Does Altered Uric Acid Metabolism Contribute to Diabetic Kidney Disease Pathophysiology?

  • Ambreen Gul
  • Philip Zager
Microvascular Complications—Nephropathy (M Afkarian and B Roshanravan, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Microvascular Complications—Nephropathy


Purpose of Review

Multiple experimental and clinical studies have identified pathways by which uric acid may facilitate the development and progression of chronic kidney disease (CKD) in people with diabetes. However, it remains uncertain if the association of uric acid with CKD represents a pathogenic effect or merely reflects renal impairment.

Recent Findings

In contrast to many published reports, a recent Mendelian randomization study did not identify a causal link between uric acid and CKD in people with type 1 diabetes. Two recent multicenter randomized control trials, Preventing Early Renal Function Loss in Diabetes (PERL) and FEbuxostat versus placebo rAndomized controlled Trial regarding reduced renal function in patients with Hyperuricemia complicated by chRonic kidney disease stage 3 (FEATHER), were recently designed to assess if uric acid lowering slows progression of CKD.


We review the evidence supporting a role for uric acid in the pathogenesis of CKD in people with diabetes and the putative benefits of uric acid lowering.


Uric acid Hyperuricemia Diabetic nephropathy Kidney disease Type 1 diabetes Type 2 diabetes 



We would like to thank Ms. Leslie Firkins and Ms. Serena Cumber for their help in preparation of this manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Dialysis Clinic, Inc.

Compliance with Ethical Standards

Conflict of Interest

Ambreen Gul is an employee of Dialysis Clinic, Inc.

Philip Zager is an employee of the University of New Mexico and Dialysis Clinic, Inc.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    De CS, Viazzi F, Pacilli A, Giorda C, Ceriello A, Gentile S, et al. Serum uric acid and risk of CKD in type 2 diabetes. Clin J Am Soc Nephrol. 2015;10:1921–9.CrossRefGoogle Scholar
  2. 2.
    Hovind P, Rossing P, Tarnow L, Johnson RJ, Parving HH. Serum uric acid as a predictor for development of diabetic nephropathy in type 1 diabetes: an inception cohort study. Diabetes. 2009;58:1668–71.CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    Jalal DI, Rivard CJ, Johnson RJ, Maahs DM, McFann K, Rewers M, et al. Serum uric acid levels predict the development of albuminuria over 6 years in patients with type 1 diabetes: findings from the Coronary Artery Calcification in Type 1 Diabetes study. Nephrol Dial Transplant. 2010;25:1865–9.CrossRefPubMedCentralPubMedGoogle Scholar
  4. 4.
    Xu Y, Zhu J, Gao L, Liu Y, Shen J, Shen C, et al. Hyperuricemia as an independent predictor of vascular complications and mortality in type 2 diabetes patients: a meta-analysis. PLoS One. 2013;8:e78206.CrossRefPubMedCentralPubMedGoogle Scholar
  5. 5.
    Zoppini G, Targher G, Chonchol M, Ortalda V, Abaterusso C, Pichiri I, et al. Serum uric acid levels and incident chronic kidney disease in patients with type 2 diabetes and preserved kidney function. Diabetes Care. 2012;35:99–104.CrossRefPubMedGoogle Scholar
  6. 6.
    • Maiuolo J, Oppedisano F, Gratteri S, Muscoli C, Mollace V. Regulation of uric acid metabolism and excretion. Int J Cardiol. 2016;213:8–14. Reviews the several enzymatic pathways for uric acid production. CrossRefPubMedGoogle Scholar
  7. 7.
    Mende C. Management of chronic kidney disease: the relationship between serum uric acid and development of nephropathy. Adv Ther. 2015;32:1177–91.CrossRefPubMedCentralPubMedGoogle Scholar
  8. 8.
    Johnson RJ, Nakagawa T, Sanchez-Lozada LG, Shafiu M, Sundaram S, Le M, et al. Sugar, uric acid, and the etiology of diabetes and obesity. Diabetes. 2013;62:3307–15.CrossRefPubMedCentralPubMedGoogle Scholar
  9. 9.
