Changgui Li

Gout is a systemic metabolic inflammatory disease driven by hyperuricemia and monosodium urate crystal deposition, and is frequently accompanied by chronic kidney disease and uric acid nephrolithiasis. Current evidence indicates that acidic urine, hypocitraturia, and insufficient ammonium excretion are common in gout patients, and may be associated with insulin resistance, impaired renal ammoniagenesis, and abnormalities in tubular acid-base regulation. Persistent urinary acidification may contribute to the development and progression of uric acid stone formation and gout-related renal injury by reducing uric acid solubility, promoting crystal formation and intratubular deposition, and decreasing renal uric acid clearance. Urinary alkalization therapy can increase urine pH, thereby enhancing uric acid solubility and excretion, and has shown potential in some studies to improve serum urate levels, proteinuria, renal function parameters, and gout flare frequency, especially when using citrate-based alkali. However, the currently available evidence is mainly derived from observational studies and small prospective investigations, and recommendations across international guidelines remain inconsistent. High-quality evidence is still lacking regarding the optimal target population, urine pH range, choice of alkalizing agents, monitoring strategies, and long-term efficacy. Well-designed prospective studies are therefore needed to clarify the clinical role of urinary alkalization in renal protection among patients with gout.

To evaluate the effect of urine alkalization with citrate mixture on reducing flare incidence during initial urate-lowering therapy period in male gout patients with renal underexcretion-type. In this prospective cohort study, patients with renal underexcretion and urinary pH < 6.2 were enrolled. All participants received febuxostat 20 mg/day during weeks 0–4, later increased to 40 mg/day if serum urate (SU) levels > 360 μmol/L. According to group assignment, patients received either alkalization therapy (Alk group; citrate mixture, 3.5 g twice/day) or no alkalization (Control group). The primary outcome measure was gout flare incidence. In total, 240 patients (Alk 114, Control 126) completed the 12-week follow-up. The Alk group had a significantly lower flare incidence (35.1%) than the Control group (59.5%, P < 0.001) and a lower recurrence of flares (14.0% vs. 31.0%, P = 0.002). At week 4, the proportion of participants with SU < 360 μmol/L was significantly higher in the Alk than in the Control group (P = 0.039). The Alk group had lower triglycerides and higher high-density lipoprotein cholesterol levels than the Control group at weeks 4, 8, and 12 (P < 0.05). The urinary albumin-to-creatinine ratio (UACR) decreased from 1.65 (0.36–7.01) to 1.08 (0.62–2.99) at week 12 in the Alk group, significantly lower than that in the Control group (P = 0.001). No significant difference was noted in the incidence of adverse events between groups. In patients with renal underexcretion gout, urine alkalization with febuxostat therapy prevented gout flares, improved lipid metabolism, and lowered UACR. ChiCTR, https://www.chictr.org.cn , ChiCTR2100043573.

Objective: To systematically evaluate the contribution of clinical heterogeneity to chronic kidney disease (CKD) progression in gout patients using data-driven phenotyping, and to assess whether incorporating genetic risk improves prediction of renal outcomes. Methods: In this prospective cohort study, 1497 Chinese gout patients were enrolled and followed for CKD progression. K-means clustering was applied to four core clinical variables: serum urate (SU), fractional excretion of uric acid (FEUA) (i.e. high- and low-excretion), gout duration and kidney stone burden. The primary outcome was the incidence of CKD stage ≥3, assessed using Cox proportional hazards models. Genetic risk was evaluated using an unweighted genetic risk score derived from 20 single nucleotide polymorphisms associated with gout and hyperuricaemia. Results: Over a follow-up of 4166 person-years, 153 participants (10.22%) developed CKD stage ≥3. Five clinical clusters were identified: Cluster 1 (high-excretion, low-urate), Cluster 2 (low-excretion, low-urate), Cluster 3 (long-duration), Cluster 4 (low-excretion, high-urate) and Cluster 5 (nephrolithiasis). Cluster 4 and Cluster 5 were significantly associated with increased risk of CKD progression, with adjusted hazard ratios of 2.19 (95% CI 1.20–4.01) and 3.52 (95% CI 1.91–6.48), respectively. Genetic predisposition, via risk score, further amplified renal risk in Cluster 4. Achieving target SU levels and reductions in kidney stone burden were independently associated with a lower risk of CKD progression. Conclusions: This study proposes a novel K-means clustering-based classification of gout, identifying subgroups with distinct CKD trajectories. Integration of clinical phenotyping and genetic profiling may enhance individualized risk stratification and guide targeted prevention strategies in gout-associated CKD.

