Clinical Rheumatology

, Volume 35, Issue 1, pp 133–141 | Cite as

Influence of urate-lowering therapies on renal handling of uric acid

  • Lili Ma
  • Lei Wei
  • Huiyong Chen
  • Zhuojun Zhang
  • Qiang Yu
  • Zongfei Ji
  • Lindi Jiang
Original Article

Abstract

The purpose of this study is to investigate the effect of urate-lowering therapies (ULTs) on renal uric acid excretion in gout patients. This prospective observational study involved 106 primary gout patients and 51 healthy controls. Gout patients received ULT with either xanthine oxidase inhibitors or the uricosuric agent benzbromarone. Parameters such as 24-h urinary uric acid, creatinine clearance, uric acid clearance, glomerular filtration load of uric acid, fractional excretion of uric acid, excretion of uric acid per volume of glomerular filtration, and urinary uric acid to urinary creatinine ratio were used to evaluate the pre- and post-treatment renal capacity for uric acid clearance in gout patients and were compared with the values in the healthy controls. Compared to healthy controls, gout patients had higher glomerular filtration load of uric acid and lower uric acid clearance, creatinine clearance, and fractional uric acid excretion. After ULT, both the xanthine oxidase inhibitor group and benzbromarone group patients showed reduction in glomerular filtration load of uric acid. Creatinine clearance was significantly improved in the xanthine oxidase inhibitor group. Excretion function was remarkably enhanced in patients who reached the treatment target (serum uric acid <6 mg/dl). Changes in glomerular uric acid filtration load were significantly correlated with changes in serum urate levels. Gout patients have impaired renal uric acid excretion. ULTs reduce renal urate load and enhance the renal capacity of uric acid clearance. Xanthine oxidase inhibitors showed superiority over benzbromarone in improving renal function.

