Physiology of Hyperuricemia and Urate-Lowering Treatments

Abstract

Gout is the most common form of inflammatory arthritis and is a multifactorial disease typically characterized by hyperuricemia and monosodium urate crystal deposition predominantly in, but not limited to, the joints and the urinary tract. The prevalence of gout and hyperuricemia has increased in developed countries over the past two decades and research into the area has become progressively more active. We review the current field of knowledge with emphasis on active areas of hyperuricemia research including the underlying physiology, genetics and epidemiology, with a focus on studies which suggest association of hyperuricemia with common comorbidities including cardiovascular disease, renal insufficiency, metabolic syndrome and diabetes. Finally, we discuss current therapies and emerging drug discovery efforts aimed at delivering an optimized clinical treatment strategy.

Keywords: URAT1; crystal deposition; diabetes; hypertension; kidney disease; uric acid; xanthine oxidase.

Figure 1

Uric acid pKa and formation of urate salts. Structures of uric acid and urate salts including acid dissociation constants.

Figure 2

Biosynthesis of uric acid from purines. Purine mononucleotides are catabolized to produce uric acid although the underlying pathway can vary in different tissues and cells. A schematic example pathway is shown.

Figure 3

Uric acid metabolism via uricase. In humans and some primates, uric acid is the final product of the purine catabolism pathway. However, most animals further degrade uric acid to allantoic acid via the sequential actions of uricase, 5-hydroxyisourate hydrolase and allantoinase.

Figure 4

Role of transporters in the renal proximal tubule on urate handling. Within an individual nephron in the kidney (yellow), filtration of water and solutes occurs in the glomerular capsule from the afferent arteriole into the renal tubule (pink shading). Tubular reabsorption (green shading) is predominantly mediated by the proximal convoluted tubule whereas tubular secretion extracts uric acid (and other substances) from peritubular capillaries (purple shading) and secretes them into the tubular fluid for urinary excretion. Urate transporters in renal proximal tubule epithelial cells actively mediate the secretion and reabsorption of urate. The balance between these processes determines the net excretion levels from the kidney. The anion transporters SLC22A6 (OAT1) and SLC22A8 (OAT3) localized on the basolateral membranes transport urate from the interstitial space in the blood depending on the gradients for exchanged anions but have not been shown to exhibit a genetic linkage with hyperuricemia or gout risk (gray box). On the apical membrane, ABCG2, SLC17A1 (NPT1), SLC17A3 (NPT4), ABCC4 (MRP4), UAT (Galectin 9) have all been shown to contribute to the secretory transport of urate into the tubule lumen and leading to urinary excretion; a number of these have been genetically associated with hyperuricemia and gout risk (green boxes). Exchange gradients upstream of urate anion exchange are enabled through the actions of SLC13A3 (NaD3), SLC5A8 (SCMT1), and SLC5A12 (SCMT2). In renal reabsorption, the apical urate-anion exchanger SLC22A12 (URAT1) has been shown to play a predominant role in urate homeostasis and indeed several variants have been identified to be associated with gout and hyperuricemia risk (green box). Additional contributions to urate reabsorption are mediated by SLC22A11 (OAT4) and SLC22A11 (OAT10) (gray boxes, not genetically associated with gout/hyperuricemia risk) and the short isoform of SLC2A9v2 (GLUT9, green box) on the apical membrane. The long isoform of SLC2A9v1 (GLUT9, green box) is the only known transporter to mediate basolateral efflux of urate back into circulation; which is in accordance with its genetic association for gout and hyperuricemia risk in addition to rare mutations associated with hypouricemia.

Figure 5

Structures of launched (marketed and withdrawn) drugs for the management of hyperuricemia. Purine-based (allopurinol and oxypurinol) and non-purine based (febuxostat and topiroxostat) XO inhibitors are shown with dates of approval for clinical use. URAT1 inhibitors are represented by benzbromarone (withdrawn in 2003) and lesinurad (RDEA594).

Figure 6

Selected recent emerging clinical compounds (where structure disclosed). The structures for arhalofenate (MBX201), tranilast, verinurad (RDEA3170), URC-102 and ulodesine (BCX4208) are shown here.