Uric Levels Research Articles

The impact of uric acid on musculoskeletal diseases: clinical associations and underlying mechanisms

Serum urate (SU) levels are significantly elevated in conditions such as gout, type 2 diabetes (T2D), obesity, and other metabolic syndromes. Recently, due to the high prevalence of hyperuricemia (HUA), numerous clinical connections between SU and musculoskeletal disorders like sarcopenia, osteoarthritis (OA), rheumatoid arthritis (RA), intervertebral disc degeneration (IDD), and osteoporosis (OP) have been identified. This review discusses the mechanisms linking SU to musculoskeletal disorders, as well as the clinical associations of SU with conditions such as sarcopenia, T2D with sarcopenia, McArdle disease, heart failure, gout, OA, IDD, OP and exercise-induced acute kidney injury (EIAKI), offering valuable insights for improved prevention and treatment strategies. Mechanisms linking SU to musculoskeletal disorders include oxidative stress, MSU (monosodium urate) crystal deposition, inflammation, and other factors. In adults, both age and SU levels should be considered for preventing sarcopenia, while gender and SU may directly impact muscle mass in children and adolescents. HUA and gout may be risk factors for OA progression, although some reports suggest otherwise. A U-shaped relationship between SU and IDD has been reported, particularly in Chinese men, indicating lower or higher SU level may be risk factors for IDD. Maintaining SU levels within a certain range may help prevent OP and fractures. Future research, including epidemiological studies and new pathogenesis findings, will further clarify the relationship between musculoskeletal diseases and SU.

Associations between lipid-lowering drugs and urate and gout outcomes: a Mendelian randomization study

ObjectiveGout is a common inflammatory arthritis and lipid metabolism plays a crucial role in urate and gout. Potential associations between urate and gout and lipid-lowering drugs have been revealed in observational studies. However, the effects of lipid-lowering drugs on urate and gout remain controversial. The aim of this study was to investigate the genetic association between lipid-lowering drugs and urate and gout.MethodsIn this study, two genetic proxies were employed to approximate lipid-lowering drug exposure: expression quantitative trait loci (eQTL) associated with drug-target genes and genetic variations proximal to or within genes targeted by these drugs, which are linked to low-density lipoprotein cholesterol (LDL-C) levels. The study’s exposures encompassed genetic variants within drug target genes (HMGCR, PCSK9, NPC1L1), each representing distinct lipid-lowering mechanisms. Causal effects were estimated using the inverse variance weighting (IVW) method, while the Summary Data-based Mendelian Randomization (SMR) method, leveraging pooled data, was applied to compute effect estimates. These estimates were further refined through various approaches including MR-Egger, the weighted median method, simple and weighted models, and leave-one-out analyses to conduct sensitivity analyses.ResultThe analytical outcomes utilizing the IVW method indicated that inhibitors of HMGCR were correlated with an elevated risk of developing gout (IVW: OR [95%CI] = 1.25 [1.03, 1.46], p=0.0436), while PCSK9 inhibitors were linked to heightened levels of urate (IVW: OR [95%CI] = 1.06 [1.01,1.10], p=0.0167). Conversely, no significant correlation between NPC1L1 inhibitors and the levels of urate or the risk of gout was established. Furthermore, the SMR analysis failed to identify significant associations between the expression levels of the HMGCR, PCSK9, and NPC1L1 genes and the risk of gout or elevated urate levels (SMR method: all P values >0.05). Sensitivity analyses further confirmed the robustness of these results, with no significant heterogeneity or pleiotropy found.ConclusionThis study furnishes novel causal evidence supporting the potential genetic correlation between the use of lipid-lowering drugs and the incidence of gout as well as urate levels. The findings indicate that inhibitors targeting HMGCR may elevate the risk associated with the development of gout, while inhibitors targeting PCSK9 are likely to increase urate concentrations.

Can Urate Lowering Therapy Be Stopped in Gout? Rationale and Design of Two Large Randomised Trials

Lifelong urate-lowering therapy (ULT) is recommended for gout to prevent flares and urate deposition. However, concerns about its adherence, long-term side effects, and the necessity of continuous treatment after achieving remission raise critical questions. Two randomised controlled trials (RCTs), GO TEST Finale and STING, aim to evaluate the safety and feasibility of ULT discontinuation in gout patients in remission. The GO TEST Finale is a superiority trial involving 310 patients in the Netherlands, comparing a treat-to-target (T2T) ULT continuation strategy with ULT discontinuation. Patients in the discontinuation arm resume ULT only after flare recurrence or tophi development. The primary outcomes focus on remission criteria failure over 24 months, while the secondary outcomes explore predictors of successful discontinuation and cost-effectiveness. The STING study, a non-inferiority trial in France, includes 450 patients without ultrasound (US) evidence of urate deposits. Patients in the discontinuation group resume ULT if a US detects urate deposition during follow-up, minimising flare risk. The primary outcomes measure the proportion of patients experiencing flares at two years, with the secondary outcomes examining the long-term health impacts and cost-effectiveness. These trials provide an opportunity for translational research into the immunological and epigenetic effects of rising serum urate levels. The results could inform personalised strategies for a drug-free period and address the critical question of whether lifelong ULT is necessary for gout management. The complementary findings from both trials are expected to contribute significantly to resolving this ongoing clinical debate.

Red blood cell urate levels are linked to hemolysis in vitro and post-transfusion as a function of donor sex, population and genetic polymorphisms in SLC2A9 and ABCG2.

Storage of packed red blood cells (RBCs) for transfusion leads to biochemical and morphological changes, increasing hemolysis risk. Urate levels in blood bags at donation contribute to the molecular heterogeneity and hemolytic propensity of stored RBCs. However, studies to date have been underpowered to investigate at scale the contribution of donor demographics and genetics to the heterogeneity in urate levels across donations. Urate levels were measured in 13,091 RBC units from the REDS study. Characteristics tested included hemolysis parameters (spontaneous, osmotic, oxidative) at storage end and post-transfusion hemoglobin (Hb) increments in recipients. Donor demographics, urate levels, and genetic variants were analyzed for associations with these outcomes. Elevated urate levels were linked to male sex, older age, high BMI, and Asian descent. Units with high urate levels exhibited increased spontaneous and osmotic hemolysis, while oxidative hemolysis was unaffected. Genetic variants in SLC2A9 (V282I) and ABCG2 (Q141K) were strongly associated with elevated urate, particularly in Asian donors. Post-transfusion analyses revealed that units from female donors carrying these variants were associated with reduced Hb increments, with up to a 31% reduction in efficacy. This effect was not observed in male donors. RBC urate levels and genetic traits significantly impact storage quality and transfusion outcomes. These findings highlight the importance of donor molecular characteristics for optimizing transfusion strategies. Moreover, genetic and metabolic insights may inform donor recruitment efforts, providing health feedback to volunteers while ensuring effective transfusion products.

Treatment-Emergent Major Adverse Cardiovascular and Thromboembolic Events were Infrequent During Clinical Trials of Pegloticase.

Long-term maintenance of serum urate (SU) levels <6 mg/dl reduces gout flare frequency. However, urate-lowering therapy (ULT) initiation can induce gout flare. The incidence of thromboembolic (TE) and cardiovascular (CV) events has been shown to increase in the 30 and 120 days following gout flare, respectively; therefore, the question of ULT initiation increasing patient risk for CV/TE events has been raised. Here, we investigate CV/TE event incidence following pegloticase initiation in clinical trials. This post hoc analysis of pooled data from 4 trials examined treatment-emergent gout flare and CV/TE events in patients with uncontrolled gout. Studies included two phase 3 trials (NCT00325195), the MIRROR open-label trial (NCT03635957), and the MIRROR randomized controlled trial (NCT03994731). Per protocol, pegloticase (8 mg) was administered every 2 (all trials) or 4 weeks (phase 3 trials); data from the first 24 weeks of therapy were included in this analysis. Some MIRROR patients received methotrexate (15 mg/week) as co-therapy. Based on prior studies, the high-risk window for CV/TE events was defined as 120 days following flare onset. Overall, 5/328 (1.5%) patients experienced ≥1 CV/TE event during pegloticase treatment, including 3/244 (1.2%) patients who received on-label (biweekly) dosing (35.4 events/1000 person-years). All events occurred within the 120-day gout flare exposure window. CV/TE event incidence during pegloticase treatment was similar to the general gout population (31.7 events/1000 person-years). These findings suggest that pegloticase initiation does not put patients at a higher risk for CV/TE events.

Pegloticase and Methotrexate Cotherapy in Patients With Uncontrolled Gout With Prior Pegloticase Monotherapy Failure: Findings of an Open-Label Trial.

Patients with uncontrolled gout have few treatment options. Pegloticase lowers serum urate (SU) levels, but antidrug antibodies limit SU-lowering response and increase infusion reaction (IR) risk. Methotrexate (MTX) cotherapy increases pegloticase response rates and lowers IR risk in pegloticase-naïve patients. Therefore, the question of re-treating patients with previous pegloticase monotherapy failure has arisen. The ADVANCE open-label trial examined pegloticase plus MTX cotherapy efficacy and safety following pegloticase monotherapy failure. Patients with uncontrolled gout (SU levels ≥6 mg/dL, oral urate-lowering therapy failure or intolerance, and ≥1 gout sign or symptom) who previously lost SU-lowering response to pegloticase monotherapy were included. Key exclusion criteria were moderate-to-severe IR or anaphylaxis to pegloticase, MTX contraindication, immunosuppressant administration, glucose-6-phosphate dehydrogenase deficiency, and estimated glomerular filtration rate <30 mL/min/1.73m2. After a 6-week subcutaneous MTX run-in (at 25 mg/wk), patients entered 24-week pegloticase (at 8 mg biweekly) plus MTX treatment. The primary end point was SU-lowering response rate during month 6 (SU levels <6 mg/dL for ≥80% of weeks 20-24). Safety was assessed via adverse events (AEs) and laboratory monitoring. Eleven patients began pegloticase plus MTX treatment (91% male patients, mean age 58.6 ± 11.3 years, mean ± SD SU levels 8.5 ± 3.2 mg/dL, 91% tophaceous). Previous pegloticase course was 2 to 27 infusions, with the last infusion admins being a mean ± SD of 3.7 ± 2.4 years before. One patient (9%) maintained response during month 6; 10 patients prematurely discontinued treatment (loss of SU lowering [n = 8], IR [n = 2]). Eight patients (73%) experienced ≥1 AE, most commonly gout flare. All AEs were mild or moderate. Pegloticase plus MTX response rate following failed monotherapy was lower (9% vs 71%) and IR rate was higher (18% vs 4%) than in pegloticase-naïve patients. These findings demonstrate the challenge of overcoming established antipegloticase antibodies and emphasize the importance of initiating immunomodulation before the first pegloticase exposure.

Serum Urate and Atrial Fibrillation: A Bidirectional Mendelian Randomization Study.

Observational studies indicate that serum urate level is associated with atrial fibrillation (AF). However, whether this association is causal remains controversial, due to confounding factors and reverse causality. We aim to evaluate the causal relationship of genetically predicted serum urate level with AF. A bidirectional Mendelian randomization (MR) study was performed. Instrumental variables were obtained from the Global Urate Genetics Consortium (110347 individuals). We obtained summary statistics of AF from two genome-wide association studies (GWAS) data sets for AF. Inverse-variance-weighted method was applied to obtain MR estimates and other statistical methods were conducted in the sensitivity analyses. The reverse MR analysis was performed to evaluate the effect of AF on serum urate levels. Genetically determined serum urate level was not associated with AF in two studies (OR, 1.03; 95% CI, 0.95-1.11; p = 0.47); (OR, 1.06; 95% CI, 0.99-1.12; p = 0.09). The main results kept robust in the most sensitivity analyses. Multivariable MR analyses suggested that the association pattern did not change, after adjusting for body mass index (BMI), HbA1c: hemoglobin A1c (HbA1c), hypertension, low-density lipoprotein cholesterol (LDL-C) and coronary heart disease. No causal effect of AF on serum urate levels was found in two studies (OR, 1.02; 95% CI, 0.98-1.05; p = 0.30); (OR, 1.00; 95% CI, 0.98-1.03; p = 0.95). Our MR study supports no bidirectional causal effect of serum urate levels and AF. This implies that treatments aimed at lowering uric acid may not reduce the risk of AF.

Association between serum urate levels, gout and breast cancer: observational and Mendelian randomization analyses

Association between serum urate levels, gout and breast cancer: observational and Mendelian randomization analyses

Association between serum urate levels and all-cause mortality, cardiovascular and renal outcomes among gout patients in Singapore

ObjectivesWe investigated the longitudinal association between Serum Urate (SU) level and Acute Myocardial Infarction (AMI), Stroke, End Stage Renal Failure (ESRF) and all-cause mortality.DesignWe conducted a retrospective hospital-based cohort study of individuals with gout managed in specialist outpatient clinics. Cox proportional hazards regression was used to estimate HR and 95% CI, with adjustments for potential confounders. Where the proportional hazard assumption was violated, stratified Cox regression was applied instead.SettingAn acute care tertiary hospital in Singapore.ParticipantsIndividuals with a first gout diagnosis between 2007–2017, identified through (i) primary discharge diagnosis, (ii) diagnosis from the Rheumatology SOC (iii) patient history of a clinical encounter at the Rheumatology SOC plus use of urate-lowering therapy/colchicine.Main outcome measuresAll-cause mortality, AMI, Stroke and ESRF ascertained through data linkage with the National Registry of Diseases Office.ResultsThe final cohort comprised 2,866 individuals. Post follow-up, there were 800 deaths and 362, 218 and 191 occurrences of AMI, ESRF and stroke respectively. Compared to the reference (second-lowest) SU quartile, being in the highest SU quartile was associated with a significantly increased hazard for mortality (HR:1.66, 95% CI:1.36–2.03), incident ESRF (HR:3.02, 95% CI:2.00-4.56), and increased hazard for incident AMI (HR:1.42, 95% CI:1.06–1.91). The p-trend for all 3 outcomes was significant. No significant association was found between SU quartile and hazard for incident stroke.ConclusionsThis study found that individuals with gout managed at SOC who had higher baseline SU levels had an increased hazard for all-cause mortality, ESRF, and AMI.Clinical trial numberNot applicable.

Retrospective analysis of the causes of uveitis in patients of the ophthalmology department of a multidisciplinary clinic: the place of hyperuricemia

Background. Prolonged, including asymptomatic hyperuricemia (HU) for 7–10 years leads to the formation of sodium monourate deposits in various organs and tissues. Aim. To study the incidence of noninfectious uveitis (NU) caused by HU. Materials and methods. A retrospective evaluation of medical records of 217 patients diagnosed with NU in the ophthalmologic department of the general clinic for 10 years was carried out. Inclusion criteria: excess of serum uric acid values beyond the reference value (464 μmol/L), absence of other reasons explaining uveitis in the medical history. Exclusion criteria: glaucoma, recurrence of uveitis, pathology of ENT organs and oral cavity. Data are presented as median and interquartile range. Spearman's rank correlation coefficient was used as a criterion to assess the relationship between quantitative variables. The threshold level of statistical significance was taken as 0.05. Results. There were 19 patients, mean age of men – 60 years (54–69 years), mean age of women – 60 years (37–67 years), leukocyte count – 7.8×109 (6.4–9.4×109), SOE – 52.5 mm/h (47–61 mm/h), CRP – 62.6 mg/L (53–68.1 mg/L), MC – 560 μmol/L (531–601 μmol/L). Among the concomitant pathology: cataract was detected in 8 patients (44.4% of the total), hypertension – in 7 (38.9%) patients, CHD in its various forms – in 6 patients (33.3%), chronic obstructive pulmonary disease and bronchial asthma – in 2 (11.1%) patients, diabetes mellitus – in 1 (5.3%) patient, gout – in 2 (11.1%) patients, and urolithiasis – in 4 (21%) patients. Statistically significant direct correlations were found between uric acid levels with COE (ρ=0.993; p0001), CRP (ρ=0.998; p0001). All identified correlations had strong closeness according to the Cheddock scale. Conclusion. Despite the low incidence of HU-induced NU, examination of serum urate levels is an important diagnostic criterion in recognizing the cause of uveitis.

Allopurinol use predicts lower LDL cholesterol in patients with pre-dialysis CKD - a prospective cohort study

Abstract Background Hyperuricemia influences lipid metabolism, yet relationships between urate-lowering therapy with allopurinol, serum urate, and lipid levels in patients with chronic kidney disease (CKD) remain underexplored. Methods This was a post-hoc analysis of 1,970 participants of the CAN AIM to PREVENT who had pre-dialysis CKD and were not receiving lipid-lowering therapy or febuxostat. Joint generalized structural equation modelling was used to investigate associations between allopurinol use (yes or no), serum urate (as a continuous or categorical variable (target if &amp;lt;6 mg/dL or high if ≥6 mg/dL)), and lipid levels (total cholesterol, LDL-C, HDL-C, and triglycerides) assessed every 6 months for up to 3 years, along with time-to-event outcomes (death or initiation of renal replacement therapy), adjusting for demographic and clinical factors. Mediation analysis was used to determine allopurinol's direct and indirect effects (via urate) on lipid levels. Results Allopurinol use independently predicted lower total cholesterol (-7.94%, 95% CI: -12.13% to -3.54%, p&amp;lt;0.001)) and LDL-C (-13.84%, (-21.14 to -5.87), p=0.001). Serum urate independently predicted a small increase in LDL-C (0.02% per mg/dL (0.009 to 0.03), p&amp;lt;0.001). Patients on allopurinol with target urate had lower LDL-C compared to those not on allopurinol with target urate (-4.46% (-8.25 to -0.50), p=0.027) and those on allopurinol with high urate (-10.15% (-13.16 to -7.04), p&amp;lt;0.001. Mediation analysis showed that serum urate indirectly mediated only 24% of the effect of allopurinol on LDL-C. Conclusion Allopurinol use predicted lower total and especially LDL cholesterol independently of serum urate in this cohort of patients with pre-dialysis CKD. Future studies could investigate underlying mechanisms, evaluate clinical implications, and confirm these findings in this and other populations.

Discovery of cyanidin-3-O-galactoside as a novel CNT2 inhibitor for the treatment of hyperuricemia.

Inhibition of human concentrative nucleoside transporter 2 (CNT2) could suppress increases in serum urate levels derived from dietary purines. However, the structural basis for substrate recognition of CNT2 is still unknown and only a few inhibitors have been reported. In this study, a homology model of CNT2 was constructed and residues T315, E316, N426, N491, E492, F536 and N538 were identified as binding sites for adenosine through site-directed mutagenesis and a 3H-adenosine uptake assay. To explore potential CNT2 inhibitors, a database containing 4704 saccharides and glycosides was constructed, followed by high-throughput virtual screening. The top 20 compounds with the highest docking scores were then evaluated their in vitro activity. Among them, cyanidin-3-O-galactoside (Cy3Gal) demonstrated the most potent inhibitory activity against CNT2, exhibiting an IC50 value of 9.40μM. Docking analysis revealed that residues M314, T315, T347, N422, F536 and S541 contributed to a strong binding affinity with Cy3Gal. In addition, Cy3Gal exhibited minimal inhibitory effects on CNT3 and equilibrative nucleoside transporters (ENTs) in vitro. At doses of 5-20mg/kg, Cy3Gal effectively reduced serum and urine levels of uric acid and adenosine in vivo. The CCK-8 assay revealed that Cy3Gal displayed minimal cytotoxicity to mTEC and hIEC cells at a concentration of 100μM. The serum CR and BUN levels indicate that Cy3Gal does not exhibit any apparent renal toxicity compared to lesinurad and allopurinol. HE examination showed no noticeable pathological changes in the kidneys or colons after treatment with Cy3Gal. In summary, Cy3Gal could be a CNT2 inhibitor with favorable drugability for the treatment of hyperuricemia.

Urate Levels as a Predictor of the Prevalence and Level of Cardiovascular Risk Factors: An Identificación de La PoBlación Española de Riesgo Cardiovascular y Renal Study.

(1) Background: Urate levels lower than the classical cut-off point for defining hyperuricemia can increase cardiovascular risks. The aim of this study is to determine if there is a relationship between different urate levels and classic cardiovascular risk factors (CVRFs). (2) Methods: A cross-sectional study of the inclusion visits of the patients recruited to the IBERICAN study was conducted. The patients were classified into quartiles according to their distribution of urate levels and separated by sex; the three lower points corresponded to normal levels of urate, and the highest quartile was determined according to the classical definition of HU. Multivariate analysis models, adjusted for epidemiological variables, were used to analyze the association of urate levels with CVRFs. (3) Results: The presence of CVRFs was higher across the quartiles of urate, with a continuous increase along the quartiles in both sexes in accordance with body mass index (p < 0.01), waist circumference (p < 0.01), blood pressure (p < 0.01), and LDL cholesterol (p < 0.01). The CV risk estimated by SCORE was associated with an increase along the quartiles in women (p = 0.02). (4) Conclusions: A progressive increase in the frequency of CVRFs, as well as in their levels, was observed across the quartiles of uricemia, which reflects an increase in the CVRs associated with uricemia.

