L-shaped association between lean body mass to visceral fat mass ratio with hyperuricemia: a cross-sectional study.

BACKGROUND: Insufficient attention has been given to examining the correlation between body composition and hyperuricemia, leading to inconsistent findings. The primary objective of this research is to explore the association between lean body mass index (LMI), visceral fat mass index (VFMI), and hyperuricemia. A specific emphasis will be placed on assessing the link between the ratio of lean body mass to visceral fat mass (LMI/VFMI) and hyperuricemia. METHODS: The present study employed a cross-sectional design and involved a total of 9,646 individuals who participated in the National Health and Nutrition Examination Survey (NHANES). To explore the associations among the variables, logistic and linear regressions were employed. Additionally, subgroup analyses and sensitivity analyses were conducted based on various characteristics. RESULTS: The results showed that LMI was positively associated with hyperuricemia (for Per-SD: OR = 1.88, 95%CI: 1.75, 2.01; for quartiles [Q4:Q1]: OR = 5.37, 95%CI: 4.31, 6.69). Meanwhile, VFMI showed a positive association with hyperuricemia (for Per-SD: OR = 2.02, 95%CI: 1.88, 2.16; for quartiles [Q4:Q1]: OR =8.37, 95%CI: 6.70, 10.47). When considering the effects of In LMI/VFMI, an L-shaped negative association with hyperuricemia was observed (for Per-SD: OR = 0.45, 95%CI: 0.42, 0.49; for quartiles [Q4:Q1]: OR = 0.16, 95%CI: 0.13, 0.20). Subgroup and sensitivity analyses demonstrated the robustness of this association across different subgroups. Additionally, the segmented regression analysis indicated a saturation effect of 5.64 for the In LMI/VFMI with hyperuricemia (OR = 0.20, 95%CI: 0.17, 0.24). For every 2.72-fold increase of In LMI/VFMI, the risk of hyperuricemia was reduced by 80%. CONCLUSION: The LMI/VFMI ratio is non-linearly associated with serum uric acid. Whether this association is causal needs to be confirmed in further longitudinal studies or Mendelian randomization.

Large-scale cross-ancestry genome-wide meta-analysis of serum urate.

Hyperuricemia is an essential causal risk factor for gout and is associated with cardiometabolic diseases. Given the limited contribution of East Asian ancestry to genome-wide association studies of serum urate, the genetic architecture of serum urate requires exploration. A large-scale cross-ancestry genome-wide association meta-analysis of 1,029,323 individuals and ancestry-specific meta-analysis identifies a total of 351 loci, including 17 previously unreported loci. The genetic architecture of serum urate control is similar between European and East Asian populations. A transcriptome-wide association study, enrichment analysis, and colocalization analysis in relevant tissues identify candidate serum urate-associated genes, including CTBP1, SKIV2L, and WWP2. A phenome-wide association study using polygenic risk scores identifies serum urate-correlated diseases including heart failure and hypertension. Mendelian randomization and mediation analyses show that serum urate-associated genes might have a causal relationship with serum urate-correlated diseases via mediation effects. This study elucidates our understanding of the genetic architecture of serum urate control.

Serum Uric Acid and Serum Lipid Levels in Patients with Acute Ischemic Stroke Admitted in Mymensingh Medical College Hospital.

Stroke is the second-leading cause of death and also a leading cause of combined death and disability. In Bangladesh, stroke prevalence is 11.39 per 1000 population, but highest prevalence of stroke is 14.71 per 1000 population in the Mymensingh division. Hyperuricemia has been reported as an independent risk factor for stroke in different studies and a significant association between serum uric acid and dyslipidemia has also been stated. On the contrary, some studies suggest that uric acid has a neuroprotective role. This cross-sectional study was completed in the Medicine Department of Mymensingh Medical College Hospital, Mymensingh, Bangladesh from March 2021 to January 2023. In this cross-sectional study, 352 adult acute ischemic stroke patients were included from the Medicine Department of Mymensingh Medical College Hospital. Serum uric acid and fasting serum lipid levels were measured within 48 hours of admission. The mean age ±SD of the respondents was 61.9±12.8 years. Hyperuricemia was found among 18.2% of respondents, whose mean ±SD serum uric acid was 5.7±1.9 mg/dl. Dyslipidemia was present in 88.4% of patients. The mean ±SD of the National Institutes of Health Stroke Scale (NIHSS) score was 12.0±5.9. Most of the patients (65.6%) were suffering from moderate stroke, followed by moderate to severe stroke (15.1%), severe stroke (10.8%) and minor stroke (8.5%). After multiple linear regressions, the independent variables age, gender, serum uric acid and total cholesterol were found to be significant predictors of the NIHSS score of the respondents. In conclusion, the majority of acute ischemic stroke patients have an association with dyslipidemia, but only around one-fifth of patients have hyperuricemia. There is a significant association of high serum uric acid and high serum total cholesterol with stroke severity (NIHSS score). But low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and, triglycerides have no association with stroke severity.

