Role of urate transporters in the kidneys and intestine in uric acid homeostasis

Abstract

Hyperuricemia is frequently observed in patients with chronic kidney disease and is recognized as a significant contributor to the progression of renal dysfunction. On the other hand, hypouricemia, although less thoroughly studied, has been implicated in exercise-induced acute kidney injury and urolithiasis. Uric acid (UA), the final product of purine metabolism, is predominantly synthesized in the liver and excreted through both renal and intestinal pathways. The metabolism and excretion of UA are intricately linked to kidney function, underscoring their clinical significance in the context of renal disease. This review provides a comprehensive overview of UA metabolism and the key urate transporters, including URAT1, GLUT9, OATs, and ABCG2, which play pivotal roles in maintaining UA homeostasis. Additionally, this review discusses the genetic and environmental factors that influence UA regulation, with a particular focus on the pathological consequences of transporter dysfunction. By elucidating the mechanisms underlying UA handling in the renal and intestinal systems, this review aims to enhance our understanding of UA-related pathophysiology, and to inform the development of targeted therapeutic strategies for modulating UA transport.

Introduction

Uric acid (UA), characterized as a weak acid with a pKa of 5.75, primarily exists as monosodium urate (MSU) at physiological pH (7.4), contributing to approximately 35% to 65% of the total antioxidant capacity in human plasma [1]. As a nonenzymatic antioxidant, UA effectively scavenges reactive oxygen (ROS) species, which may help alleviate oxidative stress, a mechanism recognized in the pathogenesis of kidney disease [2]. However, crystal formation can occur when UA concentrations surpass the solubility threshold of MSU, leading to urolithiasis and renal tubular injury. Unlike its extracellular antioxidant role, intracellular UA induces oxidative stress, disrupts mitochondrial function, and triggers inflammatory responses, thereby exacerbating renal damage [3,4].

Although the association between hyperuricemia and kidney disease is well-documented, the potential risks associated with hypouricemia remain poorly understood. Emerging studies indicate a U-shaped relationship between serum UA levels and renal function, suggesting increased risk at both low and elevated UA levels [5]. Serum UA levels are influenced by various factors, including diet, obesity, and renal function, with particular emphasis on the role of urate transporters in the kidneys and intestines [6]. Key transporters such as URAT1 and GLUT9 are responsible for renal UA reabsorption, whereas ABCG2, MRP4, and NPT1 facilitate UA excretion. Genetic variations in these transporters have been linked to both hyperuricemia and hypouricemia [7].

This review aims to critically evaluate the roles of urate transporters in regulating UA metabolism and excretion and to examine the various factors that influence UA homeostasis. Furthermore, this review integrates epidemiological and genetic findings on hyperuricemia and hypouricemia, highlighting their implications for kidney health. By providing a comprehensive analysis of UA regulatory mechanisms, this review seeks to enhance our understanding of UA-related pathophysiology and its relevance to the management of kidney disease.

The dual role of uric acid: antioxidant and pathological contributor

As previously mentioned, UA plays a complex dual role in human health, acting both as a potent antioxidant and a contributor to various pathological conditions. As an antioxidant, UA effectively neutralizes ROS and mitigates oxidative stress. Recent research underscores its potential neuroprotective properties, indicating that UA may have the capacity to delay the progression of neurodegenerative diseases, such as Alzheimer and Parkinson disease [8]. Moreover, UA has been associated with protective effects against cancer by reducing oxidative damage in certain environments [9].

However, dysregulation of serum UA levels can lead to considerable health issues [10,11]. Hypouricemia is typically characterized by a serum UA level of ≤2 mg/dL, while hyperuricemia is diagnosed when serum UA levels exceed 7.0 mg/dL in males and 6.0 mg/dL in females. A large-scale study conducted in Korea involving 30,757 participants identified a hypouricemia prevalence of 1.39%, with significantly higher rates among inpatients (4.14%) than outpatients (0.53%) [12]. Although hypouricemia is often asymptomatic, it has been associated with an increased risk of conditions such as exercise-induced acute kidney injury (EIAKI) and urolithiasis [13]. EIAKI, frequently triggered by dehydration and hypoxia due to intense physical activity, may also involve inflammatory processes, including activation of the Toll-like receptor 4 (TLR4) pathway and subsequent NOD-like receptor family pyrin domain-containing 3 inflammasome signaling [14]. Although causality between hypouricemia and chronic kidney disease (CKD) remains to be fully established, acute kidney injury and urolithiasis, which are significantly linked to hypouricemia, are well-documented contributors to CKD progression [15,16].

Conversely, elevated serum UA levels are associated with significant health risks. Hyperuricemia may contribute to the initiation of CKD and significantly accelerate its progression. Mechanistic studies have demonstrated that elevated UA levels contribute to CKD through glomerular hypertension and tubular injury [17]. A meta-analysis encompassing 15 cohort studies, involving 99,205 participants and 3,492 CKD cases, revealed a 22% increased risk of CKD for every 1 mg/dL rise in serum UA levels [18]. Clinical investigations further confirm that hyperuricemia accelerates the decline in the estimated glomerular filtration rate and increases the risk of end-stage kidney disease [19]. Additionally, hyperuricemia in patients with CKD is closely linked to cardiovascular diseases and elevated mortality rates.

