of hyperuricaemia in gout. Expet Opin. Pharmacother. 2018;19:1289–1299.
    1. Goicoechea M., de Vinuesa S.G., Verdalles U., Ruiz-Caro C., Ampuero J., Rincon A., Arroyo D., Luno J. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin. J. Am. Soc. Nephrol. : CJASN. 2010;5:1388–1393.
    1. Goicoechea M., Garcia de Vinuesa S., Verdalles U., Verde E., Macias N., Santos A., Perez de Jose A., Cedeno S., Linares T., Luno J. Allopurinol and progression of CKD and cardiovascular events: long-term follow-up of a randomized clinical trial. Am. J. Kidney Dis. : the off. j. Nat. Kid. Found. 2015;65:543–549.
    1. Pai B.H., Swarnalatha G., Ram R., Dakshinamurty K.V. Allopurinol for prevention of progression of kidney disease with hyperuricemia. Indian J. Nephrol. 2013;23:280–286.
    1. Siu Y.P., Leung K.T., Tong M.K., Kwan T.H. Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level. Am. J. Kidney Dis. : the off. j. Nat. Kid. Found. 2006;47:51–59.
    1. Kanbay M., Huddam B., Azak A., Solak Y., Kadioglu G.K., Kirbas I., Duranay M., Covic A., Johnson R.J. A randomized study of allopurinol on endothelial function and estimated glomular filtration rate in asymptomatic hyperuricemic subjects with normal renal function. Clin. J. Am. Soc. Nephrol. : CJASN. 2011;6:1887–1894.
    1. Krishnamurthy A., Lazaro D., Stefanov D.G., Blumenthal D., Gerber D., Patel S. The effect of allopurinol on renal function. J. Clin. Rheumatol. 2017;23:1–5.
    1. Momeni A., Shahidi S., Seirafian S., Taheri S., Kheiri S. Effect of allopurinol in decreasing proteinuria in type 2 diabetic patients. Iran J. Kidney Dis. 2010;4:128–132.
    1. Jalal D.I., Decker E., Perrenoud L., Nowak K.L., Bispham N., Mehta T., Smits G., You Z., Seals D., Chonchol M., Johnson R.J. Vascular function and uric acid-lowering in stage 3 CKD. J. Am. Soc. Nephrol. 2017;28:943–952.
    1. Xiao J., Deng S.B., She Q., Li J., Kao G.Y., Wang J.S., Ma Y. Allopurinol ameliorates cardiac function in non-hyperuricaemic patients with chronic heart failure. Eur. Rev. Med. Pharmacol. Sci. 2016;20:756–761.
    1. Kao M.P., Ang D.S., Gandy S.J., Nadir M.A., Houston J.G., Lang C.C., Struthers A.D. Allopurinol benefits left ventricular mass and endothelial dysfunction in chronic kidney disease. J. Am. Soc. Nephrol. 2011;22:1382–1389.
    1. Givertz M.M., Anstrom K.J., Redfield M.M., Deswal A., Haddad H., Butler J., Tang W.H., Dunlap M.E., LeWinter M.M., Mann D.L., Felker G.M., O'Connor C.M., Goldsmith S.R., Ofili E.O., Saltzberg M.T., Margulies K.B., Cappola T.P., Konstam M.A., Semigran M.J., McNulty S.E., Lee K.L., Shah M.R., Hernandez A.F., Network N.H.F.C.R. Effects of xanthine oxidase inhibition in hyperuricemic heart failure patients: the xanthine oxidase inhibition for hyperuricemic heart failure patients (EXACT-HF) study. Circulation. 2015;131:1763–1771.
    1. Hare J.M., Mangal B., Brown J., Fisher C., Jr., Freudenberger R., Colucci W.S., Mann D.L., Liu P., Givertz M.M., Schwarz R.P., Investigators O.-C. Impact of oxypurinol in patients with symptomatic heart failure. Results of the OPT-CHF study. J. Am. Coll. Cardiol. 2008;51:2301–2309.