    Lytvyn Y, Perkins BA, Cherney DZ. Uric acid as a biomarker and a therapeutic target in diabetes. Can J Diabetes. 2015;39:239–46.CrossRefPubMedGoogle Scholar
  10. 10.
    Choi JW, Ford ES, Gao X, Choi HK. Sugar-sweetened soft drinks, diet soft drinks, and serum uric acid level: the Third National Health and Nutrition Examination Survey. Arthritis Rheum. 2008;59:109–16.CrossRefPubMedGoogle Scholar
  11. 11.
    Cox CL, Stanhope KL, Schwarz JM, Graham JL, Hatcher B, Griffen SC, et al. Consumption of fructose- but not glucose-sweetened beverages for 10 weeks increases circulating concentrations of uric acid, retinol binding protein-4, and gamma-glutamyl transferase activity in overweight/obese humans. Nutr Metab (Lond). 2012;9:68.CrossRefGoogle Scholar
  12. 12.
    Stirpe F, Della CE, Bonetti E, Abbondanza A, Abbati A, De SF. Fructose-induced hyperuricaemia. Lancet. 1970;2:1310–1.CrossRefPubMedGoogle Scholar
  13. 13.
    • Bjornstad P, Lanaspa MA, Ishimoto T, Kosugi T, Kume S, Jalal D, et al. Fructose and uric acid in diabetic nephropathy. Diabetologia. 2015;58:1993–2002. Discusses the relationship between uric acid and fructose in the development of diabetic nephropathy. CrossRefPubMedCentralPubMedGoogle Scholar
  14. 14.
    Kang DH, Chen W. Uric acid and chronic kidney disease: new understanding of an old problem. Semin Nephrol. 2011;31:447–52.CrossRefPubMedGoogle Scholar
  15. 15.
    Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med. 2008;359:1811–21.CrossRefPubMedCentralPubMedGoogle Scholar
  16. 16.
    Kanbay M, Segal M, Afsar B, Kang DH, Rodriguez-Iturbe B, Johnson RJ. The role of uric acid in the pathogenesis of human cardiovascular disease. Heart. 2013;99:759–66.CrossRefPubMedGoogle Scholar
  17. 17.
    Liu WC, Hung CC, Chen SC, Yeh SM, Lin MY, Chiu YW, et al. Association of hyperuricemia with renal outcomes, cardiovascular disease, and mortality. Clin J Am Soc Nephrol. 2012;7:541–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Kuwabara M. Hyperuricemia, cardiovascular disease, and hypertension. Pulse (Basel). 2016;3:242–52.CrossRefGoogle Scholar
  19. 19.
    Tangri N, Weiner DE. Uric acid, CKD, and cardiovascular disease: confounders, culprits, and circles. Am J Kidney Dis. 2010;56:247–50.CrossRefPubMedCentralPubMedGoogle Scholar
  20. 20.
    Masuo K, Kawaguchi H, Mikami H, Ogihara T, Tuck ML. Serum uric acid and plasma norepinephrine concentrations predict subsequent weight gain and blood pressure elevation. Hypertension. 2003;42:474–80.CrossRefPubMedGoogle Scholar
  21. 21.
    Mazzali M, Kanbay M, Segal MS, Shafiu M, Jalal D, Feig DI, et al. Uric acid and hypertension: cause or effect? Curr Rheumatol Rep. 2010;12:108–17.CrossRefPubMedGoogle Scholar
  22. 22.
    Mellen PB, Bleyer AJ, Erlinger TP, Evans GW, Nieto FJ, Wagenknecht LE, et al. Serum uric acid predicts incident hypertension in a biethnic cohort: the atherosclerosis risk in communities study. Hypertension. 2006;48:1037–42.CrossRefPubMedGoogle Scholar
  23. 23.
    Dehghan A, van HM, Sijbrands EJ, Hofman A, Witteman JC. High serum uric acid as a novel risk factor for type 2 diabetes. Diabetes Care. 2008;31:361–2.CrossRefPubMedGoogle Scholar
  24. 24.
