OPINION

The case for uric acid-lowering treatment in patients with hyperuricaemia and CKD

Abstract

Hyperuricaemia is common among patients with chronic kidney disease (CKD), and increases in severity with the deterioration of kidney function. Although existing guidelines for CKD management do not recommend testing for or treatment of hyperuricaemia in the absence of a diagnosis of gout or urate nephrolithiasis, an emerging body of evidence supports a direct causal relationship between serum urate levels and the development of CKD. Here, we review randomized clinical trials that have evaluated the effect of urate-lowering therapy (ULT) on the rate of CKD progression. Among trials in which individuals in the control arm experienced progressive deterioration of kidney function (which we define as ≥4 ml/min/1.73 m² over the course of the study — typically 6 months to 2 years), treatment with ULT conferred consistent clinical benefits. In contrast, among trials where clinical progression was not observed in the control arm, treatment with ULT was ineffective, but this finding should not be used as an argument against the use of uric acid-lowering therapy. Although additional studies are needed to identify threshold values of serum urate for treatment initiation and to confirm optimal target levels, we believe that sufficient evidence exists to recommend routine measurement of serum urate levels in patients with CKD and consider initiation of ULT among those who are hyperuricaemic with evidence of deteriorating renal function, unless specific contraindications exist.

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Fig. 1: Effects of uric acid on the kidney.
Fig. 2: Purine nucleotide degradation and fructose metabolism generate uric acid.

References

  1. 1.

    Talbott, J. H. & Terplan, K. L. The kidney in gout. Medicine (Baltimore) 39, 405–467 (1960).

  2. 2.

    Beck, L. H. Requiem for gouty nephropathy. Kidney Int. 30, 280–287 (1986).

  3. 3.

    Yu, T. F. & Berger, L. Impaired renal function gout: its association with hypertensive vascular disease and intrinsic renal disease. Am. J. Med. 72, 95–100 (1982).

  4. 4.

    Yu, T. F., Berger, L., Dorph, D. J. & Smith, H. Renal function in gout. V. Factors influencing the renal hemodynamics. Am. J. Med. 67, 766–771 (1979).

  5. 5.

    Fessel, W. J. Renal outcomes of gout and hyperuricemia. Am. J. Med. 67, 74–82 (1979).

  6. 6.

    Duffy, W. B., Senekjian, H. O., Knight, T. F. & Weinman, E. J. Management of asymptomatic hyperuricemia. JAMA 246, 2215–2216 (1981).

  7. 7.

    Hande, K. R., Noone, R. M. & Stone, W. J. Severe allopurinol toxicity. Description and guidelines for prevention in patients with renal insufficiency. Am. J. Med. 76, 47–56 (1984).

  8. 8.

    Hande, K. R. Evaluation of a thiazide-allopurinol drug interaction. Am. J. Med. Sci. 292, 213–216 (1986).

  9. 9.

    Johnson, R. J., Kivlighn, S. D., Kim, Y. G., Suga, S. & Fogo, A. B. Reappraisal of the pathogenesis and consequences of hyperuricemia in hypertension, cardiovascular disease, and renal disease. Am. J. Kidney Dis. 33, 225–234 (1999).

  10. 10.

    Johnson, R. J. & Tuttle, K. R. Much ado about nothing, or much to do about something? The continuing controversy over the role of uric acid in cardiovascular disease. Hypertension 35, E10 (2000).

  11. 11.

    Johnson, R. J. Finding the truth: multivariable analysis and the assassination of Abraham Lincoln. J. R. Coll. Physicians Edinb. 48, 153–154 (2018).

  12. 12.

    Kanellis, J. et al. Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2. Hypertension 41, 1287–1293 (2003).

  13. 13.

    Kang, D. H., Park, S. K., Lee, I. K. & Johnson, R. J. Uric acid-induced C-reactive protein expression: implication on cell proliferation and nitric oxide production of human vascular cells. J. Am. Soc. Nephrol. 16, 3553–3562 (2005).

  14. 14.

    Cirillo, P. et al. Ketohexokinase-dependent metabolism of fructose induces proinflammatory mediators in proximal tubular cells. J. Am. Soc. Nephrol. 20, 545–553 (2009).

  15. 15.