    1. Mackenzie I.S., Ford I., Walker A., Hawkey C., Begg A., Avery A., Taggar J., Wei L., Struthers A.D., MacDonald T.M., group A.-H. s. Multicentre, prospective, randomised, open-label, blinded end point trial of the efficacy of allopurinol therapy in improving cardiovascular outcomes in patients with ischaemic heart disease: protocol of the ALL-HEART study. BMJ Open. 2016;6
    1. Coburn B.W., Michaud K., Bergman D.A., Mikuls T.R., Hoboken N.J. Arthritis & rheumatology; 2018. Allopurinol Dose Escalation and Mortality Among Patients with Gout: A National Propensity-Matched Cohort Study.
    1. Stamp L.K., Chapman P.T., Barclay M.L., Horne A., Frampton C., Tan P., Drake J., Dalbeth N. A randomised controlled trial of the efficacy and safety of allopurinol dose escalation to achieve target serum urate in people with gout. Ann. Rheum. Dis. 2017;76:1522–1528.
    1. Becker M.A., Schumacher H.R., Jr., Wortmann R.L., MacDonald P.A., Palo W.A., Eustace D., Vernillet L., Joseph-Ridge N. Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase: a twenty-eight-day, multicenter, phase II, randomized, double-blind, placebo-controlled, dose-response clinical trial examining safety and efficacy in patients with gout. Arthritis Rheum. 2005;52:916–923.
    1. Schumacher H.R., Jr., Becker M.A., Lloyd E., MacDonald P.A., Lademacher C. Febuxostat in the treatment of gout: 5-yr findings of the FOCUS efficacy and safety study. Rheumatology. 2009;48:188–194.
    1. Sircar D., Chatterjee S., Waikhom R., Golay V., Raychaudhury A., Chatterjee S., Pandey R. Efficacy of febuxostat for slowing the GFR decline in patients with CKD and asymptomatic hyperuricemia: a 6-month, double-blind, randomized, placebo-controlled trial. Am. J. Kidney Dis. : the off. j. Nat. Kid. Found. 2015;66:945–950.
    1. Weng S.-C. Febuxostat is superior to traditional urate-lowering agents in reducing the progression of kidney function in chronic kidney disease patients. Cognet. Med. 2016;3
    1. Kimura K., Hosoya T., Uchida S., Inaba M., Makino H., Maruyama S., Ito S., Yamamoto T., Tomino Y., Ohno I., Shibagaki Y., Iimuro S., Imai N., Kuwabara M., Hayakawa H., Ohtsu H., Ohashi Y., Investigators F.S. Febuxostat therapy for patients with stage 3 CKD and asymptomatic hyperuricemia: a randomized trial. Am. J. Kidney Dis: the off. J. of the Nat. Kid. Found. 2018
    1. Becker M.A., Schumacher H.R., Jr., Wortmann R.L., MacDonald P.A., Eustace D., Palo W.A., Streit J., Joseph-Ridge N. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N. Engl. J. Med. 2005;353:2450–2461.
    1. Schumacher H.R., Jr., Becker M.A., Wortmann R.L., Macdonald P.A., Hunt B., Streit J., Lademacher C., Joseph-Ridge N. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis Rheum. 2008;59:1540–1548.
    1. Becker M.A., Schumacher H.R., Espinoza L.R., Wells A.F., MacDonald P., Lloyd E., Lademacher C. The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res. Ther. 2010;12:R63.
    1. Becker M.A., Schumacher H.R., MacDonald P.A., Lloyd E., Lademacher C. Clinical efficacy and safety of successful longterm urate lowering with febuxostat or allopurinol in subjects with gout. J. Rheumatol. 2009;36:1273–1282.
    1. Uloric Summary Review. Division of Anesthesia, Analgesia, and Rheumatology. 2009.
    1. White W.B., Saag K.G., Becker M.A., Borer J.S., Gorelick P.B., Whelton A., Hunt B., Castillo M., Gunawardhana L., Investigators C. Cardiovascular safety of febuxostat or allopurinol in patients with gout. N. Engl. J. Med. 2018;378:1200–1210.
