Serum urate at trial entry and ALS progression in EMPOWER.
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ABSTRACT:
SUBMITTER: O'Reilly EJ
PROVIDER: S-EPMC5531275 | biostudies-literature | 2017 Feb
REPOSITORIES: biostudies-literature
Publications
Serum urate at trial entry and ALS progression in EMPOWER.
O'Reilly ÉIlis J ÉJ Liu Dawei D Johns Donald R DR Cudkowicz Merit E ME Paganoni Sabrina S Schwarzschild Michael A MA Leitner Melanie M Ascherio Alberto A
Amyotrophic lateral sclerosis & frontotemporal degeneration 20160928 1-2
Our objective was to determine whether serum urate predicts ALS progression. A study population comprised adult participants of EMPOWER (n = 942), a phase III clinical trial to evaluate the efficacy of dexpramipexole to treat ALS. Urate was measured in blood samples collected during enrollment as part of the routine block chemistry. We measured outcomes by combined assessment of function and survival rank (CAFs), and time to death, by 12 months. Results showed that in females there was not a sig ...[more]
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Project description:Higher serum urate concentrations predict more favorable prognosis in individuals with Parkinson disease (PD). The purpose of this study was to test the causality of this association using a Mendelian randomization approach.The study was conducted among participants in DATATOP and PRECEPT, 2 randomized trials among patients with early PD. The 808 patients with available DNA were genotyped for 3 SLC2A9 single nucleotide polymorphisms (SNPs) that identify an allele associated with lower urate concentrations, and for selected SNPs in other genes encoding urate transporters that have modest or no effect on serum urate levels. An SLC2A9 score was created based on the total number of minor alleles at the 3 SLC2A9 loci. Primary outcome was disability requiring dopaminergic treatment.Serum urate concentrations were 0.69mg/dl lower among individuals with ?4 SLC2A9 minor alleles as compared to those with ?2 (p?=?0.0002). The hazard ratio (HR) for progression to disability requiring dopaminergic treatment increased with increasing SLC2A9 score (HR?=?1.16, 95% confidence interval [CI]?=?1.00-1.35, p?=?0.056). In a comparative analysis, the HR was 1.27 (95% CI?=?1.00-1.61, p?=?0.0497) for a 0.5mg/dl genetically conferred decrease in serum urate, and 1.05 (95% CI?=?1.01-1.10, p?=?0.0133) for a 0.5mg/dl decrease in measured serum urate. No associations were found between polymorphisms in other genes associated with urate that do not affect serum urate and PD progression.This Mendelian randomization analysis adds to the evidence of a causal protective effect of high urate levels.
| S-EPMC4245314 | biostudies-literature
Project description:BackgroundDietary recommendations to prevent gout emphasize a low-purine diet. Recent evidence suggests that the Dietary Approaches to Stop Hypertension (DASH) diet reduces serum urate while also improving blood pressure and lipids.ObjectiveTo compare the effects of DASH-style diets emphasizing different macronutrient proportions on serum urate reduction.MethodsWe conducted a secondary analysis of the Optimal Macronutrient Intake Trial to Prevent Heart Disease feeding study, a 3-period, crossover design, randomized trial of adults with prehypertension or hypertension. Participants were provided with 3 DASH-style diets in random order, each for 6 wk. Each DASH-style diet emphasized different macronutrient proportions: a carbohydrate-rich (CARB) diet, a protein-rich (PROT) diet, and an unsaturated fat-rich (UNSAT) diet. In the PROT diet, approximately half of the protein came from plant sources. We compared the effects of these diets on serum urate at weeks 4 and 6 of each feeding period.ResultsOf the 163 individuals included in the final analysis, the mean serum urate at baseline was 5.1 mg/dL. Only the PROT diet reduced serum urate from baseline at the end of the 6-wk feeding period (-0.16 mg/dL; 95% CI: -0.28, -0.04; P = 0.007). Neither the CARB diet (-0.03 mg/dL; 95% CI: -0.14, 0.09; P = 0.66) nor the UNSAT diet (-0.01 mg/dL; 95% CI: -0.12, 0.09; P = 0.78) reduced serum urate from baseline. The PROT diet lowered serum urate by 0.12 mg/dL (95% CI: -0.20, -0.03; P = 0.006) compared with CARB and by 0.12 mg/dL (95% CI: -0.20, -0.05; P = 0.002) compared with UNSAT.ConclusionsA DASH-style diet emphasizing plant-based protein lowered serum urate compared with those emphasizing carbohydrates or unsaturated fat. Future trials should test the ability of a DASH-style diet emphasizing plant-based protein to lower serum urate and prevent gout flares in patients with gout. This trial was registered at clinicaltrials.gov as NCT00051350.