    Li C, Hsieh MC, Chang SJ. Metabolic syndrome, diabetes, and hyperuricemia. Curr Opin Rheumatol. 2013;25:210–6.CrossRefPubMedGoogle Scholar
  25. 25.
    Shani M, Vinker S, Dinour D, Leiba M, Twig G, Holtzman EJ, et al. High normal uric acid levels are associated with an increased risk of diabetes in lean, normoglycemic healthy women. J Clin Endocrinol Metab. 2016;101:3772–8.CrossRefPubMedGoogle Scholar
  26. 26.
    Krishnan E, Pandya BJ, Chung L, Hariri A, Dabbous O. Hyperuricemia in young adults and risk of insulin resistance, prediabetes, and diabetes: a 15-year follow-up study. Am J Epidemiol. 2012;176:108–16.CrossRefPubMedGoogle Scholar
  27. 27.
    Lai HM, Chen CJ, Su BY, Chen YC, Yu SF, Yen JH, et al. Gout and type 2 diabetes have a mutual inter-dependent effect on genetic risk factors and higher incidences. Rheumatology (Oxford). 2012;51:715–20.CrossRefGoogle Scholar
  28. 28.
    Sui X, Church TS, Meriwether RA, Lobelo F, Blair SN. Uric acid and the development of metabolic syndrome in women and men. Metabolism. 2008;57:845–52.CrossRefPubMedCentralPubMedGoogle Scholar
  29. 29.
    Yu TY, Jee JH, Bae JC, Jin SM, Baek JH, Lee MK, et al. Serum uric acid: a strong and independent predictor of metabolic syndrome after adjusting for body composition. Metabolism. 2016;65:432–40.CrossRefPubMedGoogle Scholar
  30. 30.
    Hsu CY, Iribarren C, McCulloch CE, Darbinian J, Go AS. Risk factors for end-stage renal disease: 25-year follow-up. Arch Intern Med. 2009;169:342–50.CrossRefPubMedCentralPubMedGoogle Scholar
  31. 31.
    Kang DH, Nakagawa T, Feng L, Watanabe S, Han L, Mazzali M, et al. A role for uric acid in the progression of renal disease. J Am Soc Nephrol. 2002;13:2888–97.CrossRefPubMedGoogle Scholar
  32. 32.
    Verzola D, Ratto E, Villaggio B, Parodi EL, Pontremoli R, Garibotto G, et al. Uric acid promotes apoptosis in human proximal tubule cells by oxidative stress and the activation of NADPH oxidase NOX 4. PLoS One. 2014;9:e115210.CrossRefPubMedCentralPubMedGoogle Scholar
  33. 33.
    Diwan V, Mistry A, Gobe G, Brown L. Adenine-induced chronic kidney and cardiovascular damage in rats. J Pharmacol Toxicol Methods. 2013;68:197–207.CrossRefPubMedGoogle Scholar
  34. 34.
    Kim SM, Choi YW, Seok HY, Jeong KH, Lee SH, Lee TW, et al. Reducing serum uric acid attenuates TGF-beta1-induced profibrogenic progression in type 2 diabetic nephropathy. Nephron Exp Nephrol. 2012;121:e109–21.CrossRefPubMedGoogle Scholar
  35. 35.
    Khosla UM, Zharikov S, Finch JL, Nakagawa T, Roncal C, Mu W, et al. Hyperuricemia induces endothelial dysfunction. Kidney Int. 2005;67:1739–42.CrossRefPubMedGoogle Scholar
  36. 36.
    Puddu P, Puddu GM, Cravero E, Vizioli L, Muscari A. Relationships among hyperuricemia, endothelial dysfunction and cardiovascular disease: molecular mechanisms and clinical implications. J Cardiol. 2012;59:235–42.CrossRefPubMedGoogle Scholar
  37. 37.
    Mazzali M, Kanellis J, Han L, Feng L, Xia YY, Chen Q, et al. Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism. Am J Physiol Ren Physiol. 2002;282:F991–7.CrossRefGoogle Scholar
  38. 38.
    Jalal DI, Maahs DM, Hovind P, Nakagawa T. Uric acid as a mediator of diabetic nephropathy. Semin Nephrol. 2011;31:459–65.CrossRefPubMedCentralPubMedGoogle Scholar
  39. 39.