Hyperuricemia as an independent risk factor for achilles tendon rupture in male: a case-control study.

OBJECTIVE: To study the correlation between achilles tendon rupture (ATR) and hyperuricemia, also verify the known risk factors for ATR. METHODS: A retrospective review of 488 subjects was performed (182 with Achilles tendon rupture, 306 controls with ankle sprains). Demographic variables and risk factors for rupture were tabulated and compared. The baseline data and related indicators were compared, and the risk factors of ATR were analyzed by constructing a binary logistic regression model. RESULTS: Univariate logistic analysis showed that BMI, smoking, and hyperuricemia were risk factors for the development of ATR (OR = 1.65, 95%CI 1.13-2.42, P = 0.01; OR = 1.47, 95%CI 1.00-2.24, P < 0.05; OR = 2.85, 95%CI 1.84-4.42, P < 0.01). Multifactorial analysis showed that BMI ≥ 25 kg/m2, smoking, and hyperuricemia were independent risk factors for the development of ATR (OR = 1.66, 95%CI 1.11-2.49, P = 0.01; OR = 2.15, 95%CI 1.28-3.60, P < 0.01; OR = 3.06, 95%CI 1.92-4.89, P < 0.01). Among the blood biochemical indicators, total cholesterol (TC) and uric acid (UA) were independent risk factors for the occurrence of ATR (OR = 1.54, 95% CI 1.12-2.12, P = 0.01; OR = 1.01, 95% CI 1.01-1.01, P < 0.01). CONCLUSION: Our study confirmed that, as in previous results, higher BMI, smoking, and total cholesterol are risk factors for ATR, Hyperuricemia may contribute to the development of ATR, and adjunctive tests for TC and UA in the blood biochemistry may be helpful in predicting the risk of ATR.

Renal interstitial fibrotic assessment using non-Gaussian diffusion kurtosis imaging in a rat model of hyperuricemia.

BACKGROUND: To investigate the feasibility of Diffusion Kurtosis Imaging (DKI) in assessing renal interstitial fibrosis induced by hyperuricemia. METHODS: A hyperuricemia rat model was established, and the rats were randomly split into the hyperuricemia (HUA), allopurinol (AP), and AP + empagliflozin (AP + EM) groups (n = 19 per group). Also, the normal rats were selected as controls (CON, n = 19). DKI was performed before treatment (baseline) and on days 1, 3, 5, 7, and 9 days after treatment. The DKI indicators, including mean kurtosis (MK), fractional anisotropy (FA), and mean diffusivity (MD) of the cortex (CO), outer stripe of the outer medulla (OS), and inner stripe of the outer medulla (IS) were acquired. Additionally, hematoxylin and eosin (H&E) staining, Masson trichrome staining, and nuclear factor kappa B (NF-κB) immunostaining were used to reveal renal histopathological changes at baseline, 1, 5, and 9 days after treatment. RESULTS: The HUA, AP, and AP + EM group MKOS and MKIS values gradually increased during this study. The HUA group exhibited the highest MK value in outer medulla. Except for the CON group, all the groups showed a decreasing trend in the FA and MD values of outer medulla. The HUA group exhibited the lowest FA and MD values. The MKOS and MKIS values were positively correlated with Masson's trichrome staining results (r = 0.687, P < 0.001 and r = 0.604, P = 0.001, respectively). The MDOS and FAIS were negatively correlated with Masson's trichrome staining (r = -626, P < 0.0014 and r = -0.468, P = 0.01, respectively). CONCLUSION: DKI may be a non-invasive method for monitoring renal interstitial fibrosis induced by hyperuricemia.

