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Impact of hyperuricemia on chronic kidney disease and atherosclerotic cardiovascular disease

Hypertension Research volume 45, pages 635–640 (2022)Cite this article

Abstract

Hyperuricemia is caused by reduced renal/extrarenal excretion and overproduction of uric acid. It is affected by genetic predisposition related to uric acid transporters and by visceral fat accumulation due to overnutrition. The typical symptomatic complication of hyperuricemia is gout caused by monosodium urate crystals. Accumulated evidence from epidemiological studies suggests that hyperuricemia is also a risk factor for hypertension, chronic kidney disease (CKD) and atherosclerotic cardiovascular disease (CVD). However, it remains to be determined whether urate-lowering therapy for asymptomatic patients with hyperuricemia is effective in preventing CKD or CVD progression. This mini review focuses mainly on recent papers investigating the relationship between hyperuricemia and CKD or CVD and studies of urate-lowering therapy. Accumulated studies have proposed mechanisms of renal damage and atherosclerosis in hyperuricemia, including inflammasome activation, decreased nitric oxide bioavailability and oxidative stress induced by uric acid, urate crystals and xanthine oxidoreductase (XOR)-mediated reactive oxygen species. Since patients with hyperuricemia are a heterogeneous population with complex pathologies, it may be important to assess whether an outcome is the result of decreasing serum uric acid levels or an inhibitory effect on XOR. To clarify the impact of hyperuricemia on CKD and CVD progression, high-quality and detailed clinical and basic science studies of hyperuricemia and purine metabolism are needed.

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References

  1. Dalbeth N, Gosling AL, Gaffo A, Abhishek A. Gout. Lancet. 2021;397:1843–55.

    Article  CAS  PubMed  Google Scholar 

  2. Hisatome I, Ichida K, Mineo I, Ohtahara A, Ogino K, Kuwahara M, et al. Japanese Society of Gout and Uric & Nucleic Acids 2019 guidelines for management of hyperuricemia and gout 3rd edition. Gout Uric Nucleic Acids. 2020;44:sp-1–sp-40.

    Google Scholar 

  3. Xu L, Shi Y, Zhuang S, Liu N. Recent advances on uric acid transporters. Oncotarget. 2017;8:100852–62.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Yamashita S, Matsuzawa Y, Tokunaga K, Fujioka S, Tarui S. Studies on the impaired metabolism of uric acid in obese subjects: marked reduction of renal urate excretion and its improvement by a low-calorie diet. Int J Obes. 1986;10:255–64.

    CAS  PubMed  Google Scholar 

  5. Matsuura F, Yamashita S, Nakamura T, Nishida M, Nozaki S, Funahashi T, et al. Effect of visceral fat accumulation on uric acid metabolism in male obese subjects: visceral fat obesity is linked more closely to overproduction of uric acid than subcutaneous fat obesity. Metabolism. 1998;47:929–33.

    Article  CAS  PubMed  Google Scholar 

  6. Li X, Meng X, Timofeeva M, Tzoulaki I, Tsilidis KK, Ioannidis JP, et al. Serum uric acid levels and multiple health outcomes: umbrella review of evidence from observational studies, randomised controlled trials, and Mendelian randomisation studies. BMJ. 2017;357:j2376.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Lanaspa MA, Andres-Hernando A, Kuwabara M. Uric acid and hypertension. Hypertens Res. 2020;43:832–4.

    Article  PubMed  Google Scholar 

  8. Kawasoe S, Kubozono T, Ojima S, Kawabata T, Miyahara H, Tokushige K, et al. J-shaped curve for the association between serum uric acid levels and the prevalence of blood pressure abnormalities. Hypertens Res. 2021;44:1186–93.

    Article  CAS  PubMed  Google Scholar 

  9. Tatsumi Y, Asayama K, Morimoto A, Satoh M, Sonoda N, Miyamatsu N, et al. Hyperuricemia predicts the risk for developing hypertension independent of alcohol drinking status in men and women: the Saku study. Hypertens Res. 2020;43:442–9.

    Article  CAS  PubMed  Google Scholar 

  10. Azegami T, Uchida K, Arima F, Sato Y, Awazu M, Inokuchi M, et al. Association of childhood anthropometric measurements and laboratory parameters with high blood pressure in young adults. Hypertens Res. 2021;44:711–9.

    Article  CAS  PubMed  Google Scholar 

  11. Soletsky B, Feig DI. Uric acid reduction rectifies prehypertension in obese adolescents. Hypertension. 2012;60:1148–56.

