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Jager KJ, Kovesdy C, Langham R, Rosenberg M, Jha V, Zoccali C. A single number for advocacy and communication-worldwide more than 850 million individuals have kidney diseases. Nephrol Dial Transplant 34: 1803-1805, 2019.","DOI":"10.1093\/ndt\/gfz174"},{"key":"2","doi-asserted-by":"crossref","unstructured":"2. Imai E, Horio M, Watanabe T, et al. Prevalence of chronic kidney disease in the Japanese general population. Clin Exp Nephrol 13: 621-630, 2009.","DOI":"10.1007\/s10157-009-0199-x"},{"key":"3","doi-asserted-by":"crossref","unstructured":"3. Tang Y, Jiang J, Zhao Y, Du D. Aging and chronic kidney disease: epidemiology, therapy, management and the role of immunity. Clin Kidney J 17: 1-16, 2024.","DOI":"10.1093\/ckj\/sfae235"},{"key":"4","doi-asserted-by":"crossref","unstructured":"4. Kon S, Konta T, Ichikawa K, et al. Association between renal function and cardiovascular and all-cause mortality in the community-based elderly population: results from the Specific Health Check and Guidance Program in Japan. Clin Exp Nephrol 22: 346-352, 2018.","DOI":"10.1007\/s10157-017-1455-0"},{"key":"5","doi-asserted-by":"crossref","unstructured":"5. Marreiros C, Viegas C, Simes D. Targeting a silent disease: vascular calcification in chronic kidney disease. Int J Mol Sci 23: 16114, 2022.","DOI":"10.3390\/ijms232416114"},{"key":"6","doi-asserted-by":"crossref","unstructured":"6. Sofue T. Hyperuricemia: the third key player for nephrosclerosis with ischemia. Hypertens Res 46: 1707-1709, 2023.","DOI":"10.1038\/s41440-023-01294-y"},{"key":"7","doi-asserted-by":"crossref","unstructured":"7. Zeng X, Yang Y. Molecular mechanisms underlying vascular remodeling in hypertension. Rev Cardiovasc Med 25: 72, 2024.","DOI":"10.31083\/j.rcm2502072"},{"key":"8","doi-asserted-by":"crossref","unstructured":"8. Hill GS, Heudes D, Bari\u00e9ty J. Morphometric study of arterioles and glomeruli in the aging kidney suggests focal loss of autoregulation. Kidney Int 63: 1027-1036, 2003.","DOI":"10.1046\/j.1523-1755.2003.00831.x"},{"key":"9","doi-asserted-by":"crossref","unstructured":"9. Guyton AC. Blood pressure control - special role of the kidneys and body fluids. Science 252: 1813-1816, 1991.","DOI":"10.1126\/science.2063193"},{"key":"10","doi-asserted-by":"crossref","unstructured":"10. Yamamoto M, Takata T, Hanada H, et al. Zinc deficiency induces hypertension by paradoxically amplifying salt sensitivity under high salt intake in mice. Clin Exp Nephrol 28: 728-739, 2024.","DOI":"10.1007\/s10157-024-02478-7"},{"key":"11","doi-asserted-by":"crossref","unstructured":"11. Takata T, Isomoto H. The versatile role of uromodulin in renal homeostasis and its relevance in chronic kidney disease. Intern Med 63: 17-23, 2024.","DOI":"10.2169\/internalmedicine.1342-22"},{"key":"12","doi-asserted-by":"publisher","unstructured":"12. Kuwabara M, Niwa K, Hisatome I, et al. Asymptomatic hyperuricemia without comorbidities predicts cardiometabolic diseases. Hypertension 69: 1036-1044, 2017.","DOI":"10.1161\/HYPERTENSIONAHA.116.08998"},{"key":"13","doi-asserted-by":"crossref","unstructured":"13. Kochi M, Kohagura K, Oshiro N, et al. Association of blood pressure and hyperuricemia with proteinuria and reduced renal function in the general population. Hypertens Res 46: 1662-1672, 2023.","DOI":"10.1038\/s41440-023-01250-w"},{"key":"14","doi-asserted-by":"crossref","unstructured":"14. Kohagura K, Kochi M, Miyagi T, et al. An association between uric acid levels and renal arteriolopathy in chronic kidney disease: a biopsy-based study. Hypertens Res 36: 43-49, 2013.","DOI":"10.1038\/hr.2012.135"},{"key":"15","doi-asserted-by":"crossref","unstructured":"15. Piani F, Johnson RJ. Does gouty nephropathy exist, and is it more common than we think? Kidney Int 99: 31-33, 2021.","DOI":"10.1016\/j.kint.2020.10.015"},{"key":"16","doi-asserted-by":"crossref","unstructured":"16. Oda M, Satta Y, Takenaka O, Takahata N. Loss of urate oxidase activity in hominoids and its evolutionary