Uric Concentration Research Articles

Association between cumulative serum urate and development of diabetes type II: the Kailuan Study

ObjectiveTo explore whether cumulative serum urate (cumSU) is correlated with diabetes type II mellitus incidence.MethodsIn this study, we recruited individuals participating in all Kailuan health examinations from 2006 to 2013 without stroke, cancer, gestation, myocardial infarction, and diabetes type II diagnosis in the first three examinations. CumSU was calculated by multiplying the average serum urate concentration and the time between the two examinations (umol/L × year). CumSU levels were categorized into five groups: Q1–Q5. The effect of cumSU on diabetes type II incidence was estimated by logistic regression.ResultsA total of 36,277 individuals (27,077 men and 9200 women) participated in the final analysis. The multivariate logistic regression model showed the odds ratios (95% confidence intervals) of diabetes type II from Q1 to Q5 were 1.00 (reference), 1.25 (1.00 to 1.56), 1.43 (1.15 to 1.79), 1.49 (1.18 to 1.87), and 1.80 (1.40 to 2.32), respectively. Multivariable odds ratios per 1-standard deviation increase in cumSU were 1.26 (1.17 to 1.37) in all populations, 1.20 (1.10 to 1.32) for men, and 1.52 (1.27 to 1.81) for women, respectively.ConclusionsCumSU is a significant risk factor for diabetes type II. Individuals with higher cumSU, especially women, are at a higher risk of diabetes type II independent of other known risk factors.Key Points• Cumulative exposure to serum urate is a significant risk factor for diabetes type II.• Individuals with higher cumSU, especially women, are at a higher risk of diabetes type II.

Hypouricemia: what the practicing rheumatologist should know about this condition.

We presented an update in the field of hypouricemia, which is defined as a serum urate concentration of < 2mg/dL (119μmol/L), for the practicing rheumatologist, who usually is the consulting physician in cases of disorders of urate metabolism. We performed a narrative review through a literature search for original and review articles in the field of human hypouricemia published between January 1950 and July 2018. We divided the etiology of hypouricemia into two main categories: those associated with a decrease in urate production and those promoting the elimination of urate via the kidneys. The most common conditions associated with these categories are discussed. Furthermore, the etiology of hypouricemia may be associated with certain medications prescribed by the practicing rheumatologists, such as the following: urate-lowering drugs (allopurinol and febuxostat); recombinant uricase (pegloticase); uricosuric agents (probenecid, benzbromarone); urate transporter URAT1 inhibitor (lesinurad); angiotensin II receptor blocker (losartan); fenofibrate; high-dose trimethoprim-sulfamethoxazole; some NSAID; and high-dose salicylate therapy. The rheumatologist is considered an expert in the metabolism of urate and its associated pathological conditions. Therefore, specialists must recognize hypouricemia as a biomarker of various pathological and potentially harmful conditions, highlighting the importance of conducting a deeper clinical investigation to reach a more accurate diagnosis and treatment.

Curcumin attenuates MSU crystal-induced inflammation by inhibiting the degradation of I\u03baB\u03b1 and blocking mitochondrial damage

BackgroundGouty arthritis is characterized by the deposition of monosodium urate (MSU) within synovial joints and tissues due to increased urate concentrations. In this study, we explored the effect of the natural compound curcumin on the MSU crystal-stimulated inflammatory response.MethodsTHP-1-derived macrophages and murine RAW264.7 macrophages were pretreated with curcumin for 1 h and then stimulated with MSU suspensions for 24 h. The protein level of TLR4, MyD88, and IκBα, the activation of the NF-κB signaling pathway, the expression of the NF-κB downstream inflammatory cytokines, and the activity of NLRP3 inflammasome were measured by western blotting and ELISA. THP-1 and RAW264.7 cells were loaded with MitoTracker Green to measure mitochondrial content, and MitoTracker Red to detect mitochondrial membrane potential. To measure mitochondrial reactive oxygen species (ROS) levels, cells were loaded with MitoSOX Red, which is a mitochondrial superoxide indicator. The effects of curcumin on mouse models of acute gout induced by the injection of MSU crystals into the footpad and synovial space of the ankle, paw and ankle joint swelling, lymphocyte infiltration, and MPO activity were evaluated.ResultsCurcumin treatment markedly inhibited the degradation of IκBα, the activation of NF-κB signaling pathway, and the expression levels of the NF-κB downstream inflammatory genes such as IL-1β, IL-6, TNF-α, COX-2, and PGE2 in the MSU-stimulated THP-1-derived macrophages. Curcumin administration protected THP-1 and RAW264.7 cells from MSU induced mitochondrial damage through preventing mitochondrial membrane potential reduction, decreasing mitochondria ROS, and then inhibited the activity of NLRP3 inflammasome. Intraperitoneal administration of curcumin alleviated MSU crystal-induced paw and ankle joint swelling, inflammatory cell infiltration, and MPO activity in mouse models of acute gout. These results correlated with the inhibition of the degradation of IκBα, the phosphorylation levels of NF-κB subunits (p65 and p50), and the activity of NLRP3 inflammasome.ConclusionCurcumin administration effectively alleviated MSU-induced inflammation by suppressing the degradation of IκBα, the activation NF-κB signaling pathway, the damage of mitochondria, and the activity of NLRP3 inflammasome. Our results provide a new strategy in which curcumin therapy may be helpful in the prevention of acute episodes of gout.