Associations between hyperuricemia and ultrasound-detected knee synovial abnormalities in middle-aged and older population: a cross-sectional study.

OBJECTIVES: Knee synovial abnormalities, potentially treatment targets for knee pain and osteoarthritis, are common in middle-aged and older population, but its etiology remains unclear. We examined the associations between hyperuricemia and knee synovial abnormalities detected by ultrasound in a general population sample. METHODS: Participants aged ≥ 50 years were from a community-based observational study. Hyperuricemia was defined as serum urate (SU) level > 416 µmol/L in men and > 357 µmol/L in women. Ultrasound of both knees was performed to determine the presence of synovial abnormalities, i.e., synovial hypertrophy, effusion, or Power Doppler signal (PDS). We examined the relation of hyperuricemia to prevalence of knee synovial abnormalities and its laterality, and the dose-response relationships between SU levels and the prevalence of knee synovial abnormalities. RESULTS: In total, 3,405 participants were included in the analysis. Hyperuricemia was associated with higher prevalence of knee synovial abnormality (adjusted odds ratio [aOR] = 1.21, 95% confidence interval [CI]: 1.02 to 1.43), synovial hypertrophy (aOR = 1.33, 95% CI: 1.05 to 1.68), and effusion (aOR = 1.21, 95% CI: 1.02 to 1.44), respectively. There were dose-response relationships between SU levels and synovial abnormalities. Additionally, the hyperuricemia was more associated with prevalence of bilateral than with that of unilateral knee synovial abnormality, synovial hypertrophy, or effusion; however, no significant association was observed between hyperuricemia and PDS. CONCLUSION: In this population-based study we found that hyperuricemia was associated with higher prevalence of knee synovial abnormality, synovial hypertrophy and effusion, suggesting that hyperuricemia may play a role in pathogenesis of knee synovial abnormalities.

Resveratrol Improves Hyperuricemia and Ameliorates Renal Injury by Modulating the Gut Microbiota.

Resveratrol (RES) has been reported to prevent hyperuricemia (HUA); however, its effect on intestinal uric acid metabolism remains unclear. This study evaluated the impact of RES on intestinal uric acid metabolism in mice with HUA induced by a high-fat diet (HFD). Moreover, we revealed the underlying mechanism through metagenomics, fecal microbiota transplantation (FMT), and 16S ribosomal RNA analysis. We demonstrated that RES reduced the serum uric acid, creatinine, urea nitrogen, and urinary protein levels, and improved the glomerular atrophy, unclear renal tubule structure, fibrosis, and renal inflammation. The results also showed that RES increased intestinal uric acid degradation. RES significantly changed the intestinal flora composition of HFD-fed mice by enriching the beneficial bacteria that degrade uric acid, reducing harmful bacteria that promote inflammation, and improving microbial function via the upregulation of purine metabolism. The FMT results further showed that the intestinal microbiota is essential for the effect of RES on HUA, and that Lactobacillus may play a key role in this process. The present study demonstrated that RES alleviates HFD-induced HUA and renal injury by regulating the gut microbiota composition and the metabolism of uric acid.

Assessment of the correlation between KAP scores regarding sugar-sweetened beverage consumption and hyperuricemia amongst Chinese young adults.