implications. Mol Biol Evol 19: 640-653, 2002.","DOI":"10.1093\/oxfordjournals.molbev.a004123"},{"key":"17","doi-asserted-by":"crossref","unstructured":"17. Ichida K, Matsuo H, Takada T, et al. Decreased extra-renal urate excretion is a common cause of hyperuricemia. Nat Commun 3: 764, 2012.","DOI":"10.1038\/ncomms1756"},{"key":"18","doi-asserted-by":"crossref","unstructured":"18. Wen S, Arakawa H, Tamai I. Uric acid in health and disease: From physiological functions to pathogenic mechanisms. Pharmacol Ther 256: 108615, 2024.","DOI":"10.1016\/j.pharmthera.2024.108615"},{"key":"19","doi-asserted-by":"crossref","unstructured":"19. Mandal AK, Mount DB. The molecular physiology of uric acid homeostasis. Annu Rev Physiol 77: 323-345, 2015.","DOI":"10.1146\/annurev-physiol-021113-170343"},{"key":"20","doi-asserted-by":"crossref","unstructured":"20. Vitart V, Rudan I, Hayward C, et al. SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat Genet 40: 437-442, 2008.","DOI":"10.1038\/ng.106"},{"key":"21","doi-asserted-by":"crossref","unstructured":"21. Kim GH, Jun JB. Altered serum uric acid levels in kidney disorders. Life 12: 1891, 2022.","DOI":"10.3390\/life12111891"},{"key":"22","doi-asserted-by":"crossref","unstructured":"22. Imbriano LJ, Ilamathi E, Ali NM, Miyawaki N, Maesaka JK. Normal fractional urate excretion identifies hyponatremic patients with reset osmostat. J Nephrol 25: 833-838, 2012.","DOI":"10.5301\/jn.5000074"},{"key":"23","doi-asserted-by":"crossref","unstructured":"23. Nigam SK, Bhatnagar V. The systems biology of uric acid transporters. Curr Opin Nephrol Hypertens 27: 305-313, 2018.","DOI":"10.1097\/MNH.0000000000000427"},{"key":"24","doi-asserted-by":"crossref","unstructured":"24. Toyoda Y, Miyata H, Uchida N, et al. Vitamin C transporter SVCT1 serves a physiological role as a urate importer: functional analyses and in vivo investigations. Pflugers Arch 475: 489-504, 2023.","DOI":"10.1007\/s00424-023-02792-1"},{"key":"25","doi-asserted-by":"crossref","unstructured":"25. Toyoda Y, Miyata H, Shigesawa R, Matsuo H, Suzuki H, Takada T. SVCT2\/SLC23A2 is a sodium-dependent urate transporter: functional properties and practical application. J Biol Chem 299: 104976, 2023.","DOI":"10.1016\/j.jbc.2023.104976"},{"key":"26","doi-asserted-by":"crossref","unstructured":"26. Khosla UM, Zharikov S, Finch JL, et al. Hyperuricemia induces endothelial dysfunction. Kidney Int 67: 1739-1742, 2005.","DOI":"10.1111\/j.1523-1755.2005.00273.x"},{"key":"27","doi-asserted-by":"crossref","unstructured":"27. Kang DH, Park SK, Lee IK, Johnson RJ. Uric acid-induced C-reactive protein expression. J Am Soc Nephrol 16: 3553-3562, 2005.","DOI":"10.1681\/ASN.2005050572"},{"key":"28","doi-asserted-by":"crossref","unstructured":"28. Zhang J, Lei W, Zhou J, Zhang Y, Huang F, Chen M. Uric acid promotes aortic valve calcification via mediating valve interstitial cell osteogenic differentiation and endothelial dysfunction. FASEB J 39: 1-21, 2025.","DOI":"10.1096\/fj.202402831R"},{"key":"29","doi-asserted-by":"crossref","unstructured":"29. Dempsey B, Pereira da Silva B, Cruz LC, et al. Unraveling the effects of uric acid on endothelial cells: a global proteomic study. Redox Biol 82: 103625, 2025.","DOI":"10.1016\/j.redox.2025.103625"},{"key":"30","doi-asserted-by":"publisher","unstructured":"30. Mazzali M, Kim YG, Suga S, et al. Hyperuricemia exacerbates chronic cyclosporine nephropathy. Transplantation 71: 900-905, 2001.","DOI":"10.1097\/00007890-200104150-00014"},{"key":"31","doi-asserted-by":"crossref","unstructured":"31. Perlstein TS, Gumieniak O, Hopkins PN, et al. Uric acid and the state of the intrarenal renin-angiotensin system in humans. Kidney Int 66: 1465-1470, 2004.","DOI":"10.1111\/j.1523-1755.2004.00909.x"},{"key":"32","doi-asserted-by":"crossref","unstructured":"32. Semenikhina M, Mathew RO, Barakat M, Van Beusecum JP, Ilatovskaya DV, Palygin O. Blood pressure management strategies and podocyte health. Am J Hypertens 38: 85-96, 2025.","DOI":"10.1093\/ajh\/hpae120"},{"key":"33","doi-asserted-by":"crossref","unstructured":"33. Takata T, Isomoto H. Pleiotropic effects of sodium-glucose cotransporter-2 inhibitors: renoprotective mechanisms beyond glycemic control. Int J Mol Sci 22: 4374, 2021.","DOI":"10.3390\/ijms22094374"},{"key":"34","doi-asserted-by":"crossref","unstructured":"34. Kanbay M, Copur S, Bakir CN, Covic A, Ortiz A, Tuttle KR. 