Current Rheumatology Reports

, Volume 14, Issue 2, pp 179–188

Regulation of Uric Acid Excretion by the Kidney

CRYSTAL ARTHRITIS (MH PILLINGER, SECTION EDITOR)

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.

Keywords

Uric acid Regulation Excretion Kidney Renal Urate Serum urate Genome-wide association study GWAS Gout Hyperuricemia Hypouricemia Dairy Dairy diet Urate transport Homeostasis Diuretics Hyperglycemia Losartan PDZK1 SMCT URAT1 GLUT9 ABCG2 NPT1 NPT4 Organic ion transporter OAT hUAT 

References

  1. 1.
    Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med. 2008;359:1811–21.PubMedCrossRefGoogle Scholar
  2. 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.PubMedCrossRefGoogle Scholar
  3. 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.Google Scholar
  4. 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.PubMedCrossRefGoogle Scholar
  5. 5.
    Maesaka JK, Fishbane S. Regulation of renal urate excretion: a critical review. Am J Kidney Dis. 1998;32:917–33.PubMedCrossRefGoogle Scholar
  6. 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.PubMedCrossRefGoogle Scholar
  7. 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.PubMedGoogle Scholar
  8. 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.PubMedCrossRefGoogle Scholar
  9. 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.PubMedCrossRefGoogle Scholar
  10. 10.
    Gutman AB, Yu TF, Berger L. Tubular secretion of urate in man. J Clin Invest. 1959;38:1778–81.PubMedCrossRefGoogle Scholar
  11. 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. 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.PubMedCrossRefGoogle Scholar
  13. 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.Google Scholar
  14. 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.PubMedCrossRefGoogle Scholar
  15. 15.
    Steele TH. Urate secretion in man: the pyrazinamide suppression test. Ann Intern Med. 1973;79:734–7.PubMedGoogle Scholar
  16. 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.PubMedCrossRefGoogle Scholar
  17. 17.
    Steele TH, Oppenheimer S. Factors affecting urate excretion following diuretic administration in man. Am J Med. 1969;47:564–74.PubMedCrossRefGoogle Scholar
  18. 18.
    Whitehead TP, Jungner I, Robinson D, Kolar W, et al. Serum urate, serum glucose and diabetes. Ann Clin Biochem. 1992;29:159–61.PubMedGoogle Scholar
  19. 19.
    Skeith MD, Healey LA, Cutler RE. Urate excretion during mannitol and glucose diuresis. J Lab Clin Med. 1967;70:213–20.PubMedGoogle Scholar
  20. 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.Google Scholar
  21. 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.Google Scholar
  22. 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.PubMedCrossRefGoogle Scholar
  23. 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.Google Scholar
  24. 24.
    Burnier M, Roch-Ramel F, Brunner HR. Renal effects of angiotensin II receptor blockade in normotensive subjects. Kidney Int. 1996;49:1787–90.PubMedCrossRefGoogle Scholar
  25. 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.PubMedGoogle Scholar
  26. 26.
    Rafey MA, Lipkowitz MS, Leal-Pinto E, Abramson RG. Uric acid transport. Curr Opin Nephrol Hypertens. 2003;12:511–6.PubMedCrossRefGoogle Scholar
  27. 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. 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.PubMedCrossRefGoogle Scholar
  29. 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.PubMedCrossRefGoogle Scholar
  30. 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.PubMedGoogle Scholar
  31. 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.PubMedCrossRefGoogle Scholar
  32. 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.PubMedGoogle Scholar
  33. 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.Google Scholar
  34. 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.PubMedCrossRefGoogle Scholar
  35. 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.PubMedCrossRefGoogle Scholar
  36. 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.PubMedCrossRefGoogle Scholar
  37. 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.PubMedCrossRefGoogle Scholar
  38. 38.
    Hediger MA. Kidney function: gateway to a long life? Nature. 2002;417:393–5.PubMedCrossRefGoogle Scholar
  39. 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.PubMedCrossRefGoogle Scholar
  40. 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.PubMedCrossRefGoogle Scholar
  41. 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.PubMedCrossRefGoogle Scholar
  42. 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.PubMedCrossRefGoogle Scholar
  43. 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.PubMedCrossRefGoogle Scholar
  44. 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.PubMedCrossRefGoogle Scholar
  45. 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.PubMedCrossRefGoogle Scholar
  46. 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.PubMedCrossRefGoogle Scholar
  47. 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.PubMedCrossRefGoogle Scholar
  48. 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.PubMedCrossRefGoogle Scholar
  49. 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.PubMedCrossRefGoogle Scholar
  50. 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.PubMedCrossRefGoogle Scholar
  51. 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.PubMedCrossRefGoogle Scholar
  52. 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.Google Scholar
  53. 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.Google Scholar
  54. 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.CrossRefGoogle Scholar
  55. 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.PubMedCrossRefGoogle Scholar
  56. 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.PubMedCrossRefGoogle Scholar
  57. 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.Google Scholar
  58. 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.PubMedCrossRefGoogle Scholar
  59. 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.Google Scholar
  60. 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.PubMedCrossRefGoogle Scholar
  61. 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.CrossRefGoogle Scholar
  62. 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.PubMedCrossRefGoogle Scholar
  63. 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.PubMedCrossRefGoogle Scholar
  64. 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. 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.PubMedCrossRefGoogle Scholar
  66. 66.
    Halestrap AP, Price NT. The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem J. 1999;343(Pt 2):281–99.PubMedCrossRefGoogle Scholar
  67. 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.CrossRefGoogle Scholar
  68. 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.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Nephrology and HypertensionGeorgetown University Medical CenterWashingtonUSA

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