Keywords

Gout Treat to target Uric acid Uricosuric agent Xanthine oxidase inhibitors 

Abbreviations

GFR

Glomerular filtration rate

ULT

Urate-lowering therapy

XOI

Xanthine oxidase inhibitors

Ccr

Clearance of creatinine

Cua

Clearance of uric acid

FEua

Fractional excretion of uric acid

FLua

Glomerular filtration load of uric acid

Uua/Ucr

Urinary uric acid to Urinary creatinine ratio

ACR

American College of Rheumatology

AKI

Acute kidney injury

RAS

Renin-angiotensin system

ARB

Angiotensin receptor blockers

CKD

Chronic kidney disease

References

  1. 1.
    Ichida K, Matsuo H, Takada T, Nakayama A, Murakami K, Shimizu T, Yamanashi Y, Kasuga H, Nakashima H, Nakamura T, Takada Y, Kawamura Y, Inoue H, Okada C, Utsumi Y, Ikebuchi Y, Ito K, Nakamura M, Shinohara Y, Hosoyamada M, Sakurai Y, Shinomiya N, Hosoya T, Suzuki H (2012) Decreased extra-renal urate excretion is a common cause of hyperuricemia. Nat Commun 3:764. doi:10.1038/ncomms1756 PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Khachadurian AK (1981) Hyperuricemia and gout: an update. Am Fam Physician 24(6):143–148PubMedGoogle Scholar
  3. 3.
    Nishida Y (1992) Relation between creatinine and uric acid excretion. Ann Rheum Dis 51(1):101–102PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    GUTMAN AB, Yu TF (1957) Renal function in gout; with a commentary on the renal regulation of urate excretion, and the role of the kidney in the pathogenesis of gout. Am J Med 23(4):600–622PubMedCrossRefGoogle Scholar
  5. 5.
    Fathallah-Shaykh SA, Cramer MT (2013) Uric acid and the kidney. Pediatr Nephrol. doi:10.1007/s00467-013-2549-x PubMedGoogle Scholar
  6. 6.
    Diamond HS, Paolino JS (1973) Evidence for a post secretory reabsorptive site for uric acid in man. J Clin Invest 52(6):1491–1499. doi:10.1172/JCI107323 PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Mount DB (2005) Molecular physiology and the four-component model of renal urate transport. Curr Opin Nephrol Hypertens 14(5):460–463PubMedCrossRefGoogle Scholar
  8. 8.
    Bellomo G (2013) Uric acid and chronic kidney disease: a time to act? World J Nephrol 2(2):17–25. doi:10.5527/wjn.v2.i2.17 PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Terkeltaub R, Bushinsky DA, Becker MA (2006) Recent developments in our understanding of the renal basis of hyperuricemia and the development of novel antihyperuricemic therapeutics. Arthritis Res Ther 8 Suppl 1:S4.doi:10.1186/ar1909
  10. 10.
    Krishnan E (2012) Reduced glomerular function and prevalence of gout: NHANES 2009–10. PLoS One 7(11):e50046. doi:10.1371/journal.pone.0050046 PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Toda A, Ishizaka Y, Tani M, Yamakado M (2014) Hyperuricemia is a significant risk factor for the onset of chronic kidney disease. Nephron Clin Pract 126(1):33–38. doi:10.1159/000355639 PubMedCrossRefGoogle Scholar
  12. 12.
    Chung W, Kim AJ, Ro H, Chang JH, Lee HH, Jung JY (2013) Hyperuricemia is an independent risk factor for mortality only if chronic kidney disease is present. Am J Nephrol 37(5):452–461. doi:10.1159/000350534 PubMedCrossRefGoogle Scholar
  13. 13.
    Zhang L, Wang F, Wang L, Wang W, Liu B, Liu J, Chen M, He Q, Liao Y, Yu X, Chen N, Zhang JE, Hu Z, Liu F, Hong D, Ma L, Liu H, Zhou X, Chen J, Pan L, Chen W, Wang W, Li X, Wang H (2012) Prevalence of chronic kidney disease in China: a cross-sectional survey. Lancet 379(9818):815–822. doi:10.1016/S0140-6736(12)60033-6 PubMedCrossRefGoogle Scholar
  14. 14.
    Koka RM, Huang E, Lieske JC (2000) Adhesion of uric acid crystals to the surface of renal epithelial cells. Am J Physiol Ren Physiol 278(6):F989–F998Google Scholar
  15. 15.
    Yu KH, Luo SF, Tsai WP, Huang YY (2004) Intermittent elevation of serum urate and 24-hour urinary uric acid excretion. Rheumatology (Oxford) 43(12):1541–1545. doi:10.1093/rheumatology/keh379 CrossRefGoogle Scholar
  16. 16.
    Wallace SL, Robinson H, Masi AT, Decker JL, McCarty DJ, Yü TF (1977) Preliminary criteria for the classification of the acute arthritis of primary gout. Arthritis Rheum 20(3):895–900. doi:10.1002/art.1780200320 PubMedCrossRefGoogle Scholar
  17. 17.
    Wang CY, Cogswell ME, Loria CM, Chen TC, Pfeiffer CM, Swanson CA, Caldwell KL, Perrine CG, Carriquiry AL, Liu K, Sempos CT, Gillespie CD, Burt VL (2013) Urinary excretion of sodium, potassium, and chloride, but not iodine, varies by timing of collection in a 24-hour calibration study. J Nutr 143(8):1276–1282. doi:10.3945/jn.113.175927 PubMedCrossRefGoogle Scholar
  18. 18.
    Kayatas S, Erdogdu E, Cakar E, Yılmazer V, Arınkan SA, Dayıcıoglu VE (2013) Comparison of 24-hour urinary protein and protein-to-creatinine ratio in women with preeclampsia. Eur J Obstet Gynecol Reprod Biol 170(2):368–371. doi:10.1016/j.ejogrb PubMedCrossRefGoogle Scholar
  19. 19.
    Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF III, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J (2009) A new equation to estimate glomerular filtration rate. Ann Intern Med 150(9):604–612PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Perez-Ruiz F, Calabozo M, Erauskin GG, Ruibal A, Herrero-Beites AM (2002) Renal underexcretion of uric acid is present in patients with apparent high urinary uric acid output. Arthritis Rheum 47(6):610–613. doi:10.1002/art.10792 PubMedCrossRefGoogle Scholar
  21. 21.
