Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 1/2006

01-04-2006 | Review

Recent developments in our understanding of the renal basis of hyperuricemia and the development of novel antihyperuricemic therapeutics

Authors: Robert Terkeltaub, David A Bushinsky, Michael A Becker

Published in: Arthritis Research & Therapy | Special Issue 1/2006

Login to get access

Abstract

Although dietary, genetic, or disease-related excesses in urate production may contribute to hyperuricemia, impaired renal excretion of uric acid is the dominant cause of hyperuricemia in the majority of patients with gout. The aims of this review are to highlight exciting and clinically pertinent advances in our understanding of how uric acid is reabsorbed by the kidney under the regulation of urate transporter (URAT)1 and other recently identified urate transporters; to discuss urate-lowering agents in clinical development; and to summarize the limitations of currently available antihyperuricemic drugs. The use of uricosuric drugs to treat hyperuricemia in patients with gout is limited by prior urolothiasis or renal dysfunction. For this reason, our discussion focuses on the development of the novel xanthine oxidase inhibitor febuxostat and modified recombinant uricase preparations.
Literature
1.
2.
Becker MA, Jolly M: Clinical gout and the pathogenesis of hyperuricemia. Arthritis and Allied Conditions. Edited by: Koopman WJ, Moreland LW. 2005, Philadelphia: Lippincott, Williams & Wilkins, 2303-2339. 15
3.
Wyngaarden JB, Kelley WN: Gout and Hyperuricemia. 1976, New York: Grune & Stratton, 1-512.
4.
Benedict JD, Forsham PH, Stetten DeW: The metabolism of uric acid in the normal and gouty human studied with the aid of isotopic uric acid. J Biol Chem. 1949, 181: 183-193.PubMed
5.
Sorensen LB: Degradation of uric acid in man. Metabolism. 1959, 8: 687-703.PubMed
6.
Watanabe S, Kang DH, Feng L, Nakagawa T, Kanellis J, Lan H, Mazzali M, Johnson RJ: Uric acid, hominoid evolution, and the pathogenesis of slat sensitivity. Hypertension. 2002, 40: 355-360. 10.1161/01.HYP.0000028589.66335.AA.CrossRefPubMed
7.
Perez-Ruiz F, Calabozo M, Garcia-Erauskin G, Ruibal A, Herrero-Beites AM: Renal underexcretion of uric acid is present in patients with apparent high urinary uric acid output. Arthritis Rheum. 2002, 47: 610-613. 10.1002/art.10792.CrossRefPubMed
8.
Becker MA, Kim M: Regulation of rates of purine synthesis de novo by purine nucleotides and phosphoribosylpyrophosphate. J Biol Chem. 1987, 262: 14532-14537.
9.
Becker MA: Phosphoribosylpyrophosphate synthetase and the regulation of phosphoribosylpyrophosphate production in human cells. Prog Nucl Acid Res Mol Biol. 2001, 69: 115-148.CrossRef
10.
11.
Rieselbach R, Sorensen LB, Shelp WD, Steele TH: Diminished renal urate secretion per nephron as a basis for gout. Ann Intern Med. 1970, 70: 359-366.CrossRef
12.
Roch-Ramel F, Diezi J: Renal transport of organic ions and uric acid. Diseases of the Kidney. Edited by: Schreier RW, Gottschalk CE. 1996, Boston: Little Brown, 231-249. 6
13.
Enomoto A, Kimura H, Chairoungdua A, Shigeta Y, Jutabha P, Cha SH, Hosoyamada M, Takeda M, Sekine T, Igarashi T, et al: Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature. 2002, 417: 447-452.PubMed
14.
Ichida K, Hosoyamada M, Hisatome I, Enomoto A, Hikita M, Endou H, Hosoya T: Clinical and molecular analysis of patients with renal hypouricemia in Japan: influence of URAT1 gene on urinary urate excretion. J Am Soc Nephrol. 2004, 15: 164-173. 10.1097/01.ASN.0000105320.04395.D0.CrossRefPubMed
15.