    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. 2015;16:58.CrossRefPubMedCentralPubMedGoogle Scholar
  40. 40.
    Kim SM, Lee SH, Kim YG, Kim SY, Seo JW, Choi YW, et al. Hyperuricemia-induced NLRP3 activation of macrophages contributes to the progression of diabetic nephropathy. Am J Physiol Ren Physiol. 2015;308:F993–F1003.CrossRefGoogle Scholar
  41. 41.
    Ryu ES, Kim MJ, Shin HS, Jang YH, Choi HS, Jo I, et al. Uric acid-induced phenotypic transition of renal tubular cells as a novel mechanism of chronic kidney disease. Am J Physiol Ren Physiol. 2013;304:F471–80.CrossRefGoogle Scholar
  42. 42.
    Yang J, Liu Y. Blockage of tubular epithelial to myofibroblast transition by hepatocyte growth factor prevents renal interstitial fibrosis. J Am Soc Nephrol. 2002;13:96–107.PubMedGoogle Scholar
  43. 43.
    Kosugi T, Nakayama T, Heinig M, Zhang L, Yuzawa Y, Sanchez-Lozada LG, et al. Effect of lowering uric acid on renal disease in the type 2 diabetic db/db mice. Am J Physiol Ren Physiol. 2009;297:F481–8.CrossRefGoogle Scholar
  44. 44.
    Lanaspa MA, Ishimoto T, Cicerchi C, Tamura Y, Roncal-Jimenez CA, Chen W, et al. Endogenous fructose production and fructokinase activation mediate renal injury in diabetic nephropathy. J Am Soc Nephrol. 2014;25:2526–38.CrossRefPubMedCentralPubMedGoogle Scholar
  45. 45.
    Sanchez-Lozada LG, Tapia E, Soto V, Avila-Casado C, Franco M, Wessale JL, et al. Effect of febuxostat on the progression of renal disease in 5/6 nephrectomy rats with and without hyperuricemia. Nephron Physiol. 2008;108:69–78.CrossRefGoogle Scholar
  46. 46.
    Weiner DE, Tighiouart H, Elsayed EF, Griffith JL, Salem DN, Levey AS. Uric acid and incident kidney disease in the community. J Am Soc Nephrol. 2008;19:1204–11.CrossRefPubMedCentralPubMedGoogle Scholar
  47. 47.
    Ohno M, Deguchi F, Izumi K, Ishigaki H, Sarui H, Sasaki A, et al. Correlation between renal function and common risk factors for chronic kidney disease in a healthy middle-aged population: a prospective observational 2-year study. PLoS One. 2014;9:e113263.CrossRefPubMedCentralPubMedGoogle Scholar
  48. 48.
    Bellomo G, Venanzi S, Verdura C, Saronio P, Esposito A, Timio M. Association of uric acid with change in kidney function in healthy normotensive individuals. Am J Kidney Dis. 2010;56:264–72.CrossRefPubMedGoogle Scholar
  49. 49.
    Iseki K, Oshiro S, Tozawa M, Iseki C, Ikemiya Y, Takishita S. Significance of hyperuricemia on the early detection of renal failure in a cohort of screened subjects. Hypertens Res. 2001;24:691–7.CrossRefPubMedGoogle Scholar
  50. 50.
    Iseki K, Ikemiya Y, Inoue T, Iseki C, Kinjo K, Takishita S. Significance of hyperuricemia as a risk factor for developing ESRD in a screened cohort. Am J Kidney Dis. 2004;44:642–50.CrossRefPubMedGoogle Scholar
  51. 51.
    Langford HG, Blaufox MD, Borhani NO, Curb JD, Molteni A, Schneider KA, et al. Is thiazide-produced uric acid elevation harmful? Analysis of data from the hypertension detection and follow-up program. Arch Intern Med. 1987;147:645–9.CrossRefPubMedGoogle Scholar
  52. 52.
    Madero M, Sarnak MJ, Wang X, Greene T, Beck GJ, Kusek JW, et al. Uric acid and long-term outcomes in CKD. Am J Kidney Dis. 2009;53:796–803.CrossRefPubMedCentralPubMedGoogle Scholar
  53. 53.
