Serum Urate Research Articles

Genetic and Physiological Effects of Insulin-Like Growth Factor-1 (IGF-1) on Human Urate Homeostasis.

Hyperinsulinemia induces hyperuricemia by activating net renal urate reabsorption in the renal proximal tubule. The basolateral reabsorptive urate transporter GLUT9a appears to be the dominant target for insulin. By contrast, IGF-1 infusion reduces serum urate (SU), through mechanisms unknown. Genetic variants of IGF1R associated with reduced SU have increased IGF-1R expression and interact with genes encoding the GLUT9 and ABCG2 urate transporters, in a sex-specific fashion, which controls the SU level. Activation of IGF-1/IGF-1R signaling in Xenopus oocytes modestly activates GLUT9a and inhibits insulin's stimulatory effect on the transporter, which also activates multiple secretory urate transporters-ABCG2, ABCC4, OAT1, and OAT3. The results collectively suggest that IGF-1 reduces SU by activating secretory urate transporters and inhibiting insulin's action on GLUT9a. Metabolic syndrome and hyperinsulinemia are associated with hyperuricemia. Insulin infusion in healthy volunteers elevates serum urate (SU) by activating net urate reabsorption in the renal proximal tubule, whereas IGF-1 infusion reduces SU by mechanisms unknown. Variation within the IGF1R gene also affects SU levels. Colocalization analyses of a SU genome-wide association studies signal at IGF1R and expression quantitative trait loci signals in cis using COLOC2, RT-PCR, Western blotting, and urate transport assays in transfected HEK 293T cells and in Xenopus laevis oocytes. Genetic association at IGF1R with SU is stronger in women and is mediated by control of IGF1R expression. Inheritance of the urate-lowering homozygous genotype at the SLC2A9 locus is associated with a differential effect of IGF1R genotype between men and women. IGF-1, through IGF-1R, stimulated urate uptake in human renal proximal tubule epithelial cells and transfected HEK 293T cells, through activation of IRS1, PI3/Akt, MEK/ERK, and p38 MAPK; urate uptake was inhibited in the presence of uricosuric drugs, specific inhibitors of protein tyrosine kinase, PI3 kinase (PI3K), ERK, and p38 MAPK. In X. laevis oocytes expressing ten individual urate transporters, IGF-1 through endogenous IGF-1R stimulated urate transport mediated by GLUT9, OAT1, OAT3, ABCG2, and ABCC4 and inhibited insulin's stimulatory action on GLUT9a and OAT3. IGF-1 significantly activated Akt and ERK. Specific inhibitors of PI3K, ERK, and PKC significantly affected IGF-1 stimulation of urate transport in oocytes. The combined results of infusion, genetics, and transport experiments suggest that IGF-1 reduces SU by activating urate secretory transporters and inhibiting insulin's action.

Evaluation of ABCG2-mediated extra-renal urate excretion in hemodialysis patients

Two-thirds of urate is excreted via the renal pathway and the remaining one-third via the extra-renal pathway, the latter mainly via the intestine in healthy individuals. ABCG2, a urate exporter, is expressed in various tissues including the kidney and intestine, and its dysfunction leads to hyperuricemia and gout. ABCG2 is regarded as being responsible for most of the extra-renal urate excretion. However, the extra-renal urate excretion capacity via ABCG2 remains undefined in end-stage kidney diseases. Therefore, we evaluated the capacity of extra-renal ABCG2 using 123 anuric hemodialysis patients whose urate excretion depended on only the extra-renal pathway. ABCG2 function in each participant was estimated based on ABCG2 dysfunctional variants. We computed the uric acid pool (PoolUA) from bodyweight and serum urate level (SUA) using previously reported radio-isotopic data, and we analyzed the association between ABCG2 function and the PoolUA. SUA and PoolUA increased significantly with ABCG2 dysfunction, and extra-renal ABCG2 could excrete up to approximately 60% of the daily uric acid turnover in hemodialysis patients. Our findings indicate that the extra-renal urate excretion capacity can expand with renal function decline and highlight that the extra-renal pathway is particularly important in the uric acid homeostasis for patients with renal dysfunction.

