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Comparative effect of allopurinol and febuxostat on long-term renal outcomes in patients with hyperuricemia and chronic kidney disease: a systematic review

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A Letter to the Editor to this article was published on 20 September 2021

Abstract

Patients with chronic kidney disease (CKD) are more likely to develop hyperuricemia and gout. Allopurinol and febuxostat are the most commonly used urate-lowering therapies with established safety and efficacy in CKD patients. The objective of the systematic review is to assess the long-term renal outcomes of allopurinol compared with febuxostat in patients with hyperuricemia and CKD or kidney transplantation. PubMed MEDLINE, Embase, Web of Science, Scopus, and Cochrane CENTRAL databases were searched from inception to December 2019 using the key terms “allopurinol,” “febuxostat,” “xanthine oxidase inhibitors,” “gout suppressants,” “hyperuricemia,” “gout,” “chronic renal insufficiency,” and “kidney transplantation.” Studies with follow-up duration ≥ 12 months were included. Risk of bias was assessed using the Cochrane Risk Of Bias In Non-randomized Studies-of Interventions (ROBINS-I) tool. Three retrospective observational studies with follow-up duration ranging from 1 to 5 years were reviewed. Febuxostat patients had a significantly higher estimated glomerular filtration rate, reduced risk for renal disease progression, and reduced serum uric acid levels compared with allopurinol patients. All studies had a serious risk of bias. Febuxostat may be more renoprotective than allopurinol in patients with both hyperuricemia and CKD based on evidence from small long-term retrospective studies with serious risk of bias. More methodologically rigorous studies are needed to determine the clinical applicability of these results.

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References

  1. Krishnan E (2012) Reduced glomerular function and prevalence of gout: NHANES 2009-10. PLoS One 7(11):e50046. https://doi.org/10.1371/journal.pone.0050046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lipkowitz MS (2012) Regulation of uric acid excretion by the kidney. Curr Rheumatol Rep 14(2):179–188. https://doi.org/10.1007/s11926-012-0240-z

    Article  CAS  PubMed  Google Scholar 

  3. Nakagawa T, Mazzali M, Kang DH, Sanchez-Lozada LG, Herrera-Acosta J, Johnson RJ (2006) Uric acid--a uremic toxin? Blood Purif 24(1):67–70. https://doi.org/10.1159/000089440

    Article  CAS  PubMed  Google Scholar 

  4. Li L, Yang C, Zhao YL, Zeng XX, Liu F, Fu P (2014) 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 15:12. https://doi.org/10.1186/1471-2369-15-122

    Article  CAS  Google Scholar 

  5. Weiner DE, Tighiouart H, Elsayed EF, Griffith JL, Salem DN, Levey AS (2008) Uric acid and incident kidney disease in the community. J Am Soc Nephrol 19(6):1204–1211. https://doi.org/10.1681/ASN.2007101075

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Tsai C-W, Lin S-Y, Kuo C-C, Huang C-C (2017) Serum uric acid and progression of kidney disease: a longitudinal analysis and mini-review. PLoS One 12(1):e0170393–e0170393. https://doi.org/10.1371/journal.pone.0170393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hsu CY, Iribarren C, McCulloch CE, Darbinian J, Go AS (2009) Risk factors for end-stage renal disease: 25-year follow-up. Arch Intern Med 169(4):342–350. https://doi.org/10.1001/archinternmed.2008.605

    Article  PubMed  PubMed Central  Google Scholar 

  8. Xia X, Luo Q, Li B, Lin Z, Yu X, Huang F (2016) Serum uric acid and mortality in chronic kidney disease: a systematic review and meta-analysis. Metabolism 65(9):1326–1341. https://doi.org/10.1016/j.metabol.2016.05.009

    Article  CAS  PubMed  Google Scholar 

  9. Khanna D, Fitzgerald JD, Khanna PP, Bae S, Singh MK, Neogi T, Pillinger MH, Merill J, Lee S, Prakash S, Kaldas M, Gogia M, Perez-Ruiz F, Taylor W, Liote F, Choi H, Singh JA, Dalbeth N, Kaplan S, Niyyar V, Jones D, Yarows SA, Roessler B, Kerr G, King C, Levy G, Furst DE, Edwards NL, Mandell B, Schumacher HR, Robbins M, Wenger N, Terkeltaub R, American College of R (2012) 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken) 64(10):1431–1446. https://doi.org/10.1002/acr.21772

