Uric Concentration Research Articles

Effect of Urate-Elevating Inosine on Early Parkinson Disease Progression

Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data. To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression. Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019. Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years. The primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity. Based on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine (MDS-UPDRS score, 11.1 [95% CI, 9.7-12.6] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, -0.59 to 3.11] points per year; P = .18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years). Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD. ClinicalTrials.gov Identifier: NCT02642393.

Longitudinal development of incident gout from low-normal baseline serum urate concentrations: individual participant data analysis

IntroductionElevated serum urate (SU) concentration is the central risk factor for the development of gout. The aim of this study was to examine the incidence of gout in people with low and normal SU levels (< 7.00 mg/dL).MethodsLongitudinal cohort data from the Atherosclerosis Risk in Communities Study (ARIC), Coronary Artery Risk Development in Young Adults Study (CARDIA), and both the Original and Offspring cohorts of the Framingham Heart Study (FHS) were used to determine incident gout by baseline SU over 3, 5, 10, 12 and 15 year periods. A Cox proportional hazards model with covariables of age, gender, ethnicity, and cohort was calculated to report the hazard ratios (HR) for incident gout.ResultsThe incidence of gout at 15 years for a baseline SU < 4.00 mg/dL was 0.59%, 4.00–4.49 mg/dL was 1.28%, 4.50–4.99 mg/dL was 0.86%, 5.00–5.49 mg/dL was 0.94%, 5.50–5.99 mg/dL was 1.52%, 6.00–6.49 mg/dL was 2.91%, 6.50–6.99 mg/dL was 3.2%, and > 7.00 mg/dL was 12.2%. In an adjusted Cox proportional hazards model, compared to the referent baseline SU < 4.00 mg/dL, there was a non-significant increase in incident gout for baseline SU bands between 4.00–5.49 mg/dL, whereas incident gout was significantly increased for SU 5.50–5.99 mg/dL (HR 2.60), 6.00–6.49 mg/dL (HR 3.70), 6.50–6.99 mg/dL (HR 5.24) and > 7.00 mg/dL (HR 18.62).ConclusionA baseline SU of 5.50 mg/dL or more is a risk factor for development of gout over 15 years. However, incident gout does occur over time in a small proportion of people with lower baseline SU levels.

Urate-induced epigenetic modifications in myeloid cells

ObjectivesHyperuricemia is a metabolic condition central to gout pathogenesis. Urate exposure primes human monocytes towards a higher capacity to produce and release IL-1β. In this study, we assessed the epigenetic processes associated to urate-mediated hyper-responsiveness.MethodsFreshly isolated human peripheral blood mononuclear cells or enriched monocytes were pre-treated with solubilized urate and stimulated with LPS with or without monosodium urate (MSU) crystals. Cytokine production was determined by ELISA. Histone epigenetic marks were assessed by sequencing immunoprecipitated chromatin. Mice were injected intraarticularly with MSU crystals and palmitate after inhibition of uricase and urate administration in the presence or absence of methylthioadenosine. DNA methylation was assessed by methylation array in whole blood of 76 participants with normouricemia or hyperuricemia.ResultsHigh concentrations of urate enhanced the inflammatory response in vitro in human cells and in vivo in mice, and broad-spectrum methylation inhibitors reversed this effect. Assessment of histone 3 lysine 4 trimethylation (H3K4me3) and histone 3 lysine 27 acetylation (H3K27ac) revealed differences in urate-primed monocytes compared to controls. Differentially methylated regions (e.g. HLA-G, IFITM3, PRKAB2) were found in people with hyperuricemia compared to normouricemia in genes relevant for inflammatory cytokine signaling.ConclusionUrate alters the epigenetic landscape in selected human monocytes or whole blood of people with hyperuricemia compared to normouricemia. Both histone modifications and DNA methylation show differences depending on urate exposure. Subject to replication and validation, epigenetic changes in myeloid cells may be a therapeutic target in gout.

Elevated Urate Levels Do Not Alter Bone Turnover Markers: Randomized Controlled Trial of Inosine Supplementation in Postmenopausal Women.