Serum Urate, Genetic Variation, and Prostate Cancer Risk: Atherosclerosis Risk in Communities (ARIC) Study.

Evidence is mounting that intraprostatic inflammation influences prostate cancer development. Uric acid crystals depositing in the prostate could result in injury and inflammation, increasing prostate cancer risk. Included were 6,574 men ages 45-64 years who enrolled in the Atherosclerosis Risk in Communities study in 1987 to 1989. We used Cox proportional hazards regression to estimate the association of serum urate concentration alone and to improve accuracy, jointly with a genetic risk score (GRS, N = 4,983) derived from variants predictive of urate concentration, with prostate cancer (N = 813) risk. Serum urate concentration or joint categories of urate concentration and GRS were not associated with prostate cancer risk (P trend for quartiles = 0.3). Results were generally similar by race and after excluding users of medications that influence uric acid. Serum urate alone and with a urate-associated GRS were not associated with prostate cancer risk. It is unlikely that circulating urate concentration influences prostate cancer development.

Value of ABCG2 Q141K and Q126X genotyping in predicting risk of preeclampsia in Chinese Han women population.

Hyperuricemia (HUA) in women with preeclampsia (PE) not only indicates a reminder of severity but also contributes directly to the pathogenesis of PE. ATP-binding cassette subfamily G member 2 (ABCG2) has a very strong effect on the serum urate concentrations. Our aim was to investigate the association between polymorphisms of ABCG2 with PE in Chinese Han female population. A cohort of 793 preeclamptic women (466 PE with HUA and 327 PE without HUA) and 744 normal pregnant women recruited in this study were genotyped for genetic distribution of Q141K (rs2231142) and Q126X (72552713) in ABCG2 by the TaqMan allelic discrimination real-time PCR. There was no statistically significant difference of genotypic and allelic frequencies between PE and the normal pregnant women in Q141K (Χ2 = 1.11, P = 0.58 by genotype; Χ2 = 0.32, P = 0.57 by allele) and Q126X (P = 0.33 by genotype; P = 0.33 by allele), and no significant difference was found in the genetic distribution of Q141K and Q126X between PE with HUA, PE without HUA and controls. Additionally, this study observed no significant difference in genotypic and allelic distribution between early/late-onset PE with/without HUA or mild/severe PE with/without HUA and control subgroups. Based on our findings, the ABCG2 Q141K and Q126X polymorphisms may not be associated with PE in Chinese Han women.

Urate transport capacity of glucose transporter 9 and urate transporter 1 in cartilage chondrocytes.