    Article  CAS  Google Scholar 

  10. Richette P, Doherty M, Pascual E, Barskova V, Becce F, Castaneda-Sanabria J, Coyfish M, Guillo S, Jansen TL, Janssens H, Liote F, Mallen C, Nuki G, Perez-Ruiz F, Pimentao J, Punzi L, Pywell T, So A, Tausche AK, Uhlig T, Zavada J, Zhang W, Tubach F, Bardin T (2017) 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis 76(1):29–42. https://doi.org/10.1136/annrheumdis-2016-209707

    Article  CAS  PubMed  Google Scholar 

  11. Singh JA (2018) Goals of gout treatment: a patient perspective. Clin Rheumatol 37(9):2557–2566. https://doi.org/10.1007/s10067-018-4243-7

    Article  PubMed  Google Scholar 

  12. Keenan RT, O'Brien WR, Lee KH, Crittenden DB, Fisher MC, Goldfarb DS, Krasnokutsky S, Oh C, Pillinger MH (2011) Prevalence of contraindications and prescription of pharmacologic therapies for gout. Am J Med 124(2):155–163. https://doi.org/10.1016/j.amjmed.2010.09.012

    Article  PubMed  Google Scholar 

  13. Siu YP, Leung KT, Tong MK, Kwan TH (2006) Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level. Am J Kidney Dis 47(1):51–59. https://doi.org/10.1053/j.ajkd.2005.10.006

    Article  CAS  PubMed  Google Scholar 

  14. Goicoechea M, de Vinuesa SG, Verdalles U, Ruiz-Caro C, Ampuero J, Rincon A, Arroyo D, Luno J (2010) Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin J Am Soc Nephrol 5(8):1388–1393. https://doi.org/10.2215/cjn.01580210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kao MP, Ang DS, Gandy SJ, Nadir MA, Houston JG, Lang CC, Struthers AD (2011) Allopurinol benefits left ventricular mass and endothelial dysfunction in chronic kidney disease. J Am Soc Nephrol 22(7):1382–1389. https://doi.org/10.1681/ASN.2010111185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Shi Y, Chen W, Jalal D, Li Z, Chen W, Mao H, Yang Q, Johnson RJ, Yu X (2012) Clinical outcome of hyperuricemia in IgA nephropathy: a retrospective cohort study and randomized controlled trial. Kidney Blood Press Res 35(3):153–160. https://doi.org/10.1159/000331453

    Article  CAS  PubMed  Google Scholar 

  17. Tsuruta Y, Kikuchi K, Tsuruta Y, Sasaki Y, Moriyama T, Itabashi M, Takei T, Uchida K, Akiba T, Tsuchiya K, Nitta K (2015) Febuxostat improves endothelial function in hemodialysis patients with hyperuricemia: a randomized controlled study. Hemodial Int 19(4):514–520. https://doi.org/10.1111/hdi.12313

    Article  PubMed  Google Scholar 

  18. Sircar D, Chatterjee S, Waikhom R, Golay V, Raychaudhury A, Chatterjee S, Pandey R (2015) 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(6):945–950. https://doi.org/10.1053/j.ajkd.2015.05.017

    Article  CAS  PubMed  Google Scholar 

  19. Tanaka K, Nakayama M, Kanno M, Kimura H, Watanabe K, Tani Y, Hayashi Y, Asahi K, Terawaki H, Watanabe T (2015) Renoprotective effects of febuxostat in hyperuricemic patients with chronic kidney disease: a parallel-group, randomized, controlled trial. Clin Exp Nephrol 19(6):1044–1053. https://doi.org/10.1007/s10157-015-1095-1