    1. FDA), F. a. D. A. FDA Adds Boxed Warning for Increased Risk of Death with Gout Medicine Uloric (Febuxostat).
    1. Mackenzie I.S., Ford I., Nuki G., Hallas J., Hawkey C.J., Webster J., Ralston S.H., Walters M., Robertson M., De Caterina R., Findlay E., Perez-Ruiz F., McMurray J.J.V., MacDonald T.M. Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial. Lancet. 2020;396:1745–1757.
    1. Su C.Y., Shen L.J., Hsieh S.C., Lin L.Y., Lin F.J. Comparing cardiovascular safety of febuxostat and allopurinol in the real world: a population-based cohort study. Mayo Clin. Proc. 2019;94:1147–1157.
    1. Singh J.A., Cleveland J.D. Comparative effectiveness of allopurinol and febuxostat for the risk of atrial fibrillation in the elderly: a propensity-matched analysis of Medicare claims data. Eur. Heart J. 2019;40:3046–3054.
    1. Kang E.H., Choi H.K., Shin A., Lee Y.J., Lee E.B., Song Y.W., Kim S.C. Comparative cardiovascular risk of allopurinol versus febuxostat in patients with gout: a nation-wide cohort study. Rheumatology. 2019;58:2122–2129.
    1. Kojima S., Matsui K., Hiramitsu S., Hisatome I., Waki M., Uchiyama K., Yokota N., Tokutake E., Wakasa Y., Jinnouchi H., Kakuda H., Hayashi T., Kawai N., Mori H., Sugawara M., Ohya Y., Kimura K., Saito Y., Ogawa H. Febuxostat for cerebral and CaRdiorenovascular events PrEvEntion StuDy. Eur. Heart J. 2019;40:1778–1786.
    1. Yokota T., Fukushima A., Kinugawa S., Okumura T., Murohara T., Tsutsui H. Randomized trial of effect of urate-lowering agent febuxostat in chronic heart failure patients with hyperuricemia (LEAF-CHF) Int. Heart J. 2018;59:976–982.
    1. Bardin T., Richette P. FAST: new look at the febuxostat safety profile. Lancet. 2020;396:1704–1705.
    1. Bredemeier M., Lopes L.M., Eisenreich M.A., Hickmann S., Bongiorno G.K., d'Avila R., Morsch A.L.B., da Silva Stein F., Campos G.G.D. Xanthine oxidase inhibitors for prevention of cardiovascular events: a systematic review and meta-analysis of randomized controlled trials. BMC Cardiovasc. Disord. 2018;18:24.
    1. Miner J.N., Tan P.K., Hyndman D., Liu S., Iverson C., Nanavati P., Hagerty D.T., Manhard K., Shen Z., Girardet J.L., Yeh L.T., Terkeltaub R., Quart B. Lesinurad, a novel, oral compound for gout, acts to decrease serum uric acid through inhibition of urate transporters in the kidney. Arthritis Res. Ther. 2016;18:214.
    1. Terkeltaub R., Saag K.G., Goldfarb D.S., Baumgartner S., Schechter B.M., Valiyil R., Jalal D., Pillinger M., White W.B. Integrated safety studies of the urate reabsorption inhibitor lesinurad in treatment of gout. Rheumatology. 2019;58:61–69.
    1. Saag K.G., Fitz-Patrick D., Kopicko J., Fung M., Bhakta N., Adler S., Storgard C., Baumgartner S., Becker M.A. Lesinurad combined with allopurinol: a randomized, double-blind, placebo-controlled study in gout patients with an inadequate response to standard-of-care allopurinol (a US-based study) Arthritis Rheumatol. 2017;69:203–212.
    1. Bardin T., Keenan R.T., Khanna P.P., Kopicko J., Fung M., Bhakta N., Adler S., Storgard C., Baumgartner S., So A. Lesinurad in combination with allopurinol: a randomised, double-blind, placebo-controlled study in patients with gout with inadequate response to standard of care (the multinational CLEAR 2 study) Ann. Rheum. Dis. 2017;76:811–820.