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Circ J 80: 1857-1862, 2016.","DOI":"10.1253\/circj.CJ-16-0030"},{"key":"44","doi-asserted-by":"crossref","unstructured":"44. 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 9: e100801, 2014.","DOI":"10.1371\/journal.pone.0100801"},{"key":"45","doi-asserted-by":"crossref","unstructured":"45. Madero M, Sarnak MJ, Wang X, et al. Uric acid and long-term outcomes in CKD. Am J Kidney Dis 53: 796-803, 2009.","DOI":"10.1053\/j.ajkd.2008.12.021"},{"key":"46","doi-asserted-by":"crossref","unstructured":"46. Sturm G, Kollerits B, Neyer U, Ritz E, Kronenberg F; MMKD Study Group. Uric acid as a risk factor for progression of non-diabetic chronic kidney disease? The Mild to Moderate Kidney Disease (MMKD) Study. Exp Gerontol 43: 347-352, 2008.","DOI":"10.1016\/j.exger.2008.01.006"},{"key":"47","doi-asserted-by":"crossref","unstructured":"47. Johnson RJ, Nakagawa T, Jalal D, S\u00e1nchez-Lozada LG, Kang DH, Ritz E. Uric acid and chronic kidney disease: which is chasing which? Nephrol Dial Transplant 28: 2221-2228, 2013.","DOI":"10.1093\/ndt\/gft029"},{"key":"48","doi-asserted-by":"crossref","unstructured":"48. Ghang B, Park J, Lee JS, et al. Post-hoc analysis of the CARES trial suggests delayed progression of chronic kidney disease in patients with gout during urate-lowering therapy. Kidney Int 107: 521-529, 2025.","DOI":"10.1016\/j.kint.2024.10.022"},{"key":"49","doi-asserted-by":"crossref","unstructured":"49. Wang Y, Dalbeth N, Terkeltaub R, et al. Target serum urate achievement and chronic kidney disease progression in patients with gout and kidney disease. JAMA Intern Med 185: 74-82, 2025.","DOI":"10.1001\/jamainternmed.2024.6212"},{"key":"50","doi-asserted-by":"crossref","unstructured":"50. Shibagaki Y, Ohno I, Hosoya T, Kimura K. Safety, efficacy and renal effect of febuxostat in patients with moderate-to-severe kidney dysfunction. Hypertens Res 37: 919-925, 2014.","DOI":"10.1038\/hr.2014.107"},{"key":"51","doi-asserted-by":"crossref","unstructured":"51. Kanji T, Gandhi M, Clase CM, Yang R. Urate lowering therapy to improve renal outcomes in patients with chronic kidney disease: systematic review and meta-analysis. BMC Nephrol 16: 58, 2015.","DOI":"10.1186\/s12882-015-0047-z"},{"key":"52","doi-asserted-by":"crossref","unstructured":"52. Bose B, Badve SV, Hiremath SS, et al. Effects of uric acid-lowering therapy on renal outcomes: a systematic review and meta-analysis. Nephrol Dial Transplant 29: 406-413, 2014.","DOI":"10.1093\/ndt\/gft378"},{"key":"53","doi-asserted-by":"crossref","unstructured":"53. Badve SV, Pascoe EM, Tiku A, et al. Effects of allopurinol on the progression of chronic kidney disease. N Engl J Med 382: 2504-2513, 2020.","DOI":"10.1056\/NEJMoa1915833"},{"key":"54","doi-asserted-by":"crossref","unstructured":"54. Doria A, Galecki AT, Spino C, et al. Serum urate lowering with allopurinol and kidney function in type 1 diabetes. N Engl J Med 382: 2493-2503, 2020.","DOI":"10.1056\/NEJMoa1916624"},{"key":"55","doi-asserted-by":"crossref","unstructured":"55. Chou H, Chiu H, Tsai C, et al. Comparative effectiveness of allopurinol, febuxostat and benzbromarone on renal function in chronic kidney disease patients with hyperuricemia: a 13-year inception cohort study. Nephrol Dial Transplant 50: 1620-1627, 2017.","DOI":"10.1093\/ndt\/gfx313"},{"key":"56","doi-asserted-by":"publisher","unstructured":"56. Yanai H, Katsuyama H, Hakoshima M, Adachi H. Urate transporter 1 can be a therapeutic target molecule for chronic kidney disease and diabetic kidney disease: a retrospective longitudinal study. 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