Maintaining optimal serum UA levels is essential, as it balances the beneficial antioxidant effects of UA against its potential pathological impacts, thereby reducing the risks associated with either extreme hypouricemia or hyperuricemia.

Uric acid metabolism

UA is the end-product of purine nucleotide catabolism, primarily resulting from the breakdown of DNA, RNA, and ATP in humans. Its production predominantly occurs in the liver, with excretion regulated by the kidneys and intestines via complex physiological mechanisms [6,7]. Purines are sourced from dietary intake, such as meat, fish, and fructose, as well as from endogenous processes, including degradation of RNA, DNA, and ATP. Approximately 10% to 20% of UA production is attributed to dietary purines, whereas the remaining 80% to 90% is derived from endogenous metabolism. Excessive fructose intake, particularly through fructose-1-phosphate, induces ATP depletion, which accelerates purine nucleotide breakdown and significantly increases UA production [20].

The degradation of purine nucleotides follows two main pathways: adenine and guanine (Fig. 1). Adenine monophosphate (AMP) is converted into hypoxanthine and xanthine, whereas guanine monophosphate (GMP) is first transformed into guanine and then further degraded into xanthine. Subsequently, xanthine is oxidized by xanthine oxidase to produce UA, which enters the bloodstream [21].

Figure 1. Uric acid (UA) production and urine metabolism pathways in humans.

The diagram illustrates the pathways involved in UA production from purines in the human body. The continuous breakdown of RNA and DNA releases purines, which are further activated by adenosine monophosphate (ATP) depletion. The pink section depicts how fructose is metabolized to ATP in the liver, thus promoting activation of this pathway. The green section details the purine metabolic pathway, showing the conversion of adenine monophosphate (AMP) and guanine monophosphate (GMP) to adenosine and guanosine, respectively. AMP deaminase converts AMP to inosine, which is further broken down into hypoxanthine, whereas GMP deaminase converts GMP to guanine, which is subsequently converted to xanthine. Ultimately, both hypoxanthine and xanthine are oxidized to UA by xanthine oxidase. In contrast to rodents and other animals, humans lack uricase enzymes, which usually convert UA to allantoin. This results in UA accumulation in humans. IMP, inosine monophosphate.

A distinctive feature of human and higher primate metabolism is the absence of uricase, an enzyme responsible for converting UA into allantoin, a water-soluble compound. This evolutionary loss, occurring approximately 10 million years ago, has led to elevated serum UA levels compared with other species [22]. While this adaptation may have conferred benefits, such as enhanced antioxidant capacity and sodium conservation in early humans, it also predisposes modern humans to hyperuricemia-related conditions, including gout and UA nephrolithiasis. In contrast, rodents retain uricase, enabling them to metabolize UA into allantoin, whereas birds and reptiles excrete UA directly as a nitrogenous waste product to conserve water [23].

Urate transporters

Reabsorption, secretion, and excretion of UA in the kidneys is a complex, multistep process that involves several specialized transporters (Fig. 2) [6]. Dysfunction or disruption of the balance of these transporters can lead to hyperuricemia, gout, and CKD. Key transporters involved in maintaining UA homeostasis include URAT1, GLUT9, OAT1, OAT3, OAT4, ABCG2, and NPT1/4, all of which are crucial for UA homeostasis (Table 1).

Figure 2. Pathways and mechanisms of uric acid (UA) excretion.

This diagram illustrates how UA is excreted from the body. The kidneys eliminate approximately 70% of UA, while the remaining 30% is excreted through the intestine via the ABCG2 transporter (BCRP). The kidneys handle UA in the proximal tubules, which is involved in reabsorption and secretion. During reabsorption, UA moves from the tubular lumen into epithelial cells through URAT1 (SLC22A12) and OAT4 (SLC22A11), which exchange UA with organic anions and H+ ions, respectively. The voltage-dependent transporter GLUT9a (SLC2A9v1) transfers UA into the bloodstream. During secretion, OAT1 (SLC22A6) and OAT3 (SLC22A8) take up UA from the blood in exchange for α-ketoglutarate (α-KG), whereas NaDC3 maintains the necessary sodium gradient. Subsequently, UA is transported into the tubular lumen by apical transporters including BCRP (ABCG2), MRP4 (ABCC4), NPT1 (SLC17A1), and NPT4 (SLC17A3).

ABCG2, ATP-binding cassette subfamily G member 2; ATP, adenosine triphosphate; GLUT9a, glucose transporter 9 isoform a; MRP4, multidrug resistance-associated protein 4; NaDC3, sodium-dependent dicarboxylate transporter 3; NPT1, sodium-dependent phosphate transporter 1; NPT4, sodium-dependent phosphate transporter 4; OAT1, organic anion transporter 1; OAT3, organic anion transporter 3; OAT4, organic anion transporter 4; SMCT1, sodium-coupled monocarboxylate transporter 1; SMCT2, sodium-coupled monocarboxylate transporter 2; URAT1, urate transporter 1.

Table 1.

