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Other Original Articles: Naoki Wakida, Do Gia Tuyen, Masataka Adachi, Taku Miyoshi, Hiroshi Nonoguchi, Toshiaki Oka, Osamu Ueda, Masahiro Tazawa, Satoshi Kurihara, Yoshitaka Yoneta, Hajime Shimada, Takashi Oda, Yuichi Kikuchi, Hirotaka Matsuo, Makoto Hosoyamada, Hitoshi Endou, Masaki Otagiri, Kimio Tomita, and Kenichiro Kitamura Mutations in Human Urate Transporter 1 Gene in Presecretory Reabsorption Defect Type of Familial Renal Hypouricemia J Clin Endocrinol Metab 2005; 90: 2169-2174 [Abstract] [Full text] [PDF]

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The relation between renal hypouricemic subtype and genotype based on pharmacological loading tests.

Kimiyoshi Ichida, Tadashi Sato, and Tatsuo Hosoya.   (15 August 2006)

The relation between renal hypouricemic subtype and genotype based on pharmacological loading tests. 15 August 2006
Kimiyoshi Ichida, lecturer Jikei University School of Medicine, Tadashi Sato, and Tatsuo Hosoya. Send letter to journal: Re: The relation between renal hypouricemic subtype and genotype based on pharmacological loading tests. ichida{at}jikei.ac.jp Kimiyoshi Ichida, et al.	To the Editor: In a recent article, Wakida et al. (1) demonstrated that urate transporter 1, URAT1, is responsible for presecretory reabsorption defect- type renal hypouricemia. They based their conclusions on the fact that seven patients with pathogenic SLC22A12 mutations encoding URAT1 harbored presecretory reabsorption defect-type renal hypouricemia, and one patient without a pathogenic SLC22A12 mutation harbored postsecretory reabsorption defect-type renal hypouricemia (1). Renal hypouricemia has been classified into five subtypes according to responses to the uricosuric drug, probenecid, and antiuricosuric drug, pyrazinamide (PZA): a presecretory reabsorption defect, a postsecretory reabsorption defect, total inhibition of urate reabsorption, enhanced secretion, and a subtotal defect in urate transport. These subtypes are categorized based on a supposition in the 1970s that PZA inhibits tubular secretion of uric acid. Guggino and Roch- Ramel, however, demonstrated that the anti-uricosuric effect of PZA was due to enhanced urate reabsorption through exchange of PZA via the urate/anion exchanger at the brush-border membrane, after PZA moved into proximal cells by sodium-cotransport (2, 3). Thus, this classification has lost its scientific basis. Additionally, renal hypouricemia is sometimes classified into multiple subtypes because of ambiguous criteria of a response pattern to the loading tests. Accordingly, this has been used as a traditional classification. Recently, we investigated SLC22A12 mutations in renal hypouricemic patients who had been previously reported (4). The serum uric acid levels of the proposita, the mother, and the father were 0.5, 2.6, and 2.3 mg/dl, respectively, while the corresponding fractional excretions of uric acid were 54%, 23%, and 21%, respectively. Based on loading tests, the proposita and the mother were classified as either a subtotal defect or a presecretory reabsorption defect, while the father was classified as a postsecretory reabsorption defect (4). In their SLC22A12s, we identified a homozygous G774A mutation in the proposita and a heterozygous mutation in the mother and the father. Furthermore, we classified another eighteen renal hypouricemic patients, most of whom were previously reported, but not classified (5). Out of thirteen renal hypouricemic patients with homozygous or compound heterozygous SLC22A12 mutations, nine patients showed a presecretory reabsorption defect, one a total inhibition of urate reabsorption, and three a subtotal defect. Three heterozygous patients were classified as a presecretory reabsorption defect or a subtotal defect, while one was classified as a postsecretory reabsorption defect. One patient with wild type URAT1 was classified as enhanced secretion type. These results demonstrate that most renal hypouricemia with SLC22A12 mutations are classified as presecretory reabsorption defects as Wakida N et al. reported. We, however, need to keep in mind that renal hypouricemia with SLC22A12 mutations show several subtypes, and the subtype classification does not exactly correspond with the genotype of renal hypouricemia. References 1. Wakida N, Tuyen do G, Adachi M, Miyoshi T, Nonoguchi H, Oka T, Ueda O, Tazawa M, Kurihara S, Yoneta Y, Shimada H, Oda T, Kikuchi Y, Matsuo H, Hosoyamada M, Endou H, Otagiri M, Tomita K, Kitamura K 2005 Mutations in human urate transporter 1 gene in presecretory reabsorption defect type of familial renal hypouricemia. J Clin Endocrinol Metab 90:2169-2174 2. Guggino SE, Aronson PS 1985 Paradoxical effects of pyrazinoate and nicotinate on urate transport in dog renal microvillus membranes. J Clin Invest 76:543-547 3. Roch-Ramel F, Guisan B, Diezi J 1997 Effects of uricosuric and antiuricosuric agents on urate transport in human brush-border membrane vesicles. J Pharmacol Exp Ther 280:839-845 4. Sato T, Kuno T, Tashiro K, Fujita I, Miyazaki S 1998 Exercise-induced acute renal failure in a girl with renal hypouricemia. Acta Paediatr Jpn 40:93-95 5. Ichida K, Hosoyamada M, Hisatome I, Enomoto A, Hikita M, Endou H, Hosoya T 2004 Clinical and molecular analysis of patients with renal hypouricemia in Japan-influence of URAT1 gene on urinary urate excretion. J Am Soc Nephrol 15:164-173