    Obermayr RP, Temml C, Gutjahr G, Knechtelsdorfer M, Oberbauer R, Klauser-Braun R. Elevated uric acid increases the risk for kidney disease. J Am Soc Nephrol. 2008;19:2407–13.CrossRefPubMedCentralPubMedGoogle Scholar
  54. 54.
    Sonoda H, Takase H, Dohi Y, Kimura G. Uric acid levels predict future development of chronic kidney disease. Am J Nephrol. 2011;33:352–7.CrossRefPubMedGoogle Scholar
  55. 55.
    Sturm G, Kollerits B, Neyer U, Ritz E, Kronenberg F. Uric acid as a risk factor for progression of non-diabetic chronic kidney disease? The Mild to Moderate Kidney Disease (MMKD) Study. Exp Gerontol. 2008;43:347–52.CrossRefPubMedGoogle Scholar
  56. 56.
    Rosolowsky ET, Ficociello LH, Maselli NJ, Niewczas MA, Binns AL, Roshan B, et al. High-normal serum uric acid is associated with impaired glomerular filtration rate in nonproteinuric patients with type 1 diabetes. Clin J Am Soc Nephrol. 2008;3:706–13.CrossRefPubMedCentralPubMedGoogle Scholar
  57. 57.
    Ficociello LH, Rosolowsky ET, Niewczas MA, Maselli NJ, Weinberg JM, Aschengrau A, et al. High-normal serum uric acid increases risk of early progressive renal function loss in type 1 diabetes: results of a 6-year follow-up. Diabetes Care. 2010;33:1337–43.CrossRefPubMedCentralPubMedGoogle Scholar
  58. 58.
    •• Ahola AJ, Sandholm N, Forsblom C, Harjutsalo V, Dahlstrom E, Groop PH. The serum uric acid concentration is not causally linked to diabetic nephropathy in type 1 diabetes. Kidney Int. 2017;91:1178–85. Mendelian randomization study that concluded that there was no causal link between serum uric acid and progression of kidney disease in type 1 diabetes. CrossRefPubMedGoogle Scholar
  59. 59.
    Gul A, Harford A, Zager P. Mendelian randomization to establish the causality of uric acid with diabetic nephropathy in type 1 diabetics. Kidney Int. 2017;91:1005–7.CrossRefPubMedGoogle Scholar
  60. 60.
    Lyngdoh T, Vuistiner P, Marques-Vidal P, Rousson V, Waeber G, Vollenweider P, et al. Serum uric acid and adiposity: deciphering causality using a bidirectional Mendelian randomization approach. PLoS One. 2012;7:e39321.CrossRefPubMedCentralPubMedGoogle Scholar
  61. 61.
    Todd JN, Dahlstrom EH, Salem RM, Sandholm N, Forsblom C, McKnight AJ, et al. Genetic evidence for a causal role of obesity in diabetic kidney disease. Diabetes. 2015;64:4238–46.CrossRefPubMedCentralPubMedGoogle Scholar
  62. 62.
    Altemtam N, Russell J, El NM. A study of the natural history of diabetic kidney disease (DKD). Nephrol Dial Transplant. 2012;27:1847–54.CrossRefPubMedGoogle Scholar
  63. 63.
    Bartakova V, Kuricova K, Pacal L, Nova Z, Dvorakova V, Svrckova M, et al. Hyperuricemia contributes to the faster progression of diabetic kidney disease in type 2 diabetes mellitus. J Diabetes Complicat. 2016;30:1300–7.CrossRefPubMedGoogle Scholar
  64. 64.
    Kim WJ, Kim SS, Bae MJ, Yi YS, Jeon YK, Kim BH, et al. High-normal serum uric acid predicts the development of chronic kidney disease in patients with type 2 diabetes mellitus and preserved kidney function. J Diabetes Complicat. 2014;28:130–4.CrossRefPubMedGoogle Scholar
  65. 65.
