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      Decreased extra-renal urate excretion is a common cause of hyperuricemia

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          ABCG2, also known as BCRP, is a high-capacity urate exporter, the dysfunction of which raises gout/hyperuricemia risk. Generally, hyperuricemia has been classified into urate 'overproduction type' and/or 'underexcretion type' based solely on renal urate excretion, without considering an extra-renal pathway. Here we show that decreased extra-renal urate excretion caused by ABCG2 dysfunction is a common mechanism of hyperuricemia. Clinical parameters, including urinary urate excretion, are examined in 644 male outpatients with hyperuricemia. Paradoxically, ABCG2 export dysfunction significantly increases urinary urate excretion and risk ratio of urate overproduction. Abcg2-knockout mice show increased serum uric acid levels and renal urate excretion, and decreased intestinal urate excretion. Together with high ABCG2 expression in extra-renal tissues, our data suggest that the 'overproduction type' in the current concept of hyperuricemia be renamed 'renal overload type', which consists of two subtypes—'extra-renal urate underexcretion' and genuine 'urate overproduction'—providing a new concept valuable for the treatment of hyperuricemia and gout.


          Hyperuricemia, or gout, is thought to arise either from urate overproduction or from decreased renal excretion of urate. Ichida et al. show that the extra-renal excretion of urate also has a role in the pathogenesis of hyperuricemia, and propose a new classification for patients with this disease.

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          Most cited references 28

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          Molecular identification of a renal urate anion exchanger that regulates blood urate levels.

          Urate, a naturally occurring product of purine metabolism, is a scavenger of biological oxidants implicated in numerous disease processes, as demonstrated by its capacity of neuroprotection. It is present at higher levels in human blood (200 500 microM) than in other mammals, because humans have an effective renal urate reabsorption system, despite their evolutionary loss of hepatic uricase by mutational silencing. The molecular basis for urate handling in the human kidney remains unclear because of difficulties in understanding diverse urate transport systems and species differences. Here we identify the long-hypothesized urate transporter in the human kidney (URAT1, encoded by SLC22A12), a urate anion exchanger regulating blood urate levels and targeted by uricosuric and antiuricosuric agents (which affect excretion of uric acid). Moreover, we provide evidence that patients with idiopathic renal hypouricaemia (lack of blood uric acid) have defects in SLC22A12. Identification of URAT1 should provide insights into the nature of urate homeostasis, as well as lead to the development of better agents against hyperuricaemia, a disadvantage concomitant with human evolution.
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            Preliminary criteria for the classification of the acute arthritis of primary gout.

            The American Rheumatism Association sub-committe on classification criteria for gout analyzed data from more than 700 patients with gout, pseudogout, rheumatoid arthritis, or septic arthritis. Criteria for classifying a patient as having gout were a) the presence of characteristic urate crystals in the joint fluid, and/or b) a topus proved to contain urate crystals by chemical or polarized light microscopic means, and/or c) the presence of six of the twelve clinical, laboratory, and X-ray phenomena listed in Table 5.
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              SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout.

              Uric acid is the end product of purine metabolism in humans and great apes, which have lost hepatic uricase activity, leading to uniquely high serum uric acid concentrations (200-500 microM) compared with other mammals (3-120 microM). About 70% of daily urate disposal occurs via the kidneys, and in 5-25% of the human population, impaired renal excretion leads to hyperuricemia. About 10% of people with hyperuricemia develop gout, an inflammatory arthritis that results from deposition of monosodium urate crystals in the joint. We have identified genetic variants within a transporter gene, SLC2A9, that explain 1.7-5.3% of the variance in serum uric acid concentrations, following a genome-wide association scan in a Croatian population sample. SLC2A9 variants were also associated with low fractional excretion of uric acid and/or gout in UK, Croatian and German population samples. SLC2A9 is a known fructose transporter, and we now show that it has strong uric acid transport activity in Xenopus laevis oocytes.

                Author and article information

                Nat Commun
                Nat Commun
                Nature Communications
                Nature Pub. Group
                03 April 2012
                : 3
                : 764
                [1 ]simpleDepartment of Pathophysiology, Tokyo University of Pharmacy and Life Sciences , 1432-1 Horinouchi, Hachiouji, Tokyo 192-0392, Japan.
                [2 ]simpleDivision of Kidney and Hypertension, Department of Internal Medicine, Jikei University School of Medicine , 3-19-18 Shinbashi, Minato-ku, Tokyo 105-8471, Japan.
                [3 ]simpleDepartment of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College , 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
                [4 ]simpleDepartment of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo , 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
                [5 ]simpleThird Division, Aeromedical Laboratory, Japan Air Self-Defense Force , 2-3 Inariyama, Sayama, Saitama 350-1324, Japan.
                [6 ]simpleMidorigaoka Hospital , 3-13-1 Makami-cho, Takatsuki, Osaka 569-1121, Japan.
                [7 ]simpleDepartment of Preventive Medicine and Public Health, National Defense Medical College , 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
                [8 ]simpleLaboratory for Mathematics, Premedical Course, National Defense Medical College , 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
                [9 ]simpleLaboratory for Statistical Analysis, Center for Genomic Medicine, Institute of Physical and Chemical Research (RIKEN) , 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
                [10 ]simpleLaboratory for Biofunctions, The Central Research Institute, National Defense Medical College , 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
                [11 ]simpleDepartment of Human Physiology and Pathology, Teikyo University School of Pharmaceutical Sciences , 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
                [12 ]These authors contributed equally to this work.
                Author notes
                Copyright © 2012, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

                This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit




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