Skip to main content

Advertisement

SpringerLink
Log in

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

  • Antihypertensive Agents: Mechanisms of Drug Action (M Ernst, Section Editor)
  • Published:
Current Hypertension Reports Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

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

  1. Borghi C, Cicero AF. Serum uric acid and cardiometabolic disease: another brick in the wall? Hypertension. 2017;69(6):1011–3.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  3. Gustafsson D, Unwin R. The pathophysiology of hyperuricaemia and its possible relationship to cardiovascular disease, morbidity and mortality. BMC Nephrol. 2013;14:164.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Choi HK, Ford ES. Prevalence of the metabolic syndrome in individuals with hyperuricemia. Am J Med. 2007;120(5):442–7.

    Article  PubMed  Google Scholar 

  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. Galassi FM, Borghi C. A brief history of uric acid: from gout to cardiovascular risk factor. Eur J Intern Med. 2015;26(5):373.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ce B, Hare JM. Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications. J Physiol. 2004;555:589–606.

    Article  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  15. Krishnan E, Kwoh CK, Schumacher HR, Kuller L. Hyperuricemia and incidence of hypertension among men without metabolic syndrome. Hypertension. 2007;49:298–303.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  21. Emokpae AM, Abdu A. Serum uric acid levels among Nigerians with essential hypertension. Niger J Physiol Sci. 2013;28:41–4.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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. 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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  33. Gliozzi M, Malara N, Muscoli S, Mollace V. The treatment of hyperuricemia. Int J Cardiol. 2016;213:23–7.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Soletsky B, Feig DI. Uric acid reduction rectifies prehypertension in obese adolescents. Hypertension. 2012;60:1148–56.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. 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.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Hypertension Research Unit, Medical and Surgical Sciences Department, University of Bologna, Bologna, Italy

    Marilisa Bove, Arrigo F. G. Cicero & Claudio Borghi

Authors
  1. Marilisa Bove
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Arrigo F. G. Cicero
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Claudio Borghi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Claudio Borghi.

Ethics declarations

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.

Additional information

This article is part of the Topical Collection on Antihypertensive Agents: Mechanisms of Drug Action

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bove, M., Cicero, A.F.G. & Borghi, C. The Effect of Xanthine Oxidase Inhibitors on Blood Pressure and Renal Function. Curr Hypertens Rep 19, 95 (2017). https://doi.org/10.1007/s11906-017-0793-3

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11906-017-0793-3

Keywords

Search

Navigation