    Article  CAS  PubMed  Google Scholar 

  12. Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial. JAMA. 2008;300:924–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhu P, Liu Y, Han L, Xu G, Ran JM. Serum uric acid is associated with incident chronic kidney disease in middle-aged populations: a meta-analysis of 15 cohort studies. PLoS One. 2014;9:e100801.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Kamei K, Konta T, Hirayama A, Suzuki K, Ichikawa K, Fujimoto S, et al. A slight increase within the normal range of serum uric acid and the decline in renal function: associations in a community-based population. Nephrol Dial Transplant. 2014;29:2286–92.

    Article  CAS  PubMed  Google Scholar 

  15. Zhao G, Huang L, Song M, Song Y. Baseline serum uric acid level as a predictor of cardiovascular disease related mortality and all-cause mortality: a meta-analysis of prospective studies. Atherosclerosis. 2013;231:61–8.

    Article  CAS  PubMed  Google Scholar 

  16. Zhang W, Iso H, Murakami Y, Miura K, Nagai M, Sugiyama D, et al. Serum uric acid and mortality form cardiovascular disease: EPOCH-JAPAN Study. J Atheroscler Thromb 2016;23:692–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mori K, Furuhashi M, Tanaka M, Numata K, Hisasue T, Hanawa N, et al. U-shaped relationship between serum uric acid level and decline in renal function during a 10-year period in female subjects: BOREAS-CKD2. Hypertens Res. 2021;44:107–16.

    Article  PubMed  Google Scholar 

  18. Li J, Muraki I, Imano H, Cui R, Yamagishi K, Umesawa M, et al. Serum uric acid and risk of stroke and its types: the Circulatory Risk in Communities Study (CIRCS). Hypertens Res. 2020;43:313–21.

    Article  CAS  PubMed  Google Scholar 

  19. Sakata S, Hata J, Honda T, Hirakawa Y, Oishi E, Shibata M, et al. Serum uric acid levels and cardiovascular mortality in a general Japanese population: the Hisayama Study. Hypertens Res. 2020;43:560–8.

    Article  CAS  PubMed  Google Scholar 

  20. Ae R, Kanbay M, Kuwabara M. The causality between the serum uric acid level and stroke. Hypertens Res. 2020;43:354–6.

    Article  PubMed  Google Scholar 

  21. Kuwabara M, Hisatome I, Niwa K, Bjornstad P, Roncal-Jimenez CA, Andres-Hernando A, et al. The optimal range of serum uric acid for cardiometabolic diseases: a 5-year Japanese Cohort Study. J Clin Med. 2020;9:942.

    Article  CAS  PubMed Central  Google Scholar 

  22. Hakoda M, Masunari N, Yamada M, Fujiwara S, Suzuki G, Kodama K, et al. Serum uric acid concentration as a risk factor for cardiovascular mortality: a longterm cohort study of atomic bomb survivors. J Rheumatol. 2005;32:906–1.

    CAS  PubMed  Google Scholar 

  23. FitzGerald JD, Dalbeth N, Mikuls T, Brignardello-Petersen R, Guyatt G, Abeles AM, et al. 2020 American College of Rheumatology Guideline for the Management of Gout. Arthritis Rheumatol. 2020;72:744–60.

    Article  Google Scholar 

  24. Doria A, Galecki AT, Spino C, Pop-Busui R, Cherney DZ, Lingvay I, et al. Serum urate lowering with allopurinol and kidney function in type 1 diabetes. N Engl J Med. 2020;382:2493–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Badve SV, Pascoe EM, Tiku A, Boudville N, Brown FG, Cass A, et al. Effects of allopurinol on the progression of chronic kidney disease. N Engl J Med. 2020;382:2504–13.

    Article  CAS  PubMed  Google Scholar 

  26. Chewcharat A, Chen Y, Thongprayoon C, Harrison AM, Mao MA, Cheungpasitporn W. Febuxostat as a renoprotective agent for treatment of hyperuricaemia: a meta-analysis of randomised controlled trials. Intern Med J. 2021;51:752–62.

    Article  CAS  PubMed  Google Scholar 

  27. Stack AG, Dronamraju N, Parkinson J, Johansson S, Johnsson E, Erlandsson F, et al. Effect of intensive urate lowering with combined verinurad and febuxostat on albuminuria in patients with type 2 diabetes: a randomized trial. Am J Kidney Dis. 2021;77:481–9.

    Article  CAS  PubMed  Google Scholar 

  28. Kimura K, Hosoya T, Uchida S, Inaba M, Makino H, Maruyama S, et al. Febuxostat therapy for patients with stage 3 CKD and asymptomatic hyperuricemia: a randomized trial. Am J Kidney Dis. 2018;72:798–810.