| S-EPMC8168362 | biostudies-literature
Project description:ImportanceApproximately 12 million adults in the US have a history of gout, but whether serum urate levels can help predict recurrence is unclear.ObjectiveTo assess associations of a single serum urate measurement with subsequent risk of acute gout flares and subsequent risk of hospitalizations for gout among patients in the UK with a history of gout.Design, setting, and participantsThis retrospective study included patients with a history of gout identified from the UK between 2006 and 2010 who were followed up through Primary Care Linked Data medical record linkage until 2017 and through the Hospital Episode Statistics database until 2020.ExposuresSerum urate levels at enrollment.Main outcome and measureRate of recurrent acute gout, ascertained by hospitalization, outpatient, and prescription/procedure records, and adjusted rate ratios using negative binomial regressions.ResultsAmong 3613 patients with gout (mean age, 60 years; 3104 [86%] men), 1773 gout flares occurred over a mean follow-up of 8.3 years. Of these, 1679 acute gout flares (95%) occurred in people with baseline serum urate greater than or equal to 6 mg/dL and 1731 (98%) occurred in people with baseline serum urate greater than or equal to 5 mg/dL. Rates of acute gout flares per 1000 person-years were 10.6 for participants with baseline urate levels less than 6 mg/dL, 40.1 for levels of 6.0 to 6.9 mg/dL, 82.0 for levels of 7.0 to 7.9 mg/dL, 101.3 for levels of 8.0 to 8.9 mg/dL, 125.3 for urate levels of 9.0 to 9.9 mg/dL, and 132.8 for levels greater than or equal to 10 mg/dL. Rate ratio of flares were 1.0, 3.37, 6.93, 8.67, 10.81, and 11.42, respectively, over 10 years (1.61 [1.54-1.68] per mg/dL). Rates of hospitalization per 1000 person-years during follow-up were 0.18 for those with baseline serum urate less than 6 mg/dL, 0.97 for serum urate of 6.0 to 6.9 mg/dL, 1.8 for serum urate of 7.0 to 7.9 mg/dL, 2.2 for serum urate of 8.0 to 8.9 mg/dL, 6.7 for serum urate of 9.0 to 9.9 mg/dL, and 9.7 for serum urate greater than or equal to 10 mg/dL. Rate ratios of hospitalization for gout, adjusting for age, sex, and race were 1.0, 4.70, 8.94, 10.37, 33.92, and 45.29, respectively (1.87 [1.57-2.23] per mg/dL).Conclusions and relevanceIn this retrospective study of patients with a history of gout, serum urate levels at baseline were associated with the risk of subsequent gout flares and rates of hospitalization for recurrent gout. These findings support using a baseline serum urate level to assess risk of recurrent gout over nearly 10 years of follow-up.
| S-EPMC10848075 | biostudies-literature
Project description:ObjectiveIn comparison with amyotrophic lateral sclerosis (ALS), the contribution of neuroinflammation in spinobulbar muscular atrophy (SBMA) has been less explored. We investigated the role of neuroinflammation in the pathogenesis of ALS and SBMA by analyzing systemic inflammatory markers and osteopontin (Spp1).MethodsThis study involved 105 ALS, 77 SBMA, and 55 healthy controls. We measured their systemic inflammatory markers, serum Spp1, and cytokine levels (interferon-γ, interleukin [IL]-1β, IL-6, IL-8, IL-10, tumor necrosis factor-α, and IL-17A), investigated correlations between Spp1 levels and clinical features, and evaluated ALS survival rates according to Spp1 levels.ResultsIn the ALS group, systemic inflammatory markers were significantly higher than in the control and SBMA groups. Spp1 levels were observed to be higher in ALS patients, but the difference was not statistically significant among the study groups. Cytokine profiles were comparable. In ALS, higher Spp1 levels were correlated with lower ALS Functional Rating Scale-Revised (ALSFRS-R) scores (r = -0.25, p = 0.02) and faster disease progression rate (r = 0.37, p < 0.001). After adjusting for other prognostic indicators, high Spp1 levels were independently associated with shorter survival in ALS patients (hazard ratio 13.65, 95% confidence interval 2.57-72.53, p < 0.01).InterpretationNeuroinflammation does not appear to be a primary contributor to the pathogenesis of SBMA. Serum Spp1 levels may serve as a reliable biomarker for disease progression and prognosis in ALS. These findings expand our understanding of these two distinct motor neuron disorders and offer a potential biomarker for future studies.