Observational studies have consistently demonstrated that serum urate level positively correlates with bone mineral density (BMD). We undertook this study to determine whether moderate hyperuricemia induced by inosine supplements influences bone turnover markers in postmenopausal women over a 6-month period. One hundred twenty postmenopausal women were recruited for a 6-month randomized, double-blind, placebo-controlled trial. Key exclusion criteria were osteoporosis, previous fragility fracture, bisphosphonate therapy, gout, kidney stones, and a urine pH level of ≤5.0. Participants were randomized in a 1:1 ratio to receive placebo or inosine. The coprimary end points were change in levels of N-propeptide of type I procollagen (PINP) and change in levels of β-C-telopeptide of type I collagen (β-CTX). Change in BMD, as measured by dual x-ray absorptiometry, was an exploratory end point. Administration of inosine led to a significant increase in serum urate concentration over the study period (P < 0.0001 for all follow-up time points). At week 26, the mean change in serum urate concentration was +0.13 mmoles/liter (+2.2 mg/dl) in the inosine group and 0.00 mmoles/liter (0 mg/dl) in the placebo group. There was no difference in PINP or β-CTX levels between groups over the 6 months. There were no significant changes in bone density between groups over the 6 months. Adverse events and serious adverse events were similar between the 2 groups. This clinical trial shows that although inosine supplementation leads to sustained increases in serum urate levels over a 6-month period, it does not alter markers of bone turnover in postmenopausal women. These findings do not support the concept that urate has direct biologic effects on bone turnover.

Serum urate and cardiovascular events in the DCCT/EDIC study

In type 2 diabetes, hyperuricemia is associated with cardiovascular disease (CVD) and the metabolic syndrome (MetS), but associations in type 1 diabetes (T1D) have not been well-defined. This study examined the relationships between serum urate (SU) concentrations, clinical and biochemical factors, and subsequent cardiovascular events in a well-characterized cohort of adults with T1D. In 973 participants with T1D in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC), associations were defined between SU, measured once in blood collected 1997–2000, and (a) concurrent MetS and (b) incident ‘any CVD’ and major adverse cardiovascular events (MACE) through 2013. SU was higher in men than women [mean (SD): 4.47 (0.99) vs. 3.39 (0.97) mg/dl, respectively, p < 0.0001], and was associated with MetS features in both (men: p = 0.0016; women: p < 0.0001). During follow-up, 110 participants (11%) experienced “any CVD”, and 53 (5%) a MACE. Analyzed by quartiles, SU was not associated with subsequent CVD or MACE. In women, SU as a continuous variable was associated with MACE (unadjusted HR: 1.52; 95% CI 1.07–2.16; p = 0.0211) even after adjustment for age and HbA1c (HR: 1.47; 95% CI 1.01–2.14; p = 0.0467). Predominantly normal range serum urate concentrations in T1D were higher in men than women and were associated with features of the MetS. In some analyses of women only, SU was associated with subsequent MACE. Routine measurement of SU to assess cardiovascular risk in T1D is not merited.Trial registration clinicaltrials.gov NCT00360815 and NCT00360893.

Gout Flare Burden, Diagnosis, and Management: Navigating Care in Older Patients with Comorbidity.

Gout is the most common form of inflammatory arthritis, and its incidence is highest in middle-aged and older patients. Adding to the diagnostic complexity, up to 50% of patients aged > 65 years present atypically, with subacute oligo- or polyarticular flares. Comorbidity and polypharmacy, common in older populations, affect real-world treatment decisions in gout management, and no specific guidelines are available to address these issues in these at-risk groups. Despite the growing public health burden posed by gout, suboptimal management has led to increased morbidity and substantial healthcare utilization and cost burden, as reflected by an increased incidence of emergency department visits and hospitalizations in recent years. Colchicine, nonsteroidal anti-inflammatory drugs, or glucocorticoids (oral, intraarticular, or intramuscular) should be considered as first-line agents for gout flare management. Urate-lowering therapy, with the goal of lowering and maintaining serum urate concentrations at < 6 mg/dL (< 360 μmol/L), is recommended to achieve optimal outcomes, including regression of tophi, reduction (or elimination) of flares, and reductions in total urate burden. In this review, we summarize the current burden posed by gout and discuss best practices in its diagnosis and management, focusing on best practices in the context of gout flare in older patients with comorbid conditions.

Sex-Specific Association of Uric Acid and Kidney Function Decline in Taiwan.