Objective: This study investigated that serum metabolomics, before urate‐lowering therapy (ULT) initiation, could serve as a biomarker for responsiveness to colchicine prophylaxis in patients with gout commencing treat‐to‐target ULT. Methods: We studied a multicenter prospective cohort (n = 409) initiating treat‐to‐target ULT plus colchicine prophylaxis. Untargeted metabolomics were measured at enrollment. We defined putative colchicine response or colchicine nonresponse as no flare or one or more flares, respectively, during six months after first colchicine dose. Cox regression and machine learning models defined the metabolomic signatures associated with reported flare activity on colchicine prophylaxis in the cohort. Results: In our cohort, 36.9% participants experienced at least one flare. Many inflammation‐related metabolites were differentially abundant in the recurrent flare group and correlated with recurrent flare risk. A significant association was found between a four‐metabolite risk score and gout flare activity (adjusted hazard ratio 3.21, 95% confidence interval [CI] 2.24–4.59), independent of the adjusted clinical factors. The machine learning model, which incorporated the top‐ranked metabolites selected by multivariable methods with unbiased variable selection along with traditional clinical factors, reached an area under the receiver operating characteristic of 0.771 (95% CI 0.713–0.828) and 0.724 (95% CI 0.611–0.837) for predicting flare risk in the discovery and validation cohort, respectively. Conclusion: Metabolomic profile–defined inflammation status was associated with gout flare outcomes in ULT initiators receiving colchicine prophylaxis. Identification of these novel metabolomic predictive signatures before ULT could potentially help optimize clinical decision‐making for flare prophylaxis colchicine dosing and duration in the first six months after initiation of treat‐to‐target ULT in gout. image

Objective: Asymptomatic hyperuricemia is a precursor of gout and is also associated with cardiovascular disease and chronic kidney disease. The aim of this study was to understand perceptions about asymptomatic hyperuricemia and views about urate‐lowering therapy in people with asymptomatic hyperuricemia. Methods: Participants in a multinational study of asymptomatic hyperuricemia completed questionnaires about their perceptions of hyperuricemia, concern about hyperuricemia‐associated health conditions, and willingness to take urate‐lowering medication. All had a screening serum urate of ≥0.48 mmol/L (8 mg/dL) and no current or previous symptoms of gout. Results: Overall, participants perceived that hyperuricemia had no or very few consequences on their life. Dietary factors were the most reported cause, whereas 37% did not know the cause. Participants reported a wide range in concern about hyperuricemia and the risk of developing gout. Concern about the risk of developing kidney disease or cardiovascular disease was also highly variable but was higher than concern about elevated serum urate ( P < 0.001). Most did not think a urate‐lowering medication was necessary, and there was moderate concern about the long‐term use of urate‐lowering medication. Medication necessity beliefs were most strongly associated with whether participants were willing to take urate‐lowering medication (partial R ² = 0.27, P < 0.001). Conclusion: Most participants perceived minimal consequences of asymptomatic hyperuricemia. Hyperuricemia was not well understood by participants, and biologic causes were generally underrecognized. Despite a range of concerns about hyperuricemia‐associated conditions, particularly kidney disease and cardiovascular disease, a urate‐lowering medication for asymptomatic hyperuricemia was not considered necessary, which aligns with most current management guidelines.