| S-EPMC11251464 | biostudies-literature
Project description:ImportanceConvergent biological, epidemiological, and clinical data identified urate elevation as a candidate strategy for slowing disability progression in Parkinson disease (PD).ObjectiveTo determine the safety, tolerability, and urate-elevating capability of the urate precursor inosine in early PD and to assess its suitability and potential design features for a disease-modification trial.Design, setting, and participantsThe Safety of Urate Elevation in PD (SURE-PD) study, a randomized, double-blind, placebo-controlled, dose-ranging trial of inosine, enrolled participants from 2009 to 2011 and followed them for up to 25 months at outpatient visits to 17 credentialed clinical study sites of the Parkinson Study Group across the United States. Seventy-five consenting adults (mean age, 62 years; 55% women) with early PD not yet requiring symptomatic treatment and a serum urate concentration less than 6 mg/dL (the approximate population median) were enrolled.InterventionsParticipants were randomized to 1 of 3 treatment arms: placebo or inosine titrated to produce mild (6.1-7.0 mg/dL) or moderate (7.1-8.0 mg/dL) serum urate elevation using 500-mg capsules taken orally up to 2 capsules 3 times per day. They were followed for up to 24 months (median, 18 months) while receiving the study drug plus 1 washout month.Main outcomes and measuresThe prespecified primary outcomes were absence of unacceptable serious adverse events (safety), continued treatment without adverse event requiring dose reduction (tolerability), and elevation of urate assessed serially in serum and once (at 3 months) in cerebrospinal fluid. RESULTS Serious adverse events (17), including infrequent cardiovascular events, occurred at the same or lower rates in the inosine groups relative to placebo. No participant developed gout and 3 receiving inosine developed symptomatic urolithiasis. Treatment was tolerated by 95% of participants at 6 months, and no participant withdrew because of an adverse event. Serum urate rose by 2.3 and 3.0 mg/dL in the 2 inosine groups (P < .001 for each) vs placebo, and cerebrospinal fluid urate level was greater in both inosine groups (P = .006 and <.001, respectively). Secondary analyses demonstrated nonfutility of inosine treatment for slowing disability.Conclusions and relevanceInosine was generally safe, tolerable, and effective in raising serum and cerebrospinal fluid urate levels in early PD. The findings support advancing to more definitive development of inosine as a potential disease-modifying therapy for PD.Trial registrationclinicaltrials.gov Identifier: NCT00833690.
| S-EPMC3940333 | biostudies-literature
Project description:BackgroundSerum urate (SU) associates with cardiovascular (CV) events, mortality, and gout.ObjectivesThe purpose of this study was to assess whether SU predicts CV risk in a trial of interleukin (IL)-1β inhibition with canakinumab, and whether IL-1β blockade, kidney function, or gout alter these associations.MethodsThis study is a subanalysis of the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS), which randomized 10,061 patients with prior myocardial infarction and elevated high-sensitivity C-reactive protein to 3 doses of canakinumab or placebo. SU was measured at baseline. Cox proportional hazards models compared major adverse cardiovascular events (MACE), CV death, and all-cause mortality among those with SU ≤6.8 mg/dL (normal), 6.8 to 9.0 mg/dL (elevated), and ≥9.0 mg/dL (markedly elevated). Cox regressions were repeated within subgroups, including canakinumab vs placebo, estimated glomerular filtration rate ≥60 vs <60 mL/min, and gout vs no gout.ResultsMarkedly elevated SU associated with MACE (HR: 1.66 [95% CI: 1.38-1.99]; P < 0.0001), CV death (HR: 2.52 [95% CI: 1.98-3.21]; P < 0.0001), and all-cause mortality (HR: 2.43 [95% CI: 2.01-2.94]; P < 0.0001) compared to normal SU. After multivariable adjustment for a minimal set of potential confounders, SU independently predicted all 3 endpoints. Associations were unchanged after IL-1β blockade with canakinumab. For normal estimated glomerular filtration rate, SU associated with CV and all-cause mortality, but not MACE. Participants with gout had higher event rates independent of SU.ConclusionsIn over 10,000 patients with coronary artery disease, individuals with markedly elevated SU have elevated CV risk despite aggressive treatment. IL-1β blockade did not modify these associations. Baseline kidney function and monosodium urate deposition may function as effect modifiers.
| S-EPMC11803220 | biostudies-literature
Project description:BackgroundPrevious studies have noted significant variation in serum urate (sUA) levels, and it is unknown how this influences the accuracy of hyperuricemia classification based on single data points. Despite this known variability, hyperuricemic patients are often used as a control group in gout studies. Our objective was to determine the accuracy of hyperuricemia classifications based on single data points versus multiple data points given the degree of variability observed with serial measurements of sUA.MethodsData was analyzed from a cross-over clinical trial of urate-lowering therapy in young adults without a gout diagnosis. In the control phase, sUA levels used for this analysis were collected at 2-4 week intervals. Mean coefficient of variation for sUA was determined, as were rates of conversion between normouricemia (sUA ≤6.8 mg/dL) and hyperuricemia (sUA > 6.8 mg/dL).ResultsMean study participant (n = 85) age was 27.8 ± 7.0 years, with 39% female participants and 41% African-American participants. Mean sUA coefficient of variation was 8.5% ± 4.9% (1 to 23%). There was no significant difference in variation between men and women, or between participants initially normouricemic and those who were initially hyperuricemic. Among those initially normouricemic (n = 72), 21% converted to hyperuricemia during at least one subsequent measurement. The subgroup with initial sUA < 6.0 (n = 54) was much less likely to have future values in the range of hyperuricemia compared to the group with screening sUA values between 6.0-6.8 (n = 18) (7% vs 39%, p = 0.0037). Of the participants initially hyperuricemic (n = 13), 46% were later normouricemic during at least one measurement.ConclusionSingle sUA measurements were unreliable in hyperuricemia classification due to spontaneous variation. Knowing this, if a single measurement must be used in classification, it is worth noting that those with an sUA of < 6.0 mg/dL were less likely to demonstrate future hyperuricemic measurements and this could be considered a safer threshold to rule out intermittent hyperuricemia based on a single measurement point.Trial registrationData from parent study ClinicalTrials.gov Identifier: NCT02038179 .
| S-EPMC8425059 | biostudies-literature
Project description:BackgroundThe ABCG2 Q141K (rs2231142) and rs10011796 variants associate with hyperuricaemia (HU). The effect size of ABCG2 rs2231142 on urate is ~ 60% that of SLC2A9, yet the effect size on gout is greater. We tested the hypothesis that ABCG2 plays a role in the progression from HU to gout by testing for association of ABCG2 rs2231142 and rs10011796 with gout using HU controls.MethodsWe analysed 1699 European gout cases and 14,350 normouricemic (NU) and HU controls, and 912 New Zealand (NZ) Polynesian (divided into Eastern and Western Polynesian) gout cases and 696 controls. Association testing was performed using logistic and linear regression with multivariate adjusting for confounding variables.ResultsIn Europeans and Polynesians, the ABCG2 141K (T) allele was associated with gout using HU controls (OR = 1.85, P = 3.8E- 21 and ORmeta = 1.85, P = 1.3E- 03, respectively). There was evidence for an effect of 141K in determining HU in European (OR = 1.56, P = 1.7E- 18) but not in Polynesian (ORmeta = 1.49, P = 0.057). For SLC2A9 rs11942223, the T allele associated with gout in the presence of HU in European (OR = 1.37, P = 4.7E- 06), however significantly weaker than ABCG2 rs2231142 141K (PHet = 0.0023). In Western Polynesian and European, there was epistatic interaction between ABCG2 rs2231142 and rs10011796. Combining the presence of the 141K allele with the rs10011796 CC-genotype increased gout risk, in the presence of HU, 21.5-fold in Western Polynesian (P = 0.009) and 2.6-fold in European (P = 9.9E- 06). The 141K allele of ABCG2 associated with increased gout flare frequency in Polynesian (Pmeta = 2.5E- 03).ConclusionThese data are consistent with a role for ABCG2 141K in gout in the presence of established HU.
| S-EPMC7069001 | biostudies-literature
Project description:ImportanceUrate 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.ObjectiveTo determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression.Design, participants, and settingRandomized, 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.InterventionsInosine, 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.Main outcomes and measuresThe 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.ResultsBased 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).Conclusions and relevanceAmong 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.Trial registrationClinicalTrials.gov Identifier: NCT02642393.
| S-EPMC8441591 | biostudies-literature
Project description:ObjectiveControversy 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.MethodsWe 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.ResultsAmong 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).ConclusionSarcopenia 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.
| S-EPMC10600587 | biostudies-literature