    1. Tausche A.K., Alten R., Dalbeth N., Kopicko J., Fung M., Adler S., Bhakta N., Storgard C., Baumgartner S., Saag K. Lesinurad monotherapy in gout patients intolerant to a xanthine oxidase inhibitor: a 6 month phase 3 clinical trial and extension study. Rheumatology. 2017;56:2170–2178.
    1. Dalbeth N., Jones G., Terkeltaub R., Khanna D., Kopicko J., Bhakta N., Adler S., Fung M., Storgard C., Baumgartner S., Perez-Ruiz F. Combination With Febuxostat in Patients With Tophaceous Gout: Findings of a Phase III Clinical Trial. Arthritis Rheumatol. Vol. 69. 2017. Lesinurad, a selective uric acid reabsorption inhibitor; pp. 1903–1913.
    1. Perez-Gomez M.V., Bartsch L.A., Castillo-Rodriguez E., Fernandez-Prado R., Kanbay M., Ortiz A. Potential dangers of serum urate-lowering therapy. Am. J. Med. 2019;132:457–467.
    1. CHMP Assessment Report - Krystexxa . European Medicines Agency; 2012.
    1. Hosoya T., Ohno I., Nomura S., Hisatome I., Uchida S., Fujimori S., Yamamoto T., Hara S. Effects of topiroxostat on the serum urate levels and urinary albumin excretion in hyperuricemic stage 3 chronic kidney disease patients with or without gout. Clin. Exp. Nephrol. 2014;18:876–884.
    1. Wada T., Hosoya T., Honda D., Sakamoto R., Narita K., Sasaki T., Okui D., Kimura K. Uric acid-lowering and renoprotective effects of topiroxostat, a selective xanthine oxidoreductase inhibitor, in patients with diabetic nephropathy and hyperuricemia: a randomized, double-blind, placebo-controlled, parallel-group study (UPWARD study) Clin. Exp. Nephrol. 2018;22:860–870.
    1. Neogi T., George J., Rekhraj S., Struthers A.D., Choi H., Terkeltaub R.A. Are either or both hyperuricemia and xanthine oxidase directly toxic to the vasculature? A critical appraisal. Arthritis Rheum. 2012;64:327–338.
    1. Kanellis J., Watanabe S., Li J.H., Kang D.H., Li P., Nakagawa T., Wamsley A., Sheikh-Hamad D., Lan H.Y., Feng L., Johnson R.J. Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2. Hypertension. 2003;41:1287–1293.
    1. Kang D.H., Nakagawa T., Feng L., Watanabe S., Han L., Mazzali M., Truong L., Harris R., Johnson R.J. A role for uric acid in the progression of renal disease. J. Am. Soc. Nephrol. 2002;13:2888–2897.
    1. Mazzali M., Kanellis J., Han L., Feng L., Xia Y.Y., Chen Q., Kang D.H., Gordon K.L., Watanabe S., Nakagawa T., Lan H.Y., Johnson R.J. Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism. Am. J. Physiol. Ren. Physiol. 2002;282:F991–F997.
    1. Johnson R.J., Sanchez-Lozada L.G., Mazzali M., Feig D.I., Kanbay M., Sautin Y.Y. What are the key arguments against uric acid as a true risk factor for hypertension? Hypertension. 2013;61:948–951.
    1. Johnson, R. J., Sanchez-Lozada, L. G., Mazzali, M., Feig, D. I., Kanbay, M., and Sautin, Y. Y. What are the key arguments against uric acid as a true risk factor for hypertension? Hypertension 61, 948-951.
    1. Neogi, T., George, J., Rekhraj, S., Struthers, A. D., Choi, H., and Terkeltaub, R. A. Are either or both hyperuricemia and xanthine oxidase directly toxic to the vasculature? A critical appraisal. Arthritis Rheum.
    1. Puddu, P., Puddu, G. M., Cravero, E., Vizioli, L., and Muscari, A. Relationships among hyperuricemia, endothelial dysfunction and cardiovascular disease: molecular mechanisms and clinical implications. J. Cardiol. 59, 235-242.