    Chang YH, Lei CC, Lin KC, Chang DM, Hsieh CH, Lee YJ. Serum uric acid level as an indicator for CKD regression and progression in patients with type 2 diabetes mellitus—a 4.6-year cohort study. Diabetes Metab Res Rev. 2016;32:557–64.CrossRefPubMedGoogle Scholar
  66. 66.
    Tanaka K, Hara S, Hattori M, Sakai K, Onishi Y, Yoshida Y, et al. Role of elevated serum uric acid levels at the onset of overt nephropathy in the risk for renal function decline in patients with type 2 diabetes. J Diabetes Investig. 2015;6:98–104.CrossRefPubMedGoogle Scholar
  67. 67.
    Fukui M, Tanaka M, Shiraishi E, Harusato I, Hosoda H, Asano M, et al. Serum uric acid is associated with microalbuminuria and subclinical atherosclerosis in men with type 2 diabetes mellitus. Metabolism. 2008;57:625–9.CrossRefPubMedGoogle Scholar
  68. 68.
    Behradmanesh S, Horestani MK, Baradaran A, Nasri H. Association of serum uric acid with proteinuria in type 2 diabetic patients. J Res Med Sci. 2013;18:44–6.PubMedCentralPubMedGoogle Scholar
  69. 69.
    Takagi M, Babazono T, Uchigata Y. Differences in risk factors for the onset of albuminuria and decrease in glomerular filtration rate in people with type 2 diabetes mellitus: implications for the pathogenesis of diabetic kidney disease. Diabet Med. 2015;32:1354–60.CrossRefPubMedCentralPubMedGoogle Scholar
  70. 70.
    Anzai N, Endou H. Urate transporters: an evolving field. Semin Nephrol. 2011;31:400–9.CrossRefPubMedGoogle Scholar
  71. 71.
    Bobulescu IA, Moe OW. Renal transport of uric acid: evolving concepts and uncertainties. Adv Chronic Kidney Dis. 2012;19:358–71.CrossRefPubMedCentralPubMedGoogle Scholar
  72. 72.
    Reginato AM, Mount DB, Yang I, Choi HK. The genetics of hyperuricaemia and gout. Nat Rev Rheumatol. 2012;8:610–21.CrossRefPubMedCentralPubMedGoogle Scholar
  73. 73.
    Perez-Ruiz F, Aniel-Quiroga MA, Herrero-Beites AM, Chinchilla SP, Erauskin GG, Merriman T. Renal clearance of uric acid is linked to insulin resistance and lower excretion of sodium in gout patients. Rheumatol Int. 2015;35:1519–24.CrossRefPubMedGoogle Scholar
  74. 74.
    Chino Y, Samukawa Y, Sakai S, Nakai Y, Yamaguchi J, Nakanishi T, et al. SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria. Biopharm Drug Dispos. 2014;35:391–404.CrossRefPubMedCentralPubMedGoogle Scholar
  75. 75.
    Krishnan E, Kwoh CK, Schumacher HR, Kuller L. Hyperuricemia and incidence of hypertension among men without metabolic syndrome. Hypertension. 2007;49:298–303.CrossRefPubMedGoogle Scholar
  76. 76.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  77. 77.
    Kang DH, Park SK, Lee IK, Johnson RJ. Uric acid-induced C-reactive protein expression: implication on cell proliferation and nitric oxide production of human vascular cells. J Am Soc Nephrol. 2005;16:3553–62.CrossRefPubMedGoogle Scholar
  78. 78.
    Sanchez-Lozada LG, Tapia E, Lopez-Molina R, Nepomuceno T, Soto V, Avila-Casado C, et al. Effects of acute and chronic L-arginine treatment in experimental hyperuricemia. Am J Physiol Ren Physiol. 2007;292:F1238–44.CrossRefGoogle Scholar
  79. 79.
    Perlstein TS, Gumieniak O, Hopkins PN, Murphey LJ, Brown NJ, Williams GH, et al. Uric acid and the state of the intrarenal renin-angiotensin system in humans. Kidney Int. 2004;66:1465–70.CrossRefPubMedGoogle Scholar
  80. 80.
