Skip to main content
SpringerLink
Log in

Regulation of Uric Acid Excretion by the Kidney

  • CRYSTAL ARTHRITIS (MH PILLINGER, SECTION EDITOR)
  • Published:
Current Rheumatology Reports Aims and scope Submit manuscript

Abstract

It has been known for many years that the kidney plays a major role in uric acid homeostasis, as more than 70% of urate excretion is renal. Furthermore, hyperuricemia in gout is most commonly the result of relative urate underexcretion, as the kidney has enormous capacity for urate reabsorption. A clear understanding of the mechanisms of renal handling of urate has been hampered by the differences between humans and animal models. The power of human genetics and genome-wide association studies has now provided new insight into the molecular mechanisms of urate transport by identifying the transporters that have critical roles in urate transport. This review surveys the new evidence for a molecular model of urate transport in the renal proximal tubule and uses these data to refute the popular four-component model for urate transport that has long been in vogue. It also discusses data that help us understand the relation of diuretics to hyperuricemia, losartan-induced uricosuria, variations in uric acid levels in hyperglycemia, and the effects of dairy diets on serum urate levels. In the end, several of these clinical findings are explained, and the remaining gaps in our knowledge will become evident.

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

Similar content being viewed by others

References

  1. Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med. 2008;359:1811–21.

    Article  PubMed  CAS  Google Scholar 

  2. Mazzali M, Hughes J, Kim YG, Jefferson JA, et al. Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension. 2001;38:1101–6.

    Article  PubMed  CAS  Google Scholar 

  3. Mazzali M, Kanellis J, Han L, Feng L, et al. Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism. Am J Physiol Ren Physiol. 2002;282:F991–997.

    CAS  Google Scholar 

  4. Shi Y, Evans JE, Rock KL. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature. 2003;425:516–21.

    Article  PubMed  CAS  Google Scholar 

  5. Maesaka JK, Fishbane S. Regulation of renal urate excretion: a critical review. Am J Kidney Dis. 1998;32:917–33.

    Article  PubMed  CAS  Google Scholar 

  6. Levinson DJ, Sorensen LB. Renal handling of uric acid in normal and gouty subject: evidence for a 4-component system. Ann Rheum Dis. 1980;39:173–9.

    Article  PubMed  CAS  Google Scholar 

  7. Abramson RG, Levitt MF. Use of pyrazinamide to assess renal uric acid transport in the rat: a micropuncture study. Am J Physiol. 1976;230:1276–83.

    PubMed  CAS  Google Scholar 

  8. Podevin R, Ardaillou R, Paillard F, Fontanelle J, et al. Study in man of the kinetics of the appearance of uric acid 2–14 C in the urine. Nephron. 1968;5:134–40.

    Article  PubMed  CAS  Google Scholar 

  9. Gutman AB, Yu T-F. 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. 1957;23:600–22.

    Article  PubMed  CAS  Google Scholar 

  10. Gutman AB, Yu TF, Berger L. Tubular secretion of urate in man. J Clin Invest. 1959;38:1778–81.

    Article  PubMed  CAS  Google Scholar 

  11. Praetorius E, Kirk JE. Hypouricemia: with evidence for tubular elimination of uric acid. J Lab Clin Med. 1950;35:856–68.

    Google Scholar 

  12. Matsuo H, Chiba T, Nagamori S, Nakayama A, et al. Mutations in glucose transporter 9 gene SLC2A9 cause renal hypouricemia. Am J Hum Genet. 2008;83:744–51.

    Article  PubMed  CAS  Google Scholar 

  13. Dinour D, Gray NK, Ganon L, Knox AJ, et al. Two novel homozygous SLC2A9 mutations cause renal hypouricemia type 2. Nephrol Dial Transplant. 2011.

  14. Dinour D, Gray NK, Campbell S, Shu X, et al. Homozygous SLC2A9 mutations cause severe renal hypouricemia. J Am Soc Nephrol. 2010;21:64–72.

    Article  PubMed  CAS  Google Scholar 

  15. Steele TH. Urate secretion in man: the pyrazinamide suppression test. Ann Intern Med. 1973;79:734–7.

    PubMed  CAS  Google Scholar 

  16. Anzai N, Ichida K, Jutabha P, Kimura T, et al. Plasma urate level is directly regulated by a voltage-driven urate efflux transporter URATv1 (SLC2A9) in humans. J Biol Chem. 2008;283:26834–8.

    Article  PubMed  CAS  Google Scholar 

  17. Steele TH, Oppenheimer S. Factors affecting urate excretion following diuretic administration in man. Am J Med. 1969;47:564–74.