    Article  CAS  PubMed  Google Scholar 

  29. Feig DI. Urate-lowering therapy and chronic kidney disease progression. N Engl J Med. 2020;382:2567–8.

    Article  PubMed  Google Scholar 

  30. Tanaka A, Taguchi I, Teragawa H, Ishizaka N, Kanzaki Y, Tomiyama H, et al. Febuxostat does not delay progression of carotid atherosclerosis in patients with asymptomatic hyperuricemia: a randomized, controlled trial. PLoS Med. 2020;17:e1003095.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Kario K, Nishizawa M, Kiuchi M, Kiyosue A, Tomita F, Ohtani H, et al. Comparative effects of topiroxostat and febuxostat on arterial properties in hypertensive patients with hyperuricemia. J Clin Hypertens. 2021;23:334–44.

    Article  CAS  Google Scholar 

  32. Kojima S, Matsui K, Hiramitsu S, Hisatome I, Waki M, Uchiyama K, et al. Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy. Eur Heart J. 2019;40:1778–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kojima S, Uchiyama K, Yokota N, Tokutake E, Wakasa Y, Hiramitsu S, et al. Optimal uric acid levels by febuxostat treatment and cerebral, cardiorenovascular risks: post hoc analysis of a randomised controlled trial. Rheumatology. 2021 Oct:keab739. https://doi.org/10.1093/rheumatology/keab739.

  34. White WB, Saag KG, Becker MA, Borer JS, Gorelick PB, Whelton A, et al. Cardiovascular safety of febuxostat or allopurinol in patients with gout. N Engl J Med. 2018;378:1200–10.

    Article  CAS  PubMed  Google Scholar 

  35. Mackenzie IS, Ford I, Nuki G, Hallas J, Hawkey CJ, Webster J, et al. 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;396:1745–57.

    Article  CAS  PubMed  Google Scholar 

  36. Ju C, Lai RWC, Li KHC, Hung JKF, Lai JCL, Ho J, et al. Comparative cardiovascular risk in users versus non-users of xanthine oxidase inhibitors and febuxostat versus allopurinol users. Rheumatology. 2020;59:2340–9.

    Article  CAS  PubMed  Google Scholar 

  37. Sánchez-Lozada LG. The pathophysiology of uric acid on renal diseases. Contrib Nephrol. 2018;192:17–24.

    Article  PubMed  Google Scholar 

  38. Maruhashi T, Hisatome I, Kihara Y, Higashi Y. Hyperuricemia and endothelial function: from molecular background to clinical perspectives. Atherosclerosis. 2018;278:226–31.

    Article  CAS  PubMed  Google Scholar 

  39. Kushiyama A, Okubo H, Sakoda H, Kikuchi T, Fujishiro M, Sato H, et al. Xanthine oxidoreductase is involved in macrophage foam cell formation and atherosclerosis development. Arterioscler Thromb Vasc Biol. 2012;32:291–8.

    Article  CAS  PubMed  Google Scholar 

  40. Nomura J, Busso N, Ives A, Matsui C, Tsujimoto S, Shirakura T, et al. Xanthine oxidase inhibition by febuxostat attenuates experimental atherosclerosis in mice. Sci Rep. 2014;4:4554.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Ives A, Nomura J, Martinon F, Roger T, LeRoy D, Miner JN, et al. Xanthine oxidoreductase regulates macrophage IL1β secretion upon NLRP3 inflammasome activation. Nat Commun. 2015;6:6555.

    Article  CAS  PubMed  Google Scholar 

  42. Nakagawa T, Johnson RJ, Andres-Hernando A, Roncal-Jimenez C, Sanchez-Lozada LG, Tolan DR, et al. Fructose production and metabolism in the kidney. J Am Soc Nephrol. 2020;31:898–906.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Fujii K, Kubo A, Miyashita K, Sato M, Hagiwara A, Inoue H, et al. Xanthine oxidase inhibitor ameliorates postischemic renal injury in mice by promoting resynthesis of adenine nucleotides. JCI Insight. 2019;4:e124816.

    Article  PubMed Central  Google Scholar 

  44. Kimura Y, Yanagida T, Onda A, Tsukui D, Hosoyamada M, Kono H. Soluble uric acid promotes atherosclerosis via AMPK (AMP-Activated Protein Kinase)-Mediated Inflammation. Arterioscler Thromb Vasc Biol. 2020;40:570–82.

    Article  CAS  PubMed  Google Scholar 

  45. Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med. 2019;381:2497–505.

    Article  CAS  PubMed  Google Scholar 

  46. Furuhashi M, Higashiura Y, Koyama M, Tanaka M, Murase T, Nakamura T, et al. Independent association of plasma xanthine oxidoreductase activity with hypertension in nondiabetic subjects not using medication. Hypertens Res. 2021;44:1213–20.

    Article  CAS  PubMed  Google Scholar 

  47. Nagao H, Nishizawa H, Tanaka Y, Fukata T, Mizushima T, Furuno M, et al. Hypoxanthine secretion from human adipose tissue and its increase in hypoxia. Obesity. 2018;26:1168–78.