    McMullan CJ, Borgi L, Fisher N, Curhan G, Forman J. Effect of uric acid lowering on renin-angiotensin-system activation and ambulatory BP: a randomized controlled trial. Clin J Am Soc Nephrol. 2017;12:807–16.CrossRefPubMedGoogle Scholar
  81. 81.
    Bonventre JV, Weinberg JM. Recent advances in the pathophysiology of ischemic acute renal failure. J Am Soc Nephrol. 2003;14:2199–210.CrossRefPubMedGoogle Scholar
  82. 82.
    Friedewald JJ, Rabb H. Inflammatory cells in ischemic acute renal failure. Kidney Int. 2004;66:486–91.CrossRefPubMedGoogle Scholar
  83. 83.
    Krishnan E. Inflammation, oxidative stress and lipids: the risk triad for atherosclerosis in gout. Rheumatology (Oxford). 2010;49:1229–38.CrossRefGoogle Scholar
  84. 84.
    Kanbay M, Ozkara A, Selcoki Y, Isik B, Turgut F, Bavbek N, et al. Effect of treatment of hyperuricemia with allopurinol on blood pressure, creatinine clearence, and proteinuria in patients with normal renal functions. Int Urol Nephrol. 2007;39:1227–33.CrossRefPubMedGoogle Scholar
  85. 85.
    Siu YP, Leung KT, Tong MK, Kwan TH. Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level. Am J Kidney Dis. 2006;47:51–9.CrossRefPubMedGoogle Scholar
  86. 86.
    Talaat KM, el-Sheikh AR. The effect of mild hyperuricemia on urinary transforming growth factor beta and the progression of chronic kidney disease. Am J Nephrol. 2007;27:435–40.CrossRefPubMedGoogle Scholar
  87. 87.
    Levy GD, Rashid N, Niu F, Cheetham TC. Effect of urate-lowering therapies on renal disease progression in patients with hyperuricemia. J Rheumatol. 2014;41:955–62.CrossRefPubMedGoogle Scholar
  88. 88.
    Goicoechea M, de Vinuesa SG, Verdalles U, Ruiz-Caro C, Ampuero J, Rincon A, et al. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin J Am Soc Nephrol. 2010;5:1388–93.CrossRefPubMedCentralPubMedGoogle Scholar
  89. 89.
    •• Liu P, Chen Y, Wang B, Zhang F, Wang D, Wang Y. Allopurinol treatment improves renal function in patients with type 2 diabetes and asymptomatic hyperuricemia: 3-year randomized parallel-controlled study. Clin Endocrinol (Oxf). 2015;83:475–82. Randomized controlled trial in patients with type 2 diabetes which showed decrease in urinary albumin excretion rate and renal protective effects in the allopurinol group. CrossRefGoogle Scholar
  90. 90.
    Bose B, Badve SV, Hiremath SS, Boudville N, Brown FG, Cass A, et al. Effects of uric acid-lowering therapy on renal outcomes: a systematic review and meta-analysis. Nephrol Dial Transplant. 2014;29:406–13.CrossRefPubMedGoogle Scholar
  91. 91.
    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;4:128–32.PubMedGoogle Scholar
  92. 92.
    Online Source: National Institutes of Health, United States. A multicenter clinical trial of allopurinol to prevent kidney function loss in type 1 diabetics. Identifier NTC02017171; last updated 03/07/2017. Accessed 4 Dec 2017.
  93. 93.
    Maahs DM, Caramori L, Cherney DZ, Galecki AT, Gao C, Jalal D, et al. Uric acid lowering to prevent kidney function loss in diabetes: the preventing early renal function loss (PERL) allopurinol study. Curr Diab Rep. 2013;13:550–9.CrossRefPubMedCentralPubMedGoogle Scholar
  94. 94.
    Molitch ME, Steffes M, Sun W, Rutledge B, Cleary P, de Boer IH, et al. Development and progression of renal insufficiency with and without albuminuria in adults with type 1 diabetes in the diabetes control and complications trial and the epidemiology of diabetes interventions and complications study. Diabetes Care. 2010;33:1536–43.CrossRefPubMedCentralPubMedGoogle Scholar
  95. 95.