An elevated serum urate concentration is associated with kidney damage. Men’s uric acid levels are usually higher than women’s. However, postmenopausal women have a higher risk of gout than men, and comorbidities are also higher than in men. This study examined the sex differences in the relationship between hyperuricemia and renal progression in early chronic kidney disease (CKD) and non-CKD, and further examined the incidence of CKD in non-CKD populations among patients over 50 years of age. We analyzed 1856 women and 1852 men participating in the epidemiology and risk factors surveillance of the CKD database. Women showed a significantly higher risk of renal progression and CKD than men within the hyperuricemia group. After adjusting covariates, women, but not men resulted in an hazard ratio (HR) for developing renal progression (HR = 1.12; 95% CI 1.01–1.24 in women and HR = 1.03; 95% CI 0.93–1.13 in men) and CKD (HR = 1.11; 95% CI 1.01–1.22 in women and HR = 0.95; 95% CI 0.85–1.05 in men) for each 1 mg/dL increase in serum urate levels. The association between serum urate levels and renal progression was stronger in women. Given the prevalence and impact of kidney disease, factors that impede optimal renal function management in women and men must be identified to provide tailored treatment recommendations.

Association between triglyceride-glucose index (TyG) and serum urate concentrations in young adults

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Dual-energy computed tomography: Tube current settings and detection of uric acid tophi

PurposeTo derive optimal scanning parameters for single-source dual-energy computed tomography (DECT) in the detection of urate by analyzing influence of tube current ratio (TCR) and total radiation exposure in a phantom. MethodSpecimens with different urate concentrations in a realistic porcine bio-phantom were repeatedly imaged with sequential single-source DECT scans at 80 kVp (16.5–220 mA s) and 135 kVp (2.75–19.25 mA s). Detection index (DI - true positive minus false positive urate volume) was calculated for every possible tube current combination. Optimal tube current combinations reaching at least 85 % of the highest measured DI of all combinations without exceeding 150 % of equivalent single-energy radiation dose were identified. TCR, DLP and DI were plotted and compared. ResultsCubic regression analysis showed a flattening increase in the DI with increasing tube currents. Five out of the 100 tube current combinations analyzed achieved the detection target: the lowest DLP of 53.9 mGy*cm at 19.25/16.5 mAs (135/80 kVp) achieved a DI of 2.07 mL and the highest DI of 2.11 mL at a dose of 65.3 mGy*cm and 8.25/79.75 mAs. The optimal TCR is between two and four, while both, higher and lower ratios decreased DI. ConclusionsA minimum tube current of the high-energy scans is needed before an acceptable overall sensitivity is achieved and before increases in low-energy exposure result in more urate detection. High TCRs above 10 are not beneficial while the optimal TCR ranges between two and four, indicating that special care has to be taken in designing a suitable DECT protocol.

Genetic Predisposition to Type 2 Diabetes and Insulin Levels Is Positively Associated With Serum Urate Levels.

Previous epidemiological evidence showed that type 2 diabetes (T2D) is related with gout. However, the causality and the direction of this association are still not definitely elucidated. We investigated bidirectional associations of T2D and glycemic traits with serum urate concentrations and gout using a Mendelian randomization approach. Summary statistics from the large-scale genomewide association studies conducted for T2D (Ncase = 62 892, Ncontrol = 596 424), fasting glucose (N = 133 010), fasting insulin (N = 133 010), hemoglobin A1c (N = 123 665), homeostasis model assessment of insulin resistance (N = 46 186), urate (N = 110 347), and gout (Ncase = 2115, Ncontrol = 67 259) among participants of European ancestry were analyzed. For each trait of interest, independent genomewide significant (P < 5 × 10-8) single nucleotide polymorphisms were selected as instrumental variables. The inverse-variance weighted method was used for the primary analyses. Genetic predisposition to higher risk of T2D [beta = 0.042; 95% confidence interval (CI) = 0.016-0.068; P = 0.002] and higher levels of fasting insulin (beta = 0.756; 95% CI = 0.408-1.102; P = 1.96e-05) were significantly associated with increased serum urate concentrations. Moreover, we found suggestively significant evidence supporting a causal role of fasting insulin on risk of developing gout (odds ratio = 3.06; 95% CI = 0.88-10.61; P = 0.078). In the reverse direction analysis, genetic predisposition to both urate and gout were not associated with T2D or any of 4 glycemic traits being investigated. This study provides supportive evidence on causal associations of T2D and fasting insulin with serum urate concentrations and a suggestive association of fasting insulin with risk of gout. Future research is required to examine the underlying biological mechanisms on such relationships.