Chronic gouty arthritis, caused by a persistent increase in, and the deposition of, soluble uric acid (sUA), can induce pathological chondrocyte destruction; however, the effects of urate transport and intracellular sUA on chondrocyte functionality and viability are yet to be fully determined. Thus, the aim of the present study was to investigate the presence and functionality of a urate transport system in chondrocytes. The expression profiles of two primary urate reabsorptive transporters, glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1), in human articular cartilage and chondrocyte cell lines were examined via western blotting, reverse transcription-quantitative PCR, immunohistochemistry and immunofluorescence. Then, chondrocytes were incubated with exogenous sUA at increasing concentrations. Negative control assays were conducted via the specific knockdown of GLUT9 and URAT1 with lentiviral short hairpin (sh)RNAs, and by pretreatment with benzbromarone, a known inhibitor of the two transporters. Intracellular UA concentrations were measured using colorimetric assays. The expression levels of GLUT9 and URAT1 were determined in cartilage tissues and chondrocyte cell lines. Incubation of chondrocytes with sUA led to a concentration-dependent increase in intracellular urate concentrations, which was inhibited by GLUT9 or URAT1 knockdown, or by benzbromarone pretreatment (27.13±2.70, 44.22±2.34 and 58.46±2.32% reduction, respectively). In particular, benzbromarone further decreased the already-reduced intracellular UA concentrations in HC-shGLUT9 and HC-shURAT1 cells by 46.79±2.46 and 39.79±2.22%, respectively. Cells overexpressing GLUT9 and URAT1 were used as the positive cell control, which showed increased intracellular UA concentrations that could be reversed by treatment with benzbromarone. In conclusion, chondrocytes may possess an active UA transport system. GLUT9 and URAT1 functioned synergistically to transport UA into the chondrocyte cytoplasm, which was inhibited by specific gene knockdowns and drug-induced inhibition. These results may be fundamental in the further investigation of the pathological changes to chondrocytes induced by sUA during gouty arthritis, and identified UA transport processes as potential targets for the early control of chronic gouty arthritis.

Cohort Study of Repeated Measurements of Serum Urate and Risk of Incident Atrial Fibrillation.

BackgroundCurrent evidence on the association between serum urate and risk of atrial fibrillation (AF) is limited by cross‐sectional designs and 1‐time measurement of serum urate. The roles of serum urate, gout‐related inflammation, and systemic inflammation in the etiology of AF are currently unknown. This gap is important, given that systemic inflammation is a recognized risk factor for AF.Methods and ResultsWe conducted a prospective cohort study of 123 238 Chinese patients from 2006 to 2014. Serum urate concentrations were measured in 2006, 2008, 2010, and 2012. Incident AF cases were identified via biennial 12‐lead ECG assessment. We used a Cox proportional hazards model to examine the sex‐specific associations of cumulative average serum urate and changes in serum urate accounting for baseline level with risk of incident AF. We also assessed the joint associations of serum urate and high‐sensitivity C‐reactive protein levels. Comparing extreme categories, participants with the highest quintile of serum urate had 1.91‐fold higher risk of AF (adjusted hazard ratio: 1.91; 95% CI, 1.32–2.76; P=0.001 for trend). Participants with both high serum urate and high‐sensitivity C‐reactive protein had 2.6‐fold elevated risk of incident AF compared with those with normal levels of serum urate and high‐sensitivity C‐reactive protein (adjusted hazard ratio: 2.63; 95% CI, 1.63–4.23).ConclusionsHigh serum urate levels and increases in serum urate over time were associated with increased risk of incident AF. Patients with high levels of both serum urate and high‐sensitivity C‐reactive protein had substantially higher risk of AF.

Usefulness of Triglyceride-glucose Index for estimating Hyperuricemia risk: Insights from a general Population

ABSTRACTObjectives: Hyperuricemia is a metabolic abnormality that has cast an enormous burden on global healthcare. Previous studies have revealed the close association between insulin resistance and hyperuricemia. Therefore, monitoring insulin sensitivity may be a possible way to prevent hyperuricemia. Recent studies have demonstrated the usefulness of triglyceride-glucose index (TyG) as a simple surrogate of insulin resistance. Hence, our study aimed to explore the impact of TyG on hyperuricemia and its value to improve the risk stratification and prevention of hyperuricemia.Methods: This cross-sectional study included 6466 subjects (mean age: 59.57 years, 60.19% females) from northeast China between September 2017 to May 2018. TyG was determined as ln[fasting TG(mg/dL)×FPG(mg/dL)/2]. Hyperuricemia was defined as serum uric acid ≥ 357 μmol/L for females and ≥ 417 μmol/L for males.Results: The prevalence of hyperuricemia was 5.24%. In the full model, each SD increment of TyG caused a 12.528 μmol/L elevation of serum urate concentration and a 54.1% additional risk for hyperuricemia. When dividing TyG into quartiles, the top quartile had a 2.730 times risk for hyperuricemia than the bottom one. Moreover, smooth curve fitting demonstrated this association was linear. Additionally, subgroup analysis revealed the association was robust to several risk factors of hyperuricemia. Finally, AUC displayed an improvement when introducing TyG into clinical risk factors (0.751 vs 0.772, p < 0.001), category-free net reclassification index (0.304, 95% CI: 0.195–0.413, P < 0.001) and integrated discrimination index (0.009, 95% CI: 0.004–0.013, P < 0.001) also showed the improvement from TyG.Conclusion: Our work revealed the linear and robust association between TyG and hyperuricemia. Furthermore, our results suggest the importance of simultaneous glycemic and lipids control in the prevention of hyperuricemia. Most importantly, our findings implicate the value of TyG to optimize the risk stratification and prevention of hyperuricemia.

Association between Serum Urate and Risk of Hypertension in Menopausal Women with XDH Gene.

Elevated serum urate (sUA) concentrations have been associated with an increased risk of hypertension. We aimed to examine the association of sUA concentration on the risk of hypertension in pre- and post-menopausal women and investigated the association between the polymorphism of the xanthine dehydrogenase gene and the risk of hypertension. Among 7294 women, 1415 premenopausal and 5879 postmenopausal women were recruited. Anthropometric parameters as risk factors of hypertension were identify by logistic regression models. In addition, we investigated an association between xanthine dehydrogenase gene and sUA and their combined associations on the risk of hypertension. Body mass index (BMI) and waist circumference (WC) were significantly increased in accordance to the increase of sUA levels (p < 0.001). Multivariate logistic regression analysis showed postmenopausal women with a high sUA and high BMI were 3.18 times more likely to have hypertension than in those with normal and lower sUA (Odds ratio: 3.18, 95% confidence interval: 2.54–3.96). Postmenopausal women with a high WC were 1.62 times more likely to have hypertension than in those with normal and lower sUA. Subjects with the AG genotype of rs206860 was found to be at lower risk of hypertension (odd ratio: 0.287, 95% confidence interval: 0.091–0.905, p = 0.033). This cross-sectional study indicated a high sUA is associated with a higher risk of hypertension in postmenopausal women. Further well-designed prospective studies in other populations are warranted to validate our results.

Mouse models for human hyperuricaemia: a critical review.

Hyperuricaemia (increased serum urate concentration) occurs mainly in higher primates, including in humans, because of inactivation of the gene encoding uricase during primate evolution. Individuals with hyperuricaemia might develop gout - a painful inflammatory arthritis caused by monosodium urate crystal deposition in articular structures. Hyperuricaemia is also associated with common chronic diseases, including hypertension, chronic kidney disease, type 2 diabetes and cardiovascular disease. Many mouse models have been developed to investigate the causal mechanisms for hyperuricaemia. These models are highly diverse and can be divided into two broad categories: mice with genetic modifications (genetically induced models) and mice exposed to certain environmental factors (environmentally induced models; for example, pharmaceutical or dietary induction). This Review provides an overview of the mouse models of hyperuricaemia and the relevance of these models to human hyperuricaemia, with an emphasis on those models generated through genetic modifications. The challenges in developing and comparing mouse models of hyperuricaemia and future research directions are also outlined.

Urate and Homocysteine: Predicting Motor and Cognitive Changes in Newly Diagnosed Parkinson's Disease.

Background:Urate and homocysteine are potential biomarkers for disease progression in Parkinson’s disease (PD). Baseline serum urate concentration has been shown to predict motor but not cognitive decline. The relationship between serum homocysteine concentration and cognitive and motor impairment is unknown.Objectives:The aim of this study was to examine the association between baseline serum urate and homocysteine, and prospective measures of disease progression and cognition over 54 months in early PD.Methods:154 newly diagnosed PD participants and 99 age-matched controls completed a schedule of assessments at baseline, 18, 36 and 54 months. The Movement Disorders Society Unified Parkinson’s Disease Scale Part III (MDS-UPDRS III) was used to assess motor severity. The Montreal Cognitive Assessment (MoCA) was used to assess global cognition. Serum samples drawn at baseline were analysed for urate, homocysteine, red cell folate and vitamin B12 concentrations.Results:Baseline urate was 331.4±83.8 and 302.7±78.0μmol/L for control and PD participants, respectively (p = 0.015). Baseline homocysteine was 9.6±3.3 and 11.1±3.8μmol/L for controls and PD participants, respectively (p < 0.01). Linear mixed effects modelling showed that lower baseline urate (β= 0.02, p < 0.001) and higher homocysteine (β= 0.29, p < 0.05) predicted decline in motor function. Only higher homocysteine concentrations at baseline, however, predicted declining MoCA scores over 54 months (β= 0.11, p < 0.01).Conclusions:Lower serum urate concentration is associated with worsening motor function; while higher homocysteine concentration is associated with change in motor function and cognitive decline. Therefore, urate and homocysteine may be suitable biomarkers for predicting motor and cognitive decline in early PD.

Higher urate in LRRK2 mutation carriers resistant to Parkinson disease

LRRK2 mutations, the most common genetic cause of Parkinson disease (PD), display incomplete penetrance, indicating the importance of other genetic and environmental influences on disease pathogenesis in LRRK2 mutation carriers. The present study investigates whether urate, an antioxidant, Nrf2 activator, and inverse risk factor for idiopathic PD, is one such candidate biomarker of PD risk modulation in pathogenic LRRK2 mutation carriers. Banked plasma samples or urate levels were obtained for 3 cohorts of age- and sex-matched subjects with and without a known LRRK2 mutation in PD and unaffected controls to conduct a pilot study of 192 subjects from the LRRK2 Cohort Consortium (LCC) and 2 validation studies of 380 additional subjects from the LCC and 922 subjects from the Parkinson's Progression Markers Initiative. Urate levels were compared by multiple regression between subjects with and without a PD diagnosis conditional on LRRK2 status, controlling for age and sex. Nonmanifesting LRRK2 mutation carriers had significantly higher levels of urate than those who developed PD in each of the 3 independent cohorts. A meta-analysis demonstrated an adjusted mean difference of 0.62 mg/dL (p < 0.001), with similar results for separate assessments of women (p < 0.02) and men (p < 0.001). A 2 mg/dL increment in urate concentration decreased the odds of having PD by approximately 50% (odds ratio = 0.48, p = 0.004). These findings identify and substantiate urate as a biomarker of resistance to PD among LRRK2 mutation carriers. Ann Neurol 2019;85:593-599.

Pacific Islands Families Study: Physical growth to age 14 and metabolic risk.

The relationships between the trajectories of weight gain from early childhood to adolescence and risk for metabolic disease are not well understood. The objective of the study is to examine the relationships between weight gain from 2 to 14years and metabolic risk factors at age 14years in Pacific Island children. z scores for weight were calculated at each of the ages 2.5, 4, 6, 9, 11, and 13.5years in 1053 children. Growth trajectories were determined by estimating the linear trend of z scores with age for each child. In a subgroup of 204 children, biomarkers of metabolic risk were measured and related to linear trend intercepts and slopes. More rapid growth (greater slope of z score trajectory) was associated with higher concentrations of insulin, leptin (boys), urate, and markers of liver function, insulin resistance and inflammation. Children with higher weights in early life (greater intercept) showed fewer associations with metabolic markers, but considered together, intercept and slope were independently associated with a range of metabolic risk factors. Both rapid weight gain and a higher body weight in early childhood were associated with higher risk for metabolic disease. Monitoring growth trajectories may help target interventions to optimize nutrition, physical activity, and growth.

Effects of exogenous Fibroblast Growth Factor-21 on characteristic parameters related to energy metabolism in dairy cows

Negative energy balance (NEB) is a common pathological foundation of fatty liver and ketosis. Liver and fat tissue are the major organs of lipid metabolism, which is also a key metabolic pathway that regulates NEB development during the perinatal period. Fibroblast growth factor-21 (FGF-21) is a protein hormone that plays an important role in adipose lipid metabolism and liver gluconeogenesis. Our aim was to investigate the effects of exogenous FGF-21 on characteristic parameters related to energy balance in dairy cows. Ten non-pregnant, non-lactating Holstein-Friesian dairy cows were randomly allocated into two groups. The interventions were exogenous FGF-21 injection group received 1 ug/kg BW (body weight) of recombinant bovine FGF-21 by intravenous injection, and control group received physiological saline injections by intravenous injection. In comparison to saline injections, intravenous injections of FGF-21 either increased or tended to increase concentrations of FGF-21 (p &lt; 0.05), BHBA (p &lt; 0.05), adiponectin, leptin and HDL-C. FGF-21 injections decreased or tended to decrease concentrations of insulin, glucose, glucagon (p &lt; 0.05), ALT/GPT (p &lt; 0.05), AST/GOT (p &lt; 0.05), urate, creatinine (p &lt; 0.05), BUN, triglyceride (p &lt; 0.05), T-CHO and LDL-C (p &lt; 0.05). The results indicate that FGF-21 has only negative effects on the metabolites and metabolic hormones related to NEB in serum of dairy cows, but it has more beneficial effects on prominent adipokines, liver function index, renal function index, lipoprotein profiles related to the pathological changes that occurred in NEB.

Nutritional status of hemodialysis patients

Hemodialysis patients are vulnerable population group and they, among other, should take special care on food and fluid intake with emphasis on energy, potassium, phosphorus, sodium and protein intake. The nutritional status of patients (n=14) was assessed through measurement of body weight, body height, upper arm circumference, lower leg circumference and handgrip dynamometry; as well as selected biochemical parameters: urate concentration, calcium and phosphate levels, total protein, creatinine, albumin and globulin ratio and C-reactive protein; and dietary assessment method: 3-day food record (3DD). Using range between 18.5 and 24.9 kg/m2 as cut-off, 35.7 and 57% of patients were classified as adequately nourished and overweight, respectively. According to results of 3DD, most of the subjects are supposed to align their micro- and macro- nutrients intake with the recommendations, with emphasis on the increasing intake of protein and energy as well as on decreasing intake of potassium, phosphorus, sodium and energy.

High urate concentration is associated with elevated blood pressure in schoolchildren.

Background Studies in adults have shown a relationship between high blood pressure and hyperuricemia, but few studies have investigated this association in children and adolescents. The aim of the present study was to associate urate concentration with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in schoolchildren. Methods This cross-sectional study used a sample of 2335 schoolchildren in basic education between 7 and 17 years old. Blood pressure was classified by percentile according to Brazilian parameters for sex and age, reclassified into two categories: normal and borderline/hypertension. Blood collection to obtain serum for urate concentration analysis was performed after a 12-h fast. Values above 5.5 mg/dL were considered hyperuricemia. Descriptive data were presented in frequency and percentage. Linear regression and Poisson regression (prevalence ratio [PR]) was used to test the association between urate concentration and blood pressure. Results Urate concentration was weakly associated with SBP (β: 0.05; 95% CI: 0.02-0.08) and DBP (β: 0.03; 95% CI: 0.01-0.05) z-scores. Schoolchildren with hyperuricemia had a higher prevalence of high SBP (PR: 1.12; p<0.001) and DBP (PR: 1.08; p<0.001). Conclusions Elevated urate concentration is associated with altered blood pressure in schoolchildren.

Efficacy and cost-effectiveness of nurse-led care involving education and engagement of patients and a treat-to-target urate-lowering strategy versus usual care for gout: a randomised controlled trial

SummaryBackgroundIn the UK, gout management is suboptimum, with only 40% of patients receiving urate-lowering therapy, usually without titration to achieve a target serum urate concentration. Nurses successfully manage many diseases in primary care. We compared nurse-led gout care to usual care led by general practitioners (GPs) for people in the community.MethodsResearch nurses were trained in best practice management of gout, including providing individualised information and engaging patients in shared decision making. Adults who had experienced a gout flare in the previous 12 months were randomly assigned 1:1 to receive nurse-led care or continue with GP-led usual care. We assessed patients at baseline and after 1 and 2 years. The primary outcome was the percentage of participants who achieved serum urate concentrations less than 360 μmol/L (6 mg/dL) at 2 years. Secondary outcomes were flare frequency in year 2, presence of tophi, quality of life, and cost per quality-adjusted life-year (QALY) gained. Risk ratios (RRs) and 95% CIs were calculated based on intention to treat with multiple imputation. This study is registered with www.ClinicalTrials.gov, number NCT01477346.Findings517 patients were enrolled, of whom 255 were assigned nurse-led care and 262 usual care. Nurse-led care was associated with high uptake of and adherence to urate-lowering therapy. More patients receiving nurse-led care had serum urate concentrations less than 360 μmol/L at 2 years than those receiving usual care (95% vs 30%, RR 3·18, 95% CI 2·42–4·18, p<0·0001). At 2 years all secondary outcomes favoured the nurse-led group. The cost per QALY gained for the nurse-led intervention was £5066 at 2 years.InterpretationNurse-led gout care is efficacious and cost-effective compared with usual care. Our findings illustrate the benefits of educating and engaging patients in gout management and reaffirm the importance of a treat-to-target urate-lowering treatment strategy to improve patient-centred outcomes.FundingArthritis Research UK.