    Article  PubMed  CAS  Google Scholar 

  18. Whitehead TP, Jungner I, Robinson D, Kolar W, et al. Serum urate, serum glucose and diabetes. Ann Clin Biochem. 1992;29:159–61.

    PubMed  Google Scholar 

  19. Skeith MD, Healey LA, Cutler RE. Urate excretion during mannitol and glucose diuresis. J Lab Clin Med. 1967;70:213–20.

    PubMed  CAS  Google Scholar 

  20. Bailey CJ, Gross JL, Pieters A, Bastien A, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet. 375: 2223–33.

  21. Dalbeth N, Wong S, Gamble GD, Horne A, et al. Acute effect of milk on serum urate concentrations: a randomised controlled crossover trial. Ann Rheum Dis. 69:1677–82.

  22. Choi HK, Atkinson K, Karlson EW, Willett W, et al. Purine-rich foods, dairy and protein intake, and the risk of gout in men. N Engl J Med. 2004;350:1093–103.

    Article  PubMed  CAS  Google Scholar 

  23. Dolaeus J, Stephens W. Dolaeus Upon the Cure of the Gout by Milk-Diet. To which is prefixed an Essay upon diet. By William Stephens, M.D. F.R.S. Fellow of the King and Queen’s College of Physicians in Ireland, Physician to the Royal Hospital, and Botany Lecturer in the University of Dublin. Printed for J. Smith and W. Bruce on the Blind-Key in Dublin: And Sold by John Osborn and Thomas Longman in Pater-noster-Row, 1732.

  24. Burnier M, Roch-Ramel F, Brunner HR. Renal effects of angiotensin II receptor blockade in normotensive subjects. Kidney Int. 1996;49:1787–90.

    Article  PubMed  CAS  Google Scholar 

  25. Edwards RM, Trizna W, Stack EJ, Weinstock J. Interaction of nonpeptide angiotensin II receptor antagonists with the urate transporter in rat renal brush-border membranes. J Pharmacol Exp Ther. 1996;276:125–9.

    PubMed  CAS  Google Scholar 

  26. Rafey MA, Lipkowitz MS, Leal-Pinto E, Abramson RG. Uric acid transport. Curr Opin Nephrol Hypertens. 2003;12:511–6.

    Article  PubMed  CAS  Google Scholar 

  27. Abramson RG, Lipkowitz MS. Evolution of the uric acid transport mechanisms in vertebrate kidney. In: Kinne RKH, editor. Basic principles in transport, vol. 3. Basel: Karger; 1990. p. 115–53.

    Google Scholar 

  28. Wu XW, Muzny DM, Lee CC, Caskey CT. Two independent mutational events in the loss of urate oxidase during hominoid evolution. J Mol Evol. 1992;34:78–84.

    Article  PubMed  CAS  Google Scholar 

  29. Wu X, Wakamiya M, Vaishnav S, Geske R, et al. Hyperuricemia and urate nephropathy in urate oxidase-deficient mice. Proc Natl Acad Sci U S A. 1994;91:742–6.

    Article  PubMed  CAS  Google Scholar 

  30. Enomoto A, Kimura H, Chairoungdua A, Shigeta Y, et al. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature. 2002;417:447–52.

    PubMed  CAS  Google Scholar 

  31. Guggino SE, Aronson PS. Paradoxical effects of pyrazinoate and nicotinate on urate transport in dog renal microvillus membranes. J Clin Invest. 1985;76:543–7.

    Article  PubMed  CAS  Google Scholar 

  32. Guggino SE, Martin GJ, Aronson PS. Specificity and modes of the anion exchanger in dog renal microvillus membranes. Am J Physiol. 1983;244:F612–21.

    PubMed  CAS  Google Scholar 

  33. Jang WC, Nam YH, Ahn YC, Park SM, et al. G109T polymorphism of SLC22A12 gene is associated with serum uric acid level, but not with metabolic syndrome. Rheumatol Int. 2011.

  34. Dinour D, Bahn A, Ganon L, Ron R, et al. URAT1 mutations cause renal hypouricemia type 1 in Iraqi Jews. Nephrol Dial Transplant. 2011;26:2175–81.

    Article  PubMed  CAS  Google Scholar 

  35. Kenny EE, Kim M, Gusev A, Lowe JK, et al. Increased power of mixed models facilitates association mapping of 10 loci for metabolic traits in an isolated population. Hum Mol Genet. 2011;20:827–39.