Hyperuricemia causes kidney damage by promoting autophagy and NLRP3-mediated inflammation in rats with urate oxidase deficiency.

ABSTRACTEpidemiological research has shown that elevated serum urate concentration is a risk factor for the development of kidney disease; however, the mechanisms underlying this process have not yet been elucidated. To examine the role of urate in the kidney, we used Wistar rats to functionally disrupt expression of urate oxidase (UOX) by using the CRISPR/Cas9 system. In comparison to wild-type (WT) rats, serum urate levels spontaneously and persistently increased in UOX-KO rats, without showing a significant decrease in survival rate. Architecture and function of the kidneys in UOX-KO rats were impaired. Injury to the kidney resulted in increased interstitial fibrosis, macrophage infiltration, increased expression of NLRP3 and IL-1β, and activation of multiple cell-signaling pathways associated with autophagy, such as AMPK, p38 MAPK, ERK and JNK pathways. Inhibition of autophagy with the PI3K inhibitor 3-MA abrogated the development of kidney damage and attenuated renal fibrosis, macrophage infiltration, and expression of NLRP3 and IL-1β in injured kidneys. In conclusion, the UOX-KO rat is a great model to study hyperuricemia-related diseases. Hyperuricemia-induced autophagy and NLRP3-dependent inflammation are critically involved in the development of renal damage and, therefore, highlight the inhibition of autophagy and inflammation in search of therapeutic strategies to treat uric acid nephropathy.

Incidence and Risk Factors of Hyperuricemia among 2.5 Million Chinese Adults during the Years 2017-2018.

Objective: To assess the incidence and risk factors of hyperuricemia among Chinese adults in 2017–2018. Methods: A total of 2,015,847 adults (mean age 41.2 ± 12.7, 53.1% men) with serum uric acid concentrations assayed on at least two separate days in routine health examinations during 2017–2018 were analyzed. Hyperuricemia was defined as fasting serum urate concentration >420 μmol/L in men and >360 μmol/L in women. The overall and sex-specific incidence rate were stratified according to age, urban population size, geographical region, annual average temperature and certain diseases. Logistic regression analyses were performed to explore risk factors associated with hyperuricemia. Results: 225,240 adults were newly diagnosed with hyperuricemia. The age- and sex-standardized incidence rate per 100 person-years was 11.1 (95%CI: 11.0–11.1) (15.2 for men and 6.80 for women). The risk of hyperuricemia was positively associated with younger age, being male, larger urban population size, higher annual temperature, higher body mass index, lower estimate glomerular filtration rate, hypertension, dyslipidemia and fat liver. Conclusions: The incidence of hyperuricemia was substantial and exhibited a rising trend among younger adults, especially among men. Socioeconomic and geographic variation in incidence were observed. The risk of hyperuricemia was associated with estimate glomerular filtration rate, fat liver and metabolic factors.

Gender-Specific Inverse Associations Between Beans Intake, Serum Urate Levels, and Hyperuricemia: A Cross-Sectional Analysis Based on the Henan Rural Cohort Study

Background and Aims: Beans are rich in purines, which are important substances that lead to elevated serum urate, especially exogenous purines. Few studies were conducted to assess the relationship between beans intake and serum urate or hyperuricemia, especially in rural people. The purpose of this study was to validate the association by gender in the rural Chinese population.Methods: A total of 38,855 participants aged 18–79 years old were enrolled from the Henan Rural Cohort Study (Registration number: ChiCTR-OOC-15006699). Dietary data were collected using a validated food frequency questionnaire (FFQ). Linear regression models and logistic regression models were used to examine the associations between beans intake and serum urate levels or hyperuricemia. Restricted cubic spline regression was performed to display the dose–response relationship.Results: In multivariate-adjusted linear regression, an inverse correlation was found between beans intake and serum urate level (the highest quartile Q4 vs. the bottom quartile Q1) in both men (P = 0.008) and women (P < 0.001). Per 10-g increment in beans intake was associated with 0.30 μmol/L decreased concentration of serum urate in men and 0.71 μmol/L in women. The multivariate-adjusted odds ratios (ORs) of hyperuricemia were 0.83 (0.71, 0.97) in men and 0.73 (0.63, 0.84) in women (Q4 vs. Q1). Per 10-g increment in beans intake created a 1% decreased risk of hyperuricemia in men and 3% in women. The cubic spline suggested a risk reduction for hyperuricemia with increasing intake of beans.Conclusion: A higher beans intake was associated with a lower serum urate level and a reduced risk of hyperuricemia in both sexes, and the association was more pronounced in women.

