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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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).

    CAS  Google Scholar 

  2. 2.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

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

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  29. 29.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  40. 40.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  47. 47.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

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

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

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

    Google Scholar 

  74. 74.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Google Scholar 

  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).

    Google Scholar 

  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).

    Google Scholar 

  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).

    Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  98. 98.

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

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

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

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

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

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    Article  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

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

Affiliations

Authors

Contributions

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.

Corresponding author

Correspondence to Richard J. Johnson.

Ethics declarations

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.

Additional information

Peer review information

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

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

CKD-Fix trial: https://aktn.org.au/ckd-fix PERL study: http://www.perl-study.org/

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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). https://doi.org/10.1038/s41581-019-0174-z

Download citation

Further reading

Search

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing