Back to the Physiology: Renal Tubular Handling of Uric Acid and Emerging Strategies for Managing Hyperuricemia

Abstract

Hyperuricemia is a common comorbidity of chronic kidney disease (CKD) and contributes to kidney dysfunction through mechanisms involving glomerular, tubular, and vascular injuries. Although hyperuricemia has traditionally been classified into overproduction and underexcretion types, recent evidence highlights the importance of intrarenal urate handling, particularly tubular reabsorption, in the pathogenesis of CKD. In this review, we revisit the physiology of renal urate transport and summarize the clinical evidence that links hyperuricemia to CKD progression. We also summarize the current evidence regarding urate-lowering therapies, mainly focusing on novel selective urate reabsorption inhibitors and kidney outcomes. Based on emerging data, we propose a refined classification of hyperuricemia in CKD that stratifies patients into glomerular under-filtration and tubular over-reabsorption subtypes using a novel index that integrates both glomerular filtration and tubular reabsorption. This new classification may better guide individualized treatment strategies for CKD patients with hyperuricemia.

1. Introduction

Chronic kidney disease (CKD) is a progressive condition characterized by a progressive loss of the kidney function. It has become a major public health burden, with its prevalence continuing to rise worldwide (1,2). CKD is particularly common among the elderly because of age-related physiological changes (3). It is associated with poor clinical outcomes, including the development of end-stage kidney disease (ESKD) and an elevated risk of cardiovascular morbidity and mortality (4,5). The causes of CKD are diverse and encompass diabetes mellitus, glomerulonephritis, and nephrosclerosis. Among these, diabetic nephropathy remains the leading cause of CKD, followed by nephrosclerosis. Notably, the proportion of CKD cases attributable to nephrosclerosis has been increasing in recent years, particularly among the elderly, emphasizing the need for comprehensive management strategies that address not only blood pressure control, but also metabolic, lifestyle, and cardiovascular risk factors to mitigate the growing burden of CKD.

Nephrosclerosis is a pathological condition characterized by vascular remodeling, including arterial thickening and luminal narrowing, primarily induced by long-standing hypertension (6-8). These structural changes contribute to glomerulosclerosis, interstitial fibrosis, and progressive decline in the kidney function. Blood pressure regulation is governed by multiple factors, including renal sodium handling, vascular tone, and mineral balance (9-11). In addition, hyperuricemia has emerged as an important contributor to vascular injury and blood pressure dysregulation. Epidemiological studies conducted in Japan have demonstrated that elevated serum uric acid levels are associated with hypertension (12). Clinical studies have further demonstrated an association between hyperuricemia, hypertension, and proteinuria, suggesting that hyperuricemia is an important risk factor for the development and progression of nephrosclerosis and CKD (13). A pivotal study demonstrated that elevated serum uric acid levels are associated with the severity of arteriosclerotic changes in afferent arteries (14). These findings emphasize that hyperuricemia should be considered as a modifiable target in the management of nephrosclerosis to prevent further kidney and cardiovascular complications.

The kidney plays a pivotal role in regulating serum uric acid levels, with approximately 90% of filtered uric acid being reabsorbed in the proximal tubules. Gout is highly prevalent among patients with CKD, and “gouty nephropathy,” resulting from monosodium urate crystal deposition, is recognized as an important cause of CKD (15). However, growing evidence suggests that even asymptomatic hyperuricemia may contribute to kidney injury. Thus, the pathogenic role of hyperuricemia extends beyond the clinical manifestation of gout, suggesting that asymptomatic hyperuricemia may also represent a potential therapeutic target in CKD management.

In this review, we summarize the current evidence regarding the relationship between hyperuricemia and CKD and propose desirable therapeutic strategies for managing hyperuricemia in CKD patients.

2. Physiological Handling of Uric Acid in the Kidney

Uric acid is the final metabolite of purines in humans, since the uricase is lost during evolution (16). Serum uric acid levels are regulated by a balance of hepatic production, intestinal excretion, and renal excretion (17). Among these pathways, the kidney serves as the primary regulator of serum uric acid levels. Approximately 60-70% of uric acid elimination occurs via the kidneys (18). In the kidney, uric acid is freely filtered at the glomerulus, and approximately 90% of the filtered uric acid is subsequently reabsorbed in the proximal tubules, primarily through urate transporter 1 (URAT1) and glucose transporter 9 (19,20). A portion of uric acid is secreted back into the tubular lumen via active transport mechanisms, including ATP-binding cassette transporter G2 (ABCG2) and organic anion transporters (21,22). Other transporters involved in uric acid regulation include multidrug resistance-associated protein (MRP)2, MRP4, sodium-dependent phosphate transport protein (NPT)1, NPT4, and sodium-dependent vitamin C transporters (23-25). Through this coordinated handling, approximately 10% of the filtered uric acid is excreted in urine under normal physiological conditions. In addition to renal excretion, approximately 30% of uric acid is eliminated through extrarenal routes, mainly via intestinal secretion mediated by ABCG2 (17). Disruption in the balance of filtration, reabsorption, secretion, or extrarenal elimination can lead to hyperuricemia.

3. Pathophysiological Impact of Hyperuricemia on the Kidney

The mechanisms by which elevated serum uric acid levels contribute to kidney injury can be broadly categorized into three pathways: vascular injury and ischemia, glomerular hyperfiltration, and tubular injury.

First, hyperuricemia promotes vascular injury and ischemia. Uric acid impairs the endothelial function through multiple mechanisms. It reduces nitric oxide bioavailability, enhances oxidative stress (26,27), and activates hypoxia-inducible factor-1α, leading to endothelial barrier dysfunction and inflammatory cell infiltration (28). Furthermore, uric acid oxidation mediated by peroxidases, such as peroxidasin, generates reactive intermediates, including free radicals and hydroperoxide, which exacerbate oxidative stress (29). Uric acid can also induce a novel post-translational modification called uratylation, which alters the protein function and promotes proteostasis disruption (29). These effects lead to endothelial cell injury, subsequent afferent arteriolar narrowing, and glomerular hypoperfusion (6,14).

Second, hyperuricemia activates the intrarenal renin-angiotensin system (RAS), leading to glomerular hyperfiltration. Experimental studies have demonstrated that elevated uric acid levels stimulate renin expression and promote angiotensin II production, resulting in increased intraglomerular pressure (30,31). In humans, higher serum uric acid concentrations are independently associated with a blunted renal plasma flow response to exogenous angiotensin II, reflecting an activated intrarenal RAS (31). Chronic glomerular hypertension imposes mechanical stress on podocytes and glomerular capillaries, leading to glomerular injury and nephron loss (32-34). Ischemia and glomerular hyperfiltration closely mirror the pathological heterogeneity of nephrosclerosis. Nephrosclerosis with ischemia is characterized by afferent arteriolar hyalinosis and glomerular collapse, typically presenting as CKD without proteinuria. In contrast, nephrosclerosis with hyperfiltration features dilated arterioles and enlarged glomeruli, frequently accompanied by proteinuria (6). Hyperuricemia is likely to contribute to both forms by promoting hemodynamic and structural alterations.

Third, hyperuricosuria may directly induce tubular epithelial cell injury and tubulointerstitial damage. At high luminal concentrations, particularly under acidic conditions, uric acid becomes less soluble and may precipitate as crystals, potentially triggering epithelial cell stress, macrophage infiltration, and interstitial fibrosis (35). A cross-sectional study of patients with untreated gout found that over one-third exhibited hyperechoic renal medulla on ultrasound, suggesting an underlying tubulointerstitial injury linked to urate accumulation (36,37). Furthermore, a recent retrospective study in patients with CKD found that a lower fractional excretion of uric acid (FEUA) and urinary uric acid-to-creatinine ratio were independently associated with an increased risk of decline in the kidney function, independent of serum uric acid levels (38). Although the exact mechanism remains to be clarified, one possible explanation is that reduced urinary excretion reflects increased tubular reabsorption of urate, leading to its intracellular accumulation. If this assumption holds true, such an intracellular urate overload could promote tubular injury through mechanisms such as oxidative stress, inflammasome activation, and lysosomal dysfunction (37).

4. Clinical Evidence of Hyperuricemia and the Impact of Urate-lowering Therapy on CKD

Epidemiological studies have identified hyperuricemia as a risk factor for both the development and progression of CKD (39-42). Multiple community-based cohort studies and meta-analyses have reported that elevated serum uric acid levels are significantly associated with an increased risk of incident CKD and decline in the kidney function (43,44). However, contradicting observations have also been reported, showing no significant association between hyperuricemia and kidney outcomes (45,46). These discrepancies raise the question of whether elevated uric acid is an independent exacerbating factor or merely a marker of kidney dysfunction. Nevertheless, given that serum uric acid is a modifiable factor, urate-lowering therapy has been proposed as a potential strategy to prevent or delay CKD progression (47). Xanthine oxidase inhibitors (XOIs), such as allopurinol and febuxostat, have been widely studied. While some trials have suggested possible renoprotective effects (48-52), others have reported inconsistent results (53,54).

Recently, attention has shifted toward agents that modulate renal uric acid handling. A long-term observational study evaluating different urate-lowering agents in patients with CKD found that benzbromarone, a uricosuric drug, was associated with a significantly lower risk of ESKD than allopurinol (55). Dotinurad, a recently developed selective urate reabsorption inhibitor (SURI), specifically targets URAT1 in the proximal tubules and promotes urinary uric acid excretion. Several observational studies involving dotinurad, either as a monotherapy or in combination with XOIs, have demonstrated effective serum uric acid reduction; however, their effects on the kidney function have been inconsistent (56-58). A summary of these studies is presented in Table. A recent study reported that dotinurad monotherapy was associated with both a significant decline in serum uric acid and a reversal of the estimated glomerular filtration rate (eGFR) decline in patients with CKD (59). Furthermore, a retrospective comparison of dotinurad and febuxostat in hyperuricemic patients with CKD demonstrated that only dotinurad led to significant improvement, despite achieving similar reductions in serum uric acid levels (60).

Table.

Clinical Studies on Dotinurad.

Number of patients	Concomitant XOIs	Duration (months)	Serum UA (mg/dL)	Kidney outcome	Ref No.
84	no	6	6.6±1.6 to 6.1±1.2	eGFR 60.0±20.3 to 59.6±19.5	56
68 (34 with matched control)	yes (44%)	12	7.1±5.9 to 5.9±1.0	eGFR slope -6.0±12.9 to -0.9±4.6 in dotinurad (p<0.05) 0.9±4.7 to -3.4±6.7 in control (p<0.05)	57
53	yes (58%)	9.8±4.5	8.3±1.0 to 6.1±1.0	eGFR 38.7±17.2 to 39.2±17.2 (ns)	58
35	no	3	8.1±1.7 to 6.7±1.0	eGFR 31.8±16.4 to 36.5±17.5 (p<0.01)	59
58 (29 with febuxostat)	no	3	8.4±1.1 to 6.5±0.8	eGFR 33.9±15.2 to 36.2±15.9 in dotinurad (p<0.001) 33.4±19.6 to 34.1±21.6 in febuxostat (NS)	60

XOI: xanthine oxidase inhibitors, UA: uric acid, eGFR: estimated glomerular filtration rate

These findings support the notion that targeting urate reabsorption may provide renoprotective benefits beyond serum urate control, particularly in patients with CKD with reduced renal urate excretion. In contrast to previous urate-lowering therapies, which have predominantly focused on XOIs and produced inconsistent kidney outcomes, SURIs offer a novel approach with promising clinical potential. Collectively, these data support the rationale for identifying and treating reabsorption-dominant hyperuricemia as a distinct therapeutic target.

5. A Proposed Classification of Hyperuricemia in CKD

Hyperuricemia has been classified into three types: overproduction, underexcretion, and a combined type involving both mechanisms. This classification is primarily based on the measurements of urate clearance and uric acid excretion. A modified framework has since been proposed in which the traditional overproduction type is redefined as a renal overload type, focusing on the overall urate burden delivered to the kidney. Within this category, two distinct subtypes are recognized: urate overproduction, reflecting increased endogenous synthesis, and extra-renal underexcretion, reflecting impaired intestinal urate elimination (17). However, these classifications primarily address the total amount of urate excreted and do not sufficiently reflect intrarenal urate handling, particularly in CKD patients. In CKD, hyperuricemia may result from glomerular and tubular dysfunctions. Specifically, reduced glomerular filtration can limit the filtered urate load, whereas excessive tubular reabsorption may decrease urinary uric acid excretion even when filtration is relatively preserved.

To better reflect the pathophysiological heterogeneity of hyperuricemia in CKD, we propose that the under-excretion type of hyperuricemia is further subdivided into two categories: (1) glomerular under-filtration type, characterized by reduced filtration, is the primary cause of urate retention, and (2) tubular over-reabsorption type, in which disproportionately increased tubular reabsorption contributes to urate retention. A classification system based on two parameters, the GFR and FEUA, is a reasonable gold standard for distinguishing between the two subtypes. To support this concept, we suggest the development of a new indicator: the tubulo-glomerular urate handling (TUH) index. This parameter reflects the relative contributions of glomerular filtration and tubular reabsorption to net urate excretion. One theoretical formulation of the TUH index incorporates the GFR and tubular reabsorption of uric acid (TRUA) and may be calculated as follows:

TUH index=GFR×TRUA

=creatinine clearance (CCr)×(100-FEUA)

=(CCr-uric acid clearance (CUA))×100

where CCr and CUA represent creatinine and uric acid clearance, respectively, and the FEUA is calculated as follows:

FEUA=100×(CUA/CCr)

Although this formulation remains theoretical, it provides a foundation for future validation studies aimed at refining hyperuricemia in CKD and guiding therapeutic strategies, particularly in identifying those who would benefit the most from therapies targeting tubular uric acid transport, such as SURIs. A schematic representation of the proposed classification system is shown in Figure. Although further clinical validation is needed, this approach highlights the importance of evaluating urate-handling mechanisms in greater detail, particularly in patients with CKD.

Figure.

Schematic illustration of a proposed classification of hyperuricemia. The conventional classification of hyperuricemia is based on two axes, urate clearance and urinary urate excretion, yielding three clinical phenotypes: underexcretion type, renal overload (formerly overproduction and extra-renal underexcretion), and combined type. In the proposed classification, a third axis representing tubulo-glomerular urate handling was introduced, incorporating the concepts of glomerular filtration and tubular reabsorption. This allows further stratification of the under-excretion type into glomerular under-filtration and tubular over-reabsorption subtypes, reflecting distinct mechanisms of impaired urate excretion in patients with CKD.

6. Conclusion

In conclusion, we summarized the current evidence that links hyperuricemia and CKD and proposed desirable strategies for managing hyperuricemia. Notably, we propose a refined classification that subdivides the underexcretion type into glomerular under-filtration and tubular over-reabsorption types. This perspective will accelerate future research and offer more individualized treatment strategies to manage hyperuricemia and slow CKD progression.

The authors state that they have no Conflict of Interest (COI).