BACKGROUND: The prevalence of hyperuricemia in China has been consistently increasing, particularly among the younger generation. The excessive consumption of sugar-sweetened beverages is associated with hyperuricemia. This study examined the knowledge, attitudes, and practices (KAP) of Chinese young adults regarding sugar-sweetened beverage consumption and the correlation with hyperuricemia. METHODS: This cross-sectional investigation was conducted from June 28th, 2023, to July 21st, 2023, and enrolled Chinese young adults. Demographics and KAP were evaluated using a questionnaire (Cronbach's α = 0.787). Factors influencing KAP scores were analyzed using multivariable analyses. RESULTS: A total of 1288 valid questionnaires were analyzed. The median knowledge, attitude, and practice scores were 16 (12,19)/22, 22 (20,24)/30, and 27.5 (23,31.75)/40. The multivariable analysis showed that bachelor's/associate education (OR = 1.912, 95%CI: 1.128-3.239), white collar/employee (OR = 0.147, 95%CI: 0.105-0.206), educator (OR = 0.300, 95%CI: 0.174-0.518), healthcare worker (OR = 0.277, 95%CI: 0.188-0.407), not suffering from hyperuricemia (OR = 0.386, 95%CI: 0.253-0.590), and not having gout (OR = 0.456, 95%CI: 0.282-0.736) were independently associated with knowledge. Age 26-30 (OR = 1.470, 95%CI: 1.052-2.052), age 31-35 (OR = 1.489, 95%CI: 1.097-2.022), age 36-40 (OR = 0.328, 95%CI: 1.010-1.746), age 41-44 (OR = 1.548, 95%CI: 1.091-2.198), and not having hyperuricemia (OR = 0.512, 95%CI: 0.345-0.760) were independently associated with attitude. White collar/employee (OR = 0.386, 95%CI: 0.285-0.521), educator (OR = 0.534, 95%CI: 0.317-0.899), healthcare worker (OR = 0.341, 95%CI: 0.236-0.493), having siblings (OR = 0.725, 95%CI: 0.573-0.917), and not suffering from hyperuricemia (OR = 0.442, 95%CI: 0.296-0.659), were independently associated with practice. CONCLUSION: Chinese young adults display moderate KAP toward sugar-sweetened beverages. Notably, an association was observed between hyperuricemia and each KAP dimension.

Development and Internal Validation of a Risk Prediction Model for Carotid Atherosclerosis in the Hyperuricemia Population.

Purpose: The aim of this study was to identify independent risk factors for carotid atherosclerosis (CAS) in a population with hyperuricemia (HUA) and develop a CAS risk prediction model. Patients and Methods: This retrospective study included 3579 HUA individuals who underwent health examinations, including carotid ultrasonography, at the Zhenhai Lianhua Hospital in Ningbo, China, in 2020. All participants were randomly assigned to the training and internal validation sets in a 7:3 ratio. Multivariable logistic regression analysis was used to identify independent risk factors associated with CAS. The characteristic variables were screened using the least absolute shrinkage and selection operator combined with 10-fold cross-validation, and the resulting model was visualized by a nomogram. The discriminative ability, calibration, and clinical utility of the risk model were validated using the receiver operating characteristic curve, calibration curve, and decision curve analysis. Results: Sex, age, mean red blood cell volume, and fasting blood glucose were identified as independent risk factors for CAS in the HUA population. Age, gamma-glutamyl transpeptidase, serum creatinine, fasting blood glucose, total triiodothyronine, and direct bilirubin, were screened to construct a CAS risk prediction model. In the training and internal validation sets, the risk prediction model showed an excellent discriminative ability with the area under the curve of 0.891 and 0.901, respectively, and a high level of fit. Decision curve analysis results demonstrated that the risk prediction model could be beneficial when the threshold probabilities were 1-87% and 1-100% in the training and internal validation sets, respectively. Conclusion: We developed and internally validated a risk prediction model for CAS in a population with HUA, thereby contributing to the CAS early identification.

Interaction between anemia and hyperuricemia in the risk of all-cause mortality in patients with chronic kidney disease.

Aim: Both hyperuricemia and anemia are not only the manifestation of chronic kidney disease (CKD) but also related to its occurrence and development. A recent study has found that there was a synergetic effect between hyperuricemia and anemia on new-onset CKD. Herein we aimed to explore the roles of hyperuricemia and anemia in the all-cause mortality in patients with CKD. Methods: Data of adult patients with CKD were extracted from the National Health and Nutrition Examination Surveys (NHANES) database in 2009-2018 in this retrospective cohort study. Weighted univariate and multivariate COX regression analyses were used to investigate the associations of hyperuricemia and anemia with all-cause mortality, and the evaluation indexes were hazard ratios (HRs) and 95% confidence intervals (CIs). The interaction effect between hyperuricemia and anemia on the risk of all-cause mortality was assessed via relative excess risk due to interaction (RERI) and attributable proportion of interaction (AP). Subgroup analyses of age, gender, CVD, hypertension, DM, and cancer were also performed to assess this interaction effect. Results: Among 3,678 eligible patients, 819 died from all causes. After adjusting for covariables, we found that CKD patients with anemia (HR = 1.72, 95%CI: 1.42-2.09) or hyperuricemia (HR = 1.21, 95%CI: 1.01-11.45) had a higher risk of all-cause mortality. There was a potential synergetic effect between anemia and hyperuricemia on all-cause mortality, with RERI of 0.630 and AP of 0.291. Moreover, this synergetic effect was also observed in ≥65 years old (AP = 0.330), male (AP = 0.355), hypertension (AP = 0.736), non-hypertension (AP = 0.281), DM (AP = 0.371), and cancer (AP = 0.391) subgroups. Conclusion: A potential synergetic effect between anemia and hyperuricemia on all-cause mortality was found in patients with CKD. However, further studies are needed to clarify the causal relationship between them.