    Article  CAS  PubMed  Google Scholar 

  20. Alshahawey M, Shaheen SM, Elsaid T, Sabri NA (2019) Effect of febuxostat on oxidative stress in hemodialysis patients with endothelial dysfunction: a randomized, placebo-controlled, double-blinded study. Int Urol Nephrol 51(9):1649–1657. https://doi.org/10.1007/s11255-019-02243-w

    Article  CAS  PubMed  Google Scholar 

  21. Hande KR, Noone RM, Stone WJ (1984) Severe allopurinol toxicity. Description and guidelines for prevention in patients with renal insufficiency. Am J Med 76(1):47–56. https://doi.org/10.1016/0002-9343(84)90743-5

    Article  CAS  PubMed  Google Scholar 

  22. Dalbeth N, Stamp L (2007) Allopurinol dosing in renal impairment: walking the tightrope between adequate urate lowering and adverse events. Semin Dial 20(5):391–395. https://doi.org/10.1111/j.1525-139X.2007.00270.x

    Article  PubMed  Google Scholar 

  23. Ernst ME, Fravel MA (2009) Febuxostat: a selective xanthine-oxidase/xanthine-dehydrogenase inhibitor for the management of hyperuricemia in adults with gout. Clin Ther 31(11):2503–2518. https://doi.org/10.1016/j.clinthera.2009.11.033

    Article  CAS  PubMed  Google Scholar 

  24. Hosoya T, Ohno I (2011) A repeated oral administration study of febuxostat (TMX-67), a non-purine-selective inhibitor of xanthine oxidase, in patients with impaired renal function in Japan: pharmacokinetic and pharmacodynamic study. J Clin Rheumatol 17(4 Suppl 2):S27–S34. https://doi.org/10.1097/RHU.0b013e31821d36f2

    Article  PubMed  Google Scholar 

  25. Shibagaki Y, Ohno I, Hosoya T, Kimura K (2014) Safety, efficacy and renal effect of febuxostat in patients with moderate-to-severe kidney dysfunction. Hypertens Res 37(10):919–925. https://doi.org/10.1038/hr.2014.107

    Article  CAS  PubMed  Google Scholar 

  26. Kim S, Kim HJ, Ahn HS, Oh SW, Han KH, Um TH, Cho CR, Han SY (2017) Renoprotective effects of febuxostat compared with allopurinol in patients with hyperuricemia: a systematic review and meta-analysis. Kidney Res Clin Pract 36(3):274–281. https://doi.org/10.23876/j.krcp.2017.36.3.274

    Article  PubMed  PubMed Central  Google Scholar 

  27. Liu X, Liu K, Sun Q, Wang Y, Meng J, Xu Z, Shi Z (2018) Efficacy and safety of febuxostat for treating hyperuricemia in patients with chronic kidney disease and in renal transplant recipients: a systematic review and meta-analysis. Exp Ther Med 16(3):1859–1865. https://doi.org/10.3892/etm.2018.6367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6(7):e1000097. https://doi.org/10.1371/journal.pmed.1000097

    Article  PubMed  PubMed Central  Google Scholar 

  29. Sterne JA, Hernan MA, Reeves BC, Savovic J, Berkman ND, Viswanathan M, Henry D, Altman DG, Ansari MT, Boutron I, Carpenter JR, Chan AW, Churchill R, Deeks JJ, Hrobjartsson A, Kirkham J, Juni P, Loke YK, Pigott TD, Ramsay CR, Regidor D, Rothstein HR, Sandhu L, Santaguida PL, Schunemann HJ, Shea B, Shrier I, Tugwell P, Turner L, Valentine JC, Waddington H, Waters E, Wells GA, Whiting PF, Higgins JP (2016) ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ 355:i4919. https://doi.org/10.1136/bmj.i4919

    Article  PubMed  PubMed Central  Google Scholar 

  30. Tsuruta Y, Mochizuki T, Moriyama T, Itabashi M, Takei T, Tsuchiya K, Nitta K (2014) Switching from allopurinol to febuxostat for the treatment of hyperuricemia and renal function in patients with chronic kidney disease. Clin Rheumatol 33(11):1643–1648. https://doi.org/10.1007/s10067-014-2745-5