Overview of urate transporters

Transporter	Gene	Location in the kidney	Function	Key features	Associated disease	Inhibitor
URAT1	SLC22A12	Apical membrane of the proximal tubule	UA reabsorption	Primary urate transporter in the kidneys; target for uricosuric drugs	Gout, hyperuricemia, type 1 renal hypouricemia	Probenecid, benzbromarone, lesinurad, losartan, fenofibrate, verinurad, dotinurad
OAT4	SLC22A11	Apical membrane of the proximal tubule	UA reabsorption and secretion	Involved in the bidirectional transport of organic anions; contributes to UA homeostasis	Gout, hyperuricemia	Lesinurad, tranilast
GLUT9	SLC2A9	Basolateral membrane of the proximal tubule	UA reabsorption	Voltage-dependent UA transport	Type 2 renal hypouricemia, gout	Benzbromarone, losartan, probenecid, tranilast
OAT1	SLC22A6	Basolateral membrane of the proximal tubule	UA excretion	Exchanges α-ketoglutarate for organic anions; involved in drug interactions	Renal tubular acidosis	Probenecid
OAT3	SLC22A8	Basolateral membrane of the proximal tubule	UA excretion	Exchanges α-ketoglutarate for organic anions; involved in drug interactions	Chronic kidney disease	Probenecid
ABCG2	ABCG2	Apical membrane of the proximal tubule, distal convoluted tubule	UA excretion	Plays a role in the extrarenal elimination of UA	Gout, hyperuricemia	-
NPT1	SLC17A1	Apical membrane of the proximal tubule	UA excretion	Sodium-phosphate cotransporter	Hyperuricemia, gout	-
NPT4	SLC17A3	Apical membrane of the proximal tubule	UA excretion	Functions similarly to NPT1	Hyperuricemia, gout	-
MRP4	ABCC4	Apical membrane of the proximal tubule, collecting duct	UA excretion	Contributes to drug resistance; key role in drug efflux and resistance	Hyperuricemia, multidrug resistance	-

ABCG2, ATP-binding cassette subfamily G member 2; GLUT9, glucose transporter 9; MRP4, multidrug resistance-associated protein 4; OAT1, organic anion transporter 1; OAT3, organic anion transporter 3; OAT4, organic anion transporter 4; NPT1, sodium-dependent phosphate transporter 1; NPT4, sodium-dependent phosphate transporter 4; UA, uric acid; URAT1, urate transporter 1.

URAT1 (SLC22A12)

Urate anion exchanger 1 (URAT1), encoded by SLC22A12, is a key transporter responsible for UA reabsorption [24]. Located on the apical membrane of proximal tubular cells in the kidneys, URAT1 facilitates the exchange of UA with organic anions such as lactate, β-hydroxybutyrate, acetoacetate, and nicotinate. URAT1 exhibits a relatively higher affinity for organic anions such as nicotinate and pyrazinoic acid (PA), a metabolite of the anti-tuberculosis drug pyrazinamide, than lactate, β-hydroxybutyrate, and acetoacetate [25]. URAT1 interacts with sodium-coupled monocarboxylate transporter 1 (SMCT1) and SMCT2, which are encoded by SLC5A8 and SLC5A12, respectively [26]. This interaction is important for the sodium-driven reabsorption of sodium-bound organic anions. These transporters together form a “transportasome” in the proximal tubule, enhancing UA handling efficiency [27]. Notably, experiments with SLC5A8 or SLC5A12 knockout mice demonstrated a significant increase in UA excretion despite unchanged URAT1 expression, underscoring the importance of these transporters in UA management [28].

OAT4 (SLC22A11)

Organic anion transporter 4 (OAT4), encoded by SLC22A11, is expressed on the apical membrane of proximal tubular epithelial cells in the kidneys and plays a dual role in UA reabsorption and secretion [7]. It facilitates the entry of UA into cells while simultaneously exchanging it with intracellular dicarboxylates such as α-ketoglutarate. This process allows the reabsorption of UA from the tubular lumen into the cells or its secretion into the lumen, contingent on the concentration gradients of these substances. Although OAT4 is typically considered a weak urate transporter in vitro, it remains a critical regulator of UA levels [29].

GLUT9 (SLC2A9)

Glucose transporter 9 (GLUT9), encoded by SLC2A9 is a voltage-driven, high-capacity urate transporter predominantly expressed in the proximal tubules of the kidney, liver, placenta, and small intestine [30]. Initially identified as a glucose transporter, subsequent research confirmed its primary function as a urate transporter [31]. The transporter exists in two isoforms, GLUT9a and GLUT9b, which have distinct cellular localization and roles in UA handling. GLUT9a is located on the basolateral membrane of renal proximal tubular cells, where it facilitates the reabsorption of UA from tubular cells into the bloodstream, thus playing a vital role in maintaining urate homeostasis by minimizing its excretion in urine [32]. In contrast, GLUT9b is expressed in the apical membrane of renal tubular cells and in various tissues, including the liver and intestine, and is involved in the uptake and reabsorption of UA from the tubular lumen [33].