Gender-specific association between blood cell parameters and hyperuricemia in high-altitude areas.

Background: Hyperuricemia is a common metabolic disorder linked to various health conditions. Its prevalence varies among populations and genders, and high-altitude environments may contribute to its development. Understanding the connection between blood cell parameters and hyperuricemia in high-altitude areas can shed light on the underlying mechanisms. This study aimed to investigate the relationship between blood cell parameters and hyperuricemia in high-altitude areas, with a particular focus on gender differences. Methods: We consecutively enrolled all eligible Tibetan participants aged 18-60 who were undergoing routine medical examinations at the People's Hospital of Chaya County between January and December 2022. During this period, demographic and laboratory data were collected to investigate the risk factors associated with hyperuricemia. Results: Among the participants, 46.09% were diagnosed with hyperuricemia. In the male cohort, significant correlations were found between serum uric acid (SUA) levels and red blood cell (RBC) count, creatinine (Cr). Urea, alanine transaminase (ALT), and albumin (ALB). Notably, RBC exhibited the strongest association. Conversely, in the female cohort, elevated SUA levels were associated with factors such as white blood cell (WBC) count. Urea, ALT, and ALB, with WBC demonstrating the most significant association. Further analysis within the female group revealed a compelling relationship between SUA levels and specific white blood cell subtypes, particularly neutrophils (Neu). Conclusion: This study revealed gender-specific associations between SUA levels and blood cell parameters in high-altitude areas. In males, RBC count may play a role in hyperuricemia, while in females, WBC count appears to be a significant factor. These findings contribute to our understanding of metabolic dynamics in high-altitude regions but require further research for comprehensive mechanistic insights.

Caspase-11/GSDMD contributes to the progression of hyperuricemic nephropathy by promoting NETs formation.

Hyperuricemia is an independent risk factor for chronic kidney disease (CKD) and promotes renal fibrosis, but the underlying mechanism remains largely unknown. Unresolved inflammation is strongly associated with renal fibrosis and is a well-known significant contributor to the progression of CKD, including hyperuricemia nephropathy. In the current study, we elucidated the impact of Caspase-11/Gasdermin D (GSDMD)-dependent neutrophil extracellular traps (NETs) on progressive hyperuricemic nephropathy. We found that the Caspase-11/GSDMD signaling were markedly activated in the kidneys of hyperuricemic nephropathy. Deletion of Gsdmd or Caspase-11 protects against the progression of hyperuricemic nephropathy by reducing kidney inflammation, proinflammatory and profibrogenic factors expression, NETs generation, α-smooth muscle actin expression, and fibrosis. Furthermore, specific deletion of Gsdmd or Caspase-11 in hematopoietic cells showed a protective effect on renal fibrosis in hyperuricemic nephropathy. Additionally, in vitro studies unveiled the capability of uric acid in inducing Caspase-11/GSDMD-dependent NETs formation, consequently enhancing α-smooth muscle actin production in macrophages. In summary, this study demonstrated the contributory role of Caspase-11/GSDMD in the progression of hyperuricemic nephropathy by promoting NETs formation, which may shed new light on the therapeutic approach to treating and reversing hyperuricemic nephropathy.

Peripheral artery disease mediating the effect of metabolic syndrome related diseases on lower limb ulcers: Mendelian randomization analysis.