Anzai N, Miyazaki H, Noshiro R, Khamdang S, Chairoungdua A, Shin HJ, Enomoto A, Sakamoto S, Hirata T, Tomita K, Kanai Y, Endou H: The multivalent PDZ-domain-containing protein PDZKi1 regulates transport activity of renal urate-anion exchanger urate1 via its C terminus. J Biol Chem. 2004, 279: 45942-45950. 10.1074/jbc.M406724200.CrossRefPubMed
16.
Taniguchi A, Urano W, Yamanaka M, Yamanaka H, Hosoyamada M, Endou H, Kamatani N: A common mutation in an organic ion transporter gene, SLC22A12, is a suppressing factor for the development of gout. Arthritis Rheum. 2005, 52: 2576-2577. 10.1002/art.21242.CrossRefPubMed
17.
Ljubojevic M, Herak-Kramberger CM, Hagos Y, Bahn A, Endou H, Burckhardt G, Sabolic I: Rat renal OAT1 and OAT3 exhibit gender differences determined by both androgen stimulation and estrogen inhibition. Am J Physiol Renal Physiol. 2004, 287: F124-F138. 10.1152/ajprenal.00029.2004.CrossRefPubMed
18.
Kim GH, Na KY, Kim SY, Joo KW, Oh YK, Chae SW, Endou H, Han JS: Up-regulation of organic anion transporter 1 protein is induced by chronic furosemide or hydrochlorothiazide infusion in rat kidney. Nephrol Dial Transplant. 2003, 18: 1505-1511. 10.1093/ndt/gfg186.CrossRefPubMed
19.
Kojima R, Sekine T, Kawachi M, Cha SH, Suzuki Y, Endou H: Immunolocalization of multispecific organic anion transporters, OAT1, OAT2, and OAT3, in rat kidney. J Am Soc Nephrol. 2002, 13: 848-857.PubMed
20.
Habu Y, Yano I, Takeuchi A, Saito H, Okuda M, Fukatsu A, Inui K: Decreased activity of basolateral organic ion transports in hyperuricemic rat kidney: roles of organic ion transporters, rOAT1, rOAT3 and rOCT2. Biochem Pharmacol. 2003, 66: 1107-1114. 10.1016/S0006-2952(03)00466-0.CrossRefPubMed
21.
Lipkowitz MS, Leal-Pinto E, Rappoport JZ, Najfeld V, Abramson RG: Functional reconstitution, membrane targeting genomic structure, and chromosomal localization of a human urate transporter. J Clin Invest. 2001, 107: 1103-1115.PubMedCentralCrossRefPubMed
22.
Lipkowitz MS, Leal-Pinto E, Cohen BE, Abramson RG: Galectin 9 is the sugar-regulated urate transporter/channel UAT. Glycoconj J. 2004, 19: 491-498. 10.1023/B:GLYC.0000014078.65610.2f.CrossRefPubMed
23.
Anzai N, Enomoto A, Endou H: Renal urate handling: clinical relevance of recent advances. Curr Rheumatol Rep. 2005, 7: 227-234.CrossRefPubMed
24.
Rafey MA, Lipkowitz MS, Leal-Pinto E, Abramson RG: Uric acid transport. Curr Opin Nephrol Hypertens. 2003, 12: 511-516.CrossRefPubMed
25.
Hediger MA, Johnson RJ, Miyazaki H, Endou H: Molecular physiology of urate transport. Physiology. 2005, 20: 125-133. 10.1152/physiol.00039.2004.CrossRefPubMed
26.
Calabrese G, Simmonds HA, Cameron JS, Davies PM: Precocious familial gout with reduced fractional urate clearance and normal purine enzymes. QJM. 1990, 78: 441-445.
27.