Mice with knockout mutations in SLC2A9 in both the liver and kidneys exhibit moderate hyperuricemia, excessive urinary UA excretion (hyperuricosuria), and urate nephropathy, underscoring the systemic significance of GLUT9 and its role in liver UA metabolism [34].

OAT1 (SLC22A6) and OAT3 (SLC22A8)

OAT1 and OAT3, which are located on the basolateral membrane of proximal tubular cells, mediate the exchange of UA and other organic anions with intracellular dicarboxylates (e.g., α-ketoglutarate). This process is indirectly linked to sodium transport into the cells via NaDC3, which is encoded by SLC13A3 [29]. These transporters are essential for the uptake of organic anions, including UA, from the blood into proximal tubular cells. Coupled with URAT1 and GLUT9, they further facilitate the reabsorption of UA from tubular fluid back into the bloodstream. Additionally, OAT1 and OAT3 play vital roles in the renal clearance of various medications, including diuretics, nonsteroidal anti-inflammatory drugs, and antiviral agents. Consequently, inhibition of these transporters can hinder drug excretion and disrupt UA handling, potentially resulting in elevated serum UA levels [35].

Knockouts of either OAT1 or OAT3 lead to decreased renal UA excretion and increased blood UA concentration [36]. Similar to OAT1, OAT3 is involved secretion of UA by proximal tubular cells, thereby playing a significant role in the renal handling of UA and other organic anions [37].

ABCG2 (ABCG2 protein/gene)

ATP-binding cassette subfamily G member 2 (ABCG2) is a member of the ATP-binding cassette (ABC) transporter family, encoding membrane proteins responsible for transporting diverse substances. ABCG2 is a key efflux transporter that plays a crucial role in regulating UA levels via intestinal and renal excretion [38]. In the kidney, it is located on the apical membrane of proximal tubular epithelial cells, where it facilitates ATP-dependent UA secretion into the tubular lumen [39]. Initially identified as the breast cancer resistance protein in 1998, ABCG2’s role in UA transport has garnered recent attention [40].

Beyond the kidney, ABCG2 significantly contributes to extrarenal UA excretion, particularly in the intestine, by transporting UA from enterocytes into the intestinal lumen [41]. This pathway serves as a compensatory mechanism for reduced renal UA clearance, which is commonly observed in CKD [42]. ABCG2 also works with other transporters, such as MRP4 (ABCC4), to optimize UA excretion and maintain serum UA homeostasis.

MRP4 (ABCC4)

Multidrug resistance-associated protein 4 (MRP4), encoded by ABCC4, is another critical ABC transporter that is involved in UA excretion. Located on the apical membrane of proximal tubular cells, MRP4 facilitates ATP-dependent UA secretion into the tubular lumen, complementing ABCG2’s function [43]. Unlike ABCG2, which also plays a significant role in intestinal UA excretion, MRP4 activity is predominantly renal, where it collaborates with other renal transporters to enhance UA clearance [44].

In addition to UA, MRP4 mediates the transport of a broad range of endogenous and exogenous compounds including nucleotides, leukotrienes, and drugs [43]. Its ability to handle multiple substrates underscores its importance in both the UA metabolism and drug elimination pathways.

NPT1 (SLC17A1) and NPT4 (SLC17A3)

Sodium-phosphate transporters 1 (NPT1) and 4 (NPT4), encoded by SLC17A1 and SLC17A3, respectively, belong to the SLC17 transporter family. These transporters are primarily expressed in the apical membranes of proximal tubular cells and are responsible for sodium-phosphate cotransport [45]. NPT1 also plays a role in chloride-dependent urate transport, whereas NPT4 facilitates voltage-dependent urate transport [46].

Urate transportasome

The scaffolding protein PDZ domain-containing 1 (PDZK1, also known as NHERF3) organizes epithelial urate transporters into a “transportasome,” thereby improving UA handling efficiency in the kidneys (Fig. 3) [47]. PDZK1, a genetic determinant of serum urate levels, increases the expression and activity of URAT1, thereby enhancing urate reabsorption. In addition, SMCT1 which transports monocarboxylates such as nicotinate, indirectly supports URAT1 function, with PDZK1 colocalizing these two proteins to coordinate their activity [48]. Furthermore, PDZK1 directly interacts with both OAT4 [49] and NPT1 [50], thereby regulating and positioning multiple urate transporters in the proximal tubule to maintain a balance between urate secretion and reabsorption. Conversely, NHERF1 downregulates MRP4/ABCC4 expression, indicating an inverse regulatory relationship [51]. These findings support a model in which multiple urate transporters are jointly regulated and function collaboratively.

Figure 3. Urate transportasome in proximal tubular cells.

This schematic illustrates the renal proximal tubule “transportasome,” where the scaffolding protein PDZK1 (also known as NHERF3) organizes several urate transporters, including URAT1, OAT4, and NPT1, to regulate urate reabsorption and secretion. NHERF1 has an inverse regulatory effect on MRP4, indicating a coordinated control of these transport processes.

