The Effect of Xanthine Oxidase Inhibitors on Blood Pressure and Renal Function

  • Marilisa Bove
  • Arrigo F. G. Cicero
  • Claudio Borghi
Antihypertensive Agents: Mechanisms of Drug Action (M Ernst, Section Editor)
First Online:
Part of the following topical collections:
  1. Topical Collection on Antihypertensive Agents: Mechanisms of Drug Action

Abstract

Several epidemiological studies have demonstrated the existence of a correlation between high serum uric acid (SUA) levels, hypertension, and chronic kidney disease (CKD). Xantine oxidase inhibitors (XOI) are the most powerful uric acid lowering drugs, with presumed beneficial effects on cardiovascular and renal system. The multifactorial mechanism linking hyperuricemia with cardiovascular and renal diseases involves both the SUA level and the xanthine oxidase (XO) activity. In this context, the clinical research has been recently focused at assessing the efficacy of urate-lowering drugs active on XO in patients with abnormal blood pressure values and renal dysfunction. The mechanism of action responsible for the beneficial effect of XOI has not completely elucidated, and long-term studies involving large population samples are needed. In particular, XOI could play an important role in the management of hypertension and CKD, especially in patients not entirely controlled by conventional therapies. In the present review, we summarize the results of recent clinical trials that largely support a positive effect of allopurinol and febuxostat on blood pressure, glomerular filtration rate (GFR), and serum creatinine in different populations of patients. Will these drugs be considered a reliable choice or alternative to currently used drugs for the hypertension and kidney failure treatment? The debate is open, but much evidence is accumulating and supporting this role.

Keywords

Xantine oxidase inhibitors Hyperuricemia Hypertension Chronic kidney disease 
This is a preview of subscription content, log in to check access.

Notes

Compliance with Ethical Standards

Conflict of Interest

Prof. Borghi is a scientific consultant for Menarini International SpA. Dr. Bove and Dr. Cicero declare no conflicts of interest relevant to this manuscript.

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.