    Baldwin, W. et al. Hyperuricemia as a mediator of the proinflammatory endocrine imbalance in the adipose tissue in a murine model of the metabolic syndrome. Diabetes 60, 1258–1269 (2011).

  16. 16.

    Roncal, C. A. et al. Effect of elevated serum uric acid on cisplatin-induced acute renal failure. Am. J. Physiol. Renal Physiol. 292, F116–F122 (2007).

  17. 17.

    Kang, D. H. et al. A role for uric acid in the progression of renal disease. J. Am. Soc. Nephrol. 13, 2888–2897 (2002).

  18. 18.

    Mazzali, M. et al. Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension 38, 1101–1106 (2001).

  19. 19.

    Mazzali, M. et al. Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism. Am. J. Physiol. Renal Physiol. 282, F991–F997 (2002).

  20. 20.

    Sanchez-Lozada, L. G. et al. Mild hyperuricemia induces glomerular hypertension in normal rats. Am. J. Physiol. Renal Physiol. 283, F1105–F1110 (2002).

  21. 21.

    Sanchez-Lozada, L. G. et al. Mild hyperuricemia induces vasoconstriction and maintains glomerular hypertension in normal and remnant kidney rats. Kidney Int. 67, 237–247 (2005).

  22. 22.

    Roncal-Jimenez, C. et al. Heat stress nephropathy from exercise-induced uric acid crystalluria: a perspective on mesoamerican nephropathy. Am. J. Kidney Dis. 67, 20–30 (2016).

  23. 23.

    Bjornstad, P. et al. Role of bicarbonate supplementation on urine uric acid crystals and diabetic tubulopathy in adults with type 1 diabetes. Diabetes Obes. Metab. 20, 1776–1780 (2018).

  24. 24.

    Bjornstad, P. et al. Hyperfiltration and uricosuria in adolescents with type 1 diabetes. Pediatr. Nephrol. 31, 787–793 (2016).

  25. 25.

    Ryu, E. S. et al. Uric acid-induced phenotypic transition of renal tubular cells as a novel mechanism of chronic kidney disease. Am. J. Physiol. Renal Physiol. 304, F471–F480 (2013).

  26. 26.

    Johnson, R. J. et al. 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. 71, 851–865 (2018).

  27. 27.

    Li, L. et al. 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. 15, 122 (2014).

  28. 28.

    Zhu, P., Liu, Y., Han, L., Xu, G. & Ran, J. M. 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).

  29. 29.

    Kuwabara, M. et al. Asymptomatic hyperuricemia without comorbidities predicts cardiometabolic diseases: five-year Japanese cohort study. Hypertension 69, 1036–1044 (2017).

  30. 30.

    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. 47, 51–59 (2006).

  31. 31.

    Goicoechea, M. et al. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin. J. Am. Soc. Nephrol. 5, 1388–1393 (2010).

  32. 32.

    Jordan, D. M. et al. No causal effects of serum urate levels on the risk of chronic kidney disease: a Mendelian randomization study. PLOS Med. 16, e1002725 (2019).

  33. 33.

    Yang, Q. et al. Genome-wide search for genes affecting serum uric acid levels: the Framingham Heart Study. Metabolism 54, 1435–1441 (2005).

  34. 34.

    Bose, B. et al. Effects of uric acid-lowering therapy on renal outcomes: a systematic review and meta-analysis. Nephrol. Dial. Transplant. 29, 406–413 (2014).

  35. 35.

    Sampson, A. L., Singer, R. F. & Walters, G. D. Uric acid lowering therapies for preventing or delaying the progression of chronic kidney disease. Cochrane Database Syst. Rev. 10, CD009460 (2017).

  36. 36.

    Su, X., Xu, B., Yan, B., Qiao, X. & Wang, L. Effects of uric acid-lowering therapy in patients with chronic kidney disease: a meta-analysis. PLOS ONE 12, e0187550 (2017).

  37. 37.

    Wang, H., Wei, Y., Kong, X. & Xu, D. Effects of urate-lowering therapy in hyperuricemia on slowing the progression of renal function: a meta-analysis. J. Ren. Nutr. 23, 389–396 (2013).

  38. 38.

    Zhang, Y. F. et al. Effect of uric-acid-lowering therapy on progression of chronic kidney disease: a meta-analysis. J. Huazhong Univ. Sci. Technol. Med. Sci. 34, 476–481 (2014).