Puig JG, Miranda ME, Mateos FA, Picazo ML, Jimenez ML, Calvin TS, Gil AA: Hereditary nephropathy associated with hyperuricemia and gout. Arch Intern Med. 1993, 153: 357-365. 10.1001/archinte.153.3.357.CrossRefPubMed
28.
Dahan K, Devuyst O, Smaers M, Vertommen D, Loute G, Poux JM, Viron B, Jacquot C, Gagnadoux MF, Chauveau D, et al: A cluster of mutations in the UMOD gene causes familial juvenile hyperuricemic nephropathy with abnormal expression of uromodulin. J Am Soc Nephrol. 2003, 14: 2883-2893. 10.1097/01.ASN.0000092147.83480.B5.CrossRefPubMed
29.
Kudo E, Kamatani N, Tezuka O, Taniguchi A, Yamanaka H, Yabe S, Osabe D, Shinohara S, Nomura K, Segawa M, et al: Familial juvenile hyperuricemic nephropathy: Detection of mutations in the uromodulin gene in five Japanese families. Kidney Int. 2004, 65: 1589-1597. 10.1111/j.1523-1755.2004.00559.x.CrossRefPubMed
30.
Weichhart T, Zlabinger GJ, Saemann MD: The multiple functions of Tamm-Horsfall protein in human health and disease: a mystery clears up. Wien Klin Wochenschr. 2005, 117: 316-322. 10.1007/s00508-005-0353-8.CrossRefPubMed
31.
Cameron JS, Simmonds HA: Hereditary hyperuricemia and renal disease. Semin Nephrol. 2005, 25: 9-18.CrossRefPubMed
32.
Rampoldi L, Caridi G, Santon D, Boaretto F, Bernascone I, Lamorte G, Tardanico R, Dagnino M, Colussi G, Scolari F, et al: Allelism of MCKD, FJHN, and GCKD caused by impairment of uromoduline export dynamics. Hum Molec Genet. 2003, 12: 3369-3384. 10.1093/hmg/ddg353.CrossRefPubMed
33.
Perez-Ruiz F, Inaki H, Herrero-Beites AM: Uricosuric therapy. Crystal-induced Arthropathies. Edited by: Wortmann RL, Schumacher HR Jr, Becker MA, Ryan LM. New York: Elsevier
34.
Emmerson BT: The management of gout. N Engl J Med. 1996, 334: 445-451. 10.1056/NEJM199602153340707.CrossRefPubMed
35.
Bieber JD, Terkeltaub RA: Gout: on the brink of novel therapeutic options for an ancient disease. Arthritis Rheum. 2004, 50: 2400-2414. 10.1002/art.20438.CrossRefPubMed
36.
Hille R, Nishino T: Flavoprotein structure and mechanism. 4. Xanthine oxidase and xanthine dehydrogenase. FASEB J. 1995, 9: 995-1003.PubMed
37.
Raivio KO, Saksela M, Lapatto R: Xanthine oxidoreductase-role in human pathophysiology and in hereditary xanthinuria. The Metabolic and Molecular Bases of Inherited Disease. Edited by: Scriver CR, Beaudet AL, Sly WS, Valle D. 2001, New York: McGraw-Hill, 2639-2652. 8
38.
Berry CE, Hare JM: Xanthine oxidoreductase and cardiovascular disease. Molecular mechanisms and pathophysiological implications. J Physiol. 2004, 555: 589-606. 10.1113/jphysiol.2003.055913.PubMedCentralCrossRefPubMed
39.
Perez-Ruiz F, Alonso-Ruiz A, Calabozo M, Herrero-Beites A, Garcia-Erauskin G, Ruiz-Lucea E: Efficacy of allopurinol and benzbromarone for the control of hyperuricaemia. A pathogenic approach to the treatment of primary chronic gout. Ann Rheum Dis. 1998, 57: 545-549.PubMedCentralCrossRefPubMed
40.