Objective: The objective of this study was to examine changes of age of onset and disease characteristics of gout between 2003 and 2022 in multiple centres in mainland China. Methods: A cross-sectional cohort study was conducted among people with gout from two geographically separate centres in China. Baseline gout clinic data were collected through a electronic medical records review. The onset age trends and disease characteristics of patients who developed gout between 2003 and 2012 (first decade) and between 2013 and 2022 (second decade) were compared. Results: A total of 10 658 patients were included. The age of gout onset declined over the two decades (Ptrend < 0.001), with the average onset age decreasing from 42.0 in 2003 to 38.9 years in 2022. The proportion of patients with an onset age of ≤19 and of 20–29 years increased annually by 5.8% and 9.6%, respectively (Ptrend < 0.05). Compared with age-, sex- and disease duration–matched patients in the first decade, patients who developed gout in the second decade were more likely to have a history of smoking and alcohol consumption, and less likely to engage in regular exercise (P < 0.001). Additionally, those with onset of gout in the second decade had higher rates of s.c. tophi, frequent gout flares, nephrolithiasis, hypertension and diabetes, though lower rates of dyslipidaemia (P < 0.05). Conclusion: Over the past two decades in mainland China, there has been a noticeable trend towards younger onset of gout, alongside an increase in disease severity and metabolic comorbidities.

Objective: Dotinurad is a selective urate reabsorption inhibitor that reduces serum urate levels. We compared the efficacy and safety of dotinurad with febuxostat in Chinese patients with gout. Methods: This phase 3, multicenter, randomized, double‐blind, parallel‐group study randomly allocated (1:1) eligible patients with gout to receive oral dotinurad or febuxostat. The primary end point was the responder rate (proportion of patients achieving serum urate levels ≤6.0 mg/dL) at week 24 in the full analysis set (FAS) to demonstrate superiority of dotinurad 4 mg/day to febuxostat 40 mg/day. The secondary end points included the responder rate at week 12 to show the noninferiority of dotinurad 2 mg/day to febuxostat 40 mg/day. Treatment‐emergent adverse events (TEAEs) were also recorded. Results: A total of 451 patients were randomized, and 441 were included in the FAS. Baseline characteristics were well balanced between treatment groups. The responder rate at week 24 was significantly higher for dotinurad 4 mg/day versus febuxostat 40 mg/day (73.6% vs 38.1%; adjusted difference 35.9% [95% confidence interval (CI) 27.4%–44.4%]; P < 0.0001), and at week 12, dotinurad 2 mg/day was noninferior to febuxostat 40 mg/day (55.5% vs 50.5%; adjusted difference 5.2% [95% CI −3.7% to 14.2%]). Incidences of TEAEs in the dotinurad and febuxostat groups were similar. Conclusion: Dotinurad 4 mg/day was superior to febuxostat 40 mg/day in achieving serum urate levels ≤6.0 mg/dL at week 24 and was well tolerated in Chinese patients with gout.

Objective: The aim of this updated guideline is to provide comprehensive recommendations for the management of gout in patients with common comorbidities, such as chronic kidney disease (CKD), cardiovascular disease (CVD), diabetes, osteoarthritis (OA), and gastrointestinal disorders.Methods: This guideline was developed by a multidisciplinary expert panel consisting of specialists in endocrinology, rheumatology, nephrology, cardiology, gastroenterology, and methodology. The development process adhered to standard methodologies, including PICO (population, intervention, comparator, and outcomes) question deconstruction, systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) for evidence and recommendation evaluation, Delphi voting, and expert consensus.Results: The guideline presents 26 evidence‐based recommendations addressing seven clinical questions for patients with hyperuricemia and gout in the context of comorbidities. Key recommendations include the maintenance of strict serum urate targets, particularly for patients with CKD stage ≥ 3, chronic gouty arthritis, and OA, in order to prevent disease progression. In patients with CVD or diabetes, intra‐articular triamcinolone is preferred over systemic glucocorticoids. Prioritized anti‐inflammatory treatments for patients with CKD, gastrointestinal diseases, and OA are recommended. The guideline also introduces emerging therapies, such as interleukin‐1 inhibitors and selective urate transport inhibitors, as potential treatment options for refractory cases.Conclusion: The update offers a comprehensive, patient‐centered approach to managing gout, particularly in individuals with associated comorbidities. Multidisciplinary collaboration and emerging new treatments and evidence ensure the optimization of the recommendations.