Cichoric Acid Ameliorates Monosodium Urate-Induced Inflammatory Response by Reducing NLRP3 Inflammasome Activation via Inhibition of NF-kB Signaling Pathway.

Gouty arthritis is characterized by the deposition of monosodium urate (MSU) within synovial joints and tissues due to increased urate concentrations. Here, we elucidated the role of the natural compound cichoric acid (CA) on the MSU crystal-stimulated inflammatory response. The THP-1-derived macrophages (THP-Ms) were pretreated with CA and then stimulated with MSU suspensions. The protein levels of p65 and IκBα, the activation of the NF-κB signaling pathway by measuring the expression of its downstream inflammatory cytokines, and the activity of NLRP3 inflammasome were measured by western blotting and ELISA. CA treatment markedly inhibited the degradation of IκBα and the activation of NF-κB signaling pathway and reduced the levels of its downstream inflammatory genes such as IL-1β, TNF-α, COX-2, and PGE2 in the MSU-stimulated THP-M cells. Therefore, we infer that CA effectively alleviated MSU-induced inflammation by suppressing the degradation of IκBα, thereby reducing the activation of the NF-κB signaling pathway and the NLRP3 inflammasome. These results suggest that CA could be a novel therapeutic strategy in averting acute episodes of gout.

Alterations in the Serum Urate Concentrations after Bariatric Surgery: a Short-Term Prospective Observational Study.

Bariatric surgery is associated with a reduced incidence of hyperuricaemia during the long follow-up time. However, few studies have elucidated the alterations in serum urate (SU) levels in the short-term post-surgery period. To identify the alterations in SU concentrations in individuals with obesity at 1week, 1month, and 3months after bariatric surgery and determine the risk factors for alterations during the first 3 post-surgery months. Thirty-four patients were enrolled. Pre- and post-operative variables were collected at baseline and at each follow-up point. A paired t-test was applied to investigate the relationship between the major parameters. A linear mixed model was performed to analyse the variations of SU concentrations with time. Compared with baseline levels, SU levels significantly increased at 1week, then declined significantly at 1month after surgery (P < 0.05). At the 3-month follow-up, a significant decrease in SU levels was detected compared with that in baseline levels (P< 0.001). In univariate regression analysis, age, sex, weight, body mass index, triglyceride (TG), total cholesterol (TC), creatinine (Cr), and medications were all risk factors for alterations in SU concentrations post-surgery. In the final model, sex, weight, Cr, age, TC, Cr * age, and Cr * TC were established. Surgeons should be cognizant of the significant increase in SU levels in the first postoperative week. Alterations in SU concentrations during the first 3 post-operative months were associated with sex, age, weight, Cr, and TC levels at baseline.

Association between serum urate and CSF markers of Alzheimer's disease pathology in a population‐based sample of 70‐year‐olds

IntroductionThe relationship between urate and biomarkers for Alzheimer's disease (AD) pathophysiology has not been investigated.MethodsWe examined whether serum concentration of urate was associated with cerebrospinal fluid biomarkers, amyloid beta (Aβ)42, Aβ40, phosphorylated tau (p‐tau), total tau (t‐tau), neurofilament light (NfL), and Aβ42/Aβ40 ratio, in cognitively unimpaired 70‐year‐old individuals from Gothenburg, Sweden. We also evaluated whether possible associations were modulated by the apolipoprotein E (APOE) ε4 allele.ResultsSerum urate was positively associated with Aβ42 in males (β = 0.55 pg/mL, P = .04). There was a positive urate–APOE ε4 interaction (1.24 pg/mL, P interaction = .02) in relation to Aβ42 association. The positive urate and Aβ42 association strengthened in male APOE ε4 carriers (β = 1.28 pg/mL, P = .01).DiscussionThe positive association between urate and Aβ42 in cognitively healthy men may suggest a protective effect of urate against deposition of amyloid protein in the brain parenchyma, and in the longer term, maybe against AD dementia.