Background: Previous observational studies have demonstrated a correlation between metabolic syndrome related diseases and an elevated susceptibility to ulcers of lower limb. It has been suggested that this causal relationship may be influenced by the presence of peripheral artery disease (PAD). Nevertheless, the precise contribution of these factors as determinants of ulcers of lower limb remains largely unexplored. Method: This research incorporated information on hypertension, BMI, hyperuricemia, type 2 diabetes, PAD, and ulcers of lower limb sourced from the GWAS database. Univariate Mendelian randomization (SVMR) and multivariate Mendelian randomization (MVMR) methods were employed to assess the association between metabolic syndrome related diseases, including hypertension, obesity, hyperuricemia, and type 2 diabetes, as well as to investigate whether this association was influenced by PAD. Results: Univariate Mendelian randomization analysis showed that genetically predicted hypertension, BMI, and type 2 diabetes were associated with an increased risk of PAD and ulcers of lower limb, and PAD was associated with an increased risk of ulcers of lower limb, but there is no causal relationship between hyperuricemia and ulcers of lower limb. The results of multivariate Mendelian randomization showed that PAD mediated the causal relationship between hypertension, obesity and ulcers of lower limb, but the relationship between type 2 diabetes and ulcers of lower limb was not mediated by PAD. Conclusion: Hypertension, BMI and type 2 diabetes can increase the risk of ulcers of lower limb, and PAD can be used as a mediator of hypertension and obesity leading to ulcers of lower limb, These findings may inform prevention and intervention strategies directed toward metabolic syndrome and ulcers of lower limb.

Robust positive association between serum urate and the risk of chronic obstructive pulmonary disease: hospital-based cohort and Mendelian randomisation study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and hyperuricaemia are both characterised by systemic inflammation. Preventing chronic diseases among the population with common metabolic abnormality is an effective strategy. However, the association of hyperuricaemia with the higher incidence and risk of COPD remains controversial. Therefore, replicated researches in populations with distinct characteristics or demographics are compellingly warranted. METHODS: This cohort study adopted a design of ambispective hospital-based cohort. We used propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) to minimise the effects of potential confounding factors. A Cox regression model and restricted cubic spline (RCS) model were applied further to assess the effect of serum urate on the risk of developing COPD. Finally, we conducted a two-sample Mendelian randomisation (MR) analysis to explore evidence of causal association. RESULTS: There is a higher incidence in the population with hyperuricaemia compared with the population with normal serum urate (22.29/1000 person-years vs 8.89/1000 person-years, p=0.009). This result is robust after performing PSM (p=0.013) and IPTW (p<0.001). The Cox model confirms that hyperuricaemia is associated with higher risk of developing COPD (adjusted HR=3.35 and 95% CI=1.61 to 6.96). Moreover, RCS shows that the risk of developing COPD rapidly increases with the concentration of serum urate when it is higher than the reference (420 µmol/L). Finally, in MR analysis, the inverse variance weighted method evidences that a significant causal effect of serum urate on COPD (OR=1.153, 95% CI=1.034 to 1.289) is likely to be true. The finding of MR is robust in the repeated analysis using different methods and sensitivity analysis. CONCLUSIONS: Our study provides convincing evidence suggesting a robust positive association between serum urate and the risk of developing COPD, and indicates that the population with hyperuricaemia is at high risk of COPD in the Chinese population who seek medical advice or treatment in the hospital.

Causal association study of the dynamic development of the metabolic syndrome based on longitudinal data.

The dynamic progression of metabolic syndrome (MetS) includes developmental deterioration and reverse recovery; however, the key factors in this bidirectional progression have not been identified. Our study aimed to use the data obtained from the China Health and Retirement Longitudinal Study (CHARLS) and construct a Bayesian network to explore the causal relationship between influential factor and the development and recovery of MetS. Followed up at 4 years, forward progression of MetS occurred in 1543 and reverse recovery of MetS occurred in 1319 of 5581 subjects. Bayesian Networks showed that hyperuricemia and body mass index (BMI) levels directly influenced progression of MetS, and gender, exercise and age play an indirect role through hyperuricemia and BMI levels; high hemoglobin A1c (HbA1c) and BMI levels directly influenced recovery of MetS, and gender and exercise play an indirect role through BMI levels. Bayesian Network inference found that the rate of progression of MetS in subjects with hyperuricemia increases from 36 to 60%, the rate of progression of MetS in subjects with overweight or obese increases from 36 to 41% and the rate of reverse recovery rate of MetS in subjects with high HbA1c decreased from 33 to 20%. Therefore, attention to individuals at high risk of hyperuricemia, high HbA1c levels, and overweight/obesity should be enhanced, with early detection and following healthy behavioral interventions to prevent, control and delay the progression of MetS and its components.