  39. 39.

    Kanji, T., Gandhi, M., Clase, C. M. & 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).

  40. 40.

    Kanbay, M. et al. Serum uric acid and risk for acute kidney injury following contrast. Angiology 68, 132–144 (2017).

  41. 41.

    Liu, X. et al. Effects of uric acid-lowering therapy on the progression of chronic kidney disease: a systematic review and meta-analysis. Ren. Fail. 40, 289–297 (2018).

  42. 42.

    Li, X. 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 357, j2376 (2017).

  43. 43.

    Tiku, A., Badve, S. V. & Johnson, D. W. Urate-lowering therapy for preventing kidney disease progression: are we there yet? Am. J. Kidney Dis. 72, 776–778 (2018).

  44. 44.

    Feig, D. I., Madero, M., Jalal, D. I., Sanchez-Lozada, L. G. & Johnson, R. J. Uric acid and the origins of hypertension. J. Pediatr. 162, 896–902 (2013).

  45. 45.

    Xu, C. et al. Activation of renal (pro)renin receptor contributes to high fructose-induced salt sensitivity. Hypertension 69, 339–348 (2017).

  46. 46.

    Yu, M. A., Sanchez-Lozada, L. G., Johnson, R. J. & Kang, D. H. Oxidative stress with an activation of the renin-angiotensin system in human vascular endothelial cells as a novel mechanism of uric acid-induced endothelial dysfunction. J. Hypertens. 28, 1234–1242 (2010).

  47. 47.

    Eraranta, A. et al. Oxonic acid-induced hyperuricemia elevates plasma aldosterone in experimental renal insufficiency. J. Hypertens. 26, 1661–1668 (2008).

  48. 48.

    Feig, D. I., Soletsky, B. & Johnson, R. J. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial. JAMA 300, 924–932 (2008).

  49. 49.

    Tani, S., Nagao, K. & Hirayama, A. Effect of febuxostat, a xanthine oxidase inhibitor, on cardiovascular risk in hyperuricemic patients with hypertension: a prospective, open-label, pilot study. Clin. Drug Investig. 35, 823–831 (2015).

  50. 50.

    Talaat, K. M. & El-Sheikh, A. R. The effect of mild hyperuricemia on urinary transforming growth factor beta and the progression of chronic kidney disease. Am. J. Nephrol. 27, 435–440 (2007).

  51. 51.

    Roncal, C. A. et al. Combination of captopril and allopurinol retards fructose-induced metabolic syndrome. Am. J. Nephrol. 30, 399–404 (2009).

  52. 52.

    Johnson, R. J. et al. Sugar, uric acid, and the etiology of diabetes and obesity. Diabetes 62, 3307–3315 (2013).

  53. 53.

    Neogi, T. Gout. Ann. Intern. Med. 165, ITC1–ITC16 (2016).

  54. 54.

    Sanchez-Lozada, L. G. et al. Uric acid-induced endothelial dysfunction is associated with mitochondrial alterations and decreased intracellular ATP concentrations. Nephron Exp. Nephrol. 121, e71–e78 (2012).

  55. 55.

    Sautin, Y. Y., Nakagawa, T., Zharikov, S. & Johnson, R. J. Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress. Am. J. Physiol. Cell Physiol. 293, C584–C596 (2007).

  56. 56.

    Lanaspa, M. A. et al. Uric acid induces hepatic steatosis by generation of mitochondrial oxidative stress: potential role in fructose-dependent and -independent fatty liver. J. Biol. Chem. 287, 40732–40744 (2012).

  57. 57.

    Ames, B. N., Cathcart, R., Schwiers, E. & Hochstein, P. Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc. Natl Acad. Sci. USA 78, 6858–6862 (1981).

  58. 58.

    Crisan, T. O. et al. Soluble uric acid primes TLR-induced proinflammatory cytokine production by human primary cells via inhibition of IL-1Ra. Ann. Rheum. Dis. 75, 755–762 (2016).

  59. 59.

    Kim, K. M. et al. A sensitive and specific liquid chromatography-tandem mass spectrometry method for the determination of intracellular and extracellular uric acid. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 877, 2032–2038 (2009).

  60. 60.