A case report of hyperuricaemia with nephrolithiasis treated with homoeopathy

Introduction: Hyperuricaemia is serum urate concentration exceeding the limit of solubility, leading to its precipitation and predisposing the affected persons to gout. The increased level of uric acid in urinary excretion can also lead to nephrolithiasis. It has also been implicated as an indicator for diseases such as metabolic syndrome, diabetes mellitus, cardiovascular disease and chronic renal disease. Whereas homoeopathic literature enlists many medicines for this condition, there is a paucity of evidence-based published studies. Case Summary: The case presented here reported with the complaint of renal stone secondary to high serum uric acid levels. A single homoeopathic medicine Lycopodium was prescribed after thorough case taking which led to improvement in subjective symptoms and objectively reflecting in gradually decreasing levels of serum uric acid after elimination of stone. During the course of treatment, old symptoms also re-appeared depicting improvement in accordance with Hering's law of cure. The Modified Naranjo Criteria score after treatment was 8, which explicitly shows the positive causal attribution of the individualised homoeopathic medicine Lycopodium in this case. Homoeopathic treatment has shown favourable results in this case and demonstrates the scope of Homoeopathy in such cases.

Effect of body mass index on serum urate and renal uric acid handling responses to an oral inosine load: experimental intervention study in healthy volunteers

BackgroundHigh body mass index (BMI) is strongly associated with hyperuricaemia. It is unknown whether overweight and obesity influences serum urate primarily through increased urate production or reduced renal clearance of uric acid. The aim of this study was to determine the influence of BMI on the response to inosine, a purine nucleoside that functions as an intermediate in the purine salvage and degradation pathways.MethodsFollowing an overnight fast, 100 healthy participants without gout attended a study visit. Blood and urine samples were taken prior to and over 180 min after 1.5 g oral inosine. Serum urate and fractional excretion of uric acid (FEUA) were analysed according to high BMI (≥ 25 kg/m2) and low/normal BMI (< 25 kg/m2) groups, and according to BMI as a continuous variable.ResultsParticipants in the high BMI group (n = 52, mean BMI 30.8 kg/m2) had higher serum urate concentrations at baseline (P = 0.002) compared to those with low/normal BMI (mean BMI 21.8 kg/m2). However, the high BMI group had a smaller increase in serum urate following the inosine load (P = 0.0012). The two BMI groups had a similar FEUA at baseline (P = 0.995), but those in the high BMI group had a smaller increase in FEUA following the inosine (P = 0.0003). Similar findings were observed when analysing BMI as a continuous variable. Those with high BMI had a smaller increase in FEUA per increase in serum urate, compared to those with low BMI (P = 0.005).ConclusionsIn a fasting state, people with high BMI have elevated serum urate levels but similar FEUA values compared with those with low/normal BMI. Following a purine load, those with high BMI have an attenuated renal excretion of uric acid. These data, using an experimental method to dynamically assess human urate handling, suggest that people with high BMI have a higher renal capacity for uric acid reabsorption when fasted and following a dietary purine intake have reduced renal clearance.Trial registrationAustralia and New Zealand Clinical Trials Registry, ACTRN12615001302549, date of registration 30 November 2015.

Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial

Febuxostat and allopurinol are urate-lowering therapies used to treat patients with gout. Following concerns about the cardiovascular safety of febuxostat, the European Medicines Agency recommended a post-licensing study assessing the cardiovascular safety of febuxostat compared with allopurinol. We did a prospective, randomised, open-label, blinded-endpoint, non-inferiority trial of febuxostat versus allopurinol in patients with gout in the UK, Denmark, and Sweden. Eligible patients were 60 years or older, already receiving allopurinol, and had at least one additional cardiovascular risk factor. Those who had myocardial infarction or stroke in the previous 6 months or who had severe congestive heart failure or severe renal impairment were excluded. After a lead-in phase in which allopurinol dose was optimised towards achieving a serum urate concentration of less than 0·357 mmol/L (<6 mg/dL), patients were randomly assigned (1:1, with stratification according to previous cardiovascular events) to continue allopurinol (at the optimised dose) or start febuxostat at 80 mg/day, increasing to 120 mg/day if necessary to achieve the target serum urate concentration. The primary outcome was a composite of hospitalisation for non-fatal myocardial infarction or biomarker-positive acute coronary syndrome; non-fatal stroke; or cardiovascular death. The hazard ratio (HR) for febuxostat versus allopurinol in a Cox proportional hazards model (adjusted for the stratification variable and country) was assessed for non-inferiority (HR limit 1·3) in an on-treatment analysis. This study is registered with the EU Clinical Trials Register (EudraCT 2011-001883-23) and ISRCTN (ISRCTN72443728) and is now closed. From Dec 20, 2011, to Jan 26, 2018, 6128 patients (mean age 71·0 years [SD 6·4], 5225 [85·3%] men, 903 [14·7%] women, 2046 [33·4%] with previous cardiovascular disease) were enrolled and randomly allocated to receive allopurinol (n=3065) or febuxostat (n=3063). By the study end date (Dec 31, 2019), 189 (6·2%) patients in the febuxostat group and 169 (5·5%) in the allopurinol group withdrew from all follow-up. Median follow-up time was 1467 days (IQR 1029-2052) and median on-treatment follow-up was 1324 days (IQR 870-1919). For incidence of the primary endpoint, on-treatment, febuxostat (172 patients [1·72 events per 100 patient-years]) was non-inferior to allopurinol (241 patients [2·05 events per 100 patient-years]; adjusted HR 0·85 [95% CI 0·70-1·03], p<0·0001). In the febuxostat group, 222 (7·2%) of 3063 patients died and 1720 (57·3%) of 3001 in the safety analysis set had at least one serious adverse event (with 23 events in 19 [0·6%] patients related to treatment). In the allopurinol group, 263 (8·6%) of 3065 patients died and 1812 (59·4%) of 3050 had one or more serious adverse events (with five events in five [0·2%] patients related to treatment). Randomised therapy was discontinued in 973 (32·4%) patients in the febuxostat group and 503 (16·5%) patients in the allopurinol group. Febuxostat is non-inferior to allopurinol therapy with respect to the primary cardiovascular endpoint, and its long-term use is not associated with an increased risk of death or serious adverse events compared with allopurinol. Menarini, Ipsen, and Teijin Pharma Ltd.

Effect of Intensive Urate Lowering With Combined Verinurad and Febuxostat on Albuminuria in Patients With Type 2 Diabetes: A Randomized Trial

Hyperuricemia has been implicated in the development and progression of chronic kidney disease. Verinurad is a novel, potent, specific urate reabsorption inhibitor. We evaluated the effects on albuminuria of intensive urate-lowering therapy with verinurad combined with the xanthine oxidase inhibitor febuxostat in patients with hyperuricemia and type 2 diabetes mellitus (T2DM). Phase 2, multicenter, prospective, randomized, double-blind, parallel-group, placebo-controlled trial. Patients 18 years or older with hyperuricemia, albuminuria, and T2DM. Patients randomly assigned 1:1 to verinurad (9mg) plus febuxostat (80mg) or matched placebo once daily for 24 weeks. The primary end point was change in urinary albumin-creatinine ratio (UACR) from baseline after 12 weeks' treatment. Secondary end points included safety and tolerability and effect on glomerular filtration. 60 patients were enrolled (n=32, verinurad and febuxostat; n=28, placebo). UACRs after treatment with verinurad plus febuxostat were lower than after placebo at 1, 12, and 24 weeks:-38.6% (90% CI,-60.9% to-3.6%),-39.4% (90% CI,-61.8% to-3.8%), and-49.3% (90% CI,-68.2% to-19.0%), respectively. Serum urate levels after treatment with verinurad plus febuxostat were 59.6% and 63.7% lower than after placebo at 12 and 24 weeks, respectively. No clinically meaningful changes were observed in estimated glomerular filtration rate or serum creatinine or serum cystatin C concentrations. Verinurad plus febuxostat was well tolerated. Sample size and study duration were insufficient to evaluate definitive effects of verinurad plus febuxostat on UACR and glomerular filtration. Generalizability was limited by exclusion of patients with stages 4 and 5 chronic kidney disease. Verinurad plus febuxostat reduced albuminuria and lowered serum urate concentrations in patients with T2DM, albuminuria, and hyperuricemia. Definitive assessment of their combined impact on preservation of kidney function awaits larger clinical studies. This study was supported by AstraZeneca. Registered at ClinicalTrials.gov with study number NCT03118739.