    Article  PubMed  CAS  Google Scholar 

  36. Kolz M, Johnson T, Sanna S, Teumer A, et al. Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations. PLoS Genet. 2009;5:e1000504.

    Article  PubMed  Google Scholar 

  37. Komoda F, Sekine T, Inatomi J, Enomoto A, et al. The W258X mutation in SLC22A12 is the predominant cause of Japanese renal hypouricemia. Pediatr Nephrol. 2004;19:728–33.

    Article  PubMed  Google Scholar 

  38. Hediger MA. Kidney function: gateway to a long life? Nature. 2002;417:393–5.

    Article  PubMed  CAS  Google Scholar 

  39. Dehghan A, Kottgen A, Yang Q, Hwang SJ, et al. Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study. Lancet. 2008;372:1953–61.

    Article  PubMed  CAS  Google Scholar 

  40. Li S, Sanna S, Maschio A, Busonero F, et al. The GLUT9 gene is associated with serum uric acid levels in Sardinia and Chianti cohorts. PLoS Genet. 2007;3:e194.

    Article  PubMed  Google Scholar 

  41. Wallace C, Newhouse SJ, Braund P, Zhang F, et al. Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia. Am J Hum Genet. 2008;82:139–49.

    Article  PubMed  CAS  Google Scholar 

  42. Phay JE, Hussain HB, Moley JF. Cloning and expression analysis of a novel member of the facilitative glucose transporter family, SLC2A9 (GLUT9). Genomics. 2000;66:217–20.

    Article  PubMed  CAS  Google Scholar 

  43. Keembiyehetty C, Augustin R, Carayannopoulos MO, Steer S, et al. Mouse glucose transporter 9 splice variants are expressed in adult liver and kidney and are up-regulated in diabetes. Mol Endocrinol. 2006;20:686–97.

    Article  PubMed  CAS  Google Scholar 

  44. Augustin R, Carayannopoulos MO, Dowd LO, Phay JE, et al. Identification and characterization of human glucose transporter-like protein-9 (GLUT9): alternative splicing alters trafficking. J Biol Chem. 2004;279:16229–36.

    Article  PubMed  CAS  Google Scholar 

  45. Caulfield MJ, Munroe PB, O’Neill D, Witkowska K, et al. SLC2A9 is a high-capacity urate transporter in humans. PLoS Med. 2008;5:e197.

    Article  PubMed  Google Scholar 

  46. Vitart V, Rudan I, Hayward C, Gray NK, et al. SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat Genet. 2008;40:437–42.

    Article  PubMed  CAS  Google Scholar 

  47. Preitner F, Bonny O, Laverriere A, Rotman S, et al. Glut9 is a major regulator of urate homeostasis and its genetic inactivation induces hyperuricosuria and urate nephropathy. Proc Natl Acad Sci U S A. 2009;106:15501–6.

    Article  PubMed  CAS  Google Scholar 

  48. Mobasheri A, Neama G, Bell S, Richardson S, et al. Human articular chondrocytes express three facilitative glucose transporter isoforms: GLUT1, GLUT3 and GLUT9. Cell Biol Int. 2002;26:297–300.

    Article  PubMed  CAS  Google Scholar 

  49. Yang Q, Kottgen A, Dehghan A, Smith AV, et al. Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors. Circ Cardiovasc Genet. 2010;3:523–30.

    Article  PubMed  CAS  Google Scholar 

  50. Woodward OM, Kottgen A, Coresh J, Boerwinkle E, et al. Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout. Proc Natl Acad Sci U S A. 2009;106:10338–42.

    Article  PubMed  CAS  Google Scholar 

  51. Yamane S, Reddi AH. Induction of chondrogenesis and superficial zone protein accumulation in synovial side population cells by BMP-7 and TGF-beta1. J Orthop Res. 2008;26:485–92.

    Article  PubMed  CAS  Google Scholar 

  52. Iharada M, Miyaji T, Fujimoto T, Hiasa M, et al. Type 1 sodium-dependent phosphate transporter (SLC17A1 protein) is a Cl(−)-dependent urate exporter. J Biol Chem. 285:26107–13.

  53. Jutabha P, Anzai N, Kitamura K, Taniguchi A, et al. Human sodium phosphate transporter 4 (hNPT4/SLC17A3) as a common renal secretory pathway for drugs and urate. J Biol Chem. 285:35123–32.

  54. Eraly SA, Vallon V, Rieg T, Gangoiti JA, et al. Multiple organic anion transporters contribute to net renal excretion of uric acid. Physiol Genom. 2008;33:180–92.