    Hu, Q. H., Zhang, X., Pan, Y., Li, Y. C. & Kong, L. D. Allopurinol, quercetin and rutin ameliorate renal NLRP3 inflammasome activation and lipid accumulation in fructose-fed rats. Biochem. Pharmacol. 84, 113–125 (2012).

  61. 61.

    Sanchez-Lozada, L. G. et al. Role of oxidative stress in the renal abnormalities induced by experimental hyperuricemia. Am. J. Physiol. Renal Physiol. 295, F1134–F1141 (2008).

  62. 62.

    Clifford, A. J., Riumallo, J. A., Youn, V. R. & Scrimshaw, N. S. Effect of oral purines on serum and urinary uric acid of normal, hyperuricemic and gouty humans. J. Nutr. 106, 428–450 (1976).

  63. 63.

    Lin, P. Y. et al. Rasburicase improves hyperuricemia in patients with acute kidney injury secondary to rhabdomyolysis caused by ecstasy intoxication and exertional heat stroke. Pediatr. Crit. Care Med. 12, e424–427 (2011).

  64. 64.

    Chino, Y. et al. SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria. Biopharm. Drug Dispos. 35, 391–404 (2014).

  65. 65.

    Lytvyn, Y. et al. Glycosuria-mediated urinary uric acid excretion in patients with uncomplicated type 1 diabetes mellitus. Am. J. Physiol. Renal Physiol. 308, F77–F83 (2015).

  66. 66.

    Shi, Y., Evans, J. E. & Rock, K. L. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425, 516–521 (2003).

  67. 67.

    Gasse, P. et al. Uric acid is a danger signal activating NALP3 inflammasome in lung injury inflammation and fibrosis. Am. J. Respir. Crit. Care Med. 179, 903–913 (2009).

  68. 68.

    Martinon, F., Petrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006).

  69. 69.

    Xiao, J. et al. Soluble uric acid increases NALP3 inflammasome and interleukin-1beta expression in human primary renal proximal tubule epithelial cells through the Toll-like receptor 4-mediated pathway. Int. J. Mol. Med. 35, 1347–1354 (2015).

  70. 70.

    Zhou, Y. et al. Uric acid induces renal inflammation via activating tubular NF-kappaB signaling pathway. PLOS ONE 7, e39738 (2012).

  71. 71.

    Verzola, D. et al. Uric acid promotes apoptosis in human proximal tubule cells by oxidative stress and the activation of NADPH oxidase NOX 4. PLOS ONE 9, e115210 (2014).

  72. 72.

    Horita, Y. et al. Cause of residual hypertension after adrenalectomy in patients with primary aldosteronism. Am. J. Kidney Dis. 37, 884–889 (2001).

  73. 73.

    Wilson, C. & Byrom, F. The vicious circle in chronic Bright’s disease experimental evidence. QJM 10, 65–96 (1940).

  74. 74.

    Rodriguez-Iturbe, B., Pons, H. & Johnson, R. J. Role of the immune system in hypertension. Physiol. Rev. 97, 1127–1164 (2017).

  75. 75.

    Watanabe, S. et al. Uric acid, hominoid evolution, and the pathogenesis of salt-sensitivity. Hypertension 40, 355–360 (2002).

  76. 76.

    Gunawardhana, L. et al. Effect of febuxostat on ambulatory blood pressure in subjects with hyperuricemia and hypertension: a phase 2 randomized placebo-controlled study. J. Am. Heart Assoc. 6, e006683 (2017).

  77. 77.

    Goicoechea, M. et al. Allopurinol and progression of CKD and cardiovascular events: long-term follow-up of a randomized clinical trial. Am. J. Kidney Dis. 65, 543–549 (2015).

  78. 78.

    Zhou, D., Zhao, Y., Xiao, X., Lu, Z. & Liu, Y. Treatment of hyperuricemia in chronic kidney disease patients and its effect. Mod. Med. J. China 7, 36–39 (2009).

  79. 79.

    Malaguarnera, M. et al. A single dose of rasburicase in elderly patients with hyperuricaemia reduces serum uric acid levels and improves renal function. Expert Opin. Pharmacother. 10, 737–742 (2009).

  80. 80.

