Background/Aims: Exercise-induced acute renal failure [exercise-induced acute kidney injury (EI-AKI)] is defined as AKI due to heavy anaerobic exercise. Although hypouricemia is known to be a risk factor for the onset of EI-AKI, a direct causal link between EI-AKI and serum uric acid has not been established. This study aimed to analyze urate transporter genes in patients with EI-AKI and its molecular mechanism. Methods: Genomic DNA and total RNA were isolated from peripheral blood leukocytes of patients with a history of EI-AKI. Mutations were analyzed by PCR and a direct sequencing method. We first analyzed the SLC22A12 gene, and then the SLC2A9 gene if no mutations were found in SLC22A12. Results: Seventeen patients were enrolled in this study and 16 had mutations: 15 in SLC22A12 and 1 in SLC2A9. Fourteen (82.4%) patients showed hypouricemia, and all of the patients with hypouricemia had either homozygous or compound heterozygous mutations in SLC22A12 or SLC2A9, which confirmed that all of them had renal hypouricemia. Two patients had heterozygous mutations of SLC22A12, and they were not accompanied by hypouricemia. One patient was found to have no mutations in SLC22A12 or SLC2A9. Conclusion: We were able to determine the genetic background of urate transporter genes in patients with EI-AKI. Decreased function of urate transporters, rather than decreased serum uric acid levels, may be of great importance for the onset of EI-AKI.

Keywords:
Exercise-induced acute kidney injury, Renal hypouricemia, Urate transporter
1.
Ishikawa I: Acute renal failure with severe loin pain and patchy renal ischemia after anaerobic exercise in patients with or without renal hypouricemia. Nephron 2002;91:559-570.
2.
Erley CM, Hirschberg RR, Hoefer W, Shaefer K: Acute renal failure due to uric acid nephropathy in a patient with renal hypouricemia. Klin Wochenschr 1989;67:308-312.
3.
Komoda F, Sekine T, Inatomi J, Enomoto A, Endou H, Ota T, Matsuyama T, Ogata T, Ikeda M, Awazu M, Muroya K, Kamimaki I, Igarashi T: The W258X mutation in SLC22A12 is the predominant cause of Japanese renal hypouricemia. Pediatr Nephrol 2004;19:728-733.
4.
Anzai N, Kanai Y, Endou H: New insights into renal transport of urate. Curr Opin Rheumatol 2007;19:151-157.
5.
Takahashi T, Tsuchida S, Oyamada T, Ohno T, Miyashita M, Saito S, Komatsu K, Takashina K, Takada G: Recurrent URAT1 gene mutations and prevalence of renal hypouricemia in Japanese. Pediatr Nephrol 2005;20:576-578.
6.
Vitart V, Rudan I, Hayward C, Gray NK, Floyd J, Palmer CN, Knott SA, Kolcic I, Polasek O, Graessler J, Wilson JF, Marinaki A, Riches PL, Shu X, Janicijevic B, Smolej-Narancic N, Gorgoni B, Morgan J, Campbell S, Biloglav Z, Barac-Lauc L, Pericic M, Klaric IM, Zgaga L, Skaric-Juric T, Wild SH, Richardson WA, Hohenstein P, Kimber CH, Tenesa A, Donnelly LA, Fairbanks LD, Aringer M, McKeigue PM, Ralston SH, Morris AD, Rudan P, Hastie ND, Campbell H, Wright AF: SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat Genet 2008;40:437-442.
7.
Anzai N, Ichida K, Jutabha P, Kimura T, Babu E, Jin CJ, Srivastava S, Kitamura K, Hisatome I, Endou H, Sakurai H: Plasma urate level is directly regulated by a voltage-driven urate efflux transporter URATv1 (SLC2A9) in humans. J Biol Chem 2008;283:26834-26838.
8.
Matsuo H, Chiba T, Nagamori S, Nakayama A, Domoto H, Phetdee K, Wiriyasermkul P, Kikuchi Y, Oda T, Nishiyama J, Nakamura T, Morimoto Y, Kamakura K, Sakurai Y, Nonoyama S, Kanai Y, Shinomiya N: Mutations in glucose transporter 9 gene SLC2A9 cause renal hypouricemia. Am J Hum Genet 2008;83:744-751.
9.
Dinour D, Gray NK, Campbell S, Shu X, Sawyer L, Richardson W, Rechavi G, Amariglio N, Ganon L, Sela BA, Bahat H, Goldman M, Weissgarten J, Millar MR, Wright AF, Holtzman EJ: Homozygous SLC2A9 mutations cause severe renal hypouricemia. J Am Soc Nephrol 2010;21:64-72.
10.
Kikuchi Y, Koga H, Yasutomo Y, Kawabata Y, Shimizu E, Naruse M, Kiyama S, Nonoguchi H, Tomita K, Sasatomi Y, Takebayashi S: Patients with renal hypouricemia with exercise-induced acute renal failure and chronic renal dysfunction. Clin Nephrol 2000;53:467-472.
11.
Tanaka M, Itoh K, Matsushita K, Matsushita K, Wakita N, Adachi M, Nonoguchi H, Kitamura K, Hosoyamada M, Endou H, Tomita K: Two male siblings with hereditary renal hypouricemia and exercise-induced ARF. Am J Kidney Dis 2003;42:1287-1292.
12.
Ohta T, Sakano T, Ogawa T, Kato J, Awaya Y, Kihara H, Kinoshita Y: Exercise induced acute renal failure with renal hypouricemia: a case report and a review of the literature. Clin Nephrol 2002;58:313-316.
13.
Fujinaga S, Ito A, Nakagawa M, Watanabe T, Ohtomo Y, Shimizu T: Posterior reversible encephalopathy syndrome with exercise-induced acute kidney injury in renal hypouricemia type 1. Eur J Pediatr DOI: 10.1007/s00431-013-1986-7.
14.
Shima Y, Nozu K, Nozu Y, Togawa H, Kaito H, Matsuo M, Iijima K, Nakanishi K, Yoshikawa N: Recurrent EIARF and PRES with severe renal hypouricemia by compound heterozygous SLC2A9 mutation. Pediatrics 2011;127:e1621-e1625.
15.
Iwai N, Mino Y, Hosoyamada M, Tago N, Kokubo Y, Endou H: A high prevalence of renal hypouricemia caused by inactive SLC22A12 in Japanese. Kidney Int 2004;66:935-944.
16.
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: Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature 2002;417:447-452.
17.
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.
18.
Ames BN, Cathcart R, Schwiers E, Hochstein P: Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci USA 1981;78:6858-6862.
19.
Kaneko K, Taniguchi N, Tanabe Y, Nakano T, Hasui M, Nozu K: Oxidative imbalance in idiopathic renal hypouricemia. Pediatr Nephrol 2009;24:869-871.
20.
Price KL, Sautin YY, Long DA, Zhang L, Miyazaki H, Mu W, Endou H, Johnson RJ: Human vascular smooth muscle cells express a urate transporter. J Am Soc Nephrol 2006;17:1791-1795.
21.
Anzai N, Endou H: Urate transporters: an evolving field. Semin Nephrol 2011;31:400-409.
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2013
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