References

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

  1. 1.
    Borghi C, Cicero AF. Serum uric acid and cardiometabolic disease: another brick in the wall? Hypertension. 2017;69(6):1011–3.CrossRefPubMedGoogle Scholar
  2. 2.
    Borghi C, Rosei EA, Bardin T, Dawson J, Dominiczak A, Kielstein JT, et al. Serum uric acid and the risk of cardiovascular and renal disease. J Hypertens. 2015;33:1729–41.CrossRefPubMedGoogle Scholar
  3. 3.
    Gustafsson D, Unwin R. The pathophysiology of hyperuricaemia and its possible relationship to cardiovascular disease, morbidity and mortality. BMC Nephrol. 2013;14:164.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Choi HK, Ford ES. Prevalence of the metabolic syndrome in individuals with hyperuricemia. Am J Med. 2007;120(5):442–7.CrossRefPubMedGoogle Scholar
  5. 5.
    Billiet L, Doaty S, Katz JD, Velasquez MT. Review of hyperuricemia as new marker for metabolic syndrome. ISRN heumatology. 2014;2014:852954.Google Scholar
  6. 6.
    Galassi FM, Borghi C. A brief history of uric acid: from gout to cardiovascular risk factor. Eur J Intern Med. 2015;26(5):373.CrossRefPubMedGoogle Scholar
  7. 7.
    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(1):99–104.CrossRefPubMedGoogle Scholar
  8. 8.
    Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007–2008. Arthritis Rheum. 2011;63:3136–41.CrossRefPubMedGoogle Scholar
  9. 9.
    McGillicuddy FC, de la Llera MM, Hinkle CC, Joshi MR, Chiquoine EH, Billheimer JT, et al. Inflammation impairs reverse cholesterol transport in vivo. Circulation. 2009;119:1135–45.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Grayson PC, Kim SY, LaValley M, Choi HK. Hyperuricemia and incident hypertension: a systematic review and meta-analysis. Arthritis Care Res. 2011;63:102–10.CrossRefGoogle Scholar
  11. 11.
    • Loeffler LF, Navas-Acien A, Brady TM, Miller ER 3rd, Fadrowski JJ. Uric acid level and elevated blood pressure in US adolescents: National Health and Nutrition Examination Survey. Hypertension. 2012;59:811–7. Impressive epidemiological data on relationship between uric acid level and hypertension in young people.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Ce B, Hare JM. Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications. J Physiol. 2004;555:589–606.CrossRefGoogle Scholar
  14. 14.
    Sabán-Ruiz J, Alonso-Pacho A, Fabregate-Fuente M, et al. Xanthine oxidase inhibitor febuxostat as a novel agent postulated to act against vascular inflammation. Antiinflamm Antiallergy Agents Med Chem. 2013;12(1):94–9.CrossRefPubMedGoogle Scholar
  15. 15.
    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
  16. 16.
    Nakanishi N, Okamoto M, Yoshida H, Matsuo Y, Suzuki K, Tatara K. Serum uric acid and risk for development of hypertension and impaired fasting glucose or Type II diabetes in Japanese male office workers. Eur J Epidemiol. 2003;18:523–30.CrossRefPubMedGoogle Scholar
  17. 17.
    •• Grayson PC, Kim SY, LaValley M, Choi HK. Hyperuricemia and incident hypertension: a systematic review and meta-analysis. Arthritis Care Res. 2011;63(1):102–10. A definitive demonstration of the association between hyperuricemia and incident hypertension.CrossRefGoogle Scholar
  18. 18.
    Cicero AF, Rosticci M, Bove M, Fogacci F, Giovannin M, Urso R, et al. Serum uric acid change and modification of blood pressure and fasting plasma glucose in an overall healthy population sample: data from the Brisighella heart study. Ann Med. 2017;49(4):275–82.CrossRefPubMedGoogle Scholar
  19. 19.
    Dyer AR, Liu K, Walsh M, Kiefe C, Jacobs DR Jr, Bild DE. Ten-year incidence of elevated blood pressure and its predictors: the CARDIA study. Coronary Artery Risk Development in (Young) Adults. J Hum Hypertens. 1999;13:13–21.CrossRefPubMedGoogle Scholar
  20. 20.
    Nagahama K, Inoue T, Iseki K, Touma T, Kinjo K, Ohya Y, et al. Hyperuricemia as a predictor of hypertension in a screened cohort in Okinawa. Jpn Hypertens Res. 2004;27:835–41.CrossRefGoogle Scholar
  21. 21.
    Emokpae AM, Abdu A. Serum uric acid levels among Nigerians with essential hypertension. Niger J Physiol Sci. 2013;28:41–4.PubMedGoogle Scholar
  22. 22.
    Forman JP, Choi H, Curhan GC. Plasma uric acid level and risk for incident hypertension among men. J Am Soc Nephrol. 2007;18:287–92.CrossRefPubMedGoogle Scholar
  23. 23.
    Corry DB, Eslami P, Yamamoto K, Nyby MD, Makino H, Tuck ML. Uric acid stimulates vascular smooth muscle cell proliferation and oxidative stress via the vascular renin-angiotensin system. J Hypertens. 2008;26(2):269–75.CrossRefPubMedGoogle Scholar
  24. 24.
    Chonchol M, Shlipak MG, Katz R, Sarnak MJ, Newman AB, Siscovick DS, et al. Relationship of uric acid with progression of kidney disease. Am J Kidney Dis. 2007;50:239–47.CrossRefPubMedGoogle Scholar
  25. 25.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    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
  28. 28.
    Chien KL, Lin HJ, Lee BC, Hsu HC, Lee YT, Chen MF. A prediction model for the risk of incident chronic kidney disease. Am J Med. 2010;123(9):836–846.e2.CrossRefPubMedGoogle Scholar
  29. 29.