Fam AG: Difficult gout and new approaches for control of hyperuricemia in the allopurinol-allergic patient. Curr Rheumatol Rep. 2001, 3: 29-35.CrossRefPubMed
41.
Arellano F, Sacristan JA: Allopurinol hypersensitivity syndrome: a review. Ann Pharmacother. 1993, 27: 337-343.PubMed
42.
Hung S-I, Chung W-H, Liou L-B, Chu CC, Lin M, Huang HP, Lin YL, Lan JL, Yang LC, Hong HS, et al: HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci USA. 2005, 102: 4134-4139. 10.1073/pnas.0409500102.PubMedCentralCrossRefPubMed
43.
Fam AG, Dunne SM, Iazetta J, Paton TW: Efficacy and safety of desensitization to allopurinol following cutaneous reactions. Arthritis Rheum. 2001, 44: 231-238. 10.1002/1529-0131(200101)44:1<231::AID-ANR30>3.0.CO;2-7.CrossRefPubMed
44.
Riedel AA, Nelson M, Joseph-Ridge N, Wallace K, MacDonald P, Becker M: Compliance with allopurinol therapy among managed care enrollees with gout: a retrospective analysis of administrative claims. J Rheumatol. 2004, 31: 1575-1581.PubMed
45.
Walter-Sack I, de Vries JX, Kutschker C, Ittensohn A, Voss A: Disposition and uric acid lowering effect of oxipurinol: comparison of different oxipurinol formulations and allopurinol in healthy individuals. Eur J Clin Pharmacol. 1995, 49: 215-220. 10.1007/BF00192382.CrossRefPubMed
46.
Okamoto K, Eger BT, Nishino T, Kondo S, Pai EF, Nishino T: An extremely potent inhibitor of xanthine oxidoreductase. Crystal structure of the enzyme-inhibitor complex and mechanism of inhibition. J Biol Chem. 2003, 278: 1848-1855. 10.1074/jbc.M208307200.CrossRefPubMed
47.
Horiuchi H, Ota M, Kobayashi M, Kaneko H, Kasahara Y, Nishimura S, Kondo S, Komoriya K: A comparative study on the hypouricemic activity and potency in renal xanthine calculus formation of two xanthine oxidase/xanthine dehydrogenase inhibitors: TEI-6720 and allopurinol in rats. Res Commun Mol Pathol Pharmacol. 1999, 104: 307-319.PubMed
48.
Osada Y, Tsuchimoto M, Fukushima H, Takahashi K, Kondo S, Hasegawa M, Komoriya K: Hypouricemic effect of the novel xanthine oxidase inhibitor, TEI-6720, in rodents. Eur J Pharmacol. 1993, 241: 183-188. 10.1016/0014-2999(93)90201-R.CrossRefPubMed
49.
Komoriya K, Osada Y, Hasegawa M, Horiuchi H, Kondo S, Couch RC, Griffin TB: Hypouricemic effect of allopurinol and the novel xanthine oxidase inhibitor TEI-6720 in chimpanzees. Eur J Pharmacol. 1993, 250: 455-460. 10.1016/0014-2999(93)90033-E.CrossRefPubMed
50.
Takano Y, Hase-Aoki K, Horiuchi H, Zhao L, Kasahara Y, Kondo S, Becker MA: Selectivity of febuxostat, a novel non-purine inhibitor of xanthine oxidase/xanthine dehydrogenase. Life Sci. 2005, 76: 1835-1847. 10.1016/j.lfs.2004.10.031.CrossRefPubMed
51.
Hoshide S, Nishimura S, Ishii S, Matsuzawa K, Saito N, Tanaka T: Metabolites of TMX-67, a new pharmaceutical entity for the treatment of gout or hyperuricemia, and their pharmaco-kinetic profiles in humans. Drug Metab Rev. 2000, 269-Suppl 2
52.