Protecting against ferroptosis in hyperuricemic nephropathy: The potential of ferrostatin-1 and its inhibitory effect on URAT1.

Hyperuricemic nephropathy (HN) is characterized by renal fibrosis and tubular necrosis caused by elevated uric acid levels. Ferroptosis, an iron-dependent type of cell death, has been implicated in the pathogenesis of kidney diseases. The objective of this study was to explore the role of ferroptosis in HN and the impact of a ferroptosis inhibitor, ferrostatin-1 (Fer-1). The study combined adenine and potassium oxonate administration to establish a HN model in mice and treated HK-2 cells with uric acid to simulate HN conditions. The effects of Fer-1 on the renal function, fibrosis, and ferroptosis-associated molecules were investigated in HN mice and HK-2 cells treated with uric acid. The HN mice presented with renal dysfunction characterized by elevated tissue iron levels and diminished antioxidant capacity. There was a significant decrease in the mRNA and protein expression levels of SLC7A11, GPX4, FTL-1 and FTH-1 in HN mice. Conversely, treatment with Fer-1 reduced serum uric acid, serum creatinine, and blood urea nitrogen, while increasing uric acid levels in urine. Fer-1 administration also ameliorated renal tubule dilatation and reduced renal collagen deposition. Additionally, Fer-1 also upregulated the expression levels of SLC7A11, GPX4, FTL-1, and FTH-1, decreased malondialdehyde and iron levels, and enhanced glutathione in vivo and in vitro. Furthermore, we first found that Fer-1 exhibited a dose-dependent inhibition of URAT1, with the IC50 value of 7.37 ± 0.66 µM. Collectively, the current study demonstrated that Fer-1 effectively mitigated HN by suppressing ferroptosis, highlighting the potential of targeting ferroptosis as a therapeutic strategy for HN.

Cardiovascular safety of febuxostat versus allopurinol among the Asian patients with or without gout: A systematic review and meta-analysis.

The cardiovascular (CV) safety of febuxostat compared to allopurinol for the treatment of hyperuricemia among Asian patients is uncertain. In this study, we conducted a systematic review and meta-analysis to compare the CV safety profiles of febuxostat with allopurinol in Asian patients with hyperuricemia. A total of 13 studies were included. On the basis of the pooled results of cohort studies, febuxostat users were at a significantly higher risk for acute coronary syndrome (ACS; hazard ratio [HR]: 1.06, 95% confidence interval [CI]: 1.03-1.09, p < 0.01), atrial fibrillation (HR: 1.19, 95% CI: 1.05-1.35, p < 0.01) than allopurinol users, whereas no significant difference between febuxostat and allopurinol existed for urgent coronary revascularization (HR: 1.07, 95% CI: 0.98-1.16, p = 0.13), and stroke (HR: 0.96, 95% CI: 0.91-1.01, p = 0.13). Nevertheless, that difference in results of acute decompensated heart failure (ADHF; HR: 0.73, 95% CI: 0.35-1.53, p = 0.40) and all-cause death (HR = 0.86, 95% CI: 0.49-1.51, p = 0.60) was not significant based on randomized controlled trials. In the Chinese subgroup, febuxostat could increase the risk of ADHF (HR: 1.22, 95% CI: 1.01-1.48, p < 0.05), CV death (HR: 1.25, 95% CI: 1.03-1.50, p < 0.05), and all-cause mortality (HR: 1.07, 95% CI: 1.01-1.14, p < 0.05) compared to allopurinol. In conclusion, the use of febuxostat, compared with allopurinol among Asian patients, was associated with a significantly increased risk of adverse CV events.

Proline-derived quinoline formamide compounds as human urate transporter 1 inhibitors with potent uric acid-lowering activities.