    Article  PubMed  PubMed Central  Google Scholar 

  31. Tsuji T, Ohishi K, Takeda A, Goto D, Sato T, Ohashi N, Fujigaki Y, Kato A, Yasuda H (2018) The impact of serum uric acid reduction on renal function and blood pressure in chronic kidney disease patients with hyperuricemia. Clin Exp Nephrol 22(6):1300–1308. https://doi.org/10.1007/s10157-018-1580-4

    Article  CAS  PubMed  Google Scholar 

  32. Lee J-W, Lee K-H (2019) Comparison of renoprotective effects of febuxostat and allopurinol in hyperuricemic patients with chronic kidney disease. Int Urol Nephrol 51(3):467–473. https://doi.org/10.1007/s11255-018-2051-2

    Article  CAS  PubMed  Google Scholar 

  33. Sezai A, Soma M, Nakata K, Osaka S, Ishii Y, Yaoita H, Hata H, Shiono M (2015) Comparison of febuxostat and allopurinol for hyperuricemia in cardiac surgery patients with chronic kidney disease (NU-FLASH trial for CKD). J Cardiol 66(4):298–303. https://doi.org/10.1016/j.jjcc.2014.12.017

    Article  PubMed  Google Scholar 

  34. Fuldeore MJ, Riedel AA, Zarotsky V, Pandya BJ, Dabbous O, Krishnan E (2011) Chronic kidney disease in gout in a managed care setting. BMC Nephrol 12:36. https://doi.org/10.1186/1471-2369-12-36

    Article  PubMed  PubMed Central  Google Scholar 

  35. Stamp LK, O'Donnell JL, Zhang M, James J, Frampton C, Barclay ML, Chapman PT (2011) Using allopurinol above the dose based on creatinine clearance is effective and safe in patients with chronic gout, including those with renal impairment. Arthritis Rheum 63(2):412–421. https://doi.org/10.1002/art.30119

    Article  CAS  PubMed  Google Scholar 

  36. White WB, Saag KG, Becker MA, Borer JS, Gorelick PB, Whelton A, Hunt B, Castillo M, Gunawardhana L, Investigators C (2018) Cardiovascular safety of febuxostat or allopurinol in patients with gout. N Engl J Med 378(13):1200–1210. https://doi.org/10.1056/NEJMoa1710895

    Article  CAS  PubMed  Google Scholar 

  37. Paul BJ, Anoopkumar K, Krishnan V (2017) Asymptomatic hyperuricemia: is it time to intervene? Clin Rheumatol 36(12):2637–2644. https://doi.org/10.1007/s10067-017-3851-y

    Article  PubMed  Google Scholar 

  38. Stamp LK (2017) Major unanswered questions in the clinical gout field. Curr Opin Rheumatol 29(2):171–177. https://doi.org/10.1097/BOR.0000000000000367

    Article  PubMed  Google Scholar 

  39. Mu Z, Wang W, Wang J, Lv W, Chen Y, Wang F, Yu X, Wang Y, Cheng B, Wang Z (2019) Predictors of poor response to urate-lowering therapy in patients with gout and hyperuricemia: a post-hoc analysis of a multicenter randomized trial. Clin Rheumatol 38(12):3511–3519. https://doi.org/10.1007/s10067-019-04737-5

    Article  PubMed  Google Scholar 

  40. Lin YJ, Lin SY, Lin CH, Wang ST, Chang SS (2020) Evaluation of urate-lowering therapy in hyperuricemia patients: a systematic review and Bayesian network meta-analysis of randomized controlled trials. Clin Rheumatol:1–16. https://doi.org/10.1007/s10067-019-04893-8

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  1. Durham Veterans Affairs Health Care System, Pharmacy Department, Durham, NC, 27705, USA

    Anna M. Hu & Jamie N. Brown

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Hu, A.M., Brown, J.N. Comparative effect of allopurinol and febuxostat on long-term renal outcomes in patients with hyperuricemia and chronic kidney disease: a systematic review. Clin Rheumatol 39, 3287–3294 (2020). https://doi.org/10.1007/s10067-020-05079-3

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