Hypouricemic Actions of the Pericarp of Mangosteen in Vitro and in Vivo.

Hyperuricemia is the result of overproduction and/or underexcretion of uric acid, and it is a well-known risk factor for gout, hypertension, and diabetes. However, available drugs for hyperuricemia in the clinic are limited. Recently, a lot of research has been conducted in order to discover new uric acid-lowering agents from plants and foods. We found that the extracts from the pericarp of mangosteen reduced urate. Bioactivity-guided study showed that α-mangostin was the principal constituent. Herein, we reported for the first time the hypouricemic activities and underling mechanism of α-mangostin. The α-mangostin dose- and time-dependently decreased the levels of serum urate in hyperuricemic mice and markedly increased the clearance of urate in hyperuricemic rats, exhibiting a promotion of urate excretion in the kidney. Further evidence showed that α-mangostin significantly decreased the protein levels of GLUT9 in the kidneys. The change in the expression of URAT1 was not observed. Moreover, α-mangostin did not inhibit the activities of xanthine oxidoreductase and uricase in vitro or in vivo. Taken together, these findings suggest that α-mangostin has potential to be developed as a new anti-hyperuricemic agent with promoting uric acid excretion.

Efficacy and safety of switching from febuxostat to dotinurad, a novel selective urate reabsorption inhibitor, in hyperuricemic patients with type 2 diabetic kidney disease: Protocol for a single-arm, open-label, prospective, exploratory study.

Dotinurad is a novel uricosuric drug in Japan with selective and potent urate transporter 1 (URAT1) inhibitory activity. This study aims to evaluate the efficacy and safety of dotinurad in hyperuricemic patients with type 2 diabetic kidney disease by comparing serum levels of urate and plasma and urinary levels of indoxyl sulfate excreted via the urate excretion transporter ATP binding cassette subfamily G member 2 (ABCG2), as indices, with baseline levels after switching from febuxostat to dotinurad. This single-center, single-arm, open-label, prospective, exploratory study aims to evaluate the effect of switching from febuxostat to dotinurad on serum urate levels and its background factors. The study will include 50 hyperuricemic patients with type 2 diabetic kidney disease and urate levels exceeding 6 mg/dL despite administration of febuxostat 20 mg/day for at least 3 months. The primary outcome is the achievement rate of serum urate levels of ≤6 mg/dL after 24 weeks of treatment with dotinurad at 0.5 mg to a maximum of 4 mg once daily. Secondary outcomes include the changes in serum urate levels, plasma and urinary indoxyl sulfate levels, and renal injury-related markers from baseline to observation points at weeks 4, 12, and 24. The study hypothesizes that switching to dotinurad may reduce the plasma levels of indoxyl sulfate and increase its urinary levels in patients with hyperuricemia. These suggest that dotinurad can potently lower the serum urate level by inhibiting URAT1 without adversely affecting ABCG2. Thus, findings of this study are expected to provide useful insights into the treatment of hyperuricemia associated with type 2 diabetic kidney disease and the discovery of new possibilities for dotinurad. Prior to the study, its study protocol was scientifically and ethically reviewed and approved by the Japan Physicians Association Clinical Research Review Board (approval number: JPA007-2204-02). In addition, patients who provide written informed consent will participate in the study. The results of this study will be published through submission to a peer-reviewed scientific journal. https://jrct.niph.go.jp/en-latest-detail/jRCTs031220080, identifier jRCTs031220080.