Becker MA, Schumacher HR, Wortmann RL, MacDonald PA, Palo WA, Eustace D, Vernillet L, Joseph-Ridge N: Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase: a twenty-eight-day, multicenter, phase II, randomized, double-blind, placebo-controlled, dose-response clinical trial examining safety and efficacy in patients with gout. Arthritis Rheum. 2005, 52: 916-923. 10.1002/art.20935.CrossRefPubMed
53.
Becker MA, Schumacher HR, Wortmann RL, MacDonald PA, Eustace D, Palo WA, Streit J, Joseph-Ridge N: Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005, 353: 2450-2461. 10.1056/NEJMoa050373.CrossRefPubMed
54.
Kelly SJ, Delnomdedieu M, Oliverio MI: Diabetes insipidus in uricase-deficient mice: a model for evaluating therapy with poly(ethylene glycol)-modified uricase. J Am Soc Nephrol. 2001, 12: 1001-1009.PubMed
55.
Pui C-H, Jeha S, Carnitta B: Recombinant urate oxidase (ras-buricase) in the prevention and treatment of malignancy-associated hyperuricemia in pediatric and adult patients: results of a compassionate-use trial. Leukemia. 2001, 15: 1505-1509. 10.1038/sj.leu.2402235.CrossRefPubMed
56.
Baraf HSB, Kim S, Matsumoto AK, et al: Resolution of tophi with intravenous Peg-uricase in refractory gout. Arthritis Rheum. 2005, 52: S105-10.1002/art.20724.CrossRef
57.
Pui CH: Urate oxidase in the prophylaxis or treatment of hyperuricemia: the United States experience. Semin Hematol. 2001, 13-21. 10.1016/S0037-1963(01)90039-3. Suppl 10
58.
Goldman SC: Rasburicase: potential role in managing tumor lysis in patients with hematological malignancies. Expert Rev Anticancer Ther. 2003, 3: 429-433. 10.1586/14737140.3.4.429.CrossRefPubMed
59.
Yim BT, Sims-McCallum RP, Chong PH: Rasburicase for the treatment and prevention of hyperuricemia. Ann Pharmacother. 2003, 37: 1047-1054. 10.1345/aph.1C336.CrossRefPubMed
60.
Chu R, Lin Y, Reddy KC, Pan J, Rao MS, Reddy JK, Yeldandi AV: Transformation of epithelial cells stably transfected with H2O2-generating peroxisomal urate oxidase. Cancer Res. 1996, 56: 4846-4852.PubMed
61.
Patetsios P, Rodino W, Wisselink W, Bryan D, Kirwin JD, Panetta TF: Identification of uric acid in aortic aneurysms and athero-sclerotic artery. Ann N Y Acad Sci. 1996, 800: 243-245.CrossRefPubMed
62.
Langemann H, Feuerstein T, Mendelowitsch A, Gratzl O: Microdialytical monitoring of uric and ascorbic acids in the brains of patients after severe brain injury and during neurovascular surgery. J Neurol Neurosurg Psychiatry. 2001, 71: 169-174. 10.1136/jnnp.71.2.169.PubMedCentralCrossRefPubMed
63.
Sundy JS, Becker MA, Baraf HSB, Barkhuizen A, Moreland L, Huang B, Alton M: A phase 2 study of multiple doses of intravenous polyethylene glycol (PEG)-uricase in patients with hyperuricemia and refractory gout. Arthritis Rheum. 2005, 52: S679-10.1002/art.20959.CrossRef
64.
Bomalaski JS, Goddard DH, Grezlak D: Phase I study of uricase formulated with polyethylene glycol (Uricase-PEG 20). Arthritis Rheum. 2002, 46: S141-
Metadata
Title
Recent developments in our understanding of the renal basis of hyperuricemia and the development of novel antihyperuricemic therapeutics
Authors
Robert Terkeltaub
David A Bushinsky
Michael A Becker
Publication date
01-04-2006
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue Special Issue 1/2006
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/ar1909
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits