Hypouricemia and Urate Transporters

Abstract

Hypouricemia is recognized as a rare disorder, defined as a serum uric acid level of 2.0 mg/dL or less. Hypouricemia is divided into an overexcretion type and an underproduction type. The former typical disease is xanthinuria, and the latter is renal hypouricemia (RHUC). The frequency of nephrogenic hypouricemia due to a deficiency of URAT1 is high in Japan, accounting for most asymptomatic and persistent cases of hypouricemia. RHUC results in a high risk of exercise-induced acute kidney injury and urolithiasis. It is vital to promote research on RHUC, as this will lead not only to the elucidation of its pathophysiology but also to the development of new treatments for gout and hyperuricemia.

Keywords: URAT1; hypouricemia; renal hypouricemia; urate transporter; xanthinuria.

Figure 1

Flowchart for diagnosing RHUC in routine clinical practice. When low serum uric acid levels are detected, especially when the value is <2.0 mg/dL, uric acid and creatinine levels in blood and urine should be retested, and a diagnosis should be made based on the diagnostic guidelines on renal hypouricemia (RHUC). Modified from Nakayama et al. [34] under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/ access date: 4 May 2022).

Figure 2

Transport mechanism of urate in the kidney. Urate is freely filtered at the glomerulus; most of it is reabsorbed via the urate transporter in the proximal tubule, while about one-tenth is secreted into the proximal tubules. URAT1/SLC22A12 reabsorbs urate and is located in the apical membrane of the proximal tubules, and GLUT9/SLC2A9 excretes urate through the basolateral side of the proximal tubule cells. The loss of function of these transporters due to genetic mutations causes RHUC, which is referred to as RHUC type 1 due to URAT1/SLC22A12 (a) and RHUC type 2 due to GLUT9/SLC2A9 (b).