    Article  CAS  PubMed  Google Scholar 

  48. Brass CA, Narciso J, Gollan JL. Enhanced activity of the free radical producing enzyme xanthine oxidase in hypoxic rat liver. Regulation and pathophysiologic significance. J Clin Invest. 1991;87:424–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Battelli MG, Abbondanza A, Stirpe F. Effects of hypoxia and ethanol on xanthine oxidase of isolated rat hepatocytes: conversion from D to O form and leakage from cells. Chem Biol Interact. 1992;83:73–84.

    Article  CAS  PubMed  Google Scholar 

  50. Houston M, Estevez A, Chumley P, Aslan M, Marklund S, Parks DA, et al. Binding of xanthine oxidase to vascular endothelium. Kinetic characterization and oxidative impairment of nitric oxide-dependent signaling. J Biol Chem. 1999;274:4985–94.

    Article  CAS  PubMed  Google Scholar 

  51. Battelli MG, Bolognesi A, Polito L. Pathophysiology of circulating xanthine oxidoreductase: new emerging roles for a multi-tasking enzyme. Biochim Biophys Acta. 2014;1842:1502–17.

    Article  CAS  PubMed  Google Scholar 

  52. Kelley EE. A new paradigm for XOR-catalyzed reactive species generation in the endothelium. Pharm Rep. 2015;67:669–74.

    Article  CAS  Google Scholar 

  53. Murase T, Nampei M, Oka M, Miyachi A, Nakamura T. A highly sensitive assay of human plasma xanthine oxidoreductase activity using stable isotope-labeled xanthine and LC/TQMS. J Chromatogr B Anal Technol Biomed Life Sci. 2016;1039:51–58.

    Article  CAS  Google Scholar 

  54. Washio KW, Kusunoki Y, Murase T, Nakamura T, Osugi K, Ohigashi M, et al. Xanthine oxidoreductase activity is correlated with insulin resistance and subclinical inflammation in young humans. Metabolism. 2017;70:51–56.

    Article  CAS  PubMed  Google Scholar 

  55. Furuhashi M, Matsumoto M, Tanaka M, Moniwa N, Murase T, Nakamura T, et al. Plasma xanthine oxidoreductase activity as a novel biomarker of metabolic disorders in a general population. Circ J. 2018;82:1892–9.

    Article  CAS  PubMed  Google Scholar 

  56. Kawachi Y, Fujishima Y, Nishizawa H, Nagao H, Nakamura T, Akari S, et al. Plasma xanthine oxidoreductase activity in Japanese patients with type 2 diabetes across hospitalized treatment. J Diabetes Investig. 2021;12:1512–20.

    Article  CAS  PubMed  Google Scholar 

  57. Washio K, Kusunoki Y, Tsunoda T, Osugi K, Ohigashi M, Murase T, et al. Xanthine oxidoreductase activity correlates with vascular endothelial dysfunction in patients with type 1 diabetes. Acta Diabetol. 2020;57:31–39.

    Article  CAS  PubMed  Google Scholar 

  58. Watanabe K, Watanabe T, Otaki Y, Shishido T, Murase T, Nakamura T, et al. Impact of plasma xanthine oxidoreductase activity in patients with heart failure with preserved ejection fraction. ESC Heart Fail. 2020;7:1735–43.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Kawachi Y, Fujishima Y, Nishizawa H, Nakamura T, Akari S, Murase T, et al. Increased plasma XOR activity induced by NAFLD/NASH and its possible involvement in vascular neointimal proliferation. JCI Insight. 2021;6:e144762.

    Article  PubMed Central  Google Scholar 

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Acknowledgements

We thank Drs Yuya Fujishima and Yusuke Kawachi, Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, for reviewing the manuscript.

Funding

This work was supported in part by Grants-in-Aid for Scientific Research (C) no. 19K09023 (to HN) and no. 19K08980 (to NM) and Grants-in-Aid for Scientific Research (B) no. 18H02863 (to IS).

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  1. Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2, Yamada-oka, Suita, Osaka, 565-0871, Japan

    Hitoshi Nishizawa & Iichiro Shimomura

  2. Department of Metabolism and Atherosclerosis, Graduate School of Medicine, Osaka University, 2-2, Yamada-oka, Suita, Osaka, 565-0871, Japan

    Norikazu Maeda

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  1. Hitoshi Nishizawa
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Correspondence to Hitoshi Nishizawa.

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Nishizawa, H., Maeda, N. & Shimomura, I. Impact of hyperuricemia on chronic kidney disease and atherosclerotic cardiovascular disease. Hypertens Res 45, 635–640 (2022). https://doi.org/10.1038/s41440-021-00840-w

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