    Tan, Y., Fu, J., Liang, M., Lin, Z. & Huang, J. Clinical observation of the effect of allopurinol to protect renal function in patients with diabetic nephropathy. Mod. Hosp. 11, 36–38 (2011).

  81. 81.

    Sarris, E., Bagiatudi, G., Stavrianaki, D., Salpigidis, K. & Siakotos, M. Use of allopurinol in slowing the progression of chronic renal disease [abstract FP128]. Nephrol. Dial. Transplant. 22 (Suppl. 6), vi61 (2007).

  82. 82.

    Liu, J. & Sheng, D. Allopurinol in lowering serum uric acid level for the delay of the progression of chronic renal disease. China Pharm. 18, 2524–2525 (2007).

  83. 83.

    Shen, H. & Liu, D. Clinical research on allopurinol in lowering serum uric acid level for the delay of the progression of chronic renal disease. China Foreign Med. Treat. 12, 88–89 (2010).

  84. 84.

    Lei, J. & Li, S. Clinical research on allopurinol lowering of uric acid level of chronic renal disease for the delay of the progression of renal disease. Shanxi Med. J. 38, 1191–1192 (2009).

  85. 85.

    Deng, Y., Zhang, P., Liu, H. & Jia, Q. Observation on allopurinol in lowering blood uric acid for slowing the progression of chronic renal failure. J. Pract. Med. 26, 982–984 (2010).

  86. 86.

    Tuta, L., Sburlan, A. & Vonea, F. Early allopurinol therapy slows progression of renal disease in predialysis patients with hyperuricemia [abstract MP261]. Nephrol. Dial. Transplant. 21 (Suppl. 4), iv386 (2006).

  87. 87.

    Sircar, D. et al. 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. 66, 945–950 (2015).

  88. 88.

    Kimura, K. et al. Febuxostat therapy for patients with stage 3 CKD and asymptomatic hyperuricemia: a randomized trial. Am. J. Kidney Dis. 72, 798–810 (2018).

  89. 89.

    Hosoya, T. et al. 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. 18, 876–884 (2014).

  90. 90.

    Tuta, L. & Stanigut, A. Allopurinol therapy for hyperuricemia reduces inflammation and progression of renal disease in moderate chronic kidney disease [abstract SP148]. Nephrol. Dial. Transplant. 29 (Suppl. 3), iii118 (2014).

  91. 91.

    Saag, K. G. et al. Impact of febuxostat on renal function in gout patients with moderate-to-severe renal impairment. Arthritis Rheumatol. 68, 2035–2043 (2016).

  92. 92.

    Kao, M. P. et al. Allopurinol benefits left ventricular mass and endothelial dysfunction in chronic kidney disease. J. Am. Soc. Nephrol. 22, 1382–1389 (2011).

  93. 93.

    Beddhu, S. et al. A randomized controlled trial of the effects of febuxostat therapy on adipokines and markers of kidney fibrosis in asymptomatic hyperuricemic patients with diabetic nephropathy. Can. J. Kidney Health Dis. 3, 2054358116675343 (2016).

  94. 94.

    Shi, Y. et al. Clinical outcome of hyperuricemia in IgA nephropathy: a retrospective cohort study and randomized controlled trial. Kidney Blood Press Res. 35, 153–160 (2012).

  95. 95.

    Tanaka, K. et al. Renoprotective effects of febuxostat in hyperuricemic patients with chronic kidney disease: a parallel-group, randomized, controlled trial. Clin. Exp. Nephrol. 19, 1044–1053 (2015).

  96. 96.

    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. 4, 128–132 (2010).

  97. 97.

    Johnson, R. J. & Rodriguez-Iturbe, B. Rethinking progression of CKD as a process of punctuated equilibrium. Nat. Rev. Nephrol. 14, 411–412 (2018).

  98. 98.

    Craig, J. C. Interpreting trial results-time for confidence and magnitude and not P values please. Kidney Int. 95, 28–30 (2019).

  99. 99.

    Brymora, A. et al. Low-fructose diet lowers blood pressure and inflammation in patients with chronic kidney disease. Nephrol. Dial. Transplant. 27, 608–612 (2012).

  100. 100.

    Fam, A. G. Gout, diet, and the insulin resistance syndrome. J. Rheumatol. 29, 1350–1355 (2002).

  101. 101.