Triglyceride-glucose index and its additive interaction with ABCG2/SLC2A9 polygenic risk score on hyperuricemia in middle age and older adults: findings from the DLCC and BHMC study

Objective We aim to investigate the joint effect of triglyceride-glucose (TyG) index and polygenic risk scores (PRS) of urate transporter genes ABCG2 and SLC2A9 on hyperuricemia. Methods Baseline data from two prospective population-based cohort studies, including 30,453 individuals aged 50 years or older, were used to analyze the association between TyG index and hyperuricemia. A case-control study was then designed from the cohorts to investigate the interaction between genetic predisposition and TyG index on hyperuricemia among 595 matched pairs. PRS was constructed using 14 single nucleotide polymorphisms located in the ABCG2 and SLCA29 genes. Results In both sexes, higher TyG index levels were correlated with elevated serum urate (SUA) levels (p values in both sexes < 0.001). In men, per unit increase of TyG was associated with a 1.44-fold (95% confidence interval [CI]: 1.35–1.55) higher risk of hyperuricemia after adjusted for covariates. In women, this estimate was 1.69 (1.51–1.89). Demonstrated by the restrict cubic spline model, TyG index was both linearly and non-linearly associated with elevated SUA (both p values < 0.001). Association between TyG index and hyperuricemia was stronger among people with higher genetic risk, and vice versa. Compared to people with TyG < 9 and PRS < 2, the odds ratios (ORs) (95% CIs) for hyperuricemia in the TyG <9 but PRS ≥2, TyG ≥9 but PRS < 2, TyG ≥9 and PRS ≥2 groups were 3.30 (1.53–7.14), 3.16 (1.23–8.11) and 7.55 (2.76–20.65), respectively. Additive interaction was also significant, with 57.5% (30.5%–84.4%) of the excess risk attributable to the additive gene-TyG index interaction. Conclusions The impact of genetic predisposition on hyperuricemia was significantly greater among individuals with a higher TyG index. Over 50% of the increased risk can be attributed to the interaction, indicating a crucial synergy between genetic factors and TyG index when estimating hyperuricemia risk.

Target Serum Urate Achievement and Chronic Kidney Disease Progression in Patients With Gout and Kidney Disease

Clinicians often approach urate-lowering therapy (ULT) cautiously in patients with gout and impaired kidney function because they are concerned about the risk of progression to severe or end-stage kidney disease. However, evidence from randomized clinical trials of this association remains inconclusive. To evaluate the association between achieving target serum urate level with ULT and progression of chronic kidney disease (CKD) to severe or end-stage in patients with gout and impaired kidney function. This was a cohort study using the target trial emulation approach using data from a general practice database (IQVIA Medical Research Database) for 2000 to 2023. Eligible patients were 40 to 89 years old and had gout and CKD stage 3. Data analyses were performed from November 2023 to September 2024. Lowering serum urate level to target level (<6 mg/dL) using ULT. Severe or end-stage kidney disease, determined by an estimated glomerular filtration rate of less than 30 mL/min/1.73 m2 on at least 2 occasions more than 90 days apart within 1 year, or at least 1 Read code (per the Refined Etiology, Anatomical Site, and Diagnosis classification) for CKD stages 4 or 5, hemodialysis, peritoneal dialysis, or kidney transplant. The prespecified noninferiority margin of the hazard ratio (HR) was set at 1.2, comparing those who achieved the target serum urate level with those who did not. Among the 14 792 participants (mean [SD] age, 73.1 [9.5] years; 9215 men [62.3%] and 5577 women [37.7%]) with gout and with CKD stage 3, the 5-year risk of severe or end-stage kidney disease was 10.32% for those who achieved the target serum urate level and 12.73% for those who did not. Compared with those not achieving the target level, the adjusted 5-year risk difference and HR of severe or end-stage kidney disease for patients achieving the target serum urate level was -2.41% (95% CI, -4.61% to -0.21%) and 0.89 (95% CI, 0.80 to 0.98), respectively. The findings of this cohort study indicate that in patients with gout and CKD stage 3, lowering serum urate level to less than 6 mg/dL vs 6 mg/dL or greater using ULT was not associated with an increased risk of severe or end-stage kidney disease. These findings support optimizing ULT to achieve target serum urate levels when treating patients with gout and impaired kidney function.