    Khanna D, Khanna PP, Fitzgerald JD, Singh MK, Bae S, Neogi T, Pillinger MH, Merill J, Lee S, Prakash S, Kaldas M, Gogia M, Perez-Ruiz F, Taylor W, Lioté 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 Rheumatology (2012) 2012 American College of Rheumatology guidelines for management of gout. Part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis. Arthritis Care Res 64(10):1447–1461. doi:10.1002/acr.21773 CrossRefGoogle Scholar
  22. 22.
    Simkin PA, Hoover PL, Paxson CS, Wilson WF (1979) Uric acid excretion: quantitative assessment from spot, midmorning serum and urine samples. Ann Intern Med 91(1):44–47. doi:10.7326/0003-4819-91-1-44 PubMedCrossRefGoogle Scholar
  23. 23.
    Perez-Ruiz F, Alonso-Ruiz A, Calabozo M, Herrero-Beites A, García-Erauskin G, Ruiz-Lucea E (1998) Efficacy of allopurinol and benzbromarone for the control of hyperuricaemia. A pathogenic approach to the treatment of primary chronic gout. Ann Rheum Dis 57(9):545–549. doi:10.1136/ard.57.9.545 PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Taniguchi A, Kamatani N (2008) Control of renal uric acid excretion and gout. Curr Opin Rheumatol 20(2):192–197. doi:10.1097/BOR.0b013e3282f33f87 PubMedCrossRefGoogle Scholar
  25. 25.
    Lin KC, Lin HY, Chou P (2000) The interaction between uric acid level and other risk factors on the development of gout among asymptomatic hyperuricemic men in a prospective study. J Rheumatol 27(6):1501–1505PubMedGoogle Scholar
  26. 26.
    Mazzali M, Kanellis J, Han L, Feng L, Xia YY, Chen Q, Kang DH, Gordon KL, Watanabe S, Nakagawa T, Lan HY, Johnson RJ (2002) Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism. Am J Physiol Ren Physiol 282(6):991–997CrossRefGoogle Scholar
  27. 27.
    Perlstein TS, Gumieniak O, Hopkins PN, Murphey LJ, Brown NJ, Williams GH, Hollenberg NK, Fisher ND (2004) Uric acid and the state of the intrarenal renin-angiotensin system in humans. Kidney Int 66(4):1465–1470PubMedCrossRefGoogle Scholar
  28. 28.
    Berni A, Boddi M, Fattori EB, Cecioni I, Berardino S, Montuschi F, Chiostri M, Poggesi L (2010) Serum uric acid levels and renal damage in hyperuricemic hypertensive patients treated with renin-angiotensin system blockers. Am J Hypertens 23(6):675–680PubMedCrossRefGoogle Scholar
  29. 29.
    Enomoto A, Kimura H, Chairoungdua A, Shigeta Y, Jutabha P, Cha SH, Hosoyamada M, Takeda M, Sekine T, Igarashi T, Matsuo H, Kikuchi Y, Oda T, Ichida K, Hosoya T, Shimokata K, Niwa T, Kanai Y, Endou H (2002) Molecular identification of a renal urate-anion exchanger that regulates blood urate levels. Nature 417(6887):447–452PubMedGoogle Scholar
  30. 30.
    Iwanaga T, Sato M, Maeda T, Ogihara T, Tamai I (2007) Concentration-dependent mode of interaction of angiotensin II receptor blockers with uric acid transporter. J Pharmacol Exp Ther 320(1):211–217PubMedCrossRefGoogle Scholar
  31. 31.
    Kang DH, Nakagawa T, Feng L, Watanabe S, Han L, Mazzali M, Truong L, Harris R, Johnson RJ (2002) A role for uric acid in the progression of renal disease. J Am Soc Nephrol 13(12):2888–2897PubMedCrossRefGoogle Scholar
  32. 32.
    Obermayr RP, Temml C, Gutjahr G, Knechtelsdorfer M, Oberbauer R, Klauser-Braun R (2008) Elevated uric acid increases the risk for kidney disease. J Am Soc Nephrol 19(12):2407–2413. doi:10.1681/ASN.2008010080 PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Feig DI (2014) Serum uric acid and the risk of hypertension and chronic kidney disease. Curr Opin Rheumatol 26(2):176–185. doi:10.1097/BOR.0000000000000033 PubMedCrossRefGoogle Scholar
  34. 34.
    Emmerson BT, Nagel SL, Duffy DL, Martin NG (1992) Genetic control of the renal clearance of urate: a study of twins. Ann Rheum Dis 51(3):375–377PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Storhaug HM, Norvik JV, Toft I, Eriksen BO, Løchen ML, Zykova S, Solbu M, White S, Chadban S, Jenssen T (2013) Uric acid is a risk factor for ischemic stroke and all-cause mortality in the general population: a gender specific analysis from The Tromsø Study. BMC Cardiovasc Disord 13:115. doi:10.1186/1471-2261-13-115 PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Nagahama K, Inoue T, Kohagura K, Ishihara A, Kinjo K, Ohya Y (2013) Hyperuricemia predicts future metabolic syndrome: a 4-year follow-up study of a large screened cohort in Okinawa, Japan. Hypertens Res 37(3):232–238PubMedCrossRefGoogle Scholar
  37. 37.
    Anker SD, Doehner W, Rauchhaus M, Sharma R, Francis D, Knosalla C, Davos CH, Cicoira M, Shamim W, Kemp M, Segal R, Osterziel KJ, Leyva F, Hetzer R, Ponikowski P, Coats AJ (2003) Uric acid and survival in chronic heart failure: validation and application in metabolic, functional, and hemodynamic staging. Circulation 107(15):1991–1997PubMedCrossRefGoogle Scholar
  38. 38.
    Ramasamy SN, Korb-Wells CS, Kannangara DR, Smith MW, Wang N, Roberts DM, Graham GG, Williams KM, Day RO (2013) Allopurinol hypersensitivity: a systematic review of all published cases, 1950–2012. Drug Saf 36(10):953–980PubMedCrossRefGoogle Scholar

Copyright information

© International League of Associations for Rheumatology (ILAR) 2014

Authors and Affiliations

  • Lili Ma
    • 1
  • Lei Wei
    • 1
  • Huiyong Chen
    • 1
  • Zhuojun Zhang
    • 1
  • Qiang Yu
    • 1
  • Zongfei Ji
    • 1
  • Lindi Jiang
    • 1
  1. 1.Department of RheumatologyZhongshan HospitalShanghaiPeople’s Republic of China

Personalised recommendations