ABCG2, adenosine triphosphate-binding cassette subfamily G member 2; α-KG, α-ketoglutarate; GLUT9a, glucose transporter 9 isoform a; MRP4, multidrug resistance-associated protein 4; NaDC3, sodium-dependent dicarboxylate transporter 3; NHERF1, Na^⁺/H^⁺ exchanger regulatory factor 1 ; NHERF3, Na^⁺/H^⁺ exchanger regulatory factor 3 ; NPT1, sodium-dependent phosphate transporter 1; NPT4, sodium-dependent phosphate transporter 4; OAT1, organic anion transporter 1; OAT3, organic anion transporter 3; OAT4, organic anion transporter 4; PDZK1, PDZ domain-containing 1 ; SMCT1, sodium-coupled monocarboxylate transporter 1; SMCT2, sodium-coupled monocarboxylate transporter 2; URAT1, urate transporter 1.

Renal handling in uric acid

UA excretion can be quantified through clearance (in healthy males: 8.7 ± 2.5 mL/min) or by measuring the fractional excretion of UA (FEUA). In healthy males, FEUA is approximately 7.25% ± 2.98%, with typical values ranging between 6% and 8% [52]. In contrast, patients with gout often exhibit FEUA values between 3% and 5%, reflecting increased tubular reabsorption.

In the kidneys, the majority of filtered UA undergoes reabsorption, with only approximately 3% to 10% ultimately excreted in urine. The traditional four-component model describes the processes involved in renal UA handling, including glomerular filtration, tubular reabsorption, tubular secretion, and post-secretory reabsorption (Fig. 4) [53]. According to this model, UA is entirely filtered at the glomerulus, with 98% to 100% being reabsorbed in the proximal tubule. Approximately 50% of this reabsorbed UA is secreted back into the tubular lumen, resulting in a net reabsorption of 40% to 48%. Consequently, only 8% to 12% of the initially filtered UA is excreted in urine. This model was established using probenecid, which inhibits UA reabsorption, and PA, which has historically been thought to block UA secretion [53].

Figure 4. Theories regarding uric acid (UA) handling in kidneys.

Schematic representation of two distinct theories of UA handling in the kidney, focusing on filtration, reabsorption, and secretion in the proximal tubule. (A) The four-component model proposes that 100% UA is initially filtered into the proximal tubule. In the early segment, 98% to 100% of UA is reabsorbed into the bloodstream. Subsequently, 40% to 48% of the reabsorbed UA is secreted back into the tubular lumen, with 8% to 12% excretion . (B) The post-secretory reabsorption model suggests that 100% of UA is filtered into the proximal tubule, with 99% being reabsorbed early in the tubule. A significant secretion phase occurs later in the proximal tubule, which balances reabsorbed UA to maintain homeostasis. These theories highlight the different mechanisms of UA reabsorption and secretion and contribute to our understanding of renal UA management.

Interestingly, subsequent studies challenged this model. In 1996, research using brush border membrane vesicles from the proximal tubule demonstrated that PA enhances UA reabsorption rather than inhibits secretion [25]. PA stimulates UA reabsorption via URAT1 (SLC22A12), highlighting the significance of the reabsorptive mechanisms in UA homeostasis [24]. Notably, PA exhibits a dose-dependent dual effect; low doses enhance reabsorption, whereas high doses may inhibit UA transport [54]. This suggests the involvement of additional transporters or pathways influenced by the PA concentration. Pyrazinamide and its metabolites also trans-stimulate URAT1, altering UA transport dynamics.

While the traditional model posits that UA reabsorption and secretion occur in distinct nephron segments, emerging evidence strongly indicates that these processes may occur within the same regions, particularly in the S1 and S2 segments of the proximal tubules [55]. However, it remains unclear whether secretion occurs during reabsorption. Approximately 90% to 97% of filtered UA is reabsorbed in the proximal tubules, with intricate molecular mechanisms facilitating this process. URAT1 (SLC22A12) in the apical membrane is essential for UA reabsorption from the lumen, whereas GLUT9 (SLC2A9) at the basolateral membrane aids in the intracellular transfer of UA into the bloodstream.

The complex and highly regulated mechanisms governing UA excretion and reabsorption in the kidneys remain a subject of ongoing research and debate. This dynamic discourse presents opportunities for researchers to contribute to advancing the field of nephrology and related disciplines.

Intestinal handling of uric acid

Intestinal excretion is also crucial for regulating UA concentrations within the body. Urate transporters located in intestinal epithelial cells facilitate the transport of UA from the bloodstream to the intestinal lumen, primarily involving ABCG2 and SLC2A9 [56]. Specifically, UA enters the cells via GLUT9 and is subsequently secreted into the intestinal lumen through the action of ABCG2.

Approximately 30% of UA is excreted through the intestines, and this pathway becomes increasingly vital in cases of renal impairment. In mouse models exhibiting ABCG2 deficiency, the blockade of uricase using potassium oxonate led to hyperuricemia, which was associated with diminished intestinal UA excretion and a compensatory increase in UA excretion via the kidneys [57]. Furthermore, in CKD mouse models, urinary UA excretion was notably lower than that in the control group, whereas ABCG2 overexpression was observed in the ileum [58]. These findings suggest that non-renal tissues such as the intestine may engage in compensatory mechanisms mediated by ABCG2 when renal UA transport is compromised.