Exploring the link between serum uric acid and colorectal cancer: Insights from genetic evidence and observational data.

Colorectal cancer (CRC) is a major cause of cancer-related mortality worldwide. Urate, known for its antioxidant properties, may influence CRC risk and prognosis, but research on this is limited. We used Mendelian randomization (MR) analysis to explore the causal relationship between serum urate levels and CRC risk. Additionally, we analyzed National Health and Nutrition Examination Survey data to assess the impact of serum urate on CRC prognosis. MR analysis in the European population indicated that higher serum urate levels are associated with a reduced CRC risk (odds ratios [OR] inverse-variance weighted: 0.90, 95% CI: 0.81-0.99, P = .04; OR MR-Egger: 0.86, 95% CI: 0.75-0.98, P = .03; OR Weighted-Median: 0.85, 95% CI: 0.74-0.96, P = .01; OR Weighted-Mode: 0.83, 95% CI: 0.74-0.94, P = .002). Validation datasets supported this (OR inverse-variance weighted: 0.83, 95% CI: 0.72-0.96, P = .011). However, National Health and Nutrition Examination Survey data showed that higher serum urate levels are linked to poorer CRC outcomes (HR 1.50, 95% CI: 1.08-2.10, P = .02). This study suggests that elevated serum urate levels may reduce CRC risk but are associated with worse prognosis in CRC patients, highlighting its potential as a biomarker for CRC risk and prognosis.

Insulin resistance has closer correlation with the occurrence of metabolic dysfunction associated steatotic liver disease diagnosed by liver biopsy.

To explore any correlation between serum urate (SU) level or insulin resistance (IR) and metabolic dysfunction associated steatotic liver disease (MASLD) in patients with metabolic syndrome (MS). Data from all MASLD patients, diagnosed by liver biopsy, were enrolled and divided into MASLD alone group and MASLD with MS group. They were subdivided into hyperuricemia group and normal SU group to find correlation between SU/IR and MASLD in patients with MS and independent risk factors for MASLD. Data from 539 MASLD patients were analyzed. Body mass index (BMI) (p = 0.000), waist circumference (WC) (p = 0.004), and low-density lipoprotein (LDL) (p = 0.000) were dramatically higher in MASLD with MS group than those with MASLD alone; MASLD with MS patients had significantly more family history of diabetes (p = 0.000) and hypertension (p = 0.000) than patients with MASLD alone. Height (p = 0.000), weight (p = 0.000), BMI (p = 0.000) and WC (p = 0.001), and LDL (p = 0.007) were dramatically higher in hyperuricemia patients than those with normal SU. SU was inversely associated with age (p = 0.000) and high-density lipoprotein (HDL) (p = 0.003), and positively correlated with weight (p = 0.000), BMI (p = 0.000) and WC (p = 0.000), TG (p = 0.000), and LDL (p = 0.000). Logistic Regression analysis showed that age (p = 0.031), TG (p = 0.002), LDL (p = 0.010), HbA1c (p = 0.026), and family history of hypertension (p = 0.000) may be independent risk factors for MASLD in patient with MS. Insulin resistance (IR) in MASLD patients with MS, but not higher SU levels, has closer correlation with the occurrence of MASLD in patients with family history of hypertension and diabetes having higher BMI, LDL, HbA1c.