The current treatment strategy for gouty arthritis

Febuxostat is a non-purine selective inhibitor of isoforms of xanthine oxidoreductase (XOR), the effect of which is aimed at lowering the level of serum uric acid (UA). Febuxostat is a more potent inhibitor of XOR than allopurinol, as confirmed by that target UA levels have been achieved more frequently with febuxostat than with allopurinol, particularly in patients with high serum urate concentrations. The pharmacokinetic properties of febuxostat are not dependent on renal clearance, which distinguishes it from allopurinol and may benefit patients with chronic kidney disease. A number of studies are being conducted to further evaluate the cardiovascular safety of febuxostat and its possible positive effects in preserving renal function. Of importance is the fact that febuxostat does not require dose adjustment in elderly patients.

Genetics of serum urate concentrations and gout in a high-risk population, patients with chronic kidney disease

We evaluated genetics of hyperuricemia and gout, their interaction with kidney function and medication intake in chronic kidney disease (CKD) patients. Genome-wide association studies (GWAS) of urate and gout were performed in 4941 CKD patients in the German Chronic Kidney Disease (GCKD) study. Effect estimates of 26 known urate-associated population-based single nucleotide polymorphisms (SNPs) were examined. Interactions of urate-associated variants with urate-altering medications and clinical characteristics of gout were evaluated. Genome-wide significant associations with serum urate and gout were identified for known loci at SLC2A9 and ABCG2, but not for novel loci. Effects of the 26 known SNPs were of similar magnitude in CKD patients compared to population-based individuals, except for SNPs at ABCG2 that showed greater effects in CKD. Gene-medication interactions were not significant when accounting for multiple testing. Associations with gout in specific joints were significant for SLC2A9 rs12498742 in wrists and midfoot joints. Known genetic variants in SLC2A9 and ABCG2 were associated with urate and gout in a CKD cohort, with effect sizes for ABCG2 significantly greater in CKD compared to the general population. CKD patients are at high risk of gout due to reduced kidney function, diuretics intake and genetic predisposition, making treatment to target challenging.

The polymorphism rs35767 at IGF1 locus is associated with serum urate levels

Previous studies suggested that the IGF-1/IGF-1 receptor signaling pathway may contribute to regulate uric acid levels. To confirm this hypothesis, we assessed the effects of the IGF-1-raising genetic variant rs35767 on urate levels in serum and urine, and we investigated IGF-1 ability to modulate the expression of transporters involved in reabsorption and secretion of uric acid in the kidney. The study population included 2794 adult Whites. 24-hour urinary uric acid concentration was available for 229 subjects. rs35767 polymorphism was screened using TaqMan genotyping assays. HEK293 (human embryonic kidney-293) cell line was treated with IGF-1 (1, 5, 10, 50 nM) for 24-hours, and differences in the expression of urate transporters were evaluated via Western Blot and real time rtPCR. Individuals carrying the IGF-1-raising allele (rs35767 T) exhibited significantly lower levels of serum urate according to both additive and recessive models, after correction for gender, age, BMI, glucose tolerance, glomerular filtration rate, and anti-hypertensive treatment. TT genotype carriers displayed higher uricosuria than C allele carriers did, after adjusting for confounders. Exposure of HEK293 cells to IGF-1 resulted in a dose-dependent increase of uric acid transporters deputed to uric acid excretion (MRP4, NPT1 and BCRP), and reduction of GLUT9 expression, the major mediator of uric acid reabsorption, both at mRNA and protein level. We observed a significant association between the functional polymorphism rs35767 near IGF1 with serum urate concentrations and we provide a mechanistic explanation supporting a causal role for IGF-1 in the regulation of uric acid homeostasis.