    Article  CAS  Google Scholar 

  55. Xu G, Bhatnagar V, Wen G, Hamilton BA, et al. Analyses of coding region polymorphisms in apical and basolateral human organic anion transporter (OAT) genes [OAT1 (NKT), OAT2, OAT3, OAT4, URAT (RST)]. Kidney Int. 2005;68:1491–9.

    Article  PubMed  CAS  Google Scholar 

  56. Ekaratanawong S, Anzai N, Jutabha P, Miyazaki H, et al. Human organic anion transporter 4 is a renal apical organic anion/dicarboxylate exchanger in the proximal tubules. J Pharmacol Sci. 2004;94:297–304.

    Article  PubMed  CAS  Google Scholar 

  57. Hyink DP, Rappoport JZ, Wilson PD, Abramson RG. Expression of the urate transporter/channel is developmentally regulated in human kidneys. Am J Physiol Ren Physiol. 2001;281:F875–886.

    CAS  Google Scholar 

  58. Lipkowitz MS, Leal-Pinto E, Rappoport JZ, Najfeld V, et al. Functional reconstitution, membrane targeting, genomic structure, and chromosomal localization of a human urate transporter. J Clin Invest. 2001;107:1103–15.

    Article  PubMed  CAS  Google Scholar 

  59. Leal-Pinto E, Cohen BE, Lipkowitz MS, Abramson RG. Functional analysis and molecular model of the human urate transporter/channel, hUAT. Am J Physiol Ren Physiol. 2002;283:F150–163.

    CAS  Google Scholar 

  60. Lipkowitz MS, Leal-Pinto E, Cohen BE, Abramson RG. Galectin 9 is the sugar-regulated urate transporter/channel UAT. Glycoconj J. 2004;19:491–8.

    Article  PubMed  Google Scholar 

  61. Van Aubel RA, Smeets PH, van den Heuvel JJ, Russel FG. Human organic anion transporter MRP4 (ABCC4) is an efflux pump for the purine end metabolite urate with multiple allosteric substrate binding sites. Am J Physiol Ren Physiol. 2005;288:F327–333.

    Article  Google Scholar 

  62. Gopal E, Umapathy NS, Martin PM, Ananth S, et al. Cloning and functional characterization of human SMCT2 (SLC5A12) and expression pattern of the transporter in kidney. Biochim Biophys Acta. 2007;1768:2690–7.

    Article  PubMed  CAS  Google Scholar 

  63. Anzai N, Miyazaki H, Noshiro R, Khamdang S, et al. The multivalent PDZ domain-containing protein PDZK1 regulates transport activity of renal urate-anion exchanger URAT1 via its C terminus. J Biol Chem. 2004;279:45942–50.

    Article  PubMed  CAS  Google Scholar 

  64. Jutabha P, Anzai N, Endou H. Interaction of the multivalent PDZ damain protein PDZK1 with type 1 sodium-phosphate cotransporter (NPT1). J Am Soc Nephrol. 2005;16:350A.

    Google Scholar 

  65. Miyazaki H, Anzai N, Ekaratanawong S, Sakata T, et al. Modulation of renal apical organic anion transporter 4 function by two PDZ domain-containing proteins. J Am Soc Nephrol. 2005;16:3498–506.

    Article  PubMed  CAS  Google Scholar 

  66. Halestrap AP, Price NT. The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem J. 1999;343(Pt 2):281–99.

    Article  PubMed  CAS  Google Scholar 

  67. Jutabha P, Anzai N, Kitamura K, Taniguchi A, et al. Human sodium phosphate transporter 4 (hNPT4/SLC17A3) as a common renal secretory pathway for drugs and urate. J Biol Chem. 2011;285:35123–32.

    Article  Google Scholar 

  68. Dalbeth N, Wong S, Gamble GD, Horne A, et al. Acute effect of milk on serum urate concentrations: a randomised controlled crossover trial. Ann Rheum Dis. 2010;69:1677–82.

    Article  PubMed  CAS  Google Scholar 

Download references

Disclosure

No potential conflicts of interest relevant to this article were reported.

Author information

Authors and Affiliations

  1. Nephrology and Hypertension, Georgetown University Medical Center, 6PHC, Suite F6003, 3800 Reservoir Road, NW, Washington, DC, 20007, USA

    Michael S. Lipkowitz

Authors
  1. Michael S. Lipkowitz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael S. Lipkowitz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lipkowitz, M.S. Regulation of Uric Acid Excretion by the Kidney. Curr Rheumatol Rep 14, 179–188 (2012). https://doi.org/10.1007/s11926-012-0240-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11926-012-0240-z

Keywords

Search

Navigation