    Galvan AQ, Natali A, Baldi S, et al. Effect of insulin on uric acid excretion in humans. Am J Phys. 1995;268:1–5.Google Scholar
  30. 30.
    Muscelli E, Natali A, Bianchi S, Frascerra S, Sanna G, Ciociaro D, et al. Effect of insulin on renal sodium and uric acid handling in essential hypertension. Am J Hypertens. 1996;9:746–52.CrossRefPubMedGoogle Scholar
  31. 31.
    Artunc F, Schleicher E, Weigert C, Fritsche A, Stefan N, Häring HU. The impact of insulin resistance on the kidney and vasculature. Nat Rev Nephrol. 2016;12(12):721–37.CrossRefPubMedGoogle Scholar
  32. 32.
    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(4):642–50.CrossRefPubMedGoogle Scholar
  33. 33.
    Gliozzi M, Malara N, Muscoli S, Mollace V. The treatment of hyperuricemia. Int J Cardiol. 2016;213:23–7.CrossRefPubMedGoogle Scholar
  34. 34.
    • Becker MA, Schumacher HR Jr, Wortmann RL, MacDonald PA, Eustace D, Palo WA, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005;353:2450–61. Direct demonstration of superiority of febuxostat vs. allopurinol as uric acid lowering drug.CrossRefPubMedGoogle Scholar
  35. 35.
    Schumacher HR Jr, Becker MA, Wortmann RL, Macdonald PA, Hunt B, Streit J, et al. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis Rheum. 2008;59:1540–8.CrossRefPubMedGoogle Scholar
  36. 36.
    Li S, Yang H, Guo Y, Wei F, Yang X, Li D, et al. Comparative efficacy and safety of urate lowering therapy for the treatment of hyperuricemia: a systematic review and network meta-analysis. Sci Rep. 2016;6:33082.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Mayer MD, Khosravan R, Vernillet L, Wu JT, Joseph-Ridge N, Mulford DJ. Pharmacokinetics and pharmacodynamics of febuxostat, a new non-purine selective inhibitor of xanthine oxidase in subjects with renal impairment. Am J Ther. 2005;12:22–34.CrossRefPubMedGoogle Scholar
  38. 38.
    Mitsuboshi S, Yamada H, Nagai K, Okajima H. Switching from allopurinol to febuxostat: efficacy and tolerability in hemodialysis patients. J Pharm Health Care Sci. 2015;1:28.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Jian-Ming L, Yao Q, Chen C. 3,4-Dihydroxy-5-nitrobenzaldehyde (DHNB) is a potent inhibitor of xanthine oxidase: a potential therapeutic agent for treatment of hyperuricemia and gout. Biochem Pharmacol. 2013;86:1328–37.CrossRefGoogle Scholar
  40. 40.
    Bove M, Cicero AF, Veronesi M, Borghi C. An evidence-based review on urate-lowering treatments: implications for optimal treatment of chronic hyperuricemia. Vasc Health Risk Manag. 2017;13:23–8.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Soletsky B, Feig DI. Uric acid reduction rectifies prehypertension in obese adolescents. Hypertension. 2012;60:1148–56.CrossRefPubMedGoogle Scholar
  43. 43.
    • 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 clearance, and proteinuria in patients with normal renal functions. Int Urol Nephrol. 2007;39:1227–33. First suggestion of the blood pressure lowering effect of a serum uric acid lowering agent.CrossRefPubMedGoogle Scholar
  44. 44.
    Kostka-Jeziorny K, Uruski P, Tykarski A. Effect of allopurinol on blood pressure and aortic compliance in hypertensive patients. Blood Press. 2011;20:104–10.CrossRefPubMedGoogle Scholar
  45. 45.
    MacIsaac RL, Salatzki J, Higgins P, Walters MR, Padmanabhan S, Dominiczak AF, et al. Allopurinol and cardiovascular outcomes in adults with hypertension. Hypertension. 2016;67(3):535–40.PubMedGoogle Scholar
  46. 46.
    Mazzali M, Hughes J, Kim YG, Jefferson JA, Kang DH, Gordon KL, et al. Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension. 2001;38:1101–6.CrossRefPubMedGoogle Scholar
  47. 47.
    Beattie CJ, Fulton RL, Higgins P, Padmanabhan S, McCallum L, Walters MR, et al. Allopurinol initiation and change in blood pressure in older adults with hypertension. Hypertension. 2014;64:1102–7.CrossRefPubMedGoogle Scholar
  48. 48.
    Fairbanks LD, Cameron JS, Venkat-Raman G, Rigden SP, Rees L, Van'T Hoff W, et al. Early treatment with allopurinol in familial juvenile hyperuricaemic nephropathy (FJHN) ameliorates the long-term progression of renal disease. QJM. 2002;95:597–607.CrossRefPubMedGoogle Scholar
  49. 49.
    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
  50. 50.
    Goicoechea M, de Vinuesa SG, Verdalles U, Ruiz-Caro C, Ampuero J, Rincón A, et al. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin J Am Soc Nephrol. 2010;5:1388–93.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Satirapoj B, Wirajit O, Burata A, Supasyndh O, Ruangkanchanasetr P. Benefits of allopurinol treatment on blood pressure and renal function in patients with early stage of chronic kidney disease. J Med Assoc Thail. 2015;98(12):1155–61.Google Scholar
  52. 52.
    Krishnamurthy AL, Lazaro D, Stefanov DG, Blumenthal D, Gerber D, Patel S. The effect of allopurinol on renal function. J Clin Rheumatol. 2017;23(1):1–5.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Marilisa Bove
    • 1
  • Arrigo F. G. Cicero
    • 1
  • Claudio Borghi
    • 1
  1. 1.Hypertension Research Unit, Medical and Surgical Sciences DepartmentUniversity of BolognaBolognaItaly

Personalised recommendations