    1. Park, J. H., Jin, Y. M., Hwang, S., Cho, D. H., Kang, D. H., and Jo, I. Uric acid attenuates nitric oxide production by decreasing the interaction between endothelial nitric oxide synthase and calmodulin in human umbilical vein endothelial cells: a mechanism for uric acid-induced cardiovascular disease development. Nitric Oxide 32, 36-42.
    1. Salvi, E., Kutalik, Z., Glorioso, N., Benaglio, P., Frau, F., Kuznetsova, T., Arima, H., Hoggart, C., Tichet, J., Nikitin, Y. P., Conti, C., Seidlerova, J., Tikhonoff, V., Stolarz-Skrzypek, K., Johnson, T., Devos, N., Zagato, L., Guarrera, S., Zaninello, R., Calabria, A., Stancanelli, B., Troffa, C., Thijs, L., Rizzi, F., Simonova, G., Lupoli, S., Argiolas, G., Braga, D., D'Alessio, M. C., Ortu, M. F., Ricceri, F., Mercurio, M., Descombes, P., Marconi, M., Chalmers, J., Harrap, S., Filipovsky, J., Bochud, M., Iacoviello, L., Ellis, J., Stanton, A. V., Laan, M., Padmanabhan, S., Dominiczak, A. F., Samani, N. J., Melander, O., Jeunemaitre, X., Manunta, P., Shabo, A., Vineis, P., Cappuccio, F. P., Caulfield, M. J., Matullo, G., Rivolta, C., Munroe, P. B., Barlassina, C., Staessen, J. A., Beckmann, J. S., and Cusi, D. Genomewide association study using a high-density single nucleotide polymorphism array and case-control design identifies a novel essential hypertension susceptibility locus in the promoter region of endothelial NO synthase. Hypertension 59, 248-255.
    1. Fujimura Y., Yamauchi Y., Murase T., Nakamura T., Fujita S.I., Fujisaka T., Ito T., Sohmiya K., Hoshiga M., Ishizaka N. Relationship between plasma xanthine oxidoreductase activity and left ventricular ejection fraction and hypertrophy among cardiac patients. PLoS One. 2017;12
    1. Cingolani H.E., Plastino J.A., Escudero E.M., Mangal B., Brown J., Perez N.G. The effect of xanthine oxidase inhibition upon ejection fraction in heart failure patients: La Plata Study. J. Card. Fail. 2006;12:491–498.
    1. Cardillo C., Kilcoyne C.M., Cannon R.O., 3rd, Quyyumi A.A., Panza J.A. Xanthine oxidase inhibition with oxypurinol improves endothelial vasodilator function in hypercholesterolemic but not in hypertensive patients. Hypertension. 1997;30:57–63.
    1. George J., Carr E., Davies J., Belch J.J., Struthers A. High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid. Circulation. 2006;114:2508–2516.
    1. Ogino K., Kato M., Furuse Y., Kinugasa Y., Ishida K., Osaki S., Kinugawa T., Igawa O., Hisatome I., Shigemasa C., Anker S.D., Doehner W. Uric acid-lowering treatment with benzbromarone in patients with heart failure: a double-blind placebo-controlled crossover preliminary study. Circ. Heart Fail. 2010;3:73–81.
    1. Cuspidi C., Facchetti R., Bombelli M., Sala C., Tadic M., Grassi G., Mancia G. Uric acid and new onset left ventricular hypertrophy: findings from the PAMELA population. Am. J. Hypertens. 2017;30:279–285.
    1. Kuwabara M., Sato Y., Kanbay M., Johnson R.J. Uric acid and left ventricular hypertrophy: a potentially new modifiable target? Am. J. Hypertens. 2017;30:229–231.
    1. Kelley E.E. A new paradigm for XOR-catalyzed reactive species generation in the endothelium. Pharmacol. Rep. : PR. 2015;67:669–674.
    1. Johnson R.J., Bakris G.L., Borghi C., Chonchol M.B., Feldman D., Lanaspa M.A., Merriman T.R., Moe O.W., Mount D.B., Sanchez Lozada L.G., Stahl E., Weiner D.E., Chertow G.M. Hyperuricemia, acute and chronic kidney disease, hypertension, and cardiovascular disease: report of a scientific workshop organized by the national kidney foundation. Am. J. Kidney Dis. 2018;71:851–865.