The intestinal microbiome, which comprises bacteria, fungi, and viruses, is pivotal for UA metabolism. Notable differences in gut microbiota composition have been observed between patients with gout and healthy individuals, particularly within the genera Bacteroides and Clostridium [59]. Oral administration of the microbiome has been reported to actually increase the messenger RNA expression of the ABCG2 transporter in the intestine [60,61]. In addition, short-chain fatty acids, which are bacterial metabolites in the intestine, enhance the expression of the intestinal urate transporter ABCG2, thereby promoting UA excretion [62]. Modulating the gut microbiome through approaches such as probiotics, prebiotics, or other microbiome-targeted therapies emerges as a promising strategy for managing hyperuricemia and its associated complications [63].

Genetic variations influencing serum uric acid levels

Serum UA levels are regulated by genetic variations in key urate transporters including URAT1 (SLC22A12), GLUT9 (SLC2A9), ABCG2, OAT4, and others. These genetic variations contribute to conditions, such as hypouricemia, hyperuricemia, and gout, by altering UA excretion and reabsorption.

Loss-of-function mutations in URAT1 lead to type 1 renal hypouricemia, a condition characterized by excessive urinary UA excretion, low serum UA levels, and increased risk of EIAKI [13,64]. In such cases, FEUA ranges from 40% to 100%, with serum UA levels as low as 0.93 mg/dL [65]. GLUT9 mutations are associated with type 2 renal hypouricemia, which impairs renal UA reabsorption and results in abnormally low serum UA levels. Severe cases can lead to FEUA exceeding 100% [66]. Variations in the SLC2A9 gene encoding GLUT9 also contribute to differences in serum UA levels across ethnic groups, highlighting the complexity of the genetic mechanisms underlying UA regulation [63].

Polymorphisms in OAT4 have been associated with reduced serum UA levels and may influence the effectiveness of UA-lowering therapies (ULTs) [67]. Similarly, OAT3 (SLC22A8) variants have been linked to increased susceptibility to hyperuricemia and altered interaction between OAT3 and drugs including angiotensin II receptor blockers [68].

Mutations in ABCG2 impair UA excretion, elevate serum UA levels, and increase the risk of gout. Genetic association studies have established a strong link between ABCG2 polymorphisms and hyperuricemia. A Japanese study emphasized that ABCG2 dysfunction has a more significant impact on UA levels than lifestyle factors such as smoking, obesity, alcohol consumption, or aging [69].

Gain-of-function variants of NPT1 (SLC17A1) increase urate efflux, thereby reducing susceptibility to hyperuricemia and gout [70]. The MRP4 (ABCC4), which regulates drug-induced UA transport, has also been implicated in hyperuricemia due to its role in UA handling [35].

Factors influencing serum uric acid levels

As discussed earlier, genetic predispositions play a significant role in regulating serum UA levels. Beyond these genetic factors, UA homeostasis is influenced by various factors, including dietary habits, obesity, insulin resistance, kidney function, sodium and fluid balance, sex hormones, gut microbiota, and medications. These factors collectively affect UA production, reabsorption, and excretion through physiological and pathological mechanisms (Fig. 5)

Figure 5. Factors influencing uric acid levels.

This diagram illustrates the factors that affect uric acid levels by modulating production, reabsorption, and excretion. Note that the effect of coffee on uric acid excretion remains controversial.

ABCG2, adenosine triphosphate-binding cassette subfamily G member 2; GLUT9, glucose transporter 9; Metabolic SD, Metabolic syndrome; SGLT2, sodium-glucose cotransporter 2; URAT1, urate transporter 1.

Lifestyle factors including diet

Diet and lifestyle habits play a significant role in the regulation of serum UA levels. Purine-rich foods (e.g., meat and seafood) increase UA production through purine metabolism [71]. Similarly, high fructose intake and excessive alcohol consumption, particularly purine-rich beer, promote hyperuricemia by increasing UA production and reducing UA excretion through lactate generation [72]. Lack of sleep and insufficient physical activity are also associated with elevated UA levels.

Conversely, adequate dairy intake, plant-based diets, and regular physical activity are associated with lower UA levels [73–75]. The impact of coffee consumption remains debatable; meta-analyses suggest that caffeine enhances UA excretion and reduces serum levels [76], but randomized controlled trials have reported conflicting results, with decaffeinated coffee lowering UA levels and regular coffee potentially increasing them [77].

Obesity and metabolic syndrome

Obesity and metabolic syndrome are major contributors to elevated serum UA levels, primarily due to insulin resistance linked to increased body fat [78]. A clinical study reported an inverse correlation between the clearance of UA and the levels of insulin resistance [79]. Furthermore, studies conducted on both healthy individuals and those with essential hypertension have shown that experimentally induced hyperinsulinemia inhibits renal excretion of UA and sodium [80,81].

Supporting these observations, animal models of streptozotocin-induced insulin deficiency demonstrated increased UA excretion, attributed to lower URAT1 expression and higher ABCG2 expression; these effects were reversed following the administration of exogenous insulin [82].