Early urate-lowering therapy in gouty arthritis with acute flares: a double-blind placebo controlled clinical trial

BackgroundGouty arthritis (GA) is a chronic systemic disease with recurrent acute monoarthritis. In a previous study, a higher incidence of acute flares was observed during the initial marked decrease in serum urate level. Our study evaluated the effect of early urate-lowering therapy in patients with acute GA flares.MethodsThis study included 40 patients with acute GA; of them, 20 received colchicine 0.5 mg colchicine twice daily, while 20 received probenecid 500 mg and colchicine 0.5 mg twice daily. We evaluated GA severity and laboratory data for 2 weeks after the initial therapy. Medians and interquartile ranges (IQRs) were calculated to evaluate clinical presentations between these two groups.ResultsRapidly decreasing median serum uric acid levels was found in the patients treated with probenecid and colchicine compared with the patients treated with colchicine alone on day 8 (− 1.9 [IQR, − 3.7 to 0] vs 0.8 [IQR, − 0.1–2.2]; P < 0.001). However, the median decrease in visual analog scale score did not differ significantly between the two groups (− 5.5 [IQR, − 8.0 to − 3.0] vs − 3.5 [IQR, − 5.9 to − 2.0]; P = 0.080).ConclusionNo significant increase was noted in acute gout flare severity or duration among GA patients treated with early aggressive control of hyperuricemia using probenecid plus colchicine.

PS-C04-6: ASSOCIATION BETWEEN SERUM URATE LEVEL AND CAROTID ATHEROSCLEROSIS: AN INSIGHT FROM A POST-HOC ANALYSIS OF THE RANDOMIZED CLINICAL TRIAL (PRIZE)

Objectives: Elevated serum urate (SU) levels are associated with arterial atherosclerosis and subsequent cardiovascular events. However, an optimal therapeutic target SU level for delaying atherosclerotic progression in patients with hyperuricemia remains uncertain. The aim of this analysis was to assess an association between changes in SU level and carotid intima-media thickness (IMT) to examine whether an optimal SU concentration exists to delay atherosclerotic progression. Design and method: This was a post-hoc analysis of the PRIZE (program of vascular evaluation under uric acid control by xanthine oxidase inhibitor, febuxostat: multicenter, randomized controlled) study of Japanese adults with asymptomatic hyperuricemia (UMIN000041322). Among the full analysis set population treated with febuxostat (n = 239), subjects who had both data on SU level and mean common carotid artery (CCA)-IMT at baseline and 24 months were included in the present analysis. The primary endpoint of this analysis was an association between changes in SU levels and mean CCA-IMT after 24 months of febuxostat treatment. Results: A total of 204 eligible subjects were included in this analysis. The mean age was 69.1 +/- 9.6 years, and one fifth were female. Most had a history of treated hypertension and/or dyslipidemia. The mean baseline SU level was 7.7 ± 1.0 mg/dL, and febuxostat treatment significantly reduced SU concentrations at 24 months (estimated mean change -3.1 mg/dL, 95% confidence interval -3.2 to -2.9). A multivariable linear regression analysis revealed that a reduction in SU level was associated with changes in mean CCA-IMT values at 24 months (Figure A). In contrast, the achieved SU concentrations were not associated with changes in mean CCA-IMT at 24 months (Figure B). Conclusion: A greater reduction in SU, but not its achieved concentrations, may be associated with delayed progression of carotid IMT in patients with asymptomatic hyperuricemia treated with febuxostat.

Detection of Monosodium Urate Crystal of Hand and Wrist in Suspected Gouty Arthritis Patients on Dual-Energy CT and Relationship with Serum Urate Level

We retrospectively investigated the characteristics of patients with monosodium urate (MSU) deposits of the hand and wrist on dual-energy CT (DECT) compared to those without. We also attempted to determine the pattern of MSU distribution in DECT. In total, 93 patients were included who had undergone DECT for evaluation of the hand or wrist pain under the clinical impression of gouty arthritis. The total volume of MSU deposits on DECT was calculated and the pattern of MSU distribution on DECT was analyzed. Also, the level of the serum urate at the time of DECT and the highest level of the serum urate of the patients were obtained from their records and the relationship between MSU and serum urate level was evaluated. The range of the volume of MSU deposits on DECT was 0.01-16.11 cm3 (average: 1.07 cm3). The average level of serum urate was significantly higher in the MSU positive group than that in the MSU negative group. MSU deposits were most frequently observed in the wrists followed by fingers and digitorum tendons. On DECT, MSU deposits were most frequently detected in the wrist and related with high serum urate level.

Reliability and Validity of the Korean Version of the Gout Impact Scale.

The Gout Impact Scale (GIS), part of the Gout Assessment Questionnaire 2.0, measures gout-specific health-related quality of life (HRQOL). This study aimed to translate the GIS into Korean and validate the Korean version (K-GIS) using generic HRQOL measures. The GIS was translated into Korean and back-translated into English. We asked patients aged 18 years or older who met the 2015 gout classification criteria to fill out the questionnaires (from January 2022 to June 2022); the K-GIS (5 scales [0-100 scores each]), along with the Korean version of Health Assessment Questionnaire (HAQ) and EuroQol-5 dimension (EQ-5D). We investigated the internal consistency, construct validity, and discriminative validity for gout characteristics of K-GIS. The K-GIS form was administrated to patients 4 weeks later to assess the test-retest reliability using the intraclass correlation coefficient (ICC). One hundred patients completed the questionnaire. The mean ± standard deviation age of the patients was 53.0 ± 15.1 years, and 99.0% of the patients were men. All scales had high degree of internal consistency (Cronbach's α = 0.59 to 0.96) and test-retest reliability (n = 18, ICC = 0.83 to 0.94, all P < 0.001), except for unmet gout treatment needs. Weak-to-moderate correlations were observed between the K-GIS scales and HAQ or EQ-5D (r = 0.21 to 0.46). The K-GIS scores were significantly higher in the presence of bone erosion, absence of urate-lowering therapy, serum urate levels > 6 mg/dL, frequent gout flares in the past year, and fewer comorbidities. In contrast, neither the HAQ nor the EQ-5D could discern these subsets of patients. The K-GIS is a reliable and valid HRQOL measure for patients with gout. Higher K-GIS scores were associated with clinical characteristics leading to unfavorable outcomes, which were not demonstrated by the HAQ and EQ-5D.

S-17-1: URIC ACID AND CARDIOVASCULAR DISEASES

Uric acid (UA) is the final product of purine metabolism and its increase in the circulating blood defines the presence of hyperuricaemia commonly considered as a concentration of uric acid in serum above the threshold level of 7 mg/dL (416 mol/L) in men and &gt; 6 mg/dL in women. The typical consequence of elevated UA levels is the development of gout, a condition affecting 2–3% of the general population but beside the effects on gout, the elevated levels of UA have been associated with a significant increase in the risk of hypertension, metabolic syndrome, and cardiovascular disease (CVD) regardless of the presence of serum urate deposition. All this evidence clearly supports a primary cardiovascular role for elevated serum UA probably based on multiple and interactive mechanisms of action not necessarily involving the articular and tissue deposition. The interaction between elevated UA and cardiovascular diseases has been extensively investigated in the last 10 years providing interesting results in terms of patients identification, threshold of risk, pathophysiology, results of clinical trials and effects of drugs not primary involved in the management of uric acid levels. In particular, the evidence supports an increase of CV mortality and morbidity in patients with levels of SUA between 4.5 and 5.5 that are common in a large proportion of subjects and patients with overt cardiovascular diseases. This observation along with the differences in the mechanism leading to elevated UA (hyperproduction vs. underexcretion) will allow a more functional identification of patients suitable for pharmacological treatment with urate lowering drugs (ULT). Furthermore, the dynamic analysis of time-dependent trajectories of UA levels is a new approach to the interpretation and clinical management of cardiovascular disease. The overall representativity of a pattern of modification seems to better define the prognostic role of elevated UA and could be probably improved by an integrated interpretation of the different patterns beyond the role of risk cards and algorithms. Very recently, the management of elevated UA has also included the effects of non-ULT drugs as Losartan, SGLT-2 inhibitors, vericiguat whose administration in randomized clinical trials has improved uric acid levels with a linear proportion with the amount of UA reduction. The interaction between hyperuricemia and CVD is a very dynamic issue that has been recently enriched with several additional information that have allowed a more effective identification of those subsets of patients that can successfully treated in daily clinical practice

SERUM URIC ACID TO HDL CHOLESTEROL RATIO IS ASSOCIATED WITH DIABETIC CONTROL IN NEW ONSET TYPE 2 DIABETIC POPULATION.

Since uric acid to HDL cholesterol ratio (UHR) is proposed as a novel predictor of metabolic and inflammatory disorders, we aimed to study UHR levels in patients with new onset type 2 diabetes mellitus (T2DM) and compare them to those in healthy controls. Patients with new onset T2DM were enrolled and control subjects were volunteers to participate without any established diseases. Laboratory data including UHR, fasting blood glucose (FBG) and glycated hemoglobin (HbA1c) were compared. The mean UHR of the T2DM and control groups was 16±8% and 10±3%, respectively (p<0.001). Moreover, UHR was significantly and positively correlated with HbA1c (r=0.75, p<0.001), FBG (r=0.64, p<0.001), waist circumference (r=0.35, p<0.001), body mass index (r=0.20, p=0.002) and inversely correlated with glomerular filtration rate (r=-0.24, p<0.001). High levels of UHR might be associated with increased mean blood glucose levels for a long time, since UHR was correlated with both FBG and HbA1c in patients with new onset T2DM.

Single Nucleotide Polymorphisms Associated with the Safety and Efficacy of Anti-Gout Medications

Single Nucleotide Polymorphisms Associated with the Safety and Efficacy of Anti-Gout Medications

Predictors of Patient and Physician Assessments of Gout Control.

To understand the clinical variables that contribute to the patient and physician assessments of gout control and which variables predict discordant assessments. Patients (n=223) with gout taking allopurinol ≥300 mg daily attended a standardized gout assessment visit. Participants and physicians completed questionnaires rating their assessment of current gout control using a numerical rating scale (0=not at all controlled, 10=fully controlled). Discordance between patients' and physicians' scores was defined as an absolute difference of >2 units. The mean ± SD patient gout control score was 8.09 ± 2.24, and the physician gout control score was 7.38 ± 2.63 (P < 0.001 for comparison). Absence of gout flares in the last 12 months and in the last 3 months and serum urate at the treatment target (<6 mg/dl) were associated with higher patient and physician gout control scores. Absence of tophus also predicted higher physician, but not patient, gout control scores. Discordant scores for gout control were present in 50 participants (22.3%), mostly due to lower assessment of disease control by physicians. Gout flare in the preceding 3 months (odds ratio [OR] 5.9, P < 0.001) and tophus (OR 3.1, P=0.007) predicted discordant disease-control assessments in which physicians scored lower gout control than patients. For both patients and physicians, absence of gout flares and serum urate levels at the treatment target predict assessment of gout control. However, discordance between patients and physicians in their assessment of disease control is not uncommon, with recent gout flares and tophus predicting lower scores by physicians than patients.

Improved joint and patient-reported health assessments with pegloticase plus methotrexate co-therapy in patients with uncontrolled gout: 12-month exploratory outcomes of the MIRROR open-label trial

BackgroundUncontrolled/refractory gout patients are recalcitrant/intolerant to oral urate-lowering therapies (ULTs), experiencing frequent gout flares, functionally limiting tophi, and low quality of life. Pegloticase lowers urate, but anti-pegloticase antibodies limit urate-lowering efficacy and increase infusion reaction (IR) risk. Immunomodulator + pegloticase co-administration may improve treatment response rates, with 79% of MIRROR open-label trial (MIRROR-OL, pegloticase + oral methotrexate) participants meeting 6-month response criteria. Exploratory outcomes from MIRROR-OL are described here.MethodsAdults with uncontrolled gout (serum urate [SU] ≥ 6 mg/dL and ULT-intolerance/recalcitrance or functionally limiting tophi) were included. Oral methotrexate (15 mg/week) was administered 4 weeks before and during pegloticase treatment (biweekly 8 mg infusion, ≤ 52 weeks). Exploratory outcomes included change from baseline (CFB) in number of affected joints, Health Assessment Questionnaires (HAQs), and Gout Global Assessments.ResultsFourteen patients received ≥ 1 pegloticase infusion, with 13 included in 52-week analyses (1 enrolled before treatment-extension amendment, exited at 24 weeks). Three patients prematurely exited due to SU rise; 10 completed 52-week evaluations (8 completed 52 weeks of co-therapy, 2 completed 24 weeks [met treatment goals]). At 52 weeks, SU averaged 1.1 ± 2.5 mg/dL, with improvements in HAQ pain and health (CFB: − 33.6 and − 0.7, respectively), Patient and Physician Global Assessments (CFB: − 4.6 and − 5.7, respectively), and joint involvement (CFB: − 5.6, − 8.4, − 6.0 tender, swollen, tophi-affected joints, respectively). Two patients underwent dual-energy computed tomography, showing concomitant monosodium urate volume reductions. All patients had ≥ 1 AE, with 92.9% experiencing acute flare. One mild IR (“cough”) occurred and no new safety signals were identified.ConclusionPegloticase + methotrexate co-therapy resulted in sustained SU-lowering with meaningful improvements in clinical measures, urate burden, and patient-reported outcomes.Trial registrationClinicalTrials.gov (NCT03635957)