Assessing the causal associations of atrial fibrillation with serum uric acid level and gout: insights from a bidirectional mendelian randomization study

BackgroundNumerous observational studies consistently highlight a strong association between serum uric acid (sUA) levels and atrial fibrillation (AF). However, the causal relationship and the direction of this association remain elusive, despite extensive research efforts.ObjectiveThis study aimed to investigate the bidirectional causal relationships between sUA, gout, and the risk of AF using the two-sample Mendelian randomization (MR) approach.MethodsWe conducted a comprehensive analysis utilizing publicly available genome-wide association studies (GWAS) summary statistics, employing stringent criteria to meticulously select genetic variants associated with sUA, gout, and AF. Our primary analytical approach was the inverse-variance weighted (IVW) method, complemented by some sensitivity analyses, including MR-Egger, weighted median, simple mode, and weighted mode, to estimate the causal effects. To identify potential violations, we conducted Egger regression and leave-one-SNP-out analyses. We assessed the strength of instrumental variables using F values to evaluate weak instruments. Additionally, we referenced the Phenoscanner database to exclude single nucleotide polymorphisms (SNPs) associated with confounding factors or outcomes.ResultsOur forward Mendelian randomization analysis suggests that there is no causal relationship between UA levels/gout from different populations and the risk of AF [IVW OR 1.03, 95% CI: 0.97–1.08; p = 0.335; IVW OR 0.99, 95% CI: 0.97–1.02; p = 0.583; and IVW OR 1.07, 95% CI: 0.84–1.37; p = 0.575], respectively. We did not detect significant heterogeneity or potential pleiotropy, and we also excluded the possibility of weak instrumental variables. Furthermore, we did not find any reverse causal effects of AF on sUA levels and gout risk.ConclusionOur findings challenge the widely held belief that lowering urate levels is uniformly effective in reducing the risk of atrial fibrillation (AF). Our study fails to substantiate the existence of a causal link between uric acid (UA) levels or gout and the development of AF, regardless of direction.

Evaluation of continued 2-monthly or annual urate monitoring in gout: an extension of the GoutSMART randomised controlled feasibility trial

Aim: Improved outcomes for patients with gout are associated with reduced urate levels and many guidelines recommend regular urate monitoring. There is no consensus on how frequently monitoring should be performed, and so we have used a supported self-management approach which incorporates urate self-testing to evaluate 2-monthly urate monitoring compared to annual monitoring. Methods: This study was an extension of a 12-month feasibility trial in 60 gout patients randomised 2:1 to support gout self-management or usual care. Participants exiting the self-management arm were offered 2-monthly urate monitoring, with usual care participants offered annual monitoring. Additional participants were randomised 1:1 to either arm. All participants were offered initial dose titration to a urate target of 0.3 mmol/L. The primary outcome was the proportion of participants with urate ≤ 0.36 mmol/L at 24 months with an intention-to-treat analysis. Results: Between September 2020, and September 2021, 67 patients were enrolled. The mean age was 55.5 (SD 14.0) years. 61 (91%) self-reported as cisgender male, 5 (7.5%) as cisgender female and 1 (1.5%) as transgender female. 62 (92.5%) were White, 4 (6.0%) were Asian and 1 (1.5%) was Black. 40 participants were allocated to 2-monthly monitoring (including 10 new participants), and 27 participants to annual monitoring (including 12 new participants). The primary study outcome of urate ≤ 0.36 mmol/L at 24 months was achieved by 38 (95%) 2-monthly monitoring participants, compared to 17 (62.9%) annual monitoring participants (risk difference 0.32 [95% CI 0.13 to 0.52]; p = 0.0021). 5 (7.5%) participants withdrew with 4 allocated to annual monitoring. 2 annual monitoring participants died. Conclusions: 2-monthly monitoring of urate is associated with improved maintenance of urate targets after 2 years compared to annual monitoring, a result influenced by an increased withdrawal rate amongst annual monitoring participants. Further trials evaluating the cost-effectiveness and optimal frequency of urate monitoring are now needed (ClinicalTrials.gov identifier: NCT03274063).

The development of a novel high-throughput membrane potential assay and a solid-supported membrane (SSM)-based electrophysiological assay to study the pharmacological inhibition of GLUT9/SLC2A9 isoforms in a drug discovery program

GLUT9/SLC2A9 is a urate transporter and takes a fundamental role in the maintenance of normal serum urate levels. GLUT9 is the sole transporter of reabsorbed urate from renal epithelial cells to blood, thus making it an ideal pharmacological target for the development of urate-lowering drugs. None of the three currently available assays for studying GLUT9 pharmacological inhibition can support a high throughput drug discovery screening campaign. In this manuscript we present two novel assay technologies which can be used in a drug discovery screening cascade for GLUT9: a GLUT9 membrane potential assay for primary screening; and a solid-supported membrane (SSM)-based supported electrophysiological assay for secondary screening.