    Anderson, B. E. & Adams, D. R. Allopurinol hypersensitivity syndrome. J. Drugs Dermatol. 1, 60–62 (2002).

  102. 102.

    Jung, J. W. et al. HLA-B58 can help the clinical decision on starting allopurinol in patients with chronic renal insufficiency. Nephrol. Dial. Transplant. 26, 3567–3572 (2011).

  103. 103.

    Jutkowitz, E., Dubreuil, M., Lu, N., Kuntz, K. M. & Choi, H. K. The cost-effectiveness of HLA-B*5801 screening to guide initial urate-lowering therapy for gout in the United States. Semin. Arthritis Rheum. 46, 594–600 (2017).

  104. 104.

    Vargas-Santos, A. B., Peloquin, C. E., Zhang, Y. & Neogi, T. Association of chronic kidney disease with allopurinol use in gout treatment. JAMA Intern. Med. 178, 1526–1533 (2018).

  105. 105.

    Singh, J. A., Ramachandaran, R., Yu, S. & Curtis, J. R. Allopurinol use and the risk of acute cardiovascular events in patients with gout and diabetes. BMC Cardiovasc. Disord. 17, 76 (2017).

  106. 106.

    White, W. B. et al. Cardiovascular safety of febuxostat or allopurinol in patients with gout. N. Engl. J. Med. 378, 1200–1210 (2018).

  107. 107.

    Zhang, M. et al. Assessment of cardiovascular risk in older patients with gout initiating febuxostat versus allopurinol. Circulation 138, 1116–1126 (2018).

  108. 108.

    Neogi, T. et al. 2015 Gout Classification Criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheumatol. 67, 2557–2568 (2015).

  109. 109.

    Levy, G. D., Rashid, N., Niu, F. & Cheetham, T. C. Effect of urate-lowering therapies on renal disease progression in patients with hyperuricemia. J. Rheumatol. 41, 955–962 (2014).

  110. 110.

    Afkarian, M. et al. PERL in Diabetes Study: a randomized double-blinded trial of allopurinol — rationale, design, and baseline data. Diabetes Care https://doi.org/10.2337/dc19-0342 (2019).

  111. 111.

    Yang, Q. et al. Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors. Circ. Cardiovasc. Genet. 3, 523–530 (2010).

  112. 112.

    Soletsky, B. & Feig, D. I. Uric acid reduction rectifies prehypertension in obese adolescents. Hypertension 60, 1148–1156 (2012).

  113. 113.

    Johnson, R. J., Choi, H. K., Yeo, A. E. & Lipsky, P. E. Pegloticase treatment significantly decreases blood pressure in patients with chronic gout. Hypertension 74, 95–101 (2019).

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Acknowledgements

Y.S. was a JSPS Overseas Research Fellow in the laboratories of R.J.J and M.A.L. D.-H.K. was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (MSIP) (NRF-2015R1A2A1A15053374, NRF-2017R1A2B2005849).

Author information

Y.S., D.I.F., A.G.S., D.-H.K., L.G.S.-L. and R.J.J. researched data for the article, contributed substantially to discussion of the article’s content and wrote the article. All authors contributed to review/editing of the manuscript before submission.

Correspondence to Richard J. Johnson.

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Competing interests

A.G.S. has had an unrestricted educational grant from the Menarini International Operations Luxemburg and has consulted for Menarini and Grunenthal Pharma. L.G.S.-L has received funding from Relburn Metabolomic and Danone Research Foundation. R.J.J. has equity with XORT Therapeutics, which is developing novel xanthine oxidase inhibitors and is an inventor involved in several patents on the role of uric acid in hypertension, metabolic syndrome and diabetic nephropathy that have resulted from his research (US Patent No. 7,799,794; US Patent No. 8,236,488; US Patent No. 8,557,831; US Patent No. 9,155,740B). He has also consulted for Danone Research Foundation, for Horizon Pharmaceuticals and for AstraZeneca. The other authors declare no competing interests.

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Nature Reviews Nephrology thanks G. Walters and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Sato, Y., Feig, D.I., Stack, A.G. et al. The case for uric acid-lowering treatment in patients with hyperuricaemia and CKD. Nat Rev Nephrol 15, 767–775 (2019) doi:10.1038/s41581-019-0174-z

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