    1. Choi H., Neogi T., Stamp L., Dalbeth N., Terkeltaub R. New perspectives in Rheumatology: implications of the cardiovascular safety of febuxostat and allopurinol in patients with gout and cardiovascular morbidities trial and the associated food and drug administration public safety alert. Arthritis Rheumatol. 2018;70:1702–1709.
    1. Fini M.A., Gaydos J., McNally A., Karoor V., Burnham E.L. Alcohol abuse is associated with enhanced pulmonary and systemic xanthine oxidoreductase activity. Am. J. Physiol. Lung Cell Mol. Physiol. 2017;313:L1047–L1057.
    1. Wright R.M., Ginger L.A., Kosila N., Elkins N.D., Essary B., McManaman J.L., Repine J.E. Mononuclear phagocyte xanthine oxidoreductase contributes to cytokine-induced acute lung injury. Am. J. Respir. Cell Mol. Biol. 2004;30:479–490.
    1. Chinnaiyan A.M., Huber-Lang M., Kumar-Sinha C., Barrette T.R., Shankar-Sinha S., Sarma V.J., Padgaonkar V.A., Ward P.A. Molecular signatures of sepsis: multiorgan gene expression profiles of systemic inflammation. Am. J. Pathol. 2001;159:1199–1209.
    1. Ratliff B.B., Abdulmahdi W., Pawar R., Wolin M.S. Oxidant mechanisms in renal injury and disease. Antioxidants Redox Signal. 2016;25:119–146.
    1. Wolin M.S., Alruwaili N., Kandhi S. Studies on hypoxic pulmonary vasoconstriction detect a novel role for the mitochondrial complex I subunit Ndufs2 in controlling peroxide generation for oxygen-sensing. Circ. Res. 2019;124:1683–1685.
    1. Feelisch M., Akaike T., Griffiths K., Ida T., Prysyahna O., Goodwin J.J., Gollop N.D., Fernandez B.O., Minnion M., Cortese-Krott M.M., Borgognone A., Hayes R.M., Eaton P., Frenneaux M.P., Madhani M. Long-lasting blood pressure lowering effects of nitrite are NO-independent and mediated by hydrogen peroxide, persulfides and oxidation of protein kinase G 1alpha redox signaling. Cardiovasc. Res. 2019
    1. Fini M.A., Stenmark K.R. Pegloticase and lowering blood pressure in refractory gout; is it uric acid or hydrogen peroxide? Eur. J. Intern. Med. 2019
    1. Polito L., Bortolotti M., Battelli M.G., Bolognesi A. Xanthine oxidoreductase: a leading actor in cardiovascular disease drama. Redox Biol. 2021;48:102195.
    1. Alvarez-Lario B., Macarron-Vicente J. Uric acid and evolution. Rheumatology. 2010;49:2010–2015.
    1. Oda M., Satta Y., Takenaka O., Takahata N. Loss of urate oxidase activity in hominoids and its evolutionary implications. Mol. Biol. Evol. 2002;19:640–653.
    1. Lu J., Dalbeth N., Yin H., Li C., Merriman T.R., Wei W.H. Mouse models for human hyperuricaemia: a critical review. Nat. Rev. Rheumatol. 2019
    1. Tan P.K., Liu S., Gunic E., Miner J.N. Discovery and characterization of verinurad, a potent and specific inhibitor of URAT1 for the treatment of hyperuricemia and gout. Sci. Rep. 2017;7:665.
    1. Richette P., Doherty M., Pascual E., Bardin T. SUA levels should not be maintained <3 mg/dL for several years. Response to 'EULAR gout treatment guidelines by Richette et al: uric acid and neurocognition by Singh et al. Ann. Rheum. Dis. 2018;77:e21.
    1. Mouradjian M.T., Plazak M.E., Gale S.E., Noel Z.R., Watson K., Devabhakthuni S. Pharmacologic management of gout in patients with cardiovascular disease and heart failure. Am. J. Cardiovasc. Drugs. 2020;20:431–445.

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