Kidney function

Because the kidneys are the primary organs responsible for UA excretion, impaired kidney function is a major contributor to elevated serum UA levels. Reduced renal UA excretion is strongly associated with hyperuricemia [24,83]. The prevalence of hyperuricemia in the general population ranges from 11% to 20%, but it increases dramatically to 60% to 80% in patients with CKD, correlating with declining renal function [84]. In the KNOW-CKD (KoreaN cohort study for Outcome in patients With Chronic Kidney Disease) study involving 2,042 participants, the proportion of patients with hyperuricemia increased significantly with CKD progression [85].

Compensatory mechanisms such as increased intestinal UA excretion play a critical role in decreasing renal UA clearance. The intestinal transporter ABCG2 has been identified as a key factor influencing serum UA levels in patients with CKD, as demonstrated in the CRIC (Chronic Renal Insufficiency Cohort) study [38].

Sodium intake and volume status

Sodium intake plays a critical role in modulating UA handling in the kidneys. Increased sodium intake enhances sodium and UA reabsorption in proximal tubules, which can contribute to elevated serum UA levels [86]. This phenomenon is consistent with previous studies demonstrating that sodium and UA reabsorption are often regulated by similar physiological stimuli [80]. However, the impact of sodium intake on UA levels varies between short-term and long-term exposure, and the mechanisms underlying these differences remain incompletely elucidated. The PREVEND (Prevention of Renal and Vascular End-stage Disease) study, a longitudinal analysis of 4,062 individuals over 6.4 years, revealed a modest positive association between higher sodium intake and serum UA levels (0.02 mg/dL per 1 g sodium), potentially mediated through mechanisms such as endothelial dysfunction [87]. In contrast, findings from the short-term DASH-Sodium (Dietary Approaches to Stop Hypertension-Sodium) trial indicated a reduction in serum UA levels within 30 days of increased sodium intake, likely attributable to improved renal perfusion and enhanced UA excretion due to fluid volume expansion [88]. Conversely, some evidence suggests that short-term sodium intake may activate the renin-angiotensin system, as supported by observations that acute angiotensin II infusion suppresses UA excretion [89].

The volume status further influences UA regulation. In states of volume depletion, increased UA reabsorption occurs via activation of transporters such as URAT1, thereby reducing UA excretion [90]. Conversely, adequate volume status promotes UA excretion and results in lower serum UA levels. Similar dynamics are observed in hyperuricemia induced by thiazide and loop diuretics, where sodium and fluid repletion mitigate changes in the FEUA and serum UA levels. These interactions are particularly relevant in conditions characterized by altered fluid distribution, such as nephrotic syndrome, cirrhosis, and heart failure, where the total body fluid volume increases despite reduced effective plasma volume [91].

Sex and hormonal factors

Serum UA levels are also influenced by sex and hormonal factors. Male generally exhibit higher UA levels than women, partly because of the uricosuric effects of estrogen [92]. Postmenopausal women show an average increase of 0.34 mg/dL in UA levels compared to premenopausal women, while men’s levels are approximately 1 mg/dL higher than those of women [93]. Hormone replacement therapy in postmenopausal women has been shown to decrease UA levels by 0.24 mg/dL after 1 year, highlighting the significant role of gonadal hormones in UA regulation [93]. Estradiol also directly affects renal UA transporters by suppressing the protein levels of URAT1, GLUT9, and ABCG2, as demonstrated in mouse studies [94].

In addition to estrogen, other hormones also play important roles in UA metabolism through various mechanisms. Glucocorticoids influence UA levels by increasing UA production through enhanced protein catabolism and stimulation of xanthine oxidase activity [95]. They also reduce serum UA levels by downregulating URAT1 in the kidneys, which facilitates increased urinary UA excretion [96]. Thyroid hormones similarly affect UA metabolism; hypothyroidism is associated with reduced renal UA clearance and hyperuricemia, while hyperthyroidism enhances UA excretion, potentially lowering serum UA levels [97].

In hyperthyroidism, hyperuricemia is due to increased urate production, whereas in hypothyroidism, hyperuricemia is secondary to decreased renal plasma flow and impaired glomerular filtration.

Gut microbiota

Approximately 30% of UA in the body is excreted through the gastrointestinal tract, highlighting the significant role of the gut microbiota in UA regulation. Certain gut bacteria capable of breaking down UA have been identified, suggesting that microbial purine metabolism influences systemic UA levels. Kasahara et al. [98] demonstrated that purine-degrading bacteria effectively reduced blood UA levels in germ-free mice colonized with specific gut microbes, supporting the role of gut microbiota in UA homeostasis. Similarly, Liu et al. [99] reported that gut bacteria not only lowered blood UA levels but also alleviated gout-related symptoms in a rat model of hyperuricemia, underscoring the therapeutic potential of targeting the gut microbiota in managing hyperuricemia and gout.

Medications

Various medications can significantly influence serum UA levels by affecting its excretion or production. Medications known to increase UA levels include thiazide and loop diuretics, which impair renal UA excretion and may lead to elevated serum levels [100]. Additionally, low-dose aspirin increases UA levels by enhancing the activity of URAT1, which promotes UA reabsorption and consequently reduces its secretion [83]. Conversely, high-dose aspirin exerts an opposing effect by inhibiting URAT1, thereby decreasing UA reabsorption and promoting its excretion. Moreover, certain anti-tuberculosis medications, such as pyrazinamide and ethambutol, have been shown to elevate UA levels by affecting renal clearance [101].