We report the design and synthesis of a series of proline-derived quinoline formamide compounds as human urate transporter 1 (URAT1) inhibitors via a ligand-based pharmacophore approach. Structure-activity relationship studies reveal that the replacement of the carboxyl group on the polar fragment with trifluoromethanesulfonamide and substituent modification at the 6-position of the quinoline ring greatly improve URAT1 inhibitory activity compared with lesinurad. Compounds 21c, 21e, 24b, 24c, and 23a exhibit potent activities against URAT1 with IC50 values ranging from 0.052 to 0.56 µM. Furthermore, compound 23a displays improved selectivity towards organic anion transporter 1 (OAT1), good microsomal stability, low potential for genotoxicity and no inhibition of the hERG K+ channel. Compounds 21c and 23a, which have superior pharmacokinetic properties, also demonstrate significant uric acid-lowering activities in a mouse model of hyperuricemia. Notably, 21c also exhibits moderate anti-inflammatory activity related to the gout inflammatory pathway. Compounds 21c and 23a with superior druggability are potential candidates for the treatment of hyperuricemia and gout.

Serum uric acid level is associated with glomerular ischemic lesions in patients with primary membranous nephropathy: an analytical, cross-sectional study.

To investigate the relationship between serum uric acid level and glomerular ischemic lesions (GIL) in patients with primary membranous nephropathy (PMN) and identify relevant risk factors. A total of 201 patients with PMN but normal renal function confirmed by renal biopsy executed in the Liaocheng People's Hospital, China, during January 2020-January 2023 were analyzed retrospectively. The enrolled patients were divided into a hyperuricemia group and a normal serum uric acid group (control group) according to their serum uric acid levels. Then, the participants were further divided into a non-GIL group or a GIL group based on the patient's renal biopsy results. The two groups' clinical and pathological data and meaningful indicators for differences were analyzed by binary logistic regression analysis. Additionally, the serum uric acid level prediction value on GIL was investigated using receiver operating characteristic (ROC) curves. Compared with the control group, the hyperuricemia group exhibited high serum uric acid, the prevalence of GIL, serum albumin, the prevalence of hypertension, and low-density lipoprotein cholesterol (LDL) levels (P < 0.05). Compared with the non-GIL group, the GIL group exhibited were older, had enhanced serum uric acid, serum albumin, and an increased prevalence of tubular atrophy/interstitial fibrosis (TA/IF), arteriolosclerosis, and low eGFR levels (P < 0.05). The binary logistic regression analysis revealed that the serum uric acid and the TA/IF are independent risk factors of GIL (P < 0.05). The AUC of ROC of GIL of PMN patients, predicted based on the serum uric acid concentration, was 0.736 (P < 0.05), wherein the threshold = 426.5 µmol/L and the Youden's index = 0.41. Serum uric acid concentration and the TA/IF are independent risk factors of GIL in patients with PMN, and the former exhibits prediction value on GIL in patients with PMN.

Discovery of a Novel Thienopyrimidine Compound as a Urate Transporter 1 and Glucose Transporter 9 Dual Inhibitor with Improved Efficacy and Favorable Druggability.

Gout and hyperuricemia are metabolic diseases characterized with high serum uric acid (SUA) levels that significantly impact human health. Lesinurad, a uricosuric agent, is limited to concurrent use with xanthine oxidase inhibitors (XOIs) in clinical practice due to its restricted efficacy and potential nephrotoxicity. Herein, extensive structural modifications of lesinurad were conducted through scaffold hopping and substituent modification strategies, affording 54 novel derivatives containing pyrimidine-fused cyclic structures. Notably, the thienopyrimidine compound 29 demonstrated a remarkable 2-fold increase in SUA-lowering in vivo activity compared to lesinurad, while exhibiting potent inhibitory activity against the urate transporter 1 (URAT1, IC50 = 2.01 µM) and glucose transporter 9 (GLUT9, IC50 = 18.21 µM). Furthermore, it possessed a lower effective dosage of 0.5 mg/kg, favorable safety profile without any apparent acute toxicity at doses of 1000 mg/kg, and improved pharmacokinetic properties. Overall, we have discovered an efficacious URAT1/GLUT9 dual inhibitor for inhibiting urate reabsorption with favorable pharmacokinetic profiles.