Nontraditional Risk Factors for Progression Through Chronic Kidney Disease Risk Categories: The Coronary Artery Risk Development in Young Adults Study

BackgroundThere may be nontraditional pathways of chronic kidney disease (CKD) progression that are complementary to classical pathways. Therefore, we aimed to examine nontraditional risk factors for incident CKD and its progression. MethodsWe used the generally healthy population (n = 4382) starting at age 27-41 years in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort, which is an observational longitudinal study. Nontraditional risk factors included forced vital capacity, inflammation, serum urate, and serum carotenoids. CKD risk category was classified using the estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) measured in 1995-1996 and repeated every 5 years for 20 years: No CKD, low risk, moderate risk, high risk, and very high risk. ResultsAt baseline, 84.8% had no CKD (eGFR ≥60 mL/min/1.73 m2 and UACR <10 mg/g), 10.3% were in the low risk (eGFR ≥60 and UACR 10-29), and 4.9% had CKD (eGFR <60 and/or UACR ≥ 30). Nontraditional risk factors were significantly associated with the progression of CKD to higher categories. Hazard ratios per standard deviation of the predictor for incident CKD and its progression from the No CKD and low and moderate risk into CKD were inverse for forced vital capacity and serum carotenoids and positive for serum urate, GlycA, and C-reactive protein, the first 3 even after adjustment for conventional risk factors. ConclusionSeveral nontraditional markers were significantly associated with an increased risk of progression to higher CKD categories in generally healthy young to middle-aged adults.

Associations between serum urate and telomere length and inflammation markers: Evidence from UK Biobank cohort.

Hyperuricemia and gout have become gradually more common. The effect of serum urate on organism aging and systematic inflammation is not determined. This study aims to evaluate whether serum urate is causally associated with cellular aging markers and serum inflammation markers. A Mendelian randomization study was performed on summary-level data from the largest published genome-wide association studies. Single nucleotide polymorphisms with a genome-wide significance level were selected as instrumental variables for leukocyte telomere length (LTL), and serum soluble makers of inflammation (CRP, IL-6, TNF-α, and IGF-1). Standard inverse variance weighted (IVW) method was used as the primary statistical method. The weighted median, MR-Egger regression, and MR-PRESSO methods were used for sensitivity analysis. An inverse causal association of genetically predicted serum urate levels and LTL was found using IVW method (OR: 0.96, 95%CI 0.95, 0.97; β=-0.040; SE=0.0072; P=4.37×10-8). The association was also supported by MR results using MR-Egger method and weighted median method. The MR-PRESSO analysis and leave-one-out sensitivity analysis supported the robustness of the combined results. In terms of other aging-related serum biomarkers, there was no evidence supporting a causal effect of serum urate on CRP, IL-6, TNF-α, or IGF-1 levels. Serum urate levels are negatively associated with telomere length but are not associated with serum soluble indicators of inflammation. Telomere length may be a critical marker that reflects urate-related organismal aging and may be a mechanism in the age-related pathologies and mortality caused by hyperuricemia.

Associations Between Low Serum Urate, Body Composition, and Mortality.

Controversy remains as to whether low serum urate or uric acid (UA) levels contribute to adverse outcomes. We evaluated the relation between low serum UA levels and sarcopenia and assessed whether sarcopenia confounds associations between these low levels and mortality. We utilized data from the National Health and Nutrition Examination Survey (1999-2006). Participants with available whole-body dual x-ray absorptiometry body composition measurements and serum UA concentrations were included. Body composition assessments included body mass index (BMI), waist circumference, maximum lifetime BMI, and age-, sex-, and race-specific appendicular lean mass index (ALMI) and fat mass index (FMI) Z scores. We also calculated Z scores for ALMI relative to FMI (ALMIFMI ). We evaluated associations between serum UA levels and body composition using logistic regression and assessed associations between serum UA levels and mortality before and after adjusting for differences in body composition using Cox proportional hazards regression. Among the 13,979 participants, low serum UA concentrations (<2.5 mg/dl in women, <3.5 mg/dl in men) were associated with low lean mass (ALMI and ALMIFMI Z scores), underweight BMI (<18.5 kg/m2 ), and higher rates of weight loss. The proportion of patients with low ALMI Z scores was 29% in the low serum UA group and 16% in the normal serum UA group (P=0.001). Low serum UA levels were associated with increased mortality before we adjusted for body composition (hazard ratio 1.61 [95% confidence interval 1.14-2.28]; P=0.008) but was attenuated and not significant after adjustment for body composition and weight loss (hazard ratio 1.30 [95% confidence interval 0.92-1.85], P=0.13). Sarcopenia and weight loss are more common among patients with low serum UA concentrations. Differences in body composition may help to explain associations between low levels of serum UA and higher mortality.

Uricase-Deficient Larval Zebrafish with Elevated Urate Levels Demonstrate Suppressed Acute Inflammatory Response to Monosodium Urate Crystals and Prolonged Crystal Persistence.

Gout is caused by elevated serum urate leading to the deposition of monosodium urate (MSU) crystals that can trigger episodes of acute inflammation. Humans are sensitive to developing gout because they lack a functional urate-metabolizing enzyme called uricase/urate oxidase (encoded by the UOX gene). A hallmark of long-standing disease is tophaceous gout, characterized by the formation of tissue-damaging granuloma-like structures ('tophi') composed of densely packed MSU crystals and immune cells. Little is known about how tophi form, largely due to the lack of suitable animal models in which the host response to MSU crystals can be studied in vivo long-term. We have previously described a larval zebrafish model of acute gouty inflammation where the host response to microinjected MSU crystals can be live imaged within an intact animal. Although useful for modeling acute inflammation, crystals are rapidly cleared following a robust innate immune response, precluding analysis at later stages. Here we describe a zebrafish uox null mutant that possesses elevated urate levels at larval stages. Uricase-deficient 'hyperuricemic' larvae exhibit a suppressed acute inflammatory response to MSU crystals and prolonged in vivo crystal persistence. Imaging of crystals at later stages reveals that they form granuloma-like structures dominated by macrophages. We believe that uox-/- larvae will provide a useful tool to explore the transition from acute gouty inflammation to tophus formation, one of the remaining mysteries of gout pathogenesis.

Treat-to-target urate-lowering therapy and hospitalizations for gout: results from a nationwide cohort study in England.

To investigate associations between treat-to-target urate-lowering therapy (ULT) and hospitalizations for gout. Using linked Clinical Practice Research Datalink and NHS Digital Hospital Episode Statistics data, we described the incidence and timing of hospitalizations for flares in people with index gout diagnoses in England from 2004-2020. Using Cox proportional hazards and propensity models, we investigated associations between ULT initiation, serum urate target attainment, colchicine prophylaxis, and the risk of hospitalizations for gout. Of 292 270 people with incident gout, 7719 (2.64%) had one or more hospitalizations for gout, with an incidence rate of 4.64 hospitalizations per 1000 person-years (95% CI 4.54, 4.73). There was an associated increased risk of hospitalizations within the first 6 months after ULT initiation, when compared with people who did not initiate ULT [adjusted Hazard Ratio (aHR) 4.54; 95% CI 3.70, 5.58; P < 0.001]. Hospitalizations did not differ significantly between people prescribed vs not prescribed colchicine prophylaxis in fully adjusted models. From 12 months after initiation, ULT associated with a reduced risk of hospitalizations (aHR 0.77; 95% CI 0.71, 0.83; P < 0.001). In ULT initiators, attainment of a serum urate <360 micromol/l within 12 months of initiation associated with a reduced risk of hospitalizations (aHR 0.57; 95% CI 0.49, 0.67; P < 0.001) when compared with people initiating ULT but not attaining this target. ULT associates with an increased risk of hospitalizations within the first 6 months of initiation but reduces hospitalizations in the long term, particularly when serum urate targets are achieved.

Palpable tophi and more comorbidities associated with adherence to urate-lowering medical therapy in a Chinese gout cohort.

Urate-lowering therapy (ULT) nonadherence is common and problematic in gout. Since, sociocultural factors affect adherence, we analyzed a Chinese cohort. We studied 903 Chinese gout patients aged 46.4±14.7 years (mean±SD), uniquely extending to assay of 2-year medication possession ratio (MPR) ≥80% defined as high adherence. Multivariable logistic regression analyses evaluated factors linked with adherence and ULT target attainment. Characterization of ULT outcomes in this cohort revealed that after 2 years ULT, MPR ≥80% patients had better target serum urate (SU) achievement (from 23.3% to 71.0%, P <0.001), lower flare frequency and palpable tophi compared to MPR <80%. However, only 44.7% of cohort subjects had MPR ≥80%. Male sex (OR 3.68), gout onset age >60 years (OR 3.51), disease duration >5 years (OR 1.70), more comorbidities (OR 1.74), baseline palpable tophi (OR 1.53), SU <6mg/dL (360μmol/L) (OR 1.92) and more frequent follow-up visits (OR 1.98) were significantly associated with high adherence. Nevertheless, significant independent risk factors for failed SU target achievement included male sex (OR 0.36) and more comorbidities (OR 0.85). Despite adherence to ULT linked to better outcomes for flares and tophi, the more adherent Chinese male patients and those with more comorbidities had decreased target SU attainment. Differences in adherence of Chinese gout patients compared to several primarily Western studies emphasize the importance of not stereotyping gout patients for projected nonadherence. Results underline the dual importance of identifying gout patients more likely to be ULT-adherent and leveraging adherence to drive treatment to SU target.

Risk of Parkinson's disease in a gout Mediterranean population: A case-control study.

High levels of serum urate has been associated to a neuroprotective effect in Parkinson's disease (PD) as an antioxidant agent. However, the relation between gout and PD remains contradictory. To study if the neuroprotective effect of serum urate is maintained in patients with gout in a large urban Mediterranean population. Primary care based matched case-control study, carried out using an electronic health record database from the public primary care health system of Barcelona. The database contains anonymous data from 1,520,934 patients. All patients, over 40 years old, with a new diagnostic record of PD, or a new prescription of dopaminergic drugs were included (incident cases). We randomly selected four controls for each case, matched by gender and age, with the frequency matching approach. Retrospective data of PD risk factors were also collected for each individual. A multivariate logistic regression model was used to evaluate the association of gout and PD, adjusted by the presence of other risk factors. A new PD diagnosis was found in 17,629 individuals (incident diagnosis rate of 2.2 per 1000 individuals). Multivariate logistic regression model showed for gout: aOR=0.83 (0.76-0.91). When stratified by age, aOR for those under 75years was 0.99 (0.85-1.16) and 75 or over OR=0.77 (0.70-0.86). Dyslipidemia, hypertension and diabetes mellitus were associated with an increased risk of PD. Tobacco consumption was protective. Our study, the first one made in a Mediterranean population, shows a PD protective effect of gout in both men and women over 75years old.