In contrast, medications like losartan and fenofibrate possess uricosuric properties; they inhibit URAT1, which enhances UA excretion [102]. Emerging therapies, including sodium–glucose cotransporter 2 inhibitors inhibitors utilized in the management of diabetes, indirectly promote UA excretion by reducing sodium-glucose reabsorption, which subsequently suppresses the activity of UA-sodium cotransporters [103]. Similarly, glucagon-like peptide-1 receptor agonists have been associated with modest reductions in UA levels, primarily as secondary effects of weight loss and improved metabolic function [104].

Uric acid-lowering therapy: clinically approved agents

Uricosuric agents are essential in the management of hyperuricemia and gout, as they facilitate and enhance the excretion of UA. These agents primarily act on the URAT1 transporter to inhibit UA reabsorption, resulting in decreased serum UA levels. Clinically approved uricosuric agents include probenecid, lesinurad, benzbromarone, and dotinurad (Table 2). Importantly, some uricosuric agents also target additional transporters such as OAT4 and GLUT9, broadening their therapeutic mechanisms. Lesinurad, a dual inhibitor of URAT1 and OAT4, broadens the therapeutic mechanisms and demonstrates significant efficacy in reducing serum UA levels, particularly when used as adjunctive therapy for gout [7].

Table 2.

Uric acid lowering agents

Class	Drug name	Target	Regions approved	Indication	Adverse effects/limitations
Uric acid excretion enhancers (uricosurics)	Probenecid	URAT1	USA	Gout, hyperuricemia	Gastrointestinal upset, nephrolithiasis, ineffective in renal impairment
	Lesinurad	URAT1 and OAT4	USA, Europe (withdrawn in some markets)	Gout (adjunctive therapy)	Renal toxicity, withdrawn in some markets
	Benzbromarone	URAT1 and GLUT9	Japan, Europe (limited use)	Gout, hyperuricemia	Hepatotoxicity, not approved in the USA
	Dotinurad	URAT1	Japan	Gout, hyperuricemia	Mild renal effects (rare), limited to Japan
Uric acid synthesis inhibitors	Allopurinol	Competitive inhibitor of xanthine oxidase	USA, Japan, Europe	Gout, hyperuricemia	Rash, hypersensitivity (HLA-B*5801), Stevens-Johnson syndrome
	Febuxostat	Non-purine selective inhibitor of xanthine oxidase	USA, Japan, Europe	Gout, hyperuricemia	Cardiovascular risk, liver enzyme elevation
	Topiroxostat	Non-purine selective inhibitor of xanthine oxidase	Japan	Gout, hyperuricemia	Liver dysfunction, rare hypersensitivity reactions
Urate conversion agents	Rasburicase	Recombinant uricase	USA, Europe, Japan	Tumor lysis syndrome	Anaphylaxis, hemolysis (G6PD deficiency), methemoglobinemia
	Pegloticase	Pegylated recombinant uricase	USA, Europe	Refractory chronic gout	Immunogenicity, infusion reactions, high cost

G6PD, glucose-6-phosphate dehydrogenase; GLUT9, glucose transporter 9; OAT4, organic anion transporter 4; URAT1, urate transporter 1.

Benzbromarone and dotinurad, both approved in Japan, serve as valuable treatment options for patients unresponsive or intolerant to other medications. However, the use of benzbromarone is restricted in some regions because of potential adverse effects, including hepatotoxicity or its withdrawal from the market in certain areas [105]. Table 2 categorizes ULT on their mechanisms of action, target transporters, approved regions, indications, and adverse effects, providing a comprehensive comparison of currently available options.

Additionally, it is noteworthy that agents still seeking widespread clinical approval, such as verinurad and tranilast, represent promising advancements in hyperuricemia management [106].

Conclusion

UA regulation is a complex process influenced by renal and intestinal transporters such as URAT1, GLUT9, and ABCG2, along with genetic, environmental, and metabolic factors. The kidneys play a pivotal role in maintaining UA homeostasis through filtration, reabsorption, and secretion, whereas the intestines significantly contribute to UA excretion. Serum UA levels are also affected by dietary factors (e.g., purine-rich foods and alcohol), systemic conditions (e.g., metabolic syndrome and insulin resistance), and genetic polymorphisms in key UA transporters. Dysregulation of these pathways can result in hyperuricemia, which is linked to an increased risk of gout, CKD, cardiovascular disorders, or hypouricemia, which is associated with oxidative stress and EIAKI.

Recent studies highlight that UA transport is tightly regulated by complex interactions between renal and extrarenal pathways. Understanding these mechanisms is crucial for identifying the factors that modulate UA levels and their implications for health. Future research should focus on delineating the precise molecular mechanisms governing UA transport and identifying therapeutic targets within key UA transporters and associated signaling pathways to develop more effective and personalized interventions for managing serum UA levels and mitigating related complications such as gout, CKD, and cardiovascular diseases.