    Perkins BA, Ficociello LH, Ostrander BE, Silva KH, Weinberg J, Warram JH, et al. Microalbuminuria and the risk for early progressive renal function decline in type 1 diabetes. J Am Soc Nephrol. 2007;18:1353–61.CrossRefPubMedGoogle Scholar
  96. 96.
    Caramori ML, Fioretto P, Mauer M. The need for early predictors of diabetic nephropathy risk: is albumin excretion rate sufficient? Diabetes. 2000;49:1399–408.CrossRefPubMedGoogle Scholar
  97. 97.
    Paisansinsup T, Breitenstein MK, Schousboe JT. Association between adverse reactions to allopurinol and exposures to high maintenance doses: implications for management of patients using allopurinol. J Clin Rheumatol. 2013;19:180–6.CrossRefPubMedGoogle Scholar
  98. 98.
    Online Source: UMIN Clinical Trials Registry, Japan. FEbuxostat versus placebo rAndomized controlled Trial (FEATHER study). Unique trial number UMIN000008343; last updated 12/17/2015. Accessed 14 Sept2017.
  99. 99.
    Hosoya T, Kimura K, Itoh S, Inaba M, Uchida S, Tomino Y, et al. The effect of febuxostat to prevent a further reduction in renal function of patients with hyperuricemia who have never had gout and are complicated by chronic kidney disease stage 3: study protocol for a multicenter randomized controlled study. Trials. 2014;15:26.CrossRefPubMedCentralPubMedGoogle Scholar
  100. 100.
    Ye P, Yang S, Zhang W, Lv Q, Cheng Q, Mei M, et al. Efficacy and tolerability of febuxostat in hyperuricemic patients with or without gout: a systematic review and meta-analysis. Clin Ther. 2013;35:180–9.CrossRefPubMedGoogle Scholar
  101. 101.••
    Online Source: Department of Health and Human Services, United States. FDA to evaluate increased risk of heart-related death and death from all causes with the gout medicine febuxostat (Uloric). FDA Drug Safety Communication; last updated 11/15/2017. Accessed 20 Nov 2017. The United States Food and Drug Administration warning regarding increased risk of cardiovascular and all-cause mortality in patients using febuxostat as compared to allopurinol.
  102. 102.
    Online Source: National Institutes of Health, United States. Cardiovascular safety of febuxostat and allopurinol in patients with gout and cardiovascular comorbidities (CARES). Identifier NCT01101035; last updated 08/11/2017. Accessed 20 Nov2017.
  103. 103.
    White WB, Chohan S, Dabholkar A, Hunt B, Jackson R. Cardiovascular safety of febuxostat and allopurinol in patients with gout and cardiovascular comorbidities. Am Heart J. 2012;164:14–20.CrossRefPubMedGoogle Scholar
  104. 104.
    Whelton A, MacDonald PA, Zhao L, Hunt B, Gunawardhana L. Renal function in gout: long-term treatment effects of febuxostat. J Clin Rheumatol. 2011;17:7–13.CrossRefPubMedGoogle Scholar
  105. 105.
    Sircar D, Chatterjee S, Waikhom R, Golay V, Raychaudhury A, Chatterjee S, 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. 2015;66:945–50.CrossRefPubMedGoogle Scholar
  106. 106.
    Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–28.CrossRefPubMedGoogle Scholar
  107. 107.
    van Bommel EJ, Muskiet MH, Tonneijck L, Kramer MH, Nieuwdorp M, van Raalte DH. SGLT2 inhibition in the diabetic kidney—from mechanisms to clinical outcome. Clin J Am Soc Nephrol. 2017;12:700–10.CrossRefPubMedGoogle Scholar
  108. 108.
    Miao Y, Ottenbros SA, Laverman GD, Brenner BM, Cooper ME, Parving HH, et al. Effect of a reduction in uric acid on renal outcomes during losartan treatment: a post hoc analysis of the reduction of endpoints in non-insulin-dependent diabetes mellitus with the Angiotensin II Antagonist Losartan Trial. Hypertension. 2011;58:2–7.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Dialysis Clinic, Inc., Quality ManagementAlbuquerqueUSA
  2. 2.University of New MexicoAlbuquerqueUSA

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